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    • 专利摘要:
    The present invention provides novel thyroid receptor ligands which are compounds of formula (I) (I) Wherein, X is oxygen (-O-), sulfur (-S-), carbonyl (-CO-), methylene (-CH 2 -) or -NH-; Y is - (CH 2 ) n -, wherein n is an integer from 1 to 5, or cis or trans-methylene; R 1 is halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms; R 2 and R 3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein at least one of R 2 and R 3 is not hydrogen; R < 4 > is hydrogen or lower alkyl; R < 5 > is hydrogen or lower alkyl; R < 6 > is a carboxylic acid or an ester or prodrug thereof; R 7 is hydrogen, an alkanoyl group or an aroyl group, or other group capable of biotransformation to produce a free phenolic structure (where R 7 = H). The present invention also provides a method of preventing, inhibiting or treating a metabolic dysfunction-related disease or a disease dependent on the expression of a T 3 regulatory gene, which comprises administering a therapeutically effective amount of the compound described above. Examples of such metabolic dysfunction-related diseases or diseases which depend on expression of a T 3 regulatory gene include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmia, depression, osteoporosis, hypothyroidism, thyroid gland, thyroid cancer, Congestive heart failure and skin disorders.
    公开号:KR20020075799A
    申请号:KR1020027010684
    申请日:2001-01-12
    公开日:2002-10-05
    发明作者:토드 제이슨 프렌즈；데니스 이. 라이오노；민솅 창
    申请人:브리스톨-마이어스스퀴브컴파니；
    IPC主号:
    专利说明:

    Aniline-Derived Ligands for the Thyroid Receptor < RTI ID = 0.0 >
    [2] The wide role of thyroid hormones in the regulation of metabolism in the body is well recognized, but the discovery and development of new specific agents to improve the treatment of hyperthyroidism and hypothyroidism is less common. It also limits the development of thyroid hormone agonists and antagonists for the treatment of other important clinical signs such as hypercholesterolemia, obesity and cardiac arrhythmia.
    [3] Thyroid hormones actually affect all somatic metabolism. At the normal level, these hormones maintain body weight, metabolic rate, body temperature and mood, and also affect serum low density lipoprotein (LDL) levels. That is, hypothyroidism has weight gain, high levels of LDL cholesterol and depression. If hyperthyroidism is excessive, thyroid hormones lead to weight loss, overdosage, reduced serum LDL levels, cardiac arrhythmia, heart failure, muscle weakness, osteoporosis in postmenopausal women, and anxiety.
    [4] Thyroid hormones have recently been used as an alternative therapy for patients with hypothyroidism. Therapeutic methods using L-thyroxine restore the metabolic function to normal and include thyroid-stimulating hormone (TSH), thyroxine (3,5,3 ', 5'-tetraiodo-L-thyronine or T 4 ) tree iodo Dottie Ronin (3,5,3'- tree iodo -L- T Ronin or T 3) it is possible to easily monitor the level of a routine serum measurements. However, alternative therapies are limited, especially for the elderly, because of the harmful effects of thyroid hormones.
    [5] In addition, if the adverse effects of thyroid hormones can be minimized or eliminated, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders. These potentially useful influences include weight loss, decreased serum LDL levels, improved depression, and stimulation of bone formation. Conventional attempts to use thyroid hormones to pharmacologically treat these disorders have been limited by the symptoms of hyperthyroidism, particularly cardiovascular toxicity.
    [6] The development of specific and selective thyroid hormone receptor agonists can lead to specific therapies for these common disorders while avoiding other toxicities of cardiovascular and natural thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or excretion, local or local delivery, cell targeting through other ligands bound to the agonist, and targeting of the receptor subtype. Thyroid hormone receptor agonists, which selectively interact with the beta form of the thyroid hormone receptor, present a particularly interesting method of avoiding cardio-toxicity.
    [7] Thyroid hormone receptors (TRs), like other nuclear receptors, are a single polypeptide chain. Various receptor forms are believed to be products of two different genes a and b. Another difference in isoform is that two or more homozygotes are generated from each gene as a result of different RNA processing. TRα 1 , TRβ 1 and TRβ 2 homozygotes bind to thyroid hormones and act as ligand-regulated transcription factors. In adults, the TRβ 1 polymorph copper is the predominant form in most tissues, especially liver and muscle. The TRα 2 polymorph is predominantly copper in the pituitary and other parts of central nervous system, and does not bind thyroid hormones, and acts as a transcription suppressor in various environments. In addition, even though the level of the TRα 1 East TRβ shape generally lower than the level of the first dynamic clamping and, TRα 1 building shape is widely distributed. This homozygote can be particularly important for development. Many mutations are found in the TRβ gene and a generalized resistance to thyroid hormone is induced, but mutations that impair TRα function have not been found.
    [8] Growing body of data that is the heart, in particular, while many or most effects of thyroid hormones on the heart rate simbaksugwa is mediated through the type of α- TRα 1 copper shapes, for example the liver, most of the hormone to the muscles and other tissues The action is mediated through the β-form of the receptor. Thus, TR-beta-selective agonists can not elicit effects on the heart rate and heart rate of the hormone, but will lead to many other actions of the hormone. It is believed that the [alpha] -form of the receptor is a major driving force for heart rate for the following reasons:
    [9] 1) Atrial tachycardia is a very common symptom of generalized resistance to thyroid hormones with deficiencies in the TR beta form and a high circulating level of T 4 and T 3 ;
    [10] 2) The atrial tachycardia is only present in patients with double deletion of the TRβ gene (Takeda et al., J. Clin. Endrocrinol. & Metab. 1992, Vol.
    [11] 3) Rats with a knockout TRα gene (but not a β-gene) are slower to beat than control rats;
    [12] 4) Weston blot analysis of human myocardial TRs are non TRβ 1, it seems that the TRα 1, TRα 2 and TRβ 2 exists.
    [13] If these indications are correct, TRβ-selective agonists can be used to mimic the action of multiple thyroid hormones while less affecting the heart. Such compounds include (1) alternative therapies for older patients with hypothyroidism at risk for cardiovascular complications; (2) alternative therapy for asymptomatic hypothyroidism in elderly patients at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevated levels of plasma LDL; (5) depression, and (6) osteoporosis inhibitors.
    [1] The present invention is a thyroid receptor ligand, preferably a novel compound which is preferentially selective for thyroid hormone receptor beta, a method for its preparation, and a method of using the compound, for example, in metabolic control.
    [14] According to the present invention there is provided a compound having the structure of formula 1, all stereoisomers thereof, a prodrug or a pharmaceutically acceptable salt thereof, which is a thyroid receptor ligand.
    [15]
    [16] Wherein,
    [17] X is oxygen (-O-), sulfur (-S-), carbonyl (-CO-), methylene (-CH 2 -) or -NH-;
    [18] Y is - (CH 2 ) n -, wherein n is an integer from 1 to 5, or cis or trans-C = C-;
    [19] R 1 is halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms;
    [20] R 2 and R 3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein at least one of R 2 and R 3 is not hydrogen;
    [21] R < 4 > is hydrogen or lower alkyl;
    [22] R < 5 > is hydrogen or lower alkyl;
    [23] R < 6 > is a carboxylic acid or an ester or prodrug thereof;
    [24] R 7 is hydrogen, an alkanoyl group or an aroyl group, or other group capable of biotransformation to produce a free phenolic structure (where R 7 = H).
    [25] According to the present invention, there is also provided a method for the prevention, inhibition, or treatment of a metabolic dysfunction-related disease or a disease dependent on the expression of a T 3 regulatory gene, which comprises administering a therapeutically effective amount of the compound of formula (1). The compounds of formula I are preferred for thyroid hormone receptor beta preferentially. Examples of diseases which are dependent on the expression of metabolic dysfunction related diseases or T 3 -regulated genes include, but are not limited to, obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmia, depression, osteoporosis, hypothyroidism, And congestive heart failure.
    [26] The following definitions apply to the terms used throughout this specification, unless the context clearly dictates otherwise.
    [27] The term " thyroid receptor ligand " as used herein includes all residues that bind to the thyroid receptor. The ligand may act as an agonist, antagonist, partial agonist or partial antagonist. Another term for " thyroid receptor ligand " is " thyromimetic ".
    [28] Unless otherwise indicated, the term " lower alkyl ", " alkyl " or " alk ", as used herein alone or as part of another group, refers to an alkyl group having from 1 to 12 carbon atoms in the normal chain , Preferably 1 to 4, straight chain and branched chain hydrocarbons such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl , Octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, Amino, and / or carboxyl or alkyl ester thereof. The term " alkyl "
    [29] The term " aryl ", as used herein alone or as part of another group, refers to a monovalent and bicyclic aromatic group having 6 to 10 carbon atoms in the ring portion (e.g., phenyl or naphthyl including 1-naphthyl and 2- Alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, and / Lt; / RTI > may optionally be substituted through a carbon atom usable as one, two or three groups selected from the group consisting of carboxyl and alkyl esters thereof.
    [30] The term " heteroaryl " or " heteroaromatic moiety ", as used herein alone or as part of another group, means one, two, three or four heteroatoms (one of which is a nitrogen atom, And the other atom may be nitrogen, oxygen or sulfur, which ring may be fused to another aryl or heteroaryl ring and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, cyano, nitro, amino, and / have.
    [31] Unless otherwise indicated, the term " lower alkenyl " or " alkenyl ", as used herein by itself or as part of another group, refers to an alkyl group having from 2 to 12, preferably from 2 to 5, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-pentenyl, 3-pentenyl, Heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl and the like, Quot; alkyl " as used herein.
    [32] Unless otherwise stated, the term " lower alkynyl " or " alkynyl ", as used herein by itself or as part of another group, refers to a straight chain having from 2 to 12, preferably from 2 to 8, Straight chain or branched chain radicals comprising one triple bond in the normal chain such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 4-decenyl, 4-decenyl, 4-heptynyl, 4-heptynyl, 3-octynyl, Quot; alkyl " as used herein.
    [33] The term " alkanoyl ", as used herein alone or as part of another group, is alkyl linked to a carbonyl group.
    [34] The term " aroyl ", as used herein alone or as part of another group, is aryl linked to a carbonyl group.
    [35] Unless otherwise indicated, the term " cycloalkyl ", as used herein alone or as part of another group, refers to an alkyl group containing from 3 to 7, preferably from 3 to 6, carbons forming a ring and a ring Saturated cyclic hydrocarbon groups or partially unsaturated (including one to two double bonds) cyclic hydrocarbon groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, and cyclohexenyl , Which may be substituted as in the case of " alkyl ".
    [36] The term "halogen" or "halo" as used herein alone or as part of another group refers to CF 3 as well as chlorine, bromine, fluorine and iodine, with chlorine and bromine being preferred.
    [37] (CH 2 ) n group is an alkylene group having 1 to 5 carbon atoms in the normal chain which may contain 1, 2 or 3 alkyl substituents.
    [38] Examples of (CH 2 ) n groups include compounds having the structure of the following formula:
    [39]
    [40] The compound of formula 1 may exist as a salt, especially as a pharmaceutically acceptable salt. If the compound of formula (1) has, for example, at least one base center, they can form acid addition salts. Mines, for example, sulfuric, phosphoric or hydrohalic acids; For example, alkanecarboxylic acids having 1 to 4 carbon atoms which are unsubstituted or substituted with halogen such as acetic acid, saturated or unsaturated dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, (Such as acetic acid, phthalic acid or terephthalic acid), hydroxycarboxylic acids (such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid), amino acids (such as aspartic acid or glutamic acid or lysine or arginine) Bicic acid; It is formed with an organic acid, such as (for example methanesulfonic acid or p- toluenesulfonic acid), or substituted with halogen or unsubstituted (C 1 -C 4) alkyl or arylsulfonic acid. Further, a corresponding acid addition salt having an additional existing base center may be formed if necessary. In addition, compounds of formula (I) having at least one acid group (e.g., COOH) can form salts with bases. Suitable salts with bases include, for example, metal salts such as alkali metal or alkaline earth metal salts; For example sodium, potassium or magnesium salts; Or salts with ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine; Salts with lower mono-, di- or tri-alkylamines such as ethyl-, t-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine; Or a salt with a lower mono-, di- or trihydroxyalkylamine such as mono-, di- or tri-ethanolamine. Corresponding internal salts may be additionally formed. Salts which may not be suitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the free compounds of formula I or their pharmaceutically acceptable salts.
    [41] Preferred salts of compounds of formula (I) containing a basic group include the monohydrochloride, the hydrogen sulfate, the methanesulfonate, the phosphate or the nitrate.
    [42] Preferred salts of compounds of formula (I) containing an acid group include sodium, potassium and magnesium salts, and pharmaceutically acceptable organic amines.
    [43] Carboxylic acid prodrugs and prodrugs. Are described in standard references such as Chapter 31 of Camille G. Wermuth et al. ("The Practice of Medicinal Chemistry" ed. C. G. Wermuth. Academic Press, 1996;
    [44] Preferred prodrugs include lower alkyl esters such as ethyl esters or acyloxyalkyl esters such as pivaloyloxymethyl (POM).
    [45] Compounds of the invention of formula I wherein X is O are preferred.
    [46] In addition, preferred compounds are
    [47] X is O;
    [48] Y is cis- or trans-ethylene;
    [49] R 1 is halogen, trifluoromethyl, alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 7 carbon atoms;
    [50] R 2 and R 3 are independently bromo, chloro or methyl;
    [51] R < 4 > is hydrogen or methyl;
    [52] R < 5 > is hydrogen;
    [53] R < 6 > is carboxyl;
    [54] Lt; 7 > is hydrogen.
    [55] Another preferred compound of the invention is
    [56] X is O;
    [57] Y is - (CH 2 ) n -, wherein n is 1 or 2;
    [58] R 1 is halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms;
    [59] R 2 and R 3 are independently bromo, chloro or methyl;
    [60] R < 4 > is hydrogen or methyl;
    [61] R < 5 > is hydrogen;
    [62] R < 6 > is carboxyl;
    [63] Lt; 7 > is hydrogen.
    [64] The most preferred compounds are
    [65] X is O;
    [66] Y is - (CH 2 ) n -, where n is 1;
    [67] R 1 is halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms (most preferably isopropyl);
    [68] R 2 and R 3 are independently bromo and chloro;
    [69] R < 4 > is hydrogen or methyl;
    [70] R < 5 > is hydrogen;
    [71] R < 6 > is carboxyl;
    [72] Lt; 7 > is hydrogen.
    [73] Accordingly, preferred compounds of the invention are compounds having the structure of formula (Ia) or (Ib) or alkyl esters thereof.
    [74]
    [75]
    [76] Preferred compounds are those having the structure of the formula: or an alkyl ester thereof such as methyl or ethyl esters thereof.
    [77]
    [78] The most preferred compounds of the present invention are those having the structure of the formula: or an alkyl ester thereof such as methyl or ethyl esters thereof.
    [79]
    [80] The compounds of formula (I) can be prepared by the representative methods described in the following reaction schemes and by the methods of the relevant publications used by those skilled in the art. Representative reagents and methods for these reactions are shown in the following Examples and Examples.
    [81] Protection and deprotection of the following scheme can be carried out by methods generally known in the art (e.g. TW Greene & PGM Wuts, "Protecting Groups in Organic Synthesis", 3 rd Edition, Wiley, 1999).
    [82] Scheme 1 illustrates a general synthesis method for a compound of formula I wherein X is 0, using coupling an appropriately substituted iodonium salt 1 to the appropriate phenol 2 to obtain intermediate 3 Lt; / RTI > In Structure I and all other applicable structures included in the additional reaction schemes described below, PG refers to a protecting group suitable for the indicated functional group (in the case of oxygen of the phenolic acid in the example). Specific protecting groups for each particular intermediate are readily understood by those skilled in the art (see the " Protecting Groups in Organic Synthesis " cited above). Subsequent protecting groups and functional group manipulation provide the preferred compounds of formula (I). For example, intermediate 2 can be a nitrophenol, wherein R 'and R "are oxygen, and the resulting coupling product is the corresponding diarylether nitro compound 3, wherein R' = R " = 0). This nitro intermediate can be readily reduced to the corresponding arylamine (see discussion below). The resulting arylamine can then be readily acylated to provide the desired compound of formula I, wherein X = O. Furthermore, intermediate (2) is a protected amino functional group (for example, R '= R 5 and R "= PG Im) may be the. Protecting group (PG) is a carbamate, for example, t- butyloxycarbonyl (BOC) Or benzyloxycarbonyl (CBZ), which can be subsequently removed by acidolysis and / or hydrolysis under standard conditions. Reacylation of the resulting arylamine by methods well known to those skilled in the art gives the desired compound of formula (3), wherein R '= R " = H, resulting from the reduction of the nitrobenzene coupling product is reacted with an aldehyde in a reductive amination reaction and an aldehyde the R 5 groups can be derived from the installation. For example, reductive amination methods using sodium cyanoborohydride or sodium triacetoxyborohydride are well known to those skilled in the art. The resulting product can then be acylated by standard methods to provide compounds of formula (I).
    [83]
    [84] The iodonium salt method shown in Scheme 1 is a method for synthesizing thyroid hormone analogs (" Novel Thyroid Receptor Ligands and Methods ", Y.-L. Li, Y. Liu, A. Hedfors, J. Malm. Mellin, M. Zhang, PCT Int. App., WO 9900353 Al 990107, DMB Hickey et al., J. Chem. Soc. Perkin Trans. I, 3103-3111, 1988, N. Yokoyama et al., J. Med. , 695-707, 1995), and in general diaryl ethers (EA Couladouros, VI Moutsos, Tetrahedron Lett., 40, 7023-7026, 1999).
    [85] Scheme 2 below illustrates the preparation of a compound of formula I wherein X = 0, wherein the suitably substituted nitrobenzene intermediate 5 is alkylated with an appropriately substituted phenol 4 to provide the nitro intermediate 6 Lt; RTI ID = 0.0 > synthesis. ≪ / RTI > The nitro functionality of intermediate (6) can be reduced to amino groups using methods well known in the art, such as catalytic hydrogenation in the presence of Raney nickel or palladium on charcoal in polar solvents such as glacial acetic acid or ethanol.
    [86] Alternatively, the reduction can be accomplished using iron powder in aqueous glacial acetic acid at ambient temperature. Subsequent manipulations of the protecting groups and functional groups provide the desired compounds of formula (I).
    [87]
    [88] (PD Leeson, JC Emmett, J. Chem. Perkin Trans. I, 3085-3096, 1988; N. Yokoyama et al., J Med. Chem., 38, 595-707, 1995).
    [89] An additional method for the synthesis of compounds of formula I wherein X is O, NH, S, CO or CH 2 is described in DMB Hickey et al., J. Chem. Soc. Perkin Trans. I, 3097-3102, 1988; Z.-W. Guo et al., J. Org. Chem., 62, 6700-6701, 1997; DMT Chan et al., Tetrahedron Lett., 39, 2933-2936, 1998; DA Evans et al., Tetrahedron Lett., 39, 2937-2940, 1998; GM Salamonczyk et al., Tetrahedron Lett., 38, 6965-6968, 1997; J.-F. Marcoux, J. Am. Chem. Soc., 119, 10539-10540, 1997; AV Kalinin et al., J. Org. Chem., 64, 2986-2987, 1999; For compounds of formula (I) wherein X is N: DMT Chan et al., Tetrahedron Lett., 39, 2933-2936, 1998; JP Wolfe et al., J. Am. Chem. Soc., 118, 7215, 1996; MS Driver, JF Hartwig, J. Am. Chem. Soc., 118, 7217, 1996; CG Frost, P. Mendonca (J. Chem. Soc. Perkin I, 2615-2623, 1998); For compounds of formula (I) wherein X is S: CR Harrington, Biochem. J., 43, 434-437, 1948; A. Dibbo et al., J. Chem. Soc., 2890-2902, 1961; N. Yokoyama et al., United States Patent 5, 401, 772, 1995; For compounds of formula (I) wherein X is CO or CH 2 : L. Horner, HHG Medem, Chem. Ber., 85, 520-530, 1952; G. Chiellini et al., Chemistry & Biology, 5, 299-306, 1998).
    [90] Methods applicable to the synthesis of compounds of formula I, wherein X is O and R 2 and R 3 are independently hydrogen, halogen and alkyl, are described in "Novel Thyroid Receptor Ligands and Methods", Y. Li Li, Y. Liu, A. Hedfors, J. Malm, C. Mellin, M. Zhang, PCT Int. App., WO 9900353 Al 990107).
    [91] Another general method for the synthesis of compounds of formula I wherein X is 0 is shown in Scheme 3 below. In this method, an appropriately substituted iodonium salt (1) is coupled to an appropriately substituted 4-hydroxybenzoic acid intermediate (7). The carboxyl protecting group (PG ') in the resulting coupling product (8) is then removed. The resulting free carboxylic acid intermediate corresponding to compound (8) is then rearranged using Curtius reagents known for transformation such as diphenylphosphoryl azide (DPPA). The crotius rearranged intermediate can be trapped with t-butanol or benzyl alcohol to give t-butyloxycarbonyl (BOC) or benzyloxycarbonyl protected aniline (CBZ), respectively, which is the product (9). These protecting groups can be removed by methods well known in the art to give the corresponding free amine groups. The amine can then be reacted with a compound of formula (I) by one of any of a number of established methods, for example, using dicyclohexylcarbodiimide (DCC) or (1- [3- (dimethylamino) Acylation with a free carboxylic acid using a coupling agent such as, for example, EDCI, to give a compound of formula I wherein X is O. Alternatively, the free amine may be reacted with a certain equivalent of triethylamine or May be acylated using a chlorinated carboxylic acid derivative in the presence of a tertiary organic amine such as N-methyl morpholine.
    [92]
    [93] All stereoisomers of the compounds of the present invention are considered to be in admixture, pure form or substantially pure form. The compounds of the present invention may have asymmetric centers at any of these carbon atoms, including any carbon atom or R substituent. Thus, the compounds of formula (I) may exist in enantiomeric or diastereoisomeric forms, or mixtures thereof. The preparation method may employ racemates, enantiomers or diastereomers as starting materials. When preparing diastereoisomeric or enantiomeric products, such products may be separated by conventional methods such as chromatography or fractional crystallization.
    [94] The compounds of the present invention are preferential antagonists to the thyroid hormone receptor beta, and such compounds may be used alone or in combination with other agents such as HMG-CoA reductase inhibitors, fibrates, MTP inhibitors, squalene synthetase inhibitors and / And / or optionally in combination with an anti-diabetic agent to lower serum LDL levels, thereby being useful for treating obesity, hypercholesterolemia and atherosclerosis; Alone or in combination with an antidepressant such as < RTI ID = 0.0 > dixifamine < / RTI > Alone or in combination with known bone resorption inhibitors, such as sodium alendronate, to stimulate bone formation to treat osteoporosis. In addition, the compounds of the present invention are useful for the treatment of elderly patients with hypothyroidism or asymptomatic hypothyroidism who are at risk for cardiovascular complications, treatment of the elderly to provide euphoria, and treatment of nontoxic goiters; Management of papillary or bovine thyroid cancer (alone or with T 4 ); In the treatment of cardiovascular diseases and congestive heart failure, such as in the prevention or treatment of skin disorders such as psoriasis, glaucoma, atherosclerosis and the like.
    [95] The compounds of the present invention may be used alone or in combination with an anabolic agent such as sibutramine, an anti-obesity agent such as orlistat and / or a 3 agonist for the treatment of obesity.
    [96] The compounds of the present invention are also useful for the treatment of skin disorders or diseases associated with skin atrophy, such as glucocorticoid-induced skin atrophy, including the recovery of focal glucocorticoid-induced skin atrophy, the treatment of topical glucocorticoid-induced skin atrophy (I. E. Simultaneous treatment with topical glucocorticoids or pharmaceutical products comprising both glucocorticoids and the compounds of the invention), recovery / prevention of skin atrophy induced by systemic treatment with glucocorticoids, use of glucocorticoids (Wrinkles, etc.), wound healing, keloids, stria, cellulite, rough skin, chemistry, and the like. Lichenplanus, ichtyosis, acne, psoriasis, < RTI ID = 0.0 > Can be used for the recovery / prevention of skin atrophy induced by Dernier's desease, eczema, atopic dermatitis, chloracne, pityriasis and skin wounds.
    [97] In treating skin disorders or diseases as described above, the compounds of the present invention may be used alone or in combination with retinoids, such as tretinoin, or vitamin D analogs, in an amount disclosed in the Physicians' Desk Reperence (PDR).
    [98] Hypolipidemic agents that may optionally be used in combination with the compounds of formula I of the present invention include thiazolidinediones, MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrinic acid derivatives, ACAT inhibitors, cholesterol absorption inhibitors, Bile acid co-carrier inhibitors, bile acid sequestrants and / or nicotinic acid, and derivatives thereof.
    [99] MTP inhibitors as used herein include those disclosed in U.S. Patent Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875, 5,885,983, and 5,962,440 (issued October 20, 1998 U.S. Patent Application Serial No. 09 / 175,180). Preferred MTP inhibitors disclosed in each of the above patents and patent applications are preferred.
    [100] All US patents and patent applications are incorporated herein by reference.
    [101] The most preferred MTP inhibitors used in accordance with the present invention include the preferred MTP inhibitors disclosed in U.S. Patent Nos. 5,739,135, 5,712,279 and 5,760,246.
    [102] The most preferred MTP inhibitor is 9- [4- [4 - [[2- (2,2,2-trifluoroethoxy) benzoyl] amino] -1- piperidyl] butyl] -N- 2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide.
    [103]
    [104] Hypolipidemic agents include, but are not limited to, mevastatin and related compounds (disclosed in U.S. Patent No. 3,983,140), lovastatin (mebinolin) and related compounds (disclosed in U.S. Patent No. 4,231,938), pravastatin and related compounds 4,346,227), simvastatin and related compounds (disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171). Other HMG CoA reductase inhibitors that may be used herein include, but are not limited to, fluvastatin (disclosed in U.S. Patent No. 5,354,772), cerivastatin (disclosed in U.S. Patent Nos. 5,006,530 and 5,177,080) ), Atorvastatin (disclosed in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104), pyrazole analogues of mevalonolactone derivatives (disclosed in U.S. Patent No. 4,613,610) 6- (2- (substituted-pyrrol-1-yl) -alkyl) pyran-2-one and its derivatives (described in U.S. Pat. 4,647,576), SC-45355 (3-substituted pentanedioic acid derivative) dichloroacetate of Searle, imidazole analogs of mevalonolactone (disclosed in PCT application WO 86/07054), 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives (disclosed in French Patent No. 2,596,393), 2,3- (Disclosed in European Patent Application No. 0221025), naphthyl analogs of mevalonolactone (disclosed in U.S. Patent No. 4,686,237), octahydronaphthalene (disclosed in U.S. Patent No. 4,499,289) (Disclosed in European Patent Application No. 0,142,146 A2), as well as other known HMG CoA reductase inhibitors.
    [105] In addition, phosphinic acid compounds useful for inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
    [106] Suitable squalene synthetase inhibitors for use herein include, but are not limited to, squalene synthetase inhibitors including alpha-phosphonosulfonates (disclosed in U.S. Patent No. 5,712,396), isoprenoid (phosphinylmethyl) (As disclosed in Biller et al., J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871) as well as other squalene synthetase inhibitors (U.S. Patent Nos. 4,871,721 and 4,924,024, And Biller, SA, Neuenschwander, K., Ponpipom, MM, and Poulter, CD, Current Pharmaceutical Design, 2, 1-40, 1996).
    [107] Other squalene synthetase inhibitors suitable for use in the present disclosure include terpenoid pyrophosphate (disclosed in P. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249) , Parunecyl diphosphate homolog A and prequalene pyrophosphate (PSQ-PP) homologues (Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293) (Reported in McClard, RW et al., JACS, 1987, 109, 5544) and cyclopropane (Capson, TL, PhD dissertation, June, 1987, Dept. Med. Chem. U. Utah, Abstract , Table of Contents, pp. 16, 17, 40-43, 48-51, Summary).
    [108] Other hypolipidemic agents suitable for use herein include, but are not limited to, fibrinic acid derivatives such as, but not limited to, fenobibrate, gemfibrozil, clofibrate, bezafibrate, cyprofibrate, clinofibrate, (Disclosed in U.S. Patent No. 3,674,836) (preferred pro-becol and gemfibrozil), bile acid sequestrants such as cholestyramine, cholestipol, and DEAE-sephadex (Secholex®) As well as Rhone-Poulenc, Eisai E-5050 (N-substituted ethanolamine derivative), imanicyl (HOE-402), tetrahydroborate Statins such as statins (THL), estigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrins (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivatives), melinamide (Sumitomo), Sandoz 58-035, American Shianami (American Cyanamid) CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly (diallylmethylamine) derivatives (U.S. Patent No. 4,759,923 ), Quaternary amine poly (diallyldimethylammonium chloride) and iodine (disclosed in U.S. Patent No. 4,027,009), and other known serum cholesterol lowering agents.
    [109] Other hypolipidemic agents are described in Drugs of the Future 24, 9-15 (1999), (Avasimibe); " The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters ", Nicolosi et al. Atherosclerosis (Shannon, Irel). (1998), 137 (1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein" , Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C., et al., Bioorg. (1996), 6 (1), 47-50; " ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals ", Krause et al., Editor (s): Ruffolo, Robert R., Jr .; Hollinger , Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla .; "ACAT inhibitors: potential anti-atherosclero tic agents ", Sliskovic et al., Curr. Med. Chem. (1994), 1 (3), 204-25; 6. The first water-soluble ACAT inhibitor with lipid-regulating activity: inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). a series of substituted N-phenyl-N '- [(1-phenylcyclopentyl) methyl] ureas with enhanced hypocholesterolemic activity ", Stout et al., Chemtracts: Org. Chem. (1995), 8 (6), 359-62).
    [110] Hypolipidemic agents may be used in combination with a cholesterol absorption inhibitor, preferably SCH48461 from Schering-Plow, as well as from Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 May be a disclosed cholesterol absorption inhibitor.
    [111] Hypolipidemic agents can be the Na + / bile acid co-transporter inhibitors disclosed in Drugs of the Future, 24, 425-430, 1999.
    [112] Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin.
    [113] The above-mentioned US patents are incorporated herein by reference. The amount and dose used will be as indicated in the PDR and / or the above-mentioned patents.
    [114] The compounds of formula (I) of the present invention may be administered at a dose of about 500: 1 to about 0.005: 1, preferably about 300: 1, to a hypolipidemic, antidepressant, and / or bone resorption inhibitor and / : 1 to about 0.01: 1.
    [115] Anti-diabetic agents that may optionally be used in combination with the compounds of formula (I) of the present invention include, but are not limited to, acetaminophen, sulfonylurea, glucosidase inhibitors, thiazolidinedione and / or aP2 inhibitors and / Or PPAR alpha / gamma dual agonists, and / or SGLT2 inhibitors, or meglitinide.
    [116] The antidiabetic agent may be an oral anticoagulant, preferably a biguanide, for example metformin or phenformin, or a salt thereof.
    [117] When the antidiabetic agent is an anhydride, the compound of formula I will be used in a weight ratio ranging from about 0.01: 1 to about 100: 1, preferably from about 0.5: 1 to about 2: 1, based on the bean gum.
    [118] The antidiabetic agent is also preferably selected from the group consisting of sulfonylureas such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Patent No. 4,379,785), glipizide, glyclazide, or chlorproper , Other known sulfonylureas or other antagonists acting on the ATP-dependent channel of the -Cells, glyburide and glypedide being preferred.
    [119] The compounds of formula I will be used in a weight ratio ranging from about 0.01: 1 to about 100: 1, preferably from about 0.2: 1 to about 10: 1, based on the sulfonylurea.
    [120] In addition, the oral antidiabetic agent may be a glucosidase inhibitor such as acarbose (disclosed in U.S. Patent No. 4,904,769) or miglitol (disclosed in U.S. Patent No. 4,639,436), and may be administered orally .
    [121] The compounds of formula I will be used in a weight ratio of from about 0.01: 1 to about 100: 1, preferably from about 0.5: 1 to about 50: 1, relative to the glucosidase inhibitor.
    [122] The compounds of formula I can be used in combination with thiazolidinedione oral antidiabetic or troglitazone (Rezulin TM from Warner-Lambert, US Pat. No. 4,572,912), rosiglitazone (SKB) MCP-555 (disclosed in U.S. Patent No. 5,594,016), GI-262570 (Glaxo-Welcome), Enclitezone (CP-68722, Pfizer) May be used in combination with other insulin sensitizers such as Ritazone (CP-86325, Pfizer), which have insulin sensitizers in NIDDM patients.
    [123] The compounds of formula I will be used in a weight ratio of from about 0.01: 1 to about 100: 1, preferably from about 0.5: 1 to about 5: 1, based on thiazolidinediones.
    [124] Sulfonylureas and thiazolidinediones may be incorporated into a single tablet having the compound of formula I in an amount less than about 150 mg of oral antidiabetic agent.
    [125] In addition, the compounds of formula (I) can also be used in the treatment of hyperproliferative hyperglycemia, such as insulin, or GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP- (GLP-1), such as those disclosed in Habener, the disclosure of which is incorporated herein by reference, and can be administered by injection, intranasal, or transdermal or buccal ) ≪ / RTI > device.
    [126] When present, metformin, sulfonylureas such as glyburide, glimepiride, glypyrid, glypidide, chlorpropamide and glyclazide, and glucosidase inhibitor acarbose or miglitol, or insulin, And can be used in the amounts and dosages indicated in the PDR.
    [127] When present, metformin or a salt thereof may be used in an amount ranging from about 500 mg / day to about 2000 mg / day, and may be administered at once or divided once to four times daily.
    [128] When present, the thiazolidinedione antidiabetics may be used in an amount ranging from about 0.01 to about 2000 mg / day, and may be administered at one time or one to four times daily.
    [129] When present, insulin may be used in the formulations, amounts and doses indicated in the PDR.
    [130] If present, the GLP-1 peptide may be administered as an oral oral preparation or may be administered in the form of a pharmaceutical composition as described in U.S. Patent Nos. 5,346,701 (TheraTech), 5,614,492, and 5,631,224 (which patents are incorporated herein by reference) Nasal administration, or parenteral administration.
    [131] Also, anti-diabetic agents have been described in Murakami et al., &Quot; A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR Gamma.Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats ", Diabetes 47, 1841-1847, 1998).
    [132] Antidiabetic agents may be the aP2 inhibitors disclosed in U.S. Patent Application Serial No. 09 / 391,053 (filed September 7, 1999) and U.S. Provisional Patent Application Serial No. 60 / 127,745 (filed April 5, 1999, Attorney Docket LA27 * , The dosage amounts set forth herein are used.
    [133] The antidiabetic agent may be an SGLT2 inhibitor as disclosed in U.S. Provisional Patent Application Serial No. 60 / 158,773 (filed October 12, 1999, Attorney Docket LA0049 *).
    [134] The compound of formula I is used in an amount of from about 0.01: 1 to about 100: 1, preferably from about 0.5: 1 to about 5: 1, for a PPAR alpha agonist, a PPAR gamma agonist, a PPAR gamma alpha agonist, an SGLT2 inhibitor and / : 1. ≪ / RTI >
    [135] The dosage should be carefully adjusted according to the patient's age, weight, condition, as well as the route of administration, dosage form and therapy, and the desired result.
    [136] Dosages and formulations of hypolipidemic and antidiabetic agents will be as disclosed in various patents and patent applications, and PDRs discussed above.
    [137] Dosages and formulations for other hypolipidemic agents, antidepressants, bone resorption inhibitors, appetite suppressants and anti-obesity agents, if applicable, will be as described in the current edition of the PDR.
    [138] For oral administration, satisfactory results can be obtained when the MTP inhibitor is used in an amount ranging from about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 75 mg, per 1 kg body weight, once to four times daily.
    [139] A preferred oral dosage form, such as tablets or capsules, contains an amount of MTP inhibitor ranging from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and most preferably from about 5 to about 250 mg, ≪ / RTI >
    [140] For parenteral administration, the MTP inhibitor will be used in an amount ranging from about 0.005 mg to about 10 mg, preferably from about 0.005 mg to about 8 mg, per kg of body weight, once to four times daily.
    [141] For oral administration, an HMG CoA reductase inhibitor such as pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin is administered at the dose used, for example from about 1 to 2000 mg, Preferably in an amount ranging from about 4 mg to about 200 mg, satisfactory results can be obtained.
    [142] The squalene synthetase inhibitor may be used in a dosage ranging from about 10 mg to about 2000 mg, preferably from about 25 mg to about 200 mg.
    [143] Preferred oral dosage forms, such as tablets or capsules, contain the HMG CoA reductase inhibitor in an amount of from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, more preferably from about 10 to about 40 mg something to do.
    [144] A preferred oral dosage form, such as a tablet or capsule, will contain the squalene synthetase inhibitor in an amount of about 10 to about 500 mg, preferably about 25 to about 200 mg.
    [145] The compounds of formula I and hypolipidemic agents, antidepressants or bone resorption inhibitors may be used together in the same oral dosage form or in different oral dosage forms taken simultaneously.
    [146] The above-described composition may be administered in a single dose form as described above or one to four divided doses per day. It is prudent for the patient to be treated with a combination of gradually increasing doses beginning with a low dosage combination.
    [147] Preferred hypolipidemic agents are pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.
    [148] The compounds of formula (I) of the present invention can be administered to a variety of mammals, such as humans, cats, dogs, etc., suffering from the disease in an amount of about 0.1 to about 100 mg per kg of body weight, preferably once or twice to four times, Is administered orally or parenterally in an effective amount within a dosage range of from about 0.2 to about 50 mg, more preferably from about 0.5 to about 25 mg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) For example, subcutaneously or intravenously, and nasally, rectally or sublingually.
    [149] The active substance may be in the form of a composition such as tablets, capsules, ointments, hydrophilic ointments, creams, lotions, solutions or suspensions, or other types of carrier materials such as transdermal delivery devices, iontophoresis devices, rectal suppositories, . ≪ / RTI > The composition or carrier may contain from about 5 to about 500 mg per unit dose of the compound of formula (I). These may be typically combined with physiologically acceptable vehicles or carriers, excipients, binders, preservatives, stabilizers and flavoring agents, as required by the accepted pharmaceutical practice. The following examples illustrate preferred embodiments of the present invention.
    [150] Example 1
    [151]
    [152] 3- [[3,5-dibromo- [4-hydroxy-3- (1-methylethyl) phenoxy] phenyl] amino] -3-oxopropanoic acid
    [153] Compound 1a :
    [154]
    [155] 4-Nitrophenol (12.6 g, 42 mmol) and Cu powder (32.8 g, 64 mmol) were added to a solution of bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate [Lancaster 300 mesh (6.8 g, 108 mmol)] was suspended in 400 ml of CH 2 Cl 2 in a flask surrounding the aluminum foil. With stirring, triethylamine (18.4 ml, 219 mmol) was added and the reaction mixture was stirred under argon in the dark for 4 days. The crude reaction mixture was concentrated to about 70 ml and then chromatographed in two portions via 1.8 L each of Merck silica gel using 3% to 5% ethyl acetate in hexanes. The combined yield of Compound 1a was 15.4 g (81.9%).
    [156] Compound 1b :
    [157]
    [158] Compound 1a (15.2 g, 34.15 mmol) was dissolved in 129 ml of glacial acetic acid and 13 ml of water. Iron powder (Aldrich <10 microns, 12 g, 215 mmol) was added and the reaction was stirred under argon overnight. The reaction mixture was filtered through celite and the pad was washed with about 50 ml of acetic acid. The filtrate was concentrated to about 60 ml and poured into Na 2 CO 3 400 g. Water (400 ml) was added and the product was extracted with ethyl acetate (3x x 500 ml each). The ethyl acetate was concentrated in vacuo and the residue (13.2 g) was chromatographed over 1.8 L of Merck silica gel using an ethyl acetate: hexane mixture (8: 2). Compound Ib (8.75 g) was obtained in a yield of 61.7% as a solid. The protons and carbon NMR were consistent with the desired structure.
    [159] Compound 1c :
    [160]
    [161] The compound 1b (8.1 g, 19.7 mmol) was dissolved in dichloromethane 20 ml, pre-cooled (about -60 ℃) of BBr 3 (18 ml, 10 eq.) In dichloromethane 180 ml and this solution under argon solution of . At this low temperature, solid matter was precipitated. The reaction was slowly warmed to 0 &lt; 0 &gt; C and then stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction was diluted with CH 2 Cl 2 200 ml, and was quenched by pouring the cooled, vigorously stirred solution of saturated Na 2 CO 3 (300 ml) and CH 2 Cl 2 (300 ml) . The organic layer was separated, diluted with 100 ml of MeOH, concentrated in vacuo, dissolved in MeOH (100 ml) and concentrated 3 times. To the residue was dissolved in EtOAc 400 ml, washed twice with saturated NaHCO 3 and brine, dried (Na 2 SO 4), filtered, and concentrated in vacuo to give the compound 1c as solids (7.2 g, yield 91%) . The protons and carbon NMR were consistent with the desired structure.
    [162] Compound 1d :
    [163]
    [164] A solution of compound 1c (6.23 g, 15.5 mmol), malonic acid monoethyl ester (2.9 g, 22 mmol), N-methylmorpholine (1.75 ml, 15.8 mmol) and hydroxy- mmol) were partially dissolved in 200 ml of CH 2 Cl 2 . The reaction was cooled to 0 C and the reaction was stirred for 2 hours. (1- [3- (Dimethylamino) propyl] -3- ethylcarbodiimide hydrochloride (4.4 g, 23 mmol) The mixture was diluted with 200 mL of CH 2 Cl 2 and washed with water, saturated aqueous NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by column chromatography using 30% ethyl acetate in hexanes, And chromatographed in two batches via Merck silica gel, 300 g each. The intermediate fractions were charged and concentrated to give 5.3 g (66.7%) of pure product. The combined initial and late fractions were separated as starting material malonate and unknown impurities The slightly contaminated product 1d was 0.96 g.
    [165] Example 1 :
    [166]
    [167] Malonic acid ester 1d (5.180 g, 9.91 mmol) was dissolved in 29.5 ml of methanol and cooled to 0 &lt; 0 &gt; C. 29.7 ml of 1N sodium hydroxide (29.73 mmol, 3 eq) was then added to the reaction over 5 minutes and the reaction was allowed to warm to room temperature. After 15 minutes, the methanol was removed in vacuo. The remaining basic solution was then diluted with 29.7 ml of water and cooled in an ice bath. To the basic solution, 1N hydrochloric acid was added dropwise until the pH reached 1. The resulting white semi-solid was collected on a large fritted funnel. The solid was washed 5 times with cold water and then dried over potassium hydroxide under vacuum for 3 days. The final weight of the title compound was 5.01 g (99% yield). The product was consistent with mass spectrometry data.
    [168]
    [169] Example 2
    [170]
    [171] 3- [[3,5-Dichloro-4- [4-hydroxy-3- (1-methylethyl) phenoxy] phenyl] amino-
    [172] Compound 2a :
    [173]
    [174] (15.0 g, 29.4 mmol), 2,6-dichloro-4-nitrophenol (4.16 g, 20 mmol) and Cu powder [ Lancaster 300 mesh (3.2 g, 50 mmol)] was suspended in 200 ml of CH 2 Cl 2 in a flask enclosed with aluminum foil. With stirring, triethylamine (8.4 ml, 100 mmol) was added and the reaction mixture was stirred under argon in the dark for 5 days. The crude reaction mixture was concentrated to about 50 ml, then chromatographed over 2.0 L of Merck silica gel using 3% ethyl acetate in hexanes. The combined yield of compound 2a was 4.9 g (68.8%). The product was consistent with the proton NMR spectrum.
    [175] Compound 2b :
    [176]
    [177] Compound 2a (4.9 g, 13.8 mmol) was dissolved in 80 ml of glacial acetic acid and 8 ml of water. Iron powder (Aldrich < 10 microns, 4.6 g, 81.6 mmol) was added and the reaction was stirred overnight. The reaction mixture was filtered through celite and the pad was thoroughly washed with about 50 ml of methanol. The filtrate was concentrated in vacuo. The addition of a saturated Na 2 CO 3 (400 ml), and the product was extracted with ethyl acetate (3 x 500 ml each). The ethyl acetate extract was concentrated in vacuo and the residue was chromatographed over 1.8 L of Merck silica gel using an ethyl acetate: hexane mixture (8: 2). Compound 2b (2.2 g) was obtained in a yield of 49.4% as a solid. The protons and carbon NMR were consistent with the desired structure.
    [178] Compound 2c :
    [179]
    [180] Was added dropwise to compound 2b (1.8 g, 5.65 mmol) of dichloro-methane was dissolved in 15 ml, pre-cooled solution of BBr 3 (5.3 ml, 56.5 mmol ) in dichloromethane 40 ml under argon (about -60 ℃) solution Respectively. At this low temperature, solid matter was precipitated. The reaction was slowly warmed to 0 &lt; 0 &gt; C and then stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction was diluted with CH 2 Cl 2 200 ml, and was quenched by pouring the cooled, vigorously stirred solution of saturated Na 2 CO 3 (200 ml) and CH 2 Cl 2 (200 ml) . The organic layer was separated, diluted with 100 ml of MeOH, concentrated in vacuo, dissolved in MeOH (100 ml) and concentrated in vacuo three times from MeOH (50 ml each). The residue is dissolved in EtOAc 300 ml, washed twice with saturated NaHCO 3 and brine, dried (Na 2 SO 4), filtration, and concentrated in vacuo to afford Compound 2c (1.77 g, yield 99%) as solids . The protons and carbon NMR were consistent with the desired structure.
    [181] Compound 2d :
    [182]
    [183] The ice-water cooling twos CH 2 compound 2c in the Cl 2 (24 ml) (700 mg, 2.24 mmol), malonic oxyhydrogen acetate (440 mg, 3.32 mmol), 1- [3- ( dimethylamino) propyl] -3-ethyl-1-carboxylic N-Methylmorpholine (41 [mu] L, 2.46 mmol) was added to a mixture of boronic acid, boronic acid, hydrochloric acid (632 mg, 3.33 mmol) and 1-hydroxybenzotriazole (450 mg, 3.40 mmol). The temperature was allowed to warm to room temperature and stirred under argon overnight (about 18 hours). The mixture was diluted with 30 ml of CH 2 Cl 2 and then sequentially washed with H 2 O (3 x 100 ml), 1N HCl (3 x 150 ml), saturated NaHCO 3 (3 x 120 ml) ml). The CH 2 Cl 2 layer was dried over Na 2 SO 4 and concentrated in vacuo to give 632 mg of a white foam. The crude product was purified by chromatography (75 g silica gel, 20% EtOAc in hexanes) to give 500 mg (52%) of purified compound 2d as a white solid. The protons and carbon NMR and LC / MS were consistent with the product.
    [184] Example 2 :
    [185]
    [186] To a solution of compound 2d (330 mg, 0.78 mmol) in methyl alcohol (3.9 ml) was added IN aqueous sodium hydroxide solution (2.3 ml, 2.3 mmol). After 20 minutes, the mixture was concentrated in vacuo to an aqueous solution and this aqueous solution was diluted with 3.2 ml of distilled water. The solution was cooled to 0 &lt; 0 &gt; C and acidified to pH 1 by the dropwise addition of 1N HCl. The white precipitate was collected and dried in vacuo over potassium hydroxide for 18 hours to give 288 mg (74%) of the title compound as a white solid. Proton and carbon NMR and LC / MS were consistent with the desired product.
    [187] Example 3
    [188]
    [189] 2-methylphenyl] amino] -3-oxopropanoic acid &lt; / RTI &gt;
    [190] Compound 3a :
    [191]
    [192] (0.92 g, 0.62 ml, 4.39 mmol) was added to a solution of 4-amino-2,6-dichloro-3-methylphenol (0.70 g, 3.64 mmol) in anhydrous THF (18 ml) Was added. The mixture was allowed to warm to room temperature. After 1 hour, the mixture was dissolved in EtOAc (50 ml) and then washed with brine (2 x 25 ml). Dry the EtOAc extracts over Na 2 SO 4, filtered, concentrated, were concentrated under vacuum to give the 1.07 g of crude product. The crude product was purified by chromatography (50 g silica gel, 20% EtOAc in hexanes) to afford 0.93 mg (89%) of compound 3a as a pale orange solid.
    [193]
    [194] Compound 3b :
    [195]
    [196] CH 2 Cl 2-bis (3-isopropyl-4-methoxyphenyl) iodonium CH 2 To a mixture of borate (3.11 g, 6.07 mmol) and copper (0.31 g, 4.86 mmol) in iodonium tetrafluoroborate in the (12 ml) A solution of compound 3a (0.70 g, 2.43 mmol) and triethylamine (0.49 g, 0.68 ml, 4.88 mmol) in Cl 2 (12 ml) was added. The mixture was stirred at room temperature under N 2 for 92 hours in the dark. The mixture was filtered through a pad pad of Celite and the filtrate was concentrated in vacuo. The crude product was purified by chromatography (200 g of silica gel, hexane 10% EtOAc) to give compound 3b, 0.42 g (40%) as a pale orange solid.
    [197]
    [198] Compound 3c :
    [199]
    [200] To a solution of compound 3b (243 mg, 0.557 mmol) in glacial acetic acid was added 48% HBr aqueous solution (5 ml). The mixture was heated to 120 &lt; 0 &gt; C and held at this temperature for 2 hours. The mixture was cooled to room temperature and then concentrated in vacuo. The pH was dissolved in the concentrate in EtOAc (75 ml), then with saturated NaHCO 3 aqueous solution was adjusted to 7. The EtOAc layer was washed with brine (2 x 25 ml), dried (MgSO 4 ), filtered, concentrated and dried in vacuo to give 179 mg of crude product as a purple solid. The crude product was purified by chromatography (25 g silica gel, 25% EtOAc in hexanes) to give 117.2 mg (64%) of compound 3c as a white solid.
    [201]
    [202] Compound 3d :
    [203]
    [204] The ice-water cooling twos CH 2 C1 2 (5 ml) Compound 3c (78 mg, 0.24 mmol), ethyl hydrogen malonate (47 mg, 0.36 mmol) of 1- [3- (dimethylamino) propyl] -3-ethyl N-Methylmorpholine (25 mg, 27 [mu] L, 0.24 mmol) was added to a mixture of carbodiimide hydrochloride (69 mg, 0.36 mmol) and 1-hydroxybenzotriazole (48 mg, 0.36 mmol). It warmed to room temperature and stirred overnight (about 18 hours) under N 2. The mixture was dissolved in EtOAc (50 ml), then successively washed with H 2 O (2 x 20 ml), 1N HCl (2 x 20 ml), saturated NaHCO 3 (2 x 25 ml) Lt; / RTI &gt; The EtOAc layer was dried (MgSO 4), filtered and concentrated under vacuum to give a thick five days 136 mg of slightly crude product as a light pink. The crude product was purified by chromatography (25 g silica gel, 30% EtOAc in hexanes) to give 82 mg (78%) of compound 3d as a white solid.
    [205]
    [206] Example 3 :
    [207]
    [208] To a solution of compound 3d (70 mg, 0.16 mmol) in THF (1.5 ml) was added 1N aqueous lithium hydroxide solution (0.5 ml, 0.5 mmol). After 1 hour, the mixture was acidified with 1N HCl and then extracted with EtOAc (50 ml). Wash the EtOAc extract with brine (2 x 20 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to give the 57 mg of light yellow solids. Preparative reversed phase HPLC [gradient solvent system, 50% B: 50% A to 0% A: 100% B (A = 90% H 2 O / 10% MeOH + 0.1% TFA, B = 90% MeOH / 10% H 2 O + 0.1% TFA) for 10 min in a YMC ODS 20 x 100 mm column] to give 40 mg (61%) of the title compound as a white solid.
    [209]
    [210] Example 4
    [211]
    [212] 4- [[3,5-Dichloro- [4-hydroxy-3- (1-methylethyl) phenoxy] phenyl] amino] -4-
    [213] Compound 4a :
    [214]
    [215] To the precooled solution of compound 1c (50 mg, 0.125 mmol) in CH 2 Cl 2 (500 μL) at -78 ° C. was added triethylamine (26 μL ml, 0.18 mmol). Subsequently, 3-carbomethoxypropionyl chloride (16 L, 0.14 mmol) was added dropwise. The reaction was stirred for 2 hours. The solution was allowed to warm to room temperature and concentrated in vacuo to give 26 mg of brown oil. The crude product is then passed through a 2 g plug of silica gel with ethyl acetate. The ethyl acetate was concentrated in vacuo to give 40 mg (yield 63%) of 4a as a yellow oil. The proton NMR and LC / MS were consistent with the product contaminated by diacylated byproducts.
    [216] Example 4 :
    [217]
    [218] To a solution of 4a (23 mg, 0.045 mmol) in methanol (1.5 ml) was added a IN aqueous sodium hydroxide solution (0.08 ml, 0.08 mmol). After 3 hours, the mixture was concentrated in vacuo. The reaction was cooled in an ice bath and 1N HCl was added until the pH was 1. The aqueous solution was extracted with ethyl acetate (3 x 30 ml). The combined ethyl acetate layers were washed with brine (2 x 30 ml) and dried over Na 2 SO 4 . The ethyl acetate layer was concentrated in vacuo to yield 15 mg of a white semi-solid. The crude material was purified by preparative reverse phase HPLC (gradient solvent system, 50% A: 50% B to 0% A: 100% B (A = 90% H 2 O / 10% MeOH + 0.1% TFA, B = 90% MeOH / % H 2 O + 0.1% TFA), 15 min, YMC ODS 20 x 100 mm column] to give 8.0 mg (36%) of the title compound as a white solid. The proton NMR and LC / MS were consistent with the desired product.
    [219] Example 5
    [220]
    [221] 5 - [[3,5-Dichloro- [4-hydroxy-3- (1- methylethyl) phenoxy] phenyl] amino] -5-oxopentanoic acid
    [222] In the manner described in Example 4 above, 15.0 mg (Yield 36%) of the title compound was obtained as a white solid. The proton NMR and LC / MS were consistent with the desired structure.
    [223] Example 6
    [224]
    [225] Compound 6a :
    [226]
    [227] The ice-water cooling twos CH 2 C1 2 (50 ㎕) of compound 1c (40 mg, 0.10 mmol) , maleic acid, mono-methyl ester (36 ㎕, 0.29 mmol), 1- [3- ( dimethylamino) propyl] - To the mixture of 3-ethylcarbodiimide, hydrochloric acid (72 mg, 0.38 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol) was added triethylamine (46 μL, 0.28 mmol). The temperature was allowed to warm to room temperature and stirred overnight under nitrogen (about 18 hours). The mixture was dissolved in EtOAc (50 ml), then successively washed with H 2 O (2 x 20 ml), 1N HCl (2 x 20 ml), saturated NaHCO 3 (2 x 25 ml) and brine And washed. The EtOAc layer was dried (Na 2 SO 4), and concentrated under vacuum to give the concentrate an oil 30 mg (58%) of slightly crude product as a light pink. The crude product was hydrolyzed. The proton NMR and LC / MS were consistent with the desired product.
    [228] Example 6 :
    [229]
    [230] To a solution of compound 6a (15 mg, 0.029 mmol) in methyl alcohol (1.5 ml) was added a IN aqueous sodium hydroxide solution (0.08 ml, 0.08 mmol). After 3 h, the reaction mixture was concentrated in vacuo to remove methanol. The resulting solution was cooled in an ice bath and 1 N HCl was added until the pH was 1. The aqueous solution was extracted with ethyl acetate (3 x 30 ml). The combined ethyl acetate layer was washed with brine (2 x 30 ml), dried over Na 2 SO 4. The ethyl acetate extract was concentrated in vacuo to yield 12 mg of a white semi-solid. The crude material was purified by preparative reverse phase HPLC (gradient solvent system, 50% A: 50% B to 0% A: 100% B (A = 90% H 2 O / 10% MeOH + 0.1% TFA, B = 90% MeOH / % H 2 O + 0.1% TFA), 15 min, YMC ODS 20 x 100 mm column] to give 7.9 mg (53%) of the title compound as a white solid. The proton NMR and LC / MS were consistent with the desired structure.
    [231] Example 7
    [232]
    [233] In the manner described in Example 6 above, 17.9 mg (46%) of the title compound was obtained as a white solid. The proton NMR and LC / MS were consistent with the desired structure.
    [234] Examples 8 to 19
    [235]
    [236] The method described above was performed according to the method described in "Novel Thyroid Receptor Ligands and Methods", Y.-L. Li, Y. Liu, A. Hedfors, J. Malm, C. Mellin, M. Zhang, PCT Int. App.WO 9900353 Al Examples 9-19 described in Table 1 below were prepared by suitably applying in combination with those described for the analogous examples found in WO 00/990107.
    [237]
    权利要求:
    Claims (30)
    [1" claim-type="Currently amended] Claims 1. A compound of formula (I), all stereoisomers, prodrugs or pharmaceutically acceptable salts thereof:
    (I)

    Wherein,
    X is oxygen (-O-), sulfur (-S-), carbonyl (-CO-), methylene (-CH 2 -) or -NH-;
    Y is - (CH 2 ) n -, wherein n is an integer from 1 to 5, or cis or trans-C = C-;
    R 1 is halogen, trifluoromethyl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms;
    R 2 and R 3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein at least one of R 2 and R 3 is not hydrogen;
    R &lt; 4 &gt; is hydrogen or lower alkyl;
    R &lt; 5 &gt; is hydrogen or lower alkyl;
    R &lt; 6 &gt; is a carboxylic acid or an ester or prodrug thereof;
    R 7 is hydrogen, an alkanoyl group or an aroyl group, or other group capable of biotransformation to produce a free phenolic structure (where R 7 = H).
    [2" claim-type="Currently amended] 2. The compound according to claim 1, wherein X is oxygen.
    [3" claim-type="Currently amended] 3. A compound according to claim 2, wherein R &lt; 5 &gt; is hydrogen.
    [4" claim-type="Currently amended] 4. The compound according to claim 3, wherein R &lt; 1 &gt; is isopropyl.
    [5" claim-type="Currently amended] The compound according to claim 3, wherein R 2 and R 3 are each independently halogen.
    [6" claim-type="Currently amended] The compound according to claim 3, wherein R 2 and R 3 are each independently an alkyl group.
    [7" claim-type="Currently amended] The compound according to claim 3, wherein one of R 2 and R 3 is halogen and the other is an alkyl group.
    [8" claim-type="Currently amended] 4. The compound of claim 3, wherein one of R &lt; 2 &gt; and R &lt; 3 &gt; is halogen and the other is hydrogen.
    [9" claim-type="Currently amended] 4. The compound of claim 3 wherein one of R &lt; 2 &gt; and R &lt; 3 &gt; is alkyl and the other is hydrogen.
    [10" claim-type="Currently amended] The compound according to claim 3, wherein R 2 and R 3 are independently Cl, Br, methyl or ethyl.
    [11" claim-type="Currently amended] 4. A compound according to claim 3 wherein R &lt; 4 &gt; is hydrogen.
    [12" claim-type="Currently amended] 4. The compound according to claim 3, wherein R &lt; 4 &gt; is methyl.
    [13" claim-type="Currently amended] The method of claim 3, wherein, Y is - (CH 2) n - (At this time, n is 1 or 2) in compounds.
    [14" claim-type="Currently amended] 4. The compound according to claim 3, wherein Y is cis- or trans-ethylene.
    [15" claim-type="Currently amended] 4. The compound according to claim 3 having the structure of formula (Ia) or (Ib), or an alkyl ester thereof.
    <Formula Ia>

    (Ib)

    [16" claim-type="Currently amended] 2. The compound according to claim 1 having a structure of the formula: or an alkyl ester thereof.

    [17" claim-type="Currently amended] 2. The compound according to claim 1 having a structure of the formula: or an alkyl ester thereof.

    [18" claim-type="Currently amended] The compound according to claim 1 having the structure of the formula:

    [19" claim-type="Currently amended] The compound according to claim 1 having the structure of the formula:

    [20" claim-type="Currently amended] A method of preventing, inhibiting or treating a metabolic dysfunction-related disease, or a disease dependent on the expression of a T 3 regulatory gene, comprising administering a therapeutically effective amount of a compound as defined in claim 1 to a patient in need thereof.
    [21" claim-type="Currently amended] 21. The method according to claim 20, wherein the metabolic dysfunction-related disorder or the disease dependent on the expression of the T 3 regulatory gene is selected from the group consisting of obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, thyroid, thyroid, glaucoma, Arrhythmia, congestive heart failure, or skin disorder or disease.
    [22" claim-type="Currently amended] 1. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
    [23" claim-type="Currently amended] 22. The method of claim 21, wherein the skin disorder or disease is selected from the group consisting of skin atrophy, post surgical bruising caused by laser abrasion, marine, ancestral, cellulite, rough skin, actinic skin damage, Psoriasis, dermatitis (Dernier's disease), eczema, atopic dermatitis, goat acne, intranasal and skin wounds.
    [24" claim-type="Currently amended] A method for treating a skin disorder or disease by using the compound according to claim 1 in combination with a retinoid or a vitamin D analog.
    [25" claim-type="Currently amended] 12. A pharmaceutical formulation comprising a compound as defined in claim 1 and a hypolipidemic agent, an anti-diabetic agent, an antidepressant, an anti-bone resorption inhibitor, an appetite suppressant and / or an anti-obesity agent.
    [26" claim-type="Currently amended] The method of claim 25, wherein the low-lipid blood I thiazolidinediones, MTP inhibitor, squalene synthetase inhibitor, an HMG CoA reductase inhibitor, a fibric acid derivative, ACAT inhibitor, a cholesterol absorption inhibitor, a president Na + / bile co-transporter inhibitor, a bile acid A quencher and / or a nicotinic acid or a derivative thereof.
    [27" claim-type="Currently amended] 26. The combination according to claim 25, wherein the hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.
    [28" claim-type="Currently amended] 26. The combination of claim 25 wherein the weight ratio of compound defined in claim 1 to hypolipidemic or antidiabetic agent is within the range of from about 0.01: 1 to about 300: 1.
    [29" claim-type="Currently amended] 26. The combination according to claim 25, wherein the antidiabetic agent is a bigninoid, a sulfonylurea, a glucosidase inhibitor, a thiazolidinedione, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or an insulin.
    [30" claim-type="Currently amended] 30. The composition of claim 29, wherein the antidiabetic agent is selected from the group consisting of metformin, glyburide, glimepiride, glypyrid, glypidide, chlorpropamide, glyclazide, acarbose, miglitol, troglitazone, pioglitazone, rosiglitazone, A combination that is insulin.
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    JP2004500382A|2004-01-08|
    MXPA02007929A|2003-02-10|
    BR0108134A|2003-09-30|
    PT1257526E|2005-09-30|
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    UY26581A1|2001-09-28|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-02-17|Priority to US18322300P
    2000-02-17|Priority to US60/183,223
    2001-01-12|Application filed by 브리스톨-마이어스스퀴브컴파니
    2002-10-05|Publication of KR20020075799A
    2007-07-16|Application granted
    2007-07-16|Publication of KR100740383B1
    优先权:
    申请号 | 申请日 | 专利标题
    US18322300P| true| 2000-02-17|2000-02-17|
    US60/183,223|2000-02-17|
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