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Publication Number
US-8455525-B2
Publication Date
2013-06-04
Expiration Date
Abstract
This invention provides compounds of formulas I, Ia, Ib, Ic, Id, Ie, and or salts thereof, pharmaceutical compositions comprising a compound of formulas I, Ia, Ib, Ic, Id, Ie, and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) and processes for making compounds of formulas I, Ia, Ib, Ic, Id, Ie, and intermediates useful in the preparation of same.
Core Innovation
The disclosure describes compounds according to formula I, formula Ia, formula Ib, formula II, formula III, formula IV, formula VI, and formula IX with broad heteroaryl/phenyl-substituted structures defined by extensive R-group options, including CN, halogen, CF3, hydroxyalkyl, methoxy, and defined ring selections for A and B. The compound families include pharmaceutically acceptable salts and are presented together with heteroaryl and aromatic ring formation options.
The material relates to heteroaryl- and benzamide/ester-containing chemical series with oxadiazole-linked derivatives, including benzonitrile, naphthonitrile, and benzo[b]thiophene carbonitrile frameworks. The examples and intermediates include chiral hydroxypropylamino or amino alcohol substituents, defined stereochemistry such as (1R,2S), (1R,2R), (2R,3S), (2R,3R), and (R), and aromatic substituent patterns including chloro, fluoro, bromo, iodo, cyano, trifluoromethyl, methoxy, hydroxy, and methylsulfonyl.
The disclosure further describes benzohydrazide intermediates, oxadiazole-containing final compounds, and related thio/oxo analogs, with protection and deprotection of hydroxyl groups by TBDMS/TBS groups. It also includes formation of oxadiazole-amino derivatives, thiadiazolyl analogs, and acyl derivatives such as acetate, benzoate, sulfate, butyrate, benzamide, acetamide, and butyramide forms, supported by reported yields and characterization data.
Claims Coverage
This document contains four independent claim themes. Across these claims, the inventive coverage centers on broad Formula I compound genera with extensive substituent and ring-system definitions, an enumerated set of specific stereodefined compounds, and claims tied to androgen receptor modulator scaffold compounds, all including pharmaceutically acceptable salts.
Formula I compound genus with defined substituent and ring options
A compound according to formula I, wherein R_x is CN, Cl, Br, NO2 or R_x1; R_y is CH3, CF3 or halogen; R_z is H or selected C1-3 alkyl, C1-3 haloalkyl, NO2, NH2, OMe, halogen or OH, or related ring-forming options; A is a five member heteroaryl selected from specified options or, in another formulation, a 5- or 6-member heteroaryl substituted with hydrogen and optionally up to two substituents; B is phenyl, C1-6 alkyl, C1-6 haloalkyl, 5- or 6-member heteroaryl or bicyclic heteroaryl; and the claims include pharmaceutically acceptable salts.
Selected specific oxadiazole and related heteroaryl compounds
A compound selected from enumerated specific chemical structures including stereochemical variants such as (1R,2S), (1R,2R), (2R,3S), (2R,3R), and (R), with benzonitrile, naphthonitrile, or benzo[b]thiophene carbonitrile cores linked to oxadiazole- or thiadiazole-containing moieties. The enumerated compounds include substituted phenyl and heteroaryl variants and derivative forms such as acetate, benzoate, sulfate, butyrate, benzamide, acetamide, and butyramide, together with pharmaceutically acceptable salts.
Formula I compound genus with expanded A and B framework definitions
A compound represented by formula I with extensive variable definitions for R_x, R_y, R_z, R_x1, R_y1, A, B, R_a, n, n', n'', and R1-R9, including allowed OR3-containing positions and defined heteroaryl/aryl substitutions. The claim scope includes heteroaryl and aromatic ring formation options and pharmaceutically acceptable salts.
Androgen receptor modulator scaffold compounds
Compounds defined by formula II, formula III, formula IV, formula VI, and formula IX through stepwise conversions among the claimed scaffold forms, with extensive Markush definitions for R_x, R_y, R_z, R_1, R_2, R_4, R_3, and R_5, and with resulting compounds stated to be useful for production of an androgen receptor modulator.
The consolidated claims cover broad Formula I chemical genera with extensive heteroaryl/aryl and substituent definitions, an enumerated set of specific stereodefined oxadiazole/thiadiazole-related compounds and derivative forms, and androgen receptor modulator scaffold compounds. Across these independent claims, the recurring claim elements are the defined heteroaryl/phenyl scaffold, stereochemical variants, and pharmaceutically acceptable salts.
Stated Advantages
Reported yields and characterization data are provided for multiple intermediates and final compounds.
Provides androgen receptor binding affinity measurements (IC50 values) for disclosed examples.
Provides in vivo utility data using the Rat Herschberger assay, reporting % stimulation in prostate, seminal vesicle, and LABC.
Notes preferential levator ani stimulation versus prostate/seminal vesicles.
Useful for production of an androgen receptor modulator.
Documented Applications
Androgen receptor binding assessment using measured AR binding affinity IC50 values.
In vivo utility evaluation using the Rat Herschberger assay with reported % stimulation in prostate, seminal vesicle, and LABC at 10 mg/kg (po).
Usefulness for production of an androgen receptor modulator.
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