Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof
Inventors
Han, Sangdon • ZHU, Yunfei • Kim, Sun Hee • Zhao, Jian • Wang, Shimiao
Assignees
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Publication Number
US-11566015-B2
Publication Date
2023-01-31
Expiration Date
Abstract
Described herein are compounds that are melanocortin subtype-2 receptor (MC2R) modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of MC2R activity.
Core Innovation
The invention provides compounds defined by Formula (IX), or a pharmaceutically acceptable salt, or solvate thereof. The structure is defined by variables including V is CH, X1 is N, R2 and R3 are hydrogen or taken together with the carbon atom to which they are attached to form —C(=O)—, and Ra is —OCH2CH3, with additional substituent variables including Rb, Rc, RB, and R4.
The disclosed chemical series includes specific pyridine-2-carboxamide compounds with a 6-(2-ethoxyphenyl) core and an ethylpiperazin-1-yl substituent pattern with specified stereochemistry. The described embodiments further include benzoyl or cyclocarbonyl substituent patterns with chloro, trifluoromethyl, difluoromethyl, fluoro, and cyano motifs, together with N-substituted side rings such as dimethylaminoethyl, pyrrolidinyl, azetidinyl, and azabicyclic amine motifs.
The compound scope is expressed through enumerated structural embodiments and pharmaceutically acceptable salt and solvate forms. The claim context identifies these compounds as MC2R-targeting and associates them with administration to a mammal for specified endocrine disorders, including Cushing’s syndrome, Cushing’s disease, ectopic ACTH syndrome, and congenital adrenal hyperplasia (CAH).
Claims Coverage
The consolidated claim coverage includes one general compound claim for Formula (IX) and multiple specifically named pyridine-2-carboxamide compound claims. Across these independent claims, the inventive features are structural limitations on the pyridine-2-carboxamide scaffold, defined substituent patterns, and specified stereochemistry, with optional pharmaceutically acceptable salt or solvate coverage. Dependent claim coverage extends to pharmaceutical compositions and therapeutic administration for MC2R activity and specified endocrine disorders.
Formula (IX) pyridine-2-carboxamide compound
A compound of Formula (IX), or a pharmaceutically acceptable salt, or solvate thereof, wherein V is CH; X1 is N; R2 and R3 are hydrogen or taken together with the carbon atom to which they are attached to form —C(=O)—; Ra is —OCH2CH3; and Rb and Rc are hydrogen, with additional substituent variables including RB and R4.
Specific substituted pyridine-2-carboxamide embodiments
A compound defined by explicitly named pyridine-2-carboxamide structures, each including a 6-(2-ethoxyphenyl) core, an ethylpiperazin-1-yl substituent with specified stereochemistry, and fluorinated or halogenated benzoyl/carbonyl substituent patterns, or a pharmaceutically acceptable salt, or solvate thereof.
3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide
The explicitly named compound, or a pharmaceutically acceptable salt, or solvate thereof.
6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide
The explicitly named compound, or a pharmaceutically acceptable salt, or solvate thereof.
6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide
The explicitly named compound, or a pharmaceutically acceptable salt, or solvate thereof.
N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide
The explicitly named compound, or a pharmaceutically acceptable salt, or solvate thereof.
The claim coverage is centered on a Formula (IX) scaffold and multiple explicit substituted pyridine-2-carboxamide embodiments with defined stereochemistry and substituent patterns. The claims also include pharmaceutically acceptable salts and solvates, and dependent coverage for pharmaceutical compositions and administration-based treatment of Cushing’s syndrome, Cushing’s disease, ectopic ACTH syndrome, congenital adrenal hyperplasia, and MC2R activity modulation.
Stated Advantages
Modulates melanocortin subtype-2 receptor (MC2R) activity.
Treats Cushing’s syndrome, Cushing’s disease, ectopic ACTH syndrome, or congenital adrenal hyperplasia (CAH) in a mammal.
Documented Applications
Pharmaceutical compositions including the claimed compound and at least one pharmaceutically acceptable excipient.
Modulating melanocortin subtype-2 receptor (MC2R) activity in a mammal by administering a compound, or a pharmaceutically acceptable salt or solvate of the compound.
Treating Cushing’s syndrome, Cushing’s disease, ectopic ACTH syndrome, or congenital adrenal hyperplasia (CAH) in a mammal by administering a compound, or a pharmaceutically acceptable salt or solvate of the compound.
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