Cyclohexyl sulfonamide derivatives

Abstract

The present invention relates to compounds of formula I wherein R 1 to R 3 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl and tetrahydropyranyl; 
       R2 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; 
       R 3  is selected from the group consisting of lower alkyl, 
       —(CH 2 ) m -aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, —(CH 2 ) n -heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, and —NR 4 R 5 ; 
       R 4  is selected from the group consisting of hydrogen, lower alkyl, lower halogenalkyl, lower alkoxyalkyl and lower cyanoalkyl; 
       R 5  is selected from the group consisting of lower alkyl, lower halogenalkyl, lower alkoxyalkyl, lower cyanoalkyl, 
       phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl, and 
       lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy and lower hydroxyalkyl; or 
       R 4  and R 5  together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, a sulfinyl group or a sulfonyl group, 
       said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; 
       and pharmaceutically acceptable salts thereof. 
     
   
   
       2 . The compound according to  claim 1 , wherein R 3  is lower alkyl. 
   
   
       3 . The compound according to  claim 1 , wherein R 3  is C 3 -C 8 -alkyl. 
   
   
       4 . The compound according to  claim 1 , wherein R 3  is selected from the group consisting of —(CH 2 ) m -aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl, and —(CH 2 ) n -heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. 
   
   
       5 . The compound according to  claim 1 , wherein R 3  is —(CH2) m -aryl, wherein m is 0, 1 or 2 and wherein the aryl ring is phenyl unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. 
   
   
       6 . The compound according to  claim 1 , wherein R 3  is phenyl substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. 
   
   
       7 . The compound according to  claim 1 , wherein R 3  is —(CH 2 ) n -heteroaryl, wherein n is 0, 1 or 2 and wherein the heteroaryl ring is unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. 
   
   
       8 . The compound according to  claim 1 , wherein R 3  is —(CH 2 ) n -heteroaryl, wherein n is 0, 1 or 2 and heteroaryl is selected from the group consisting of pyridyl, thienyl, imidazolyl, isoxazolyl, thiazolyl and pyrazolyl, said heteroaryl ring being unsubstituted or substituted with one, two or three groups independently selected from lower alkyl, halogen, lower halogenalkyl, cyano, lower cyanoalkyl, lower alkoxy, lower alkanoyl, benzoyl, lower halogenalkoxy, lower hydroxyalkyl, lower alkanoylamino and lower alkylsulfonyl. 
   
   
       9 . The compound according to  claim 1 , wherein R 3  is pyridyl unsubstituted or substituted with halogen. 
   
   
       10 . The compound according to  claim 1 , wherein R 3  is —NR 4 R 5  and R 4  and R 5  are lower alkyl. 
   
   
       11 . The compound according to  claim 1 , wherein R 1  is lower alkyl or cycloalkyl. 
   
   
       12 . The compound according to  claim 1 , wherein R 1  is lower alkyl. 
   
   
       13 . The compound according to  claim 1 , wherein R 1  is isopropyl or tert-butyl. 
   
   
       14 . The compound according to  claim 1 , wherein R 1  is cycloalkyl. 
   
   
       15 . The compound according to  claim 1 , wherein R 2  is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkylalkyl. 
   
   
       16 . The compound according to  claim 1 , wherein R 2  is hydrogen. 
   
   
       17 . The compound according to  claim 1 , wherein R 2  is lower alkyl. 
   
   
       18 . The compound according to  claim 1 , wherein R 2  is lower cycloalkylalkyl. 
   
   
       19 . The compound according to  claim 1 , selected from the group consisting of
 N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-2-methylbenzene-sulfonamide,   4-cyano-N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}benzene-sulfonamide,   4-fluoro-N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-2-methylbenzene-sulfonamide,   1-(3-fluorophenyl)-N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-methanesulfonamide,   N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-2,4,6-trimethylbenzene-sulfonamide,   2,4-dichloro-N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}benzene-sulfonamide,   2-chloro-N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}benzene-sulfonamide,   3-chloro-4-fluoro-N-isopropyl-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-benzenesulfonamide,   N-cyclopropylmethyl-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-2-methyl-benzenesulfonamide,   N-cyclopropylmethyl-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-4-methoxy-benzenesulfonamide,   N-cyclopropylmethyl-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-2,4,6-trimethyl-benzenesulfonamide,   N-cyclopropylmethyl-N-[trans-4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-4-trifluoromethoxy-benzenesulfonamide,   trans-N-[4-(4-cyclopentyl-piperazine-1-carbonyl)-cyclohexyl]-2-methyl-benzenesulfonamide,   trans-4-cyano-N-[4-(4-cyclopentyl-piperazine-1-carbonyl)-cyclohexyl]-benzenesulfonamide,   trans-4-cyano-N-[4-(4-cyclobutyl-piperazine-1-carbonyl)-cyclohexyl]-benzenesulfonamide,   trans-3-bromo-5-chloro-thiophene-2-sulfonic acid[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-amide,   trans-3-bromo-5-chloro-thiophene-2-sulfonic acid[4-(4-cyclobutyl-piperazine-1-carbonyl)-cyclohexyl]-amide,   trans-N-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-2,4,6-trimethyl-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide,   trans-N-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyl]-N-(2-methoxy-ethyl)-2,4,6-trimethyl-benzenesulfonamide,   and pharmaceutically acceptable salts thereof.   
   
   
       20 . A process for the manufacture of a compound according to  claim 1 , comprising the steps of:
 reacting a compound of formula II   
     
       
         
         
             
             
         
       
       wherein R 1  is as defined in  claim 1 , 
       with a sulfonyl chloride of formula III 
     
     
       
         
         
             
             
         
       
       wherein R 3  is as defined in  claim 1 , in the presence of a base to obtain a compound of formula IA 
     
     
       
         
         
             
             
         
       
       wherein R 2  is hydrogen, and optionally alkylating the compound of formula IA to obtain a compound of formula IB 
     
     
       
         
         
             
             
         
       
       wherein R 2  is a group as defined in  claim 1  other than hydrogen, and if desired, 
       converting the compound obtained into a pharmaceutically acceptable acid addition salt. 
     
   
   
       21 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1  as well as a pharmaceutically acceptable carrier and/or adjuvant. 
   
   
       22 . A method for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors, comprising the step of administering a therapeutically active amount of a compound according to  claim 1  to a human being or animal in need thereof. 
   
   
       23 . A method for the treatment or prevention of obesity in a human being or animal, comprising the step of administering to said human being or animal in need thereof a therapeutically effective amount of a compound according to  claim 1  in combination or association with a therapeutically effective amount of a compound selected from the group consisting of a lipase inhibitor, an anorectic agent, a selective serotonin reuptake inhibitor, and an agent that stimulates metabolism of body fat. 
   
   
       24 . A method of treatment or prevention of type II diabetes in a human being or animal, comprising the step of administering to said human being or animal in need thereof a therapeutically effective amount of a compound according to  claim 1  in combination or association with a therapeutically effective amount of an anti-diabetic agent.