Compounds having activity as inhibitors of cytochrome P450RAI

Abstract

Compounds having Formulas 5 and 6 wherein the symbols have the meaning defined in the specification are inhibitors of the cytochrome P450RAI (retinoic acid inducible) enzyme, and are used for treating diseases responsive to treatment by retinoids.

What is claimed is:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2  groups; 
 X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C 1-6 -trialkylsilyl or benzyl;  
 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;  
 Z is —C≡C—, 
 —(CR 1 ═CR 1 ) n′  where n′ is an integer having the value 1-5,  
 —CO—NR 1 —,  
 NR 1 —CO—;  
 —CO—O—,  
 —O—CO—,  
 —CS—NR 1 —,  
 NR 1 —CS—,  
 —CO—S—,  
 —S—CO—,  
 —N═N—;  
 
 R 1  is independently H or alkyl of 1 to 6 carbons;  
 R 2  is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;  
 R 3  is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;  
 m is an integer having the values 0 to 3;  
 R 7  is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons;  
 n is an integer having the values of 1 to 4, and  
 R 8  is H, alkyl of 1 to 6 carbons, —CH 2 O(C 1-6 -alkyl), or a cation of a pharmaceutically acceptable base.  
 
     
     
         2 . A compound in accordance with  claim 1  where A is phenyl, naphthyl, pyridyl, thienyl or furyl.  
     
     
         3 . A compound in accordance with  claim 1  where n is 0, 1 or 2.  
     
     
         4 . A compound in accordance with  claim 1  where Z is —C≡C—, —CO—NR 1 —, —CO—O—, or —(CR 1 ═CR 1 ) n′  where n′ is 1.  
     
     
         5 . A compound in accordance with  claim 1  where the Z group is attached to the 4-position of the phenyl moiety.  
     
     
         6 . A compound in accordance with  claim 1  where X is O.  
     
     
         7 . A compound in accordance with  claim 1  where Y is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.  
     
     
         8 . A compound in accordance with  claim 1  where A is phenyl.  
     
     
         9 . A compound in accordance with  claim 1  where n is 1.  
     
     
         10 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein Y is branched-chain alkyl of 3 to 6 carbons; 
 R 2 is H or F;  
 R 3  is branched-chain alkyl of 3 to 6 carbons;  
 R 7  is lower alkyl of 1 to 6 carbons, and  
 R 8  is H, alkyl of 1 to 6 carbons, —CH 2 O(C 1-6 -alkyl), or a cation of a pharmaceutically acceptable base.  
 
     
     
         11 . A compound in accordance with  claim 10  where Y is t-butyl.  
     
     
         12 . A compound in accordance with  claim 11  where R 3  is t-butyl.  
     
     
         13 . A compound in accordance with  claim 12  where R 7  is methyl.  
     
     
         14 . A compound in accordance with  claim 13  which is selected from the group consisting of [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acid and [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base.  
     
     
         15 . A compound of the formula  
       
         
           
           
               
               
           
         
         wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2  groups;  
         X 2  is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR 7 , SR 7  or NRR 7  where R is H, alkyl of 1 to 6 carbons or benzyl;  
         Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;  
         Z is —C≡C—, 
 —(CR 1 ═CR 1 ) n′  where n′ is an integer having the value 1-5,  
 —CO—NR 1 —,  
 NR 1 —CO—;  
 —CO—O—,  
 —O—CO—,  
 —CS—NR 1 —,  
 NR 1 —CS—,  
 —CO—S—,  
 —S—CO—,  
 —N═N—;  
 
         R 1  is independently H or alkyl of 1 to 6 carbons;  
         R 2  is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;  
         R 3  is alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;  
         m is an integer having the values 0 to 3;  
         R 7  is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons or C 1-6 -trialkylsilyl.  
         n is an integer having the values of 0 to 4, and  
         R 8  is H, alkyl of 1 to 6 carbons, —CH 2 O(C 1-6 -alkyl), or a cation of a pharmaceutically acceptable base.  
       
     
     
         16 . A compound in accordance with  claim 15  where A is phenyl, naphthyl, pyridyl, thienyl or furyl.  
     
     
         17 . A compound in accordance with  claim 15  where n is 0, 1 or 2.  
     
     
         18 . A compound in accordance with  claim 15  where Z is —C≡C—, —CO—NR 1 —, —CO—O—, or —(CR 1 ═CR 1 ) n′  where n′ is 1.  
     
     
         19 . A compound in accordance with  claim 15  where the Z group is attached to the 4-position of the phenyl moiety.  
     
     
         20 . A compound in accordance with  claim 15  where X 2  is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl.  
     
     
         21 . A compound in accordance with  claim 15  where Y is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.  
     
     
         22 . A compound in accordance with  claim 15  where A is phenyl.  
     
     
         23 . A compound in accordance with  claim 15  where n is 1.  
     
     
         24 . A compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 3  is alkyl of 1 to 6 carbons;  
         X 2  is 1-imidazolyl, OR 7 , or NRR 7  where R is alkyl of 1 to 6 carbons or cyclopropyl, and R 7  is alkyl of 1 to 6 carbons, cyclopropyl or lower alkyl substituted cyclopropyl;  
         n is 0 or 1, and  
         R 8  is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.  
       
     
     
         25 . A compound in accordance with  claim 24  wherein X 2  is 1-imidazolyl.  
     
     
         26 . A compound in accordance with  claim 25  wherein n is 0.  
     
     
         27 . A compound in accordance with  claim 26  which is selected from the group consisting of 4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoic acid and [4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1-6  alkyl ester of said compound.  
     
     
         28 . A compound in accordance with  claim 25  wherein n is 1.  
     
     
         29 . A compound in accordance with  claim 28  which is selected from the group consisting of [4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetic acid and [4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1-6  alkyl ester of said compound.  
     
     
         30 . A compound in accordance with  claim 24  where X 2  is ethyl,cyclopropyl-N—.  
     
     
         31 . A compound in accordance with  claim 30  wherein n is 0.  
     
     
         32 . A compound in accordance with  claim 31  which is selected from the group consisting of 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoic and 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1-6  alkyl ester of said compound.  
     
     
         33 . A compound in accordance with  claim 30  wherein n is 1.  
     
     
         34 . A compound in accordance with  claim 33  which is (4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1-6  alkyl ester of said compound.  
     
     
         35 . A compound in accordance with  claim 24  where X 2  is (1-methyl)cyclopropyl-oxy.  
     
     
         36 . A compound in accordance with  claim 35  wherein n is 1.  
     
     
         37 . A compound in accordance with  claim 36  which is {4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1-6  alkyl ester of said compound.