Novel cyclopropane indolinone derivatives

Abstract

The present invention relates to a compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R 1 to R 4 have the significance given in claim 1 . The compound may be used, for example, for the treatment or prophylaxis of obesity, hyperglycemia, dyslipidemia, and type 1 or type 2 diabetes.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently selected from the group consisting of: hydrogen, alkyl, pyridinyl, phenyl, halophenyl, alkoxyphenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl; 
 or R 1  and R 2 , together with the carbon atom to which they are attached, form cycloalkyl or tetrahydropyranyl; 
 R 3  is selected from the group consisting of: hydrogen, pyridinyl, piperidinyl, carboxypyridinyl, tetrahydropyranyl, alkylamino, morpholinyl, morpholinylalkylamino, alkylmorpholinylalkylamino, alkylsulfonylpiperidinyl, alkylpiperazinyl, alkylaminoalkylpiperazinyl, pyridinylpiperazinyl, alkylaminopyrrolidinyl, 1H-imidazolyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl, cycloalkylsulfonylaminocarbonylpyridinyl and substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from the group consisting of: alkyl, halogen, hydroxyalkylamino, carboxy, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl, cycloalkyl-1H-pyrazolylaminocarbonyl and cycloalkylsulfonylaminocarbonyl; 
 R 4  is selected from the group consisting of: hydrogen, halogen, carboxy, cyano, trifluoromethyl and alkylsulfonyl; and 
 n is 0, 1, 2 or 3; 
 or a pharmaceutically acceptable salt or ester thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein one of R 1  and R 2  is selected from hydrogen and alkyl and the other is selected from the group consisting of: pyridinyl, halophenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl. 
     
     
         3 . A compound according to  claim 1 , wherein one of R 1  and R 2  is selected from hydrogen and isopropyl and the other is selected from the group consisting of: pyridinyl, fluorophenyl, chlorophenyl, cyanophenyl, methylsulfonylphenyl and trifluoromethylphenyl. 
     
     
         4 . A compound according to  claim 1  wherein R 3  is selected from the group consisting of: pyridinyl, carboxypyridinyl, tetrahydropyranyl, dialkylamino, morpholinyl, alkylsulfonylpiperidinyl, alkylpiperazinyl, dialkylaminoalkylpiperazinyl, dialkylaminopyrrolidinyl, carboxyalkyl-1H-imidazolyl, carboxy-1H-imidazolyl or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from alkyl, halogen, carboxy, alkylsulfonyl, alkylaminocarbonyl, alkylsulfonylaminocarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridinylpiperazinylcarbonyl, alkylpiperazinylcarbonyl, alkylsulfonylpiperazinylcarbonyl, alkylpyrrolidinylalkylaminocarbonyl, alkyl-1H-pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl and oxo-imidazolidinyl. 
     
     
         5 . A compound according to  claim 1 , wherein R 3  is selected from the group consisting of: carboxypyridinyl, carboxyalkyl-1H-imidazolyl, carboxyphenyl and phenyl substituted with carboxy and oxo-oxazolidinyl. 
     
     
         6 . A compound according to  claim 1 , wherein R 4  is selected from the group consisting of: hydrogen, halogen and carboxy. 
     
     
         7 . A compound according to  claim 1 , wherein R 4  is selected from the group consisting of: hydrogen, fluoro, chloro and carboxy. 
     
     
         8 . A compound according to  claim 1 , wherein n is 0 or 1. 
     
     
         9 . A compound according to  claim 1  selected from the group consisting of:
 (1S,2R)-3-((2-(3-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1R,2S)-3-((2-(3-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1S,2S)-3-((2-(3-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1R,2R)-3-((2-(3-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1S,2S)-3-((2-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1R,2R)-3-((2-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1S,2R)-3-((2-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; and 
 (1R,2S)-3-((2-(4-methoxyphenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid. 
 
     
     
         10 . A compound according to  claim 1  selected from the group consisting of:
 (1S,2R)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1R,2S)-3-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (1R,2S)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; and 
 (1S,2R)-4-((2′-oxo-2-(pyridin-3-yl)spiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid. 
 
     
     
         11 . A compound according to  claim 1  selected from the group consisting of:
 (R)-3-((5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (S)-3-((5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid; 
 (R)-3-(5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; 
 (S)-3-(5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoic acid; 
 (R)-methyl-3-(2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoate; 
 (S)-methyl-3-(2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoate; 
 (R)-3-(2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-hydroxyethylamino)benzoic acid; and 
 (S)-3-(2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-hydroxyethylamino)benzoic acid. 
 
     
     
         12 . A compound according to  claim 1  selected from the group consisting of:
 (R)-3-[(2-oxo-2″,3″,5″,6″-tetrahydrodispiro[indole-3,1′-cyclopropane-2′,4″-pyran]-1(2H)-yl)methyl]benzoic acid; 
 (S)-3-[(2-oxo-2″,3″,5″,6″-tetrahydrodispiro[indole-3,1′-cyclopropane-2′,4″-pyran]-1(2H)-yl)methyl]benzoic acid; 
 (R)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2″,3″,5″,6″-tetrahydrodispiro[indole-3,1′-cyclopropane-2′,4″-pyran]-1(2H)-yl)benzoic acid; 
 (S)-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2″,3″,5″,6″-tetrahydrodispiro[indole-3,1′-cyclopropane-2′,4″-pyran]-1(2H)-yl)benzoic acid; 
 (R)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2″,3″,5″,6″-tetrahydrodispiro[indole-3,1′-cyclopropane-2′,4″-pyran]-1(2H)-yl)benzoate; and 
 (S)-methyl-3-(2-oxo-1,3-oxazolidin-3-yl)-5-(2-oxo-2″,3″,5″,6″-tetrahydrodispiro[indole-3,1′-cyclopropane-2′,4″-pyran]-1(2H)-yl)benzoate. 
 
     
     
         13 . A compound according to  claim 1  selected from the group consisting of:
 (1R,2R)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; 
 (1S,2S)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; 
 (1R,2S)-2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; 
 (1S,2R)-2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; 
 (1R,2R)-2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; 
 (1S,2S)-2-(4-cyanophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; 
 (1S,2R)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid; and 
 (1R,2S)-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylic acid. 
 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  and a therapeutically inert carrier.