Novel piperidine carboxylic acid amine derivatives

Abstract

The invention relates to novel piperidine carboxylic acid amide derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of these novel compounds, pharmaceutical compositions comprising such compounds and especially the use of such compounds as inhibitors of renin.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         W is a phenyl ring, 
         wherein said ring is substituted by V in para position; 
         V represents a bond; —(CH 2 ) r —; -A-(CH 2 ) s —; CH 2 -A-(CH 2 ) t —; A-(CH 2 ) s -A-; —(CH 2 ) 2 -A-(CH 2 ) u —; -A-(CH 2 ) v —B—; —CH 2 —CH 2 —CH 2 -A-CH 2 —; -A-CH 2 —CH 2 —B—CH 2 —; —CH 2 -A-CH 2 —CH 2 —B—; —CH 2 —CH 2 —CH 2 -A-CH 2 —CH 2 —; —CH 2 —CH 2 —CH 2 —CH 2 -A-CH 2 —; -A-CH 2 —CH 2 —B—CH 2 —CH 2 —; —CH 2 -A-CH 2 —CH 2 —B—CH 2 —; —CH 2 -A-CH 2 —CH 2 —CH 2 —B—; —CH 2 —CH 2 -A-CH 2 —CH 2 —B—; —O—CH 2 —CH(OCH 3 )—CH 2 —O—; —O—CH 2 —CH(CH 3 )—CH 2 —O—; —O—CH 2 —CH(CF 3 )—CH 2 —O—; —O—CH 2 —C(CH 3 ) 2 —CH 2 —O—; —O—CH 2 —C(CH 3 ) 2 —O—; —O—C(CH 3 ) 2 —CH 2 —O—; —O—CH 2 —CH(CH 3 )—O—; —O—CH(CH 3 )—CH 2 —O—; —O—CH 2 —C(CH 2 CH 2 )—O—; or —O—C(CH 2 CH 2 )—CH 2 —O—; 
         A and B independently represent —O— or —S—; 
         U represents unsubstituted aryl; mono-, di-, tri- or tetra-substituted aryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and —CF 3 ; or mono-, di-, or tri-substituted heteroaryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and —CF 3 ; 
         Q represents methylene or ethylene; 
         M represents an aryl, quinolinyl, isoquinolinyl, dihydroquinolinyl or tetrahydroquinolinyl group wherein said groups can optionally be mono- or di-substituted with substituents independently selected from the group consisting of alkyl; alkoxy; —OCF 3 ; —CF 3 ; hydroxy-alkyl; halogen; alkyl-O—(CH 2 ) 0-4 —CH 2 —; alkyl-O—(CH 2 ) 2-4 —O—; R′ 2 N—(CH 2 ) 0-4 —CH 2 —, wherein R′ is independently selected from the group consisting of hydrogen, alkyl (optionally substituted by one, two or three fluorine atoms), cyclopropyl, cyclopropyl-methyl, —C(═O)O—R″, and —C(═O)—R″ wherein R″ is C 1 -C 4 -alkyl, —CF 3 , —CH 2 —CF 3  or cyclopropyl; and R′″NH—C(═O)—(O) 0-1 —(CH 2 ) 0-4 —CH 2 —, wherein R′″ is alkyl or cyclopropyl; 
         R 1  represents alkyl or cycloalkyl; 
         n is the integer 0; 
         r is the integer 3, 4, 5, or 6; 
         s is the integer 2, 3, 4, or 5; 
         t is the integer 1, 2, 3, or 4; 
         u is the integer 1, 2, or 3; and 
         v is the integer 2, 3, or 4; 
         and optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and meso-forms, as well as salts and solvates of such compounds, and morphological forms. 
       
     
     
         2 . (canceled) 
     
     
         3 . A compound according to  claim 1 , wherein the configurations at positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4S, respectively. 
     
     
         4 . A compound according to  claim 1 , wherein M represents an aryl, quinolinyl, isoquinolinyl, dihydroquinolinyl or tetrahydroquinolinyl group wherein said groups can optionally be mono- or di-substituted with substituents independently selected from the group consisting of alkyl; alkoxy; —OCF 3 ; —CF 3 ; hydroxy-alkyl; halogen; alkyl-O—(CH 2 ) 0-4 —CH 2 —; alkyl-O—(CH 2 ) 2-4 —O—; and R′ 2 N—(CH 2 ) 0-4 —CH 2 —, wherein R′ is independently selected from the group consisting of hydrogen, alkyl, cyclopropyl, and —C(═O)—R″ wherein R″ is C 1 -C 4 -alkyl, —CF 3 , —CH 2 —CF 3  or cyclopropyl. 
     
     
         5 . A compound according to  claim 1 , wherein M represents the following radical: 
       
         
           
           
               
               
           
         
         wherein R 2  is methyl or chlorine, R 3  is hydrogen, and R 4  is hydrogen, —CH 2 CH 2 —O—CH 3 , —CH 2 CH 2 CH 2 —O—CH 3 , or R′NH—(CH 2 ) 0-1 —CH 2 — wherein R′ is —CH 2 —CHF 2 , —CH 2 —CF 3 , cyclopropyl, —CO—CH 3 , —CO—CH 2 —CF 3 , —CO—CH 2 —CH 3 , or cyclopropyl-carbonyl, with the proviso that in case R 4  is hydrogen, R 3  represents methyl, methoxy, chlorine, or —O—CH 2 CH 2 —O—CH 3 . 
       
     
     
         6 . A compound according to  claim 5 , wherein Q is methylene. 
     
     
         7 . (canceled) 
     
     
         8 . A compound according to  claim 7 , wherein V is —CH 2 CH 2 O— or —CH 2 CH 2 CH 2 O—, wherein in both cases the bivalent radical is linked to the group U of formula (I) via its oxygen atom, or —OCH 2 CH 2 O—. 
     
     
         9 . A compound according to  claim 1 , wherein U is a mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and —CF 3 . 
     
     
         10 . A compound according to  claim 1 , wherein R 1  is cyclopropyl. 
     
     
         11 . A compound according to  claim 1 , selected from the group consisting of:
 4-{4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(3-methoxy-2-methyl-benzyl)-amide,   4-{4-[3-(2,6-dichloro-4-methyl-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(3-methoxy-2-methyl-benzyl)-amide,   4-{4-[3-(2,3,6-trifluoro-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(3-methoxy-2-methyl-benzyl)-amide,   4-{4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(2,3-dimethyl-benzyl)-amide,   4-{4-[3-(2,6-dichloro-4-methyl-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(2,3-dimethyl-benzyl)-amide,   4-{4-[3-(2-chloro-6-fluoro-3-methyl-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(2,3-dimethyl-benzyl)-amide, and   4-{4-[3-(2,3,6-trifluoro-phenoxy)-propyl]-phenyl}-piperidine-3-carboxylic acid cyclopropyl-(2,3-dimethyl-benzyl)-amide.   
     
     
         12 . A compound according to  claim 1 , selected from the group consisting of:
 (3R*,4S*)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-piperidine-3-carboxylic acid cyclopropyl-(2,3-dimethylbenzyl)-amide.   (3R,4S)-4-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)ethoxy]phenyl}-piperidine-3-carboxylic acid [2-chloro-5-(3-methoxy-propyl)-benzyl]-cyclopropyl-amide, and   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide.   
     
     
         13 . A compound according to  claim 1 , selected from the group consisting of:
 (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid {2-chloro-5-[(2,2-difluoro-ethylamino)-methyl]-benzyl}-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid {2-chloro-5-[(3,3,3-trifluoro-propionylamino)-methyl]-benzyl}-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid {2-chloro-5-[(cyclopropylmethyl-amino)-methyl]-benzyl}-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid [5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid [2-chloro-5-(2-methylamino-ethyl)-benzyl]-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid (2-chloro-5-methylaminomethyl-benzyl)-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid {2-chloro-5-[2-(3,3,3-trifluoro-propionylamino)-ethyl]benzyl}-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid [2-chloro-5-(2-ethylamino-ethyl)-benzyl]-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid [5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid {2-chloro-5-[(2-fluoro-ethylamino)-methyl]-benzyl}-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid (2-chloro-5-ethylaminomethyl-benzyl)-cyclopropyl-amide,   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid (2-chloro-5-cyclopropylaminomethyl-benzyl)-cyclopropyl-amide, and   (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-piperidine-3-carboxylic acid [2-chloro-5-(2-cyclopropylamino-ethyl)-benzyl]-cyclopropyl-amide.   
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier material. 
     
     
         15 . A compound according to  claim 1  for use as a medicament. 
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition according to  claim 14  for use as a medicament.