US2003149268A1PendingUtilityA1

8-substituted-6-trifluoromethyl-9-pyrido[3,2-g]quinoline compounds as androgen receptor modulators

47
Priority: Aug 27, 1999Filed: Dec 23, 2002Published: Aug 7, 2003
Est. expiryAug 27, 2019(expired)· nominal 20-yr term from priority
Inventors:Lawrence G. HamannJames S. KongJames P. Edwards
A61P 5/26A61P 7/00A61P 43/00A61P 35/00A61P 3/00A61P 13/08A61P 15/08A61P 17/00A61P 17/14C07D 471/04A61P 15/00
47
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Claims

Abstract

Non-steroidal compounds and compositions which are agonists, partial agonists, and antagonists for androgen receptors and methods of preparation for the non-steroidal compounds and compositions.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A compound having the formula:  
       
         
           
           
               
               
           
         
         wherein: 
 R 1  is selected from the group of hydrogen, a C 1 -C 6  alkyl, F, Cl, Br, I, NO 2 , OR 2 , NR13R14, and SR 2 ;  
 R 2  is selected from the group of hydrogen, C 1 -C 6  alkyl and C 1 -C 6  alkenyl, wherein the C 1 -C 6  alkyl and C 1 -C 6  alkenyl are optionally substituted with C 1 -C 6  alkyl, arylalkyl, aryl or heteroaryl;  
 R 3  and R 4  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ; or  
 R 3  and R 4  taken together form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ;  
 R 5  and R 6  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ; or  
 R 7  and R 8  taken together form a ═O, ═NR 2  or a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR13R14, or SR 2 ;  
 R 7  and R 8  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ; or  
 R 7  and R 8  taken together form a ═O, ═NR 2  or a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ;  
 R 9  is selected from the group of hydrogen, C 1 -C 4  alkyl, F, Cl, Br, I, OR 2 , NR 13 R 14 , and SR 2 ;  
 R 10  is selected from the group of hydrogen, F, Cl, Br, CF 3 , CF 2 OR 2 , CH 2 OR 2 , OR 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ;  
 R 11  is selected from the group of hydrogen, F, Cl, Br, I, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, perhaloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ;  
 R 12  is selected from the group of hydrogen, C(O)R 11 , SR 2 , S(O)R 13 , S(O 2 )R 13 , C 1 -C 6  alkyl, C 1 -C 6  alkenyl, aryl, arylalkyl and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkyl and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ;  
 X is selected from the group of hydrogen, F, Cl, Br, I, CN, CF 3 , SR 2 , S(O)R 13 , SO 2 R 13 , SO 3 R 13 , NR 13 R 14 , CF 3 , NO 2 , and R 13 ;  
 R 13  and R 14  each independently is selected from the group of hydrogen, C(O)R 11 , SO 2 R, C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, aryl, arylalkyl and heteroaryl, wherein the alkyl, alkenyl, haloalkyl, perhaloalkyl, aryl, arylalkyl, and heteroaryl are optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , or SR 2 ;  
 with the proviso that when the dotted line in the ring structure is a double bond, R 6  and R 7  are null;  
 and paharmacuetically accpeptable salts thereof.  
 
       
     
     
         2 . A compound according to  claim 1 , wherein R10 is selected from the group of hydrogen, F, Cl, Br, CF 3 , CF 2 OR 2 , CH 2 OR 2 , OR 2 , and C 1 -C 6  alkyl.  
     
     
         3 . A compound according to  claim 2 , wherein R10 is selected from the group of hydrogen, F, Cl, Br, and CF 3 .  
     
     
         4 . A compound according to  claim 1 , wherein R 1  and R 2  each independently is selected from the group of hydrogen and C 1 -C 4  alkyl.  
     
     
         5 . A compound according to  claim 1 , wherein R 3 , R 4 , R 5  and R 8  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  perhaloalkyl, C 1 -C 6  alkenyl, and C 1 -C 6  alkynyl.  
     
     
         6 . A compound according to  claim 5 , wherein R 3 , R 4 , R 5  and R 8  each independently is selected from the group of hydrogen and C 1 -C 6  alkyl.  
     
     
         7 . A compound according to  claim 1 , wherein R 9  and R 11  each independently is selected from the group of hydrogen, C 1 -C 4  alkyl, F, Cl, Br, and I.  
     
     
         8 . A compound according to  claim 7 , wherein R 9  and R 11  each independently is selected from the group of hydrogen, F, Cl, Br, and I.  
     
     
         9 . A compound according to  claim 1 , wherein R 12  is selected from the group of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  allyl, arylmethyl, and heteroaryl, and wherein the alkyl, allyl, arylmethyl and heteroaryl is optionally substituted with hydrogen, F, Cl, Br, C 1 -C 4  alkyl, OR 2 , NR 13 R 14 , and SR 2 .  
     
     
         10 . A compound according to  claim 1 , wherein X is selected from the group of hydrogen, F, Cl, Br, I, CN, CF 3 , SR 2 , S(O)R 13 , and NR 13 R 14 ; R 13  and R 14  each independently is selected from the group of hydrogen, C(O)R 11 , SO 2 R, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  perhaloalkyl, aryl, arylalkyl and heteroaryl.  
     
     
         11 . A compound according to  claim 10 , wherein X is selected from the group of hydrogen, F, Cl, Br, I, CN, and CF 3 ,  
     
     
         12 . A compound according to  claim 10 , wherein X is selected from the group of SR 2 , S(O)R 13 , and NR 13 R 14 .  
     
     
         13 . A compound according to  claim 12 , wherein R 13  and R 14  each independently is selected from the group of hydrogen and C 1 -C 6  alkyl.  
     
     
         14 . A compound according to  claim 1 , wherein R 6  and R 7  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  perhaloalkyl and null.  
     
     
         15 . A compound according to  claim 14 , wherein R 6  and R 7  are hydrogen.  
     
     
         16 . A compound according to  claim 1 , wherein: 
 R 1  is hydrogen or C 1 -C 4  alkyl;    R 2 , R 3 , R 4 , and R 5  each independently is hydrogen or C 1 -C 6  alkyl;    R 6  and R 7  are each hydrogen;    R 8  and R 9  each independently is hydrogen or C 1 -C 6  alkyl;    R 10  is selected from the group of hydrogen, F, Cl, Br, I, and CF 3 ;    R 11  is selected from the group of hydrogen, F, Cl, Br, and I;    R 12  is hydrogen;    X is selected from the group of hydrogen, F, Cl, Br, I and CN.    
     
     
         17 . A compound according to  claim 1 , wherein: 
 R 1  is hydrogen or C 1 -C 4  alkyl;    R 2 , R 3 , R 4 , R 8  each independently is hydrogen or C 1 -C 6  alkyl;    R 5 , R 6 , R 7  and R 9  are each hydrogen;    R 10  is CF 3 ;    R 11  is hydrogen or F;    X is selected from the group of hydrogen, F, Cl, Br, I and CN.    
     
     
         18 . A compound according to  claim 1 , wherein the compound is an androgen receptor modulator.  
     
     
         19 . A compound according to  claim 18 , wherein the compound is an androgen receptor antagonist.  
     
     
         20 . A compound according to  claim 18 , wherein the compound is an androgen receptor agonist.  
     
     
         21 . A compound according to  claim 18 , wherein the compound is an androgen receptor partial agonist.  
     
     
         22 . A compound according to  claim 18 , wherein said compound is selected from the group of 8-Chloro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Chloro-1,2-dihydro-1,2,2,4-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Chloro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Chloro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Chloro-1,2,3,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Chloro-7-fluoro-1,2,3,4-tetrahydro-. 2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Chloro-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Chloro-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Chloro-4-ethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Fluoro-1,2,3,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 7,8-Difluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 7,8-Difluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-4-Ethyl-8-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Bromo-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Bromo-1,2,3,4-tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Bromo-7-fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Bromo-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Bromo-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-1,2,3,4-Tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-1,2,2-trimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-4-Ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 7-Fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Cyano-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Cyano-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Cyano-4-ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Cyano-4-ethyl-1,2,3,4-tetrahydro-1-methyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-9-Benzoyl-8-cyano-1,2,3,4,8,9-hexahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-8-Cyano-1,2,3,4,8,9-hexahydro-2,2-dimethyl-9-p-toluoyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-2,2-dimethyl-8-methylthio-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-1,2,3,4-Tetrahydro-2,2—dimethyl-8-methylsulfinyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-2,2-dimethyl-8-methylsulfonyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-7-Fluoro-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-methylsulfinyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-2,2-dimethyl-8-(1-n-butylthio)-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-1,2,3,4-Tetrahydro-2,2-dimethyl-8-(1-h-butylsulfinyl)-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-2,2-dimethyl-8-(2,2,2-trifluoroethyl-1-thio)-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-4-Ethyl-1,2,3,4-tetrahydro-8-methylthio-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; (R/S)-4-Ethyl-1,2,3,4-tetrahydro-8-methylsulfinyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-2,2-dimethyl-6,8-di(trifluoromethyl)-9-pyrido[3,2-g]quinoline; (R/S)-4-Ethyl-1,2,3,4-tetrahydro-6,8-di(trifluoromethyl)-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-8-(4′-methoxybenzylamino)-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 8-Amino-1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; 1,2,3,4-Tetrahydro-8-methanesulfonamido-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline; and 1,2,3,4-Tetrahydro-8-bis(methanesulfon)amido-2,2-dimethyl-6-trifluoromethyl-9-pyrido[3,2-g]quinoline.  
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         24 . A pharmaceutical composition according to  claim 22 , wherein the composition is formulated for oral, topical, intravenous, suppository or parenteral administration.  
     
     
         25 . A pharmaceutical composition according to  claim 23 , wherein the composition is effective in treating and/or modulating acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirtsutism, stimulation of hematopoiesis, hypogonadism, pro static hyperplasia, hormone-dependent cancers, prostate cancer and breast cancer.  
     
     
         26 . A pharmaceutical composition according to  claim 23 , wherein the composition is effective as an anabolic agent.  
     
     
         27 . A method for affecting androgen receptor activity in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to  claim 1 .  
     
     
         28 . A method for modulating a process in a mammal mediated by androgen receptors, comprising administering to the mammal a pharmaceutically effective amount of a compound according to  claim 1 .  
     
     
         29 . A method according to  claim 28 , wherein said compound is administered to a mammal in an amount from about 1 μg/kg of body weight to about 500 mg/kg of body weight.  
     
     
         30 . A method according to  claim 29 , wherein said compound is administered to a mammal in an amount from about 10 μg/kg of body weight to about 250 mg/kg of body weight.  
     
     
         31 . A method according to  claim 30 , wherein said compound is administered to a mammal in an amount from about 20 μg/kg of body weight to about 100 mg/kg of body weight.  
     
     
         32 . A compound-according to  claim 1 , wherein the compound is effective in treating and/or modulating one or more conditions selected from the group of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirtsutism, stimulation of hematopoiesis, hypogonadism, pro static hyperplasia, hormone-dependent cancers, prostate cancer, and breast cancer.  
     
     
         33 . A compound according to  claim 32 , wherein said compound is an anabolic agent.  
     
     
         34 . A method of treating a patient susceptible to androgen receptor therapy comprising administering to said patient an effective amount of a compound according to  claim 1 .  
     
     
         35 . A method of treating a patient according to  claim 34 , wherein said compound is effective in treating and/or modulating one or more conditions selected from the group of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirtsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, hormone-dependent cancers, prostate cancer, and breast cancer, said method comprising administering to said patient a pharmaceutically effective amount of a compound according to  claim 1 .  
     
     
         36 . A method according to  claim 35 , wherein said compound is an anabolic agent.

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