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Publication Number
US-8268872-B2
Publication Date
2012-09-18
Expiration Date
Abstract
This invention provides compounds of formulas I, Ia, Ib, Ic, Id, Ie, If or Ig or salts thereof, pharmaceutical compositions comprising a compound of formulas I, Ia, Ib, Ic, Id, Ie, If or Ig 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, If or Ig and intermediates useful in the preparation of same.
Core Innovation
The invention concerns compounds according to formula Ia, including pharmaceutically acceptable salts thereof, for modulating an androgen receptor. Formula Ia is defined by extensive structural variables, including R_x, R_y, R_z, A, R_a, R_b, R_b', n, R1, R2, R3, and R4, with allowed cyano, halogen, nitro, alkyl, haloalkyl, hydroxy, methoxy, amino, and selected ring systems. The structural definition further includes a five member heteroaryl and optional formation of a five member aromatic ring.
The invention addresses modulation of an androgen receptor in a cell by administering a compound according to formula Ia, and also covers identifying a compound capable of modulating an androgen receptor by contacting an androgen receptor-expressing cell with a compound of formula Ia or a pharmaceutically acceptable salt and monitoring the effect on the cell. The same formula Ia compounds are used for ameliorating symptoms associated with sarcopenia, frailty, cachexia, muscular dystrophy, low body weight, AIDS wasting, and cancer cachexia in a mammal in need thereof.
The disclosed chemical content includes formula-Ia oxadiazole/benzonitrile androgen-receptor modulator compounds, intermediates, and example compounds with defined stereochemistry. The document describes benzohydrazide species, protected hydroxy-containing intermediates, and oxadiazole-bearing aromatic groups, with analytical characterization such as NMR and LRMS data for multiple intermediates and examples.
Claims Coverage
The independent claims cover three uses of compounds according to formula Ia, with three inventive feature sets: modulation of an androgen receptor in a cell by administration, identification of compounds capable of modulating an androgen receptor by cell contact and monitoring, and amelioration of specified sarcopenia- and cachexia-related symptoms in a mammal by administration of an effective amount of a formula Ia compound. The inventive scope is anchored by the extensive structural definition of formula Ia and its allowed substituent and ring variations.
Administration of a formula Ia compound to modulate an androgen receptor
A method of modulating an androgen receptor in a cell by administration of a compound according to formula Ia, including pharmaceutically acceptable salts thereof, where the compound is defined by the specified substituent variables and ring selections for R_x, R_y, R_z, A, R_a, R_b, R_b', n, R1, R2, R3, and R4.
Cell-contacting identification using a formula Ia compound
A method of identifying a compound capable of modulating an androgen receptor by contacting an androgen receptor-expressing cell with a compound according to formula Ia or a pharmaceutically acceptable salt thereof and monitoring the effect of the compound on the cell, where the compound is defined by the same formula Ia structural constraints.
Administering an effective amount of formula Ia to ameliorate wasting and sarcopenia-related symptoms
A method of ameliorating the symptoms of sarcopenia, frailty, cachexia, muscular dystrophy, low body weight, AIDS wasting, and cancer cachexia in a mammal in need thereof by administering an effective amount of a compound according to formula Ia or a pharmaceutically acceptable salt thereof, where formula Ia is defined by the specified substituent and ring constraints.
The independent claims center on formula Ia compounds and their structured substituent and ring definitions. They apply those compounds to androgen receptor modulation in cells, identification of androgen receptor modulators by contacting and monitoring, and therapeutic amelioration of the listed sarcopenia/cachexia-related symptoms in mammals.
Stated Advantages
Modulation of an androgen receptor in a cell.
Identification of a compound capable of modulating an androgen receptor by contacting androgen receptor-expressing cells and monitoring the effect.
Amelioration of the symptoms of sarcopenia, frailty, cachexia, muscular dystrophy, low body weight, AIDS wasting, and cancer cachexia in a mammal in need thereof.
Documented Applications
Modulating an androgen receptor in a cell by administering a compound according to formula Ia.
Identifying a compound capable of modulating an androgen receptor by contacting an androgen receptor-expressing cell with a compound according to formula Ia and monitoring the effect.
Ameliorating sarcopenia, frailty, cachexia, muscular dystrophy, low body weight, AIDS wasting, and cancer cachexia in a mammal in need thereof by administering an effective amount of a compound according to formula Ia.
Therapeutic amelioration in sarcopenia/frailty/cachexia and related indications using specific formula-Ia compounds.
Androgen receptor modulation by administering a formula-Ia compound, with stereochemically defined Ia members.
Identification method using formula-Ia compounds.
The partial content states androgen receptor binding and IC50 values for multiple numbered examples in a binding assay table and reports in vivo efficacy context using the Rat Herschberger assay, including prostate, seminal vesicle, and levator ani bulbus cavernosus (LABC).
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