Piperazine derivatives

A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate or ester thereof and a therapeutically inert carrier, wherein the compound of formula I is:

• wherein
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl, or R1 and R2, 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;
• R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
• A1 is oxygen or sulfur, wherein in case A1 is oxygen and A2 is unsubstituted phenyl, one of R1, R2, R3 and R4 is not hydrogen;
• A2 is unsubstituted cycloalkyl or cycloalkyl 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 aryl substituted with at least one substituent selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy,
• wherein the substituents of the substituted cycloalkyl and substituted aryl which are 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 optionally substituted with from one to three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy substituted with from one to three halogen, thiophenyl, unsubstituted aryl, amino, alkylcarbonyl and unsubstituted aryloxy,
• or two substituents of aryl 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;
• provided that 1-piperazinecarboxylic acid (4-(trifluoromethyl)phenyl)methyl ester is excluded.

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, wherein the compound of formula I is:

• wherein
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl, or R1 and R2, 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;
• R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
• A1 is oxygen or sulfur, wherein in case A1 is oxygen and A2 is unsubstituted phenyl, one of R1, R2, R3 and R4 is not hydrogen;
• A2 is unsubstituted cycloalkyl or cycloalkyl 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 aryl substituted with at least one substituent selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy,
• wherein the substituents of the substituted cycloalkyl and substituted aryl which are 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 optionally substituted with from one to three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy substituted with from one to three halogen, thiophenyl, unsubstituted aryl, amino, alkylcarbonyl and unsubstituted aryloxy,
• or two substituents of aryl 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;
• provided that 1-piperazinecarboxylic acid (4-(trifluoromethyl)phenyl)methyl ester is excluded.

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, 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, wherein the compound of formula I is:

• wherein
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl, or R1 and R2, 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;
• R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
• A1 is oxygen or sulfur, wherein in case A1 is oxygen and A2 is unsubstituted phenyl one of R1, R2, R3 and R4 is not hydrogen;
• A2 is unsubstituted cycloalkyl or cycloalkyl 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 aryl substituted with at least one substituent selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy,
• wherein the substituents of the substituted cycloalkyl and substituted aryl which are 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 optionally substituted with from one to three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy substituted with from one to three halogen, thiophenyl, unsubstituted aryl, amino, alkylcarbonyl and unsubstituted aryloxy,
• or two substituents of aryl 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;
• provided that 1-piperazinecarboxylic acid (4-(trifluoromethyl)phenyl)methyl ester is excluded.

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, wherein the compound of formula I is:

• wherein
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl, or R1 and R2, 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;
• R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, cycloallcyl, aryl and aralkyl;
• A1 is oxygen or sulfur, wherein in case A1 is oxygen and A2 is unsubstituted phenyl, one of R1, R2, R3 and R4 is not hydrogen;
• A2 is unsubstituted cycloalkyl or cycloalkyl 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 aryl substituted with at least one substituent selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralikoxy, aryloxy, hydroxy, cyano, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy,
• wherein the substituents of the substituted cycloalkyl and substituted aryl which are 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 optionally substituted with from one to three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy substituted with from one to three halogen, thiophenyl, unsubstituted aryl, amino, alkylcarbonyl and unsubstituted airyloxy,
• or two substituents of aryl 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;
• provided that 1-piperazinecarboxylic acid (4-(trifluoromethyl)phenyl)methyl ester is excluded.