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Publication Number
US-8629167-B2
Publication Date
2014-01-14
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, 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 patent describes substituted 1,3,4-oxadiazole-based compounds and related intermediates, including chiral benzonitrile, aminopropanol, and hydrazide-derived scaffolds. The compound family includes stereodefined (1R,2S) and (1R,2R) variants, ester and sulfamate variants, and phenyl and substituted phenyl forms such as cyanophenyl, hydroxyphenyl, fluorophenyl, and deuterophenyl forms, together with pharmaceutically acceptable salts, solvates, hydrates, polymorphs, and stereoisomers/enantiomers/diastereomers.
The disclosure also includes preparation of hydrazide intermediates, cyclization to oxadiazoles or thiadiazoles, protection and deprotection using silyl groups and tetrabutylammonium fluoride, and dehydration or activation with named dehydrating reagents. Several examples and intermediates are characterized with reported yields and 1H NMR, and the synthesis coverage extends to ester and sulfamate variants together with other explicitly listed derivative forms.
The disclosed subject matter states that the compounds are androgen receptor modulators and presents the compound family in pharmaceutical and biological contexts. The materials tie the compounds to pharmaceutical compositions with pharmaceutically acceptable excipients, cellular androgen receptor modulation, assay-style identification by contacting androgen-receptor-expressing cells and monitoring effects, and therapeutic use in cachexia-related indications, including cancer cachexia, as well as other explicit therapeutic applications.
Claims Coverage
The consolidated claim coverage centers on one independent compound-selection claim family for specified substituted oxadiazole-based organic compounds, together with dependent claims for pharmaceutical compositions, androgen receptor modulation in cells, contact-and-monitor identification of modulators, and therapeutic use. The covered inventive features are the selected compound set, pharmaceutical composition inclusion, androgen receptor modulation by administration, identification of modulators by contacting and monitoring, and treatment of cancer cachexia.
Selected substituted oxadiazole-based compounds
A compound selected from specified substituted 1,3,4-oxadiazole-based organic compounds, including stereodefined (1R,2S) and (1R,2R) variants, ester and sulfamate variants, aromatic and heteroaromatic variants, and pharmaceutically acceptable salts thereof.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising a compound according to the selected compound claim and at least one pharmaceutically acceptable excipient.
Androgen receptor modulation in a cell by administration
A method of modulating an androgen receptor in a cell by administering a compound according to the selected compound claim or a pharmaceutically acceptable salt of that compound.
Contact-and-monitor identification of androgen receptor modulators
A method of identifying a compound that modulates an androgen receptor by contacting an androgen-receptor-expressing cell with a candidate compound and monitoring the compound’s effect on the cell.
Treatment of cancer cachexia
A method specified to treat cancer cachexia.
Overall, the claims define a specified substituted oxadiazole compound set and extend that scope to excipient-containing pharmaceutical compositions, cell-based androgen receptor modulation by administration, assay-style identification by contacting and monitoring, and treatment of cancer cachexia.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Androgen receptor binding measurements and androgen receptor modulation evaluation.
Rat Herschberger assay description for androgen/anabolic outcomes.
Bone-loss prevention model descriptions including immature castrated rat and ovariectomized rat/mouse contexts.
Therapeutic treatment for cachexia, including cancer cachexia.
Pharmaceutical compositions containing the claimed compounds and pharmaceutically acceptable excipients.
Identification of compounds that modulate an androgen receptor by contacting androgen-receptor-expressing cells and monitoring effects.
Sarcopenia.
Prostate cancer.
Contraception.
Type 2 diabetes-related disorders.
Anemia.
Depression.
Renal disease.
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