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    • 专利摘要:
    Formula I Disclosed are compounds having the above formula, pharmaceutical formulations of such compounds, and methods of using such compounds to treat patients suffering from dopamine-related disorders of the central or peripheral nervous system. The compounds treat Parkinson's disease, improve cognition, improve memory, improve negative symptoms of schizophrenia, improve concentration-deficit hyperactivity disorders and related developmental disorders, treat drug abuse, dopamine Changes in receptor occupancy are expected to be useful for treating various peripheral diseases that affect physiology, including organ perfusion, cardiovascular function, selected endocrine and immune system disorders.
    公开号:KR20020010716A
    申请号:KR1020017016235
    申请日:2000-06-20
    公开日:2002-02-04
    发明作者:데이비드이. 니콜라스；러셀에이. 그루브스；리차드비. 메일맨
    申请人:추후제출；펄듀 리서치 파운데이션；유니버시티 오브 노스캐롤라이나 앳 채플 힐；
    IPC主号:
    专利说明:

    CHROMENO [4,3,2-de] ISOQUINOLINES AS POTENT DOPAMINE RECEPTOR LIGANDS} A powerful dopamine receptor ligand
    [2] Dopamine, a neurotransmitter in the central nervous system, is involved in many neurological diseases. For example, excessive palpation of the dopamine receptor subtype is believed to be associated with schizophrenia. In addition, other behavioral, neurological, psychological, and motor disorders, including Parkinson's disease, a chronic progressive disease characterized by excessive or insufficient functional dopamine activity in the central and / or peripheral nervous system, characterized by hypertension, sleep sickness, and the inability to control the spontaneous motor system. It is recognized to cause.
    [3] Dopamine receptors are traditionally classified into two groups (D 1 and D 2 dopamine receptors) based on pharmacological and functional evidence. The D 1 receptor preferentially recognizes phenyltetrahydrobenzazepine and promotes adenylate cyclase, while the D 2 receptor recognizes butyrophenone and benzamide and does not bind with adenylate cyclase. Subtypes of the dopamine receptor: At least five genes are known to exist for the D 1 , D 2 , D 3 , D 4 , D 5 receptors. However, traditional classification is still useful, where the D 1 -like type consists of the D 1 (D 1A ) and D 5 (D 1B ) receptor subtypes, and the D 2 -like type is the D 2 , D 3 , D 4 receptor subtype It consists of. Mutations can occur through splicing variants (eg, D 2L and D 2S splicing variants) as well as with different alleles (eg, multiple repetitions of the D 4 gene).
    [4] Central nervous system drugs that show affinity for dopamine receptors are generally classified as receptor selectivity and agonist (receptor activation) or antagonist (receptor blocking) activity. Although the bioactivity involved in the interaction of various receptor subtypes with dopamine has not been fully identified, ligands showing selectivity for specific receptor subtypes are known to produce somewhat predictable neuropharmacological results. The availability of selective dopamine receptor antagonists and agonists can enable the design of experiments to understand the various roles of the D 1 receptor and may result in novel therapies for various central and peripheral nervous system diseases. In addition, where agonists have high affinity for both D 1 and D 2 receptors, these agonists can be used in situations where it is advantageous to bind to both D 1 and D 2 receptors.
    [5] The initial focus of dopamine receptor research was focused on the D 2 group, but now the role of dopamine D 1 receptors in nervous system function is emerging. Early research on selective D 1 receptor ligands focused on phenyltetrahydrobenzazepine molecules such as the antagonist SCH23390 (1):
    [6]
    [7] Some of the phenyltetrahydrobenzazepine molecules have been found to be D 1 receptor agonists; However, agonists derived from these species (eg SKF38393 (+) (2)) are generally partial agonists. It was recently found that SKF82958, which was considered a complete agonist, also failed to achieve full inherent efficacy in formulations with reduced receptor storage. The difference between full and partial efficacy D 1 agonists is important in medical research because they can affect the action of these compounds on complex central nervous system mediated phenomena. For example, two complete agonists (dihydrexidine and A-77636) show exceptional anti-Parkinson effect in MPTP-treated monkey models, while partial agonists do not show significant activity. More recent data suggest that full and partial agonists differ in their effects on other complex neurological functions. In addition, there are receptor-mediated phenomena that may affect agonist activity (eg, recruitment of G proteins and related receptor kinases). These biochemical phenomena can proceed independently of changes in drug-mediated secondary messenger levels (eg cAMP).
    [8] Thus, the researchers are focusing their efforts on designing ligands that are fully agonists (ie, possessing complete intrinsic potency) for the D 1 receptor. One such compound is dihydrexidine (3), a hexahydrobenzo [a] phenanthridine having the formula:
    [9]
    [10] The structure of the dihydricdine (3) is distinguished from other D 1 agonists because the molecule is relatively rigid due to the additional ring system. In molecular modeling studies of dihydrexidine (3), it has been found that the compound has a limited number of low energy types and the aromatic rings remain in the same arrangement in all forms. The recent description of the active enantiomeric form of dihydrexidine is consistent with the expectations of this model.
    [11] Unlike other highly affinity highly active D 1 agonists such as 3-substituted aminomethylisochromances, dihydrexidine (3) provides a medium-stiff template for the development of dopamine ligand models. Essential features of the model include the presence of the transoid β-phenyldopamine component, the isolated electron pair in the equatorial direction at the basic nitrogen atom, and the coplanarity of the catechol and phenyl rings. The dihydrolexidine-based model possesses the transoid β-phenyldopamine component, while the dopaminergic phenyltetrahydrobenzazepine has the cis type β-phenyldopamine form. Dihydrexidine-based models serve as the basis for the design of additional D 1 receptor agonists. The design and synthesis of D 1 receptor agonists with high intrinsic activity is important for medical research due to the potential utility of complete agonists in the treatment of complex central nervous system phenomena and diseases involving peripheral dopamine receptors. For example, the composition according to the invention has potential utility as a drug that lowers blood pressure and affects lung and kidney function.
    [12] One embodiment according to the invention is a novel dopamine receptor antagonist, a pharmaceutically acceptable salt thereof and a pharmaceutical composition of such a compound having the formula:
    [13]
    [14] The compounds herein are useful for treating dopamine-related disorders of the central nervous system (obvious neurological, psychological, physiological or behavioral disorders) and diseases involving peripheral dopamine receptors (in tissues such as the kidneys, lungs, endocrine, cardiovascular system).
    [1] The present invention relates to novel ligands for the dopamine receptor. More specifically, the present invention provides compositions for treating optionally substituted 1,2,3,11b-tetrahydrochromeno [4,3,2-de] isoquinoline compounds and dopamine-related disorders of the central and peripheral nervous system. In regards to their use.
    [15] 1 is an affinity diagram of dioxylin (circle), dinaphsolin (diamond), and (+)-SCH23390 (triangle) for progenitor D 1 receptor. The murine progenitor D 1 receptor is labeled with [ 3 H] SCH23390 (1), and the specific binding of each compound to the D 1 receptor is determined by addition of unlabeled dioxylin, dinaphsolin or (+)-SCH23390. .
    [16] FIG. 2 is an affinity plot of dinoxiline (circle), dinaphsolin (diamond), and (+)-SCH23390 (triangle) for progenitor D 1 receptor expressed in C-6 cells. The D 1 receptor is labeled with [ 3 H] SCH23390 (1), and the specific binding of each compound to the D 1 receptor is determined by addition of unlabeled dioxylin, dinaphsolin or (+)-SCH23390.
    [17] FIG. 3 is an affinity plot of dioxylin (circle), dinaphsolin (diamond), chloropromazine for the progenitor D 2 receptor labeled [ 3 H] spireron. Unlabeled dioxylin, dinaphsolin or chloropromazine are added to determine the specific binding of each compound to the D 2 receptor.
    [18] 4 is a plot of opposite rotational speeds over time in a unilateral 6-OHDA lesion rat model treated with dioxylin (square) or dihydrexidine (circle).
    [19] According to the present invention there is provided a compound having the formula: and a pharmaceutically acceptable salt thereof.
    [20] Formula I
    [21]
    [22] Wherein R 1 -R 3 is hydrogen, C 1 -C 4 alkyl or C 2 -C 4 alkenyl;
    [23] R 8 is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group;
    [24] X 9 is hydrogen, halo (including chloro, fluorine, bromo) or —OR, wherein R is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group;
    [25] R 4 , R 5 , R 6 are hydrogen, C 1 -C 4 alkyl, phenyl, halo or —OR, wherein R is as defined above;
    [26] When X 9 is -OR, R 8 and R combine with each other to form -CH 2-.
    [27] "C 2 -C 24 alkenyl" means allyl, 2-butenyl, 3-butenyl, vinyl.
    [28] "C 1 -C 4 alkyl" means a branched or straight chain alkyl group consisting of 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclopropylmethyl But not limited to them.
    [29] In one embodiment, at least one of R 4 , R 5 or R 6 is hydrogen. In other embodiments, at least two of R 4 , R 5 or R 6 are hydrogen.
    [30] "Pharmaceutically acceptable salt" means salts made with organic or inorganic acids, which salts are suitable for use in humans and lower animals without causing unnecessary toxicity, allergic reactions. Acids suitable for preparing pharmaceutically acceptable salts of biologically active compounds having amine functionality are known in the art. These salts can be prepared according to conventional in situ methods during the final separation and purification of the compounds of this invention, or by reacting the compounds separated in free base form with a suitable salting acid.
    [31] By "phenoxy protecting group" is meant a substituent in the phenolic ring oxygen which can prevent unwanted reactions and degradation during synthesis and can subsequently be removed without affecting other functional groups in the molecule. Such protecting groups and their application and removal methods are known in the art. These include ethers such as cyclopropylmethyl, cyclohexyl, allyl ether and the like; Alkoxyalkyl ethers such as methoxymethyl and methoxyethoxymethyl ether; Alkylthioalkyl ethers such as methylthiomethyl ether; Tetrahydropyranyl ether; Arylalkyl ethers such as benzyl, o-nitrobenzyl, p-methoxybenzyl, 9-anthrylmethyl, 4-picolyl ether and the like; Trialkylsilyl ethers such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl ether and the like; Alkyl and aryl esters such as acetate, propionate, butyrate, isobutyrate, trimethyl acetate, benzoate and the like; Carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, benzyl and the like; Carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl and the like.
    [32] "C 1 -C 4 alkoxy" means a branched or straight chain alkyl group consisting of 1 to 4 carbon atoms bonded through an oxygen atom, including methoxy, ethoxy, propoxy, t-butoxy It is not limited to these.
    [33] In addition, according to another embodiment of the present invention, the compounds of the present invention may be prepared in conventional drug dosage forms for use in the treatment of patients suffering from dopamine-related disorders of the central or peripheral nervous system. The effective amount of a compound of this invention depends on a variety of factors, including symptoms, route of administration, and overall condition of the patient. Upon oral administration, an effective amount of the compound of the present application is expected to be 0.1 to 50 mg / kg, preferably 0.5 to 25 mg / kg. The intestinal effective amount is 0.01 to 5 mg / kg body weight. In general, the treatment regimen with a compound according to the invention consists of administering from 1 mg to 500 mg of the compound herein daily in multiple or single doses.
    [34] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions and syrups containing inert diluents (eg, water) commonly used in the art. Such compositions may also contain adjuvant such as wetting agents, emulsifiers, suspending agents, sweeteners, fragrances. Injectable formulations of the compounds of the present invention can be prepared by dispersing or dissolving an effective amount of the compound of the present invention in an externally acceptable diluent (eg, water), preferably an isotonic sodium chloride solution, utilizing conventionally approved products. Extra-intestinal formulations can be sterilized using conventional microfiltration techniques.
    [35] In addition, the present compounds can be prepared in solid dosage forms for oral administration such as capsules, tablets, powders, pills and the like. Generally, the active compound is mixed with an inert diluent such as sucrose or starch or with a carrier and other excipients suitable for the pharmaceutical form. Thus, tablet formulations contain acceptable lubricants, binders and / or disintegrants. Alternatively, the active compounds of the present invention and powder compositions composed of, for example, starch or sucrose, may be filled into gelatin capsules for oral administration. Other dosage forms of the compounds may be prepared utilizing existing techniques in a form suitable for the particular mode of administration.
    [36] One of the compounds provided according to the invention is (±) -8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno [4,3,2-de] isoquinoline hydrobromide (hereinafter, "Dinoxylin". Dioxylin is synthesized from 2,3-dimethoxyphenol as shown in Scheme I. The phenol group is protected with methoxymethyl (“MOM”) derivatives and then treated with butyllithium and substituted borolane to yield the borolane derivative (2).
    [37] As shown in Scheme I, the borolein derivative is used for Pd-catalyzed suzuki type crosslinking with 5-nitro-4-bromoisoquinoline. Thereafter, the resulting combined product (4) is treated with toluenesulfonic acid dissolved in methanol to remove the MOM protecting group of phenol. Treatment of the nitrophenol (5) with sodium carbonate at 80 ° C. DMF induces ring closure due to nitrogen group loss, which yields a basic tetracyclic chromenoisoquinoline nucleus (6). Compound (7) is obtained by reducing the nitrogen-bearing ring by simple catalytic hydrogenation. When the methyl ether bond is cleaved using boron tribromide, the parent compound (8) is produced.
    [38] With appropriate substitution in the isoquinoline ring, various substituted compounds can be obtained. Substitution of the nitrogen atom in compound (6) or (7) and subsequent reduction readily yields a series of compounds substituted with a lower alkyl group at the nitrogen atom. Similarly, alkyl substituents at the 1,3,6,7 or 8 positions of nitroisoquinoline (3) can be used to obtain various ring-substituted compounds. In addition, the 3-position of compound (6) may be substituted directly with various alkyl groups. Similarly, substitution of the 4-methoxy group of compound (2) in fluorine, chloro or alkyl groups in Scheme I yields the desired compound that is mutated at X 9 . Reduction can be achieved with sodium cyanoborohydride at a slightly acidic pH when functional groups are present in the nuclei that become unstable under catalytic hydrogenation conditions utilized to convert compound (6) to compound (7). In addition, N-alkyl tetravalent salt formation of derivative (6) results in a compound that is readily reduced to sodium borohydride, where derivative (7) is obtained.
    [39] Scheme I: Scheme for the synthesis of 8,9-dihydroxy-1,2,3-11b-tetrahydrochromeno [4,3,2-de] isoquinoline hydrobromide
    [40]
    [41] At (+)-trans-10,11-dihydroxy-5,6,6a, 7,8,12b-hexahydrobenzo [α] phenanthridine [(+)-dihydrexidine] and 12bS polarization center Compare the space-filled phenotype of the low energy form for the 11bR enantiomer of (+)-dihydrexidine and isopolarized dioxycillin. Two major structural features can be easily identified. First, the space provided by the C (7) -C (8) ethano bridge in dihydrexidine (3) is removed. Second, the angle of the protruding phenyl ring relative to the catechol ring side changes slightly. This is most pronounced in the front where the aromatic hydrogen H (1) protrudes over the catechol ring in the dihydrexidine (3). However, in dioxylin this position is used to link the phenyl ring protruding through the oxygen atom to the catechol ring; This causes the projected phenyl ring to twist clockwise as compared to the dihydricdine 3 when viewed from above. Given the degree of morphological flexibility of the heterocyclic ring, the amino groups are in similar positions. In addition, both molecules can provide the NH vector in the equator direction, which is characteristic of pharmacological action groups that are considered important for the D 1 receptor agonist. The pharmacological properties of these two molecules are similar, which supports these observations.
    [42] Experiments were performed to determine the binding of dioxylin at the D 1 receptor. Dynoxylin was found to have a similar affinity (K 0.5 <5 nM) to dinaphsolin for the murine progenitor D 1 receptor. In addition, in competition experiments with unlabeled SCH23390 (1) as competing substances, dioxycillin was found to have a very close competing curve (n H = ca.0.7), competing with high affinity, consistent with agonist properties. 1 and 2. The agonist properties of dioxylin at the D 1 receptor were confirmed in vitro by measuring the activity of dioxylin to increase cAMP production in rat progenitors and C-6-mD 1 cells. In both murine progenitors and C-6-mD 1 cells, dioxycillin exhibits complete action with an EC 50 of less than 30 nM and promotes cAMP synthesis through the D 1 receptor.
    [43] Thus, the pharmacological data indicates that dioxylin is a (+)-trans-10,11-dihydroxy-5,6,6a, 7,8,12b-hexahydrobenzo [α] phenanthridine (dihydrexidine It demonstrates high affinity for the dopamine D 1 receptor labeled [ 3 H] SCH23390 which is greater than (3)). In addition, dioxylin in the mouse progenitor membrane and cloned and expressed protoder D 1A receptor is a complete agonist compared to dopamine, similar to dihydrexidin (3) but partially agonist (+)-SKF38393 (FIGS. 2 and 3 (+)-SKF38393 = (+)-2; (±) -trans-10,11-dihydroxy-5,6,6a, 7,8,12b-hexahydrobenzo [α] phenanthridine = ( ±) -3; (±) -8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naphtho [1,2,3-de] isoquinoline = 4; dinaphsolin) Is different.
    [44] Based on the D 1 pharmacological step, it is expected that only one of the enantiomers of its 11bR absolute configuration (and its polarized analogs) will have the affinity and intrinsic activity of racemic dioxylin (and its substituted analogs). In the separation of racemates utilizing conventional separation techniques, it is expected that one racemic dimer will yield one dioxylin isomer having a D 1 affinity.
    [45] Dihydrexidine was found to be 10-fold D 1 : D 2 selectivity. Dihydrexidine also possesses a unique property called "selectivity of action" while retaining dopamine agonist activity. Specifically, dihydrexidines function as agonists at post-synaptic located D 2 -like receptors in mice (in vivo or in vitro), but function as antagonists at pre-synaptic D 2 -like receptors. This is believed to be due to the difference in ligand-receptor-G protein complexes located at post-synaptic vs. pre-synaptic, as measured by specific G proteins present in any cellular environment. As shown in FIG. 1 and Table 1, dioxycillin has a higher affinity than dihydrexidine for D 2 -like receptors, which is very high affinity for D 1 and D 2 receptors in mammalian brain. It is the first complete agent with In addition, dioxycillin is different from dihydrexidine in "function selectivity".
    [46] This D 2 property of dihydrexidine was found to be present in the same enantiomer (ie 6aR, 12bS), a highly affinity complete agonist at the D 1 receptor. Based on this, the D 1 and D 2 properties of dioxylin are expected to exist in the co-polar enantiomers. Optical isomers and appropriate analogs of dioxylin are excellent tools for studying "action selectivity" phenomena.
    [47] The anti-Parkinsonian effect of dihydrexidine has been reported in the MPTP model of Parkinson's disease, which is expected to have a similar effect. As shown in FIG. 4, dioxylin was tested in a rat unilateral 6-OHDA-lesion model showing dopamine agonist activity in vivo, and anti-Parkinson drug efficacy was predicted. As can be seen, dioxylin produces a significant rotation that persists approximately 5 hours after a single subcutaneous administration. This is more than twice the duration of action of the same amount of dihydrexidine administered by the same route. Preliminary studies were conducted in marmosets showing mildly-severe MPTP-induced dopamine denervation, consistent with the data. Dioxylin has been shown to possess significant anti-Parkinson's effect, increasing migration and arousal and reducing Parkinson's signs. Thus, dioxylin and its derivatives have potent clinical utility in Parkinson's disease and other diseases where perturbation of dopamine receptors is beneficial for treatment. In addition, it has been reported that appropriate modification of the dihydricidine results in the formation of analogs that target specific subgroups of the dopamine receptor group. While similar strategies utilizing dioxylin have resulted in compounds with novel receptor subtype selectivity and / or action profiles, the effect of these substituents is not the same as the dihydricidine backbone.
    [48] Although dopamine activates all dopamine receptors, it is rarely used as a drug in that it must be administered intravenously and can activate other monoamine receptors with very short pharmacokinetic half-lives. The series according to the invention differs from the existing rigid dopamine analogues in several important ways. First, it is a series of highly affinity fully D 1 agonists with at least equally high affinity for the D 2 receptor. Thus, dihydrexidine is 10-fold D 1 : D 2 selective, and dinaphsolin is 5-fold D 1 : D 2 selectivity, while dioxycillin has substantially the same affinity for both receptors. In the two previous series, D 2 affinity could be increased, but D 1 affinity had to be abandoned instead. The series according to the invention provides drugs with high affinity for both receptor populations. Drugs that show high affinity for both D 1 and D 2 offer distinct clinical advantages over drugs that show high affinity for only one major crowd. The novelty of the series according to the present invention becomes clearer by examining the interaction with specific dopamine receptor allotropes. An important difference between the series according to the invention and existing drugs (eg dihydrexidine and dinaphsolin) is that these drugs have no affinity for the D 4 receptor allotropes. In contrast, dioxycillin has a K 0.5 of less than 45 nM, compared to> 1,000 for dinaphsolin, dihydrexidine or analogs thereof at the cloned human D 4 receptor. Although D 4 antagonists seem to lack efficacy in treating schizophrenia, there is tremendous potential for the use of highly affinity D 4 agonists in selected psychological and neurological diseases.
    [49] Another important difference in the series according to the invention is the substitution effect on receptor activity. This was expected based on the availability of dihydrexidine that N-propyl or N-allyl addition significantly increased the D 2 affinity of the parent ligand. In practice, these N-substituents significantly reduce the D 2 affinity of the parent compound. This dramatic difference suggests that dioxylin binds to the D 2 receptor in unexpected ways and exhibits unique therapeutic efficacy.
    [50] Referring to the experimental procedure below, the melting point is measured and not corrected by the Thomas-Hover Melting Point apparatus. 1 H NMR spectra are recorded on a Varian VXR 500S (500 MHZ) NM apparatus, and chemical transitions are recorded in relative values (ppm) in TMS. IR spectra are recorded on KBr-pellets or liquid films with Perkin Elme 1600 series FTIR analyzers. Chemical ionization mass spectra (CIMS) are recorded on a Finnigan 4000 quadrupole mass spectrometer. High resolution CI spectra are recorded with the Kratos MS50 analyzer. Basic analytical data was obtained from a microanalysis laboratory at West Lafayette, IN.
    [51] THF is distilled from benzophenone-sodium under nitrogen just before use; 1,2-dichloroethane is distilled from pentoxide phosphate before use.
    [52] Example 1A: 8,9-dihydroxy-1,2,3,11b-tetrahydroclomeno [4,3,2-de] isoquinoline hydrobromide (dinoxylin)
    [53] 1,2-dimethoxy-3-methoxymethoxybenzene (1)
    [54] The sodium hydride slurry is prepared by adding 7.06 g (0.18 mol) sodium hydride (60% dispersion in mineral oil) in 100 ml dry THF under an 0 ° C. argon atmosphere. 2,3-dimethoxy phenol (23.64 g; 0.153 mol) is added to the slurry via a syringe. The resulting solution is warmed up to room temperature and stirred for 2 hours. The black solution is cooled to 0 ° C. and 13.2 ml chloromethyl methyl ether (14 g; 0.173 mol) is slowly added via syringe. The solution is warmed to room temperature and stirred for an additional 8 hours. The yellow mixture is concentrated to an oil, which is dissolved in 1000 ml diethyl ether. The resulting solution is washed with water (500 mL), 2N NaOH (3 × 400 mL), dried (MgSO 4 ) filtered and concentrated. After Kugelrohr distillation (90-100 ° C., 0.3 atm), 24.6 g of a clear oil (84%) are obtained: 1 H NMR: (300 MHz, CDCl 3 ): 6.97 (t, 1H, J = 8.7 Hz); 6.79 (dd, 1H, J = 7.2, 1.8 Hz); 6.62 (dd, 1H, J = 6.9, 1.2 Hz); 5.21 (s, 2 H); 3.87 (s, 3 H); 3.85 (s, 3 H); 3.51 (s, 3 H). CIMS m / z: 199 (M + H + , 50%); 167 (M + H + -CH 3 OH, 100%). Anal for C 10 H 14 O 4 . Calc'd: C, 60.59; H, 7.12. Found: C, 60.93; H, 7.16.
    [55] 2- (3,4-dimethoxy-2-methoxymethoxyphenyl) -4,4,5,5, -tetramethyl [1,3,2] dioxaborolane (2).
    [56] MOM-protected phenol (1) (10 g; 0.0505 mol) is dissolved in 1000 ml of dry diethyl ether and cooled to -78 ° C. Then, n-butyl lithium (22.2 mL, 2.5 M) solution is added via syringe. The cooling bath is removed and the solution is warmed to room temperature. After stirring the solution at room temperature for 2 hours, a yellow precipitate is observed. The mixture is cooled to -78 ° C and 15 ml 2-isopropoxy-4,4-5,5-tetramethyl-1,3,2-dioxaborolane (0.080 mol) is added via syringe. After 2 hours the cooling bath is removed. Stirring is continued for 4 hours at room temperature. The mixture is then poured into 300 ml water, extracted with diethyl ether (3x300 ml), dried (Na 2 SO 4 ) and concentrated to a yellow oil, which is used without further purification: 1 H NMR: (300 MHz, CDCl 3 ): 7.46 (d, 1 H, J = 8.4 Hz); 6.69 (dd, 1H, J = 8.4 Hz); 5.15 (s, 2 H); 3.87 (s, 3 H); 3.83 (s, 3 H); 1.327 (s, 12 H).
    [57] 4-bromo-5-nitroisoquinoline (3).
    [58] Potassium nitrate (5.34 g; 0.052 mol) is added to 20 ml of concentrated sulfuric acid and carefully heated to dissolve slowly. The resulting solution is added dropwise to a solution of 4-bromoisoquinoline (10 g; 0.048 mol) dissolved in 40 mL of the same acid at 0 ° C. After removing the cooling bath, the solution is stirred at room temperature for 1 hour. The reaction mixture is then poured into crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate is collected by filtration, the filtrate is extracted with diethyl ether (3 × 500 mL), dried (Na 2 SO 4 ) and concentrated to give a yellow solid, which is mixed with the initial precipitate. Recrystallization from methanol yields 12.1 g (89%) of pale yellow crystals: mp 172-174 ° C .; 1 H NMR: (300 MHz, CDCl 3 ): 9.27 (s, 1 H); 8.87 (s, 1 H); 8.21 (dd, 1H, J = 6.6, 1.2 Hz); 7.96 (dd, 1H, J = 6.6, 1.2 Hz); 7.73 (t, 1 H, J = 7.5 Hz); CIMS m / z: 253 (M + H + , 100%); 255 (M + H + +2, 100%). Anal for C 9 H 5 BrN 2 O 2 . Calc'd: C, 42.72; H, 1.99; N, 11.07. Found: C, 42.59; H, 1.76; N, 10.87.
    [59] 4- (3,4-dimethoxy-2-methoxymethoxyphenyl) -5-nitroisoquinoline (4).
    [60] Isoquinoline (3) (3.36 g; 0.0143 mol), pinacol boronate ester (2) (5.562 g; 0.0172 mol), 1.0 g (6 mol%) tetrakis (triphenylphosphine) palladium (0) 100 ml It is suspended in dimethoxyethane (DME). Potassium hydroxide (3.6 g; 0.064 mol) and 0.46 g (10 mol%) tetrabutylammonium bromide are dissolved in 14.5 ml of water and added to the DME mixture. The resulting suspension is degassed with argon for 30 minutes and then heated at reflux for 4 hours. The resulting black solution is cooled to room temperature, poured into 500 mL water, extracted with diethyl ether (3 × 500 mL), dried (Na 2 SO 4 ) and concentrated. The product was then purified by column chromatography (silica gel, 50% ethyl acetate: hexane) to give 5.29 g of yellow crystals (80.1%): mp 138-140 ° C .; 1 H NMR: (300 MHz, CDCl 3 ): 9.33 (s, 1 H); 8.61 (s, 1 H); 8.24 (dd, 1H, J = 7.2, 0.9 Hz); 8.0 (dd, 1H, J = 6.3, 1.2 Hz); 7.67 (t, 1 H, J = 7.8 Hz); 7.03 (t, 1H, J = 9.6 Hz); 6.81 (d, 1 H, J = 8.1 Hz); 4.86 (d, 1 H, J = 6 Hz); 4.70 (d, 1 H, J = 5.4 Hz); 3.92 (s, 3 H); 3.89 (s, 3 H); 2.613 (s, 3 H). CIMS m / z: 371 (M + H + , 100%). Anal for C 19 H 18 N 2 O 6 . Calc'd: C, 61.62; H, 4. 90; N, 7.56. Found: C, 61.66; H, 4. 90; N, 7.56.
    [61] 2,3-dimethoxy-6- (5-nitroisoquinolin-4-yl) phenol (5).
    [62] After gently heating to dissolve isoquinoline (4) (5.285 g, 0.014 mol) in 200 ml methanol, p-toluenesulfonic acid monohydrate (8.15 g; 0.043 mol) is added. Stirring is continued for 4 hours at room temperature. At the end of the reaction, the solution is made basic by addition of saturated sodium bicarbonate. The product is then extracted with dichloromethane (3 × 250 mL), dried (Na 2 SO 4 ) and concentrated. The resulting yellow solid (4.65 g; 98%) is used directly in the next reaction. Analytical samples are recrystallized from methanol: mp 170-174 ° C .; 1 H NMR: (300 MHz, CDCl 3 ): 9.33 (s, 1 H); 8.62 (s, 1 H); 8.24 (dd, 1H, J = 7.2, 0.9 Hz); 7.99 (dd, 1H, J = 6.3, 1.2 Hz); 7.67 (t, 1 H, J = 7.8 Hz); 6.96 (d, 1H, J = 8.7 Hz); 6.59 (d, 1 H, J = 8.7 Hz); 5.88 (bs, 1 H); 3.94 (s, 3 H); 3.92 (s, 3 H). CIMS m / z: 327 (M + H + , 100%). Anal for C 17 H 14 N 2 O 5 . Calc'd: C, 62.57; H, 4. 32; N, 8.58. Found: C, 62.18; H, 4.38; N, 8.35.
    [63] 8,9-dimethoxychromeno [4,3,2-de] isoquinoline (6).
    [64] Phenol (5) (4.65 g, 0.014 mol) is dissolved in 100 ml dry N, N-dimethylformamide. The solution is degassed with argon for 30 minutes. Potassium carbonate (5.80 g, 0.042 mol) is added to the yellow solution. After heating at 80 ° C. for 1 hour, when the mixture turns brown, no further starting material remains. After cooling the solution to room temperature, 200 ml water is added. The aqueous layer is extracted with dichloromethane (3x500 mL), the organic extract is extracted with water (3x500 mL), dried (Na 2 SO 4 ) and concentrated. White powder (3.65 g 92%) was obtained, which was used for the next reaction without further purification. Analytical samples are recrystallized from ethyl acetate: hexanes: mp 195-196 ° C .; 1 H NMR: (300 MHz, CDCl 3 ): 9.02 (s, 1 H); 8.82 (s, 1 H); 7.87 (d, 1 H, J = 8.7 Hz); 7.62 (m, 3 H); 7.32 (dd, 1H, J = 6.0, 1.5 Hz); 6.95 (d, J = 9.6 Hz); 3.88 (s, 3 H); 3.82 (s, 3 H). CIMS m / z: 280 (M + H + , 100%).
    [65] 8,9-dimethoxy-1,2,3,11b-tetrahydrochromeno [4,3,2-de] isoquinoline (7).
    [66] Platinum (IV) oxide (200 mg) is added to a solution containing 50 ml acetic acid and isoquinoline (6) (1 g; 3.5 mmol). After addition of 2.8 mL of concentrated HCl, the mixture is stirred at 60 psi in a Parr hydrogenator for 24 hours. The green solution is filtered through Celite to remove the catalyst and most of the acetic acid is removed by rotary evaporation. The remaining acid is neutralized with saturated sodium hydrogen carbonate solution, extracted with diethyl ether (3x250 mL), dried (Na 2 SO 4 ) and concentrated. The resulting oil (0.997 g; 99%) is used without further purification: 1 H NMR: (300 MHz, CDCl 3 ): 7.10 (t, 1H, J = 7.5 Hz); 7.00 (d, 1H, J = 8.4 Hz); 6.78 (m, 2 H); 6.60 (d, 1 H, J = 9 Hz); 4.10 (s, 2 H); 3.84 (m, 8 H); 2.93 (t, 1 H, J = 12.9 Hz).
    [67] 8,9-dimethoxy-1,2,3,11b-tetrahydrochromeno [4,3,2-de] isoquinolinehydrobromide (8).
    [68] Crude 7 (0.834 g; 3.0 mmol) was dissolved in 50 mL anhydrous dichloromethane. The solution is cooled to −78 ° C. and 15.0 mL boron tribromide solution (1.0 M / dichloromethane) is slowly added. The solution is stirred overnight and the reaction is slowly warmed to room temperature. The solution is cooled back to −78 ° C. and the reaction is allowed to settle by the slow addition of 50 ml methanol. The solution is then concentrated to dryness. Methanol is added and the solution is concentrated. This process is repeated three times. The resulting brown solid is treated with activated charcoal and recrystallized from ethanol: mp 298-302 ° C. dec; 1 H NMR: (300 MHz, D 2 O): 7.32 (t, 1 H, J = 6.6 Hz); 7.13 (d, 1 H, J = 8.4 Hz); 7.04 (d, 1H, J = 8.4 Hz); 4.37 (m, 2 H); 4.20 (t, 3H, J = 10 Hz); Anal for C 15 H 14 BrNO 3 H 2 O. Calc'd: C, 50.87; H, 4.55; N, 3.82. Found: C, 51.18; H, 4.31; N, 3.95.
    [69] N-allyl-8,9-dimethoxy-1,2,3,11b-tetrahydrochromeno [4,3,2-de] isoquinoline (10).
    [70] Tetrahydroisoquinoline (7) (1.273 g; 4.5 mmol) is dissolved in 150 ml acetone. Potassium carbonate (0.613 g; 4.5 mmol) and 0.4 mL (4.6 mmol) allyl bromide are added. The reaction is stirred at rt for 4 h. The solid is then transferred by filtration and washed several times with ether in the filter. The filtrate was concentrated and purified by flash chromatography (silica gel, 50% ethyl acetate: hexane) to yield 1.033 g (71%) yellow oil, which was used without further purification: 1 H NMR: (300 MHz, CDCl 3 ): 7.15 (t, 1 H, J = 9 Hz); 7.04 (d, 1 H, J = 9 Hz); 6.83 (m, 2 H); 6.65 (d, 1 H, J = 6 Hz); 5.98 (m, 1 H); 5.27 (m, 2 H); 4.10 (m, 3 H); 3.95 (s, 3 H); 3.86 (s, 3 H); 3.46 (d, 1 H, J = 15 Hz); 3.30 (d, 2H, J = 6 Hz); 2.56 (t, 1H, J = 12 Hz).
    [71] N-allyl-8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno [4,3,2-de] isoquinoline (11).
    [72] N-allyl amine 10 (0.625 g; 1.93 mmol) is dissolved in 50 ml dichloromethane. The solution is cooled to −78 ° C. and 10.0 ml BBr 3 solution (1.0 M / dichloromethane) is slowly added. The solution is stirred overnight and the reaction is slowly warmed to room temperature. After cooling the solution back to −78 ° C., 50 ml methanol is slowly added to settle the reaction. The reaction is then concentrated to dryness. Methanol is added and the solution is concentrated. This process is repeated three times. The brown solid is recrystallized from ethanol to give 0.68 g (61%) of a white solid: mp 251-253 ° C. dec; 1 H NMR: (300 MHz, D 2 O): 10.55 (s, 1 H); 10.16 (s, 1 H); 8.61 (t, 1H, J = 9 Hz); 8.42 (d, 1 H, J = 9 Hz); 8.31 (d, 1H, J = 9 Hz); 7.87 (d, 1 H, J = 9 Hz); 7.82 (d, 1 H, J = 9 Hz); 7.36 (q, 1 H, J = 9 Hz); 6.89 (m, 2 H); 6.85 (d, 1 H, J = 15 Hz); 5.58 (m, 3 H); 5.28 (m, 2 H); 3.76 (d, 1 H, J = 3 Hz); HRCIMS m / z: Calc'd: 295.1208; Found: 295.1214.
    [73] N-propyl-8,9-dimethoxy-1,2,3,11b-tetrahydrochromeno- (4,3,2-de) -isoquinoline (12).
    [74] N-allyl amine 10 (1.033 g; 3.2 mmol) is dissolved in 50 ml ethanol. Palladium is then added in charcoal (10% dry; 0.013 g). The mixture is stirred at 60 psi in a Parr hydrogenator for 3 hours. Once the starting material no longer appears in TLC, the mixture is filtered through Celite and concentrated to yield 0.95 g (91%) oil, which is used without further purification: 1 H NMR: (300 MHz, CDCl 3 ): 7.15 (t, 1H, J = 7.2 Hz); 7.04 (d, 1 H, J = 8.1 Hz); 6.84 (d, 2H, J = 7.5 Hz); 6.65 (d, 1 H, J = 8.4 Hz); 4.07 (m, 2 H); 3.95 (s, 3 H); 3.86 (s, 3 H); 3.71 (q, 1 H, J = 5.1 Hz); 3.42 (d, 2H, J = 15.6 Hz); 2.62 (m, 2 H); 2.471 (t, J = 10.5 Hz); 1.69 (h, 2H, J = 7.2 Hz); 0.98 (t, 3H, J = 7.5 Hz). CIMS m / z: 326 (M + H + , 100%).
    [75] N-propyl-8,9-dihydroxy-1,2,3,11b-tetrahydrochrometo [4,3,2-de] isoquinoline (13).
    [76] N-propyl amine 12 (0.90 g; 2.8 mmol) is taken up in 200 ml dichloromethane and cooled to -78 ° C. In a separate 250 ml round bottom flask 125 ml dry dichloromethane is cooled to -78 ° C and 1.4 ml (14.8 mmol) BBr 3 is added via syringe. The BBr 3 solution is transferred to a flask containing the starting material using a cannula. The solution is stirred overnight and the reaction is slowly warmed to room temperature. After cooling the solution back to −78 ° C., 50 ml methanol is slowly added to settle the reaction. The reaction is then concentrated to dryness. Methanol is added and the solution is concentrated. This process is repeated three times. The resulting brown solid is suspended in hot isopropyl alcohol. Cool slowly to room temperature to obtain a fine yellow precipitate. The solid was collected by filtration (0.660 g; 63%): mp 259-264 ° C. dec; 1 H NMR: (300 MHz, CDCl 3 ): 7.16 (t, 1H, J = 9 Hz); 6.97 (d, 1H, J = 12 Hz); 6.83 (d, 1 H, J = 9 Hz); 6.55 (d, 1 H, J = 9 Hz); 6.46 (d, 1 H, J = 9 Hz); 4.45 (d, 1 H, J = 15 Hz); 4.10 (m, 3 H); 3.17 (q, 2H, J = 6 Hz); 3.04 (t, 1 H, J = 9 Hz); 1.73 (q, 2H, J = 9 Hz); 0.90 (t, 3H, J = 6 Hz); Anal for C 18 H 20 BrNO 3 . Calc'd: C, 57.16; H, 5. 33; N, 3.70. Found: C, 56.78; H, 5. 26; N, 3.65.
    [77] Pharmacological Properties of Dioxylin
    [78] Method: Radioreceptor Studies in Brain Tissue
    [79] Frozen rat ancestors are homogenized by hand hitting 8 ml ice-cold 50 mM HEPES buffer containing 4.0 mM MgCl 2 (pH 7.4) in a Wheaton Teflon-glass homogenizer. The tissue is centrifuged at 27,000 × g for 10 minutes, the supernatant is discarded, the pellet is homogenized (5 strikes), suspended in ice-cold buffer and centrifuged once more. The final pellet was suspended at a concentration of 2.0 mg wet weight / ml. The amount of tissue added to each assay tube is 1.0 mg in 1.0 mL final assay volume. D 1 receptor is labeled with [ 3 H] SCH 23390 (0.30 nM). The D 2 receptor is labeled with [ 3 H] spiferon (0.07 nM); Unlabeled ketanserine (50 nM) is attached to the 5HT 2 position by mask binding. Total binding is defined as the radioligand bound in the absence of any competitive agent. Nonspecific binding is measured by adding unlabeled SCH23390 (1 μM) or unlabeled chlorpromazine (1M) for D 1 and D 2 receptor binding assays, respectively. In each assay, triple measurements are made for each drug concentration. The assay tube is incubated at 37 ° C. for 15 minutes. Binding is terminated by filtration with ice-cold buffer in a Skatron 12 well cell harvester (Skatron, Inc., Sterling, VA) using a glass fiber filter mat (Skatron no.7034). The filter is dried and 2.0 ml Optiphase HI-SAF II radioactivity fluid is added. After stirring for 30 minutes, radioactivity is measured on an LKB Wallac 1219 RackBeta liquid scintillation counter (Wallac, Gaithersburg, MD). Tissue protein levels are measured using BCA protein assay reagents.
    [80] Function study in brain tissue
    [81] Frozen progenitor tissue (ca. 40 mg) was homogenized by hitting 4 ml buffer (5 mM Hepes, 2 mM EGTA, pH 7.5) 10 times in Wheaton Teflon-glass homogenizer. 4 ml of 50 mM Hepes containing 2 mM EGTA buffer (pH 7.5) is added and the tissue is blown three more times to homogenize. 20 μl aliquots of this tissue homogenate are added to the prepared reactions. The reaction mixture was 100 mM Hepes (pH 7.4), 100 mM NaCl, 4 mM MgCl 2 , 2 mM EDTA, 500 μM isobutyl methylxanthine (IBMX), 0.01% ascorbic acid, 10 μM pargiline, 2 mM ATP, 5 μM GTP, 20 mM phosphocristine , 5 units of creatine phosphokinase (CPK), DA at a selected concentration. The final reaction volume is 100 μl. Basal cAMP activity is determined by tissue culture in a reaction mixture to which no drug is added. Tubes are analyzed in duplicate. After 15 minutes of incubation at 30 ° C., the reaction is stopped by the addition of 500 μl of 0.1N HCl. The tube is vortexed briefly and then spun at 15,000 × g for 5 minutes in a BHG Hermle Z 230 M microcentrifuge to remove large particles.
    [82] The cAMP concentration in each sample is measured by the RIA of acetylated cAMP modified from that previously described (Harper and Brooker, 1975). Iodination of cAMP is carried out using conventional methods (Patel and Linden, 1988). Assay buffer is 50 mM sodium acetate buffer containing 0.1% sodium azide (pH 4.75). Standard curves of cAMP are prepared in buffer at a concentration of 2 to 500 fmole / assay tube. To improve assay sensitivity, all samples and standards are acetylated with 10 μl triethylamine: acetic anhydride 2: 1 solution. Samples are analyzed in duplicate. Each assay tube contains 100 μl diluted sample, 100 μl primary antibody (amount anti-cAMP diluted 1: 100,000 with 1% BSA in buffer), 100 μl [ 125 I] -cAMP (50,000 dpm / 100 μl buffer) do; Total assay volume is 300 μl. The tube is vortexed and stored at 4 ° C. overnight (approximately 18 hours). Antibody-bound radioactivity is then separated by adding 25 μl BioMag rabbit anti-goat IgG (Advanced Magnetics, Cambridge MA), then vortexed and incubated at 4 ° C. for an additional hour. To these samples 1 ml of 12% polyethylene glycol / 50 mM sodium acetate buffer is added and all tubes are centrifuged at 1700 × g for 10 minutes. The supernatant is aspirated and the radioactivity in the resulting pellet is measured with an LKB Wallac gamma counter (Gaithersburg, MD).
    [83] Radioreceptor Studies with Expressed Receptors
    [84] Radioreceptors and functional studies are conducted on cloned human or monkey receptors transfected into one of several cell lines (eg, C-6 glioma or Chinese hamster ovary (CHO) cells). Cells are grown in appropriate medium and harvested for membrane preparation at confluence. The flasks of the same passaged cells are scraped off with a rubber polyman and collected in a 50 ml centrifuge tube. They are spun at 1200xg for 10 minutes to pellet white cells. Discard the supernatant and then resuspend the cells by adding 5 ml PBS (phosphate buffered saline) / flask to the centrifuge tube. The tube is then centrifuged once more at 28,500 × g for 20 minutes. PBS is removed and the pellet is suspended in 10% DMSO / PBS solution. Cells are homogenized with polytron at setting 5 for 10 seconds. 1 ml aliquots are stored at −80 ° C. until used for receptor binding studies. The partial solution contains approximately 1 mg / ml protein as measured by BCA protein assay reagent (Pierce, Rockford, IL).
    [85] For D 1 -like receptors, membrane proteins (50-75 g) were added to each experimental compound and [ 3 H] SCH23390 in 50 mM Tris-HCl (pH 7.4) containing 120 nM NaCl, 5 mM KCl, 2 mM CaCl 2 , mM MgCl 2 . Incubate with (0.3nM). SCH23390 (5 μM) is used to define nonspecific binding. The tubes are treated three times with 500 μl final volume. After 30 minutes of incubation at 37 ° C., the tubes were quickly filtered through a Skatron fiberglass filter mat (11734) and 5 ml ice-cooled using a Skatron micro cell harvester (Skatron Instruments Inc., Sterling, VA) Wash with wash buffer (50 mM Tris, pH 7.4). The filter is dried and then punched into a scintillation vial (Skatron Instruments Inc., Sterling, VA). Optiphase 'HiSafe' II scintillation cocktail (1 ml) is added to each well. After stirring for 30 minutes, radioactivity in each sample is measured on an LKB Wallac 1219 Rackbeta liquid scintillation counter (Wallac Inc., Gaithersburg, MD). The same protocol is used for the D 2 -like receptor, except that [ 3 H] spireron (0.07 nM) is used as the radioligand.
    [86] Functional studies with expressed receptors
    [87] Agonist intrinsic activity is assessed by the ability of adenylate cyclase-promoting the selected compound, as measured by cAMP formation in whole cells. For example, the drug response curves for each drug are fitted with an S-shape function to determine the maximum efficiency concentration (peak peak) and EC 50 . All drugs are subjected to the same assay to reduce variability during cell passage. The confluent plate of cells is incubated with the drug dissolved in DMEM-H normal medium supplemented with 20 mM Hepes, 0.01% ascorbic acid, 500 μM iso-butyl-methyl xanthine (IBMX; pH 7.2; Medium A). The final volume for each well is 500 μl. In addition to the dose response curve for each drug, basal cAMP levels and isoproterenol-promoted (positive control via endogenous β 2 receptors) cAMP levels in each plate are measured. Each condition is carried out in a double well. After 10 minutes of incubation at 37 ° C., the cells are briefly washed with medium and the reaction is stopped by addition of 500 μl of 0.1N HCl. The cells are then cooled at 4 ° C. for 5-10 minutes, the cells are scraped off, and the volume is placed in 1.7 ml centrifuge tubes. 1 ml of 0.1N HCl is further added to each tube at a final volume of 1.5 ml / tube. The tube is short vortexed and then spun at 15,000 × g for 5 minutes to remove large particles in a BHG Hermle Z 230 M microcentrifuge. CAMP levels for each sample are measured as described above.
    [88] Data is calculated for each sample and expressed in pmol / mg / min cAMP. Basal cAMP levels are subtracted from the total amount of cAMP calculated for each drug condition. To minimize the variation between assays, the reference compound (DA; 100 μM) is included as an internal standard in each assay, which allows for normalization of the data. Data for each drug is expressed relative to the percentage of stimulation calculated by 100M DA. Normalized drug-response curves are analyzed by nonlinear regression using the algorithm for the S-curve in the curve fitting program InPlot (Graphad, Inc .; San Francisco, CA). In each curve, the program provides an estimate of the EC 50 and the calculated maximum stimulus (ie, the peak of the sigmoid curve).
    [89] Additional changes in each compound
    [90] The compounds of embodiments 1-56 set forth in Table II are synthesized using the starting materials corresponding to those shown in Scheme I according to the same general procedure as described in Example 1 above, but the keromenos shown for each embodiment Substituted with a suitable functional group to provide the substitution pattern represented in the isoquinoline fusion product. Thus, for example, substituted analogs 6,7 and / or 8 of Scheme 3 (Scheme I) provide the corresponding substituents R 6 , R 5 , R 4 in formula (I), respectively. The other 1 and 3 substituted isoquinolines (analogs of compound (3) in Scheme I) are used to provide corresponding substitution patterns in C 3 and C 1 of formula (I).
    [91]
    [92]
    [93] The examples herein are intended to clarify the invention and do not limit the invention to the compounds disclosed above. Modifications of exemplified compounds apparent to those skilled in the art are included within the scope and properties of the present invention as set forth in the following claims.
    权利要求:
    Claims (26)
    [1" claim-type="Currently amended] Compounds having the formula and pharmaceutically acceptable salts thereof:
    Formula I

    Wherein R 1 , R 2 , R 3 are hydrogen, C 1 -C 4 alkyl or C 2 -C 4 alkenyl;
    R 8 is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group;
    X 9 is hydrogen, halo or —OR, where R is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group, and when X 9 is —OR, R 8 and R combine with each other to form —CH 2 —;
    R 4 , R 5 , R 6 are hydrogen, C 1 -C 4 alkyl, phenyl, halo or —OR, where R is as defined above.
    [2" claim-type="Currently amended] The compound of claim 1, wherein X 9 is hydroxy and R 8 is hydrogen.
    [3" claim-type="Currently amended] The compound of claim 1 , wherein R 1 , R 2 , R 3 are hydrogen.
    [4" claim-type="Currently amended] The compound of claim 2, wherein R 1 , R 2 , R 3 are hydrogen.
    [5" claim-type="Currently amended] A compound according to claim 1 , wherein R 1 , R 3 , R 4 , R 5 , R 6 are each hydrogen.
    [6" claim-type="Currently amended] The compound of claim 1, wherein X 9 , R 8 are hydrogen.
    [7" claim-type="Currently amended] A compound according to claim 1 , wherein R 1 , R 3 are hydrogen.
    [8" claim-type="Currently amended] The compound of claim 1 , wherein R 1 , R 3 are C 1 -C 4 alkyl.
    [9" claim-type="Currently amended] The compound of claim 1, wherein R 2 is C 2 -C 4 alkenyl.
    [10" claim-type="Currently amended] A method of treating a patient with a central nervous system, a peripheral nervous system, or a peripheral organ that contains a dopamine receptor, which manifests as an apparent neurological, psychological, physiological or motor disorder, the method having an effective amount for reducing the symptoms of the disease. And administering to the patient a compound having the formula or a pharmaceutically acceptable salt thereof:
    Formula I

    Wherein R 1 , R 2 , R 3 are hydrogen, C 1 -C 4 alkyl or C 2 -C 4 alkenyl;
    R 8 is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group;
    X 9 is hydrogen, halo or —OR, where R is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group, and when X 9 is —OR, R 8 and R combine with each other to form —CH 2 —;
    R 4 , R 5 , R 6 are hydrogen, C 1 -C 4 alkyl, phenyl, halo or —OR, where R is as defined above.
    [11" claim-type="Currently amended] The method of claim 10, wherein X 9 is hydroxy and R 8 is hydrogen.
    [12" claim-type="Currently amended] The method of claim 10, wherein R 1 , R 2 , R 3 are hydrogen.
    [13" claim-type="Currently amended] 12. The method of claim 11, wherein R 1 , R 2 , R 3 are hydrogen.
    [14" claim-type="Currently amended] The method of claim 10, wherein R 1 , R 3 , R 4 , R 5 , R 6 are each hydrogen.
    [15" claim-type="Currently amended] The method of claim 10, wherein X 9 , R 8 are hydrogen.
    [16" claim-type="Currently amended] The method of claim 10, wherein R 1 , R 3 are hydrogen.
    [17" claim-type="Currently amended] The method of claim 10, wherein R 1 , R 3 are C 1 -C 4 alkyl.
    [18" claim-type="Currently amended] The method of claim 10, wherein R 2 is C 2 -C 4 alkenyl.
    [19" claim-type="Currently amended] A pharmaceutical composition for treating a patient with a dopamine-related disorder of the central nervous system, the composition comprising a therapeutically effective amount of a compound having the formula or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier Pharmaceutical Compositions
    Formula I

    Wherein R 1 , R 2 , R 3 are hydrogen, C 1 -C 4 alkyl or C 2 -C 4 alkenyl;
    R 8 is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group;
    X 9 is hydrogen, halo or —OR, where R is hydrogen, C 1 -C 4 alkyl or phenoxy protecting group, and when X 9 is —OR, R 8 and R combine with each other to form —CH 2 —;
    R 4 , R 5 , R 6 are hydrogen, C 1 -C 4 alkyl, phenyl, halo or —OR, where R is as defined above.
    [20" claim-type="Currently amended] 20. The pharmaceutical composition of claim 19, wherein X 9 is hydroxy and R 8 is hydrogen.
    [21" claim-type="Currently amended] 20. The pharmaceutical composition of claim 19, wherein R 1 , R 2 , R 3 are hydrogen.
    [22" claim-type="Currently amended] The pharmaceutical composition of claim 20, wherein R 1 , R 2 , R 3 are hydrogen.
    [23" claim-type="Currently amended] The pharmaceutical composition of claim 20, wherein R 2 is C 1 -C 4 alkyl.
    [24" claim-type="Currently amended] The pharmaceutical composition of claim 19, wherein R 2 is C 2 -C 4 alkenyl.
    [25" claim-type="Currently amended] 20. The pharmaceutical composition of claim 19, wherein at least one of R 4 , R 5 or R 6 is hydrogen.
    [26" claim-type="Currently amended] The pharmaceutical composition of claim 19, wherein at least two of R 4 , R 5, or R 6 are hydrogen.
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    同族专利:
    公开号 | 公开日
    DE60002867D1|2003-06-26|
    JP2003502428A|2003-01-21|
    ES2199837T3|2004-03-01|
    AU777522B2|2004-10-21|
    AU777522C|2005-07-28|
    WO2000078765A3|2001-06-28|
    US6413977B1|2002-07-02|
    DE60002867T2|2004-02-26|
    CA2373497A1|2000-12-28|
    US20050080266A1|2005-04-14|
    EP1192161A2|2002-04-03|
    PT1192161E|2003-09-30|
    EP1192161B1|2003-05-21|
    DK1192161T3|2003-08-25|
    NO20016255D0|2001-12-20|
    NZ515613A|2004-03-26|
    AU4536599A|2001-01-09|
    MXPA01013229A|2002-11-04|
    BR0011711A|2002-03-26|
    NO20016255L|2001-12-20|
    US6916832B2|2005-07-12|
    AU5749200A|2001-01-09|
    WO2000078765A2|2000-12-28|
    AT240959T|2003-06-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-06-21|Priority to US14016699P
    1999-06-21|Priority to US60/140,166
    2000-06-20|Application filed by 추후제출, 펄듀 리서치 파운데이션, 유니버시티 오브 노스캐롤라이나 앳 채플 힐
    2000-06-20|Priority to PCT/US2000/016857
    2002-02-04|Publication of KR20020010716A
    优先权:
    申请号 | 申请日 | 专利标题
    US14016699P| true| 1999-06-21|1999-06-21|
    US60/140,166|1999-06-21|
    PCT/US2000/016857|WO2000078765A2|1999-06-21|2000-06-20|CHROMENO[4,3,2-de]ISOQUINOLINES AS POTENT DOPAMINE RECEPTOR LIGANDS|
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