Diaryltriazoles as Inhibitors of 11-Beta-Hydroxysteroid Dehydrogenase-1

Abstract

2,5-Diaryl-1,2,4-triazole derivatives of structural formula I are selective inhibitors of the 11&bgr;-hydroxysteroid dehydrogenase Type 1 enzyme (11&bgr;-HSD-1). The compounds are useful for the treatment of diabetes, hyperglycemia, obesity, insulin resistance, atherosclerosis, dyslipidemia, hyperlipidemia, hypertension, and Metabolic Syndrome. Also disclosed are novel compounds of structural formula II which are inhibitors of 11&bgr;-HSD-1.

1 . A method of treating a condition responsive to inhibition of 11β-hydroxysteroid dehydrogenase-1 in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 each n is 0, 1, or 2; 
 each p is 0, 1, or 2; 
 R 1  is aryl or heteroaryl wherein heteroaryl is selected from the group consisting of
 pyridyl, 
 thienyl, 
 furyl, 
 pyrazolyl, 
 thiazolyl, 
 oxazolyl, 
 imidazolyl, 
 indolyl, 
 benzothiophenyl, 
 benzofuryl, and 
 benzimidazolyl; 
 
 in which aryl and heteroaryl are substituted with one to four substituents independently selected from R 3 , R 4 , and R 5 ; 
 R 2  is selected from the group consisting of
 C 1-4  alkyl, 
 C 2-4  alkenyl, and 
 (CH 2 ) n —C 3-6  cycloalkyl; 
 
 R 3 , R 4 , and R 5  are each independently selected from the group consisting of
 hydrogen, 
 formyl, 
 C 1-6  alkyl, 
 C 2-6  alkenyl, 
 (CH 2 ) n -aryl, 
 (CH 2 ) n -heteroaryl, 
 (CH 2 ) n -heterocyclyl, 
 (CH 2 ) n C 3-7  cycloalkyl, 
 halogen, 
 OR 7 , 
 (CH 2 ) n N(R 7 ) 2 , 
 cyano, 
 (CH 2 ) n CO 2 R 7 , 
 NO 2 , 
 (CH 2 ) n NR 7 SO 2 R 6 , 
 (CH 2 ) n SO 2 N(R 7 ) 2 , 
 (CH 2 ) n S(O) p R 6 , 
 (CH 2 ) n SO 20 R 7 , 
 (CH 2 ) n NR 7 C(O)N(R 7 ) 2 , 
 (CH 2 ) n C(O)N(R 7 ) 2 , 
 (CH 2 ) n NR 6 C(O)R 6 , 
 (CH 2 ) n NR 6 CO 2 R 7 , 
 O(CH 2 ) n C(O)N(R 7 ) 2 , 
 CF 3 , 
 CH 2 CF 3 , 
 OCF 3 , 
 OCHCF 2 , and 
 OCH 2 CF 3 ; 
 
 wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4  alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4  alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3 , R 4 , and R 5  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group; 
 each R 6  is independently selected from the group consisting of
 C 1-8  alkyl, 
 C 2-4  alkynyl, 
 (CH 2 ) n -aryl, 
 (CH 2 ) n -heteroaryl, and 
 (CH 2 ) n C 3-7  cycloalkyl; 
 
 wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4  alkoxy, C 1-4  alkylthio, hydroxy, and amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4  alkyl, and C 1-4  alkoxy; 
 or two R 6  groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 0-4  alkyl; and 
 each R 7  is hydrogen or R 6 . 
 
     
     
         2 . The method of  claim 1  wherein said condition is selected from the group consisting of diabetes, obesity, insulin resistance, a lipid disorder, hypertension, atherosclerosis, and Metabolic Syndrome. 
     
     
         3 . The method of  claim 1  wherein R 2  is methyl. 
     
     
         4 . The method of  claim 1  wherein R 3  is hydrogen and R 4  and R 5  are each independently selected from the group consisting of amino, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, difluoromethoxy, C 2-3  alkynyloxy, C 1-5  alkyl, cyclopropyl, C 1-4  alkoxy, C 1-14  alkylthio, and C 1-4  alkylsulfonyl. 
     
     
         5 . The method of  claim 1  wherein R 1  is phenyl or naphthyl each of which is substituted with one to three substituents independently selected from R 3 . 
     
     
         6 . The method of  claim 5  wherein R 3  is selected from the group consisting of amino, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, difluoromethoxy, C 1-5  alkyl, C 1-4  alkoxy, C 1-4  alkylsulfonyl, phenyl, phenyloxy, phenylthio, and phenylsulfonyl, wherein the phenyl moiety of each is unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4  alkyl, and C 1-4  alkoxy. 
     
     
         7 . The method of  claim 6  wherein R 2  is methyl. 
     
     
         8 . The method of  claim 1  wherein R 1  is heteroaryl substituted with one to three substituents independently selected from R 3 . 
     
     
         9 . The method of  claim 8  wherein R 2  is methyl. 
     
     
         10 . The method of  claim 8  wherein heteroaryl is pyrazolyl or indolyl, each of which is substituted with one to three substituents independently selected from R 3 . 
     
     
         11 . The method of  claim 10  wherein R 2  is methyl. 
     
     
         12 . The method of  claim 10  wherein R 3  is selected from the group consisting of amino, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, difluoromethoxy, C 1-5  alkyl, C 1-4  alkoxy, C 1-4  alkylsulfonyl, phenyl, phenyloxy, phenylthio, and phenylsulfonyl, wherein the phenyl moiety of each is unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4  alkyl, and C 1-4  alkoxy. 
     
     
         13 . The method of  claim 12  wherein R 2  is methyl. 
     
     
         14 . The method of  claim 1  wherein the compound of structural formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 2  wherein said diabetes is Type 2 diabetes. 
     
     
         16 . A compound of structural formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 each n is 0, 1, or 2; 
 each p is 0, 1, or 2; 
 R 8  is naphthyl or heteroaryl wherein heteroaryl is selected from the group consisting of
 pyridyl, 
 thienyl, 
 furyl, 
 pyrazolyl, 
 thiazolyl, 
 oxazolyl, 
 imidazolyl, 
 indolyl, 
 benzothiophenyl, 
 benzofuryl, and 
 benzimidazolyl; 
 
 in which naphthyl and heteroaryl are substituted with one to three substituents independently selected from R 3 , R 4 , and R 5 ; 
 R 2  is methyl or cyclopropyl; 
 R 3 , R 4 , and R 5  are each independently selected from the group consisting of
 hydrogen, 
 formyl, 
 C 1-6  alkyl, 
 C 2-6  alkenyl, 
 (CH 2 ) n -aryl, 
 (CH 2 ) n -heteroaryl, 
 (CH 2 ) n -heterocyclyl, 
 (CH 2 ) n C 3-7  cycloalkyl, halogen, 
 OR 7 , 
 (CH 2 ) n N(R 7 ) 2 , cyano, 
 (CH 2 ) n CO 2 R 7 , 
 NO 2 , 
 (CH 2 ) n NR 7 SO 2 R 6 , 
 (CH 2 ) n SO 2 N(R 7 ) 2 , 
 (CH 2 ) n S(O) p R 6 , 
 (CH 2 ) n SO 20 R 7 , 
 (CH 2 ) n NR 7 C(O)N(R 7 ) 2 , 
 (CH 2 ) n C(O)N(R 7 ) 2 , 
 (CH 2 ) n NR 6 C(O)R 6 , 
 (CH 2 ) n NR 6 CO 2 R 7 , O(CH 2 ) n C(O)N(R 7 ) 2 , 
 CF 3 , 
 CH 2 CF 3 , 
 OCF 3 , 
 OCHCF 2 , and 
 OCH 2 CF 3 ; 
 
 wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4  alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4  alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3 , R 4 , and R 5  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group; 
 each R 6  is independently selected from the group consisting of
 C 1-8  alkyl, 
 (CH 2 ) n -aryl, 
 (CH 2 ) n -heteroaryl, and 
 (CH 2 ) n C 3-7  cycloalkyl; 
 
 wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4  alkoxy, C 1-4  alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4  alkyl, and C 1-4  alkoxy; 
 or two R 6  groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4  alkyl; and 
 each R 7  is hydrogen or R 6 . 
 
     
     
         17 . The compound of  claim 16  wherein R 2  is methyl. 
     
     
         18 . The compound of  claim 16  wherein R 8  is indolyl or pyrazolyl substituted with one to three substituents independently selected from R 3 . 
     
     
         19 . The compound of  claim 18  wherein R 2  is methyl. 
     
     
         20 . A compound which is selected from the group consisting of: 
       4-methyl-3,5-bis[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-methyl-3-[4-(methylthio)-2-(trifluoromethyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-methyl-3-(4-pentylphenyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(1-methoxy-2-naphthyl)-4-methyl-5-[2-trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1H-indole; 
       4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}-1-methyl-1H-indole; 
       3-(2-bromophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(7-chloro-1-methoxy-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)-4H-1,2,4-triazole; 
       4-[4-methyl-5-(1-methyl-1H-indol-4-yl)-4H-1,2,4-triazol-3-yl]phenol; 
       3-(2,4-dichlorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-[2,4-bis(trifluoromethyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-5-(2,4-dichlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2-chloro-4-fluorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2,4-dichlorophenyl)-4-methyl-5-[2-(methylthio)phenyl]-4H-1,2,4-triazole; 
       3-(2,4-dichlorophenyl)-4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-5-[5-(2-chlorophenyl)-1-methyl-1H-pyrazol-3-yl]-4-methyl-4H-1,2,4-triazole; 
       4-[5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1H-indole; 
       4-methyl-3-(2-methyl-1-naphthyl)-5-[2-(trifluoromethyl)phenyl]-4-methyl-4H-1,2,4-triazole; 
       3-(1,4-dichloro-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(4-chloro-1-methoxy-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(1-fluoro-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       N-methyl-2-{4-methyl-5-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}naphthalen-1-amine; 3,5-bis-(2,4-dimethylphenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2,4-dichlorophenyl)-5-[2-(ethylthio)phenyl]-4-methyl-4H-1,2,4-triazole; 
       3-(2-cyclopropylphenyl)-5-(2,4-dichlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-[(2-chloro-4-(ethylthio)phenyl)]-5-(2-fluorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2-methoxyphenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2,6-dichlorophenyl)-4-methyl-5-[2-trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-5-[(2-difluoromethoxy)phenyl]-4-methyl-4H-1,2,4-triazole; 
       3-(2-chloro-4-fluorophenyl)-5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2,4-dichlorophenyl)-5-[(2-difluoromethoxy)phenyl]-4-methyl-4H-1,2,4-triazole; 
       4-methyl-3-(2-phenoxyphenyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-methyl-3-[2-(trifluoromethoxy)phenyl]-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-methyl-3-[2-(prop-2-yn-1-yloxy)phenyl]-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-{2-[(4-chlorophenyl)thio]phenyl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-[2-(difluoromethoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-ethoxyphenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-methyl-3-(2-propoxyphenyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 3,5-bis(2-chlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3,5-bis(2,3-dichlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(3-chloro-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(5-chloro-6-methoxy-1-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-[2-(4-chlorophenoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-[4-(4-chlorophenoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-[4-chloro-5-(2-chlorophenyl)-1-methyl-1H-pyrazol-3-yl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       4-methyl-3-(2,4,6-trichloro-1-naphthyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-4-methyl-5-[2-(trifluoromethoxy)phenyl]-4H-1,2,4-triazole; 
       3-(2-bromophenyl)-5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2,3-dichlorophenyl)-4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazole; 
       3-(2,3-dichlorophenyl)-5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2-bromophenyl)-4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazole; 
       4-methyl-3-(2-methylphenyl)-5-[2-(trifluoromethoxyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-4-cyclopropyl-5-[(2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(4-chloro-3-methoxy-2-naphthyl)-4-methyl-5-[(2-(methylthio)phenyl]-4H-1,2,4-triazole; 
       3-[2-(4-chlorophenoxy)phenyl]-4-methyl-5-[(2-(methylthio)phenyl]-4H-1,2,4-triazole; 
       3-[2-(4-chlorophenoxy)phenyl]-4-methyl-5-[(2-(methylsulfonyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-5-(2,3-dichlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-(2-bromophenyl)-5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazole; 
       3-[2-(4-fluorophenoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole; 
       3-(2-chlorophenyl)-5-[2-chloro-3-(trifluoromethyl)phenyl]-4-methyl-4H-1,2,4-triazole; and 
       4-[4-methyl-5-(1,2,3-trimethyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl]phenol; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound in accordance with  claim 16  in combination with a pharmaceutically acceptable carrier. 
     
     
         22 . A pharmaceutical composition comprising a compound in accordance wTth  claim 20  in combination with a pharmaceutically acceptable carrier.