Substituted aryl sulfone derivatives as calcium channel blockers

Abstract

A series of substituted aryl sulfone derivatives represented by Formula I, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, calcium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, urinary incontinence, itchiness, allergic dermatitis, epilepsy, diabetic neuropathy, irritable bowel syndrome, depression, anxiety, multiple sclerosis, sleep disorder, bipolar disorder and stroke, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds.

1 - 15 . (canceled) 
     
     
         16 . compound of structural formula I: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof: 
         X is a bond, CR 10 R 11 , C═O, C═ONR 10 , CO 2 , SO 2 , C 6-10  aryl, or C 5-10  heteroaryl; 
         Y is CR 10 R 11 , C═O or absent; 
         Z is CR 10 R 11 , C═O or absent; 
         R 1  is H, C 1-6 -alkyl, C 3-7 -cycloalkyl, OR 10 , C(O)R 10 , (CH 2 ) n C 5-10  heterocycle, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, fused aryl or fused heteroaryl, wherein said alkyl, cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 2  is H, C 1-4  alkyl and C 1-4 -perfluoroalkyl, C 3-5 -cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, F, Cl, CN, NR 10 R 11 , wherein said alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 3  and R 4  are each and independently selected from H, or C 1-6  alkyl, C 1-4 -perfluoroalkyl, C 3-7 -cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, F, Cl, CN, OR 10 , NR 10 R 11 , SO 2 R 10 , SO 2 NR 10 R 11 , CO 2 R 10 , CONHR 10 , CONR 10 R 11 , or R 3  and R 4  join to form a 3-7 member carbocyclic or heterocyclic ring, wherein said alkyl, cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 5  is C 6-10  aryl, C 5-10  heteroaryl, C 3-7  cycloalkyl, C 5-10  heterocycle, wherein said cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 6 , R 7 , R 8 , and R 9  independently represent H, C 1-4 alkyl and C 1-4  perfluoroalkyl, C 3-6 -cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, F, Cl, CN, Ole, NR 10 R 11 , or R 8  and R 9  combined with the carbon atom they are attached to can form C(O); 
         R 10  and R 11  are each and independently selected from H, or C 1-6 alkyl, (CH 2 ) n C 1-4 -fluoroalkyl, C 3-7 cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, or R 10  and R 11  join to form a 3-7 member carbocyclic or heterocyclic ring with the atom to which they are attached; 
         said alkyl, aryl, or heteroaryl optionally substituted with 1 to 3 groups of R a , 
         n represents 0 to 6, and 
         R a  represents C 1-6  alkyl, C 3-7  cycloalkyl, C 1-4 -fluoroalkyl, C 6-10  aryl, C 5-10  heteroaryl, halogen, CN, —OCF 3 , —OCHF 2 , —C(O)CF 3 , —C(OR 10 )(CF 3 ) 2 , SR 10 , —OR 10 , NR 10 R 11 , SOR 10 , SO 2 R 10 , NR 10 COR 11 , NR 10 COOR 11 , NR 10 CONR 10 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 , NR 10 SO 2 R 11 , CO 2 R 10 , CONR 10 R 11 , said aryl and heteroaryl optionally substituted with 1 to 3 groups of C 1-6  alkyl, C 3-7  cycloalkyl, halogen, CF 3 , CN or OR 10 ; with the proviso that at least one of Y and Z is absent, and with the proviso that when X═SO 2 , the compound of formula I cannot be 4-[(4-Chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]-1-(trifluoromethanesulfonyl)piperidine; or 4-[(4-Chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]-1-(methanesulfonyl)piperidine; or when X═C═O, the compound of formula I cannot be 4-[[[4-[[5-[2-(2-Aminobenzothiazol-6-yl)vinyl]pyrimidin-2-yl]amino]phenyl]sulfonyl]-methyl]piperidine-1-carboxylic acid tert-butyl ester; 4-[[[4-[(5-Vinylpyrimidin-2-yl)amino]phenyl]sulfonyl]methyl]piperidine-1-carboxylic acid tert-butyl ester; Piperidinecarboxylic acid, 4-[[[4-[[5-[(1E)-2-(3-methoxyphenyl)ethenyl]-2-pyrimidinyl]amino]phenyl]sulfonyl]methyl]-,1,1-dimethylethyl ester; 4-[[(4-Bromophenyl)sulfonyl]methyl]piperidine-1-carboxylic acid tert-butyl ester; Piperidinecarboxylic acid, 4-[[(4-fluorophenyl)sulfonyl]methyl]; Piperidinecarboxylic acid, 4-[[(2-fluorophenyl)sulfonyl]methyl]-,1,1-dimethylethyl ester; Piperidinecarboxylic acid, 3-hydroxy-4-[[[4-(methylthio)phenyl]sulfonyl]methyl]-,1,1-dimethylethyl ester, (3R,4S); tert-Butyl 4-[(4-chlorobenzenesulfonyl)(2,5-difluorophenyl)methyl]piperidine-1-carboxylate; 4-[[(4-Fluorophenyl)sulfonyl]methyl]-1-piperidinecarboxylate hydrochloride; tert-Butyl 4-[[(4-fluorophenyl)sulfonyl]methyl]-1-piperidinecarboxylate; or Piperidine, 1-(bromoacetyl)-4-[[(4-methylphenyl)sulfonyl]methyl]; or when Y and Z are CH 2 , X is not CR 10 R 11 ; or the compound of formula I is not piperidinyl-1-(bromoacetyl-4-[[4-methylphenyl)sulfonyl]methyl], or benzonitrilyl-4-[4-[[(4-fluorophenyl)sulfonyl]methyl]-4-hydroxy-1-piperidinyl]-2-(trifluoromethyl). 
       
     
     
         17 . The compound according to  claim 16  wherein X is C═O, R 1  is (CH 2 ) n C 5-10  heterocycle, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, fused aryl or fused heteroaryl, and R 5  is C 6-10  aryl, C 5-10  heteroaryl, or C 5-10  heterocycle, wherein said heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a . 
     
     
         18 . The compound according to  claim 17  wherein R 1  (CH 2 ) n C 6-10  aryl. 
     
     
         19 . The compound according to  claim 17  wherein R 1  is (CH 2 ) n C 5-10  (CH 2 ) n C 5-10  heteroaryl. 
     
     
         20 . The compound according to  claim 16  represented by structural formula Ib: 
       
         
           
           
               
               
           
         
         wherein X is C═O and R 2  is H, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 
       
     
     
         21 . The compound according to  claim 16  represented by structural formula Ic: 
       
         
           
           
               
               
           
         
         wherein X is C═O and R 2  is H, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 
       
     
     
         22 . A compound which is:
 1-[5-fluoro-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   tert-butyl 3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate;   tert-butyl 3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate;   1-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-({[3-(trifluoromethyl)phenyl]sulfonyl}-methyl)azetidine;   1-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-({[3-(trifluoromethyl)phenyl]sulfonyl}-methyl)azetidine;   1-[4-(methylsulfonyl)-2-(trifluoromethoxy)benzoyl]-3-({[3-(trifluoromethyl)phenyl]sulfonyl}-methyl)azetidine;   1-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[4-(difluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-ethyl)azetidine;   1-[2-(difluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)-azetidine;   1-[5-fluoro-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-ethyl)azetidine;   1-[3-(difluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)-azetidine;   1-[4-methoxy-3-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-ethyl)azetidine;   1-[4-(difluoromethoxy)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl) azetidine;   1-[4-(tert-butylsulfonyl)-2-chlorobenzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[2-bromo-4-(tert-butylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[4-(tert-butylsulfonyl)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[2-chloro-4-(isopropylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[4-(isopropylsulfonyl)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[4-methoxy-2,6-bis(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)azetidine;   1-[4-(difluoromethoxy)-2,6-bis(methylsulfonyl)-benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)-phenyl]sulfonyl}ethyl)azetidine;   1-[4-(cyclopropyloxy)-2,6-bis(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)-phenyl]sulfonyl}ethyl)azetidine;   1-[2,6-bis(methylsulfonyl)-4-(trifluoromethoxy)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)-phenyl]sulfonyl}ethyl)azetidine;   (3R)-1-[4-(cyclopropyloxy)-2-(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)-phenyl]sulfonyl}ethyl)pyrrolidine;   (3R)-1-[4-(cyclopropyloxy)-2,6-bis(methylsulfonyl)benzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)pyrrolidine;   (3R)-1-[4-(cyclopropylsulfonyl)-2-methoxybenzoyl]-3-(1-methyl-1-{[3-(trifluoromethyl)phenyl]-sulfonyl}ethyl)pyrrolidine;   or pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.   
     
     
         23 . A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to  claim 16 . 
     
     
         24 . A method for treating or preventing chronic or acute pain in a mammalian patient in need thereof comprising administering to said patient a therapeutically effective amount, or a prophylactically effective amount, of a compound according structural formula I: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof: 
         X is a bond, CR 10 R 11 , C═O, C═ONR 10 , CO 2 , SO 2 , C 6-10  aryl, or C 5-10  heteroaryl; 
         Y is CR 10 R 11 , C═O or absent; 
         Z is CR 10 R 11 , C═O or absent; 
         R 1  is C 1-6 -alkyl, C 3-7 -cycloalkyl, OR 10 , (CH 2 ) n C 5-10  heterocycle, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, fused aryl or fused heteroaryl, wherein said alkyl, cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 2  is H, C 1-4  alkyl and C 1-4 -perfluoroalkyl, C 3-5 -cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, F, Cl, CN, NR 10 R 11 , wherein said alkyl, cycloalkyl, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 3  and R 4  are each and independently selected from H, or C 1-6  alkyl, C 1-4 -perfluoroalkyl, C 3-7 -cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, F, Cl, CN, OR 10 , NR 10 R 11 , SO 2 R 10 , SO 2 NR 10 R 11 , CO 2 R 10 , CONHR 10 , CONR 10 R 11 , or R 3  and R 4  join to form a 3-7 member carbocyclic or heterocyclic ring, wherein said alkyl, cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 5  is C 6-10  aryl, C 5-10  heteroaryl, C 3-7  cycloalkyl, C 5-10  heterocycle, wherein said cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one to three groups of R a ; 
         R 6 , R 7 , R 8 , and R 9  independently represent H, C 1-4 alkyl and C 1-4  perfluoroalkyl, C 3-6 -cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, F, Cl, CN, OR 10 , NR 10 R 11 ; 
         R 10  and R 11  are each and independently selected from H, or C 1-6 alkyl, (CH 2 ) n C 1-4 -fluoroalkyl, C 3-7 cycloalkyl, C 6-10  aryl, C 5-10  heteroaryl, or R 10  and R 11  join to form a 3-7 member carbocyclic or heterocyclic ring with the atom to which they are attached; 
         said alkyl, aryl, or heteroaryl optionally substituted with 1 to 3 groups of R a , 
         n represents 0 to 6, and 
         R a  represents C 1-6  alkyl, C 3-7  cycloalkyl, C 1-4 -fluoroalkyl, C 6-10  aryl, C 5-10  heteroaryl, halogen, CN, —OCF 3 , —OCHF 2 , —C(O)CF 3 , —C(OR 10 )(CF 3 ) 2 , SR 10 , —OR 10 , NR 10 R 11 , SO 2 R 10 , SO 2 NR 10 R 11 , NR 10 SO 2 R 11 , CO 2 R 10 , CONR 10 R 11 , said aryl and heteroaryl optionally substituted with 1 to 3 groups of C 1-6  alkyl, C 3-7  cycloalkyl, halogen or OR 10 . 
       
     
     
         25 . A method for treating or preventing chronic or acute pain in a mammalian patient in need thereof comprising administering to said patient a therapeutically effective amount, or a prophylactically effective amount, of a compound according to claim  1 , or a pharmaceutically acceptable salt thereof. 
     
     
         26 . A method for treating or controlling epilepsy in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim  1 , or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A method for enhancing the quality of sleep in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of claim  1  or a pharmaceutically acceptable salt thereof.