Novel piperazine derivatives

Abstract

The present invention is a chemical compound of formula (I) or a pharmaceutically acceptable salts, solvates and esters thereof, wherein R 1 to R 4 , A 1 , A 2 m and n are as described in the specification.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl, or R 1  and R 2 , together with the carbon atom to which they are attached, form an unsubstituted 3- to 8-membered carbocyclic ring or a 3 to 8 membered carbocyclic ring which is substituted with alkyl;  
 R 3  and R 4  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl;  
 A 1  is oxygen or sulfur, wherein in case A 1  is oxygen and A 2  is unsubstituted phenyl one of R 1 , R 2 , R 3  and R 4  is not hydrogen;  
 A 2  is unsubstituted aryl, unsubstituted heteroaryl or unsubstituted cycloalkyl or aryl, heteroaryl or cycloalkyl each substituted with at least one substituent independently selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, or wherein said alkyl, said cycloalkyl, said aryl, said aralkyl, said alkoxy, said aralkoxy, said aryloxy, said alkoxycarbonyl, said cycloalkoxycarbonyl, said aryloxycarbonyl, said aralkoxycarbonyl, said heteroaryloxycarbonyl, said cycloalkoxy, said alkylsulfonyloxy, said arylsulfonyloxy, said heteroarylalkoxy, said alkenyloxy, said tetrahydrofuranylalkoxy, said alkynyloxy and said cycloalkylalkoxy are substituted with betweenone and three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy substituted with between one and three halogen, thiophenyl, aryl, amino, alkylcarbonyl and aryloxy, or two substituents of aryl, heteroaryl or cycloalkyl form, together with the carbon atoms to which they are attached, an unsubstituted 5- to 7-membered carbocyclic ring or a substituted 5- to 7-membered carbocyclic ring with at least one substituent independently selected from the group consisting of alkyl, alkoxy and halogen;  
 n is 1 or 2; and  
 m is zero or 1;  
 or a pharmaceutically acceptable salt, solvate or ester thereof; provided that 2-methyl-1-piperazinecarboxylic acid (4-nitrophenyl)methyl ester and 1-piperazinecarboxylic acid (4-(trifluoromethyl)phenyl)methyl ester are excluded.  
 
     
     
         2 . A compound of formula I according to  claim 1 , wherein 
 A 2  is unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl or aryl, heteroaryl, cycloalkyl each substituted with at least one substituent independently selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and carbamoyl, or wherein said alkyl, said cycloalkyl, said aryl, said aralkyl, said alkoxy, said aralkoxy, said aryloxy, said alkoxycarbonyl, said cycloalkoxycarbonyl, said aryloxycarbonyl, said aralkoxycarbonyl and said heteroaryloxycarbonyl are substituted with between one and three substituents independently selected from the group consisting of alkyl, alkoxy, halogen and nitro,    or two substituents of aryl, heteroaryl or cycloalkyl form together with the carbon atoms to which they are attached an unsubstituted 5- to 7-membered carbocyclic ring or a 5- to 7-membered ring substituted with alkyl, alkoxy or halogen; and    m is zero.    
     
     
         3 . A compound according to  claim 1 , wherein R 3  and R 4  are independently selected from hydrogen or alkyl.  
     
     
         4 . A compound according to  claim 3 , wherein R 3  and R 4  are hydrogen.  
     
     
         5 . A compound according to  claim 3 , wherein R 3  and R 4  are methyl.  
     
     
         6 . A compound according to  claim 3 , wherein one of R 3  and R 4  is methyl or ethyl and the other of R 3  and R 4  is hydrogen.  
     
     
         7 . A compound according to of  claim 1 , wherein A 1  is oxygen.  
     
     
         8 . A compound according to of  claim 1 , wherein A 1  is sulfur.  
     
     
         9 . A compound according to  claim 1 , wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl and aryl.  
     
     
         10 . A compound according to  claim 1 , wherein A 2  is unsubstituted phenyl or phenyl substituted with between one and four substituents independently selected from the group consisting of halogen, alkoxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, alkynyloxy and cycloalkylalkoxy, or 
 wherein said alkoxy, said heteroarylalkoxy or said alkenyloxy are substituted with between one and three substituents independently selected from alkyl or halogen.    
     
     
         11 . A compound according to  claim 1 , wherein A 2  is unsubstituted phenyl or phenyl substituted with between one and three substituents independently selected from the group consisting of fluoro, chloro, difluoromethoxy, propoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy, 2-propenyloxy, 5-pentyloxy, cyclopropylmethoxy, 2-propynyloxy and NH(R′)—C(O)—O—, wherein R′ is selected from the group consisting of isopropyl, benzyl and tert.-butyl.  
     
     
         12 . A compound according to  claim 1 , wherein n is 1.  
     
     
         13 . A compound according to  claim 12 , wherein m is zero.  
     
     
         14 . A compound of formula I wherein the compound is selected from the group consisting of: 
 S-4-[(2-propylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate;    S-4-[(benzylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate;    S-4-[(tert-butylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate;    2,6-difluoro-4-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;    (R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;    (R)-2,6-difluoro-4-propoxybenzyl 2-methylpiperazine-1-carboxylate;    cis-2,6-dimethyl-piperazine-1-carboxylic acid 4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;    2-fluoro-5-(2-propenyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;    (R)-2-fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate;    5-(cyclopropylmethyl)oxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;    (R)-2-ethyl-piperazine-1-carboxylic acid 4-cyclopropylmethoxy-2,6-difluoro-benzyl ester;    (R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-4-propoxy-benzyl ester;    (R)-2-ethyl-piperazine-1-carboxylic acid 4-allyloxy-2,6-difluoro-benzyl ester;    (R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-4-prop-2-ynyloxy-benzyl ester;    (R)-2-ethyl-piperazine-1-carboxylic acid 4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester;    (R)-2-ethyl-piperazine-1-carboxylic acid 2-chloro-6-fluoro-4-propoxy-benzyl ester;    (R)-2-ethyl-piperazine-1-carboxylic acid 4-allyloxy-2-chloro-6-fluoro-benzyl ester; and    (R)-2-ethyl-piperazine-1-carboxylic acid 2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester.    
     
     
         15 . A compound of formula I wherein the compound is S-4-[(2-propylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate.  
     
     
         16 . A compound of formula I wherein the compound is S-4-[(benzylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate.  
     
     
         17 . A compound of formula I wherein the compound is S-4-[(tert-butylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate.  
     
     
         18 . A compound of formula I wherein the compound is 2,6-difluoro-4-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate.  
     
     
         19 . A compound of formula I wherein the compound is (R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate.  
     
     
         20 . A compound of formula I wherein the compound is (R)-2,6-difluoro-4-propoxybenzyl 2-methylpiperazine-1-carboxylate.  
     
     
         21 . A compound of formula I wherein the compound is cis-2,6-dimethyl-piperazine-1-carboxylic acid 4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester.  
     
     
         22 . A compound of formula I wherein the compound is 2-fluoro-5-(2-propenyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate.  
     
     
         23 . A compound of formula I wherein the compound is (R)-2-fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate.  
     
     
         24 . A compound of formula I wherein the compound is 5-(cyclopropylmethyl)oxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate.  
     
     
         25 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 4-cyclopropylmethoxy-2,6-difluoro-benzyl ester.  
     
     
         26 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-4-propoxy-benzyl ester.  
     
     
         27 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 4-allyloxy-2,6-difluoro-benzyl ester.  
     
     
         28 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-4-prop-2-ynyloxy-benzyl ester.  
     
     
         29 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester.  
     
     
         30 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 2-chloro-6-fluoro-4-propoxy-benzyl ester.  
     
     
         31 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 4-allyloxy-2-chloro-6-fluoro-benzyl ester.  
     
     
         32 . A compound of formula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid 2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester.  
     
     
         33 . A process for the preparation of a compound comprising deprotecting a compound of formula  
       
         
           
           
               
               
           
         
         wherein R 1  to R 4 , A 1 , A 2 , m and n are defined as in  claim 1  and (P) is a nitrogen protecting group.  
       
     
     
         34 . A method of treating a disease alleviated by modulation of 5-HT2 receptors comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or ester thereof to a patient in need of such treatment.  
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of compound of formula I or a pharmaceutically acceptable salt, solvate or ester thereof and a therapeutically inert carrier.  
     
     
         36 . The pharmaceutical composition of  claim 35  further comprising a therapeutically effective amount of a lipase inhibitor.  
     
     
         37 . The pharmaceutical composition of  claim 36  wherein said lipase inhibitor is orlistat.  
     
     
         38 . A method of treating obesity comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or ester thereof to a patient in need of such treatment.  
     
     
         39 . The method of  claim 38  further comprising the administration of a therapeutically effective amount of a lipase inhibitor to the patient.  
     
     
         40 . The method of treatment of  claim 39  wherein said lipase inhibitor is orlistat.  
     
     
         41 . A method of treatment of diabetes mellitus, Type I diabetes, Type II diabetes, diabetes, diabetes secondary to pancreatic disease, diabetes related to steroid use, Type III diabetes, hyperglycaemia, diabetic complication and insulin resistance. diabetes comprising administration of a therapeutically effective amount of the compound of formula I or a pharmaceutically effective salt solvate or ester thereof to a patient in need of such treatment.  
     
     
         42 . A method of treatment of type II diabetes comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or ester thereof to a patient in need of such treatment.  
     
     
         43 . The method of treatment of  claim 42 , further comprising administration of a therapeutically effective amount of a lipase inhibitor to the patient.  
     
     
         44 . The method of  claim 43  wherein said lipase inhibitor is orlistat.