4-aminopiperidine derivatives

Abstract

The present invention relates to compounds of the formula (I) wherein R 1 and R 2 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection.

1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of 
         phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, lower alkoxy, phenyl, phenoxy, halogen, or lower halogenalkyl; 
         naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; 
         tetrahydronaphthyl; 
         C 3-7 -cycloalkyl; 
         —(CHR 3 ) m -phenyl, wherein m is 1, 2, or 3 and phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, 
         lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein 
         R 3  is hydrogen, lower alkyl or phenyl; 
         —(CH 2 ) n -heteroaryl, wherein n is 1, 2 or 3; 
         —(CH 2 ) n -heteroaryl, wherein n is 1, 2, 3 and heteroaryl is mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; 
         —C(O)—CH 2 -phenyl, with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; 
         —C(O)—CH 2 -heteroaryl; and 
         —C(O)—CH 2 -heteroaryl, wherein heteroaryl is mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; 
         R 2  is selected from the group consisting of 
         lower alkyl, lower halogenalkyl; 
         phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, 
         by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; 
         naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; 
         heteroaryl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; 
         —COOH; 
         —C(O)—NR 4 R 5 ; wherein 
         R 4  and R 5  are lower alkyl or together with the nitrogen atom to which they are attached form a 4-, 5- or 6- membered heterocycle which may contain a further heteroatom selected from O, N or S; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
 naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;   
       —(CHR 3 ) m -phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy and wherein
 R 3  is hydrogen; 
 
       —(CH 2 ) n -heteroaryl, wherein n is 1 or 2; 
       —(CH 2 ) n -heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy, 
       —C(O)—CH 2 -phenyl, with phenyl being unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; 
       —C(O)—CH 2 -heteroaryl; and 
       —C(O)—CH 2 -heteroaryl, with heteroaryl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy;
 naphthyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; and   —(CHR 3 ) m -phenyl, wherein m is 1 or 2 and with phenyl being unsubstituted or mono-, di-, or trisubstituted by lower alkoxy and wherein   R 3  is hydrogen.   
     
     
         4 . The compound according to  claim 1 , wherein R 1  is
 phenyl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy.   
     
     
         5 . The compound according to  claim 1 , wherein R 1  is
 —(CH 2 ) n -heteroaryl, wherein n is 1 or 2; or   —(CH 2 ) n -heteroaryl, wherein n is 1 or 2 and with heteroaryl mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.   
     
     
         6 . The compound according to  claim 1 , wherein R 1  is
 —C(O)—CH 2 -phenyl, with phenyl being unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, lower alkoxy, phenyl or phenoxy; or   —C(O)—CH 2 -heteroaryl.   
     
     
         7 . The compound according to  claim 1 , wherein R 2  is selected from the group consisting of lower alkyl;
 phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy;   heteroaryl, unsubstituted or mono-, di, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy; and   —C(O)—NR 4 R 5 , wherein R 4  and R 5  together with the nitrogen atom to which they are attached form a 5-membered heterocycle which may contain a further heteroatom selected from O, N or S.   
     
     
         7 . The compound according to  claim 1 , wherein R 2  is
 n-butyl.   
     
     
         8 . The compound according to  claim 1 , wherein R 2  is
 phenyl, unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, halogenalkyl, or lower alkoxy.   
     
     
         9 . The compound according to  claim 1 , wherein R 2  is
 pyridyl or thienyl, wherein pyridyl and thienyl are unsubstituted or mono-, di-, or trisubstituted, independently, by lower alkyl, halogen, lower halogenalkyl, or lower alkoxy.   
     
     
         10 . The compound according to  claim 1 , wherein R 2  is
 —C(O)—NR 4 R 5 , wherein R 4  and R 5  together with the nitrogen atom to which they are attached form a 5-membered heterocycle which may contain a further heteroatom selected from O, N or S.   
     
     
         11 . The compound according to  claim 1 , selected from
 (cis)-3-butyl-1-phenethyl-piperidine-4-yl-amine,   (trans)-3-butyl-1-phenethyl-piperidine-4-yl-amine,   (cis)-3-butyl-1-benzyl-piperidine-4-yl-amine   (trans)-3-butyl-1-benzyl-piperidine-4-yl-amine   (cis)-3-butyl-1-[2-(1H-indol-3-yl)-ethyl]-piperidine-4-ylamine, (   (trans)-3-butyl-1-[2-(1H-indol-3-yl)-ethyl]-piperidine-4-ylamine,   (cis)-3-butyl-1-[2-(3,4-dimethoxy-phenyl-1yl)-ethyl]piperidine-4-ylamine,   (trans)-3-butyl-1-[2-(3,4-dimethoxy-phenyl-1yl)-ethyl]piperidine-4-ylamine,   (cis)-3-butyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(4-phenoxy-phenyl)-piperidine-4-yl-amine,   (trans)-3-butyl-1-(4-phenoxy-phenyl)-piperidine-4-yl-amine,   (cis/trans)-3-butyl-1-(5,6,7,8-tetrahydro-naphthalen-1yl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-1-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-1-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-naphthalen-1-yl-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3,4-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-p-tolyl-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-1-p-tolyl-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-4-methyl-1-phenyl-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-4-methyl-1-phenyl-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-cyclohexyl-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-(3,5-bis-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(6-methoxy-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-1-(6-methoxy-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-benzhydryl-4-yl-piperidine-4-yl-amine hydrochloride,   (cis)-3-phenyl-1-phenethyl-piperidine-4-yl-amine,   (trans)-3-phenyl-1-phenethyl-piperidine-4-yl-amine,   (cis)-3-phenyl-1-benzyl-piperidine-4-yl-amine,   (trans)-3-phenyl-1-benzyl-piperidine-4-yl-amine,   (cis/trans)-methyl-1′-phenethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-4′-yl-amine,   (cis)-3-(3-chloro-phenyl)-1-phenethyl-piperidine-4-yl-amine,   (cis/trans)-3-(3-chloro-phenyl)-1-benzyl-piperidine-4-yl-amine,   (cis/trans)-3-(3-methyl-phenyl)-1-benzyl-piperidine-4-yl-amine,   (cis)-3-(3-chloro-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine,   (trans)-1-benzyl-3-thiophen-2-yl-piperidine-4-yl amine   (cis)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-p-tolyl-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-(3,4-dimethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1′-(3,4-dimethoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-4′-yl-amine,   ((3R,4S)-4-amino-1-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,   ((3S,4R)-4-amino-1-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,   [(3S,4R)-4-amino-1-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidine-3-yl-methanone,   1-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-1-yl]-2-phenyl-ethanone,   1-[(3S-4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-1-yl]-2-thiophen-2-yl-ethanone,   3-[(3S,4R) and (3R,4S)-4-amino-1-[2(3,4-dimethoxy-phenyl)-ethyl]-piperidine-3-carboxylic acid,   3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-thiazolidine-3-yl-methanone   3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-yl-methanone,   3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-yl-methanone, and   pharmaceutically acceptable salts thereof.   
     
     
         12 . Compounds of formula I according to  claims 1  to  11 , selected from
 (cis)-3-butyl-1-phenethyl-piperidine-4-yl-amine,   (cis)-3-butyl-1-[2-(1H-indol-3-yl)-ethyl]-piperidine-4-ylamine,   (cis)-3-butyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(4-phenoxy-phenyl)-piperidine-4-yl-amine,   (cis)-3-butyl-1-(3,4-dimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,   (trans)-3-butyl-1-naphthalen-2-yl-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-naphthalen-1-yl-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3,4-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-p-tolyl-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-(3,5-dichloro-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-4-methyl-1-phenyl-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-butyl-1-(3-methoxy-5-trifluoromethyl-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis)-3-butyl-1-(6-methoxy-biphenyl-3-yl)-piperidine-4-yl-amine hydrochloride,   (cis)-3 -phenyl-1-phenethyl-piperidine-4-yl-amine,   (cis/trans)-methyl-1′-phenethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-4′-yl-amine,   (cis)-3-(3-chloro-phenyl)-1-phenethyl-piperidine-4-yl-amine,   (cis/trans)-3-(3-chloro-phenyl)-1-benzyl-piperidine-4-yl-amine,   (cis/trans)-3-(3-methyl-phenyl)-1-benzyl-piperidine-4-yl-amine,   (cis)-3-(3-chloro-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine,   (trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-3-o-tolyl-1-(3,4,5-trimethoxy-phenyl)-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,   (cis/trans)-1′-(3,4-dimethoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-4′-yl-amine,   ((3R,4S)-4-amino-1-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,   ((3S,4R)-4- amino-1-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,   [(3S,4R)-4-amino-1-(2-pyridin-2-yl-ethyl)-piperidine-3-yl]-thiazolidine-3-yl-methanone,   1-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-1-yl]-2-phenyl-ethanone,   1-[(3S,4R)-4-amino-3-(thiazolidine-3-carbonyl)-piperidine-1-yl]-2-thiophen-2-yl-ethanone,   3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-thiazolidin-3-yl-methanone   3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-yl-methanone,   3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-(2,5-dihydropyrrol-1-yl)-3-yl-methanone,   and pharmaceutically acceptable salts thereof.   
     
     
         13 . The compound according to  claim 1 , selected from
 (cis)-3-(3-chloro-phenyl)-1-phenethyl-piperidine-4-yl-amine,   (cis/trans)-3-(3-chloro-phenyl)-1-benzyl-piperidine-4-yl-amine,   (cis/trans)-3-(3-chloro-phenyl)-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-4-yl-amine,   (cis)-1-(3,4-dimethoxy-phenyl)-3-m-tolyl-piperidine-4-yl-amine hydrochloride,   ((3S,4R)-4-amino-1-phenethyl-piperidine-3-yl)-thiazolidine-3-yl-methanone,   ((3S,4R)-4-amino-1-(2-pyridin-2-yl-ethyl)-piperidine-3-yl)-thiazolidine-3-yl-methanone,   3-[(3S,4R) and (3R,4S)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-thiazolidine-3-yl-methanone,   3-[(3S,4S) and (3R,4R)-4-amino-1-(3,4-dimethoxy-phenyl)-piperidine-3-yl]-thiazolidin-3-yl-methanone,   and pharmaceutically acceptable salts thereof.   
     
     
         14 . A process for the manufacture of compounds of formula I according to  claim 1 , comprising the steps of:
 a) converting a compound of the formula   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined in  claim 1 , 
         with hydroxylamine or a salt thereof into an oxime of the formula 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined in  claim 1 , 
         and further reducing the oxime of formula III by catalytic hydrogenation or alternatively by a reduction with a metal hydride into the compound of formula I; or 
         b) deprotecting an 4-aminopiperidine derivative of the formula 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined before and R P  is an amino protecting group. 
       
     
     
         14 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier and/or adjuvant. 
     
     
         15 . A method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, comprising the step of administering a therapeutically effective amount of a compound according to  claim 1  to a human being or animal in need thereof. 
     
     
         16 . The method according to  claim 15 , wherein said disease is diabetes, non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, obesity, and/or metabolic syndrome or β-cell protection.