Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic compounds

专利摘要:
The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof: Formula I In the above formula, W is a bicyclic heterocyclic ring system. The compound is an α-1 adrenergic antagonist and is useful for the treatment of BPH. Also described herein are α-1 antagonist compositions and methods of antagonizing α-1 adrenal receptors and treating BPH.
公开号:KR20000057418A
申请号:KR1019990704990
申请日:1997-12-04
公开日:2000-09-15
发明作者:메이어마이클디；알텐바흐로버트제이；바샤파티마；캐롤윌리암에이；드리진아이렌；커윈제임스에프；웬트마이클디；헤이트앤소니알；창웨이쟝
申请人:스티븐 에프. 웨인스톡；아보트 러보러터리즈；
IPC主号:

专利说明:

Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic compounds {Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic compounds}
[1] This application is a partial consecutive application of US patent application Ser. No. 08 / 761,423, filed December 6, 1996.
[3] Adrenergic neurons play an important role in neurodominance of heart, blood vessels and smooth muscle tissue. Compounds that can interact with adrenal receptor sites in adrenergic neurons initiate various physiological responses, including vasoconstriction, vasodilation, and increase or decrease in heart rate (periodic variability), contractility (modulation), and metabolic activity. You can. In the past, various adrenergic compounds have been used that affect these and other physiological responses. However, many adrenergic compounds do not have practical selectivity that allows them to carry out the desired interaction with the adrenergic adrenal receptor site. That is, these adrenergic compounds do not exhibit a high degree of specificity that distinguishes the adrenal receptor types within the adrenergic neurons in order to obtain the desired physiological response, possibly but possibly less desirable than other system responses.
[4] Benign prostatic hyperplasia (BPH) is a disease state that occurs in men of middle and old age and refers to the benign development of interstitial and epithelial elements of the prostate associated with aging. Symptoms of BPH include increased urination frequency, nocturnal enuresis, weakened urine stem, and poor or first time urine. Chronic symptoms of BPH can include enlarged bladder smooth muscle, bladder dysfunction, and an increased number of urinary tract infections.
[5] Typically, BPH is the most common cause of problems associated with the urinary tract, which begins in the mid-fifties and occurs in men of this age. BPH is rarely found in men before the age of 40, but in men in their 60s, approximately 50% shows the histological characteristics of BPH. The morbidity of BPH continues to increase with age, with 80% of men in their 80s showing the pathological characteristics of BPH.
[6] Although prostatic hyperplasia is a common phenomenon in older men, the presence of urological symptoms is an essential feature in distinguishing the prostate, a clinical symptom in which the patient does not actually urinate, from the simple anatomical enlargement of the prostate gland. to be. It is common for older men to have a prominent enlarged prostate without showing symptoms of prostatosis. However, from the patient's perspective, the incidence and progression of urological symptoms is much more important than simply the presence of an enlarged prostate.
[7] In the 1970s, the discovery of a number of alpha-adrenergic adrenal receptors in the smooth muscles of the prostate gland and bladder neck [M. Caine, et al., Brit J. Urol., 47: 193-202 (1975) )], It was concluded that both static and dynamic components for bladder outlet obstruction associated with BPH exist. The static component is that the prostate with aging originates from progressive hyperplasia, which leads to narrowing of the urethra resulting in urinary obstructive symptoms. Adding to this inherent mechanistic problem are smooth muscle contractions of varying degrees regulated by the sympathetic nervous system and influenced by factors such as stress, cold and sympathetic neurostimulants. It is a dynamic component that explains the frequent and rapid fluctuations in symptoms observed in patients with prostate disease.
[8] Currently, the most effective treatment for BPH is the surgical procedure of urethral resection (TURP) of the prostate. Because it removes obstructive tissue [C. Chapple, Br. Med. Journal 304: 1198-1190 (1992)], which is the indicated therapy for the static and dynamic components of BPH. However, these surgical treatments are associated with mortality (1%) and side effects (2-4% incontinence, 5-10% infection and 5-10% erectile dysfunction). Therefore, non-invasive alternative therapies are eagerly desired.
[9] Women undergoing hypertension with prazosin [T.Thien, KP Delacre, FMJ Debruyne, RAP Koene, Br. Med. The additional clinical observation that urinary incontinence develops in Journal, 622-623 (1978) and the experimental work of Caine (see above) are potential for selective α-1 adrenal receptor blockade in lower urinary tract disease. Contributed to the recognition of phosphorus roles. Subsequent studies by several groups have demonstrated the functional role of α-1 adrenal receptors involved in α-2 adrenal receptors in the interstitial compartment of the prostate, thereby allowing specific α- in non-surgical treatment of BPH. 1 Provided putative molecular criteria for using adrenal receptor blockers. See CR Chapple, ML Aubry, S. James, M. Greengrass, G. Burnstock, RT Turner-Warwick, Br. J. Urol. 63: 487-496 (1989). The clinical efficacy of α-1 antagonists in BPH has been demonstrated using several non-selective α-1 blockers, including terazosin (Hytrin ^R ), prazosin, and doxazosin. Treatment cycles with as little as 2 to 4 weeks with α-1 adrenoreceptor blockers showed objective improvement in mean and maximum urination rates (14 to 96%) and subjective improvement in the patient's symptom score. RA Janknegt , CR Chapple, Eur. Urol. 24: 319-326 (1993). Longer studies with terrazosin, indoramine, prazosin and doxazosin have similarly demonstrated significant improvements in urination rate and subjective symptom scores. RA Janknegt, supra; H. Lepor, G. Knapp-Maloney, J. Urol. 145: 263 A (1991), W. Chow, D. Hahn, D. Sandhu, Br. J. Urol. 65: 36-38 (1990) and CR Chapple, TJ Christmas, EJG Milroy, Urol. Int. 45: 47-55 (1990). However, these agents exhibit similar dose limiting side effects: lowering blood pressure, dizziness and muscle fatigue.
[10] In recent years, it has been clarified that BPH and bladder outlet obstruction (BOO) can be distinguished clinically and that the severity of clinical BPH is associated with a number of factors other than BOO [Lepor, H., Alpha Blockade for the Treatment of Benign Prostatic Hyperplasia, Urol. Clin. N. Amer., 22: 375-386, 1995]. For example, BOO may be associated with other urological symptoms, such as detrusor instability. Rosier, P.F.W.M., J.J.M.C.H. de la Rosette, H.Wijkstra, Ph.E.V. Van Kerrebroeck and F.M.J. Debruyne, Is Detrusor Instability in Elderly Males Related to the Grade of Obstruction, Neurourol. Urodynam., 14: 625-633, 1995]. In addition, the role of the α-1 adrenal receptor outside the prostate was considered to be important in the etiology of lower urinary tract symptoms, so that the antagonism of these receptors in the spinal cord, ganglion, nerve endings, bladder and bladder or external urethral sphincter muscles is responsible for BOO and neuroinjury. It may be important for pharmacotherapy of urological diseases such as bladder [Andersson, KE., Porstatic and extraprostatic α-adrenoceptors-Contributions to the Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia, Scand. J. Urol. and Nephrol., 30: 105-111, 1996. Recognizing that women possess urethral rays with anatomical, histological and biochemical similarities to male prostates is described by Gittes, R.F. and R.M. Nakamura, Female urethral syndrome: A female prostatitis, Western J. Medicine, 164: 435-438, 1996] suggests a potential role for α-1 adrenal receptor antagonist therapy to alleviate some of the urological symptoms of women. Doing. In addition, α-adrenal receptors are functionally important for smooth muscle contraction in the uterus [Miller, M.D. and J.M Marshall, Uterine response to nerve stimulation: relation to hormonal status and catecholamines, Am. J. Physiol., 209: 859-863, 1965] Regulation of sympathetic responses to catecholamines is enhanced by raising estrogen levels. Miller and Marshall, Uterine response to nerve stimulation: relation to hormonal status and catecholamines, Am. J. Physiol., 209: 859-863, 1965. This observation is consistent with data indicating increased α-adrenal receptor response and receptor density levels after administration of estrogens to animals. Hoffman, B.B., T.N. Lavin, R. J. Lefkowitz and R.R. Ruffolo, Jr., Alpha adrenergic receptor subtypes in rabbit uterus: Mediation of myometrial contraction and regulation by estrogens, J. Pharmacol. Exp. Ther., 219: 290-295, 1981, and Roberts, J.M., P.A. Insel and A. Goldfein, Regulation of myometrial adrenoreceptors and adrenergic response by sex steroids, Mol. Pharmacol., 20: 52-58, 1981. Thus, hormonal regulation of α-1 adrenal receptor sensitivity may play an important role in promoting uterine contraction in dysmenorrhea, in which a selective adrenal receptor antagonist is therapeutically effective. Thus, there is a need for "hyposelective" α-1 antagonists that reduce side effects.
[11] Summary of the Invention
[12] In a major aspect of the present invention, the present invention provides benzopyranopyrrole and benzopyranopyridine compounds and intermediates of the general formula (I), or pharmaceutically acceptable salts thereof:
[13]
[14] In the above formula,
[15] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[16] A is methylene,
[17] n is 1 or 2,
[18] W is alkylene having 2 to 10 carbon atoms,
[19] R ₃ is , , , , , , , , , , And Is selected from the group consisting of
[20] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[21] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[22] V and V 'are independently selected from the group consisting of nitrogen and methine
[23] U is a ring fused with its adjacent ring and is (a) an unsubstituted or substituted 5-membered ring having 5 carbon atoms; (b) an unsubstituted or substituted 5-membered ring having 4 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (c) an unsubstituted or substituted 5-membered ring having 3 carbon atoms and 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; (d) substituted or unsubstituted 6 membered rings having 6 carbon atoms; (e) a substituted or unsubstituted 6 membered ring having 5 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (f) a substituted or unsubstituted 6 membered ring having 4 carbon atoms and 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; And (g) a substituted or unsubstituted 6 membered ring having 3 carbon atoms and having 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
[24] The 5-membered ring constituting U may contain 0, 1 or 2 double bonds. The six membered ring constituting U may contain 0, 1, 2 or 3 double bonds. Rings (a) to (g) of the group constituting U are independent from the group consisting of alkyl, alkoxy, cyano, nitro, carboxy, alkoxycarbonyl having 2 to 8 carbon atoms, halogen, cycloalkyl, aryl and heterocyclic It may be mono- or di-substituted by a substituent selected from.
[25] The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) together with a pharmaceutically effective carrier.
[26] The present invention also relates to a method of antagonizing alpha-1 adrenoreceptor binding in a host mammal, particularly a human, by administering a therapeutically effective amount of a composition comprising a compound of formula (I). In particular, the present invention relates to a method of treating BPH in a mammal, in particular a human, by administering to a mammal an effective amount of a compound of formula (I).
[2] The present invention relates to novel organic compounds and compositions that are alpha-1 (α-1) adrenal receptor antagonists, methods of making such compounds, synthetic intermediates used in these methods, and alpha-1 adrenal receptors that inhibit and form positive prostatic hyperplasia (which Also referred to as benign prostatic hyperplasia), or other urological diseases such as bladder outlet obstruction and neuropathy bladder or gynecological diseases such as dysmenorrhea.
[27] In one embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[28] Formula I
[29]
[30] In the above formula,
[31] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[32] A is methylene,
[33] n is 1 or 2,
[34] W is alkylene having 2 to 10 carbon atoms,
[35] R ₃ is , , , , , , , , , , And Is selected from the group consisting of
[36] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[37] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[38] V and V 'are independently selected from the group consisting of nitrogen and methine
[39] U is a ring fused with its adjacent ring and is (a) an unsubstituted or substituted 5-membered ring having 5 carbon atoms; (b) an unsubstituted or substituted 5-membered ring having 4 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (c) an unsubstituted or substituted 5-membered ring having 3 carbon atoms and 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; (d) substituted or unsubstituted 6 membered rings having 6 carbon atoms; (e) a substituted or unsubstituted 6 membered ring having 5 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (f) a substituted or unsubstituted 6 membered ring having 4 carbon atoms and 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; And (g) a substituted or unsubstituted 6-membered ring having 3 carbon atoms and having 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
[40] The 5-membered ring constituting U may contain 0, 1 or 2 double bonds. The six membered ring constituting U may contain 0, 1, 2 or 3 double bonds. Rings (a) to (g) of the group constituting U are independent from the group consisting of alkyl, alkoxy, cyano, nitro, carboxy, alkoxycarbonyl having 2 to 8 carbon atoms, halogen, cycloalkyl, aryl and heterocyclic It may be mono- or di-substituted by a substituent selected from.
[41] In a preferred embodiment, the present invention provides a compound of formula II, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[42]
[43] In the above formula,
[44] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[45] A is methylene,
[46] n is 1 or 2,
[47] W is alkylene having 2 to 10 carbon atoms,
[48] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[49] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[50] P ', Q, S' and T are independently selected from the group consisting of nitrogen and methine, provided that two or less of P ', Q, S' and T may be nitrogen,
[51] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[52] In another preferred embodiment, the present invention provides a compound of formula III, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[53]
[54] In the above formula,
[55] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[56] A is methylene,
[57] n is 1 or 2,
[58] W is alkylene having 2 to 10 carbon atoms,
[59] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[60] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[61] P 'and T are nitrogen,
[62] Q and S 'are methine,
[63] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[64] In another preferred embodiment, the present invention provides a compound of formula (IV): or a pharmaceutically acceptable salt, ester or prodrug thereof:
[65]
[66] In the above formula,
[67] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[68] A is methylene,
[69] n is 1 or 2,
[70] W is alkylene having 2 to 10 carbon atoms,
[71] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[72] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[73] P 'is nitrogen,
[74] Q, S 'and T are methine,
[75] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[76] In another preferred embodiment, the present invention provides a compound of formula V, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[77]
[78] In the above formula,
[79] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[80] A is methylene,
[81] n is 1 or 2,
[82] W is alkylene having 2 to 10 carbon atoms,
[83] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[84] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[85] Q is nitrogen,
[86] P ', S' and T are methine,
[87] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[88] In another preferred embodiment, the present invention provides a compound of formula VI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[89]
[90] In the above formula,
[91] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[92] A is methylene,
[93] n is 1 or 2,
[94] W is alkylene having 2 to 10 carbon atoms,
[95] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[96] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[97] S 'is nitrogen,
[98] P ', Q and T are methine,
[99] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[100] In another preferred embodiment, the present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[101]
[102] In the above formula,
[103] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[104] A is methylene,
[105] n is 1 or 2,
[106] W is alkylene having 2 to 10 carbon atoms,
[107] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[108] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[109] T is nitrogen,
[110] P ', Q and S' are methine,
[111] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[112] In another preferred embodiment, the present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[113]
[114] In the above formula,
[115] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[116] A is methylene,
[117] n is 1 or 2,
[118] W is alkylene having 2 to 10 carbon atoms,
[119] G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
[120] Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
[121] P ', Q, S' and T are methine,
[122] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[123] In another preferred embodiment, the present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[124]
[125] In the above formula,
[126] R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
[127] A is methylene,
[128] n is 1,
[129] W is alkylene having 2 to 10 carbon atoms,
[130] G is hydrogen,
[131] G 'does not exist,
[132] Y is nitrogen,
[133] Y 'is sulfur,
[134] P ', Q and S' are methine,
[135] T is nitrogen,
[136] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[137] In another preferred embodiment, the present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[138]
[139] In the above formula,
[140] R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
[141] A is methylene,
[142] n is 2,
[143] W is alkylene having 2 to 10 carbon atoms,
[144] G is hydrogen,
[145] G 'does not exist,
[146] Y is nitrogen,
[147] Y 'is sulfur,
[148] P ', Q and S' are methine,
[149] T is nitrogen,
[150] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[151] In another preferred embodiment, the present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[152]
[153] In the above formula,
[154] R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
[155] A is methylene,
[156] n is 2,
[157] W is alkylene having 2 to 10 carbon atoms,
[158] G is hydrogen,
[159] G 'does not exist,
[160] Y is nitrogen,
[161] Y 'is sulfur,
[162] Q and S 'are methine,
[163] P 'and T are nitrogen,
[164] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[165] In another preferred embodiment, the present invention provides a compound of formula XII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[166]
[167] In the above formula,
[168] R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
[169] A is methylene,
[170] n is 1,
[171] W is alkylene having 2 to 10 carbon atoms,
[172] G is hydrogen,
[173] G 'does not exist,
[174] Y is nitrogen,
[175] Y 'is sulfur,
[176] Q and S 'are methine,
[177] P 'and T are nitrogen,
[178] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[179] In another preferred embodiment, the present invention provides a compound of Formula XIII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
[180]
[181] In the above formula,
[182] R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
[183] A is methylene,
[184] n is 1,
[185] W is alkylene having 2 to 10 carbon atoms,
[186] G is hydrogen,
[187] G 'does not exist,
[188] Y is nitrogen,
[189] Y 'is sulfur,
[190] Q, S 'and T are methine,
[191] P 'is nitrogen,
[192] R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[193] In another preferred embodiment, the present invention provides a compound of formula (XIV), or a pharmaceutically acceptable salt, ester or prodrug thereof:
[194]
[195] In the above formula,
[196] R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
[197] Y is nitrogen,
[198] G is hydrogen,
[199] Y 'is sulfur,
[200] P 'and T are nitrogen,
[201] Q is methine,
[202] S 'is carbon.
[203] The invention also relates to a compound useful as an intermediate of formulas (I) to (IV) or salts thereof, one compound useful as an intermediate is a compound of formula (XV)
[204]
[205] In the above formula,
[206] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[207] n is 1 or 0.
[208] Another compound useful as an intermediate is a compound of Formula XVI:
[209]
[210] In the above formula,
[211] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[212] n is 1 or 0.
[213] Another compound useful as an intermediate is a compound of formula
[214]
[215] In the above formula,
[216] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[217] m is 2 to 10,
[218] n is 1 or 0.
[219] More preferred compounds useful as intermediates are those of the formula:
[220]
[221] In the above formula,
[222] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[223] n is 1 or 0.
[224] Further preferred compounds of formula (VII) have an absolute stereochemistry of 3aR and 9bR.
[225] Another more preferred compound useful as an intermediate is a compound of formula
[226]
[227] In the above formula,
[228] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[229] n is 1 or 0.
[230] Further preferred compounds of formula (VII) have an absolute stereochemistry of 3aR and 9bR.
[231] Another more preferred compound useful as an intermediate is a compound of formula
[232]
[233] In the above formula,
[234] R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
[235] m is 2 to 10,
[236] n is 1 or 0.
[237] Further preferred compounds of formula (VII) have an absolute stereochemistry of 3aR and 9bR.
[238] Another compound useful as an intermediate is a compound of Formula XI:
[239]
[240] In the above formula,
[241] U, Y ', G' are as defined in formulas (I) to (XIV),
[242] R is alkyl.
[243] Another compound useful as an intermediate is a compound of Formula XII:
[244]
[245] In the above formula,
[246] U, Y ', G' are as defined in formulas (I) to (XIV),
[247] R is alkyl.
[248] Another compound useful as an intermediate is a compound of Formula XIII:
[249]
[250] In the above formula,
[251] U, Y ', G' and m are as defined in Formulas I to IV,
[252] R is alkyl.
[253] Another compound useful as an intermediate is a compound of Formula XIV:
[254]
[255] In the above formula,
[256] R _z is alkyl.
[257] Another compound useful as an intermediate is a compound of Formula XV:
[258]
[259] In the above formula,
[260] R _z is alkyl.
[261] Another compound useful as an intermediate is a compound of Formula XVI:
[262]
[263] In the above formula,
[264] X is halogen,
[265] R is selected from alkyl and arylalkyl.
[266] Another compound useful as an intermediate is a compound of formula
[267]
[268] Another compound useful as an intermediate is a compound of formula
[269]
[270] Another compound useful as an intermediate is a compound of formula
[271]
[272] The invention also provides compounds of the formula
[273]
[274] Wherein R _a is aminoalkyl, _a compound of the formula A method of preparing a compound of the formula: or a pharmaceutically acceptable salt, ester, or prodrug thereof, comprising reacting with R is alkyl:
[275] or
[276] In the above formula,
[277] R ₁ , R ₂ , A, n, W, Y, G, Y ', G', P, Q, S, T, R ₄ and R ₅ are as defined above.
[278] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulas (I) through (IV) together with a pharmaceutically acceptable carrier.
[279] The invention further relates to a method of antagonizing α-1 adrenal receptors in host mammals, in particular humans, which need to antagonize α-1 adrenal receptors by administering a therapeutically effective amount of a compound of Formulas I-XIV. .
[280] The present invention further relates to a method of treating BPH in a host mammal, particularly a human, in need of treating BPH by administering a therapeutically effective amount of a compound of Formulas I to IV.
[281] The invention further relates to a method of treating bladder outlet obstruction in a host mammal, in particular a human, in need of treating a bladder outlet obstruction (BOO) by administering a therapeutically effective amount of a compound of Formulas I to IV.
[282] The invention further relates to a method for treating a neuropathy bladder in a host mammal, in particular a human, in need of treating a neuropathy bladder by administering a therapeutically effective amount of a compound of Formulas I to IV.
[283] The present invention further relates to a method of treating smooth muscle contraction of the uterus in a female host mammal, in particular a human, in need of treating a smooth muscle contraction of the uterus by administering a therapeutically effective amount of a compound of Formulas I to IV.
[284] As used throughout this specification and the appended claims, the following terms have the following meanings:
[285] The term "alkenyl" as used herein refers to a hydrocarbon containing one or more carbon-carbon double bonds. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
[286] As used herein, the term "alkyl" or "lower alkyl" refers to a straight or branched chain alkyl radical containing 1 to 6 carbon atoms, examples of which are methyl, ethyl, n-propyl, iso-propyl, n- Butyl, iso-butyl, secondary-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, etc. It is not limited to this.
[287] The term "alkylamino" as used herein is R ₁₀ NH-, where R ₁₀ is an alkyl group, for example ethylamino, butylamino and the like.
[288] The term "alkylene" means a divalent group derived from a straight or branched chain saturated hydrocarbon of 2 to 10 carbon atoms by removing two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1- Ethylene, 1,3-propylene, 2,2-dimethylpropylene and the like.
[289] The term "alkoxy" as used herein is R ₁₁ O-, wherein R ₁₁ is an alkyl group as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, tert-butoxy and the like.
[290] As used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined above, attached to an alkyl radical as defined above. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
[291] The term "alkoxyalkoxy" as used herein refers to R ₁₂ OR ₁₃ O-, wherein R ₁₂ is alkyl and R ₁₃ is alkylene. Examples of alkoxyalkoxy include, but are not limited to, methoxymethoxy, methoxyethoxy.
[292] As used herein, the term “alkoxycarbonyl” refers to R ₁₄ OC (O) —, wherein R ₁₄ is an alkyl group. Examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like.
[293] The term "alkylsulfonyl" refers to R ₁₅ S (O) _2- , wherein R ₁₅ is an alkyl group.
[294] The term "alkynyl" refers to a straight or branched chain hydrocarbon containing carbon-carbon triple bonds. Examples of alkynyl include -C≡C-, -C≡C-CH _2- , -C≡C-CH (CH ₃ )-and the like.
[295] The term "amino" as used herein refers to -NH ₂ .
[296] The term "aminoalkyl" as used herein refers to an alkyl group attached to an amino group (-NH ₂ ).
[297] As used herein, the term “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings, examples of which are phenyl, naphthyl, tetrahydronaphthyl, indanyl, Neal et al. The aryl group is unsubstituted or one independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, nitro, carboxy, alkoxycarbonyl and carboxamide, It may be substituted by two or three substituents.
[298] The term "arylalkyl" as used herein refers to aryl attached to the parent molecular moiety through an alkyl radical.
[299] As used herein, the term “carboxamide” refers to —C (O) NH ₂ , where the carboxylic acid hydroxy residue has been replaced with an amine.
[300] As used herein, the term “carboxyalkyl” refers to a carboxy group (—C (O) OH) attached to an alkyl radical as defined above. Examples of carboxyalkyl include carboxymethyl, carboxyethyl and the like.
[301] As used herein, the term “cyanoalkyl” refers to a cyano group (—CN) attached to the parent molecular moiety through an alkyl radical.
[302] The term "dialkylamino" as used herein refers to R ₁₆ R ₁₇ N-, wherein R ₁₆ and R ₁₇ are independently alkyl, for example diethylamino, methyl propylamino, and the like. .
[303] As used herein, the term “carboxy” refers to the carboxylic acid radical, —C (O) OH.
[304] The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, examples of which are cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamant Teal and the like, but is not limited thereto. Cycloalkyl groups are unsubstituted or substituted with alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide It may be substituted by one, two or three substituents independently selected from.
[305] The term "halogen" or "halo" as used herein refers to I, Br, Cl or F.
[306] The term "haloalkyl" as used herein refers to a lower alkyl radical as defined above having one or more halogen substituents, for example chloromethyl, fluoroethyl or trifluoromethyl and the like. .
[307] As used herein, the term “heterocyclic ring” or “heterocyclic” or “heterocycle” means any three or four membered ring containing a hetero atom selected from oxygen, nitrogen and a ring; Or a 5, 6 or 7 membered ring containing 1, 2 or 3 hetero atoms, independently selected from nitrogen, oxygen and sulfur. These five membered rings have 0 to 2 double bonds and the 6 and 7 membered rings have 0 to 3 double bonds. Nitrogen heteroatoms may optionally be quaternized. The term “heterocyclic” also includes a heterocyclic ring wherein the heterocyclic ring is a benzene ring or a cyclohexane ring or another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or Bicyclic groups fused to benzothienyl and the like). Heterocycles include azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, Homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl , Isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
[308] Heterocyclic compounds are unsubstituted, hydroxy, halo, oxo (= O), alkylamino (R ₁₈ N = where R ₁₈ is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxy Mono- or di-substituted by a substituent independently selected from alkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO ₃ H and lower alkyl. It is also possible to N-protect nitrogen containing heterocycles.
[309] The term "(heterocyclic) alkyl" as used herein refers to a heterocyclic group as defined above attached to a lower alkyl radical as defined above.
[310] As used herein, the term "hydroxy" refers to -OH.
[311] The term “hydroxyalkyl” as used herein refers to an alkyl radical attached to a hydroxy group.
[312] The term "methine, as used herein, refers to -CH =.
[313] As used herein, the term “nitro” refers to —NO ₂ .
[314] The term "thioalkoxy" as used herein refers to R ₁₉ S-, wherein R ₁₉ is alkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and the like.
[315] As used herein, the term "pharmaceutically acceptable salt" is suitable and reasonable for use in contact with human and lower animal tissues without causing harmful toxicity, irritation, allergic reactions, etc. under thorough medical judgment. A risk ratio refers to a balanced salt. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in S. M. Berg et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Such salts may be prepared in situ during the final separation and purification of the compounds of the invention, or may be prepared separately by reacting the free base functionality with a suitable organic acid. These salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl Sulfate, ethanesulfonate, glucoheptanonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lac Tate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate , Tartrate, thiocyanate, p-toluenesulfonate and undecanoate, but not limited thereto It does that. In addition, basic nitrogen-containing groups include alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; It may be quaternized with agents such as aralkyl halides such as benzyl and phenethyl bromide and the like. This gives a water soluble or fat soluble or water dispersible or oil-dispersible product.
[316] Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts may be prepared in situ during the final separation and purification of the compounds of formula (I), or the carboxylic acid functional groups may be prepared by the addition of hydroxides, carbonates or bicarbonates of suitable bases such as pharmaceutically acceptable metal cations. It can be prepared separately by reacting with a carbonate or by reacting the functional group with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc., as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine Non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
[317] As used herein, the term "pharmaceutically acceptable ester" refers to an ester that is hydrolyzed in vivo and includes readily ruptured in the human body to release the parent compound or salt thereof. Suitable ester groups include, for example, pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic acid, alkenoic acid, cycloalkanoic acid and alkanedioic acid, wherein each alkyl or alkenyl moiety is advantageously at least 6 carbons. Has an atom). Examples of specific esters are formate, acetate, propionate, butyrate, acrylate and ethyl succinate.
[318] As used herein, the term "pharmaceutically acceptable prodrug" is suitable and reasonable for use in contact with tissues of humans and lower animals without causing harmful toxicity, irritation, allergic reactions, etc. under thorough medical judgment. It refers not only to prodrugs of the compounds of the present invention, which are balanced at a risk / ratio and effective for the intended purpose, but also to the zwitterionic forms of the compounds of the present invention, where possible. The term “prodrug” refers to a compound that is rapidly converted in vivo, for example by hydrolysis in blood, to produce the parent compound of the above formula. A thorough discussion has been made in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of thd A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Both of which are incorporated herein by reference.
[319] The term metabolically cleavable group, as used throughout this specification and the appended claims, refers to a moiety that is readily cleaved in vivo from a compound having the same, wherein the compound is pharmaceutical Become active. Metabolically cleavable groups that form a class of groups reactive with the carboxyl groups of the compounds of the present invention are well known to those skilled in the art. Examples thereof include alkanoyl such as acetyl, propionyl, butyryl; Unsubstituted aroyl and substituted aroyl such as benzoyl and substituted benzoyl; Alkoxycarbonyl such as ethoxycarbonyl; Trialkylsilyls such as trimethyl- and triethylsilyl; There are monoesters formed with dicarboxylic acids such as succinyl, but are not limited thereto. Since metabolically cleavable groups of the compounds of the present invention are readily cleaved in vivo, compounds having such groups act as pro-drugs of the α-1 adrenal receptor antagonist compounds. Compounds having such metabolically cleavable groups have the advantage that their bioavailability can be enhanced as a result of the enhanced solubility and / or uptake imparted on the parent compound through the presence of the metabolically cleavable groups. It has
[320] Compounds of the invention include compounds that originate from non-natural or synthetic preparations, including in vitro and in vivo preparations, or that result from in vivo preparations, eg, in vivo metabolic results.
[321] There may be asymmetric centers in the compounds of the invention. The present invention contemplates various stereoisomers and mixtures thereof. Individual stereoisomers of the compounds of the present invention may be prepared by synthetic procedures from starting materials containing chiral centers, or prepared mixtures of enantiomeric products, and then converted, for example, to mixtures of diastereomers. It is then prepared by separation by technique using recrystallization or chromatography or by direct separation of optical enantiomers on a chiral chromatography column. Starting materials for particular stereochemistry are either commercially available or are prepared by the methods described below and resolved by techniques well known in the art of organic chemistry.
[322] Representative compounds in the category of Formula I are:
[323] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[324] 3- [4-((3aS, 9bS) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[325] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[326] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro [1] -benzopyrano [3,4-c] pyrrole-2 -Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[327] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[328] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[329] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[330] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[331] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[332] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[333] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -1- (2-methoxyethyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion,
[334] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[335] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[336] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[337] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[338] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[339] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[340] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[341] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[342] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[343] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl]-[1] benzothieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[344] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl]-[1] benzothieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[345] 3- [5-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) pentyl]-[1] benzothieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[346] 3- [5-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) pentyl]-[1] benzothieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[347] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[348] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[349] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[350] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[351] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[352] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[353] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[354] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[355] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[356] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[357] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[358] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[359] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[360] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[361] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[362] 3- [4-((3aS, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[363] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[364] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[365] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[366] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[367] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[368] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[369] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[370] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-methoxy-pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[371] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-chloro-pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[372] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[373] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-isopropoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[374] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[375] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[376] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[377] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[378] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[379] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8 (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[380] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[381] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[382] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[383] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[384] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-furyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[385] 3- [2-((±) -cis-7-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[386] 3- [3-((±) -cis-7-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[387] 3- [2-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[388] 3- [3-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[389] 3- [2-((±) -cis-6-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[390] 3- [3-((±) -cis-6-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[391] 3- [2-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) ethyl]- [1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[392] 3- [4-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- Pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[393] 3- [4-((±) -trans-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- Pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[394] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[395] 3- [4-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[396] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[397] 3- [4-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[398] 3- [4-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[399] 3- [3-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[400] 3- [2-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Il) ethyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[401] 3- [4-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[402] 3- [4-((±) -trans-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- 6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[403] 3- [4-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- 6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[404] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[405] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[406] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[407] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[408] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[409] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[410] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[411] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[412] 3- [2-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[413] 3- [2-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) ethyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione,
[414] 3- [3-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[415] 3- [3-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[416] 3- [4-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[417] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[418] 3- [4-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[419] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[420] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[421] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[422] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[423] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[424] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[425] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[426] 3- [4-(-cis-7-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[427] 3- [4-((3aR, 9bR) -cis-6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[428] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (2-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion,
[429] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion, and
[430] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (4-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -Dione, or a pharmaceutically acceptable salt, ester or prodrug thereof.
[431] Preferred compounds falling within the scope of formula (I) are:
[432] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[433] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[434] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[435] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[436] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[437] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[438] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[439] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[440] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[441] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[442] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[443] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[444] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[445] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[446] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-isopropoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[447] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[448] 3- [3-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[449] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[450] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[451] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[452] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[453] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[454] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[455] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[456] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[457] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[458] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-furyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
[459] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[460] 3- [4-(-cis-7-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
[461] 3- [4-((3aR, 9bR) -cis-6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
[462] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (2-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion,
[463] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion, and
[464] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (4-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -Dione, or a pharmaceutically acceptable salt, ester or prodrug thereof.
[465] By the synthetic schemes and methods described in the Examples contained herein the following compounds:
[466] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2,3-g] quinazolin-2,4 (1H, 3H) -dione,
[467] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,4-g] quinazolin-2,4 (1H, 3H) -dione,
[468] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4,3-g] quinazolin-2,4 (1H, 3H) -dione,
[469] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,2-g] quinazolin-2,4 (1H, 3H) -dione,
[470] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2,3-f] quinazolin-2,4 (1H, 3H) -dione,
[471] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,4-f] quinazolin-2,4 (1H, 3H) -dione,
[472] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,2-f] quinazolin-2,4 (1H, 3H) -dione,
[473] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4,3-f] quinazolin-2,4 (1H, 3H) -dione,
[474] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2,3-h] quinazolin-2,4 (1H, 3H) -dione,
[475] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,4-h] quinazolin-2,4 (1H, 3H) -dione,
[476] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,2-h] quinazolin-2,4 (1H, 3H) -dione,
[477] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4,3-h] quinazolin-2,4 (1H, 3H) -dione,
[478] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -benz [g] quinazolin-2,4 (1H, 3H) -dione,
[479] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -benz [h] quinazolin-2,4 (1H, 3H) -dione,
[480] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -benz [f] quinazolin-2,4 (1H, 3H) -dione,
[481] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2,3-f] quinazolin-2,4 (1H, 3H) -dione,
[482] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2,3-gquinazolin-2,4 (1H, 3H) -dione,
[483] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2,3-h] quinazolin-2,4 (1H, 3H) -dione,
[484] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [3,4-f] quinazolin-2,4 (1H, 3H) -dione,
[485] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,3-f] quinazolin-2,4 (1H, 3H) -dione,
[486] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,5-f] quinazolin-2,4 (1H, 3H) -dione,
[487] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [3,4-g] quinazolin-2,4 (1H, 3H) -dione,
[488] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,3-g] quinazolin-2,4 (1H, 3H) -dione,
[489] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,5-g] quinazolin-2,4 (1H, 3H) -dione,
[490] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [3,4-h] quinazolin-2,4 (1H, 3H) -dione,
[491] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,3-h] quinazolin-2,4 (1H, 3H) -dione,
[492] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,5-h] quinazolin-2,4 (1H, 3H) -dione,
[493] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [4,5-f] quinazolin-2,4 (1H, 3H) -dione,
[494] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [5,4-f] quinazolin-2,4 (1H, 3H) -dione,
[495] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [4,5-g] quinazolin-2,4 (1H, 3H) -dione,
[496] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [5,4-g] quinazolin-2,4 (1H, 3H) -dione,
[497] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [4,5-h] quinazolin-2,4 (1H, 3H) -dione,
[498] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [5,4-h] quinazolin-2,4 (1H, 3H) -dione,
[499] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2,3-g] quinazolin-2,4 (1H, 3H) -dione,
[500] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,4-g] quinazolin-2,4 (1H, 3H) -dione,
[501] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4,3-g] quinazolin-2,4 (1H, 3H) -dione,
[502] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,2-g] quinazolin-2,4 (1H, 3H) -dione,
[503] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2,3-f] quinazolin-2,4 (1H, 3H) -dione,
[504] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,4-f] quinazolin-2,4 (1H, 3H) -dione,
[505] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,2-f] quinazolin-2,4 (1H, 3H) -dione,
[506] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4,3-f] quinazolin-2,4 (1H, 3H) -dione,
[507] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2,3-h] quinazolin-2,4 (1H, 3H) -dione,
[508] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,4-h] quinazolin-2,4 (1H, 3H) -dione,
[509] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3,2-h] quinazolin-2,4 (1H, 3H) -dione,
[510] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4,3-h] quinazolin-2,4 (1H, 3H) -dione,
[511] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -benz [g] quinazolin-2,4 (1H, 3H) -dione,
[512] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -benz [h] quinazolin-2,4 (1H, 3H) -dione,
[513] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -benz [f] quinazolin-2,4 (1H, 3H) -dione,
[514] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2,3-f] quinazolin-2,4 (1H, 3H) -dione,
[515] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2,3-g] quinazolin-2,4 (1H, 3H) -dione,
[516] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2,3-h] quinazolin-2,4 (1H, 3H) -dione,
[517] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [3,4-f] quinazolin-2,4 (1H, 3H) -dione,
[518] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,3-f] quinazolin-2,4 (1H, 3H) -dione,
[519] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,5-f] quinazolin-2,4 (1H, 3H) -dione,
[520] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [3,4-g] quinazolin-2,4 (1H, 3H) -dione,
[521] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,3-g] quinazolin-2,4 (1H, 3H) -dione,
[522] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,5-g] quinazolin-2,4 (1H, 3H) -dione,
[523] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [3,4-h] quinazolin-2,4 (1H, 3H) -dione,
[524] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridazino [4,3-h] quinazolin-2,4 (1H, 3H) -dione,
[525] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyridinino [4,5-h] quinazolin-2,4 (1H, 3H) -dione,
[526] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [4,5-f] quinazolin-2,4 (1H, 3H) -dione,
[527] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [5,4-f] quinazolin-2,4 (1H, 3H) -dione,
[528] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [4,5-g] quinazolin-2,4 (1H, 3H) -dione,
[529] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [5,4-g] quinazolin-2,4 (1H, 3H) -dione,
[530] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [4,5-h] quinazolin-2,4 (1H, 3H) -dione, and
[531] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrimidino [5,4-h] quinazolin-2,4 (1H, 3H) -dione, or a pharmaceutically acceptable salt, ester or prodrug thereof can be prepared.
[532] Representative compounds of the invention are evaluated for their ability to replace prazosin from its adrenal receptor.
[533] In vitro binding assay
[534] In the following, for the purpose of discussing the alpha-1 adrenal subtype, the IUPHAR Convention was followed, using lowercase letters to define molecular clones and capital letters to indicate pharmacologically defined adrenal receptors. Moreover, the newly recommended nomenclature (α _1a , α _1b , α _1d ) for alpha- ₁ was used.
[535] For the representative compounds of the present invention, three cloned α-1 adrenal receptors expressed in ³ [H] -prazosin and LTK cells as radioligands, namely α-1a (small), α-1b (hamster) And α-1d (rat) to assess α-adrenal receptor binding affinity in vitro. In addition, binding affinity to the pharmacologically defined α-1A adrenal receptor (rat mandible) is measured.
[536] cDNA clones encoding α-1 adrenal receptors (α-1a, α-1b and α-1d) are obtained from the Triangle Universities Licensing Consortium, Research Triangle Park, NC and inserted into the eukaryotic expression vector SnaB30. In such vectors, the expression of adrenal receptor genes is under the transcriptional control of the SV40 early promoter. Positive drug selection is provided by neomycin resistance genes. Mouse fibroblast cells (LTKs) are transfected with α ₁ expressing plasmids and grown in Dulbecco's Modified Eagles Medium (DMEM) containing 10% fetal calf serum and 30 μM G418. Stable G418 resistant parent strains are generated in which expression of adrenal receptor proteins monitored using radioligand binding techniques is successful. Stable single cell clones derived from the parental lines are screened in adrenal receptor binding assays to identify clones with high adrenal receptor density. This cloned attention roller bottle culture is used to provide adrenal receptor binding characterization to provide a cell membrane for use in subsequent studies. Cell lines containing SnaB30 vectors expressing the human erythropoietin gene served as negative controls.
[537] For adrenal receptor binding assays, a large-scale membrane formulation is used in which 6 million cells are seeded in small (450 cm 2) Corning tissue culture roller bottles. 200 ml of DMEM containing 10% fetal calf serum and 300 μM G418 is added to each roller bottle. A 95% air / 5% CO ₂ gas mixture is injected into each roller bottle prior to sealing. The bottle is then incubated for 5 days at 37 ° C. on a roller rack. Three days after incubation, cells are re-supplied with fresh medium.
[538] On day 5 of the culture, growth medium was removed from cells grown in roller bottles and these cells were treated with PBS (Sigma, 120 mM NaCl, 2.7 mM KCl, 10 mM Na ₂ HPO ₄ NaH ₂ PO ₄ , pH = 7.4). Wash twice. Cells are separated from roller bottles by incubating the cells for 15 minutes at 37 ° C. in Tris-EDTA solution (10 mM Tris, 100 mM NaCl, 1 mM EDTA, pH = 7.4). Cell suspensions from each roller bottle are decanted into weighted centrifuge tubes and kept on ice. An equal volume of each cell suspension is generally taken to count the cells. Cells are centrifuged at 3000 XG for 5 minutes at 2-4 ° C., washed with PBS and then recentrifuged. Pour out the supernatant and weigh the pellets to determine the wet weight of the cells. Cells are finally washed at 40 volume 5 mM Tris-HCl, 5 mM EDTA, pH = 7.7 and centrifuged at 40,000 XG for 10 minutes. Cells are homogenized in 10 ml of 50 mM Tris-HCl, 5 mM EDTA (pH = 7.4) and diluted to 40 ml / tube. Homogenates are centrifuged at 40,000 XG for 10 minutes. Pour out the supernatant and re-homogenize the pellet in 50 mM Tris-HCl (pH = 7.4) and centrifuge as before. The supernatant is drained and the homogenate is resuspended in 6.25 volumes of 50 mM Tris-HCl (per 1 g of wet weight), and an aliquot of the collected homogenate is frozen in liquid N ₂ and stored at −70 ° C. until assay. Rat mandibles were used for the α-1 adrenal receptor and described in Michel, AD, Loury, DN and Whiting, RL, Brit. J. Pharmacol. 98: 83-889 (1989).
[539] Receptor binding assays for α-1 adrenal receptors are essentially described in Greengrass and Bremner, Eur. J. Pharmacol. 55: 323-326 (1979). Briefly, plastic Bioblock ™ (DBM Scientific, Valencia, Calif.) Was added with an additional 96 volumes [clone adrenal] in membrane homogenate (50 mM Tris-HCl buffer (pH = 7.7 at assay) for 50 minutes at 25 ° C.). For receptors, diluted to 12 volumes for mandibular) 500 μl, ³ [H] -prazosin (0.2 nM final concentration, 75 to 85 Ci / mmole, DuPont-NEN Corp., Boston, Mass.) 450 μl And 50 μl of water (for total binding) or 10 μM pentolamine (final concentration, for non-specific binding). After equilibration, the bound radioligand is separated from the free ligand on a GF / B filter (pre-soaked in 0.5% polyethyleneimine) using a Brandel or Packard cell harvester. Radioactivity is determined using standard liquid scintillation techniques. Analyze the data as described previously. See Hancock, AA, Kyncl, JJ, Martin, YC and DeBernardis, JF, J. Receptor Res. 8: 23-46 (1988).
[540] Prostate strips were used in vitro as previously described [Hieble, J.P., Boyce, A.J. and Caine, M., Fed. Proc., 45: 2609-2614 (1986)], determine the antagonist efficacy on phenylephrine induced contraction.
[541] The results are shown in Table 1. The results indicate that the compounds of the present invention are bound to the α-1 adrenal receptor and exhibit various specificities for the α-1a adrenal receptor.
[542]
[543]
[544]
[545]
[546] Functional Antagonism in α-1 Adrenal Receptors
[547] The characterization of the compounds is further confirmed using functional assays indicating pharmacologically defined α-1 adrenal receptors. Inhibition of phenylephrine (PE) -induced contraction of prostate smooth muscle in dogs may be correlated with α-1A adrenal receptor activation. Inhibition of PE-induced contraction of rat spleen is representative of α-1B adrenal receptor antagonism and inhibition of PE-induced contraction of rat capillary correlates with α-1A adrenoreceptor antagonism. [RP Burt, CR Chapple and I. Marshall, Br. J. Pharmacol. 107: P324 (1992). If each of these models, the shield (Schild) plot by repeating the agonist dose-response curve for the test preparation in increasing concentrations to induce [log (molarity of test agent) log (EC ₅₀ -1) to] pA Determine ₂ Data on prazosin, terrazosin and doxazosin show a more potent effect on splenic smooth muscle in substantially size order.
[548] Prostate strips were used in vitro as previously described [Hieble, J.P., Boyce, A.J. and Caine, M., Fed. Proc., 45: 2609-2614 (1986)], determine the antagonist efficacy on phenylephrine induced contraction.
[549] The results are shown in Table 2. The results suggest that the compounds of the present invention exhibit functional antagonism of the α-1 adrenal receptor.
[550]
[551]
[552]
[553] In Vivo Determination of Intraurethral Pressure (IUP) in Dogs
[554] Intraurethral pressure (IUP) models in older dogs are allowed to measure the effect of prostate smooth muscle contraction on urethral tone. Dogs also have a closed prostate covering the urethral shaft, providing anatomical correlation with humans.
[555] Pre-anesthesia by intravenous injection of 15 mg / kg of thiopental sodium (Pentothal ™, Abbott) into a beagle dog (Marshall Farms) weighing 12-15 kg older than 2 years, followed by general anesthesia (isoflurane) ) Lubricate the 7F Swan-Ganz balun catheter (Multiflex-list no. 41224-01, Abbott) with water-soluble jelly, insert it into the urethral cavity, and place it in the shank dog until these balun tips are well placed inside the bladder. It progressed about 40 cm (relatively less in females). The balloon is then inflated with 1 ml of room air and the catheter is slowly withdrawn after just passing through the first resistance wire supplied from the cystoscope. Preliminary experiments at the expense of dogs after this positioning confirmed that this technique consistently positions the balun in the prostate urethra in the male or at the corresponding position in the female. The balun port of this catheter is connected to a Gould Statham P23Dd transformer interfaced with a computer data acquisition system (Modular Instruments, Inc., Malvern, PA) to measure the intraurethral pressure (IUP).
[556] The dog is then treated with propranolol to block the β-adrenoreceptor antagonistic effect of the test agonist. Dose-dependent curves of the ureteric booster effect of epinephrine before and after each administration (intravenously) of up to three doses with increasing dose of test antagonist are obtained. Equilibrate for 15 minutes after each antagonist administration before initiating the next agonist dose response. Due to the increase in IUP caused by a given agonist dose, it recovered to baseline before the next dose was administered. The antagonist dissociation constant (in vivo fake pA ₂ ) thus evaluated is determined by shield analysis (Brune, et al., Drug Development Research, 34: 267-275 (1995)).
[557] The results are shown in Table 3. The results indicate that the compounds of the present invention inhibit the increase in EPI induced IUP.
[558]
[559] SHR Model of Spontaneously Hypertensive Rats
[560] The SHR model has historically been used as a predictor of the blood pressure lowering effect of α-1 adrenal receptor antagonists. Male rats with spontaneous hypertension are anesthetized, and a catheter is inserted into the left femoral artery and vein to measure the median arterial pressure (MAP) and drug administration, respectively. Connect the arterial catheter to the Goul Statam p23ID transducer and record the pressure waveform. MAP (mm Hg) and heart rate (HR, beats / minute) are determined on-line using a BUXCO cardiovascular analyzer. After a 30-minute pre-dose adjustment period, each rat is dosed intravenously with a single dose of a test antagonist and monitored for MAP and HR after 2.5 hours. The area under the hypotension response curve (T ₆₀ AUC) up to 60 minutes after dosing is determined using the ladder law integration of the percent change from the control arterial pressure dataset. The result is expressed as the pED ₅₀ value, which is defined as -log of the dose that caused the blood pressure drop response of -1250, which constitutes 50% of the area under the curve between the SHR and the normal blood pressure rat.
[561] The results are shown in Table 4. The results suggest that the compounds of the present invention weakly lower blood pressure.
[562]
[563] Pharmaceutical composition
[564] The invention also provides pharmaceutical compositions comprising a compound of the invention formulated with one or more non-toxic pharmaceutically acceptable carriers. Such pharmaceutical compositions may be specifically formulated for oral, parenteral or rectal administration in solid or liquid form.
[565] The pharmaceutical compositions of the present invention can be administered to humans and other animals as oral, rectal, parenteral, subretinal alveolar, intraperitoneal, topical (by powder, ointment or drops), intranasal, or oral or nasal spray. have. The term “parenteral” administration, as used herein, refers to dosage forms including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarterial injections and infusions.
[566] Pharmaceutical compositions of the invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. . Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (eg glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (eg olive oil), and Injectable organic esters (eg ethyl oleate). For example, proper fluidity can be maintained by using coating materials such as lecithin, maintaining the required particle size in the case of dispersants, and by using surfactants.
[567] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. The action of microorganisms can be prevented by encapsulating various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. By incorporating agents that delay release of aluminum monostearate and gelatin, the absorption of injectable pharmaceutical forms can be delayed.
[568] In some cases, to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injections. This can be done by using a liquid suspending agent of crystalline or amorphous material with low water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug type is performed by dissolving or suspending the drug in an oil vehicle.
[569] Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers are poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
[570] Injectable formulations may, for example, be filtered with a bacterial-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media immediately prior to use. Can be sterilized.
[571] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is prepared by one or more inert and pharmaceutically acceptable excipients or carriers, such as sodium citrate or dicalcium phosphate and / or a) starch, lactose, sucrose, glucose, Fillers or thickeners such as mannitol and silicic acid, b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) agar-agar, carbonic acid Disintegrants such as calcium, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate h) absorbents such as kaolin and bentonite clay and i) talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium la Mixed with a mixture of a lubricant, and mixtures thereof, such as sulfate reel. In the case of capsules, tablets and pills, such dosage forms may comprise buffering agents.
[572] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.
[573] Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain a milky agent and may also be a composition which releases the active ingredient (s) in only a specific part of the intestine or preferentially in such part, in an optionally delayed manner. Examples of sealing compositions that can be used include polymeric substances and waxes.
[574] The active compound may also be in micro-encapsulated form, optionally with one or more excipients mentioned above.
[575] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solvents, suspensions, syrups and elixirs. Such liquid dosage forms, in addition to the active compounds, are inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (especially cottonseed oil, peanut oil, corn oil, germinated oil, olive oil, castor oil, and sesame oil), glycerol, tetra Fatty acid esters of hydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof.
[576] In addition to the inert diluent, the oral composition may include auxiliaries such as wetting agents, emulsifiers and suspending agents, sweetening agents, flavoring agents and flavoring agents.
[577] In addition to the active compounds, suspending agents include, for example, suspensions such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacand. Agents and mixtures thereof.
[578] Compositions for rectal administration are suitable for non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppositories that melt in the rectum to release the active compound because they are solid at room temperature but liquid at body temperature. Preference is given to suppositories which can be prepared by mixing with waxes.
[579] The compounds of the invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystal dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid that can form liposomes can be used. The composition of the present invention in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl choline (lecithin).
[580] Methods of forming liposomes are known in the art. See Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
[581] Dosage forms for topical administration of the compounds according to the invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and with the required preservatives, buffers or propellants as required. Ophthalmic formulations, eye ointments, powders and solvents are considered to be within the scope of the present invention.
[582] Actual dosage levels of active ingredients in the pharmaceutical compositions of the invention may vary to obtain an amount of active compound (s) effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. . The dosage level chosen will depend on the activity of the particular compound; Route of administration; Severity of the disease being treated; And the condition and previous medical history of the patient being treated. However, it is within the skill in the art to start with a compound dose of less than the amount required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
[583] Generally, a dosage of about 0.01 to about 50, more preferably about 0.05 to about 5 mg / kg body weight per day of active compound is orally administered to a mammalian patient. If desired, such effective daily dosages may be administered in several divided doses, for example two to four separate doses per day.
[584] Methods for preparing the compounds of the present invention are shown in Schemes 1-9 below. In the following schemes, R ₁ and R ₂ are hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Are independently selected from the group consisting of: In the following scheme, n is 1 or 2, m is 1 to 6, R is alkyl, and Y, G, G ', U and U' are as defined above.
[585] Scheme 1 illustrates a general procedure for preparing compounds of the present invention. The secondary amine (1) is made into compound (7) of the present invention by one of two general methods. Compound (1) is alkylated with haloalkyl nitrile in the presence of a non-nucleophilic base such as ethyldiisopropylamine, K ₂ CO ₃ or the like to give intermediate nitrile (2), which is then LiAlH ₄ , AlH ₃ , BH ₃ , catalytic hydrogenation, etc., are used to produce intermediate aminoalkyl substituted homologs (3). Treatment of this amine with heterocyclic isocyanate (5) yields intermediate urea, which spontaneously closes to become pyrimidinedione product (7) or to base product (7) under base catalysis. Alternatively, when R is other than H, carbamoyl chloride (6) is replaced by isocyanate (5). Alternatively, the secondary amine (1) is reacted with haloalkyl heterocyclic urea (4) in the presence of a non-nucleophilic base such as ethyldiisopropylamine, K ₂ CO ₃ or the like to obtain the title compound (7). ) Can be created directly.
[586] The amine 1, where n is 1, is prepared as summarized in Scheme 2 (for cis ring fusion) and Scheme 3 (for trans ring fusion). In the case of cis fused products, the appropriately substituted coumarin (8) is treated with azomethine lide precursor N-trimethylsilylmethyl-N-methoxymethyl-benzylamine (9) and optionally closed as cis isomer. Product 10 is produced. The lactone is reduced with LiAlH ₄ , BH ₃ , AlH ₃ , LiBH _4, and the like to produce alcohol (11). This primary alcohol is activated as chloride (12), bromide, mesylate, and the like, and then treated with a base such as KOtBu, NaOMe, NaOH, K ₂ CO _3, and the like to be closed with cis fused benzopyranopyrrole nuclei 13. . Removal of the benzyl group from the amine, which is most conveniently accomplished by a catalytic hydrogenation reaction, yields a cis fused secondary amine 14.
[587] In the case of trans fused products, the appropriately substituted trans cinnamate (15) (Scheme 3) is treated with azomethine lide precursor N-trimethylsilylmethyl-N-methoxymethyl-benzylamine (9) This results in the ring closed product 16 as a trans isomer. This ester is reduced with LiAlH ₄ , BH ₃ , AlH _3, and the like, followed by hydrolysis of the phenol protecting group to give alcohol (17). This primary alcohol is activated as chloride (18), bromide, mesylate, and the like, and then treated with a base such as KOtBu, NaOMe, NaOH, K ₂ CO _3, and the like to be closed with the trans-fused benzopyranopyrrole nucleus (19). . Removal of the benzyl group from the amine (which is most conveniently accomplished by catalytic hydrogenation reaction) yields a trans fused secondary amine 20.
[588] In a preferred embodiment of the present invention, the substitution of azomethine lide precursor 21 derived from (R) -α-methylbenzyl amine with compound (9) derived from benzyl amine gives a preferred (3aR , 9bR) amine 22 can be synthesized (Scheme 4) and the preferred (3aS, 9bR) amine 23 can be synthesized from ethyl 2-methoxy-6-methoxymethyl-trans-cinnamate. 5). In Scheme 4, the reagent PPh3 / CC14 can be replaced using methanesulfonyl chloride and triethylamine.
[589] In another preferred embodiment of the invention, the precursor of the compound of formula (I) wherein n is 2, i.e. (4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H -[1] -benzopyrano [3,4-c] pyridine (28) is prepared as shown in Scheme 6. Imide 24 is prepared from ethyl 2-methoxy-6-methoxymethyl cinnamate and ethyl N-benzylamidomalonate according to the method of Faruk and Martin, US Pat. No. 4,902,801. . Reduction with LiAlH ₄ , BH ₃ , AlH _3, etc., followed by conversion of the primary alcohol to a suitable leaving group such as chloro, bromo, mesylate and the like; The protected phenol was hydrolyzed and intramolecularly closed, followed by debenzylation to result in racemic trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyridine (28) is obtained. This secondary amine can be reacted with chiral chloroformate such as methyl chloroformate to give a mixture of diastereomeric carbamates, which can then be separated by chromatography. Treatment with n-BuLi removes the carbamate group to yield enantiomerically degraded secondary amine 28.
[590] In another preferred embodiment of the invention, the compounds of Formulas I-XIV and the compounds of Formulas VI-XIV can be prepared as shown in Scheme 7. Phenylglyoxal mono oxime (30) is condensed with 2-aminomalononitrile tosylate (31), and the resulting pyrazine N-oxide (32) is subjected to triethyl phosphite, sodium bisulfite, triphenylphosphine and the like. Reduction to yield the reggio-selective compound (33). After diazotizing the amine functional group, substitution reaction with CuBr, CuCl, etc. to obtain intermediate chloro- or bromo-pyrazine 34, which is carried out by base-promoted condensation reaction with methylthioglycolate, leads to thienopyrazine intermediate ( 35) is generated. Use of other alkylthioglycolates such as ethyl, n-propyl, n-alkyl or substituted alkyl will result in another thienopyrazine intermediate 35 having differentiated alkyl groups on the ester. The thienopyrazine intermediate 35 is reacted with phosgene, diphosgene, triphosgene, and the like in the presence of an inert solvent to produce an isocyanate 36 of formula VII.
[591] In another preferred embodiment of the invention, the compounds of formulas XV-X can be prepared according to the method outlined in Scheme 8. The free hydroxyl of compound (37) is activated as methanesulfonate, toluenesulfonate, benzenesulfonate, etc., or as a halide, followed by nucleophilic substitution with 2-bromo- or 2-iodoresorcinolic mono methyl ether To obtain ether intermediate 40. The ether intermediate 40, wherein X is Br or I, forms an enolate of lactam with metal amides (eg, KHMDS, LiHMDS, LDA, NaNH ₂ , KNH _2, etc.) and incorporated herein by reference. See McKillop, J. Chem. Soc., Perkin Trans, I., 1993, 2433, can be closed by exposure to metal salts (Cu +, Cu2 +, Mn2 +, Fe2 +, Fe3 +, etc.). Alternatively, to prepare a compound (41) in which R is an unsubstituted benzyl group, the metal enolate 40 of the lactam is converted to a transition metal complex (eg, Pd / C or Pd (PPh ₃ ) ₄ ). ) Or transition metal salt complexes (salts of Pd 2+ which may or may not form complexes with phosphines, amines or nitriles). Catalytic hydrogenation conditions can be used to deprotect compound (41). Compound 42 is alkylated with haloalkyl nitrile in the presence of a non-nucleophilic base such as ethyldiisopropylamine, K ₂ CO ₃ or the like to give intermediate nitrile 43, followed by LiAlH ₄ , BH ₃ , AlH ₃ , catalytic hydrogenation, or the like, to produce the intermediate aminoalkyl substituted homolog 44.
[592] In another embodiment of the present invention, 1-hydroxy-2-formaldehyde-3-methoxybenzene (45) in a protic solvent such as iso-propyl alcohol and tertiary amine base such as DABCO, and methyl acrylate; By reacting to produce chromen 47, lactam intermediates can be prepared as shown in Scheme 9. Condensation of such chromene with nitromethane in the presence of non-nucleophilic bases, such as DBU or potassium tert-butoxide, results in the intermediate nitroester 48, followed by catalytic hydrogenation reactions and bases such as It is reduced to lactam 49 using sodium methoxide and the like.
[593]
[594]
[595]
[596]
[597]
[598]
[599]
[600]
[601]
[602]
[603] While the foregoing description has been provided for the purpose of illustrating the invention, it may be better understood by reference to the following examples in which the scope of the invention is not limited.
[604] The following abbreviations were used: K ₂ CO ₃ represents potassium carbonate; LiAlH ₄ represents lithium aluminum hydride; AlH ₃ represents aluminum hydrate; BH ₃ represents borane; BH ₃ · DMS represents borane dimethylsulfide complex; DABCO represents 1,4-diazabicyclo [2.2.2] octane; DBUs display 1,8-diazabicyclo [5.4.0] undec-7-ene; DMF stands for dimethylformamide; DMSO represents dimethyl sulfoxide; Et ₃ N represents triethylamine; Et ₂ O represents diethyl ether; EtOAc represents ethyl acetate; EtOH represents ethanol; KOtBu represents potassium tert-butoxide; LDA stands for linium diisopropylamide; MeOH represents methanol; NaOMe represents sodium methoxide; NaOH represents sodium hydroxide; HCl represents hydrochloric acid; H ₂ / Pd represents hydrogen and palladium catalyst; iPrOH represents isopropyl alcohol; THF represents a tetrahydrofuran catalyst; TFA stands for catalytic trifluoroacetic acid; PPh ₃ / CCl ₄ represents triphenyl phosphine / carbon tetrachloride; n-BuLi represents n-butyllithium.
[605] Example 1
[606] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[607] Example 1A
[608] (3aR, 9bR) -cis-9-methoxy-2- (R) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole-4-one
[609] 5-methoxycoumarin (22.3 g, 126 mmol) and trifluoroacetic acid (0.97 ml, 12.6 mmol) are combined in CH ₂ Cl ₂ (200 ml) and cooled to 0 ° C. To the stirred solution is added N-methoxymethyl-N-trimethylsilylmethyl- (R) -α-methylbenzylamine (63.4 g, 253 mmol) over 30 minutes. The reaction is further stirred at 0 ° C. for 30 minutes and then at 25 ° C. for 1 hour. The reaction mixture is washed with 5% NaHCO ₃ , the organic layer is dried and then evaporated. The resulting oil is suspended in diethyl ether and after 2 hours the title compound is collected by filtration (15.4 g, 38%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (d, 3H), 2.41 (dd, 1H), 3.04 (d, 1H), 3.05-3.15 (m, 2H), 3.23 (m, 1H), 3.32 ( 1, 1H), 3.75 (m, 1H), 3.79 (s, 3H), 6.61 (d, 1H), 6.67 (d, 1H), 7.18 (t, 1H), 7.20-7.35 (m, 5H).
[610] Example 1B
[611] (3aR, 9bR) -cis-9-methoxy-2- (R) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole
[612] The product (15.3 g, 47 mmol) resulting from Example 1A in THF (200 ml) was added to a suspension of LiAlH ₄ (3.6 g, 94 mol) in THF (200 ml) over 15 minutes. After 2 hours at 25 ° C., the reaction is quenched (piter post-treatment) and the solvent is evaporated to separate the intermediate alcohol. This alcohol (15.2 g, 46 mmol) is combined with triphenylphosphine (24.3 g, 93 mmol) in a 4: 1 mixture of acetonitrile and CCl ₄ , and the resulting solution is heated to reflux for 1 hour. The solvent is evaporated and the resulting product is separated as a mixture of the title compound and intermediate chlorophenol. This mixture is treated with 1M potassium t-butoxide (12 mmol) in THF (50 ml). The solvent is evaporated and the product is partitioned between dilute aqueous NaOH and ethyl acetate. The organic phase is dried and evaporated to give 11.9 g (84%) of the title compound after chromatographic purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (d, 3H), 2.23-2.31 (m, 2H), 2.59 (m, 1H), 3.04 (dd, 1H), 3.20 (q, 1H), 3.23 ( q, 1H), 3.38 (q, 1H), 3.77 (s, 3H), 3.81 (q, 1H), 4.01 (q, 1H), 6.41 (d, 1H), 6.52 (d, 1H), 7.04 (t , 1H), 7.20-7.35 (m, 5H).
[613] Example 1C
[614] (3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[615] The product from Example 1B (7.7 g, 24.9 mmol) is dissolved in methanol (300 ml) and palladium hydroxide on charcoal (1.5 g) is added. The reaction is stirred rapidly for 18 hours under 1 atm of H ₂ . The reaction is filtered and evaporated to afford the title compound (4.6 g, 90%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H); [α] _D -95.7 ° (MeOH).
[616] Example 1D
[617] (3aR, 9bR) -cis-2- (3-cyanopropyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole
[618] The product from Example 1C (7.0 g, 34 mmol) was combined with 4-bromobutyronitrile (5.6 g, 37.5 mmol) and ethyldiisopropylamine (8.9 ml, 51 mmol) in acetonitrile (50 ml) and the reaction was combined. Stir at 80 ° C. for 4 hours. The reaction is quenched in 5% aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic extract is washed with brine, dried and evaporated. The resulting product is purified by column chromatography to give the title compound (7.5 g, 81%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.82 (m, 2H), 2.30 (m, 2H), 2.43 (t, 2H), 2.45-2.65 (m, 3H), 3.04 (dd, 1H), 3.23- 3.42 (m, 2H), 3.79 (dd, 1H), 3.82 (s, 3H), 4.06 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).
[619] Example 1E
[620] (3aR, 9bR) -cis-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Pyrrole
[621] LiAlH ₄ (7.8 g, 207 mmol) is suspended in THF (200 ml) and cooled to 0 ° C. To this suspension is added AlCl ₃ (9.2 g, 69 mmol) in small portions over 15 minutes. The product from Example 1D (7.5 g, 27.5 mmol) in THF (50 ml) is then added over 15 minutes, the reaction is allowed to warm to 25 ° C. and then stirred for 1.5 hours. By the addition of 10.5ml H ₂ O, 10.5ml 15% aqueous KOH and 42ml H ₂ O, then quench the reaction. The reaction is filtered through celite and the solvent is evaporated to give the title compound (6.6 g, 87%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.80 (m, 4H), 2.19 (m, 1H), 2.25 (dd, 1H), 2.42 (m, 1H), 2.52 (t, 2H), 3.14 ( dd, 1H), 3.18-3.30 (m, 2H), 3.79 (dd, 1H), 3.80 (s, 3H), 4.04 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1 H).
[622] Example 1F
[623] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[624] Methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.624 g, 3.00 mmol) prepared by the procedure described in J. Heterocyclic Chem., 24:85 (1987). ) And triethylamine (0.84 ml, 6.0 mmol) are dissolved in THF (20 ml) and 1.7 ml of a phosgene 1.93M solution in toluene (3.3 mmol) is added to this solution. After 2 hours, the product from Example 1E (0.78 g, 2.8 mmol) is added. After 4 hours, the reaction is quenched in 5% aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic extracts are dried and then evaporated. The resulting urea is dissolved in toluene (100 ml) and heated to reflux for 18 hours. The cooled reaction mixture is filtered and the free base of the resulting title compound is treated with anhydrous HCl in ethanol. Add diethyl ether to crystallize the title compound (0.76 g, 57%): melting point 241-243 ° C. (decomposition); ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.56-1.99 (m, 2H), 1.71-1.83 (m, 2H), 2.26 (t, J = 9 Hz, 1H), 2.34 (dd, J = 6, 10Hz, 1H), 2.50-2.70 (m, 3H), 3.26 (dd, J = 7, 10Hz, 1H), 3.43 (q, J = 8Hz, 1H), 3.63 (t, J = 8Hz, 1H) , 3.79 (s, 3H), 3.76-3.86 (m, 1H), 4.01 (dd, J = 4, 11 Hz, 1H), 4.11 (t, J = 7 Hz, 1H), 6.43 (d, J = 8 Hz, 1H ), 6.49 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 7.49 (dd, J = 4.8, 1H), 8.23 (dd, J = 1, 8 Hz, 1H), 8.78 ( dd, J = 1, 4 Hz, 1H); MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ ;
[625] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ SHCl (H ₂ O) _0.25 :
[626] Calculated: C, 57.80; H, 5. 34; N, 10.78.
[627] Found: C, 57.72; H, 5. 46; N, 10.58.
[628] Example 1G
[629] (3aR, 9bR) -cis-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Another Synthesis of Pyrrole
[630] Trifluoroacetic acid is added to a solution of 5-methoxycoumarin in THF at 15 ° C. To this was added a solution of N-methoxymethyl-N-trimethylsilylmethyl- (R) -α-methylbenzylamine in t-butylmethyl ether. After the reaction was completed, the mixture was stirred at 25 ° C. for 1 hour and then concentrated in vacuo. The residue is diluted with ethyl acetate, stirred at 5 ° C. for 1.5 hours and then filtered. The filter cake was washed with ethyl acetate and dried to give (3aR, 9bR) -cis-9-methoxy-2- (R) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [ 1] -benzopyrano [3,4-c] pyrrole-4-one is obtained.
[631] Combine lithium borohydride and tetrahydrofuran and cool to below -10 ° C. The solution of pyrrolidine lactone in tetrahydrofuran is slowly added while maintaining at a temperature of 0 ° C or lower. The solution is stirred at approximately 5 ° C. for 1 hour and then distilled under vacuum. Methanol is added to the residue and the contents are refluxed for 2 hours. A solution of ammonium chloride in water is added and the reaction mixture is distilled off under vacuum at 55 ° C. The residue is extracted with toluene and the toluene layer is washed with distilled water. The layer thus washed is then distilled down at less than 55 ° C.
[632] Tetrahydrofuran is added to toluene, cooled to 0 ± 10 ° C. and triethylamine is added. Methanesulfonyl chloride in toluene is added and the mixture is stirred at 0 ± 10 ° C. for 1 hour. A solution of potassium t-butoxide in tetrahydrofuran is added and stirred at 10 ° C. for at least 1 hour. Toluene is added and the layers are washed with ammonium chloride in water and then with distilled water. The solution sample can then be concentrated in vacuo.
[633] Alternatively, the material can be purified by adding isopropanol and then concentrating to oil under vacuum while adding anhydrous hydrogen chloride in isopropanol. The solution is stirred at room temperature for 3 hours and the resulting slurry is filtered. The filter cake was washed with isopropanol and dried in an oven at 35 ° C. for 16 hours to give (3aR, 9bR) -cis-9-methoxy-2- (R) -α-methylbenzyl-1,2,3,3a, Hydrochloride salt of 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole is obtained.
[634] (3aR, 9bR) -cis-9-methoxy-2- (R) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3 in ethanol To a solution of, 4-c] pyrrole hydrochloride is added 5% palladium on 50% wet carbon. The flask is purged with hydrogen and heated to 50 ° C. for 16 hours at 50 psi. The catalyst was filtered off and the solvent was removed in vacuo at approximately 40 ° C. to give (3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [ Obtain the hydrochloride salt of 3,4-c] pyrrole.
[635] The product from Example 1C (7.0 g, 34 mmol) was combined with 4-bromobutyronitrile (5.6 g, 37.5 mmol) and ethyldiisopropylamine (8.9 ml, 51 mmol) in acetonitrile (50 ml) and the reaction was combined. Stir at 80 ° C. for 4 hours. The reaction is quenched in 5% aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic extract is washed with brine, dried and evaporated. The resulting product was purified by column chromatography (3aR, 9bR) -cis-2- (3-cyanopropyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [ 1] -benzopyrano [3,4-c] pyrrole is obtained.
[636] As an alternative to the process in Example 1E, the nitrogen purged hydrogenator is charged with Raney Nickel and Methanol. The slurry is stirred and allowed to settle. Remove the supernatant through the dip tube. The residue is then reslurried with methanol and the supernatant is removed again using a diptube. This is repeated three times and four times. The Raney Nickel is then slurried with methanol and the solution of the product from Example 1D in ethanol is added. The internal temperature is cooled to about 0 ° C. and ammonia is added. The hydrogenator is purged under pressure three times with hydrogen and pressurized to 50 psi. The solution is hydrogenated at approximately 25 ° C. for 2 hours. When the reaction is complete, the catalyst is filtered through celite phase and the filter cake is washed with methanol. The combined filtrates are then charged to another reactor and distilled under vacuum at below 40 ° C. to obtain a residue. Toluene is added followed by sodium hydroxide solution in water. The biphasic solution is filtered through a pad of celite into another reactor and the layers are separated. The organics are washed with water and toluene is distilled under vacuum at below 45 ° C. to give a primary amine.
[637] Example 1H
[638] Synthesis of Compound 40 in Scheme 8
[639] To a solution of water (500 ml) and itaconic acid (108.9 g, 0.83 mol) is added phenethylamine (101.4 g, 0.83 mol). It is heated to reflux for 24 hours, cooled to room temperature and the liquid is decanted. The solid is then dissolved under reflux in 40% aqueous ethanol (800 ml.) The solution is slowly cooled to room temperature and filtered. The filter cake is washed with water (200 ml), washed twice with ethanol (200 ml each) and dried To give 82.1 g of a white solid.
[640] The white solid (82 g, 0.35 mol) solution in methanol (500 ml) is heated to reflux with trimethylorthoformate (37.3 g, 0.35 mol) and sulfuric acid (about 0.5 g) for 16 hours. It is cooled to room temperature and sodium borohydride (26.48 g, 0.7 mol) is added dropwise. The solution is then heated to reflux for 2 hours and concentrated to approximately 300 ml under vacuum. The solution is diluted with aqueous ammonium chloride (200 ml) and extracted with ethyl acetate (once with 500 ml and three times with 300 ml). The combined organic layers are concentrated in vacuo to afford an oil (34 g) of compound 37, which is comparable to the previously reported compound. Domagala, J. Med. Chem., 1987, 30, 1711.
[641] Triethylamine (13.84 g, 0.137 mol) is added to a solution of compound 37 (30 g, 0.137 mol) which is an alcohol in THF (300 ml) followed by tosyl chloride (26.08 g, 0.137 mol). It is stirred for 14 hours at room temperature. The reaction was diluted with ethyl acetate (300 ml) and washed with 5% sodium bicarbonate (400 ml) and then twice with 1% sodium bicarbonate (300 ml), dried over sodium sulphate and concentrated in vacuo to give the oil of compound (38). Obtain: ¹ H NMR (CDCl ₃ ) δ 7.78 (d, 2H, J = 8 Hz), 7.4-7.2 (m, 7H), 5.45 (q, 1H, J = 6.5 Hz), 4.0-3.9 (m, 2H), 3.1-3.0 (m, 2H), 2.65-2.5 (m, 1H), 2.4 (d, 1H, J = 12 Hz), 2.45 (s, 3H), 2.15-2.05 (m, 1H), 1.43 ( d, 3H, J = 7 Hz).
[642] To a solution of 3-methoxyphenol (100 g, 0.81 mol) in methylene chloride (500 ml) is added dihydropyran (184 ml, 2.01 mol) and pyridinium p-toluenesulfonate (10.1 g, 0.04 mol) at room temperature. The solution is stirred at room temperature for 5 hours before quenching with saturated sodium bicarbonate (250 ml). The organics are separated and the aqueous is extracted twice with methylene chloride (250 ml). The combined organics are then washed with saturated NaCl (250 ml), dried over sodium sulphate and concentrated in vacuo to give an oil (184 g).
[643] 1.6 M butyl-lithium (45 ml, 72 mmol) is added to a solution of the oil (10.45 g, 50 mmol) as described above in heptane (210 ml) at 0 ° C. It is stirred for 3 hours and then quenched with a solution of iodine (22.1 g, 8.7 mmol) in ether (250 ml). The reaction mixture is then stirred at 0 ° C. for 30 minutes, quenched with saturated sodium bisulfate (200 ml) and extracted with other compounds (3 × 250 ml). The combined organics are washed with saturated sodium bisulfate (200 ml), saturated NaCl (200 ml) and dried over sodium sulfate. Concentration in vacuo affords an oil. The crude oil is dissolved in ethanol (250 ml) and pyridinium p-toluenesulfonate is added. The mixture is heated to 70 ° C. for 1.5 h, cooled to rt, diluted with ethyl acetate (250 ml) and washed with saturated NaCl (250 ml). The aqueous layer is extracted again with ethyl acetate (250 ml) twice. The organics are combined, dried over sodium sulphate and concentrated in vacuo to give an oil of compound 39: MS (CI) m / z (rel intensity 250 ([M + I] ⁺ 100)).
[644] Potassium tert-butoxide (1.12 g, 10 mmol) is added to a solution of 2-bromophenol (1.73 g, 10 mmol) in DMF (20 ml) at 0 ° C. It is stirred at 0 ° C. for 15 minutes before adding the compound from Example 38 (3.73 g, 10 mmol). It is heated to 60 ° C. for 16 h, cooled to rt, diluted with ethyl acetate (200 ml) and washed twice with water (1 × 200 ml, 1 × 100 ml). The organics are dried over sodium sulphate and concentrated in vacuo to give approximately 20 ml. It is diluted 1: 1 (v / v) with heptane and passed through a silica layer (1.5 g). The eluate was concentrated in vacuo to afford 40 (3 g, 80%) as an oil.
[645] Example 2
[646] 3- [4-((3aS, 9bS) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[647] Example 2A
[648] (3aS, 9bS) -cis-9-methoxy-2- (S) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole-4-one
[649] 5-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl- (S) -α-methylbenzylamine are treated in a similar manner as described in Example 1A. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (d, 3H), 2.41 (dd, 1H), 3.04 (d, 1H), 3.05-3.15 (m, 2H), 3.23 (m, 1H), 3.32 ( 1, 1H), 3.75 (m, 1H), 3.79 (s, 3H), 6.61 (d, 1H), 6.67 (d, 1H), 7.18 (t, 1H), 7.20-7.35 (m, 5H).
[650] Example 2B
[651] (3aS, 9bS) -cis-9-methoxy-2- (S) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole
[652] The product resulting from Example 2A is treated in a similar manner as described in Example 1B. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (d, 3H), 2.23-2.31 (m, 2H), 2.59 (m, 1H), 3.04 (dd, 1H), 3.20 (q, 1H), 3.23 ( q, 1H), 3.38 (q, 1H), 3.77 (s, 3H), 3.81 (q, 1H), 4.01 (q, 1H), 6.41 (d, 1H), 6.52 (d, 1H), 7.04 (t , 1H), 7.20-7.35 (m, 5H).
[653] Example 2C
[654] (3aS, 9bS) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[655] The product from Example 2B is treated in a similar manner as described in Example 1C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H); [α] _D MeOH + 95.2 °.
[656] Example 2D
[657] (3aS, 9bS) -cis-2- (3-cyanopropyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole
[658] The product from Example 2C is treated in a similar manner as described in Example 1D. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.82 (m, 2H), 2.30 (m, 2H), 2.43 (t, 2H), 2.45-2.65 (m, 3H), 3.04 (dd, 1H), 3.23- 3.42 (m, 2H), 3.79 (dd, 1H), 3.82 (s, 3H), 4.06 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).
[659] Example 2E
[660] (3aS, 9bS) -cis-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Pyrrole
[661] The product from Example 2D is treated in a similar manner as described in Example 1E. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.80 (m, 4H), 2.19 (m, 1H), 2.25 (dd, 1H), 2.42 (m, 1H), 2.52 (t, 2H), 3.14 ( dd, 1H), 3.18-3.30 (m, 2H), 3.79 (dd, 1H), 3.80 (s, 3H), 4.04 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1 H).
[662] Example 2F
[663] 3- [4-((3aS, 9bS) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[664] The product from Example 2E (0.800 g, 2.9 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.624 g, 3.00 mmol) were prepared in a similar manner as described in Example 1F. Treatment yielded 1.1 g (79%) of the title compound: melting point 241-243 ° C. (decomposition); ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.56-1.99 (m, 2H), 1.71-1.83 (m, 2H), 2.26 (t, J = 9 Hz, 1H), 2.34 (dd, J = 6, 10Hz, 1H), 2.50-2.70 (m, 3H), 3.26 (dd, J = 7, 10Hz, 1H), 3.43 (q, J = 8Hz, 1H), 3.63 (t, J = 8Hz, 1H) , 3.79 (s, 3H), 3.76-3.86 (m, 1H), 4.01 (dd, J = 4, 11 Hz, 1H), 4.11 (t, J = 7 Hz, 1H), 6.43 (d, J = 8 Hz, 1H ), 6.49 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 7.49 (dd, J = 4.8 Hz, 1H), 8.23 (dd, J = 1, 8 Hz, 1H), 8.78 (dd, J = 1, 4 Hz, 1H); MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ ;
[665] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ SHCl (H ₂ O) _0.25 :
[666] Calculated: C, 57.80; H, 5. 34; N, 10.78.
[667] Found: C, 57.85; H, 5. 46; N, 10.65.
[668] Example 3
[669] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[670] Example 3A
[671] 3- (R)-(2-hydroxy-6-methoxy) phenyl-4- (S) -hydroxymethyl-N- (R) -α-methylbenzyl-pyrrolidine
[672] Ethyl 2-methoxy-6-methoxymethyl-cinnamate (36 g, 160 mmol) and trifluoroacetic acid (1.23 ml, 16 mmol) are combined in CH ₂ Cl ₂ (800 ml) and cooled to 0 ° C. To the stirred solution is added N-methoxymethyl-N-trimethylsilylmethyl- (R) -α-methylbenzylamine (80 g, 320 mmol) in 200 ml of CH ₂ Cl ₂ over 30 minutes. This reaction is further stirred at 0 ° C. for 2.5 hours. The reaction mixture is washed with 5% NaHCO ₃ , the organic layer is dried and then evaporated. The crude product is dissolved in THF (150 ml) and added to a stirred suspension of LiAlH ₄ (12.1 g, 320 mmol). The reaction is quenched (fiber workup), filtered through celite and evaporated. This product is dissolved in methanol (850 ml) and 4N HCl (120 ml) is added. After heating to reflux for 2 hours, the solvent is evaporated and the residue is partitioned between saturated NaHCO ₃ solution and ethyl acetate. The organic extracts are dried and then evaporated. The organic extracts are dried and then evaporated. The crude product is purified by chromatography eluting with 2: 1 diethyl ether: hexanes to give the title compound (22.1 g, 42%) as a faster moving diastereomer: ¹ H NMR (300 MHz, CDCl ₃₎ ) δ 1.48 (d, 3H), 1.81 (t, 1H), 2.16 (m, 1H), 2.36 (m, 1H), 2.58 (t, 1H), 3.05 (t, 1H), 3.40 (m, 2H) , 3.53 (m, 2H), 3.80 (dd, 1H), 3.83 (s, 3H), 6.38 (d, 1H), 6.60 (d, 1H), 7.05 (t, 1H), 7.22-7.40 (m, 5H ), 12.62 (br s, 1 H).
[673] Example 3B
[674] (3aS, 9bR) -trans-9-methoxy-2- (R) -α-methylbenzyl-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole
[675] The product from Example 3A (22.1 g, 67.0 mmol) is dissolved in 290 ml of a 4: 1 mixture of acetonitrile and CCl ₄ . Triphenylphosphine (35.4 g, 135 mmol) is added to this solution and the reaction is heated at 80 ° C. for 20 minutes. The reaction is concentrated and passed through a silica gel column eluting with 1: 1 hexanes: diethyl ether. The product containing the mixture of the title compound and chloro intermediate is dissolved in THF (300 ml) and 41 ml of 1.0 M potassium t-butoxide in THF are added. After 18 hours, this THF is evaporated and the resulting product is partitioned between 1N NaOH and diethyl ether. The organic extracts are dried and then evaporated and the product is chromatographed on silica gel eluting with 1: 1 hexanes: diethyl ether to give 13.2 g (63%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45 (d, 3H), 2.28 (m, 1H), 2.44 (dd, 1H), 2.70-2.90 (m, 2H), 3.54 (m, 1H), 3.69 (s, 3H), 3.70 (q, 1H ), 3.99 (dd, 1H), 4.38 (dd, 1H), 6.37 (d, 1H), 6.47 (d, 1H), 7.04 (t, 1H), 7.20-7.40 (m, 5H).
[676] Example 3C
[677] (3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[678] The product from Example 3B (13.0 g, 42 mmol) was treated in a similar manner as described in Example 1C to give 8.08 g (94%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.07 (br s, 1H), 2.24 (m, 1H), 2.70 (m, 2H), 2.84 (t, 1H), 3.21 (dd, 1H), 3.77 (s, 3H), 3.83 (dd, 1H), 4.07 (dd , 1H), 4.53 (dd, 1H), 6.40 (d, 1H), 6.51 (d, 1H), 7.06 (t, 1H); [α] _D MeOH-94.8 °.
[679] Example 3D
[680] (3aS, 9bR) -trans-2- (3-cyanopropyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole
[681] The product from Example 3C (8.0 g, 39 mmol), 4-bromobutyronitrile (6.3 g, 43 mmol) and diisopropylethylamine (7.6 g, 58 mmol) were treated as described in Example 1D to give the title compound. 7.1 g (67%) is obtained: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.84 (m, 2H), 2.30 (m, 1H), 2.46 (t, 2H), 2.55 (dd, 1H), 2.70 -2.85 (m, 4H), 2.91 (dd, 1H), 3.52 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H), 4.45 (dd, 1H), 6.39 (d, 1H), 6.49 (d, 1 H), 7.05 (t, 1 H).
[682] Example 3E
[683] (3aS, 9bR) -trans-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Pyrrole
[684] The product from Example 3D (7.1 g, 26 mmol) was treated as described in Example 1E to give 6.29 g (87%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40-1.80 (m , 4H), 2.32 (m, 1H), 2.57 (t, 1H), 2.62-2.90 (m, 4H), 2.95 (t, 1H), 3.60 (m, 1H), 3.78 (s, 3H), 4.06 ( dd, 1H), 4.45 (dd, 1H), 6.40 (d, 1H), 6.49 (d, 1H), 7.04 (t, 1H).
[685] Example 3F
[686] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[687] The product from Example 3E (0.800 g, 2.9 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.624 g, 3.00 mmol) were treated as described in Example 1F. To 0.70 g (50%) of the title compound: melting point> 255 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ (freebase)) δ1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2.04-2.18 (m, 1H), 2.25-2.89 (m, 4H), 3.10-3.48 (m, 3H), 3.68 (s, 3H), 3.95 (t, J = 7 Hz, 2H), 4.02 (dd, J = 10, 12 Hz, 1H), 4.39 (dd, J = 4 , 10Hz, 1H), 6.39 (dd, J = 1, 8Hz, 1H), 6.44 (dd, J = 1, 8Hz, 1H), 7.01 (t, J = 8Hz, 1H), 7.64 (dd, J = 5 , 8 Hz, 1H), 8.63 (dd, J = 1, 8 Hz, 1H), 8.83 (dd, J = 1, 5 Hz, 1H); MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ .
[688] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ SHCl (H ₂ O) _0.5 :
[689] Calc .: C, 57.30; H, 5.39; N, 10.69.
[690] Found: C, 57.08; H, 5. 43; N, 10.80.
[691] Example 4
[692] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[693] Example 4A
[694] (3aR, 9bS) -trans-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Pyrrole
[695] Ethyl 2-methoxy-6-methoxymethyl-cinnamate and N-methoxymethyl-N-trimethylsilylmethyl- (S) -α-methylbenzylamine are treated in a similar manner as described in Examples 3A to 3E. . ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40-1.80 (m, 4H), 2.32 (m, 1H), 2.57 (t, 1H), 2.62-2.90 (m, 4H), 2.95 (t, 1H), 3.60 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H), 4.45 (dd, 1H), 6.40 (d, 1H), 6.49 (d, 1H), 7.04 (t, 1H).
[696] Example 4B
[697] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[698] The product from Example 4A (680 mg, 2.5 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (520 mg, 2.5 mmol) were treated as described in Example 1F to give the title 0.75 g (63%) of compound are obtained: melting point> 255 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ (freebase)) δ1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2.04-2.18 (m, 1H), 2.25-2.89 (m, 4H), 3.10-3.48 (m, 3H), 3.68 (s, 3H), 3.95 (t, J = 7 Hz, 2H), 4.02 (dd, J = 10, 12 Hz, 1H), 4.39 (dd, J = 4 , 10Hz, 1H), 6.39 (dd, J = 1, 8Hz, 1H), 6.44 (dd, J = 1, 8Hz, 1H), 7.01 (t, J = 8Hz, 1H), 7.64 (dd, J = 5 , 8 Hz, 1H), 8.63 (dd, J = 1, 8 Hz, 1H), 8.83 (dd, J = 1, 5 Hz, 1H); MS (DCI (NH ₃ ) m / e 479 (M + H) ⁺ ;
[699] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ SHCl (H ₂ O) _0.25 :
[700] Calc .: C, 57.80; H, 5. 34; N, 10.78.
[701] Found: C, 57.45; H, 5. 35; N, 10.80.
[702] Example 5
[703] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[704] Example 5A
[705] Methyl 3-amino-5-chlorothieno [3,2-b] pyridine-2-carboxylate and methyl 3-amino-7-chlorothieno [3,2-b] pyridine-2-carboxylate
[706] Hydrogen peroxide (30%, 52 g, 0.45 mol) is added dropwise to a solution of 3-chloro-2-cyanopyridine (40 g, 0.29 mol) in 500 ml of acetic acid. After stirring at 90 ° C. for 18 hours, the reaction is cooled to 25 ° C. and a solution of sodium sulfite (57 g, 0.45 mol) in H ₂ O is added dropwise. The reaction is concentrated to remove acetic acid bulk and the residue is partitioned between 1M NaOH and CH ₂ Cl ₂ . The CH ₂ Cl ₂ layer is dried (MgSO ₄ ), filtered, concentrated and recrystallized from EtOAc to give 23 g (51%) of 3-chloro-2-cyanopyridine-N-oxide. The resulting N-oxide (12.2 g, 79 mmol) is dissolved in DMF (160 ml) at 0 ° C. Methyl thioglycolate (7.1 ml, 79 mmol) is added, followed by the addition of sodium methoxide (8.5 g, 160 mmol) in several fractions. The reaction is stirred for 1 hour. The reaction is poured onto ice and the resulting solid collected by filtration, washed with water, dissolved in CH ₂ Cl ₂ , dried (MgSO ₄ ), filtered, concentrated and recrystallized from EtOAc. 10.6 g (60%) of methyl 3-amino-thieno [3,2-b] pyridine-4-oxide carboxylate are obtained. Pyridine-N-oxide (10.6 g, 47 mmol) is mixed with phosphorus oxychloride (100 ml). The reaction is heated at 80 ° C. for 30 minutes. The reaction is concentrated and fractionated with CH ₂ Cl ₂ and 5% aqueous NaHCO ₃ solution. The CH ₂ Cl ₂ layer was dried (MgSO ₄ ), filtered, concentrated and chromatographed (5: 1 hexanes: EtOAc) to methyl 3-amino-5-chlorothieno [3,2-b] pyridine-2 Obtained carboxylate (8.3 g, 73%): ¹ H NMR (300 MHz, CDCl 3) d 3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H) ; MS (DCI / NH 3) m / e 243 (M + H) ⁺ ;
[707] Then methyl 3-amino-7-chlorothieno [3,2-b] pyridine-2-carboxylate (2.0 g, 18%) is obtained: ¹ H NMR (300 MHz, CDCl 3) d 3.93 (s, 3H ), 6.20 (bs, 2 H), 7.41 (d, 1 H), 8.54 (db, 1 H); MS (DCI / NH 3) m / e 243 (M + H) ⁺ .
[708] Example 5B
[709] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[710] The product from Example 4A (0.27 g, 1.0 mmol) and methyl 3-amino-7-chloro-thieno [3,2-b] pyridine-2-carboxylate were treated as described in Example 1F to give the title compound. 0.12 g (24%) is obtained: melting point 265-267 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (freebase)) δ 8.63 (d, 1H), 7.51 (d, 1H), 7.08 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.93 (dd, 1H), 4.02-4.18 (m, 3H), 3.99 (m, 1H), 3.38 (t, 1H), 2.88-3.12 (m, 5H), 2.45 (m, 1H), 1.8 (m, 4H); MS (DCI / NH ₃ ) m / e 513 (M + H) ⁺ ;
[711] Elemental Analysis for C ₂₅ H ₂₅ N ₄ O ₄ SCl · 2HCl:
[712] Calc .: C, 51.25; H, 4. 64; N, 9.56.
[713] Found: C, 51.28; H, 4.96; N, 9.45.
[714] Example 6
[715] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[716] The product from Example 4A (0.27 g, 1.0 mmol) and methyl 3-amino-5-chloro-thieno [3,2-b] pyridine-2-carboxylate were treated as described in Example 1F to give the title compound. 0.10 g (19%) is obtained: melting point> 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (freebase)) δ8.1 (d, 1H), 7.41 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.35 (d, 1H), 4.57 (dd, 1H), 4.11 (m, 3H), 3.95 (m, 1H), 3.73 (s, 3H), 3.37 (m, 2H), 2.9-3.1 (m, 4H), 2.48 (m, 1H) , 1.8 (m, 4 H); MS (DCI / NH ₃ ) m / e 513 (M + H) ⁺ ;
[717] Elemental Analysis for C ₂₅ H ₂₅ CIN ₄ O ₄ S · 2HCl:
[718] Calc .: C, 51.25; H, 4. 64; N, 9.56.
[719] Found: C, 51.22; H, 4.77; N, 9.32.
[720] Example 7
[721] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[722] Example 7A
[723] 3-amino-5-methoxy-thieno [3,2-b] pyridine-2-carboxylate
[724] A solution of 3-amino-5-chloro-thieno [3,2-b] pyridine-2-carboxylate (5 g, 21 mmol) and sodium methoxide (4.5 g, 82 mmol) in MeOH (150 ml) was refluxed for 18 hours. Let's do it. The reaction is concentrated and partitioned between EtOAc and NaHCO ₃ solution. The EtOAc layer was dried (MgSO ₄ ), filtered, concentrated and chromatographed (5: 1 hexanes: EtOAc) to give 2.5 g (51%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ3. 80 (s, 3H), 4.02 (s, 3H), 6.05 (bs, 2H), 6.89 (d, 1H), 7.88 (d, 1H); MS (DCI / NH 3) m / e 239 (M + H) ⁺ .
[725] Example 7B
[726] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[727] To 0.10 g (0.42 mmol) of the product from Example 7A, dissolved in 100 ml of dry THF and cooled to 0 ° C., 2.2 equivalents of triethylamine (0.142 ml) was added followed by 0.23 ml of a 1.93 M solution in toluene. The reaction is stirred for 3 hours, then 0.10 g (0.36 mmol) of product from Example 4A is added. The reaction is stirred at rt overnight and partitioned between NaHCO ₃ and CH ₂ Cl ₂ . The organic phase is dried, concentrated and dissolved in THF. Potassium t-butoxide (0.8 mmol in THF) is added. The reaction is stirred at rt for 2 h and then partitioned between NaHCO ₃ and CH ₂ Cl ₂ . After purification using chromatography and conversion to the hydrochloride salt, 0.09 g (48%) of the title compound is isolated: melting point 238-240 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (freebase)) δ8.06 (d, 1H), 7.05 (t, 1H), 6.9 (d, 1H), 6.48 (d, 1H), 6.39 (d, 1H), 4.45 (dd, 1H), 4.12 (t, 1H), 4.03 (s, 3H), 4.02 (m, 1H), 3.76 (s, 3H), 3.59 (q, 1H), 2.96 (q, 1H), 2.78 (m, 4H), 2.56 (m, 1H), 2.31 (m, 1H), 1.79 (m, 2H), 1.63 (m, 2H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[728] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · HCl · 0.5H ₂ 0:
[729] Calc .: C, 56.36; H, 5. 46; N, 10.11.
[730] Found: C, 56.56; H, 5.41; N, 9.97.
[731] Example 8
[732] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[733] Example 8A
[734] 3-amino-7-methoxy-thieno [3,2-b] pyridine-2-carboxylate
[735] By carrying out the procedure described in Example 7A, 3-amino-7-chloro-thieno [3,2-b] pyridine-2-carboxylate (2.0 g, 8.2 mmol) was chromatographed with 1: 1 hexanes: EtOAc. This gives 1.1 g (56%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ3.92 (s, 3H), 4.05 (s, 3H), 6.18 (bs, 2H), 6.81 (d, 2H ), 8.52 (d, 2 H); MS (DCI / NH 3) m / e 239 (M + H) ⁺ .
[736] Example 8B
[737] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[738] To 0.24 g (1 mmol) of the product from Example 8A, dissolved in 10 ml of dry THF and cooled to 0 ° C., 2.2 equivalents of triethylamine (0.37 ml) was added followed by 0.6 ml of a 1.93 M solution of phosgene in toluene. The reaction is stirred for 3 hours, then 0.276 g (1.00 mmol) of product from Example 4A are added. The reaction is stirred at rt overnight and partitioned between NaHCO ₃ and CH ₂ Cl ₂ . The organic phase is dried, concentrated and dissolved in THF. Potassium t-butoxide (1 mmol in THF) is added. The reaction is stirred at rt for 2 h and then partitioned between NaHCO ₃ and CH ₂ Cl ₂ . After purification using chromatography and conversion to dihydrochloride salt, 0.26 g (49%) of the title compound was isolated: melting point 191-193 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (freebase)) δ 8.63 (d, 1H), 7.1 (t, 1H), 6.92 (d, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.51 (dd, 1H), 4.15 (m, 6H), 3.78 (s, 3H), 3.6 (m, 1H), 3.0-3.3 (m, 6H), 2.52 (m, 1H), 1.85 (m, 4H) ; MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[739] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · 2HCl · H ₂ O:
[740] Calc .: C, 52.09; H, 5. 38; N, 9.34.
[741] Found: C, 51.85; H, 5.47; N, 9.00.
[742] Example 9
[743] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[744] Example 9A
[745] 2-chloro-3-cyano-5-phenylpyrazine and 2-chloro-3-cyano-6-phenylpyrazine
[746] See RG Jones, J. Am. Chem. Soc. 71:78 (1949)] to a mixture of 5- and 6-phenyl-resioisomers of 2-hydroxy-3-carboxamidopyrazine (7.2 g, 33.5 mmol) prepared by the process of phosphorus oxychloride (56 ml). , 586 mmol) and triethylamine (9.3 ml, 67 mmol) and heated to reflux for 2 hours. Evaporation of the mixture yielded a black oil, which was extracted with ether (3 × 100 ml); The combined extracts are washed with 300 ml of 10% Na ₂ CO ₃ and then the aqueous layer is back extracted with ether. The combined organic layers were decolorized with activated carbon and filtered through celite and then evaporated to give a white solid as a 60:40 mixture of 5- and 6-phenyl isomers; Melting point (mixture) 121-125 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ7.52 (m, 5H majority and decimal), 8.02 (d, 2H (major)), 8.11 (d, 2H (major)), 9.0 (s, 1H (major)), 9.05 (s, 1 H (decimal)) MS (DCI / NH ₃ ) m / e 215 (M) < + >.
[747] Example 9B
[748] Methyl 7-amino-3-phenylthieno [2,3-b] pyrazine-6-carboxylate
[749] The product from Example 9A (1.20 g, 5.58 mmol) was treated sequentially with methyl thioglycolate (0.65 g, 6.14 mmol) and sodium methoxide (0.60 g, 11.2 mmol) in anhydrous DMF (5 ml) and the reaction was 25 Stir at 1 ° C. for 1 h. The reaction mixture is diluted with water, the product is collected by filtration and purified by column chromatography on silica gel eluting with CH ₂ Cl ₂ to give 0.80 g (47% isomer of the title compound) as a yellow solid (47%). : ¹ H NMR (300 MHz, CDCl ₃ ) δ3.75 (s, 3H), 6.25 (br s, 2H), 7.53 (m, 3H), 8.09 (d, 2H), 9.09 (s, 1H). MS (DCI / NH ₃ ) m / e 286 (M + H) ⁺ .
[750] Example 9C
[751] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[752] The product from Example 4A (0.10 g, 0.42 mmol) and the product from Example 9B (0.14 g, 0.43 mmol) were treated as described in Example 1F to afford 0.03 g (13%) of the title compound: melting point ≧ 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (freebase)) δ 9.18 (s, 1H), 8.11 (m, 2H), 7.6 (m, 3H), 7.1 (t, 1H), 6.5 (d, 1H), 6.38 (d, 1H), 4.5 (dd, 1H), 4.18 (m, 3H), 4.1 (m, 1H), 3.8 (s, 3H), 3.18 (m, 6H), 2.5 (m, 1H), 1.7 -1.9 (m, 4H); MS (DCI / NH ₃ ) m / e 556 (M + H) ⁺ ;
[753] Elemental Analysis for C ₃₀ H ₂₉ N ₅ O ₄ S · HCl · 2H ₂ O:
[754] Calc .: C, 57.36; H, 5. 46; N, 11.15.
[755] Found: C, 57.40; H, 5. 27; N, 10.79.
[756] Example 9D
[757] Another Synthesis of Methyl 7-amino-3-phenylthieno [2,3-b] pyrazine-6-carboxylate
[758] The flask is charged with phenylglyoxime (30) (44 g, 0.3 mol) and aminomalononitrile tosylate salt (31) (75 g, 0.3 mol) and 518 ml isopropanol. It is stirred for 2 days at ambient temperature. The reaction is then cooled to 0 ° C. for 4 hours and the solid is collected by filtration. The product was washed with 400 ml cold isopropanol and dried in an oven at 50 ° C. for 14 hours to give 60 g (95% yield) of pyrazine 32: ¹ H NMR (300 MHz, DMSO d ₆ ) δ 9.18 (s, 1H) , 8.08 (br s, 2H), 7.99-7.92 (m, 2H), 7.52-7.40 (m, 3H); ¹³ C NMR (75.5 MHz, DMSO-d ₆ ) δ 149.6, 142.2, 134.2, 131.3, 129.3, 128.8, 125.7, 115.2, 111.1.
[759] The flask is charged with Compound (32) (60 g, 0.28 mol) and 230 ml (1.34 mol) triethyl phosphite. It is heated to 100 ° C. for 7.5 hours. The solution is then cooled to ambient temperature and quenched with 480 ml of water. The slurry is stirred for 12 hours and then filtered. The filter cake was washed with 200 ml of 10% ethanol water and dried in a vacuum oven at 40 ° C. for 24 hours to give 53 g (95% yield) of compound 33; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 8.05-7.95 (m, 2H), 7.55-7.4 (m, 5H); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 155.9, 145.0, 140.9, 135.2, 128.9, 128.6, 125.2, 116.1, 110.0 .; Melting point 181.5 ° C.
[760] The flask is filled with copper (III) bromide (67.3 g, 0.3 mol) and DMF (300 ml). It is heated to approximately 60 ° C. 46.5 g (0.45 mol) of t-butylisonitrile are added to the heated solution. After stirring for about 2-5 minutes, compound (33) (58.85 g, 0.3 mol) is added dropwise. It is stirred at 60 ° C. for 20 minutes. The contents are then transferred to 2.5 l of 5% hydrochloric acid, cooled to about 15 ° C and precooled to 5 ° C. It is stirred for 20 minutes and extracted with 600 ml of methylene chloride. The aqueous layer is reextracted with 100 ml of methylene chloride and the organics are combined. This organic is washed with water (4 x 1 L) and then with 300 ml brine. 100 g of sodium sulfate and 50 g of silica are charged to the organic material. It is stirred and then filtered. The filter cake is washed with methylene chloride to remove the product. The combined filtrates and washes are then distilled down to 40 ° C. to a solid. Drying under vacuum at 30 ° C. yielded 56.5 g (72% yield) of the title compound (34): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.04-8.01 (m, 2H) , 7.58-7. 51 (m, 3 H); ¹³ C NMR (75.5 MHz, DMSO-d ₆ δ 151.8, 143.8, 140.4, 133.2, 132.2, 131.5, 129.5, 127.1, 114.8.
[761] The flask is filled with sodium carbonate (5.03 g, 0.05 mol), methylthioglycolate (5.03 g, 0.05 mol) and 400 ml methanol. To this was added Compound 34 (13.01 g, 0.05 mol). It is stirred at ambient temperature for 1 hour and then heated to 50 ° C. for 1.5 hours before cooling at 4 ° C. for 2 hours. This solid is collected by filtration, washed with cold methanol (400 ml) and dried to give 15.6 g of impure title compound. The solid is mixed with silica gel (29 g) and washed with about 1.5 L of methylene chloride. The organics were concentrated in vacuo to afford the title compound 35 (10.51 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.41-8.35 (m, 2H), 7.6-7.5 (m, 3 H), 7.2 (br s, 2 H), 3.87 (s, 3 H); Melting point 197-198 ° C.
[762] Example 9E
[763] Another Synthesis of Methyl 7-amino-3-phenylthieno [2,3-b] pyrazine-6-carboxylate
[764] To a slurry of distilled water (25 ml), malononitrile (72 g, 1.09 mol) and acetic acid (2.18 g, 0.036 mol) was added sodium nitrite (75.3 g, 1.09 mol) dissolved in water (300 ml). The reaction mixture is stirred for 2 hours and then slowly transferred to a solution of toluenesulfonyl chloride (200 g, 1.05 mol) dissolved in acetonitrile (463 g) cooled to 12 ° C. After the addition was complete, the reaction mixture was quenched slowly with water (2.6 L). The resulting slurry is stirred at room temperature and then the solid formed is filtered, washed with water (2 × 1 L) and then with heptane (200 ml). Dry the solid under vacuum to afford compound 50 (242 g, 92%): ¹ H NMR (300 MHz, CDCI ₃ ) d 7.80 (d, J = 7 Hz), 7.35 (d, J = 7 Hz), 2.41 ( s, 3H).
[765] Pyrrolidine (10 g, 0.14 mole) and sodium sulfate (5 g) are added to the flask and cooled to <0 ° C. Phenylacetaldehyde (2.4 g, 0.02 mol) is slowly added to the flask to maintain the temperature at &lt; The mixture is stirred at 0 / C for 1 h. The reaction is filtered and the solid is washed with 10 ml of heptane. The combined filtrates are distilled under vacuum (<40 ° C.) to afford an oil. Heptane (30 ml) is added and then distilled back to oil. The final oil is mixed with dimethylformamide (6 ml) and triethylamine (6.06 g, 0.06 mol). The mixture is then added to a flask containing compound 50 (4.98 g, 0.02 mole) in DMF (20 ml) at 0 ° C ± 3 ° C. This reaction mixture is stirred at 0 ° C. for 30 minutes and then thiophenol (2.4 g, 0.022 mole) is added. The mixture is stirred at ambient temperature for 3 hours before adding water (100 ml). It is stirred at room temperature for 20 minutes and the solid is filtered off. The filter cake is slurried with 50 ml methanol, stirred for 20 minutes and then filtered. The solid is washed with 10 ml of methanol and dried to give a gray solid of 51 (2.98 g, 51%): ¹ H NMR (300Mhz, CDCI ₃ ) d 8.9 (s, 1H), 8.0-7.9 (m, 2H), 7.7-7.6 (m, 2H), 7.6-7.45 (m, 6H).
[766] To a solution of compound 51 (2.89 g, 10 mmol) in acetic anhydride (25 ml) and chloroacetic acid (10 g, 106 mmol) is added 30% aqueous hydrogen peroxide (10 g, 88 mmol) at 0 ° C. The solution is stirred at room temperature for 1 hour and then heated to 35 ° C. for 6 hours. The mixture is cooled to rt, diluted with water (25 ml) and methanol (25 ml), stirred at rt for 30 min and then filtered. The filter cake was washed with 50% aqueous methanol (40 ml) and then dried to afford 52 (2.9 g, 90%): ¹ H NMR (DMSO-d ₆ ) δ 9.60 (1H, s), 8.21 ( 2H, dd, J = 7.6, 1Hz), 8.07 (2H, dd, J = 7.6, 1Hz), 7.83 (1H, dt, J = 7.6, 1Hz), 7.73 (2H, m), 7.60 (3H, m) ; ¹³ C NMR (DMSO-d ₆ ); δ 113.96, 126.13, 128.04, 129.01, 129.39, 129.81, 132.20, 132.91, 135.24, 136.97, 144.72, 153.14, 154.21.
[767] A suspension of sulfone 52 (30 mg, 0.09 mmol), sodium carbonate (0.1 g, 0.9 mmol) and methyl thioglycolate (20 mg, 0.19 mmol) in methanol (3 ml) was stirred at ambient temperature for 30 minutes and then at 50 ° C. Stir for 2 hours. After concentration in vacuo, the residue is combined with silica (1.5 g) and eluted with methylene chloride (50 ml). Concentration in vacuo affords the title compound (15 mg, 58%).
[768] Example 10
[769] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[770] Example 10A
[771] 2-Chloro-3-cyano-pyrazine-4-oxide
[772] 2-chloro-3-cyanopyrazine (5.00 g, 35.94 mmol) is dissolved in 35 ml of concentrated H ₂ SO ₄ under nitrogen and cooled to 0 ° C. 11.65 g (42.95 mmol) of K ₂ S ₂ O ₈ was added dropwise thereto. The flask is equipped with a CaCl ₂ dry tube and the reaction mixture is allowed to warm to room temperature and stirred for 24 hours. After fractionation with CHCl ₃ and ice water, the separated aqueous phase is extracted with CHCl ₃ . The combined organics are washed with water, saturated NaHCO ₃ , brine and then dried over MgSO ₄ . Concentration gives 2.01 g (36%) of the title compound as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (d, 1H), 8.38 (d, 1H). MS (DCI / NH ₃ ) m / e 173 (M + NH ₄ ). ⁺
[773] Example 10B
[774] Ethyl-7-aminothieno [2,3-b] pyrazine-6-carboxylate-1-oxide
[775] The compound (2.90 g, 18.64 mmol) resulting from Example 10A is dissolved in 100 ml of DMF under nitrogen and treated with ethyl thioglycolate (2.24 g, 18.64 mmol). After cooling the solution to 0 ° C., it was treated with solid NaOEt (2.54 g, 37.29 mmol) to warm to room temperature and then stirred for 13 hours. The reaction mixture is partitioned with ethyl acetate and brine and the layers are separated. After the aqueous phase is extracted with ethyl acetate, the combined organics are washed with water, brine and then dried over MgSO ₄ . Concentration gave a yellow solid, which was eluted with hexanes: ethyl acetate 2: 1 and purified by column chromatography on silica gel eluting with 1: 1 to afford 3.50 g (78%) of the title compound as a yellow solid: Melting point 126-127 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (t, 3H), 4.38 (q, 2H), 7.25 (br s, 2H), 8.02 (d, 1H), 8.41 (d, 1H); MS (DCI / NH ₃ ) m / e 240 (M + H) ⁺ , 257 (M + NH ₄ ) ⁺ ,
[776] Elemental Analysis for C ₉ H ₉ N ₃ O ₃ S:
[777] Calc .: C, 45.18: H, 3.79; N, 17.56.
[778] Found: C 44.94; H, 3.77; N, 17.47.
[779] Example 10C
[780] Ethyl-7-amino-2-chloro-thieno [2,3-b] pyrazine-6-carboxylate
[781] The compound (0.88 g, 3.68 mmol) resulting from Example 88B is dissolved in 50 ml POCl ₃ under nitrogen and heated to 95 ° C. for 3 hours. The reaction mixture is concentrated and partitioned between ethyl acetate and water. After extraction of the aqueous phase with ethyl acetate, the combined organics are washed with water, saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Concentration yields a two component mixture, which is separated by column chromatography on silica gel using an elution gradient of 10: 1 to 1: 1 hexanes: ethyl acetate to afford 0.56 g (59%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.41 (t, 3H), 4.40 (q, 2H), 6.11 (br s, 2H), 8.60 (s, 1H); MS (DCI / NH ₃ ) m / e 258 (M + H) ⁺ , 275 (M + NH ₄ ) ⁺ .
[782] Example 10D
[783] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[784] The product from Example 4A (0.25 g, 0.95 mmol) and the product from Example 10C (0.25 g, 1.1 mmol) were treated as described in Example 1F to yield 0.15 g (29%) of the title compound: melting point 266-267 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.7 (d, 1H), 7.53 (d, 1H), 7.1 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.51 (dd, 1H), 4.14 (t, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 3.55 (m, 1H), 3.02-3.32 (m, 5H), 2.58 (m, 2H), 1.85 (m, 4 H); MS (DCI / NH ₃ ) m / e 514 (M + H) ⁺ ;
[785] Elemental Analysis for C ₂₅ H ₂₅ CIN ₄ O ₄ SHCl1.5H ₂ O:
[786] Calculated: C, 52.09; H, 5.07; N, 9.72.
[787] Found: C, 52.21; H, 4.87; N, 9.60.
[788] Example 11
[789] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -1- (2-methoxyethyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -Dione hydrochloride
[790] Example 11A
[791] Ethyl 7- (N- (2-methoxyethyl) amino) thieno [2,3-b] pyrazine-6-carboxylate
[792] See Schneller and Clough, J. Het. Chem., 12: 513 (1975)] was used to prepare ethyl 7-amino-thieno [2,3-b] pyrazine-6-carboxylate (1.0 g, 4.48 mmol) prepared by the method of 15 ml THF at -70 ° C. In potassium bis (trimethylsilyl) amide (0.5 M in toluene, 8.96 ml) and warmed to room temperature. 2-bromoethyl methyl ether (0.454 ml, 4.70 mmol) is added and the reaction is stirred at 60 ° C. under N ₂ overnight. The mixture was cooled and evaporated and purified by column chromatography on silica gel eluting with 1: 9 ethyl acetate: hexanes to give 0.640 g (51%) of the title compound as a yellow solid: ¹ H NMR (300 MHz, DMSO- d6) d 1.32 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.25 (q, 2H), 4.32 (t, 2H), 7.70 (br t, 1H), 8.76 (s, 1H), 8.77 (s, 1 H); MS (DCI / NH 3) m / e 282 (M + H) ⁺ .
[793] Example 11B
[794] Ethyl 7- (N- (2-methoxyethyl) -N-chlorocarbamoylamino) thieno [2,3-b] pyrazine-6-carboxylate
[795] The product from Example 11A (0.620 g, 2.20 mmol) was reacted with phosgene (1.93 M in toluene, 3.41 ml, 6.6 mmol) and triethylamine (0.767 ml, 5.5 mmol) to give the title compound (0.582 g, 81%) is obtained: ¹ H NMR (300MHz DMSO-d6) d 1.31 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.23 (q, 2H), 4.3 (q, 2H ), 8.78 (2-single line, 2H); MS (DCI / NH 3) 344 (M + H) ⁺ .
[796] Example 11C
[797] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -1- (2-methoxyethyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -Dione hydrochloride
[798] The product from Example 4A (0.25 g, 0.95 mmol) was refluxed overnight with 0.1 ml of triethylamine and 0.27 g (0.82 mmol) of product from Example 11B. After workup and chromatography, 0.3 g (68%) of the title compound is isolated as its free base. The product is converted as its HCl-salt and recrystallized from ethanol / ether to give the title compound. Melting point 200-202 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.78 (d, 1H), 8.7 (d, 1H), 7.1 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 5.12 (t, 2H), 4.5 (dd, 1H), 4.05-4.2 (m, 4H), 3.8 (m, 5H), 3.5 (m, 1H), 3.12 (m, 5H), 2.5 (m, 1H), 1.85 (m, 4 H); MS (DCI / NH ₃ ) m / e 538 (M + H) ⁺ ;
[799] Elemental Analysis for C ₂₇ H ₃₁ N ₅ O ₅ S · HCl · 0.75H ₂ O:
[800] Calc .: C, 55.19; H, 5.75; N, 11.92.
[801] Found: C, 55.19; H, 5.49; N, 11.88.
[802] Example 12
[803] 3- [4-((3aR, 9bS) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[804] See Schneller and Clough, J. Het. Chem., 12: 513 (1975)] ethyl 7-amino-thieno [2,3-b] pyrazine-6-carboxylate (0.32 g, 1.35 mmol) and the product from Example 4A (0.31 g, 1.13 mmol) is treated as described in Example 1F to yield 0.28 g of the title compound as its free base. This product is converted to its HCl-salts and recrystallized from ethanol / ether to give the title compound: melting point> 250 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ (free base)) δ 8.98 (d, 1H), 8.89 (d, 1H), 7.11 (t, 1H), 6.52 (d, 1H), 6.45 (d, 1H) , 4.5 (dd, 1H), 4.2 (m, 1H), 4.1 (m, 1H), 3.92 (m, 2H), 3.73 (s, 3H), 3.0 (m, 1H), 2.6 (m, 5H), 2.3 (m, 1 H), 1.8 (m, 4 H); MS (DCI / NH ₃ ) m / e 480 (M + H) ⁺ ;
[805] Elemental Analysis for C ₂₄ H ₂₅ N ₅ O ₄ S · 2HCl · 0.5H ₂ O:
[806] Calc .: C, 51.34; H, 5.03; N, 12.47;
[807] Found: C, 51.34; H, 4.95, N, 12.32.
[808] Example 13
[809] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[810] The product from Example 10C (0.27 g, 1.0 mmol) and the product from Example 3E (0.22 g, 0.8 mmol) were treated as described in Example 1F to yield 0.22 g (66%) of the title compound. > 270 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.61 (s, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.45 (d, 1H), 4.6 (m, 1H), 4.45 (dd, 1H), 4.18 (m, 3H), 3.71 (s, 3H), 3.52 (m, 1H), 3.3 (m, 1H), 3.1 (m, 2H), 2.9 (m, 2H), 2.5 ( m, 1H), 1.8 (m, 4H); MS (DCI / NH ₃ ) m / e 514 (M + H) ⁺ ;
[811] Elemental Analysis for C ₂₄ H ₂₄ CIN ₅ O ₄ SHCl0.5H ₂ O:
[812] Calc .: C, 51.52; H, 4.68; N, 12.52.
[813] Found: C, 51.89; H, 4.38; N, 12.17.
[814] Example 14
[815] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[816] See Schneller and Clough, J. Het. Chem., 12: 513 (1975), ethyl 7-amino-thieno [2,3-b] pyrazine-6-carboxylate (0.24 g, 1.0 mmol) and the product from Example 3E. (0.22 g, 0.8 mmol) was treated as described in Example 1F to give 0.16 g (43%) of the title compound: melting point 219-222 ° C .; ¹ H NMR (300 MHz, CDCl ₂ (free base)) δ 8.62 (s, 1H), 8.45 (s, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.4 (d, 1H), 4.5 (dd, 1H), 4.2 (m, 1H), 4.1 (m, 3H), 3.72 (s, 1H), 7.7 (m, 1H), 3.3 (m, 2H), 3.2 (m, 1H), 3.05 ( m, 2H), 2.52 (m, 1H), 1.8 (m, 4H); MS (DCI / NH ₃ ) m / e 480 (M + H) ⁺ ;
[817] Elemental Analysis for C ₂₄ H ₂₅ N ₅ O ₄ S · 2HCl · 0.5H ₂ O:
[818] Calc .: C, 51.34; H, 4.96; N, 12.25.
[819] Found: C, 51.45; H, 4.96, N, 12.25.
[820] Example 15
[821] 3- [4-((3aR, 9bS) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[822] See Schneller and Clough, J. Het. Chem., 12: 513 (1975), ethyl 7-amino-thieno [2,3-b] pyrazine-6-carboxylate (0.24 g, 1.0 mmol) and the product from Example 1E. (0.2 g, 0.75 mmol) was treated as described in Example 1F to give 0.11 g (32%) of the title compound: melting point 220-222 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.7 (d, 1H), 8.6 (d, 1H), 7.02 (t, 1H), 6.4 (t, 2H), 4.1 (m, 2H), 3.7 -4.0 (m, 4H), 3.7 (s, 3H), 3.52 (m, 2H), 2.6-2.9 (m, 4H), 1.6-1.82 (m, 4H); MS (DCI / NH ₃ ) m / e 480 (M + H) ⁺ ;
[823] Elemental Analysis for C ₂₄ H ₂₅ N ₅ O ₄ S · 2HCl:
[824] Calc .: C, 52.18; H, 4.93; N, 12.68;
[825] Found: C, 52.56; H, 4.99; N, 12.64.
[826] Example 16
[827] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[828] The product from Example 10C (0.27 g, 1.0 mmol) and the product from Example 1E (0.20 g, 0.73 mmol) were treated as described in Example 1F to yield 0.29 g (77%) of the title compound. 220-222 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.68 (s, 1H), 7.0 (t, 1H), 6.48 (d, 1H), 6.45 (d, 1H), 4.28 (m, 1H), 4.12 (m, 3H), 4.0 (m, 2H), 3.75 (s, 3H), 3.6 (m, 1H), 3.08 (m, 3H), 2.9 (m, 2H), 1.75 (m, 4H); MS (DCI / NH ₃ ) m / e 514 (M + H) ⁺ ;
[829] Elemental Analysis for C ₂₄ H ₂₄ ClN ₅ O ₄ SHCl0.75H ₂ O:
[830] Calc .: C, 51.11; H, 4. 74; N, 12.42;
[831] Found: C, 51.09; H, 4.75; N, 12.43.
[832] Example 17
[833] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[834] The product from Example 8A (0.24 g, 1.0 mmol) and the product from Example 3E (0.276 g, 1.0 mmol) were treated as described in Example 1F to yield 0.26 g (51%) of the title compound: melting point 173-174 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.64 (d, 1H), 7.08 (t, 1H), 6.92 (d, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 6.5 (dd, 1H), 4.5 (dd, 1H), 4.12 (m, 8H), 3.76 (s, 3H), 3.02 (m, 4H), 2.45 (m, 2H), 1.82 (m, 4H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[835] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · 2HCl · 0.25H ₂ O:
[836] Calc .: C, 60.86; H, 5. 60; N, 10.92.
[837] Found: C, 60.84; H, 5.41; N, 10.62.
[838] Example 18
[839] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[840] The product from Example 8A (0.30 g, 1.26 mmol) and the product from Example 1E (0.345 g, 1.25 mmol) were treated as described in Example 1F to yield 0.37 g (58%) of the title compound: melting point 204-206 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.64 (d, 1H), 7.05 (t, 1H), 6.92 (d, 1H), 6.51 (d, 1H), 6.44 (d, 1H), 4.0 -4.18 (m, 6H), 3.8 (s, 4H), 3.6 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 2.6 (m, 3H), 2.3 (m, 2H), 1.78 (m, 2 H), 1.64 (m, 2 H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[841] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · 2HCl · 2H ₂ O:
[842] Calc .: C, 50.57, H, 5.55; N, 9.07.
[843] Found: C, 50.59, H, 5.74; N, 9.05.
[844] Example 19
[845] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[846] The product from Example 5A (0.24 g, 1.0 mmol) and the product from Example 3E (0.27 g, 1.0 mmol) were treated as described in Example 1F to afford 0.08 g (15%) of the title compound: melting point 266-267 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.7 (d, 1H), 7.53 (d, 1H), 7.1 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.51 (dd, 1H), 4.14 (t, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 3.55 (m, 1H), 3.02-3.32 (m, 5H), 2.58 (m, 2H), 1.85 (m, 4 H); MS (DCI / NH ₃ ) m / e 514 (M + H) ⁺ ;
[847] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ SHCl1.5H ₂ O:
[848] Calc .: C, 52.09; H, 5.07; N, 9.72.
[849] Found: C, 52.21; H, 4.87; N, 9.60.
[850] Example 20
[851] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[852] The product from Example 5A (0.24 g, 1.0 mmol) and the product from Example 1E (0.27 g, 1.0 mmol) were treated as described in Example 1F to yield 0.125 g (25%) of the title compound: melting point 180-182 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.63 (d, 1H), 7.51 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.42 (d, 1H), 4.1 (t, 2H), 4.0 (dd, 1H), 3.73 (m, 1H), 3.7 (s, 3H), 3.48 (q, 2H), 3.38 (m, 1H), 3.25 (m, 1H), 2.7 ( m, 3H), 2.5 (m, 1H), 2.4 (m, 1H), 1.78 (m, 1H), 1.65 (m, 1H); MS (DCI / NH ₃ ) m / e 513 (M + H) ⁺ ;
[853] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ SHCl0.75H ₂ O:
[854] Calc .: C, 53.34; H, 4.92; N, 9.95.
[855] Found: C, 53.42; H, 4.65; N, 9.55
[856] Example 21
[857] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[858] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.24 g, 0.97 mmol) and the product from Example 3E (0.18 g, 0.6 mmol) were treated as described in Example 1F to give the title compound 0.22 g (77%) is obtained: melting point> 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.28 (d, 1H), 7.39 (d, 1H), 7.56 (m, 2H), 7.04 (t, 1H), 6.46 (d, 1H), 6.38 (d, 1H), 4.4 (dd, 1H), 4.24 (t, 2H), 4.0 (t, 1H), 3.71 (s, 3H), 3.65 (m, 1H), 3.0 (t, 1H), 2.81 ( m, 4H), 2.58 (t, 1 H), 2.3 (m, 1 H), 1.88 (m, 2 H); MS (DCI / NH ₃ ) m / e 478 (M + H) ⁺ ;
[859] Elemental Analysis for C ₂₆ H ₂₇ N ₃ O ₄ S · HCl:
[860] Calc .: C, 60.75; H, 5.49; N, 8.17.
[861] Found: C, 60.65; H, 5.31; N, 8.03.
[862] Example 22
[863] 3- [4-((3aS, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[864] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.13 g, 0.52 mmol) and the product from Example 1E (0.10 g, 0.36 mmol) were treated as described in Example 1F to give the title compound 0.11 g (64%) is obtained: melting point 198-199 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, 1H), 8.4 (d, 1H), 7.55 (m, 2H), 7.04 (t, 1H), 6.5 (d, 1H), 6.43 (d, 1H ), 4.22 (t, 2H), 4.0 (dd, 1H), 3.78 (s, 3H), 3.72 (m, 1H), 3.48 (m, 1H), 3.39 (m, 1H), 3.11 (m, 1H) , 2.55 (m, 3H), 2.2 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H); MS (DCI / NH ₃ ) m / e 478 (M + H) ⁺ ;
[865] Elemental Analysis for C ₂₆ H ₂₇ N ₃ O ₄ SHCl:
[866] Calc .: C, 60.75; H, 5.49; N, 8.17.
[867] Found: C, 60.62, H, 5.27; N, 8.03.
[868] Example 23
[869] 3- [5-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) pentyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[870] Example 23A
[871] (3aS, 9bR) -trans-2- (4-cyanobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole
[872] The product from Example 3C (0.12 g, 0.6 mmol), 5-chlorovaleronitrile (0.08 g, 0.69 mmol) and 1.0 ml ethyldiisopropylamine are heated at reflux for 6 hours in 5 ml acetonitrile. The solvent is evaporated and the product is partitioned between ethyl acetate and water. The organic layer was dried, evaporated and purified by silica gel column chromatography to yield 0.11 g (64%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.05 (t, 1H), 6.49 ( d, 1H), 6.39 (d, 1H), 4.46 (dd, 1H), 3.77 (s, 3H), 3.56 (q, 1H), 2.92 (q, 1H), 2.68-2.88 (m, 4H), 2.57 (q, 1H), 2.42 (t, 2H), 2.32 (m, 1H), 1.71 (m, 4H); MS (DCI / NH ₃ ) m / e 287 (M + H) ⁺
[873] Example 23B
[874] (3aS, 9bR) -trans-2- (5-aminopentyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Pyrrole
[875] Lithium aluminum hydride (0.11 g, 2.88 mmol) is suspended in ether and a solution of 0.13 g (0.96 mmol) of aluminum chloride in ether is added. To this reaction is then added a solution of the product from Example 23A (0.11 g, 0.38 mmol). The reaction was stirred at 25 ° C. for 3 hours and then separated (piper workup) to yield 0.10 g (90%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.05 (t, 1H), 6.49 (d, 1H), 6.39 (d, 1H), 4.45 (dd, 1H), 4.05 (q, 1H), 3.77 (s, 3H), 3.58 (q, 1H), 2.93 (q, 1H), 2.61- 2.88 (m, 6H), 2.56 (m, 1H), 2.3 (m, 1H), 1.5 (m, 2H), 1.48 (m, 2H); MS (DCI / NH ₃ ) m / e 291 (M + H) ⁺ :
[876] Example 23C
[877] 3- [5-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) pentyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[878] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.10 g, 0.40 mmol) and the product from Example 23B (0.11 g, 0.38 mmol) were treated as described in Example 1F to give the title compound 0.11 g (60%) is obtained: Melting point 196-198 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.22 (d, 1H), 7.89 (d, 1H), 7.53 (m, 2H), 7.03 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.41 (dd, 1H), 4.21 (t, 2H), 4.02 (dd, 1H), 3.71 (s, 3H), 3.56 (m, 1H), 2.92 (m, 1H), 2.63 -2.86 (m, 3H), 2.52 (m, 1H), 2.3 (m, 1H), 1.87 (m, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.4 (m, 1H); MS (DCI / NH ₃ ) m / e 492 (M + H) ⁺ ;
[879] Elemental Analysis for C ₂₇ H ₂₉ N ₃ O ₄ S · HCl · H ₂ O:
[880] Calc .: C, 59.39: H, 5.91; N, 7.69.
[881] Found: C, 59.83; H, 5.71; N, 7.48.
[882] Example 24
[883] 3- [5-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) pentyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[884] Example 24A
[885] (3aR, 9bR) -cis-2- (4-cyanobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole
[886] The product from Example 1C (0.10 g, 0.5 mmol), 5-chlorovaleronitrile (0.067 g, 0.57 mmol) and 1.0 ml ethyldiisopropylamine are heated at reflux for 6 hours in 5 ml acetonitrile. The solvent is evaporated and the product is partitioned between ethyl acetate and water. The organic layer was dried, evaporated and purified by silica gel column chromatography to afford 0.08 g (58%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.08 (t, 1H), 6.51 (d , 1H), 6.45 (d, 1H), 4.04 (dd, 1H), 3.82 (s, 3H), 3.78 (m, 1H), 3.4 (m, 2H), 3.06 (q, 1H), 2.6 (m, 1H), 2.48 (q, 2H), 2.39 (t, 2H), 2.25 (m, 2H), 1.71 (m, 4H); MS (DCI / NH ₃ ) m / e 287 (M + H) ⁺
[887] Example 24B
[888] (3aR, 9bR) -cis-2- (5-aminopentyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c ] Pyrrole
[889] Lithium aluminum hydride (0.10 g, 2.63 mmol) is suspended in ether and a solution of 0.11 g (0.82 mmol) of aluminum chloride in ether is added. To this reaction is then added a solution of the product from Example 24A (0.08 g, 0.28 mmol). The reaction was stirred at 25 ° C. for 3 hours and then separated (piter post-treated) to give 0.07 g (86%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.08 (t, 1H), 6.51 ( d, 1H), 6.45 (d, 1H), 4.03 (dd, 1H), 3.8 (s, 3H), 3.78 (m, 1H), 3.45 (m, 2H), 3.12 (q, 1H), 2.68 (t , 2H), 2.6 (m, 1H), 2.43 (m, 2H), 2.18 (m, 2H), 1.5 (m, 2H), 1.38 (m, 2H); MS (DCI / NH ₃ ) m / e 291 (M + H) ⁺ .
[890] Example 24C
[891] 3- [5-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) pentyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[892] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.10 g, 0.40 mmol) and the product from Example 24B (0.07 g, 0.24 mmol) were treated as described in Example 1F to give the title compound 0.08 g (69%) is obtained: melting point 128-130 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base) δ 8.12 (d, 1H), 7.72 (d, 1H), 7.4 (m, 2H), 7.08 (t, 1H), 6.52 (d, 1H), 6.47 ( d, 1H), 4.4 (m, 2H), 4.3 (m, 1H), 4.04 (dd, 1H), 3.7 (s, 3H), 3.5 (m, 1H), 3.32 (m, 2H), 3.2 (m , 1H), 2.7 (m, 1H), 2.52 (m, 2H), 2.35 (m, 2H), 1.88 (m, 1H), 1.62 (m, 4H); MS (DCI / NH ₃ ) m / e 492 (M + H) ⁺ ;
[893] Elemental Analysis for C ₂₇ H ₂₉ N ₃ O ₄ S · HCl · H ₂ O:
[894] Calculated: C, 59.39; H, 5.91; N, 7.69.
[895] Found: C, 59.47; H, 5.94; N, 7.52.
[896] Example 25
[897] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[898] Methyl 3-amino-5-chloro-thieno [3,2-b] pyridine-2-carboxylate (0.24 g, 1.0 mmol) prepared as described in Example 6A and the product from Example 3E (0.20 g) , 0.7 mmol) was treated as described in Example 1F to give 0.18 g (50%) of the title compound: melting point> 250 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base) δ 8.1 (d, 1H), 7.21 (d, 1H), 7.02 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.56 ( dd, 1H), 4.1 (m, 2H), 3.88 (m, 1H), 3.73 (s, 3H), 3.3 (m, 2H), 2.85-3.12 (m, 4H), 2.44 (m, 2H), 1.8 (m, 4H) MS (DCI / NH ₃ ) m / e 513 (M + H) ⁺ ;
[899] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ S.2HCl:
[900] Calculated: C, 51.25; H, 4. 64; N, 9.56.
[901] Found: C, 51.04; H, 4.58; N, 9.27.
[902] Example 26
[903] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[904] Methyl 3-amino-5-methoxy-thieno [3,2-b] pyridine-2-carboxylate (0.20 g, 0.84 mmol) prepared as described in Example 7A and the product from Example 3E (0.23 g, 0.84 mmol) was treated as described in Example 1F to yield 0.30 g (70%) of the title compound: melting point> 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.06 (d, 1H), 7.05 (t, 1H), 6.9 (d, 1H), 6.48 (d, 1H), 6.39 (d, 1H), 4.45 (dd, 1H), 4.12 (t, 1H), 4.03 (s, 3H), 4.02 (m, 1H), 3.76 (s, 3H), 3.59 (q, 1H), 2.96 (q, 1H), 2.78 (m, 4H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[905] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · HCl · 0.25H ₂ O:
[906] Calculated: C, 56.82; H, 5.41; N, 10.19.
[907] Found: C, 56.68; H, 5. 19; N, 10.09.
[908] Example 27
[909] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[910] Example 27A
[911] 2-cyano-3,5-dichloropyridine
[912] 3,5-Dichloropyridine-N-oxide (10.0 g, 61 mmol), trimethylsilyl cyanide (25 ml, 183 mmol) and triethylamine (17 ml, 122 mmol) are combined in acetonitrile (60 ml) and heated to reflux for 6 hours. The solvent is evaporated and the residue is partitioned with diethyl ether and 5% aqueous NaHCO ₃ . The organic phase is dried (MgSO ₄ ), evaporated and the product is purified by chromatography on silica gel to give 10.0 g (97%) of the title compound: ¹ H NMR (300 MHz, CDCI ₃ ) δ 7.92 (d, 1H), 8.58 (d, 1H).
[913] Example 27B
[914] 3-chloro-2-cyano-5-methoxypyridine
[915] The product from Example 27A (0.865 g, 5.0 mmol) is dissolved in THF (10 ml) and 0.27 g NaOMe is added. After 3 hours at 25 ° C., the reaction is quenched in 5% aqueous NaHCO ₃ solution and extracted with diethyl ether. The organic phase was dried, evaporated and purified by column chromatography eluting with 70:30 hexanes: ethyl acetate to afford 0.27 g (32%, second elution component): ¹ H NMR (300 MHz, CDCl _3). ) δ 3.95 (s, 3H), 7.29 (d, 1H), 8.28 (d, 1H).
[916] Example 27C
[917] Methyl 3-amino-6-methoxy-thieno [3,2-b] pyridine-2-carboxylate
[918] The product from Example 27B (0.168 g, 1.0 mmol) and methyl thioglycolate (0.09 ml, 1.0 mmol) were combined in DMF (2 ml). To this solution is added 0.054 g of NaOMe. After 1 hour, additional 0.07 g NaOMe is added. After one more hour, the reaction is quenched in saturated aqueous NH ₄ Cl and extracted with ethyl acetate. Dry the organic phase (MgSO ₄ ) and evaporate to yield 0.17 g of the title compound: ¹ H NMR (300 MHz, CDCI ₃ ) δ 3.90 (s, 3H), 3,93 (s, 3H), 6.15 (br s , 2H), 7.44 (d, 1 H), 8.36 (d, 1 H).
[919] Example 27D
[920] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[921] The product from Example 27C (0.12 g, 0.50 mmol) and the product from Example 3E (0.15 g, 0.47 mmol) were treated as described in Example 1F to yield 0.12 g (47%) of the title compound: melting point 235-237 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.45 (d, 1H), 7.6 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.45 (dd, 1H), 4.1 (t, 2H), 4.05 (m, 1H), 3.98 (s, 3H), 3.78 (s, 3H), 3.72 (m, 1H), 3.05 (m, 1H), 2.85 (m, 4H), 2.65 (m, 1H), 2.38 (m, 1H), 1.8 (m, 2H), 1.7 (m, 2H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[922] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · HCl · H ₂ O:
[923] Calculated: C, 55.46; H, 5.55; N, 9.95.
[924] Found: C, 55.22; H, 5. 30; N, 9.75.
[925] Example 28
[926] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[927] Product from Example 1E (400 mg, 1.5 mmol), 3-amino-carbomethoxythieno [3,2-b] pyridine (0.33 g, 1.6 mmol) [J. Heterocyclic Chem., 24, 85 ( 1987)], Et ₃ N (0.50 ml, 3.6 mmol) and phosgene (1.93 M in toluene 0.82 ml, 1.6 mmol) were treated as described in Example 1F to yield 0.38 g (55%) of the title compound: melting point 207-210 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.62-1.75 (m, 2H), 1.80-1.92 (m, 2H), 2.20-2.33 (m, 2H), 2.49-2.65 (m, 3H) , 3.15 (bt, J = 8 Hz, 1H), 3.39 (q, J = 8 Hz, 1H), 3.50 (t, J = 8 Hz, 1H), 3.70-3.79 (m, 1H), 3.75 (s, 3H), 3.98 (dd, J = 4, 9 Hz, 1H), 4.22 (t, J = 7 Hz, 2H), 6.41 (dd, J = 1, 8 Hz, 1H), 6.47 (dd, J = 1 , 8 Hz, 1H), 7.03 (t, J = 8 Hz, 1H), 7.82 (dd, J = 1, 5 Hz, 1H), 8.65 (d, J = 5 Hz, 1H), 9.55 (s, 1H ); MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ ;
[928] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · (HCl) ₂ ㆍ (H ₂ O) _0.75 :
[929] Calculated: C, 53.15; H, 5. 26; N, 9.22.
[930] Found: C, 53.37; H, 5.11; N, 9.74.
[931] Example 29
[932] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[933] Product from Example 1E (400 mg, 1.5 mmol), 3-amino-carbomethoxythieno [2,3-c] pyridine (0.33 g, 1.6 mmol) [J. Heterocyclic Chem., 24, 85 ( 1987)], Et ₃ N (0.50 ml, 3.6 mmol) and phosgene (1.93 M in toluene 0.82 ml, 1.6 mmol) were treated as described in Example 1F to yield 0.50 g (72%) of the title compound: melting point 212-214 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.61-1.76 (m, 2H), 1.81-1.93 (m, 2H), 2.21-2.31 (m, 2H), 2.50-2.67 (m, 3H), 3.15 (dd, J = 7.9 Hz, 1H), 3.36-3.55 (m, 2H), 3.73-3.82 (m, 1H), 3.78 (s, 3H), 4.00 (dd, J = 5, 11 Hz, 1H) , 4.23 (t, J = 7 Hz, 2H), 6.42 (d, J = 8 Hz, 1H), 6.48 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 8.12 ( d, J = 6 Hz, 1H), 8.71 (d, J = 6 Hz, 1H), 9.24 (s, 1H); MS (DCI (NH ₃ ) m / e 479 (M + H) ⁺ ;
[934] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · (HCl) ₂ :
[935] Calculated: C, 54.45; H, 5. 12; N, 10.16.
[936] Found: C, 54.05; H, 5. 24; N, 10.05.
[937] Example 30
[938] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[939] The product from Example 7A (0.30 g, 1.26 mmol) and the product from Example 1E (0.35 g, 1.26 mmol) were treated as described in Example 1F to yield 0.37 g (58%) of the title compound: melting point 195-197 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.3 (d, 1H), 7.07 (t, 1H), 6.98 (d, 1H), 6.52 (d, 1H), 6.46 (d, 1H), 4.05 (t, 2H), 4.03 (m, 1H), 4.02 (s, 3H), 3.83 (m, 1H), 3.81 (s, 3H), 3.5 (m, 2H), 3.25 (m, 1H), 2.65 (m, 3H), 2.3 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ ;
[940] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · HCl · H ₂ O:
[941] Calculated: C, 55.46; H, 5.55; N, 9.95.
[942] Found: C, 55.40; H, 5.62; N, 9.58.
[943] Example 31
[944] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[945] Example 31A
[946] Ethyl 7-amino-2-methoxy-thieno [2,3-b] pyrazine-6-carboxylate
[947] Compound (0.700 g, 2.72 mmol) from Example 10C is dissolved in 75 ml of MeOH, treated with solid NaOMe (1.47 g, 27.2 mmol) and the resulting solution is refluxed for 12 h. The reaction mixture is partitioned between saturated NH ₄ Cl and CHCl ₃ . After extraction of the aqueous phase with CHCl ₃ , the combined organics are washed with water, then brine and dried over Na ₂ SO ₄ . Concentration to give 0.500 g (77%) of the pure title compound as a yellow solid: melting point 181-182 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.92 (s, 3H), 4.05 (s, 3H), 6.02 (br s, 2H), 8.30 (s, 1H); MS (DCI / NH ₃ ) m / e 240 (M + H) ⁺ , 257 (M + NH 4) ⁺ .
[948] Elemental Analysis for C ₉ H ₉ N ₃ O ₃ S:
[949] Calculated: C, 45.18; H, 3.79; N, 17.56.
[950] Found: C, 45.25; H, 3. 48; N, 17.41.
[951] Example 31B
[952] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[953] The product from Example 31A (0.30 g, 1.26 mmol) and the product from Example 1E (0.35 g, 1.26 mmol) were treated as described in Example 1F to yield 0.33 g (52%) of the title compound: melting point 182-184 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ (free base)) δ 8.58 (s, 1H), 7.13 (t, 1H), 6.61 (d, 1H), 6.52 (d, 1H), 4.1 (m, 1H ), 4.08 (s, 3H), 3.96 (t, 2H), 3.85 (m, 1H), 3.8 (s, 3H), 3.42 (m, 2H), 3.1 (m, 1H), 2.85 (m, 3H) , 2.75 (m, 2 H), 1.68 (m, 4 H); MS (DCI / NH ₃ ) m / e 510 (M + H) ⁺ ;
[954] Elemental Analysis for C ₂₅ H ₂₇ N ₅ O ₅ S · HCl · 2H ₂ O:
[955] Calculated: C, 51.59; H, 5.54; N, 12.03.
[956] Found: C, 51.67; H, 5. 43; N, 11.84.
[957] Example 32
[958] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[959] Example 32A
[960] Methyl 3-amino-5-chloro-thieno [2,3-b] pyridine-2-carboxylate
[961] 3-Cyano-2,6-dichloropyridine (5.19 g, 30 mmol) and methyl thioglycolate (2.7 ml, 30 mmol) are combined in DMF (25 ml) and the solution is cooled to 0 ° C. To this reaction was added KOH (50 ml) in 12 ml H ₂ O. After 1.5 hours at 0 ° C., the reaction is diluted with H ₂ O (50 ml) and the precipitate is collected. The product is recrystallized from ethyl acetate / hexanes to give 1.48 g (20%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.92 (s, 3H), 5.90 (br s, 2H), 7.33 (d , 1H), 7.87 (d, 1H).
[962] Example 32B
[963] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[964] The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 32A (0.382 g, 1.57 mmol) were treated as described in Example 1F to yield 0.30 g (25%) of the title compound: melting point 201-205 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.6-1.9 (m, 4H), 2.2-2.44 (m, 2H), 2.5-5.8 (m, 4H), 3.1-3.9 (m, 4H), 3.78 (s , 3H), 4.02 (dd, 1H), 4.18 (t, 2H), 6.42 (d, 1H), 6.49 (d, 1H), 7.05 (t, 1H), 7.49 (d, 1H), 8.49 (d, 1H); MS (DCI / NH 3) m / e 513 (515 (M + H) ⁺ );
[965] Elemental Analysis for C ₂₅ H ₂₆ Cl ₂ N ₄ O ₄ S · H ₂ O:
[966] Calculated: C, 52.91; H, 4.97; N, 9.87; Cl, 12.49.
[967] Found: C, 53.17; H, 4.87; N, 9.52; Cl, 12.43.
[968] Example 33
[969] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[970] Example 33A
[971] Methyl 3-amino-5-methoxy-thieno [2,3-b] pyridine-2-carboxylate
[972] Sodium metal (0.46 g, 20 mmol) is added to methanol (20 ml) and reacted until metallic sodium is consumed. To this solution is added the product from Example 32A (0.485 g, 2.0 mmol) and the reaction is heated to reflux for 2 hours. The reaction is quenched in saturated aqueous NH ₄ Cl and extracted with ethyl acetate. Dry the organic phase (MgSO ₄ ) and evaporate to afford 0.410 g (86%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.88 (s, 3H), 4.02 (s, 3H), 6.74 (d , 1H), 7.77 (d, 1H).
[973] Example 33B
[974] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[975] The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 33A (0.375 g, 1.57 mmol) were treated as described in Example 1F to yield 0.480 g (51%) of the title compound: melting point 210-214 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64-1.88 (m, 4H), 2.2-2.4 (m, 2H), 2.5-2.8 (m, 4H), 3.1-3.9 (m, 4H), 3.78 (s , 3H), 4.02 (dd, 1H), 4.07 (s, 3H), 4.15 (t, 2H), 6.44 (d, 1H), 6.53 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 8.54 (d, 1H); MS (DCI / NH ₃ ) m / e 509 (M + H) &lt; + &gt;;
[976] Elemental Analysis for C ₂₅ H ₂₉ ClN ₄ O ₅ S · H ₂ O:
[977] Calculated: C, 55.46; H, 5.55; N, 9.95; Cl, 6.30.
[978] Found: C, 55.64; H, 5. 35; N, 9.91; Cl, 6.24.
[979] Example 34
[980] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[981] The product from Example 1E (0.414 g, 1.5 mmol) and methyl 3-amino-thieno [2,3-b] pyridine-2-carboxylate (0.328 g, 1.57 mmol) were treated as described in Example 1F. To give 0.26 g (34%) of the title compound: melting point 195-200 ° C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.9 (m, 4H), 2.3-2.5 (m, 2H), 2.5-2.85 (m, 4H), 3.2-3.9 (m, 4H), 3.79 (s , 3H), 4.01 (dd, 1H), 4.19 (t, 2H), 6.42 (d, 1H), 6.52 (d, 1H), 7.07 (t, 1H), 7.48 (dd, 1H), 8.57 (m, 1H), 8.77 (dd, 1H); MS (DCI / NH 3) m / e 497 (M + H) +;
[982] Elemental Analysis for C ₂₅ H ₂₇ ClN ₄ O ₄ S · H ₂ O:
[983] Calculated: C, 56.33; H, 5. 48; N, 10.51; Cl, 6.65.
[984] Found: C, 56.32; H, 5. 36; N, 10.42; Cl, 6.54.
[985] Example 35
[986] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[987] Example 35A
[988] Methyl 3-amino-5-methyl-thieno [2,3-b] pyridine-2-carboxylate
[989] 2-Chloro-3-cyano-6-methyl pyridine (1.5 g, 9.8 mmol) and methyl thioglycolate (0.88 ml, 9.8 mmol) are combined in DMF (7 ml). To this solution is added 1.0 g of KOH in 5 ml of H ₂ O. The reaction was quenched by addition of ice water and the product was collected by filtration to give 1.72 g (79%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.88 (s, 3H), 3.91 (s, 3H) , 5.90 (br s, 2 H), 7.17 (d, 1 H), 7.82 (d, 1 H).
[990] Example 35B
[991] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[992] The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 35A (0.350 g, 1.57 mmol) were treated as described in Example 1F to yield 0.27 g (34%) of the title compound: melting point 215-220 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-1.9 (m, 4H), 2.3-2.5 (m, 2H), 2.5-2.8 (m, 4H), 2.71 (s, 3H), 3.2-3.9 (m , 4H), 3.77 (s, 3H), 4.02 (dd, 1H), 4.17 (t, 2H), 6.44 (d, 1H), 6.53 (d, 1H), 7.07 (t, 1H), 7.34 (d, 1H), 8.41 (d, 1H); MS (DCI / NH 3) m / e 493 (M + H) ⁺ .
[993] Elemental Analysis for C ₂₆ H ₂₉ ClN ₄ O ₄ S · 1.5H ₂ O:
[994] Calculation: C, 56.16; H, 5.80; N, 10.08; Cl 6.38.
[995] Found: C, 56.00; H, 5. 37; N, 10.01; Cl 5.99.
[996] Example 36
[997] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[998] Example 36A
[999] Methyl 3-amino-4-methoxy-thieno [2,3-b] pyridine-2-carboxylate
[1000] 1.0 M solution of KOtBu / THF (14.6 ml) is added to 2-chloro-3-cyano-4-methoxy pyridine (2.02 g) and methyl thioglycolate (1.1 ml) in DMF (24 ml) at 5 ° C. . The reaction is stirred at 5 ° C. for 20 minutes and then at room temperature for 1 hour, quenched in saturated NH ₄ Cl and the solids collected, washed with water and then dried by suction. It is recrystallized from EtOAc to give 0.89 g of the title compound.
[1001] Example 36B
[1002] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1003] The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 36A (0.350 g, 1.57 mmol) were treated as described in Example 1F to afford 0.40 g (44%) of the title compound. 180-200 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.61 (2H, br), 1.78 (2H, m), 2.23 (2H, br), 2.60 (3H, br), 3.20 (1H, br), 3.45 (2H, br ), 3.75 (1H, m), 3.81 (3H, s), 4.03 (1H, dd), 4.10 (1H, t), 4.14 (3H, s), 6.44 (1H, d), 6.51 (1H, d) , 6.82 (1 H, d), 7.04 (1 H, t), 8.60 (1 H, d), 8.90 (1 H, br s); MS (DCl / NH ₃ ) m / e 509.
[1004] Elemental Analysis for C ₂₆ H ₂₉ ClN ₄ O ₅ SHCl (H ₂ O) ₂ · (C ₄ H ₈ O ₂ ) _0.5 :
[1005] Calculation: C, 53.80; H, 5.97; N, 8.96; Cl 5.67.
[1006] Found: C, 53.54; H, 5.68; N, 8.92; Cl 5.73.
[1007] Example 37
[1008] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1009] The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 6A (0.30 g, 1.24 mmol) were treated as described in Example 1F to yield 0.30 g (47%) of the title compound. 196-198 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.15 (d, 1H), 7.47 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.42 (d, 1H), 4.08 (t, 2H), 4.02 (dd, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 3.5 (m, 2H), 2.78 (m, 4H), 2.5 (m, 2H), 1.76 ( m, 4H); MS (DC1 / NH ₃ ) m / e 513 (M + H) ⁺ _.
[1010] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ SHCl2H ₂ O:
[1011] Calculation: C, 51.09; H, 5. 28; N, 9.25.
[1012] Found: C, 51.20; H, 5. 33; N, 9.55.
[1013] Example 38
[1014] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1015] Example 38A
[1016] Methyl 3-amino-6-chloro-thieno [3,2-b] pyridine-2-carboxylate
[1017] The product from Example 27A (3.46 g, 20 mmol) and methyl thioglycolate (1.8 ml, 20 mmol) were combined in THF (40 ml). To this solution is added 1.08 g (20 mmol) of NaOMe. After 1.5 hours, additional 1.08 g NaOMe is added, and after 2 more hours, the reaction is quenched in 5% aqueous NaHCO ₃ and extracted with diethyl ether. The organic extract was dried (MgSO ₄ ), evaporated and the product was purified by silica gel column chromatography to yield 1.23 g (25%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.92 (s, 3H ), 6.20 (br s, 2 H), 8.04 (d, 1 H), 8.54 (d, 1 H).
[1018] Example 38B
[1019] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1020] The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 38A (0.30 g, 1.24 mmol) were treated as described in Example 1F to yield 0.29 g (46%) of the title compound: melting point 224-226 ° C .; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.88 (m, 2H), 7.13 (t, 1H), 6.62 (d, 1H), 6.5 (d, 1H), 4.05 (dd, 1H), 3.96 (t , 2H), 3.82 (m, 1H), 3.8 (s, 3H), 3.2 (m, 2H), 2.95 (m, 1H), 2.85 (m, 3H), 2.3 (m, 2H), 1.7 (m, 4H)
[1021] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ SHCl0.75H ₂ O:
[1022] Calculation: C, 53.22; H, 5. 16; N, 9.39.
[1023] Found: C, 53.24; H, 5.04; N, 9.93.
[1024] Example 39
[1025] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1026] The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 9B (0.356 g, 1.25 mmol) were treated as described in Example 1F and recrystallized from methanol to give 0.35 g (63%) of the title compound. ) Is obtained: melting point 291 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.08 (s, 1H), 8.07 (dd, 2H), 7.58 (m, 3H), 6.88 (t, 1H), 6.30 (d, 1H), 6.20 (d, 1H), 4.18 (m, 2H), 3.88 (dd, 1H), 3.72 (s, 3H), 3.63 (m, 2H), 3.38 (m, 2H), 2.72 (m, 3H), 2.6 ( m, 1H), 2.5 (m, 1H), 1.8 (m, 4H)
[1027] MS (DCI / NH ₃ ) m / e 556 (M + H) ⁺ .
[1028] Elemental Analysis for _{C 30 H 29 N 5 SO 4} · HCl:
[1029] Calculation: C, 60.85; H, 5. 10; N, 11.82; Cl 5.98.
[1030] Found: C, 60.50; H, 5.20; N, 11.69; Cl 6.07.
[1031] Example 40
[1032] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1033] Example 40A
[1034] 3-cyano-2-chloro-6-phenylpyrazine
[1035] See Dick and Wood, J. Chem. Soc., 1379 (1955)], 3-carboxamido-2-hydroxy-6-phenylpyrazine (7.56 g, 35.13 mmol) suspended in triethylamine (7.11 g, 70.26 mmol). Cooled to 0 ° C. and dissolved in 50 ml POCl ₃ . The mixture is refluxed for 3 hours and then concentrated in vacuo. The resulting black oil is extracted with 5 × 100 ml Et ₂ O and the combined extracts are treated with 250 ml of cold 10% Na ₂ CO ₃ . The layers are separated and the organic phase is washed with water, brine and then dried over Na ₂ SO ₄ . Concentrate to give the title compound (3.20 g, 42%) as a brown solid. Melting point: 143-145 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.57 (m, 3H), 8.10 (m, 2H), 9.05 (s, 1H) MS (DCI / NH ₃ ) m / e 233 (M + NH ₄ ) ⁺ .
[1036] Example 40B
[1037] Ethyl 7-amino-3-phenyl-thieno [2,3-b] pyrazine-6-carboxylate
[1038] Compound (1.00 g, 4.65 mmol) resulting from Example 40A is treated with ethyl thioglycolate (0.56 g, 4.65 mmol) and Na ₂ CO ₃ (0.49 g, 4.65 mmol) in 20 ml of EtOH. The crude product is recrystallized from EtOH / H ₂ O to give the title product (1.19 g, 86%) as an yellowish green solid: melting point 173-175 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.42 (t, 3H), 4.41 (q, 2H), 6.18 (br s, 2H), 7.55 (m, 3H), 8.12 (m, 2H), 9.03 (s, 1H). MS (DCI / NH ₃ ) m / e 300 (M + H) ⁺ .
[1039] Example 40C
[1040] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1041] The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 40B (0.356 g, 1.25 mmol) were treated as described in Example 1F to yield 0.30 g (59%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.13 (s, 1H), 8.18 (dd, 2H), 7.79 (m, 3H), 7.04 (t, 1H), 6.45 (t, 2H), 4.12 ( t, 2H), 4.01 (dd, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.55 (m, 2H), 3.45 (m, 1H), 2.78 (m, 3H), 2.62 (m , 2H), 1.78 (m, 4H) MS (DCI / NH ₃ ) m / e 556 (M + H) ⁺ .
[1042] Elemental Analysis for _{C 30 H 29 N 5 SO 4} · HCl · 1.5H 2 O:
[1043] Calculation: C, 58.20; H, 5. 37; N, 11.31.
[1044] Found: C, 58.51; H, 5.31; N, 11.33.
[1045] Example 41
[1046] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1047] Product from Example 3E (210 mg, 0.75 mmol), 3-amino-2-carbomethoxythieno [3,2-c] pyridine (0.17 g, 0.83 mmol), see J. Heterocyclic Chem., 24, 85 (1987)], Et ₃ N (0.40 ml, 2.9 mmol) and phosgene (1.93 M 0.43 ml in toluene, 83 mmol) were treated as described in Example 1F to yield 0.20 g (56%) of the title compound: Melting point> 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.72-1.93 (m, 4H), 2.29-2.43 (m, 1H), 2.74 (t, J = 10 Hz, 1H), 2.83-2.98 (m, 4H ), 3.16 (dd, J = 8, 10 Hz, 1H), 3.73 (s, 3H), 3.75-3.83 (m, 1H), 4.03 (dd, J = 1, 10 Hz, 1H), 4.21 (t, J = 7Hz, 2H), 4.43 (dd, J = 4, 10Hz, 1H), 6.36 (dd, J = 1, 8Hz, 1H), 6.46 (dd, J = 1, 8Hz, 1H), 7.05 (t, J = 8 Hz, 1 H), 7.80 (dd, J = 1, 6 Hz, 1H), 8.61 (d, J = 6 Hz, 1H), 9.54 (d, J = 1 Hz, 1H). MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ .
[1048] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · (HCl) ₂ · H ₂ O · (CH ₃ OH) _0.5 :
[1049] Calculation: C, 52.31; H, 5.51; N, 9.57.
[1050] Found: C, 51.95; H, 5. 22; N, 9.27.
[1051] Example 42
[1052] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1053] Product from Example 3E (200 mg, 0.72 mmol), 3-amino-2-carbomethoxythieno [2,3-c] pyridine (0.16 g, 0.79 mmol) [J. Heterocyclic Chem., 24, 85 (1987)], Et ₃ N (0.40 ml, 2.9 mmol) and phosgene (1.93 M 0.41 ml in toluene, 0.79 mmol) were treated as described in Example 1F to give 0.20 g (58%) of the title compound. Melting point 221-223 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.76-1.96 (m, 4H), 2.37-2.50 (m, 1H), 2.72-2.82 (m, 1H), 2.89-3.11 (m, 4H), 3.18-3.28 (m, 1H), 3.73 (s, 3H), 3.80-3.89 (m, 1H), 4.04 (dd, J = 1, 9 Hz, 1H), 4.22 (t, J = 7 Hz, 2H), 4.45 (dd, J = 4, 10Hz, 1H), 6.38 (d, J = 8Hz, 1H), 6.54 (d, J = 8Hz, 1H), 7.08 (t, J = 8Hz, 1H), 8.10 (d, J = 6 Hz, 1 H), 8.64 (d, J = 6 Hz, 1 H), 9.19 (s, 1 H); MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ .
[1054] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · (HCl) ₂ · (H ₂ O) _0.75 :
[1055] Calculation: C, 53.15; H, 5. 26; N, 9.92.
[1056] Found: C, 53.18; H, 5. 18; N, 9.70.
[1057] Example 43
[1058] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1059] The product from Example 3E (0.276 g, 1.00 mmol) and the product from Example 31A (0.25 g, 1.05 mmol) were treated as described in Example 1F to yield 0.10 g (50%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.02 (d, 1H), 7.04 (t, 1H), 6.92 (d, 1H), 6.48 (d, 1H), 6.39 (d, 1H), 5.39 ( m, 1H), 4.45 (dd, 1H), 4.11 (t, 2H), 4.04 (m, 1H), 3.76 (s, 3H), 3.59 (q, 1H), 2.96 (q, 1H), 2.76 (m , 4H), 2.58 (m, 1H), 2.3 (m, 1H), 1.77 (m, 4H), 1.42 (d, 6H); MS (DCI / NH ₃ ) m / e 537 (M + H) ⁺ .
[1060] Elemental Analysis for C ₂₈ H ₃₂ N ₄ O ₅ S · HCl · 1.5H ₂ O:
[1061] Calculation: C, 56.04; H, 6.05; N, 9.34.
[1062] Found: C, 56.04; H, 5. 70; N, 9.14.
[1063] Example 44
[1064] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1065] The product from Example 3E (0.276 g, 1.0 mmol) and 3-amino-thieno [2,3-b] pyridine-2-carboxylate (0.229 g, 1.1 mmol) prepared as described in Example 35A Treatment as described in Example 1F afforded 0.185 g (36%) of the title compound: melting point 217-218 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 2H), 2.8-3.5 (m, 5H), 3.78 (s, 3H), 3.97 (m, 2H), 4.10 (q, 1H), 4.47 (m, 1H), 6.46 (d, 1H), 4.56 (d, 1H), 7.13 (t, 1H), 7.65 (dd, 1H), 8.75 (dt, 1H ), 8.84 (dd, 1 H), 10.55 (br s, 1 H), 12.74 (d, 1 H); MS (DCI / NH ₃ ) m / e 479 (M + H) ⁺ .
[1066] Elemental Analysis for C ₂₅ H ₂₇ ClN ₄ O ₄ S · 1.5H ₂ O:
[1067] Calculation: C, 55.39; H, 5.57; N, 10.33.
[1068] Found: C, 55.43; H, 5. 17; N, 10.32.
[1069] Example 45
[1070] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1071] The product from Example 3E (0.276 g, 1.0 mmol) and the product from Example 35A (0.244 g, 1.1 mmol) were treated as described in Example 1F to afford 0.090 g (17%) of the title compound: melting point 243-5 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 3H), 2.66 (s, 3H), 2.8-3.8 (m, 6H), 3.77 (s, 3H), 3.96 (m, 2H), 4.12 (m, 1H), 4.45 (m, 1H), 6.46 (d, 1H), 6.56 (d, 1H), 7.12 (t, 1H), 7.51 (d, 1H ), 8.60 (d, 1 H); MS (DCI / NH ₃ ) m / e 493 (M + H) ⁺ .
[1072] Elemental Analysis for C ₂₆ H ₂₉ ClN ₄ O ₄ SH ₂ O:
[1073] Calculation: C, 57.08; H, 5.71; N, 10.24.
[1074] Found: C, 56.93; H, 5. 22; N, 9.94.
[1075] Example 46
[1076] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1077] The product from Example 3E (0.248 g, 0.90 mmol) and the product from Example 33A (0.238 g, 1.0 mmol) were treated as described in Example 1F to yield 0.301 g (61%) of the title compound: melting point 260-3 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 3H), 2.8-3.6 (m, 6H), 3.74 (s, 3H), 3.95 (m, 2H), 3.97 (s, 3H), 4.07 (t, 1H), 4.28 (m, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.07 (d, 1H), 7.11 (t, 1H ), 8.59 (d, 1 H); MS (DCI / NH ₃ ) m / e 509 (M + H) ⁺ .
[1078] Elemental Analysis for C ₂₆ H ₂₉ ClN ₄ O ₅ S · 3 / 4H ₂ O:
[1079] Calculation: C, 55.91; H, 5.50; N, 10.03; Cl 6.35
[1080] Found: C, 55.75; H, 5. 32; N, 10.00; Cl 6.44
[1081] Example 47
[1082] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1083] The product from Example 3E (0.248 g, 0.90 mmol) and the product from Example 32A (0.242 g, 1.0 mmol) were treated as described in Example 1F to yield 0.285 g (58%) of the title compound: melting point 245-50 ° C .; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 2H), 2.8-3.6 (m, 5H), 3.77 (s, 3H), 3.8-4.2 ( m, 2H), 3.95 (m, 2H), 4.10 (t, 1H), 4.47 (m, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.11 (t, 1H), 7.78 (d , 1H), 8.75 (d, 1H). MS (DC1 / NH ₃ ) m / e 513 (515 (M + H) ⁺ ).
[1084] Elemental Analysis for C ₂₅ H ₂₆ Cl ₂ N ₄ O ₄ S · 0.5H ₂ O · 0.1HCl:
[1085] Calculation: C, 53.42; H, 4.86; N, 9.97; Cl 13.24.
[1086] Found: C, 53.25; H, 7.73; N, 9.68; Cl 13.31.
[1087] Example 48
[1088] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-chloro-pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1089] Example 48A
[1090] Methyl 3-amino-4-chloro-thieno [3,2-c] pyridine-2-carboxylate
[1091] 1.0 M solution of KOtBu / THF (4.5 ml) is added to 3-cyano-2,6-chloropyridine (653 mg) and methyl thioglycolate (340 μl) in DMF (12 ml) at 5 ° C. The reaction is stirred at 5 ° C. for 20 minutes and then at room temperature for 1 hour, quenched in saturated NH ₄ Cl and the solid precipitate collected, washed with water and then dried by suction to give 800 mg (88%) of the title compound.
[1092] Example 48B
[1093] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-chloro-pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1094] The product from Example 1E (0.276 g, 1.0 mmol) and the product from Example 48A (0.242 g, 1.0 mmol) were treated as described in Example 1F to yield 0.280 g (55%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (4H, br m), 2.40 (2H, br), 2.65 (3H, br), 3.30 (1H, br), 3.50 (2H, br), 3.80 (3H, s ), 3.86 (1H, br), 4.02 (1H, dd), 4.10 (1H, t), 6.45 (1H, d), 6.52 (1H, d), 7.08 (1H, t), 7.79 (1H, d) , 8.40 (1 H, d); MS (CI (NH ₃ )) m / e 513 (M + H) ⁺ .
[1095] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ SHCl:
[1096] Calculation: C, 52.49; H, 4.89; N, 9.79
[1097] Found: C, 52.28; H. 4.55; N, 9.44
[1098] Example 49
[1099] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-methoxy-pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione fumarate
[1100] Example 49A
[1101] Methyl 3-amino-4-methoxy-thieno [3,2-c] pyridine-2-carboxylate
[1102] The product from Example 48A (1.2 g, 4.9 mmol) and sodium methoxide (1.0 g, 19 mmol) were refluxed in 30 ml MeOH for 6 hours. The reaction is partitioned between water and CH ₂ Cl ₂ . The layers are separated and the aqueous layer is extracted with CH ₂ Cl ₂ . The combined organic layers are dried (MgSO ₄ ), filtered and concentrated. Silica gel chromatography (CH ₂ Cl ₂ ) affords 1.1 g (78%) of the title compound. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.79 (s, 3H), 4.05 (s, 3H), 6.96 (bs, 2H), 7.47 (d, J = 6Hz, 1H), 8.07 (d, J = 6 Hz, 1 H);
[1103] MS (DCI (NH ₃ )) m / e 239 (M + H) ⁺ .
[1104] Example 49B
[1105] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -9-methoxy-pyrido [3 ', 4': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione fumarate
[1106] Product from Example 1E (0.140 g, 0.50 mmol), Product from Example 49A (0.145 g, 0.61 mmol), Et ₃ N (0.18 ml, 1.3 mmol) and phosgene (1.93 M in toluene 1.1 ml, 2.1 mmol ) Is treated as described in Example 1F with replacement of fumaric acid in the salt formation step to yield 0.22 g (87%) of the title compound: melting point 232-233 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.60-1.84 (m, 4H), 2.24-2.40 (m, 1H), 2.55-2.65 (m, 1H), 2.72-2.90 (m, 4H), 2.95-3.03 (m, 1H), 3.60-3.69 (m, 1H), 3.76 (s, 3H), 4.05 (dd, J = 10, 11 Hz, 1H), 4.11 (t, J = 7 Hz, 2H), 4.20 (s, 3H), 4.46 (dd, J = 4, 9Hz, 1H), 6.39 (d, J = 8Hz, 1H), 6.48 (d, J = 8Hz, 1H), 7.05 (t, J = 8Hz, 1H ), 7.39 (d, J = 6 Hz, 1H), 8.16 (d, J = 6 Hz, 1H); MS (DCI (NH ₃ )) m / e 509 (M + H) ⁺ .
[1107] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₅ S · C ₄ H ₄ O ₄ · (H ₂ O) _0.25 :
[1108] Calculation: C, 57.27; H, 5. 21; N, 8.90
[1109] Found: C, 56.96; H, 4.95; N, 8.83
[1110] Example 50
[1111] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1112] The product from Example 3E (0.276 g, 1.0 mmol) and the product from Example 9B (0.308 g, 1.08 mmol) were treated as described in Example 1F to yield 0.41 g (73%) of the title compound: melting point ≧ 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.03 (s, 1H), 8.02 (m, 2H), 7.58 (m, 3H), 7.0 (t, 1H), 6.4 (d, 1H), 6.31 (d, 1H), 3.98 (m, 2H), 4.05 (dd, 1H), 3.85 (t, 2H), 3.62 (m, 1H), 3.06 (m, 3H), 2.85 (m, 2H), 2.22 (m, 1 H), 1.82 (m, 4 H); MS (DCI / NH ₃ ) m / e 556 (M + H) ⁺ .
[1113] Elemental Analysis for C ₃₀ H ₂₉ N ₅ O ₄ S · HCl · 2H ₂ O:
[1114] Calculated: C, 57.36; H, 5. 46; N, 11.15.
[1115] Found: C, 57.31; H, 5. 23; N, 10.99.
[1116] Example 51
[1117] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-isopropoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1118] Example 51A
[1119] Isopropyl 3-amino-5-isopropoxy-thieno [3,2-b] pyridine-2-carboxylate
[1120] Na metal (0.47 g, 20 mmol) is added to 2-propanol (150 ml) and heated to reflux until all of the sodium is consumed. To this solution was added methyl 3-amino-7-chloro-thieno [3,2-b] pyridine-2-carboxylate (prepared as described in Example 5A) (0.50 g, 2.06 mmol) and the solution was added 48 Heat to reflux for hours. The solvent is evaporated and the product is partitioned between aqueous NH ₄ Cl and CH ₂ Cl ₂ . The organic phase is dried, concentrated and the product is purified by silica gel chromatography to give 0.11 g (19%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) 7.85 (d, 1H), 6.91 (d, 1H), 5.98 (bs, 1H), 5.42 (m, 1H), 5.25 (m, 1H), 1.42 (d, 6H), 1.38 (d, 6H); MS (DCI / NH ₃ ) m / e 295 (M + H) ⁺ .
[1121] Example 51B
[1122] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-isopropoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1123] The product from Example 3E (0.102 g, 0.37 mmol) and the product from Example 51A (0.11 g, 0.37 mmol) were treated as described in Example 1F to yield 0.10 g (50%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.02 (d, 1H), 7.04 (t, 1H), 6.92 (d, 1H), 6.48 (d, 1H), 6.39 (d, 1H), 5.39 (m, 1H), 4.45 (dd, 1H), 4.11 (t, 2H), 4.04 (m, 1H), 3.76 (s, 3H), 3.59 (q, 1H), 2.96 (q, 1H), 2.76 ( m, 4H), 2.58 (m, 1H), 2.3 (m, 1H), 1.77 (m, 4H), 1.42 (d, 6H); MS (DCI / NH ₃ ) m / e 537 (M + H) ⁺ .
[1124] Elemental Analysis for C ₂₈ H ₃₂ N ₄ O ₅ S · HCl · 1.5H ₂ O:
[1125] Calculated: C, 56.04; H, 6.05; N, 9.34.
[1126] Found: C, 56.04; H, 5. 70; N, 9.14.
[1127] Example 52
[1128] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1129] Example 52A
[1130] Methyl 3-amino-5-phenyl-thieno [3,2-b] pyridine-2-carboxylate
[1131] Methyl 3-amino-5-chloro-thieno [3,2-b] pyridine-2-carboxylate (0.243 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.1 mmol), prepared as described in Example 6A ) And triethylamine (0.20 ml) 3 ml DMF containing [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (1: 1 complex with CH ₂ Cl ₂ ) under N ₂ Add to The mixture is stirred at 90 ° C. for 4 hours. The reaction is then cooled and diluted with Et ₂ O. The organic layer was washed with H ₂ O, brine, dried (MgSO ₄ ), concentrated and chromatographed (2: 1 CH ₂ Cl ₂ : hexanes) to afford the title compound (140 mg, 50%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.93 (s, 3H), 6.30 (bs, 2H), 7.41-7.55 (m, 3H), 7.84 (d, J = 8 Hz, 1H), 8.07-8.13 ( m, 3H); MS (DCI (NH ₃ )) m / e 285 (M + H) ⁺ .
[1132] Example 52B
[1133] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1134] Product from Example 3E (0.21 g, 0.75 mmol), Product from Example 52A (235 mg, 0.83 mmol), Et ₃ N (0.26 ml, 1.9 mmol) and phosgene (1.93 M in toluene 0.5 ml, 0.95 mmol) Was treated as described in Example 1F to yield 0.300 g (72%) of the title compound: melting point> 250 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.59-1.71 (m, 2H), 1.74-1.87 (m, 2H), 2.19-2.34 (m, 1H), 2.59 (dd, J = 9, 11 Hz, 1H), 2.72-2.84 (m, 4H), 3.00 (dd, J = 7, 9 Hz, 1H), 3.55-3.67 (m, 1H), 3.73 (s, 3H), 4.00 (dd, J = 10, 12 Hz, 1H), 4.18 (t, J = 7 Hz, 2H), 4.38 (dd, J = 4, 10 Hz, 1H), 6.38 (dd, J = 1, 8 Hz, 1H), 6.46 (dd, J = 1, 8 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.44-7.56 (m, 3H), 7.92 (d, J = 8 Hz, 1H), 8.04-8.11 ( m, 2H), 8.26 (d, J = 8 Hz, 1H); MS (DCI (NH ₃ )) m / e 555 (M + H) ⁺ .
[1135] Elemental Analysis for C ₃₁ H ₃₀ N ₄ O ₄ S · (HCl) ₂ · (H ₂ O) _0.5 :
[1136] Calculated: C, 58.49; H, 5. 23; N, 8.80.
[1137] Found: C, 58.18; H, 5. 23; N, 8.47.
[1138] Example 53
[1139] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1140] Example 53A
[1141] Methyl 3-amino-7-chloro-thieno [2,3-c] pyridine-2-carboxylate
[1142] 3-chloro-4-cyanopyridine, prepared as described in J. Heterocyclic Chem., 15, 683 (1978), was dissolved in acetic acid (15 ml) and 30% H ₂ O ₂ (15 ml) Add over 5 minutes. The reaction is stirred at 80 ° C. for 18 hours. After cooling to room temperature, the white solid product (2.5 g) is collected by filtration and dried. The N-oxide is then dissolved in DMF (50 ml) and methyl thioglycolate (1.45 ml, 16 mmol) is added. Sodium methoxide (0.86 g, 16 mmol) is added. The reaction is stirred for 1 hour, poured into ice / water and the product is collected by filtration and dried. The resulting solid is suspended in POCl ₃ (40 ml) and heated to reflux for 1 hour. The reaction is quenched on ice, extracted with ether and the organic extract is washed several times with aqueous 5% NaHCO ₃ . Silica gel column chromatography (85:15 hexanes: ethyl acetate) 0.42 g of minor isomers (methyl-3-amino-5-chloro-thieno [2,3-c] pyridine-2-carboxylate) and the title compound 1.0 g is obtained.
[1143] Example 53B
[1144] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1145] Product from Example 1E (0.42 g, 1.5 mmol), Product from Example 53A (0.364 g, 1.5 mmol), Et ₃ N (0.5 ml, 3.0 mmol) and phosgene (1.63 ml, 1.93 M in toluene, 3.0 mmol) ) Is treated as described in Example 1F to give 0.26 g (33%) of the title compound: melting point 191 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.7-1.8 (m, 2H), 1.8-1.9 (m, 2H), 2.32-2.55 (m, 2H), 2.60-2.80 (m, 3H), 3.27 (m , 1H), 3.40-3.90 (m, 4H), 3.78 (s, 3H), 4.01 (dd, 1H), 4.19 (t, 2H), 6.43 (d, 1H), 6.48 (d, 1H), 7.06 ( t, 1H), 8.04 (d, 1H), 8.46 (d, 1H); MS (DCI / NH ₃ ) m / e 513,515 (M + H) ⁺ .
[1146] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ S · H ₂ O:
[1147] Calculated: C, 56.55; H, 5. 12; N, 10.55.
[1148] Found: C, 56.32; H, 5.03; N, 10.44.
[1149] Example 54
[1150] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -6-chloro-pyrido [4 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1151] Product from Example 3E (0.42 g, 1.5 mmol), Product from Example 53A (0.364 g, 1.5 mmol), Et ₃ N (0.5 ml, 3.0 mmol) and phosgene (1.63 ml, 1.93 M in toluene, 3.0 mmol) ) Is treated as described in Example 1F to give 0.31 g (40%) of the title compound: melting point 230 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.50-1.75 (m, 4H), 2.18 (m, 1H), 2.66 (t, 1H), 2.82 (m, 4H), 3.07 (t, 1H), 3.1- 3.9 (m, 5H), 3.71 (s, 3H), 3.95 (m, 2H), 4.05 (dd, 1H), 4.42 (dd, 1H), 6.40 (d, 1H), 6.47 (d, 1H), 7.04 (t, 1H), 8.21 (d, 1H), 8.50 (d, 1H); MS (DCI / NH ₃ ) m / e 513,515 (M + H) ⁺ .
[1152] Elemental Analysis for C ₂₅ H ₂₅ ClN ₄ O ₄ S · 0.5H ₂ O:
[1153] Calculated: C, 57.52; H, 5.02; N, 10.73.
[1154] Found: C, 57.33; H, 4.72; N, 10.73.
[1155] Example 55
[1156] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1157] Example 55A
[1158] Methyl 2-amino-5-methoxy-thieno [2,3-b] pyridine-2-carboxylate
[1159] 1.0 M solution of KOtBu / THF (3.8 ml) is added to 2-chloro-3-cyano-5-methoxypyridine (0.53 g) and methyl thioglycolate (280 μl) in DMF (10 ml) at 5 ° C. . The reaction is stirred at 5 ° C. for 20 minutes and then at room temperature for 2 hours, quenched in saturated NH ₄ Cl and the solid precipitate collected, washed with water and dried to give 0.53 g (71%) of the title compound.
[1160] Example 55B
[1161] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1162] The product from Example 3E (0.223 g, 0.80 mmol) and the product from Example 55A (0.192 g, 0.80 mmol) were treated as described in Example 1F to yield 0.315 g (77%) of the title compound: melting point 207-213 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.5 (2H, m), 1.65 (2H, m), 2.12 (1H, m), 2.57 (1H), 2.7 (4H, m), 2.9 (1H, t), 3.48 (1H, m), 3.7 (3H, s), 3.92 (3H, s), 3.94 (2H), 4.02 (1H, dd), 4.4 (1H, dd), 6.4 (1H, d), 6.45 (1 H, d), 7.02 (1 H, t), 8.32 (1 H, d), 8.56 (1 H, d); MS (CI (NH ₃ )) m / e 509.
[1163] Elemental Analysis for C ₂₆ H ₂₉ ClN ₄ O ₅ :
[1164] Calculated: C, 54.59; H, 5. 64; N, 9.79.
[1165] Found: C, 54.61; H, 5. 60; N, 9.72.
[1166] Example 56
[1167] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1168] Example 56A
[1169] Methyl 3-amino-5- (3-pyridyl) thieno [3,2-b] pyridine-2-carboxylate
[1170] Methyl 3-amino-5-chloro-thieno [3,2-b] pyridine-2-carboxylate (0.252 g), diethyl 3-, prepared as described in Example 5A in degassed DMF (5 ml). A solution of pyridyl-borane (0.155 g), Pd (dppf) Cl ₂ (0.082 g) and K ₂ CO ₃ (420 mg) was heated to 95 ° C. for 1.5 h, cooled and then quenched in saturated NH ₄ Cl , Solid precipitates were collected and chromatographed (9: 1 hexanes / EtOAc) to give 0.24 g (81%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.95 (3H, s), 6.30 (2H, br s), 7.45 (1H, dd), 7.86 (1H, d), 8.19 (1H, d), 8.42 (1H , dt), 8.70 (1H, dd), 9.32 (1H, br d).
[1171] Example 56B
[1172] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1173] The product from Example 1E (0.127 g, 0.46 mmol) and the product from Example 56A (0.14 g, 0.49 mmol) were treated as described in Example 1F to yield 0.09 g (33%) of the title compound: melting point 210-211 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.3 (d, 1H), 8.73 (dd, 1H), 8.41 (dt, 1H), 8.37 (d, 1H), 7.99 (d, 1H), 7.48 (dd, 1H), 7.12 (t, 1H), 6.53 (d, 1H), 6.48 (d, 1H), 4.12 (t, 2H), 4.0 (dd, 1H), 3.81 (s, 3H), 3.78 (m, 1H ), 3.42 (m, 2H), 3.1 (m, 1H), 2.6 (m, 3H), 2.2 (m, 2H), 1.85 (m, 2H), 1.68 (m, 2H); MS (DCI / NH ₃ ) m / e 556 (M + H) ⁺ .
[1174] Elemental Analysis for C ₃₀ H ₂₉ N ₅ SO ₄ · 2HCl:
[1175] Calculated: C, 57.33; H, 4.97; N, 11.14.
[1176] Found: C, 57.04; H, 5.09; N, 10.89.
[1177] Example 57
[1178] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1179] Example 57A
[1180] Methyl 7-amino-2- (3-thienyl) thieno [2,3-b] pyridine-6-carboxylate
[1181] Methyl 7-amino-2-chloro-thieno [2,3-b] pyridine-6-carboxylate (0.190 g), thiophene-3-boronic acid, prepared as described in Example 10C, in degassed DMF (0.100 g), a solution of Pd (dppf) Cl ₂ (0.032 g) and triethylamine (0.22 ml) were heated to 95 ° C. for 4 hours, cooled, then quenched in water, 1: 1 Et ₂ O Extract with / EtOAc (3 x). The organics are washed three times with water, washed with brine, dried (Na ₂ SO ₄ ), filtered and the solvent is evaporated to give 0.200 g (88%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H , s).
[1182] Example 57B
[1183] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1184] The product from Example 1E (0.127 g, 0.46 mmol) and the product from Example 57A (0.13 g, 0.45 mmol) were treated as described in Example 1F to yield 0.09 g (36%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.06 (s, 1H), 8.1 (dd, 1H), 7.78 (dd, 1H), 7.53 (dd, 1H), 7.05 (t, 1H), 6.45 (dd, 2H), 4.13 (t, 2H), 4.01 (dd, 1H), 3.83 (m, 1H), 3.8 (s, 3H), 3.52 (m, 2H), 3.3 (m, 1H), 2.72 ( m, 3H), 2.45 (m, 2H), 1.85 (m, 2H), 1.68 (m, 2H); MS (DCI / NH ₃ ) m / e 562 (M + H) ⁺ .
[1185] Elemental Analysis for _{C 28 H 27 N 5 O 4} S 2 · HCl · 2H 2 O:
[1186] Calculated: C, 53.00; H, 5.09; N, 11.04.
[1187] Found: C, 52.78; H, 4. 84; N, 10.72.
[1188] Example 58
[1189] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione trihydrochloride
[1190] The product from Example 3E (0.127 g, 0.46 mmol) and the product from Example 56A (0.14 g, 0.49 mmol) were treated as described in Example 1F to yield 0.095 g (35%) of the title compound. 238-241 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.34 (d, 1H), 8.76 (d, 1H), 8.47 (d, 1H), 8.38 (d, 1H), 7.99 (d, 1H), 7.52 (dd, 1H), 7.11 (t, 1H), 6.5 (d, 1H), 6.41 (d, 1H), 4.66 (dd, 1H), 4.51 (m, 2H), 4.2 (m, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 2.83 (m, 1H), 2.64 (m, 4H), 2.52 (m, 1H), 2.3 (m, 1H), 1.78 (m, 2H), 1.72 ( m, 2H); MS (DCI / NH ₃ ) m / e 456 (M + H) ⁺ .
[1191] Elemental Analysis for C ₃₀ H ₂₉ N ₅ SO ₄ · 3HCl · 2H ₂ O:
[1192] Calculated: C, 51.40; H, 5. 18; N, 9.99.
[1193] Found: C, 51.24; H, 5. 23; N, 9.82.
[1194] Example 59
[1195] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1196] The product from Example 3E (0.13 g, 0.44 mmol) and the product from Example 57A (0.13 g, 0.45 mmol) were treated as described in Example 1F to yield 0.045 g (17%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.09 (s, 1H), 8.12 (d, 1H), 7 (81, J = d Hz, 1H), 7.52 (dd, 1H), 7.11 (t , 1H), 6.51 (d, 1H), 6.42 (d, 1H), 4.52 (dd, 1H), 4.17 (m, 2H), 4.08 (m, 1H), 3.85 (m, 1H), 3.8 (s, 3H), 3.2 (m, 4H), 3.1 (m, 1H), 2.8 (m, 1H), 2.62 (m, 1H), 2.05 (m, 2H), 1.95 (m, 2H); MS (DCI / NH ₃ ) m / e 562 (M + H) ⁺ .
[1197] Example 60
[1198] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1199] Example 60A
[1200] Methyl 7-amino-2- (3-pyridyl) thieno [2,3-b] pyridine-6-carboxylate
[1201] Methyl 7-amino-2-chloro-thieno [2,3-b] pyrazine-6-carboxylate (0.468 g), diethyl 3-, prepared as described in Example 10C in degassed DMF (10 ml). A solution of pyridyl-borane (0.293 g), Pd (dppf) Cl ₂ (0.157 g) and K ₂ CO ₃ (0.800 g) was heated to 95 ° C. for 1.5 h, cooled and then quenched in saturated NH ₄ Cl Solid precipitate is collected, washed with water and dried. Purification by silica gel column chromatography yielded 0.44 g (80%) of the title compound; ¹ H NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 7.25 (2H, br s), 7.6 (1H, dd), 8.75 (2H, m), 9.49 (1H, s), 9.58 (1H, m).
[1202] Example 60B
[1203] 3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1204] The product from Example 3E (0.24 g, 0.87 mmol) and the product from Example 60A (0.25 g, 0.87 mmol) were treated as described in Example 1F to yield 0.14 g (29%) of the title compound. 235-240 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.9 (4H, br m), 2.4 (4H, br m), 3.05 (1H, br m), 3.10 (3H, br m), 3.65 (1H, m), 3.74 (3H, s), 4.03 (1H, t), 4.19 (2H, t), 4.40 (1H, dd), 6.38 (1H, d), 6.46 (1H, d), 7.07 (1H, t), 7.45 (1H, dd), 8.40 (1H, dt), 8.80 (1H, dd), 9.05 (1H, s), 9.36 (1H, d); MS (CI (NH ₃ )) m / e 557.
[1205] Elemental Analysis for C ₂₉ H ₂₈ N ₆ O ₆ S · 1.75HCl · 2.75H ₂ O:
[1206] Calculated: C, 51.99; H, 5. 30; N, 12.54; Cl, 9, 26.
[1207] Found: C, 51.78; H, 5. 12; N, 12.20; Cl, 9.14.
[1208] Example 61
[1209] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dione dihydrochloride
[1210] The product from Example 1E (0.18 g, 0.65 mmol) and the product from Example 60A (0.165 g, 0.58 mmol) were treated as described in Example 1F to yield 0.18 g (56%) of the title compound. 190-205 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.84 (4H, br m), 2.7-3.05 (6H, br m), 3.5 (4H, br m), 3.72 (3H, s), 3.87 (1H, br d ), 4.10 (2H, brm), 4.22 (1H, brm), 6.20 (1H, brm), 6.34 (1H, brd), 6.93 (1H, brt), 7.55 (1H, dd), 8 41 (1H, dt), 8.88 (1H, dd), 9.12 (1H, s), 9.34 (1H, d), MS (CI (NH ₃ )) m / e 557.
[1211] Elemental Analysis for C ₂₉ H ₂₈ N ₆ O ₄ S · 1.7HCl · 2.5H ₂ O:
[1212] Calculated: C, 52.48; H, 5. 27; N, 12.66; Cl, 9.08.
[1213] Found: C, 52.21; H, 5.11; N, 12.42; Cl, 8.80.
[1214] Example 62
[1215] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-furyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Dihydrochloride
[1216] Example 62A
[1217] Methyl 7-amino-2- (3-furyl) thieno [2,3-b] pyrazine-6-carboxylate
[1218] Methyl 7-amino-2-chloro-thieno [2,3-b] pyrazine-6-carboxylate (0.300 g, 1.23 mmol), β-furanboronic acid (0.207 g, prepared as described in Example 10C) 1.85 mmol) is dissolved in 12 ml of anhydrous DMF. Triethylamine (0.26 ml, 1.85 mmol, 1.5 equiv), DPPP (153 mg, 0.37 mmol, 0.3 equiv) and Pd (OAc) 2 (83 mg, 0.37 mmol, 0.3 equiv) were added to the solution, followed by 90 minutes for 2 hours. Heated to ° C. The solvent was evaporated and the resulting residue was chromatographed (SiO 2, 3: 1 hexanes / ethyl acetate) to give the product as a light yellow solid (93 mg); ¹ H NMR (300 MHz, CDCl ₃ ) δ7.02 (m, 1H), 7.57 (t, J = 3.0 Hz, 1H), 8.15 (m, 1H), 8.83 (s, 1H).
[1219] Example 62B
[1220] 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-furyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Dihydrochloride
[1221] Product from Example 1E (0.097 g, 0.35 mmol), Product from Example 62A (0.073 g, 0.27 mmol), Et ₃ N (0.1 ml, 0.68 mmol) and phosgene (1.93 M in toluene 0.7 ml, 1.4 mmol ) Is treated as described in Example 1F to afford 0.040 g (26%) of the title compound: melting point 183-186 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.61-1.80 (m, 5H), 2.70-2.81 (m, 1H), 1.81-2.96 (m, 2H), 3.12-3.33 (m, 2H), 3.37-3.53 (m, 1H), 3.77-3.93 (m, 1H), 3.80 (s, 3H), 3.93-4.02 (m, 2H), 4.02-4.15 (m, 2H), 6.51 (d, J = 8 Hz, 1H), 6.61 (d, J = 8Hz, 1H), 7.14 (t, J = 8Hz, 1H), 7.29 (d, J = 2Hz, 1H), 7.92 (d, J = 2Hz, 1H), 8.66 (s, 1H), 9.28 (s, 1H), 10.35 and 10.55 (bs and bs, 1H), 12.75 (bs, 1H); MS (CI (NH 3)) m / e 546 to (M + H) ⁺
[1222] Elemental Analysis for C ₂₈ H ₂₇ N ₅ O ₅ S · (HCl) ₂ :
[1223] Calc .: C, 54.37; H, 4.73; N, 11.32.
[1224] Found: C, 54.48; H, 5.03; N, 11.13.
[1225] Example 63
[1226] 3- [2-((±) -cis-7-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1227] Example 63A
[1228] (±) -cis-7-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1229] Performed from 7-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in a similar manner as described in Examples 1A-C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.92 (br s, 1H), 2.60 (m, 1H), 2.81 (m, 2H), 3.17 (q, 1H), 3.29 (dd, 1H), 3.40 ( dd, 1H), 3.77 (s, 3H), 3.78 (t, 1H), 4.10 (dd, 1H), 6.43 (d, 1H), 6.52 (dd, 1H), 7.03 (d, 1H).
[1230] Example 63B
[1231] 3- [2-((±) -cis-7-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1232] Product from Example 63A (0.41 g, 2.00 mmol), see Eur. J. Med. Chem., 28: 499-504 (1993)]-N- (2-chloroethyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (0.654 g, 2.00 mmol), and ethyldiisopropylamine (0.44 ml, 2.5 mmol) are dissolved in DMSO (3 ml) and the reaction is heated to 100 ° C. for 3 hours. Cool the reaction to room temperature and add 10 ml of water. The product is collected by filtration, recrystallized from 50% aqueous DMF and the resulting product is treated with excess anhydrous HCl in ethanol. After addition of anhydrous ether, the title compound is collected to give 0.337 g: melting point 204-7 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.75-2.9 (m, 1H), 2.9-3.2 (m, 2H), 3.4-3.7 (m, 3H), 3.71 (s, 3H), 3.85- 4.4 (m, 6H), 6.44 (dd, J = 1, 6.57, m Hz, 1H), 7.10 (d, 1H), 7.56 (m, 1H), 7.64 (m, 1H), 8.12 (b, 1H) , 8.41 (d, 1 H), 12.68 (br s, 1 H); MS (DCI / NH 3) m / e 450 (M + H) ⁺ ;
[1233] Elemental Analysis for C ₂₄ H ₂₄ ClN ₃ O ₄ S:
[1234] Calc .: C, 59.32; H, 4.98; N, 8.65.
[1235] Found: C, 59.06; H, 5.06; N, 8.45.
[1236] Example 64
[1237] 3- [3-((±) -cis-7-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1238] Product from Example 63A (0.41 g, 2.00 mmol), see Eur. J. Med. Chem., 28: 499-504 (1993)], N- (3-chloropropyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (0.750 g, 2.20 mmol) was treated as described in Example 63 to yield 0.296 g of the title compound: melting point 220-2 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.95-2.15 (m, 2H), 2.7-3.0 (m, 3H), 3.1-3.7 (m, 4H), 3.70 (s, 3H), 3.86 ( m, 1H), 3.91-4.17 (m, 4H), 6.42 (d, 1H), 6.55 (dd, J = 1, 7.56, t Hz, 1H), 7.64 (t, 1H), 8.11 (d, 1H) , 8.41 (d, 1 H), 12.59 (br s, 1 H); MS (DCI / NH 3) m / e 464 (M + H) ⁺ ;
[1239] Elemental Analysis for C ₂₄ H ₂₆ ClN ₃ O ₄ S · 1 / 2H2O:
[1240] Calc .: C, 58.99; H, 5. 34; N, 8.25.
[1241] Found: C, 59.10; H, 5. 25; N, 8.09.
[1242] Example 65
[1243] 3- [2-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1244] Example 65A
[1245] (±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1246] Performed from 5-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in a similar manner as described in Examples 1A-C; ¹ H NMR (300 MHz, CDCl ₃ ) δ2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd , 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H).
[1247] Example 65B
[1248] 3- [3-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1249] Product from Example 65A (515 mg, 2.5 mmol), see Eur. J. Med. Chem., 28: 499-504 (1993)]-N- (2-chloroethyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (915 mg, 2.8 mmol), and ethyldiisopropylamine (1.0 ml) were treated as described in Example 63B to yield 0.200 g (18%) of the title compound: melting point 224-228 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 2.40-2.53 (m, 2H), 2.56-2.68 (m, 1H), 2.81-3.01 (m, 2H), 3.30 (dd, J = 7 , 9 Hz, 1H), 3.43 (q, J = 8 Hz, 1H), 3.58 (t, J = 9 Hz, 1H), 3.72 (s, 3H), 3.77 (dd, J = 9, 11 Hz, 1H ), 4.02 (dd, J = 5, 11 Hz, 1H), 4.35 (t, J = 7 Hz, 2H), 6.39 (d, J = 8 Hz, 1H), 6.49 (d, J = 8Hz, 1H) , 7.04 (t, J = 8Hz, 1H), 7.40 (t, J = 8Hz, 1H), 7.54 (t, J = 8Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.24 (d, J = 8 Hz, 1H); (M + H) ⁺ in MS (CI (NH ₃ )) m / e 450;
[1250] Elemental Analysis for C ₂₄ H ₂₃ N ₃ O ₄ SHCl · (H ₂ O) 0.5:
[1251] Calc .: C, 58.24; H, 5.09; N, 8.49.
[1252] Found: C, 57.90; H, 4.76; N, 8.24.
[1253] Example 66
[1254] 3- [3-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1255] Product from Example 65A (500 mg, 2.4 mmol), see Eur. J. Med. Chem., 28: 499-504 (1993)], N- (3-chloropropyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (1.7 g, 5.0 mmol), and ethyldiisopropylamine (1.0 ml) were treated as described in Example 63B to yield 300 mg (27%) of the title compound: melting point 197-199 ° C .; ¹ H NMR (300 MHz, CD ₃ OD) δ2.08-2.20 (m, 2H), 2.87-3.01 (m, 1H), 3.14-3.45 (m, 3H), 3.69 (q, J = 8 Hz, 1H ), 3.77-3.87 (m, 1H), 3.85 (s, 3H), 3.92 (dd, J = 7, 12 Hz, 1H), 4.02-4.20 (m, 5H), 6.51 (dd, J = 1, 8 Hz, 1H), 6.58 (dd, J = 1, 8 Hz, 1H), 7.11 (t, J = 8 Hz, 1H), 7.54 (t, J = 8 Hz, 1H), 7.60-7.67 (m, 1H ), 7.99 (d, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1H); (M + H) ⁺ in MS (CI (NH ₃ )) m / e 464;
[1256] Elemental Analysis for C ₂₅ H ₂₅ N ₃ O ₄ SHClCH ₃ OH:
[1257] Calc .: C, 58.69; H, 5.68; N, 7.90.
[1258] Found: C, 58.43; H, 5. 23; N, 7.93.
[1259] Example 67
[1260] 3- [2-((±) -cis-6-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1261] Example 67A
[1262] (±) -cis-6-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1263] Performed from 8-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in a similar manner as described in Examples 1A-C;
[1264] Example 67B
[1265] 3- [2-((±) -cis-6-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1266] Product (600 mg, 2.9 mmol) from Example 67A, Eur. J. Med. Chem., 28: 499-504 (1993)]-N- (2-chloroethyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (1.2 g, 3.7 mmol), and ethyldiisopropylamine (1.5 ml) were treated as described in Example 63B to yield 320 mg (24%) of the title compound: melting point 251-254 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 2.43-2.52 (m, 2H), 2.67-2.79 (m, 1H), 2.90 (t, J = 7 Hz, 2H), 3.32-3.45 ( m, 2H), 3.51 (t, J = 8 Hz, 1H), 3.82 (dd, J = 8, 11 Hz, 1H), 3.85 (s, 3H), 4.13 (dd, J = 5, 9 Hz, 1H ), 4.34 (t, J = 7 Hz, 2H), 6.65-6.72 (m, 2H), 6.81 (t, J = 8 Hz, 1H), 7.39 (t, J = 8 Hz, 1H), 7.55 (t , J = 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.24 (d, J = 8 Hz, 1H); (M + H) ⁺ in MS (CI (NH ₃ )) m / e 450;
[1267] Elemental Analysis for C ₂₄ H ₂₃ N ₃ O ₄ SHCl:
[1268] Calc .: C, 59.32; H, 4.98; N, 8.65.
[1269] Found: C, 59.18, H, 5.06; N, 8.54.
[1270] Example 68
[1271] 3- [3-((±) -cis-6-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1272] Product from Example 67A (500 mg, 2.4 mmol), see Eur. J. Med. Chem., 28: 499-504 (1993)], N- (3-chloropropyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (1.7 g, 5.0 mmol), and ethyldiisopropylamine (1.5 ml) were treated as described in Example 63B to yield 610 mg (54%) of the title compound: melting point 191-195 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.95-2.07 (m, 2H), 2.20-2.34 (m, 2H), 2.57-2.74 (m, 3H), 3.21 (dd, J = 8 , 9 Hz, 1H), 3.28-3.40 (m, 2H), 3.76 (dd, J = 8, 11 Hz, 1H), 3.83 (s, 3H), 4.10 (dd, J = 5, 11 Hz, 1H) , 4.27 (t, J = 7 Hz, 2H), 6.61-6.70 (m, 2H), 6.80 (t, J = 8 Hz, 1H), 7.47 (dd, J = 1, 8 Hz, 1H), 7.56 ( dd, J = 1, 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.26 (d, J = 8 Hz, 1H); (M + H) ⁺ in MS (CI (NH ₃ )) m / e 464;
[1273] Elemental Analysis for C ₂₄ H ₂₅ N ₃ O ₄ SHCl (H ₂ O) 0.25:
[1274] Calc .: C, 59.52; H, 5. 29; N, 8.33.
[1275] Found: C, 59.17; H, 5. 22; N, 8.24.
[1276] Example 69
[1277] 3- [2-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) ethyl]- [1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1278] Example 69A
[1279] (±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1280] It is performed from coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in a similar manner as described in Examples 1A-C.
[1281] Example 69B
[1282] 3- [2-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) ethyl]- [1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1283] Product (540 mg, 2.8 mmol) from Example 69A, Eur. J. Med. Chem., 28: 499-504 (1993)]-N- (2-chloroethyl) -N '-[3-[(2-methoxycarbonyl) benzothienyl]]-urea (0.89 g, 3.6 mmol), and ethyldiisopropylamine (1.5 ml) were treated as described in Example 63B to yield 410 mg (35%) of the title compound: melting point 256-257 ° C .; ¹ H NMR (300 MHz, CD ₃ OD) δ 3.00-3.13 (m, 1H), 3.23-3.70 (m, 3H), 3.58 (t, J = 6 Hz, 1H), 3.72-3.80 (m, 1H ), 3.87-4.20 (m, 2H), 4.03 (dd, J = 6, 12 Hz, 1H), 4.15 (dd, J = 4, 12 Hz, 1H), 4.41 (t, J = 6 Hz, 2H) , 6.89 (dd, J = 1, 8 Hz, 1H), 6.96-7.02 (m, 1H), 7.18 (dt, J = 2, 8 Hz, 1H), 7.25 (dd, J = 1, 8 Hz, 1H ), 7.51-7.58 (m, 1H), 7.60-7.67 (m, 1H), 7.99 (d, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1H); (M + H) ⁺ in MS (CI (NH ₃ )) m / e 420;
[1284] Elemental Analysis for C ₂₃ H ₂₁ N ₃ O ₃ S · HCl:
[1285] Calc .: C, 60.59; H, 4.86; N, 9.22.
[1286] Found: C, 60.38; H, 4.83; N, 9.14.
[1287] Example 70
[1288] 3- [4-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- Pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1289] Example 70A
[1290] (±) -cis-2- (4-aminobutyl) -1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1291] The product from Example 69A (1.0 g, 5.71 mmol) was treated as described in Examples 1D and 1E to give 1.1 g (98%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ1.4-1.8 (m, 6H), 2.20 (dd, 1H), 2.27 (t, 1H), 2.45 (m, 2H), 2.68-2.80 (m, 3H) , 3.19 (dd, 1H), 3.37 (m, 2H), 3.75 (dd, 1H), 4.07 (dd, 1H), 6.9 (m, 2H), 7.12 (m, 1H).
[1292] Example 70B
[1293] 3- [4-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- Pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1294] The product from Example 70A (0.24 g, 1 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.30 g, 1.2 mmol) were treated as described in Example 1F. 0.20 g (44%) of the title compound is obtained: Melting point 203-205 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.78 (d, 1H), 8.28 (d, 1H), 8.48 (bs, 1H), 7.52 (dd, 1H), 7.13 (m, 2H) , 6.92 (m, 2H), 4.08 (m, 4H), 3.92 (m, 1H), 3.82 (m, 1H), 3.68 (q, 1H), 2.98 (m, 3H), 2.73 (m, 2H), 1.78 (m, 4 H); MS (DCI / NH ₃ ) m / e 449 (M + H) ⁺ ;
[1295] Elemental Analysis for C ₂₄ H ₂₄ N ₄ O ₃ S · 2HCl · H ₂ O:
[1296] Calc .: C, 53.43; H, 5. 23; N, 10.39.
[1297] Found: C, 53.24; H, 4.83; N, 10.25.
[1298] Example 71
[1299] 3- [4-((±) -trans-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- Pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1300] Example 71A
[1301] (±) -trans-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1302] In a similar manner as described in Examples 3A-C, ethyl 2-methoxymethyl-cinnamate and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine are treated.
[1303] Example 71B
[1304] (±) -trans-2- (4-aminobutyl) -1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1305] The product from Example 71A (1.22 g, 6.97 mmol) was treated as described in Examples 1D and 1E to yield 0.58 g (34%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ1.45-1.8 (m, 6H), 2.29 (m, 1H), 2.60-2.83 (m, 6H), 2.95 (m, 2H), 3.39 (dd, 1H) , 4.12 (dd, 1H), 4.50 (dd, 1H), 6.83 (m, 2H), 6.91 (m, 1H), 7.13 (m, 1H).
[1306] Example 71C
[1307] 3- [4-((±) -trans-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- Pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1308] The product from Example 71B (0.24 g, 1 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.35 g, 1.35 mmol) were treated as described in Example 1F. 0.18 g (38%) of the title compound are obtained: melting point> 205 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.78 (d, 1H), 8.3 (bs, 1H), 8.29 (d, 1H), 7.53 (dd, 1H), 7.18 (t, 1H) , 6.88 (m, 3H), 4.55 (dd, 1H), 4.12 (m, 3H), 4.05 (m, 1H), 3.51 (m, 1H), 3.23 (m, 4H), 3.08 (m, 1H), 2.48 (m, 1 H), 1.85 (m, 4 H); MS (DCI / NH ₃ ) m / e 452 (M + H) ⁺ ;
[1309] Elemental Analysis for C ₂₄ H ₂₄ N ₄ O ₃ SHCl0.5H ₂ O:
[1310] Calc .: C, 58.35; H, 5. 30; N, 11.34.
[1311] Found: C, 58.43; H, 4.97, N, 11.34.
[1312] Example 72
[1313] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1314] Example 72A
[1315] (±) -trans-2-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1316] In a manner similar to that described in Examples 3A-C, ethyl 2-methoxy-6-methoxymethyl-cinnamate and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine are treated. ¹ H NMR (300 MHz, CDCl ₃ ) δ2.07 (br s, 1H), 2.24 (m, 1H), 2.70 (m, 2H), 2.84 (t, 1H), 3.21 (dd, 1H), 3.77 ( s, 3H), 3.83 (dd, 1H), 4.07 (dd, 1H), 4.53 (dd, 1H), 6.40 (d, 1H), 6.51 (d, 1H), 7.06 (t, 1H).
[1317] Example 72B
[1318] (±) -trans-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1319] The product from Example 72A (1.2 g, 4.75 mmol) was treated as described in Examples 3D and 3E to yield 1.0 g (64%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40-1.80 (m, 4H), 2.32 (m, 1H), 2.57 (t, 1H), 2.62-2.90 (m, 4H), 2.95 (t, 1H) , 3.60 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H), 4.45 (dd, 1H), 6.40 (d, 1H), 6.49 (d, 1H), 7.04 (t, 1H).
[1320] Example 72C
[1321] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1322] The product from Example 72B (0.28 g, 1.0 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.27 g, 1.15 mmol) were treated as described in Example 1F. To give 0.22 g (46%) of the title compound: melting point> 250 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ (free base)) δ1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2.04-2.18 (m, 1H), 2.25-2.89 (m , 4H), 3.10-3.48 (m, 3H), 3.68 (s, 3H), 3.95 (t, J = 7 Hz, 2H), 4.02 (dd, J = 10, 12 Hz, 1H), 4.39 (dd, J = 4, 10 Hz, 1H), 6.39 (dd, J = 1, 8 Hz, 1H), 6.44 (dd, J = 1, 8 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 7.64 (dd, J = 5, 8 Hz, 1H), 8.63 (dd, J = 1, 8 Hz, 1H), 8.83 (dd, J = 1, 5 Hz, 1H); MS (DCI (NH ₃ )) m / e 479 (M + H) ⁺ ;
[1323] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 2HCl · 0.5H ₂ O:
[1324] Calc .: C, 53.57; H, 5. 21; N, 10.00.
[1325] Found: C, 53.49; H, 5. 35; N, 9.88.
[1326] Example 73
[1327] 3- [4-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1328] Example 73A
[1329] (±) -cis-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1330] In a manner similar to that described in Examples 1A-C, 5-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine are treated. ¹ H NMR (300 MHz, CDCl ₃ ) δ2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd , 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H).
[1331] Example 73B
[1332] (±) -cis-2- (4-aminobutyl) -9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1333] The product from Example 73A (0.2 g, 1.0 mmol) was treated as described in Examples 1D and 1E to afford 0.08 g (29%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-1.80 (m, 4H), 2.19 (m, 1H), 2.25 (dd, 1H), 2.42 (m, 1H), 2.52 (t, 2H), 3.14 (dd, 1H), 3.18-3.30 (m, 2H), 3.79 (dd, 1H), 3.80 (s, 3H), 4.04 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1 H).
[1334] Example 73C
[1335] 3- [4-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1336] The product from Example 73B (0.28 g, 1.0 mmol) and methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.27 g, 1.15 mmol) were treated as described in Example 1F. To give 0.20 g (42%) of the title compound: melting point 198-200 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.56-1.99 (m, 2H), 1.71-1.83 (m, 2H), 2.26 (t, J = 9 Hz, 1H), 2.34 (dd, J = 6, 10 Hz, 1H), 2.50-2.70 (m, 3H), 3.26 (dd, J = 7, 10 Hz, 1H), 3.43 (q, J = 8 Hz, 1H), 3.63 (t, J = 8 Hz, 1H), 3.79 (s, 3H), 3.76-3.86 (m, 1H), 4.01 (dd, J = 4, 11Hz, 1H), 4.11 (t, J = 7Hz, 1H), 6.43 (d , J = 8Hz, 1H), 6.49 (d, J = 8Hz, 1H), 7.04 (t, J = 8Hz, 1H), 7.49 (dd, J = 4, 8Hz, 1H), 8.23 (dd, J = 1 , 8 Hz, 1H), 8.78 (dd, J = 1, 4 Hz, 1H); MS (DCI / NH ₃ ) m / e 479 (M + H) ⁺ ;
[1337] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 2HCl · 0.5H ₂ O:
[1338] Calc .: C, 53.57; H, 5. 21; N, 10.00.
[1339] Found: C, 53.41; H, 5. 24; N, 9.88.
[1340] Example 74
[1341] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1342] See Schneller and Clough, J. Het. Chem., 12: 513 (1975)] ethyl 7-amino-thieno [2,3-b] pyrazine-6-carboxylate (0.25 g, 1.0 mmol) and the product from Example 72B (0.28 g, 1.0 mmol) was treated as described in Example 1F to give 0.18 g (38%) of the title compound: melting point 193-195 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ (free base)) δ 8.98 (d, 1H), 8.89 (d, 1H), 7.11 (t, 1H), 6.52 (d, 1H), 6.45 (d, 1H) , 4.5 (dd, 1H), 4.2 (m, 1H), 4.1 (m, 1H), 3.92 (m, 2H), 3.73 (s, 3H), 3.0 (m, 1H), 2.6 (m, 5H), 2.3 (m, 1 H), 1.8 (m, 4 H); MS (DCI / NH ₃ ) m / e 4809 (M + H) ⁺ ;
[1343] Elemental Analysis for C ₂₄ H ₂₅ N ₅ SO _4.2 HCl.2H ₂ O:
[1344] Calc .: C, 48.98; H, 5.31; N, 11.90.
[1345] Found: C, 48.48; H, 5.80; N, 11.94.
[1346] Example 75
[1347] 3- [4-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1348] Example 75A
[1349] (±) -cis-2-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1350] In a similar manner as described in Examples 1A-C, 6-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine are treated.
[1351] Example 75B
[1352] (±) -cis-2- (4-aminobutyl) -8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1353] The product from Example 75A (1.0 g, 4.9 mmol) was treated as described in Examples 1D and 1E to yield 0.72 g (54%) of the title compound.
[1354] Example 75C
[1355] 3- [4-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1356] Methyl 3-amino-thieno [2,3-b] pyridine-2-carboxylate (0.25 g, 1.07 mmol) and the product from Example 75B (0.26 g, 1.0 mmol) were treated as described in Example 1F. 0.20 g (46%) of the title compound was obtained: Melting point 203-204 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.72 (dd, 1H), 8.6 (d, 1H), 8.38 (bs, 1H), 7.41 (dd, 1H), 6.82 (d, 1H), 6.71 (dd, 1H), 6.6 (d, 1H), 4.12 (m, 4H), 3.98 (m, 2H), 3.78 (m, 1H), 3.73 (s, 3H), 3.12 (m, 2H), 3.05 ( m, 1H), 2.92 (m, 1H), 2.85 (m, 1H), 1.82 (m, 4H); MS (DCI / NH ₃ ) m / e 479 (M + H) ⁺ ;
[1357] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 2HCl · 0.5H ₂ O:
[1358] Calc .: C, 53.57; H, 5. 22; N, 10.00.
[1359] Found: C, 53.81; H, 5.06; N, 9.91.
[1360] Example 76
[1361] 3- [4-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1362] See Schneller and Clough, J. Het. Chem., 12: 513 (1975)], ethyl 7-amino-thieno [2,3-b] pyrazine-6-carboxylate (0.25 g, 1.05 mmol) and the product from Example 75B. (0.28 g, 1.0 mmol) was treated as described in Example 1F to yield 0.30 g (62%) of the title compound: melting point 218-220 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.72 (m, 2H), 6.8 (d, 1H), 6.68 (dd, 1H), 6.61 (d, 1H), 4.12 (t, 2H), 4.0 (dd, 1H), 3.82 (m, 1H), 3.75 (s, 3H), 3.58 (m, 3H), 2.89 (m, 1H), 2.79 (m, 2H), 2.52 (m, 2H), 1.75 ( m, 4H); MS (DCI / NH ₃ ) m / e 480 (M + H) ⁺ ;
[1363] Elemental Analysis for C ₂₄ H ₂₅ N ₅ O ₄ S · HCl · 2H ₂ O:
[1364] Calc .: C, 52.22; H, 5. 48; N, 12.69.
[1365] Found: C, 52.68; H, 5. 22; N, 12.63.
[1366] Example 77
[1367] 3- [3-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1368] Example 77A
[1369] (±) -cis-2- (3-aminopropyl) -8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1370] The product from Example 75A (1.26 g, 6.14 mmol) was treated with 0.61 ml (7.36 mmol) of 3-bromopropionitrile followed by LiAlH ₄ and AlCl ₃ in a manner similar to that described in Examples 1D and 1E. Treatment yields 0.85 g (52%) of the title compound.
[1371] Example 77B
[1372] 3- [3-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) propyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1373] Methyl 3-amino-thieno [2,3-b] pyridine-2-carboxylate (0.25 g, 1.07 mmol) and the product from Example 77A (0.26 g, 1.0 mmol) were treated as described in Example 1F. To give 0.23 g (50%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.64 (dd, 1H), 8.43 (dd, 1H), 8.45 (s, 1H), 7.32 ( dd, 1H), 6.82 (d, 1H), 6.7 (dd, 1H), 6.61 (d, 1H), 4.2 (m, 1H), 4.13 (t, 2H), 3.98 (m, 3H), 3.73 (m , 1H), 3.72 (s, 3H), 3.22 (m, 2H), 3.0 (m, 1H), 2.95 (d, 1H), 2.85 (m, 1H), 2.48 (m, 2H); MS (DCI / NH ₃ ) m / e 465 (M + H) ⁺ ;
[1374] Elemental Analysis for C ₂₄ H ₂₄ N ₄ O ₄ SHClH ₂ O:
[1375] Calc .: C, 55.54; H, 5. 24; N, 10.79.
[1376] Found: C, 55.18; H, 4.98; N, 10.63.
[1377] Example 78
[1378] 3- [2-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Il) ethyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1379] Example 78A
[1380] (±) -cis-2- (2-aminoethyl) -8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1381] The product from Example 75A (1.0 g, 4.88 mmol) was treated with 0.34 ml (5.36 mmol) of 2-chloroacetonitrile and then treated with LiAlH ₄ and AlCl ₃ in a manner similar to that described in Examples 1D and 1E. 0.72 g (59%) of the title compound are obtained; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.1 (br s, 2H), 2.25-2.45 (m, 2H), 2.52-2.65 (m, 2H), 2.72 (m, 1H), 2.83 (t, 2H), 3.17 (dd, 1H), 3.28-3.45 (m, 2H), 3.75 (dd, 1H), 3.77 (s, 3H), 4.01 (dd, 1H), 6.63 (d, 1H), 6.68 (dd, 1H) , 6.81 (d, 1 H).
[1382] Example 78B
[1383] 3- [2-((±) -cis-8-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Il) ethyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1384] Methyl 3-amino-thieno [2,3-b] pyridine-2-carboxylate (0.25 g, 1.07 mmol) and the product from Example 78A (0.25 g, 1.0 mmol) were treated as described in Example 1F. 0.20 g (44%) of the title compound was obtained: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.7 (dd, 1H), 8.48 (dd, 1H), 8.3 (bs, 1H), 7.32 ( dd, 1H), 6.81 (d, 1H), 6.7 (dd, 1H), 6.65 (d, 1H), 4.5-4.7 (m, 3H), 4.0 (m, 3H), 3.76 (s, 3H), 3.4 (m, 2H), 3.1 (m, 2H), 2.9 (m, 2H); MS (DCI / NH ₃ ) m / e 451 (M + H) ⁺ ;
[1385] Elemental Analysis for C ₂₃ H ₂₂ N ₄ O ₄ S · HCl · 0.5H ₂ O:
[1386] Calc .: C, 55.70; H, 4.88; N, 11.30.
[1387] Found: C, 55.61; H, 4. 66; N, 11.19.
[1388] Example 79
[1389] 3- [4-((±) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1390] Methyl 2-amino-4,5-dimethoxybenzoate (0.28 g, 1.18 mmol) and the product from Example 73A (0.28 g, 1.0 mmol) were treated as described in Example 1F to obtain an intermediate urea, This was treated with 1.5 ml of 1.0 M KOtBu in 20 ml THF to give 0.19 g (40%) of the title compound: melting point 178-180 ° C. (decomposition); ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 7.44 (s, 1H), 7.06 (t, 1H), 6.48 (m, 2H), 6.42 (s, 1H), 4.06 (m, 3H), 4.0 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.83 (m, 1H), 3.8 (s, 3H), 3.48 (m, 1H), 3.2 (m, 1H), 2.58 ( m, 3H), 2.3 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H); MS (DCI / NH ₃ ) m / e 482 (M + H) ⁺ ;
[1391] Elemental Analysis for _{C 26 H 31 N 3 O 6} · HCl · 2H 2 O:
[1392] Calc .: C, 56.37; H, 6.55; N, 7.58.
[1393] Found: C, 56.61; H, 6. 30; N, 7.47.
[1394] Example 80
[1395] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1396] Methyl 2-amino-4,5-dimethoxybenzoate (0.27 g, 1.15 mmol) and the product from Example 71B (0.25 g, 1.0 mmol) were treated as described in Example 1F to obtain an intermediate urea, This was treated with 1.5 ml of 1.0 M KOtBu in 20 ml THF to give 0.12 g (26%) of the title compound: melting point 182-184 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 7.41 (s, 1H), 7.18 (m, 1H), 6.88 (s, 1H), 6.86 (m, 2H), 6.71 (s, 1H), 4.55 (dd, 1H), 4.18 (t, 1H), 4.08 (t, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.9 (m, 1H), 3.48 (m, 1H), 3.22 ( m, 4H), 3.08 (m, 1 H), 2.5 (m, 1 H), 1.82 (m, 4 H); MS (DCI / NH ₃ ) m / e 452 (M + H) ⁺ ;
[1397] Elemental Analysis for _{C 25 H 29 N 3 O 5} · HCl · H 2 O:
[1398] Calc .: C, 59.34; H, 6. 37; N, 8.32.
[1399] Found: C, 59.12; H, 6. 21; N, 7.82.
[1400] Example 81
[1401] 3- [4-((±) -cis-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrol-2-yl) butyl]- 6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1402] Methyl 2-amino-4,5-dimethoxybenzoate (0.27 g, 1.15 mmol) and the product from Example 70A (0.25 g, 1.0 mmol) were treated as described in Example 1F to obtain an intermediate urea, This was treated with 1.5 ml of 1.0 M KOtBu in 20 ml THF to give 0.18 g (39%) of the title compound: ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.3 (bs, 1H), 7.46 (s, 1H ), 7.08 (m, 2H), 6.88 (m, 2H), 6.39 (s, 1H), 4.08 (m, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.72 (m, 1H) , 3.38 (m, 2H), 3.21 (m, 1H), 2.72 (m, 1H), 2.52 (m, 2H), 2.28 (m, 2H), 1.75 (m, 2H), 1.62 (m, 2H); MS (DCI / NH ₃ ) m / e 452 (M + H) ⁺ ;
[1403] Elemental Analysis for C ₂₅ H ₂₉ N ₃ O ₅ HCl2H ₂ O:
[1404] Calc .: C, 57.19; H, 6.1; N, 8.00.
[1405] Found: C, 56.63; H, 6.08; N, 7.51.
[1406] Example 82
[1407] 3- [4-((±) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2- Yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione dihydrochloride
[1408] Methyl 2-amino-4,5-dimethoxybenzoate (0.28 g, 1.18 mmol) and the product from Example 72A (0.28 g, 1.0 mmol) were treated as described in Example 1F to obtain an intermediate urea, This was treated with 1.5 ml of 1.0 M KOtBu in 20 ml THF to give 0.38 g (79%) of the title compound: melting point 189-191 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 7.44 (s, 1H), 7.05 (t, 1H), 6.49 (d, 1H), 6.41 (s, 1H), 6.39 (d, 1H), 4.44 (dd, 1H), 4.1 (m, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.76 (s, 3H), 3.6 (m, 1H), 2.99 (t, 1H), 2.78 ( m, 4H), 2.58 (t, 1H), 2.3 (m, 1H), 1.75 (m, 2H), 1.65 (m, 2H); MS (DCI / NH ₃ ) m / e 482 (M + H) ⁺ ;
[1409] Elemental Analysis for C ₂₆ H ₃₁ N ₃ O ₆ · 2HCl · 2H ₂ O:
[1410] Calc .: C, 52.89; H, 6. 32; N, 7.12.
[1411] Found: C, 52.89; H, 5.99; N, 7.02.
[1412] Example 83
[1413] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1414] Example 83A
[1415] (±) -trans-N-benzyl-3-carboethoxy-4- (2-methoxy-6-methoxymethyl) phenyl-piperidine-2,5-dione
[1416] Ethyl 2-methoxy-6-methoxymethyl-cinnamate (13.2 g, 59.7 mmol) was converted into ethyl N-benzylamidomalonate according to the method of US Pat. No. 4,902,801 to Faruk and Martin. Treatment yields 8.34 g (39%) of the title compound: ¹ H NMR (300 MHz, DMSO) δ 7.47-7.24 (m, 5H), 7.19 (dd, 1H), 6.71 (d, 1H), 6.68 (d, 1H), 5.19 (dd, 2H), 4.88 (s, 2H), 4.70 (d, 2H), 4.25 (dt, 1H), 3.90 (dq, 2H), 3.78 (s, 3H), 3.41 (dd, 1H ), 3.40 (s, 3 H), 2.63 (dd, 1 H), 0.87 (t, 3 H). MS (DCI / NH ₃ ) m / e 442 (M + H) ⁺ .
[1417] Example 83B
[1418] (±) -trans-N-benzyl-3-chloromethyl-4- (2-hydroxy-6-methoxy) phenyl-piperidine
[1419] To a solution of LiAlH ₄ (2.45 g, 64.6 mmol) in THF (250 ml) was added dropwise a solution of Example 83A (9.50 g, 21.5 mmol) in THF (50 ml) at 0 ° C. The reaction is allowed to warm to room temperature and then refluxed for 3 hours. The reaction is cooled to 0 ° C. and quenched by successively adding water (4 ml), 1M NaOH (4 ml), and water (10 ml) and stirred for 1 hour. The mixture is filtered through a pad of celite and washed with EtOAc (500 ml). The organic layer is dried over MgSO ₄ and condensed in vacuo to afford 8.0 g of clean oil. This oil is taken up in methanol (250 ml) and concentrated HCl (15 ml) and stirred at reflux for 6 hours. The mixture is cooled, condensed in vacuo, and the residue is partitioned between a saturated solution of EtOAc and NaHCO ₃ . The layers are separated and the aqueous layer is extracted with 2 x EtOAc. The combined organic layers are dried over MgSO ₄ and condensed in vacuo to give 7.0 g of a clean oil. To a solution of the oil in CCl ₄ (75 ml) and CH ₃ CN (75 ml) was added triphenylphosphine (11.3 g, 43.1 mmol) and the solution was refluxed for 1 hour. The mixture is cooled and condensed in vacuo and the residue is chromatographed on SiO ₂ with NH ₃ -saturated 35% EtOAc / hexanes to give the title compound (5.30 g, 71%); ¹ H NMR (300MHz, DMSO) δ 9.32 (br s, 1H), 7.35-7.22 (m, 5H), 6.96 (dd, 1H), 6.44 (br d, 2H), 3.72 (s, 3H), 3.51 ( dd, 2H), 3.26 (m, 1H), 3.16 (m, 2H), 2.98 (dt, 1H), 2.85 (m, 2H), 2.24 (m, 1H), 1.93 (m, 1H), 1.78 (m , 1H), 1.39 (m, 1H). MS (DCI / NH ₃ ) m / e 346 (M + H) ⁺ .
[1420] Example 83C
[1421] (±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyridine
[1422] To a solution of the product from Example 83B (5.30 g, 15.3 mmol) in THF (125 ml) was added 1.0 M solution (16 ml) of potassium t-butoxide and the reaction was refluxed for 2 hours. The reaction is cooled, poured into water and extracted with 3 × EtOAc. This extract is dried over MgSO ₄ and condensed in vacuo to give 4.7 g of clean oil. To a solution of 10% Pd (2 g) on oil and carbon in MeOH (125 ml) is added ammonium formate (4.7 g, 75 mmol) and the reaction is refluxed for 2 hours. The reaction mixture is cooled down, filtered through a small pad of celite and washed with EtOAc (200 ml). The filtrate is dried over Na ₂ SO ₄ and condensed in vacuo to afford the title compound (3.01 g, 90%); ¹ H NMR (300MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.36 (d, 1H), 4.03 (dd, 1H), 3.72 (s, 3H), 3.55 (dd, 1H) , 3.01 (m, 1H), 2.94 (dd, 1H), 2.83 (ddd, 1H), 2.62 (dt, 1H), 2.51 (dt, 1H), 2.29 (t, 1H), 1.64 (ddt, 1H), 1.05 (ddd, 1 H). MS (DCI / NH ₃ ) m / e 220 (M + H) ⁺ .
[1423] Example 83D
[1424] (±) -trans-3- (2-cyanoethyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4- c] pyridine
[1425] A mixture of product from Example 83C (340 mg, 1.55 mmol), 3-bromopropionitrile (193 μl, 2.33 mmol) and ethyldiisopropylamine (675 μl, 3.88 mmol) in acetonitrile (4 mL) was obtained. Reflux for time. The reaction is cooled and partitioned between EtOAc and 1M NaOH. The organic layer is dried over MgSO ₄ , the solvent is condensed in vacuo and the crude product is chromatographed on SiO ₂ with EtOAc to afford the title compound (0.335 g, 79%). ¹ H NMR (300MHz, DMSO) δ 7.03 (dd, 1H), 6.49 (d, 1H), 6.38 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H) , 3.04-2.86 (m, 3H), 2.65 (m, 4H), 2.41 (m, 1H), 2.16 (m, 1H), 1.81 (m, 2H), 1.18 (m, 1H). MS (DCI / NH ₃ ) m / e 273 (M + H) ⁺ .
[1426] Example 83E
[1427] (±) -trans-3- (3-aminopropyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c ] Pyridine
[1428] The product from Example 83D (355 mg, 1.30 mmol) was treated with 7.5 equivalents of LiAlH ₄ and 2.5 equivalents of AlCl ₃ by the procedure described in Example 1E to afford the title compound (0.347 g, 96%); ¹ H NMR (300MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H) , 2.96 (m, 2H), 2.89 (m, 1H), 2.57 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.01 (dt, 1H), 1.77 (m, 1H), 1.66 (t, 1 H), 1.51 (m, 2 H), 1.17 (m, 1 H). MS (DCI / NH ₃ ) m / e 277 (M + H) ⁺ .
[1429] Example 83F
[1430] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1431] Methyl 2-amino-4,5-dimethoxybenzoate (258 mg, 1.09 mmol) and the product from Example 83E (250 mg, 0.905 mmol) were treated as described in Example 1F to give 347 mg (71%) of the title compound. Obtained: melting point 230 DEG C; ¹ H NMR (300MHz, DMSO) δ 11.35 (s, 1H), 10.61 (br s, 1H), 7.31 (s, 1H), 7.08 (t, 1H), 6.74 (s, 1H), 6.54 (d, 1H ), 6.42 (d, 1H), 4.13 (dd, 1H), 3.98 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H), 3.63 (m, 1H) , 3.58 (m, 2H), 3.10 (m, 4H), 2.84 (m, 1H), 2.76 (m, 1H), 2.24 (m, 1H), 2.19 (m, 2H), 1.57 (m, 1H). MS (DCI / NH ₃ ) m / e 482 (M + H) ⁺ .
[1432] Elemental Analysis for C ₂₆ H ₃₁ N ₃ O ₆ · 1.6HCl:
[1433] Calc .: C, 57.85; H, 6.09; N, 7.78.
[1434] Found: C, 57.73; H, 5.99; N, 7.57.
[1435] Example 84
[1436] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1437] Methyl 3-amino-thieno [2,3-b] pyridine-2-carboxylate (254 mg, 1.09 mmol) and the product from Example 83E (250 mg, 0.904 mmol) were treated as described in Example 1F to give the title 281 mg (59%) of compound are obtained: melting point> 300 ° C .; ¹ H NMR (300MHz, DMSO) δ 12.80 (s, 1H), 10.44 (br s, 1H), 8.83 (d, 1H), 8.78 (d, 1H), 7.67 (dd, 1H), 7.09 (t, 1H ), 6.53 (d, 1H), 6.42 (d, 1H), 4.14 (dd, 1H), 4.03 (m, 2H), 3.76 (s, 3H), 3.64 (m, 1H), 3.59 (m, 2H) , 3.24-3.02 (m, 4H), 2.85 (m, 1H), 2.76 (m, 1H), 2.22 (m, 1H), 2.13 (m, 2H), 1.53 (m, 1H). MS (DCI / NH ₃ ) m / e 479 (M + H) ⁺ .
[1438] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 1.35HCl:
[1439] Calc .: C, 56.89; H, 5. 22; N, 10.62.
[1440] Found: C, 57.03; H, 5.06; N, 10.45.
[1441] Example 85
[1442] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1443] Example 85A
[1444] (±) -trans-3- (3-cyanopropyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4- c] pyridine
[1445] The product from Example 83C (380 mg, 1.73 mmol) was treated with 1.5 equivalents of 4-bromobutyronitrile and 2.5 equivalents of ethyldiisopropylamine by the procedure described in Example 83D to give the title compound (0.38 g, 71%). To obtain. ¹ H NMR (300 MHz, DMSO) δ 7.03 (dd, 1H), 6.49 (d, 1H), 6.38 (d, 1H), 4.09 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H ), 2.93 (m, 3H), 2.39 (m, 2H), 2.08 (m, 1H), 1.74 (m, 3H), 1.30 (m, 1H). MS (DCI / NH ₃ ) m / e 287 (M + H) ⁺ .
[1446] Example 85B
[1447] (±) -trans-3- (4-aminobutyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c ] Pyridine
[1448] The product from Example 85A (380 mg, 1.33 mmol) was treated with 7.5 equivalents of LiAlH ₄ and 2.5 equivalents of AlCl ₃ by the procedure described in Example 83E to afford the title compound (0.358 g, 93%); ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H ), 2.97 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.38 (m, 1H), 2.29 (m, 2H), 2.01 (dt, 1H), 1.78 (m, 1H) , 1.67 (t, 1 H), 1.46 (m, 2 H), 1.34 (m, 2 H), 1.18 (m, 1 H). MS (DCI / NH ₃ ) m / e 291 (M + H) ⁺ .
[1449] Example 85C
[1450] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1451] Methyl 3-amino-thieno [2,3-b] pyridine-2-carboxylate (0.194 g, 1.09 mmol) and the product from Example 85B (0.200 g, 0.69 mmol) were treated as described in Example 1F. To give 0.245 g (59%) of the title compound: melting point 251-4 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.76 (br s, 1H), 8.77 (d, 1H), 8.74 (d, 1H), 7.61 (dd, 1H), 7.04 (t, 1H), 6.50 (d, 1H), 6.38 (d, 1H), 4.12 (dd, 1H), 3.92 (t, 2H), 3.71 (s, 3H), 3.62 (t, 1H), 3.52 (m, 2H ), 3.06 (m, 4H), 2.78 (m, 2H), 2.25 (m, 1H), 1.76 (m, 2H), 1.64 (m, 2H), 1.54 (m, 1H). MS (DCI / NH ₃ ) m / e 493 (M + H) ⁺ .
[1452] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₄ S · 2HCl:
[1453] Calculated: C, 51.88; H, 5. 19; N, 9.31.
[1454] Found: C, 52.24; H, 5.52; N, 9.32.
[1455] Example 86
[1456] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1457] Methyl 2-amino-4,5-dimethoxybenzoate (0.196 g, 0.83 mmol) and the product from Example 85B (0.200 g, 0.69 mmol) were treated as described in Example 1F to give 0.140 g (37) of the title compound. %) Is obtained: melting point 220 ° C .; ¹ H NMR (300 MHz, DMSO) δ 11.27 (s, 1H), 10.54 (br s, 1H), 7.25 (s, 1H), 7.04 (t, 1H), 6.68 (s, 1H), 6.50 (d, 1H), 6.39 (d, 1H), 4.12 (dd, 1H), 3.87 (t, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.62 (t, 1H ), 3.62 (m, 2H), 3.06 (m, 4H), 2.76 (m, 2H), 2.21 (m, 1H), 1.71 (m, 2H), 1.59 (m, 2H), 1.51 (m, 1H) . MS (DCI / NH ₃ ) m / e 496 (M + H) ⁺ .
[1458] Elemental Analysis for C ₂₇ H ₃₃ N ₃ O ₆ · 1.4HCl:
[1459] Calculated: C, 59.37; H, 6. 35; N, 7.69.
[1460] Found: C, 59.36; J, 6.56; N, 7.57.
[1461] Example 87
[1462] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1463] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.143 g, 58 mmol) and the product from Example 85B (0.14 g, 0.48 mmol) were treated as described in Example 1F to give 0.121 g of the title compound. (48%) is obtained: Melting point> 305 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.56 (s, 1H), 10.44 (br s, 1H), 8.37 (d, 1H), 8.07 (d, 1H), 7.60 (t, 1H), 7.52 (t, 1H), 7.04 (t, 1H), 6.50 (d, 1H), 6.38 (d, 1H), 4.12 (dd, 1H), 3.93 (t, 2H), 3.71 (s, 3H), 3.62 (t, 1H ), 3.53 (m, 2H), 3.06 (m, 4H), 2.77 (m, 2H), 2.20 (m, 1H), 1.76 (m, 2H), 1.65 (m, 2H), 1.52 (m, 1H) . MS (DCI / NH ₃ ) m / e 492 (M + H) ⁺ .
[1464] Elemental Analysis for C ₂₇ H ₂₉ N ₃ O ₄ SHCl:
[1465] Calculated: C, 61.41; H, 5.73; N, 7.96.
[1466] Found: C, 61.16; H, 5. 48; N, 7.79.
[1467] Example 88
[1468] 3- [4-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1469] Methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.135 g, 0.58 mmol) and the product from Example 85B (0.14 g, 0.48 mmol) were treated as described in Example 1F. To 0.15 g (54%) of the title compound: melting point> 325 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.65 (br s, 1H), 8.85 (d, 1H), 8.66 (d, 1H), 7.68 (dd, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.58 (m, 2H ), 3.11 (m, 4H), 2.81 (m, 2H), 2.28 (m, 1H), 1.79 (m, 2H), 1.69 (m, 2H), 1.58 (m, 1H). MS (DCI / NH ₃ ) m / e 493 (M + H) ⁺ .
[1470] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₄ S · 2HCl · 0.5H ₂ O:
[1471] Calculated: C, 54.36; H, 5. 44; N, 9.75.
[1472] Found: C, 54.25; H, 5.59; N, 9.68.
[1473] Example 89
[1474] 3- [3-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) propyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1475] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.177 g, 0.72 mmol) and the product from Example 83E (0.165 g, 0.60 mmol) were treated as described in Example 1F to give the title compound 0.187 g (61%) is obtained: melting point> 300 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 10.41 (br s, 1H), 8.43 (d, 1H), 8.13 (d, 1H), 7.66 (t, 1H), 7.57 (t, 1H), 7.08 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.14 (dd, 1H), 4.02 (m, 2H), 3.76 (s, 3H), 3.63 (m, 1H ), 3.59 (m, 2H), 3.22-3.03 (m, 4H), 2.86 (m, 1H), 2.77 (m, 1H), 2.22 (m, 1H), 2.13 (m, 2H), 1.54 (m, 1H). MS (DCI / NH ₃ ) m / e 478 (M + H) ⁺ .
[1476] Elemental Analysis for C ₂₆ H ₂₇ N ₃ O ₄ S · 1.0HCl:
[1477] Calculated: C, 60.75; H, 5.49; N, 8.17.
[1478] Found: C, 60.48; H, 5.50; N, 8.02.
[1479] Example 90
[1480] 3- [2-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1481] Example 90A
[1482] (±) -trans-3- (cyanomethyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyridine
[1483] To a solution of the product from Example 83C (0.80 g, 3.65 mmol) and K ₂ CO ₃ (1.21 g, 8.8 mmol) in acetone (20 ml) and water (2 ml) was added chloroacetonitrile (278 μl, 4.4 mmol) The solution is stirred under reflux for 18 hours. The reaction is cooled and poured into brine, the solution is extracted with 3 x EtOAc and the combined extracts are dried over MgSO ₄ . The solvent is condensed under vacuum and the crude product is chromatographed on SiO ₂ with 30% EtOAc / hexanes to give the title compound (0.55 g, 58%). ¹ H NMR (300 MHz, DMSO) δ 7.04 (dd, 1H), 6.50 (d, 1H), 6.38 (d, 1H), 4.08 (dd, 1H), 3.74 (s, 3H), 3.68 (t, 1H ), 2.91 (m, 2H), 2.39 (ddt, 2H), 2.03 (m, 1H), 1.83 (m, 1H), 1.24 (m, 1H). MS (DCI / NH ₃ ) m / e 259 (M + H) ⁺ .
[1484] Example 90B
[1485] (±) -trans-3- (2-aminoethyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c ] Pyridine
[1486] To a solution of LiAlH ₄ (285 mg, 7.50 mmol) in Et ₂ O (25 ml) was added dropwise a solution of AlCl ₃ (333 mg, 2.50 mmol) in Et ₂ O (10 ml) and the reaction stirred for 10 minutes. A solution of the product from Example 90A (259 mg, 1.00 mmol) in THF (10 ml) was added via syringe and the reaction stirred for 1 hour. The reaction is cooled to &lt; RTI ID = 0.0 &gt; C, &lt; / RTI &gt; The mixture is filtered through a pad of celite and washed with EtOAc (100 ml) and CHCl ₃ (100 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford the title compound (0.225 g, 86%). ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.49 (d, 1H), 6.38 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.61 (t, 1H ), 2.93 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.07 (dt, 1H), 1.79 (m, 1H) , 1.62 (m, 2 H), 1.19 (m, 1 H). MS (DCI / NH ₃ ) m / e 263 (M + H) ⁺ .
[1487] Example 90C
[1488] 3- [2-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) ethyl]-[1] benzthieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride
[1489] Methyl 3-amino-benzo [b] thiophene-2-carboxylate (0.158 g, 0.64 mmol) and the product from Example 90B (0.140 g, 0.53 mmol) were treated as described in Example 1F to give the title compound 0.143. g (54) is obtained: melting point> 305 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.74 (s, 1H), 10.34 (s, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.67 (dd, 1H), 7.58 (dd, 1H ), 7.09 (dd, 1H), 6.55 (d, 1H), 6.43 (d, 1H), 4.34 (m, 2H), 4.15 (dd, 1H), 3.85 (m, 2H), 3.76 (s, 3H) , 3.71 (t, 1H), 3.42 (m, 2H), 3.15 (m, 2H), 2.98 (m, 1H), 2.82 (m, 1H), 2.20 (m, 1H), 1.54 (m, 1H). MS (DCI / NH ₃ ) m / e 464 (M + H) ⁺ .
[1490] Elemental Analysis for C ₂₅ H ₂₅ N ₃ O ₄ SHCl:
[1491] Calculated: C, 60.05; H, 5. 24; N, 8.40.
[1492] Found: C, 59.68; H, 5. 21; N, 8.25.
[1493] Example 91
[1494] 3- [2-((±) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyrido -3-yl) ethyl] -6,7-dimethoxy-quinazolin-2,4 (1H, 3H) -dione hydrochloride
[1495] Methyl 2-amino-4,5-dimethoxybenzoate (0.152 g, 0.64 mmol) and the product from Example 90B (0.140 g, 0.53 mmol) were treated as described in Example 1F to give 0.060 g (22) of the title compound. %) Is obtained: melting point 291-2 ° C .; ¹ H NMR (300 MHz, DMSO) δ 11.44 (s, 1H), 10.09 (s, 1H), 7.30 (s, 1H), 7.09 (dd, 1H), 6.72 (s, 1H), 6.55 (d, 1H ), 6.42 (d, 1H), 4.30 (m, 2H), 4.14 (dd, 1H), 3.85 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H) , 3.71 (t, 1H), 3.42 (m, 2H), 3.15 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.16 (m, 1H), 1.50 (m, 1H). MS (DCI / NH ₃ ) m / e 468 (M + H) ⁺ .
[1496] Elemental Analysis for C ₂₄ H ₂₉ N ₃ O ₆ · 1.25HCl:
[1497] Calculated: C, 58.52; H, 5.94; N, 8.19.
[1498] Found: C, 58.79; H, 6.00; N, 8.01.
[1499] Example 92
[1500] 3- [3-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1501] Example 92A
[1502] (4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyridine-4-methyl carba Mate and (4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyridine-4- Methyl carbamate
[1503] (+)-Methyl chloroformate (3.71 ml, 17.3) in a solution of the product from Example 83C (3.16 g, 14.41 mmol) and ethyldiisopropylamine (5.02 g, 28.8 mmol) in CH ₂ Cl ₂ (200 ml) mmol) is added at 0 ° C. The reaction is warmed to 23 ° C. and stirred for 3 hours. The reaction is poured into 1M NaOH, the layers are separated, the aqueous layer is extracted with 3 x Et ₂ O and the combined organic layers are dried over MgSO ₄ . The solvent is condensed under vacuum and the crude product is chromatographed on SiO ₂ with 10% EtOAc / hexanes to give a mixture of diastereomers (5.30 g, 92%). A 1: 1 mixture of two diastereomers is separated on a preparative chiral HLPC column. ¹ H NMR (300 MHz, DMSO) δ 7.04 (dd, 1H), 6.50 (d, 1H), 6.39 (d, 1H), 4.46 (m, 1H), 4.10 (m, 3H), 3.74 (s, 3H ), 3.61 (t, 1H), 2.94 (m, 2H), 2.63 (m, 2H), 1.89 (m, 2H), 1.83 (m, 1H), 1.62 (m, 3H), 1.41 (m, 1H) , 1.36 (m, 1H), 1.00 (m, 4H), 0.87 (m, 6H), 0.72 (m, 3H). MS (DCI / NH ₃ ) m / e 402 (M + H) ⁺ .
[1504] Example 92B
[1505] (4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyridine
[1506] To a solution of diastereomer (4aS, 10bR) (2.38 g, 5.93 mmol) from slower moving Example 92A in THF (125 ml) was added a solution of 1.6 M n-BuLi (15.0 ml, 24.0 mmol) at 0 ° C. Drop wise and the reaction is stirred for 15 minutes. The reaction is quenched with 1M NaOH, poured into brine and extracted with 3 x EtOAc and 2 x CH ₂ Cl ₂ . The combined extracts are dried over Na ₂ SO ₄ , the solvent is condensed in vacuo and the crude product is chromatographed on SiO ₂ with NH ₃ -saturated 5% MeOH / CH ₂ Cl ₂ to give the title compound (1.07 g, 82 %) Is obtained; ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.36 (d, 1H), 4.03 (dd, 1H), 3.72 (s, 3H), 3.55 (dd, 1H ), 3.01 (m, 1H), 2.94 (dd, 1H), 2.83 (ddd, 1H), 2.62 (dt, 1H), 2.51 (dt, 1H), 2.29 (t, 1H), 1.64 (ddt, 1H) , 1.05 (ddd, 1 H). MS (DCI / NH ₃ ) m / e 220 (M + H) ⁺ .
[1507] Example 92C
[1508] (4aS, 10bR) -trans-3- (3-aminopropyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4 -c] pyridine
[1509] The product from Example 92B was treated as described in Examples 83D and 83E to afford the title compound; ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H ), 2.96 (m, 2H), 2.89 (m, 1H), 2.57 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.01 (dt, 1H), 1.77 (m, 1H) , 1.66 (t, 1 H), 1.51 (m, 2 H), 1.17 (m, 1 H). MS (DCI / NH ₃ ) m / e 277 (M + H) ⁺ .
[1510] Example 92D
[1511] 3- [3-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1512] Methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (107 mg, 0.456 mmol) and the product from Example 92C (105 mg, 0.380 mmol) were treated as described in Example 1F to give the title 135 mg (64%) of compound are obtained: Melting point 235 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.66 (br s, 1H), 8.86 (d, 1H), 8.68 (d, 1H), 7.68 (dd, 1H), 7.09 (t , 1H), 6.53 (d, 1H), 6.41 (d, 1H), 4.14 (dd, 1H), 4.00 (m, 2H), 3.76 (s, 3H), 3.63 (m, 1H), 3.59 (m, 2H), 3.21-3.03 (m, 4H), 2.86 (m, 1H), 2.76 (m, 1H), 2.28 (m, 1H), 2.12 (m, 2H), 1.56 (m, 1H). MS (DCI / NH ₃ ) m / e 479 (M + H) ⁺ .
[1513] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 2.0HCl · 0.5H ₂ O:
[1514] Calculated: C, 53.57; H, 5. 22; N, 10.00.
[1515] Found: C, 53.35; H, 5.05; N, 9.92.
[1516] [α] _D ^{25.0 ° C.} =-79.4 °.
[1517] Example 93
[1518] 3- [3-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1519] Example 93A
[1520] (4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] pyridine
[1521] A solution of 1.6 M n-BuLi (15.0 ml, 24.0 mmol) in THF (125 ml) in a solution of faster moving diastereomers (4aR, 10bS) (2.27 g, 5.74 mmol) from Example 92A was charged at 0 ° C. Drop wise and the reaction is stirred for 15 minutes. The reaction is quenched with 1M NaOH, poured into brine and extracted with 3 x EtOAc and 2 x CH ₂ Cl ₂ . The combined extracts were dried over Na ₂ SO ₄ , the solvent was condensed in vacuo and the crude product was chromatographed on SiO ₂ with NH ₃ -saturated 5% MeOH / CH ₂ Cl ₂ to give the title compound (0.96 g, 80 %) Is obtained; ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.36 (d, 1H), 4.03 (dd, 1H), 3.72 (s, 3H), 3.55 (dd, 1H ), 3.01 (m, 1H), 2.94 (dd, 1H), 2.83 (ddd, 1H), 2.62 (dt, 1H), 2.51 (dt, 1H), 2.29 (t, 1H), 1.64 (ddt, 1H) , 1.05 (ddd, 1 H). MS (DCI / NH ₃ ) m / e 220 (M + H) ⁺ .
[1522] Example 93B
[1523] (4aR, 10bS) -trans-3- (3-aminopropyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4 -c] pyridine
[1524] The product from Example 93A was treated as described in Examples 83D and 83E to afford the title compound; ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H ), 2.96 (m, 2H), 2.89 (m, 1H), 2.57 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.01 (dt, 1H), 1.77 (m, 1H) , 1.66 (t, 1 H), 1.51 (m, 2 H), 1.17 (m, 1 H). MS (DCI / NH ₃ ) m / e 277 (M + H) ⁺ .
[1525] Example 93C
[1526] 3- [3-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1527] Methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.116 g, 0.495 mmol) and the product from Example 93B (0.114 g, 0.413 mmol) were treated as described in Example 1F. This affords 0.091 g (39%) of the title compound: melting point 235 ° C; ¹ H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.66 (br s, 1H), 8.86 (d, 1H), 8.68 (d, 1H), 7.68 (dd, 1H), 7.09 (t, 1H), 6.53 (d, 1H), 6.41 (d, 1H), 4.14 (dd, 1H), 4.00 (m, 2H), 3.76 (s, 3H), 3.63 (m, 1H), 3.59 (m, 2H ), 3.21-3.03 (m, 4H), 2.86 (m, 1H), 2.76 (m, 1H), 2.28 (m, 1H), 2.12 (m, 2H), 1.56 (m, 1H). MS (DCI / NH ₃ ) m / e 479 (M + H) ⁺ .
[1528] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 2.0HCl · H ₂ O:
[1529] Calculated: C, 52.73; H, 5.31; N, 9.84.
[1530] Found: C, 52.59; H, 5.04; N, 9.75.
[1531] [α] _D 25.0 ° C. = + 77.7 °.
[1532] Example 94
[1533] 3- [4-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1534] Example 94A
[1535] (4aR, 10bS) -trans-3- (4-aminobutyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4 -c] pyridine
[1536] The product from Example 93A was treated as described in Examples 85A and 85B to afford the title compound; ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H ), 2.97 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.38 (m, 1H), 2.29 (m, 2H), 2.01 (dt, 1H), 1.78 (m, 1H) , 1.67 (t, 1 H), 1.46 (m, 2 H), 1.34 (m, 2 H), 1.18 (m, 1 H). MS (DCI / NH ₃ ) m / e 291 (M + H) ⁺ .
[1537] Example 94B
[1538] 3- [4-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1539] Methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.087 g, 0.372 mmol) and the product from Example 94A (0.090 g, 0.310 mmol) were treated as described in Example 1F. 0.080 g (43%) of the title compound is obtained: ¹ H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.65 (br s, 1H), 8.85 (d, 1H), 8.66 (d, 1H). ), 7.68 (dd, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H) , 3.67 (t, 1H), 3.58 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.28 (m, 1H), 1.79 (m, 2H), 1.69 (m, 2H), 1.58 (m, 1 H). MS (DCI / NH ₃ ) m / e 493 (M + H) ⁺ .
[1540] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₄ S · 2.0HCl · 2.0H ₂ O:
[1541] Calculated: C, 51.92; H, 5. 70; N, 9.31.
[1542] Found: C, 52.27; H, 5.56; N, 9.24.
[1543] [a] _D 25.0 ° C = + 83.2 °.
[1544] Example 95
[1545] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1546] Example 95A
[1547] (4aS, 10bR) -trans-3- (4-aminobutyl) -10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4 -c] pyridine
[1548] The product from Example 92B was treated as described in Examples 85A and 85B to afford the title compound; ¹ H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H ), 2.97 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.38 (m, 1H), 2.29 (m, 2H), 2.01 (dt, 1H), 1.78 (m, 1H) , 1.67 (t, 1 H), 1.46 (m, 2 H), 1.34 (m, 2 H), 1.18 (m, 1 H). MS (DCI / NH ₃ ) m / e 291 (M + H) ⁺ .
[1549] Example 95B
[1550] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione dihydrochloride
[1551] Methyl 3-amino-thieno [3,2-b] pyridine-2-carboxylate (0.097 g, 0.413 mmol) and the product from Example 95A (0.100 g, 0.344 mmol) were treated as described in Example 1F. 0.114 g (55%) of the title compound are obtained: ¹ H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.65 (br s, 1H), 8.85 (d, 1H), 8.66 (d, 1H). ), 7.68 (dd, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H) , 3.67 (t, 1H), 3.58 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.28 (m, 1H), 1.79 (m, 2H), 1.69 (m, 2H), 1.58 (m, 1 H). MS (DCI / NH ₃ ) m / e 493 (M + H) ⁺ .
[1552] Elemental Analysis for C ₂₆ H ₂₈ N ₄ O ₄ S · 2.0HCl · 2.0H ₂ O:
[1553] Calculated: C, 51.92; H, 5. 70; N, 9.31.
[1554] Found: C, 51.48; H, 5.62; N, 9.05.
[1555] [α] _D 25.0 ° C. = -82.4 °
[1556] Example 96
[1557] 3- [4-((4aR, 10bS) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione di Hydrochloride
[1558] The product from Example 10C (0.106 g, 0.372 mmol) and the product from Example 94A (0.090 g, 0.310 mmol) were treated as described in Example 1F to yield 0.020 g (11%) of the title compound: melting point 253-4 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.92 (s, 1H), 10.45 (br s, 1H), 9.02 (s, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.57 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H ), 2.25 (m, 1H), 1.78 (m, 2H), 1.69 (m, 2H), 1.56 (m, 1H). MS (DCI / NH ₃ ) m / e 528 (M + H) ⁺ .
[1559] Elemental Analysis for C ₂₅ H ₂₆ N ₅ O ₄ SCl · 2.0HCl · 0.5H ₂ O:
[1560] Calc .: C, 49.23; H, 4.79; N, 11.48.
[1561] Found: C, 48.95; H, 4.77; N, 11.22.
[1562] [α] _D 25.0 ° C. = + 57.6 °
[1563] Example 97
[1564] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione di Hydrochloride
[1565] The product from Example 10C (0.189 g, 0.667 mmol) and the product from Example 95A (0.176 g, 0.606 mmol) were treated as described in Example 1F to yield 0.192 g (55%) of the title compound. 254-5 ° C .; ¹ H NMR (300 MHz, DMSO) δ 12.92 (s, 1H), 10.45 (br s, 1H), 9.02 (s, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.57 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H ), 2.25 (m, 1H), 1.78 (m, 2H), 1.69 (m, 2H), 1.56 (m, 1H). MS (DCI / NH ₃ ) m / e 528 (M + H) ⁺ .
[1566] Elemental Analysis for C ₂₅ H ₂₆ N ₄ O ₄ S · 2.0HCl · 3.0H ₂ O:
[1567] Calculated: C, 45.84; H, 5. 23; N, 10.69.
[1568] Found: C, 45.47; H, 5.03; N, 10.51.
[1569] [α] _D 25.0 ° C. = -58.4 °
[1570] Example 98
[1571] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Hydrochloride
[1572] The product from Example 7A (0.24 g, 1.00 mmol) and the product from Example 95A (0.276 g, 1.00 mmol) were treated as described in Example 1F to yield 0.30 g (57%) of the title compound: melting point ≧ 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.04 (d, 1H), 7.03 (t, 1H), 6.98 (d, 1H), 6.46 (d, 1H), 6.41 (d, 1H), 4.12 (t, 2H), 4.08 (dd, 1H), 4.04 (s, 3H), 3.79 (s, 3H), 3.67 (m, 1H), 3.08 (m, 1H), 2.98 (m, 2H), 2.42 (m, 3H), 2.13 (m, 1H), 2.02 (m, 1H), 1.76 (m, 3H), 1.62 (m, 2H), 1.38 (m, 1H); MS (DCI / NH ₃ ) m / e 523 (M + H) ⁺ ;
[1573] Elemental Analysis for C ₂₇ H ₃₀ N ₄ O ₅ S · HCl · 0.5H ₂ O:
[1574] Calculated: C, 57.09; H, 5.68; N, 9.86.
[1575] Found: C, 57.01; H, 5. 43; N, 9.64.
[1576] Example 99
[1577] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Hydrochloride
[1578] The product from Example 31A (0.167 g, 0.70 mmol) and the product from Example 95A (0.195 g, 0.70 mmol) were treated as described in Example 1F to yield 0.29 g (78%) of the title compound. 220-224 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 8.39 (s, 1H), 7.04 (t, 1H), 6.46 (d, 1H), 6.41 (d, 1H), 4.11 (m, 3H), 4.08 (s, 3H), 3.79 (s, 3H), 3.67 (t, 1H), 3.08 (m, 1H), 2.98 (m, 2H), 2.42 (m, 3H), 2.15 (m, 1H), 2.0 (m, 1H), 1.78 (m, 3H), 1.6 (m, 2H), 1.4 (m, 1H); MS (DCI / NH ₃ ) m / e 524 (M + H) ⁺ ;
[1579] Elemental Analysis for C ₂₆ H ₂₉ N ₅ O ₅ S · HCl · 2H ₂ O:
[1580] Calculated: C, 52.39; H, 5.75; N, 11.75.
[1581] Found: C, 52.59; H, 5. 70; N, 11.65.
[1582] Example 100
[1583] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydro Chloride
[1584] The product from Example 9B (0.16 g, 0.56 mmol) and the product from Example 95A (0.154 g, 0.56 mmol) were treated as described in Example 1F to yield 0.17 g (53%) of the title compound: melting point ≧ 250 ° C .; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 9.16 (s, 1H), 8.08 (m, 2H), 7.59 (m, 3H), 7.02 (t, 1H), 6.42 (d, 1H), 6.38 (d, 1H), 4.18 (m, 2H), 3.93 (dd, 1H), 3.77 (s, 3H), 3.6 (t, 1H), 3.18 (m, 1H), 3.07 (m, 1H), 2.93 (m, 1H), 2.5 (m, 2H), 2.41 (m, 1H), 2.16 (m, 1H), 1.97 (m, 1H), 1.8 (m, 3H), 1.76 (m, 2H), 1.18 ( m, 1 H); MS (DCI / NH ₃ ) m / e 570 (M + H) ⁺ .
[1585] Elemental Analysis for _{C 31 H 31 N 5 SO 4} · HCl · 1.5H 2 O:
[1586] Calculated: C, 58.81; H, 5.57; N, 11.06.
[1587] Found: C, 58.69; H, 5.52; N, 11.03.
[1588] Example 101
[1589] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione di Hydrochloride
[1590] The product from Example 95B (0.145 g, 0.50 mmol) and the product from Example 52A (0.15 g, 0.53 mmol) were treated as described in Example 1F to yield 0.230 g (80%) of the title compound: melting point 255 ° C; ¹ H NMR (300 MHz, CDCl ₃ (free base)) δ 1.35 (dd, J = 3, 12 Hz, 1H), 1.58-1.72 (m, 2H), 1.72-1.87 (m, 3H), 1.91-2.05 ( m, 1H), 2.12 (dd, J = 3, 12 Hz, 1H), 2.36-2.50 (m, 3H), 2.89-3.02 (m, 2H), 3.04-3.13 (m, 1H), 3.63 (dd, J = 10, 11Hz, 1H), 3.77 (s, 3H), 4.03 (dd, J = 3, 10Hz, 1H), 4.18 (t, J = 7Hz, 2H), 6.39 (dd, J = 1, 8Hz, 1H ), 6.45 (dd, J = 1, 8 Hz, 1H), 7.03 (t, J = 8 Hz, 1H), 7.45-7.56 (m, 3H), 7.93 (d, J = 9 Hz, 1H), 8.05-8.11 ( m, 2H), 8.27 (d, J = 9 Hz, 1H); (M + H) ⁺ in MS (CI (NH ₃ )) m / e 569;
[1591] Elemental Analysis for C ₃₂ H ₃₂ N ₄ O ₄ S · (HCl) ₂ · (H ₂ O) _0.5 :
[1592] Calculated: C, 59.07; H, 5. 42; N, 8.61.
[1593] Found: C, 59.04; H, 5.53; N, 8.35.
[1594] Example 102
[1595] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione hydro Chloride
[1596] The product from Example 95B (0.290 g, 1.0 mmol) and methyl 3-amino-6-chloro-thieno [2,3-b] pyridine-2-carboxylate (0.242 g, 1.00 mmol) were added to Example 1F. Treatment as described yields 0.375 g (66%) of the title compound: melting point 236 ° C. (decomposition); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.4-1.6 (m, 2H), 1.6-1.85 (n, 4H), 2.04-2.24 (m, 2H), 2.7-3.6 (m, 6H), 3.66 (t, 2H), 3.77 (s, 3H), 3.95 (t, 2H), 4.15 (m, 1H), 6.41 (d, 1H), 6.52 (d, 1H), 7.07 (t, 1H), 7.78 ( d, 1 H), 8.77 (d, 1 H); MS (DCI / NH ₃ ) m / e 527 (529 (M + H) &lt; + &gt;);
[1597] Elemental Analysis for C ₂₆ H ₂₈ Cl ₂ N ₄ O ₄ S · 1.25H20:
[1598] Calculated: C, 53.29; H, 5. 25; N, 9.56; Cl, 12.10.
[1599] Found value; C, 53.26; H, 5. 28; N, 9.27; Cl, 11.82.
[1600] Example 103
[1601] 3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Hydrochloride
[1602] The product from Example 95B (0.290 g, 1.0 mmol) and methyl 3-amino-6-methoxy-thieno [2,3-b] pyridine-2-carboxylate (0.238 g, 1.00 mmol) were prepared in Example 1F. Treatment as described in yields 0.315 g (56%) of the title compound: melting point 224 ° C. (decomposition); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.4-1.6 (m, 2H), 1.6-1.85 (m, 4H), 2.04-2.15 (m, 2H), 2.7-3.6 (m, 6H), 3.67 ( t, 2H), 3.77 (s, 3H), 3.96 (m, 2H), 3.98 (s, 3H), 4.15 (m, 1H), 6.41 (d, 1H), 6.54 (d, 1H), 7.07 (d , 1H), 7.08 (t, 1 H), 8.58 (d, 1 H); MS (DCI / NH ₃ ) m / e 523 (M + H) &lt; + &gt;;
[1603] Elemental Analysis for C ₂₇ H ₃₁ ClN ₄ O ₅ S · 1.4H ₂ O:
[1604] Calculated: C, 54.65; H, 5,78; N, 9.44; Cl, 7.47.
[1605] Found: C, 54.52, H, 5.91; N, 9.31; Cl, 7.55.
[1606] Example 104
[1607] 3- [4-(-cis-7-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1608] Example 104A
[1609] 3- [4-(-cis-7-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1610] A solution of 7-hydroxy-5-methoxycoumarin (300 mg, 1.6 mmol) prepared as described in Monatsh, Chem., 1333, (1988) in anhydrous DMF (10 ml) was dissolved in sodium hydride (70 mg). , 1.7 mmol), stirred for 1 hour, treated with benzyl bromide (0.37 ml, 3.1 mmol) and then stirred for 1 hour. The mixture is diluted with diethyl ether (100 ml), washed with water and then brine, dried (MgSO ₄ ), filtered and concentrated. The residue was purified on silica gel with dichloromethane and then 25: 1 dichloromethane: ethyl acetate to give 420 mg (95%) of intermediate benzylated derivatives.
[1611] A solution of 7-benzyloxy-5-methoxycoumarin (0.42 g, 1.5 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (0.15 ml of a 1M solution in dichloromethane) at 0 ° C. and dichloromethane (5 ml The solution is added dropwise with a solution of N-methoxymethyl-N-trimethylsilylmethylbenzylamine (750 mg, 3.0 mmol) in) and then stirred at ambient temperature for 1 hour. The mixture is diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO ₄ ), filtered and concentrated. The residue is dissolved in THF (5 ml), added to a stirred suspension of lithium aluminum hydride (115 mg, 3.0 mmol) in THF (10 ml), stirred for 1 hour and treated with sodium sulfate decahydrate (5 g) in portions. . The mixture is diluted with ethyl acetate, filtered and concentrated. Purification on silica gel with 2: 1 ethyl acetate: hexanes affords 620 mg (96%) of intermediate diols.
[1612] A solution of diol (0.60 g, 1.4 mmol) in a mixture of acetonitrile (16 ml) and carbon tetrachloride (4 ml) was treated with triphenylphosphine (0.73 g, 2.8 mmol), heated to reflux for 10 minutes and cooled to ambient temperature And concentrate. Purification on silica gel with 2: 1 diethyl ether: hexanes saturated with ammonia gave 530 mg (92%) of intermediate chloro-phenol. This chlorophenol (530 mg, 1.3 mmol) was dissolved in THF (30 ml), treated with potassium tert-butoxide (1 M 3 ml in THF solution), stirred for 1 hour, concentrated and diluted with dichloromethane (100 ml). Treated, washed with water (25 ml), dried (MgSO ₄ ), filtered and concentrated to give 0.40 g (76%) ring closure product. The suspension of the product (0.40 g, 0.96 mmol) and 10% palladium on carbon (0.070 g) in methanol (20 ml) is stirred for 16 h under hydrogen atmospheric pressure. This atmosphere is replaced with nitrogen, the palladium on carbon is filtered off and the mixture is concentrated. The residue was purified on silica gel with 8: 1: 1 ethyl acetate: water: formic acid to give an impure product, which was purified again on silica gel using 40% ethanol in dichloromethane saturated with ammonia to give the title compound. 0.060 g (28%) is obtained; ¹ H NMR (300 MHz, DMSO-d ₆ ) d 2.25-2.39 (m, 1H), 2.34 (dd, 1H), 2.48-2.55 (m, 1H), 2.89 (q, 1H), 3.10 (dd, 1H ), 3.33-3.42 (m, 1H), 3.49 (t, 1H), 3.70 (s, 3H), 3.98 (dd, 1H), 5.86 (d, J = 1 Hz, 2H), 5.99 (d, J = 1 Hz , 2H), 9.23 (bs, 1H); MS (DCI / NH ₃ ) m / e 222 (M + NH ₄ ) ⁺ .
[1613] Example 104B
[1614] 3- [4-(-cis-7-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1615] A solution of the product from Example 104A (60 mg, 0.27 mmol) in DMF (1.5 ml) was treated with 4-bromobutyronitrile (0.030 ml, 0.30 mmol) and sodium bicarbonate (25 mg, 0.30 mmol) and 3 hours Heated to 70 ° C. and then concentrated. Purification on silica gel using 2% ethanol in dichloromethane saturated with ammonia yields 70 mg (90%) of intermediate nitrile.
[1616] A suspension of lithium aluminum hydride (70 mg, 1.8 mmol) in a mixture of diethyl ether (3 ml) and THF (3 ml) was treated with aluminum hydride (81 mg, 0.61 mmol) in diethyl ether (3 ml) and stirred for 1 hour. , Treated with nitrile (70 mg, 0.24 mmol), stirred for 2 hours, treated with water (0.080 ml), treated with 4M sodium hydroxide (0.080 ml), treated with water (0.24 ml), for 15 minutes Stir and concentrate. The residue is purified on silica gel using 12: 5: 3 ethyl acetate: formic acid: water to give the formic acid salt of the primary amine product.
[1617] The solution of the product from Example 9B (82 mg, 0.29 mmol) in THF (5 ml) was treated with sodium bicarbonate (100 mg, 1.2 mmol), phosgene (3.75 ml of a 1.93 M solution in toluene), stirred for 1 hour and concentrated And dried at 60 ° C. for 1 hour under high vacuum and cooled to ambient temperature. The residue is treated with a suspension of primary amine intermediate in DMF (4.5 ml), stirred for 1 hour, heated to 150 ° C. for 30 minutes under nitrogen and then concentrated. The residue was purified on silica gel using 10% ethanol in dichloromethane saturated with ammonia followed by 20% ethanol to give 60 mg (43%) of the title compound; ¹ H NMR (300 MHz, DMSO-d ₆ ) d 1.42-1.54 (m, 2H), 1.58-1.71 (m, 2H), 2.14-2.25 (m, 2H), 2.38-2.51 (m, 2H), 2.99 (t, 1H), 3.10 (q, 1H), 3.17-3.26 (m, 1H), 3.39-3.49 (m, 1H), 3.62 (t, 1H), 3.69 (s, 3H), 3.90-4.00 (m , 3H), 5.84 (d, J = 1Hz, 2H), 5.98 (d, J = 1Hz, 2H), 7.53-7.65 (m, 3H), 8.40-8.47 (m, 2H), 9.24 (bs, 1H) , 9.51 (s, 1 H), 12.60 (bs, 1 H); MS (ESI) m / e 572 (M + H) ⁺ ; 570 (MH) ^_ .
[1618] Example 105
[1619] 3- [4- (3aR, 9bR) -cis-6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1620] Example 105A
[1621] (3aR, 9bR) -cis-6-bromo-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1622] The HCl salt (1 g, 4.14 mmol) of the product from Example 1C is dissolved in formic acid, cooled to 0 ° C. and Br ₂ (0.68 g, 4.25 mmol) is added. The reaction is stirred at 0 ° C. for 1 h and then the solvent is evaporated and the product is partitioned with 1N NaOH / CH ₂ Cl ₂ . The organic extracts are dried and then concentrated. The resulting product was purified by column chromatography on silica gel eluting with 5% EtOH / CH ₂ Cl ₂ saturated with NH ₄ OH to afford 0.45 g (38%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) d 2.58 (m, 1H), 2.64 (m, 1H), 2.84 (dd, 1H), 3.24 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.80 (m, 1H), 3.81 (s, 3H), 6.38 (d, 1H), 7.32 (d, 1H); MS (DCI (NH ₃ )) m / e 284 (M + H) ⁺ .
[1623] Example 105B
[1624] (3aR, 9bR) -cis-6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1625] The product from Example 105A (0.45 g, 1.6 mmol) is dissolved in CH ₂ Cl ₂ and di-t-butyl-dicarbonate (0.69 g, 3.2 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour, after which it is evaporated and the residue is purified by column chromatography on silica gel eluting with 1: 1 hexanes: EtOAc to give a t-BOC-protected product (0.42 g). To a solution of t-BOC-protected product (0.18 g, 0.46 mmol) in THF cooled to −78 ° C. is added 0.22 ml of a 2.5 M n-BuLi solution in hexane. The reaction mixture is stirred at −78 ° C. for 1 hour and triisopropyl borate (0.11 g, 0.59 mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. Acetic acid (0.55 mmol) is then added to the reaction mixture followed by H ₂ O ₂ (0.78 mmol). The reaction mixture is stirred at rt for 16 h, then quenched into NH ₄ Cl solution and extracted with CH ₂ Cl ₂ . The organic phase is dried over MgSO ₄ and concentrated to give the t-BOC protected title compound (0.8 g). To a solution of t-BOC protected title compound (0.12 g, 0.37 mmol) in CH ₂ Cl ₂ is added CF ₃ COOH and the reaction mixture is stirred overnight. The solvent was evaporated and the residue was purified by column chromatography eluting with 2% EtOH / CH ₂ Cl to afford 0.08 g of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) d 2.67 (m, 1H), 2.82 (dd, 1H), 2.97 (dd, 1H), 3.39 (m, 2H), 3.62 (dd, 1H), 3.78 (m, 1H), 3.77 (s, 3H), 3.81 (m, 1H), 4.18 (dd, 1H), 6.37 (d, 1H), 6.74 (d, 1H);
[1626] Example 105C
[1627] (3aR, 9bR) -cis-2- (3-cyanopropyl) -6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole
[1628] To the product of Example 105B (0.075 g, 0.34 mmol) in DMF (2 ml) was added NaHCO ₃ (0.032 g, 0.38 mmol) and 4-bromobutyronitrile (0.056 g, 0.38 mmol). The reaction mixture is heated at 90 ° C. for 3 hours and then evaporated. The residue was purified by column chromatography on silica gel eluting with 2% EtOH / CH ₂ Cl ₂ saturated with ammonia to afford 0.086 g (88%) of the title compound; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.82 (m, 2H), 2.26 (m, 2H), 2.43 (t, 2H), 2.6 (m, 3H), 3.39 (m, 2H), 3.75 (s, 3H), 3.87 (m, 1H), 4.12 (dd, 1H), 5.15 (d, 1H), 6.73 (d, 1H).
[1629] Example 105D
[1630] (3aR, 9bR) -cis-2- (4-aminobutyl) -6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [ 3,4-c] pyrrole
[1631] The product of Example 105C (0.084 g, 0.3 mmol) in THF is added to a solution of LiAlH ₄ (0.085 g, 2.3 mmol) in THF and AlCl ₃ (0.1 g, 0.75 mmol) in ether. The reaction mixture is stirred at rt for 3 h and after work-piper treatment, 0.075 g (88%) of the title compound are obtained; ¹ H NMR (300 MHz, CDCl ₃ ) d1.48-1.7 (m, 4H), 2.38 (m, 1H), 2.43 (m, 3H), 2.73 (m, 2H), 3.06 (m, 1H), 3.39 (m, 2H), 3.47 (m, 1H), 3.77 (s, 3H), 3.84-33.95 (m, 2H), 4.05 (m, 1H), 6.38 (d, 1H), 6.73 (d, 1H).
[1632] Example 105E
[1633] 3- [4- (3aR, 9bR) -cis-6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4- c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione
[1634] The product from Example 105D (0.084 g, 0.3 mmol) and the product from Example 9B (0.087 g, 0.3 mmol) were treated as described in Example 1F to yield 0.03 g (17%) of the title compound: ¹ H NMR (500 MHz, CDCl ₃ ) d 1.72 (m, 2H), 1.81 (m, 1H), 2.45 (m, 1H), 2.57 (m, 1H), 2.73 (m, 3H), 3.32 (m, 1H ), 3.5 (m, 1H), 3.7 (s, 3H), 3.86 (m, 1H), 4.06 (m, 1H), 4.15 (m, 2H), 6.28 (d, 1H), 6.67 (d, 1H) , 7.55 (m, 3H), 8.08 (m, 2H), 9.12 (s, 1H); MS (ESI) m / e 572 (M + H) ^{+ S.}
[1635] Example 106
[1636] 3- [4- (3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2 -Yl) butyl] -8- (2-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion
[1637] To a solution of the product from Example 16 (0.075 g, 0.136 mmol) in DMF (2 ml), Pd (dppf) Cl ₂ (0.03 g, 0.034 mmol), 2- (benzyloxy) benzeneboronic acid (0.033 g, 0.145 mmol) And triethylamine (0.05 ml). The reaction mixture is heated at 90 ° C. for 3 hours. It is then distilled off with water and the precipitate formed is filtered off. The filtrate is extracted with EtOAc, dried over MgSO ₄ and evaporated. The residue was chromatographed on silica gel eluting with 5% ethanol / CH ₂ Cl ₂ saturated with ammonia to give 0.05 g (55%) of oil. To a solution of this product (0.08 g, 0.12 mmol) in CH ₃ OH (2 ml) is added ammonium formate (0.07 g) and Pd / C (0.07 g). The reaction mixture was refluxed for 2 hours and then filtered and the evaporated residue was column chromatographed on silica gel eluting with 10% EtOH / CH ₂ Cl ₂ saturated with NH ₄ OH to afford 0.022 g (32%) of the title compound. do; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.8 (m, 4H), 2.5 (m, 1H), 2.58 (m, 1H), 2.8 (m, 3H), 3.58 (m, 2H), 3.78 (s, 3H), 3.82 (m, 2H), 3.88 (dd, 1H), 4.28 (m, 2H), 6.42 (m, 2H), 7.06 (m, 3H), 7.42 (t, 1H), 7.92 (dd, 1H ), 9.33 (s, 1 H); MS (ESI) m / e 572 (M + H) ⁺ .
[1638] Example 107
[1639] 3- [4- (3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2 -Yl) butyl] -8- (3-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion
[1640] The product of Example 16 (0.07 g, 0.105 mmol) and 3- (benzyloxy) benzeneboronic acid were treated as described in Example 106 to yield 0.03 g (43%) of the benzyl-protected product. To a solution of the product (0.015 g, 0.02 mmol) in CH ₃ COOH is added a few drops of H ₂ SO ₄ and the solution is refluxed for 5 hours. Cool the reaction mixture, neutralize and extract with CH ₂ Cl ₂ / CH ₃ OH to afford 0.003 g (26%) of the title compound: ¹ H NMR (500 MHz, CDCl ₃ ) d 1.81 (m, 2H), 1.98 (m, 2H), 2.25 (m, 1H), 2.62 (m, 1H), 2.85 (m, 1H), 3.03 (m, 2H), 3.25 (m, 2H), 3.8 (s, 3H), 3.82 ( m, 2H), 4.0 (m, 2H), 4.42 (m, 1H), 6.52 (m, 3H), 7.12 (m, 3H), 7.42 (t, 1H), 7.85 (s, 1H), 9.11 (s , 1H); MS (ESI) m / e 572 (M + H) ⁺ .
[1641] Example 108
[1642] 3- [4- (3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole-2 -Yl) butyl] -8- (4-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion
[1643] The product of Example 16 (0.07 g, 0.105 mmol) and Tetr. Lett., 331, 27 (1990)] treated 4- (methoxymethyloxy) phenyl boronic acid (0.02 g, 0.11 mmol) prepared by the procedure described in Example 106 to give a MOM-protected product. 0.029 g (45%) is obtained. To a solution of the product (0.11 g, 0.17 mmol) in CH ₃ OH / THF is added 2N HCl (0.2 ml) and the reaction mixture is refluxed for 1 hour. The reaction was evaporated and partitioned between NaHCO ₃ solution and CH ₂ Cl ₂ / CH ₃ OH to afford 0.005 g (51%) of the title compound; ¹ H NMR (500 MHz, CDCl ₃ ) d 1.81 (m, 2H), 1.98 (m, 2H), 2.25 (m, 1H), 2.65 (m, 1H), 2.88 (m, 1H), 3.08 (m, 2H), 3.22 (m, 2H), 3.65 (m, 1H), 3.73 (m, 1H), 3.82 (s, 3H), 3.9 (m, 1H), 4.25 (m, 1H), 4,42 (m , 1H), 6.52 (m, 2H), 7.38 (m, 2H), 7.49 (m, 1H), 7.9 (t, 1H), 8.09 (d, 1H), 9.12 (s, 1H); MS (ESI) m / e 572 (M + H) ⁺ .
[1644] The foregoing is intended to illustrate the invention and is not intended to limit the invention to the compounds previously described herein. Various changes and modifications apparent to those skilled in the art are considered to be within the scope and spirit of the invention as defined in the appended claims.

权利要求:
Claims (54)
[1" claim-type="Currently amended] A compound of formula (I), or a pharmaceutically acceptable salt, ester, or prodrug thereof
Formula I

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
R ₃ is , , , , , , , , , , And Is selected from the group consisting of
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
V and V 'are independently selected from the group consisting of nitrogen and methine
U is a ring fused with its adjacent ring and is (a) an unsubstituted or substituted 5-membered ring having 5 carbon atoms; (b) an unsubstituted or substituted 5-membered ring having 4 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (c) an unsubstituted or substituted 5-membered ring having 3 carbon atoms and 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; (d) substituted or unsubstituted 6 membered rings having 6 carbon atoms; (e) a substituted or unsubstituted 6 membered ring having 5 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (f) a substituted or unsubstituted 6 membered ring having 4 carbon atoms and 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; And (g) a substituted or unsubstituted 6-membered ring having 3 carbon atoms and having 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; The 5-membered ring constituting U may contain 0, 1 or 2 double bonds; The six-membered ring constituting U may contain 0, 1, 2 or 3 double bonds; Rings (a) to (g) of the group constituting U are independent from the group consisting of alkyl, alkoxy, cyano, nitro, carboxy, alkoxycarbonyl having 2 to 8 carbon atoms, halogen, cycloalkyl, aryl and heterocyclic It may be mono- or di-substituted by a substituent selected from.
[2" claim-type="Currently amended] The compound of claim 1, wherein the 5- and 6-membered rings comprising U contain one or more double bonds.
[3" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula II

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
P ', Q, S' and T are independently selected from the group consisting of nitrogen and methine, provided that two or less of P ', Q, S' and T may be nitrogen,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[4" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula III

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
P 'and T are nitrogen,
Q and S 'are methine,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[5" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula IV

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
P 'is nitrogen,
Q, S 'and T are methine,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[6" claim-type="Currently amended] The compound of formula (V), or a pharmaceutically acceptable salt, ester or prodrug thereof, according to claim 1.
Formula V

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
Q is nitrogen,
P ', S' and T are methine,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[7" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula VI

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
S 'is nitrogen,
P ', Q and T are methine,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[8" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula Ⅶ

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
T is nitrogen,
P ', Q and S' are methine,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[9" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula Ⅷ

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
A is methylene,
n is 1 or 2,
W is alkylene having 2 to 10 carbon atoms,
G and G 'are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl Selected,
Y and Y 'are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G 'is absent,
P ', Q, S' and T are methine,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[10" claim-type="Currently amended] The method of claim 1,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-isopropoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [3-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-furyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione , And
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- A compound selected from the group consisting of diones, or a pharmaceutically acceptable salt, ester or prodrug thereof.
[11" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula Ⅸ

In the above formula,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
A is methylene,
n is 1,
W is alkylene having 2 to 10 carbon atoms,
G is hydrogen,
G 'does not exist,
Y is nitrogen,
Y 'is sulfur,
P ', Q and S' are methine,
T is nitrogen,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[12" claim-type="Currently amended] The method of claim 11,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-isopropoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione, and
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Selected compound of formula (VIII), or a pharmaceutically acceptable salt, ester or prodrug thereof.
[13" claim-type="Currently amended] A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Formula Ⅹ

In the above formula,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
A is methylene,
n is 2,
W is alkylene having 2 to 10 carbon atoms,
G is hydrogen,
G 'does not exist,
Y is nitrogen,
Y 'is sulfur,
P ', Q and S' are methine,
T is nitrogen,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[14" claim-type="Currently amended] The method of claim 13,
3- [3-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) propyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione , And
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione A compound of formula (VIII) selected from the group consisting of: or a pharmaceutically acceptable salt, ester or prodrug thereof.
[15" claim-type="Currently amended] A compound of formula (XI), or a pharmaceutically acceptable salt, ester or prodrug thereof, according to claim 1.
Formula (XI)

In the above formula,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
A is methylene,
n is 2,
W is alkylene having 2 to 10 carbon atoms,
G is hydrogen,
G 'does not exist,
Y is nitrogen,
Y 'is sulfur,
Q and S 'are methine,
P 'and T are nitrogen,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[16" claim-type="Currently amended] The method of claim 15,
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione , And
3- [4-((4aS, 10bR) -trans-10-methoxy-1,3,4,4a, 5,10b-hexahydro-2H- [1] -benzopyrano [3,4-c] Pyrido-3-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione A compound of formula (XI) selected from the group consisting of: or a pharmaceutically acceptable salt, ester or prodrug thereof.
[17" claim-type="Currently amended] The compound of formula XII, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Chemical Formula XII

In the above formula,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
A is methylene,
n is 1,
W is alkylene having 2 to 10 carbon atoms,
G is hydrogen,
G 'does not exist,
Y is nitrogen,
Y 'is sulfur,
Q and S 'are methine,
P 'and T are nitrogen,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[18" claim-type="Currently amended] The method of claim 17,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-chloro-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-methoxy-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrido [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-pyridyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-furyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione ,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-thienyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-(-cis-7-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-6-hydroxy-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4 -c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H)- Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (2-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (3-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) Dion, and
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -8- (4-hydroxyphenyl) -pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -A compound of formula XII selected from the group consisting of dione, or a pharmaceutically acceptable salt, ester or prodrug thereof.
[19" claim-type="Currently amended] The compound of formula (XIII), or a pharmaceutically acceptable salt, ester or prodrug thereof.
Chemical Formula XIII

In the above formula,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
A is methylene,
n is 1,
W is alkylene having 2 to 10 carbon atoms,
G is hydrogen,
G 'does not exist,
Y is nitrogen,
Y 'is sulfur,
Q, S 'and T are methine,
P 'is nitrogen,
R ₄ and R ₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic.
[20" claim-type="Currently amended] The method of claim 19,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione,
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-methoxy-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione, and
3- [4-((3aS, 9bR) -trans-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3,4-c] pyrrole- 2-yl) butyl] -7-chloro-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione Selected compound of formula (XIII), or a pharmaceutically acceptable salt, ester or prodrug thereof.
[21" claim-type="Currently amended] The compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.
Chemical Formula XIV

In the above formula,
R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkoxy,
Y is nitrogen,
G is hydrogen,
Y 'is sulfur,
P 'and T are nitrogen,
Q is methine,
S 'is carbon.
[22" claim-type="Currently amended] The process of claim 21, wherein 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3, 4-c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -A compound of formula (IV), or a pharmaceutically acceptable salt, ester or prodrug thereof, which is dione.
[23" claim-type="Currently amended] The compound of claim 22, wherein 3- [4-((3aR, 9bR) -cis-9-methoxy-1,2,3,3a, 4,9b-hexahydro- [1] -benzopyrano [3, 4-c] pyrrole-2-yl) butyl] -8-phenyl-pyrazino [2 ', 3': 4,5] thieno [3,2-d] pyrimidine-2,4 (1H, 3H) A compound of formula (IV) which is dione hydrochloride.
[24" claim-type="Currently amended] A compound of Formula XV or a pharmaceutically acceptable salt thereof
Formula XV

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
n is 1 or 0.
[25" claim-type="Currently amended] A compound of Formula (VI) or a pharmaceutically acceptable salt thereof
Chemical Formula XVI

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
n is 1 or 0.
[26" claim-type="Currently amended] A compound of formula (VIII) or a pharmaceutically acceptable salt thereof
Formula ⅩⅦ

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
m is 2 to 10,
n is 1 or 0.
[27" claim-type="Currently amended] The compound of formula (24) according to claim 24, or a pharmaceutically acceptable salt thereof.
Formula ⅩⅧ

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
n is 1 or 0.
[28" claim-type="Currently amended] The compound of claim 27, wherein the absolute stereochemistry is 3aR and 9bR.
[29" claim-type="Currently amended] The compound of formula (VII) or a pharmaceutically acceptable salt thereof.
Formula ⅩⅨ

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
n is 1 or 0.
[30" claim-type="Currently amended] The compound of claim 29, wherein the absolute stereochemistry is 3aR and 9bR.
[31" claim-type="Currently amended] The compound of formula (VII): or a pharmaceutically acceptable salt thereof.
Formula ⅩⅩ

In the above formula,
R ₁ and R ₂ are independent from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl Is selected,
m is 2 to 10,
n is 1 or 0.
[32" claim-type="Currently amended] 32. The compound of claim 31, wherein the absolute stereochemistry is 3aR and 9bR.
[33" claim-type="Currently amended] A compound of Formula (XI) or a pharmaceutically acceptable salt thereof
Formula (XI)

In the above formula,
U, Y 'and G' are as defined in formulas (I) to (XIV),
R is alkyl.
[34" claim-type="Currently amended] The compound of formula XII or a pharmaceutically acceptable salt thereof
Chemical Formula XII

In the above formula,
U, Y 'and G' are as defined in formulas (I) to (XIV),
R is alkyl.
[35" claim-type="Currently amended] The compound of formula XIII or a pharmaceutically acceptable salt thereof
Chemical Formula XIII

In the above formula,
U, Y ', G' and m are as defined in Formulas I to IV,
R is alkyl.
[36" claim-type="Currently amended] A compound of formula (VII)
Chemical Formula XIV

In the above formula,
R _z is alkyl.
[37" claim-type="Currently amended] A compound of formula (XV)
Formula XV

In the above formula,
R _z is alkyl.
[38" claim-type="Currently amended] A compound of formula (VI)
Chemical Formula VI

In the above formula,
X is halogen,
R is selected from alkyl and arylalkyl.
[39" claim-type="Currently amended] A compound of formula (VII)
Formula ⅩⅩⅦ

[40" claim-type="Currently amended] A compound of formula (VII)
Formula ⅩⅩⅧ

[41" claim-type="Currently amended] A compound of formula (VII)
Formula ⅩⅩⅨ

[42" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 in association with a pharmaceutically acceptable carrier.
[43" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 22 in association with a pharmaceutically acceptable carrier.
[44" claim-type="Currently amended] A method of antagonizing α-1 adrenal receptors in a host mammal in need of antagonizing the α-1 adrenoreceptor, comprising administering a therapeutically effective amount of the compound of claim 1.
[45" claim-type="Currently amended] A method of antagonizing an α-1 adrenal receptor in a host mammal in need of antagonizing the α-1 adrenal receptor, comprising administering a therapeutically effective amount of the compound of claim 22.
[46" claim-type="Currently amended] A method of treating BPH in a host mammal in need of treating benign prostatic hyperplasia (BPH), comprising administering a therapeutically effective amount of the compound of claim 1.
[47" claim-type="Currently amended] A method of treating BPH in a host mammal in need of treating benign prostatic hyperplasia (BPH), comprising administering a therapeutically effective amount of the compound of claim 22.
[48" claim-type="Currently amended] A method of treating bladder outlet obstruction in a host mammal in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1.
[49" claim-type="Currently amended] A method of treating bladder outlet obstruction in a host mammal in need thereof, comprising administering a therapeutically effective amount of the compound of claim 22.
[50" claim-type="Currently amended] A method of treating a neuropathy bladder in a host mammal in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 1.
[51" claim-type="Currently amended] A method of treating a neuropathy bladder in a host mammal in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 22.
[52" claim-type="Currently amended] A method of treating smooth muscle contraction of the uterus in a host mammal in need of treating the smooth muscle contraction of the uterus, comprising administering a therapeutically effective amount of the compound of claim 1.
[53" claim-type="Currently amended] A method of treating smooth muscle contraction of the uterus in a host mammal in need of treating the smooth muscle contraction of the uterus, comprising administering a therapeutically effective amount of the compound of claim 22.
[54" claim-type="Currently amended] a) chemical formula Wherein R _a is aminoalkyl] b) chemical formula or A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising reacting with a compound of the formula wherein R is alkyl.
Formula I

In the above formula,
R ₁ , R ₂ , A, n, W, Y, G, Y ', G', P, Q, S, T, R ₄ and R ₅ are as defined above.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US10654857B2|2020-05-19|Bicyclic compounds as autotaxin | and lysophosphatidic acid | production inhibitors

---

EP3080121B1|2019-09-04|Fused tricyclic benzimidazoles derivatives as modulators of tnf activity

---

CA2930414C|2020-02-11|Tetrahydroquinoline compositions as bet bromodomain inhibitors

---

US10647719B2|2020-05-12|Bicyclic compounds as dual ATX/CA inhibitors

---

JP6445560B2|2018-12-26|Fused tricyclic imidazole derivatives as modulators of TNF activity

---

US9139594B2|2015-09-22|Fused aminodihydropyrimidone derivatives

---

TWI412525B|2013-10-21|Quinoline amide m1 receptor positive allosteric modulators

---

KR101564634B1|2015-10-30|Condensed aminodihydrothiazine derivative

---

KR100744893B1|2007-08-01|Hexahydropyridoisoqinolines as dpp-iv inhibitors

---

US7199119B2|2007-04-03|Antiinflammation agents

---

TWI531571B|2016-05-01|Aryl-and heteroarylcarbonyl derivatives of hexahydroindenopyridine and octahydrobenzoquinoline

---

EP2276756B1|2011-11-30|Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists

---

KR101712786B1|2017-03-06|4-|dihydropyrimidinones and use thereof

---

US8338592B2|2012-12-25|Fused thiazole derivatives as kinase inhibitors

---

US10004737B2|2018-06-26|Fused imidazole and pyrazole derivatives as modulators of TNF activity

---

AU2006327866B2|2012-06-14|Carbonylamino pyrrolopyrazoles, potent kinase inhibitors

---

TWI462914B|2014-12-01|New dihydroquinoline-2-one derivatives

---

JP4252797B2|2009-04-08|Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors

---

EP1294725B1|2006-01-04|Multicyclic compounds and their use as inhibitors of parp, vegfr2 and mlk3 enzymes

---

JP4450365B2|2010-04-14|Polycyclic guanine phosphodiesterase V inhibitor

---

JP5490030B2|2014-05-14|Fused heterocyclic derivatives and uses thereof

---

KR100854050B1|2008-08-26|Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors

---

TWI359814B|2012-03-11|Novel heterocyclic compounds useful for the treatm

---

CA2409715C|2010-09-14|.beta.-carboline derivatives useful as inhibitors of phosphodiesterase

---

CN1251097B|2011-10-19|Phthalazines with angiogenesis inhibiting activity

同族专利:

---

公开号 | 公开日

---

CN1246861A|2000-03-08|

---

PT942911E|2002-04-29|

---

DK942911T3|

---

ES2168682T3|2002-06-16|

---

NO992661L|1999-07-30|

---

JP2002504088A|2002-02-05|

---

CN1130365C|2003-12-10|

---

CZ194499A3|1999-11-17|

---

EP0942911A1|1999-09-22|

---

EP0942911B1|2001-10-17|

---

NZ335711A|2000-10-27|

---

CA2272330A1|1998-06-11|

---

SK283580B6|2003-09-11|

---

AT207071T|2001-11-15|

---

AU5516998A|1998-06-29|

---

NO992661D0|1999-06-02|

---

AU735764B2|2001-07-12|

---

BG103553A|2000-06-30|

---

TR199901883T2|1999-12-21|

---

BG63975B1|2003-08-29|

---

DK0942911T3|2002-12-02|

---

CY2260B1|2003-07-04|

---

WO1998024791A1|1998-06-11|

---

SK71799A3|2000-01-18|

---

DE69707497D1|2001-11-22|

---

DE69707497T2|2002-07-11|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1996-12-06|Priority to US76142396A

---

1996-12-06|Priority to US8/761,423

---

1997-11-26|Priority to US08/980,130

---

1997-11-26|Priority to US8/980,130

---

1997-12-04|Application filed by 스티븐 에프. 웨인스톡, 아보트 러보러터리즈

---

2000-09-15|Publication of KR20000057418A

优先权:

---

申请号 | 申请日 | 专利标题

---

US76142396A| true| 1996-12-06|1996-12-06|

---

US8/761,423|1996-12-06|

---

US08/980,130|US6046207A|1996-12-06|1997-11-26|Benzopyranopyrrole and benzopyranopyridine α-1 adrenergic compounds|

---

US8/980,130|1997-11-26|