PROGESTERONE ANALOGS AND USES RELATED THERETO
This disclosure relates to progesterone derivatives and uses related thereto. In certain embodiments, the disclosure relates to compounds disclosed herein and uses for managing inflammation resulting from traumatic brain injury or stroke.
1 . A compound of Formula I,
or esters, prodrugs, or salts thereof wherein
X is O or N—OR 1 ;
Y is O or N—OR 1 ;
R 1 is hydrogen or a group selected from alkyl and formyl further substituted with one or more, the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 2 ;
R 2 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 3 ;
R 3 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 4 ; and
R 4 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
2 . A compound of claim 1 having Formula IA
or esters, prodrugs, or salts thereof wherein
R 1 is hydrogen or a group selected from alkyl and formyl substituted with one or more, the same or different, alkyl, amino, hydroxyl, thiol, halogen, aryl, carbocyclyl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 2 ;
R 2 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 3 ;
R 3 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 4 ; and
R 4 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
3 . The compound of claim 1 , wherein R 1 is alkyl substituted with a heterocyclyl further optionally substituted with one or more, the same or different R 2 .
4 . The compound of claim 1 having Formula IB
or esters, prodrugs, or salts thereof wherein
R 2 is alkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 3 ;
R 3 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 4 ; and
R 4 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
5 . The compound of claim 4 , wherein R 2 is heterocyclyl or alkyl substituted with a group selected from amino and heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 3 .
6 . A compound of claim 1 having Formula IC
or esters, prodrugs, or salts thereof wherein
n is 1, 2, 3, or 4;
R 5 and R 6 and the attached nitrogen form a 5 or 6 membered heterocyclyl optionally substituted with one or more, the same or different, R 7 ; or
R 5 is alkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 7 ;
R 6 is alkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 7 ;
R 7 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 7 is optionally substituted with one or more, the same or different, R 8 ; and
R 8 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
7 . The compound of claim 6 , wherein R 5 and R 6 is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring optionally substituted with one or more, the same or different, R 7 .
8 . The compound of claim 1 having Formula ID
or esters, prodrugs, or salts thereof wherein
m is 1, 2, 3, or 4;
R 9 and R 10 and the attached nitrogen form a 5 or 6 membered heterocyclyl optionally substituted with one or more, the same or different, R 11 ; or
R 9 is alkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 11 ;
R 10 is alkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 11 ;
R 11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 12 ; and
R 12 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
9 . The compound of claim 1 having Formula IE
or esters, prodrugs, or salts thereof wherein
m is 1, 2, 3, or 4;
R 13 and R 14 and the attached carbon form a 5 or 6 membered aryl or heterocyclyl optionally substituted with one or more, the same or different, R 15 ;
R 15 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 16 ; and
R 16 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
10 . The compound of claim 9 wherein, R 13 and R 14 is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring optionally substituted with one or more, the same or different, R 11 .
11 . The compound of claim 1 selected from:
17-(1-(hydroxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
17-(1-(methoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
10,13-dimethyl-17-(1-((2-morpholinoethoxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
17-(1-(acetoxyimino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
17-(1-(((2-amino-3-methylbutanoyl)oxy)imino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
10,13-dimethyl-17-(1-(((pyrrolidine-2-carbonyl)oxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
2-((((1-(10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylidene)amino)oxy)carbonyl)-1,1-dimethylpyrrolidin-1-ium;
2-(((1-(10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylidene)amino)oxy)-N,N,N-trimethyl-2-oxoethanaminium;
17-(1-((2-(dimethylamino)acetoxy)imino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one
10,13-dimethyl-17-(1-((2-morpholinoacetoxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
10,13-dimethyl-17-(1-((2-(4-methylpiperazin-1-yl)acetoxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
10,13-dimethyl-17-(1-((nicotinoyloxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
3-((((1-(10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylidene)amino)oxy)carbonyl)-1-methylpyridin-1-ium;
17-(1-(((4-(aminomethyl)benzoyl)oxy)imino)ethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3 (2H)-one;
10,13-dimethyl-17-(1-(((4-((4-methylpiperazin-1-yl)methyl)benzoyl)oxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
10,13-dimethyl-17-(1-(((piperidine-4-carbonyl)oxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3 (2H)-one;
4om Ox((((1-(10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylidene)amino)oxy)carbonyl)-1,1-dimethylpiperidin-1-ium;
10,13-dimethyl-17-(1-(((piperidine-3-carbonyl)oxy)imino)ethyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one;
or salts thereof.
12 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
13 . A pharmaceutical composition of claim 12 , further comprising a second active therapeutic agent.
14 . A method of treating or preventing inflammation or CNS injury comprising administering an effective amount of a pharmaceutical composition of claim 11 to a subject in need thereof.
15 . The method of claim 14 , wherein the pharmaceutical composition is administered to a subject that incurred trauma to the head or other organ or tissue.
16 . The method of claim 15 , wherein the pharmaceutical composition is administered after a medical procedure.
17 . The method of claim 16 , wherein the pharmaceutical composition is administered in combination with a second anti-inflammatory agent.
18 . A method of treating stroke or traumatic brain injury comprising administering an effective amount of a pharmaceutical composition of claim 11 to a subject in need thereof.
19 . A method of treating a neurodegenerative disease or condition comprising administering an effective amount of a pharmaceutical composition of claim 11 to a subject in need thereof.
20 . The method of claim 19 , wherein the neurodegenerative disease or condition is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia, extrapyramidal and movement disorders, motor neurone disease, systemic atrophies primarily affecting the central nervous system, Tay-Sachs disease, ataxia telangiectasia, Batten disease, corticobasal degeneration, Creutzfeldt-Jakob disease, fatal familial insomnia, infantile Refsum disease, lyme disease, Machado-Joseph disease, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, refsum disease, Sandhoff disease, Shy-Drager syndrome, spinocerebellar ataxia, tabes dorsalis, toxic encephalopathy, and Wobbly hedgehog syndrome.