Novel carboxylic acid derivatives, their preparation and use

Abstract

Carboxylic acid derivatives where R—R 6 , X, Y and Z have the meanings stated in the description, and the preparation thereof, are described. The novel compounds are suitable for controlling diseases.

1 . (canceled) 
     
     
         2 . A method of treating hypertension or pulmonary hypertension, the method comprising the step of administering a therapeutically effective amount of a compound of formula I to a patient in need thereof 
       
         
           
           
               
               
           
         
         wherein 
         R is formyl, tetrazole, nitrile, —CO 2 H or another radical which can be hydrolyzed to —CO 2 H; 
         R 2  is hydrogen, hydroxyl, —NH 2 , —NH(C 1 -C 4 -alkyl), —N(C 1 -C 4 -alkyl) 2 , halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio; 
         X is CR 14 , where R 14  is hydrogen or C 1 -C 5 -alkyl; 
         R 3  is hydrogen, hydroxyl, —NH 2 , —NH(C 1 -C 4 -alkyl), —N(C 1 -C 4 -alkyl) 2 , halogen, C 1 -C 4 -alkyl, or C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, —NH—O—C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio or CR 3  is linked to CR 14  to give a 5- or 6-membered ring; 
         R 4  and R 5 , which can be identical or different, are phenyl or naphthyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, cyano, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy,
 C 1 -C 4 -alkylthio, amino, C 1 -C 4 -alkylamino and C 1 -C 4 -dialkylamino; or R 4  and R 5  are phenyl or naphthyl, which are connected together in the ortho position via a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom, an SO 2 , NH or N-alkyl group or a C 3 -C 7 -cycloalkyl group; 
 
         R 6  is hydrogen, C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, where each of these can be substituted by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy,
 C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino, phenyl and phenoxy which phenyl or phenoxy is substituted by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and C 1 -C 4 -alkylthio; or 
 phenyl or naphthyl, each of which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, 
 C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylamino, C 1 -C 4 -dialkylamino, dioxomethylene and dioxoethylene; or 
 a five or six-membered heteroaromatic moiety containing (i) one to three nitrogen atoms, (ii) one sulfur atom, (iii) one oxygen atom, (iv) one to three nitrogen atoms and one sulfur atom, or (v) one to three nitrogen atoms and one oxygen atom, which heteroaromatic moiety can carry one or more substituents selected from the group consisting of: one to four halogen atoms, and one or two of the following selected from the group consisting of: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy and phenylcarbonyl, it being possible for the phenyl in turn to carry one or more substituents selected from the group consisting of: one to five halogen atoms, and one to three of the following selected from the group consisting of: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and C 1 -C 4 -alkylthio; 
 
         Y is sulfur, oxygen or a single bond; and 
         Z is sulfur, oxygen, —SO— or —SO 2 —. 
       
     
     
         3 . The method of  claim 2 , wherein
 X is CH;   Y is oxygen;   Z is oxygen;   R is CO 2 H;   R 2  is C 1 -C 4 -alkoxy;   R 3  is C 1 -C 4 -alkoxy;   R 4  is phenyl;   R 5  is phenyl; and   R 6  is C 1 -C 8 -alkyl.   
     
     
         4 . The method of  claim 3 , wherein
 R 2  is methoxy; and   R 3  is methoxy.   
     
     
         5 . The method of  claim 2 , wherein
 X is CH;   Y is oxygen;   Z is oxygen;   R is —CO 2 H;   R 2  is C 1 -C 4 -alkyl;   R 3  is C 1 -C 4 -alkyl;   R 4  is phenyl;   R 5  is phenyl; and   R 6  is C 1 -C 8 -alkyl.   
     
     
         6 . The method of  claim 5 , wherein
 R 2  is methyl; and   R 3  is methyl.   
     
     
         7 . The method of  claim 2 , wherein
 R is formyl, —CO 2 H or a radical which can be hydrolyzed to —CO 2 H;   R 2  is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy;   X is CR 14 , where R 14  is hydrogen or C 1 -C 5 -alkyl;   R 3  is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy;   R 4  and R 5  which can be identical or different, are phenyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, hydroxyl,
 C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio; or 
 phenyl which are connected together in the ortho positions by a direct linkage, methylene, ethylene, ethenylene, oxygen, sulfur, —SO 2 —, —NH—, N-alkyl group or C 3 -C 7 -cycloalkyl; 
   R 6  is C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 8 -cycloalkyl, where each of these can be substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy and C 1 -C 4 -alkylthio; or
 phenyl or naphthyl, each of which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, 
 C 1 -C 4  haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4  alkylthio, C 1 -C 4 -alkylamino and C 1 -C 4 -dialkylamino; or 
 a five- or six-membered heteroaromatic moiety containing (i) a nitrogen atom, (ii) a sulfur atom, (iii) an oxygen atom, (iv) a nitrogen atom and a sulfur atom, or (v) a nitrogen atom and an oxygen atom which heteroaromatic moiety can carry one or more substituents selected from the group consisting of: one to four halogen atoms, and one or two of the following selected from the group consisting of: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy and phenylcarbonyl, it being possible for the phenyl in turn to carry one or more substituents selected from the group consisting of: one to five halogen atoms, and one to three of the following selected from the group consisting of: C 1 -C 4 -alkyl, C 1 -C 4  haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio; 
   Y is sulfur, oxygen or a single bond; and   Z is sulfur, oxygen, SO or SO 2 .   
     
     
         8 . The method of  claim 7 , wherein
 R is —CO 2 H;   R 2  is C 1 -C 4 -alkyl;   X is CR 14 , where R 14  is hydrogen;   R 3  is C 1 -C 4 -alkyl;   R 4  and R 5  which can be identical or different, are phenyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, hydroxyl,
 C 1 -C 4  alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio; 
   R 6  is C 1 -C 8 -alkyl, which can be substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy and C 1 -C 4 -alkylthio;   Y is oxygen; and   Z is oxygen.   
     
     
         9 . The method of  claim 8 , wherein R 4  and R 5  are each phenyl. 
     
     
         10 . The method of  claim 7 , wherein
 R is —CO 2 H;   R 2  is C 1 -C 4 -alkoxy;   X is CR 14 , where R 14  is hydrogen;   R 3  is C 1 -C 4 -alkoxy;   R 4  and R 5  which can be identical or different, are phenyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, hydroxyl,
 C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio; 
   R 6  is C 1 -C 8 -alkyl, which can be substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy and C 1 -C 4 -alkylthio;   Y is oxygen; and   Z is oxygen.   
     
     
         11 . The method of  claim 10 , wherein R 4  and R 5  are each phenyl. 
     
     
         12 . The method of  claim 2 , wherein
 R is —CO 2 H or a radical which can be hydrolyzed to —CO 2 H;   R 2  is C 1 -C 4 -alkyl or a C 1 -C 4 -alkoxy;   X is CR 14 , where R 14  is hydrogen;   R 3  is C 1 -C 4 -alkyl or a C 1 -C 4 -alkoxy;   R 4  and R 5  which can be identical or different, are phenyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C b 4 -alkylthio;   R 6  is C 1 -C 8 -alkyl, which can by substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy and C 1 -C 4 -alkylthio;   Y is oxygen; and   Z is oxygen.   
     
     
         13 . The method of  claim 12 , where R 2  and R 3  are each C 1 -C 4 -alkyl. 
     
     
         14 . The method of  claim 12 , where R 2  and R 3  are each C 1 -C 4 -alkoxy. 
     
     
         15 . The method of  claim 12 , where R 4  and R 5  are each phenyl. 
     
     
         16 . A method of treating hypertension or pulmonary hypertension, the method comprising the step of administering a therapeutically effective amount of a compound of formula I to a patient in need thereof 
       
         
           
           
               
               
           
         
         wherein R is —CO 2 H;
 R 2  is C 1 -C 4 -alkyl; 
 X is CR 14 , where R 14  is hydrogen; 
 R 3  is C 1 -C 4 -alkyl; 
 R 4  and R 5  which can be identical or different, are phenyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio; 
 R 6  is a C 1 -C 8 -alkyl, which can substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy and C 1 -C 4 -alkylthio; 
 Y is oxygen; and 
 Z is oxygen. 
 
       
     
     
         17 . The method of  claim 16 , wherein R 4  and R 5  are each phenyl. 
     
     
         18 . A method of treating hypertension or pulmonary hypertension, the method comprising the step of administering a therapeutically effective amount of a compound of formula I to a patient in need thereof 
       
         
           
           
               
               
           
         
         where R is —CO 2 H;
 R 2  is C 1 -C 4 -alkoxy; 
 X is CR 14 , where R 14  is hydrogen; 
 R 3  is C 1 -C 4 -alkoxy; 
 R 4  and R 5  which can be identical or different, are phenyl, which can be substituted by one or more of the following selected from the group consisting of: halogen, nitro, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylthio; 
 R 6  is a C 1 -C 8 -alkyl, which can substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy and C 1 -C 4 -alkylthio; 
 Y is oxygen; and 
 Z is oxygen. 
 
       
     
     
         19 . The method of  claim 18 , wherein R 4  and R 5  are each phenyl. 
     
     
         20 . The method of 17, wherein R 6  is methyl. 
     
     
         21 . The method of  claim 19 , wherein R 6  is methyl.