Indolyl or indolinyl derivatives and medicinal use thereof as ACAT or lipid peroxidation inhibitors

Abstract

A heterocyclic derivative of the formula (I) wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof exhibit superior ACAT inhibitory activity and lipoperoxidation inhibitory activity in mammals, and are useful as ACAT inhibitors and lipoperoxidation inhibitors. Specifically, they are useful for the prophylaxis and treatment of arteriosclerosis, hyperlipemia, arteriosclerosis in diabetes, and cerebrovascular and cardiovascular ischemic diseases.

1. A heterocyclic compound of the formula (I) 
                   
       wherein
 one of R 1 , R 2  and R 3  is hydroxy, carboxy, alkoxycarbonyl, a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently hydrogen atom or lower alkyl, or alkyl or alkenyl substituted by hydroxy, carboxy, sulfonic add group or phosphoric acid group, alkoxy-carbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy;  
 either R 3  or R 4  is a group of the formula —NHCOR 7  wherein R 7  is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR 8  wherein R 8  is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy;  
 R 6  is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl; and Z is 
                 
 
 
       or a pharmaceutically acceptable salt thereof, provided that when one of R 1 , R 2  and R 3  its carboxy or alkoxycarbonyl, Z should be a group of the formula 
                 
 
       
        
       
     
     
       2. The heterocyclic compound of  claim 1 , wherein, in the formula (I), one of R 1 , R 2  and R 3  is alkyl or alkenyl substituted by hydroxy, carboxy, sulfonic acid group or phosphoric acid group, alkoxycarbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently hydrogen atom or loaner alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof. 
     
     
       3. The heterocyclic compound of  claim 2 , wherein, in the formula (I), Z is 
                   
       or a pharmaceutically acceptable salt thereof. 
     
     
       4. The heterocyclic compound of  claim 3 , wherein, in the formula (I), one of R 1 , R 2  and R 3  is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, and either R 3  or R 4  is a group of the formula —NHCOR 7  wherein R 7  is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl aryl, arylalkyl or a group of the formula —NHR 8  wherein R 8  is alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof. 
     
     
       5. The heterocyclic compound of  claim 4 , wherein, in the formula (I), R 2  and R 3  are each independently hydrogen atom, lower alkyl or lower alkoxy, either R 2  or R 5  is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently lower alkyl, and the other is hydrogen atom, lower alkyl or lower alkoxy, and R 4  is a group of the formula —NHCOR 7  wherein R 7  is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, a arylalkyl or a group of the formula —NHR 8  wherein R 8  is alkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       6. The heterocyclic compound of  claim 5 , wherein, in the formula (I), either R 2  or R 3  is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently lower alkyl, and the other is hydrogen atom, or a pharmaceutically acceptable salt thereof. 
     
     
       7. The heterocyclic compound of  claim 6 , wherein, in the formula (I), R 1  and R 3  are each independently hydrogen atom or lower alkyl, either R 2  or R 5  is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently lower alkyl, and the others hydrogen atom, R 4  is a group of the formula —NHCOR 7  wherein R 7  is alkyl, cycloalkyl or cycloalkylalkyl, and R 6  is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       8. The heterocyclic compound of  claim 7 , wherein, in the formula (I), R 2  is alkyl substituted by hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR 9 R 10  wherein R 9  and R 10  are each independently lower alkyl, and R 5  is hydrogen atom, or a pharmaceutically acceptable salt thereof. 
     
     
       9. The heterocyclic compound of  claim 8 , which is represented by the formula (IIa) 
                   
       wherein R 1a  is hydrogen atom or lower alkyl, R 3a  is lower alkyl, R 2a  is alkyl substituted by hydroxy or carboxy, R 4a  is a group of the formula —NHCOR 7a  wherein R 7a  is alkyl, cycloalkyl or cycloalkylalkyl, and R 6a  is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       10. The heterocyclic compound of  claim 9 , wherein, in the formula (IIa), R 3a  is hydrogen atom or lower alkyl, R 3a  lower alkyl, R 2a  is alkyl substituted by hydroxy or carboxy, R 4a  is a group of the formula —NHCOR 7a  wherein R 7a  is alkyl, and R 6a  is alkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       11. The  A heterocyclic compound of  claim 10 , wherein the compound of the formula (IIa) is  selected from the group consisting of:
 (1) N-(1-hexyl-5-carboxythyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, 
 ( 1 )  N- (   1   - hexyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide,   
 (2) N-(1-heptyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (3) N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (4) N-(1-nonyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (5) N-(1-decyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (6) N-(1-undecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, and 
 (7) N-(1-dodecyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (8) N-(1-hexyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide,  
 (9) N-(1-hexyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (10) N-(1-heptyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide,  
 (11) N-(1-heptyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 (12) N-(1-octyl-5-hydroxymethyl-6-methylindolin-7-yl)-2,2-dimethylpropanamide, and  
 (13) N-(1-octyl-5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,  
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. The heterocyclic compound of  claim 1 , wherein, in the formula (I), one of R 1 , R 2  and R 3  is hydroxy, carboxy, alkoxycarbonyl or a grip of the formula —NR   9 R 10  wherein R 9  and R 10  are each, independently hydrogen atom or lower alkyl, and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof. 
     
     
       13. The heterocyclic compound of  claim 12 , which is represented by the formula (IIc) 
                   
       wherein one of R 1c , R 2c  and R 3c  is hydroxy, carboxy, alkoxycarbonyl or a group of the formula —NR 9c R 10c  wherein R 9c  and R 10c  are each independently hydrogen atom or lower alkyl and the other two are each independently hydrogen atom, lower alkyl or lower alkoxy, either R 3c  or R 4c  is a group of the formula —NHCOR 7c , wherein R 7c  is alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group of the formula —NHR 8c  wherein R 8c  is alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl and the other is hydrogen atom, lower alkyl or lower alkoxy, and R 6c  is alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       14. The heterocyclic compound of  claim 13 , wherein, in the formula (IIc), R 1c  and R 3c  are each independently hydrogen atom, lower alkyl or lower alkoxy, R 5c  is carboxy, R 4c  is a group of the formula —NHCOR 7c  wherein R 7c  is alkyl, cycloalkyl or cycloalkylalkyl, R 6c  is hydrogen atom, and R 6c  is alkyl, cycloalkyl or cycloalkylalkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       15. The heterocyclic compound of  claim 14 , wherein, in the formula (IIc), R 1c  is hydrogen atom or lower alkyl, R 3c  is lower alkyl, R 2c  is carboxyl, R 4c  is a group of the formula —NHCOR 7c  wherein R 7c  is alkyl, R 5c  is hydrogen atom, and R 6c  is alkyl, or a pharmaceutically acceptable salt thereof. 
     
     
       16. The heterocyclic compound of  claim 15 , wherein the compound of the formula (IIc) is selected from the group consisting of:
 (1) N-(1-hexyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide,    (2) N-(1-octyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide,    (3) N-(1-decyl-5-carboxy-6-methylindolin-7-yl)-2,2-dimethylpropanamide,    (4) N-(1-hexyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,    (5) N-(1-octyl-5-carboxy-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide, and    (6) N-(1-decyl-5-carboxy-4,6dimethylindolin-7-yl)-2,2-dimethylpropanamide,    
       or a pharmaceutically acceptable salt thereof. 
     
     
       17. A pharmaceutical composition comprising an effective amount of a heterocyclic compound of claim  1    11  or a pharmaceutically acceptable salt thereof. 
     
     
       18. A method of inhibiting acyl-CoA:cholesterol acyl-transferase in a patient in need of same which comprises administering to such patient the composition of  claim 17 . 
     
     
       19. A method of inhibiting lipoperoxidation in a patient in need of same which comprises administering to such patient the composition of  claim 17 . 
     
     
       20. The heterocyclic compound of  claim 11  wherein the compound is in the form of a pharmaceutically acceptable salt which is an acid addition malt with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. 
     
     
       21. The heterocyclic compound of  claim 11 , which is N-(   1   - hexyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.   
     
     
       22. The heterocyclic compound of  claim 11 , which is N-(   1   - heptyl -   5   -carboxymethyl-   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.   
     
     
       23. The heterocyclic compound of  claim 11 , which is N-(   1   - octyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.   
     
     
       24. The heterocyclic compound of  claim 11 , which is N-(   1   - nonyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.   
     
     
       25. The heterocyclic compound of  claim 11 , which is N-(   1   - decyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.   
     
     
       26. The heterocyclic compound of  claim 11 , which is N-(   1   - undecyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.    
     
     
       27. The heterocyclic compound of  claim 11 , which is N-(   1   - dodecyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide or its pharmaceutically acceptable salt.   
     
     
       28. The heterocyclic compound of  claim 11 , which is a hydrochloric acid addition salt of N-(   1   - octyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide.   
     
     
       29. The heterocyclic compound of  claim 11 , which is a sulfuric acid addition salt of N-(   1   - octyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - yl )-   2 , 2   - dimethylpropanamide.   
     
     
       30. The heterocyclic compound of  claim 11 , which is a nitric acid addition salt of N-(   1   - octyl -   5   - carboxymethyl -   4 , 6   - dimethylindolin -   7   - vl )-   2 , 2   - dimethylpropanamide.