Diarylsulfones as 5-HT2A Antagonists

Abstract

Compounds of formula I: are potent and selective antagonists of the human 5-HT 2A receptor, and hence useful in treatment of a variety of adverse conditions of the CNS.

1 - 21 . (canceled) 
   
   
       22 . A method for treatment of a subject suffering from or prone to a condition mediated by 5-HT 2A  receptor activity which comprises administering to that subject an effective amount of a compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 m is 0, 1, 2 or 3; 
 n is 0, 1 or 2; 
 t is 1 or 2; 
 A represents the residue of a phenyl or 5- or 6-membered heteroaromatic ring optionally bearing up to 2 additional substituents selected from halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b , NR a R b  and C 1-4 alkyl which is optionally substituted with halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b  or NR a R b ; 
 W represents —CR 3 R 4 —CR 5 R 6 , —CR 3 ═CR 5 — or —C═C— where R 3 , R 4 , R 5 , and R 6  are selected from H, OH and F but not more than one of R 3 , R 4 , R 5 , and R 6  is other than H; or R 3  and R 4  together or R 5  and R 6  together complete a keto group; or R 4  and R 6  together complete a cyclopropyl ring; 
 E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally incorporating an oxygen atom to form an ether linkage and optionally comprising a hydroxy substituent; 
 Z is selected from H, halogen, CN, nitro, CF 3 , OCF 3 , —R a , —OR a , —SR a , —SOR a , —SO 2 R a , —SO 2 NR a R b , —NR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , NR a SOR b , NR a SO 2 R b , CONHCOR a , NHCH 2 CO 2 R a , NHCH 2 CONR a R b , —NR a SO 2 NR a R b , —COR a , —CO 2 R a , —CONR a R b , —CH═NOR a  or a five- or six-membered heteroaromatic ring optionally bearing up to 2 substituents selected from halogen, CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, amino, C 1-6 alkylamino and di(C 1-6 )alkylamino; 
 or the moiety -E-Z may combine with an adjacent R 2  group as defined below; 
 R a  and R b  independently represent H or a hydrocarbon group of up to 7 carbon atoms which is optionally substituted with up to 3 halogen atoms or with CN, OH, C 1-4 alkoxy, C 1-4 alkylthio, amino, C 1-4 alkylamino or di(C 1-4 )alkylamino; or R a  and R b , when linked through a nitrogen atom, together represent the residue of a heterocyclic ring of 4, 5 or 6 members, optionally bearing up to 3 substituents selected from halogen, CN, CF 3 , oxo, OH, C 1-4 alkyl and C 1-4 alkoxy; 
 each R 1  independently represents halogen, CN, CF 3 , OCF 3 , C 1-6  alkyl, OH, benzylthio, C 1-6  alkoxy or hydroxymethyl; and 
 each R 2  independently represents halogen, CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy; or an R 2  group and the moiety -E-Z when attached to adjacent ring positions may complete a fused 5- or 6-membered carbocyclic or heterocyclic ring optionally bearing up to 3 substituents selected from halogen, CN, CF 3 , oxo, R a  and amino; 
 
     with the proviso that when A represents the residue of a phenyl ring and W represents —CH═CH— or —C≡C—, m is not zero and at least one R 1  represents F; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       23 . The method of  claim 22  wherein the compound of formula I, W is selected from —CH 2 CH 2 —, —CHFCH 2 —, —CH 2 CHF—, —CH(OH)CH 2 —, —CH 2 CH(OH)—, —COCH 2 —, —CH 2 CO—, —CH═CH—, —C≡C—, —CF═CH—, —CH═CF—, —C(OH)═CH—, —CH═C(OH)— and cyclopropane-1,2-diyl. 
   
   
       24 . The method of  claim 22  wherein the compound is of the formula II: 
     
       
         
         
             
             
         
       
       wherein each A 1  represents CH or N provided at least one A 1  is CH; 
       R 7  represents H, halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b , NR a R b  or C 1-4 alkyl which is optionally substituted with halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b  or NR a R b ; 
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       25 . The method of  claim 22  wherein the compound of formula I, Z represents hydroxyC 1-6 alkyl. 
   
   
       26 . The method of  claim 22  wherein the compound of formula I, Z represents SOR a , SO 2 R a , CONHCOR a , NHCH 2 CO 2 R a  or CO 2 R a  and R a  represents C 1-6 alkyl. 
   
   
       27 . The method of  claim 22  wherein the compound of formula I, Z represents a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, oxazole, thiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole, which optionally is substituted with methyl. 
   
   
       28 . The method of  claim 22  wherein the compound is of the formula IV: 
     
       
         
         
             
             
         
       
     
     wherein:
 n is 0 or 1; 
 R 11  represents H or F; 
 R 22  represents halogen, CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy; 
 R 77  represents H or C 1-4 alkyl; and 
 Z 1  represents hydroxyC 1-6 alkyl; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       29 . The method of  claim 22  wherein the compound is selected from the group consisting of: 
     (1S)-1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol; 
     (1S)-1-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol; 
     (1S)-1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]-3-methylphenyl}sulfonyl)phenyl]ethanol; 
     [2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]methanol; 
     [2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]methanol; 
     2-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]propan-2-ol 
     2-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]propan-2-ol; and 
     2-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       30 . The method of  claim 22  wherein the compound is: 
     (1S)-1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       31 . The method of  claim 22  wherein the compound is: 
     (1S)-1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol. 
   
   
       32 . The method of  claim 22  wherein the compound is selected from the group consisting of: 
     methyl 2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzoate; 
     methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate; 
     methyl 3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate; and 
     methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)-3-methylbenzoate; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       33 . The method of  claim 22  wherein the compound is selected from: 
     2-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazole; 
     2-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1H-imidazole; 
     2-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazole; and 
     2-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1,3,4-oxadiazole; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       34 . The method of  claim 22  wherein the compound is of the formula Ia: 
     
       
         
         
             
             
         
       
     
     wherein:
 m is 0, 1, 2 or 3; 
 n is 0, 1 or 2; 
 t is 1 or 2; 
 A represents a phenyl ring optionally bearing up to 2 additional substituents selected from halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b , NR a R b  and C 1-4 alkyl which is optionally substituted with halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b  or NR a R b ; 
 W represents —CR 3 ═CR 5 —, where R 3  and R 5  are selected from H, OH and F but not more than one of R 3  and R 5  is other than H; 
 E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally incorporating an oxygen atom to form an ether linkage and optionally comprising a hydroxy substituent; 
 Z is selected from H, halogen, CN, nitro, CF 3 , OCF 3 , —R a , —OR a , —SR a , —SOR a , —SO 2 R a , —SO 2 NR a R b , —NR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , NR a SOR b , NR a SO 2 R b , CONHCOR a , NHCH 2 CO 2 R a , NHCH 2 CONR a R b , —NR a SO 2 NR a R b , —COR a , —CO 2 R a , —CONR a R b , —CH═NOR a  or a five- or six-membered heteroaromatic ring optionally bearing up to 2 substituents selected from halogen, CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, amino, C 1-6 alkylamino and di(C 1-6 )alkylamino; 
 or the moiety -E-Z may combine with an adjacent R 2  group as defined below; 
 R a  and R b  independently represent H or a hydrocarbon group of up to 7 carbon atoms which is optionally substituted with up to 3 halogen atoms or with CN, OH, C 1-4 alkoxy, C 1-4 alkylthio, amino, C 1-4 alkylamino or di(C 1-4 )alkylamino; or R a  and R b , when linked through a nitrogen atom, together represent the residue of a heterocyclic ring of 4, 5 or 6 members, optionally bearing up to 3 substituents selected from halogen, CN, CF 3 , oxo, OH, C 1-4 alkyl and C 1-4 alkoxy; 
 each R 1  independently represents halogen, CN, CF 3 , OCF 3 , C 1-6  alkyl, OH, benzylthio, C 1-6 alkoxy or hydroxymethyl; and 
 each R 2  independently represents halogen, CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy; or an R 2  group and the moiety -E-Z when attached to adjacent ring positions may complete a fused 5- or 6-membered carbocyclic or heterocyclic ring optionally bearing up to 3 substituents selected from halogen, CN, CF 3 , oxo, R a  and amino; 
 
     with the proviso that when A represents a phenyl ring and W represents —CH═CH—, m is not zero and at least one R 1  represents F; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       35 . The method of  claim 22  wherein the compound is of the formula IIa: 
     
       
         
         
             
             
         
       
       wherein each A 1  represents CH; 
       R 7  represents H, halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b , NR a R b  or C 1-4 alkyl which is optionally substituted with halogen, CN, CF 3 , OR a , CO 2 R a , CONR a R b  or NR a R b ; or a pharmaceutically acceptable salt thereof. 
     
   
   
       36 . The method of  claim 22  wherein the compound is of the formula IVa: 
     
       
         
         
             
             
         
       
     
     wherein:
 n is 0 or 1; 
 R 11  represents H or F; 
 R 22  represents halogen, CN, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy; 
 R 77  represents H or C 1-4 alkyl; and 
 Z 1  represents C 1-6 alkoxycarbonyl, or a 5- or 6-membered heteroaromatic ring which optionally bears a methyl substituent; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       37 . The method of  claim 22  wherein the compound is selected from the group consisting of: 
     methyl 2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzoate; 
     methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate; 
     methyl 3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate; and 
     methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)-3-methylbenzoate; 
     or a pharmaceutically acceptable salt thereof. 
   
   
       38 . The method of  claim 22  wherein the compound is methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate, or a pharmaceutically acceptable salt thereof. 
   
   
       39 . The method of  claim 22  wherein the compound is methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate thereof. 
   
   
       40 . The method of  claim 22  wherein the compound is methyl 2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzoate. 
   
   
       41 . The method of  claim 22  wherein the condition is selected from the group consisting of: sleep disorders, psychiatric disorders, depression, anxiety, panic disorders, obsessive-compulsive disorder, pain, eating disorders, dependency or acute toxicity associated with narcotic agents, and hot flushes.