Mevinolin derivatives

Abstract

Mevinolin derivatives wherein the lactone ring is modified have interesting pharmaceutical properties, particularly in preventing or treating disorders or diseases mediated by LFA-1/ICAM-1 interactions.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 each of a-b and α-β independently, is either a single bond or a double bond;  
 R 1  is 
 . . . H, . . . C 1-4 alkyl or —OR a    
 
 wherein R a  is H, C 1-6 alkyl optionally substituted by OH or C 1-4 alkoxy, C 2-6 alkenyl or aryl-0 1 4alkyl;  
 R 2  is OH; —O—CO—R 5  wherein R 5  is C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, aryl or aryl-C 1-4 alkyl; or —O—R 6  wherein R 6  is the residue of an α-amino-acid attached to O through its carbonyl residue or —CHR 7 COR 8  wherein R 7  is H, C 1-4 alkyl, heteroC 1-4 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, aryl or aryl-C 1-4 alkyl and R 8  is OH, C 1-4 alkoxy or NR 9 R 10  wherein each of R 9  and R 10  independently is H, C 1-4 alkyl or R 9  and R 10  form together with the nitrogen to which they are bound, a heteroaryl group;  
 R 3  is a substituted lactam, piperidyl, linear amino alcohol or cyclic carbamate, or a residue of formula (i)  
                     
 wherein  
 R 13  is OH; C 1-6 alkoxy; —O—CO—C 1-6 alkyl; or —CO—NHC 1-6 alkyl;  
 R 14  is OH; C 1-4 alkoxy; C 1-4 alkyl; C 1-4 alkoxy-carbonyl-C 1-4 alkoxy; hydroxy-C 1-5 alkoxy;  
 C 1-4 alkoxy-C 1-5 alkoxy; C 1-4 alkoxy-carbonyl-C 1-4 alkyl; or NR 9a R 10a -C 1-5 alkoxy wherein each of R 9a  and R 10a  independently has one of the significances given for R 9  and R 10 ;  
 R 15  is H or C 1-4 alkyl; and  
 R 16  is CONR 17 R 18  wherein one of R 17  and R 18  is H and the other is C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl or aryl-C 1-4 alkyl; or C 1-6 alkoxy-carbonyl;  
 each of a-b and α-β being a single bond when each of R 13  or R 14  is OH; and  
 R 4  is H or OR 19  wherein R 19  is C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, aryl-C 1-4 alkyl or C 1-4 alkoxycarbonyl-C 1-4 alkyl,  
 and wherever “aryl” appears as is or in the significances of “aryl-C 1-4 alkyl” in the above definition, it is “phenyl” or “naphthyl” optionally substituted by halogen, OH, NR 11 R 12 , COOH, CF 3 , C 1-4 alkoxy, C 1-4 alkyl, hydroxy-C 1-4 alkyl, hydroxy-C 1-4 alkoxy, C 1-4 alkoxy-carbonyl, cyano or CONR 11 R 12 , each of R 11  and R 12  independently being H, C 1-4 alkyl, phenyl, naphthyl, phenyl-C 1-4 alkyl or naphthyl-C 1-4 alkyl or R 11  and R 12  together with the nitrogen to which they are bound forming heteroaryl; and wherever “heteroaryl” appears, it is a 5- or 6-membered heterocyclic residue optionally fused to a benzene ring;  
 in free form or in salt form.  
 
     
     
         2 . A compound according to  claim 1  wherein R 3  is a radical of formula (a), (b), (c 1 ) or (C 2 )  
       
         
           
           
               
               
           
         
       
       wherein 
 R 30  is C 1-8 alkyl; C 3-7 cycloalkyl; aryl; C 3-7 cycloalkyl-C 1-4 alkyl; aryl-C 1-4 alkyl; heteroaryl; or heteroaryl-C 1-4 alkyl;  
 R 31  is OH; C 1-4 alkoxy; C 1-4 alkyl; C 1-4 alkoxy-carbonyl-C 1-4 alkoxy; hydroxy-C 1-5 alkoxy; C 1-4 alkoxy-C 1-5 alkoxy; C 1-4 alkoxy-carbonyl-C 1-4 alkyl; amino-C 1-4 alkoxy; HOOC-C 1-4 alkoxy; HOOC-C 1-4 alkyl; or NR 9a R 10a -C 1-5 alkoxy wherein each of R 9a  and R 10a  independently is H, C 1-4 alkyl or R 9a  and R 10a  form together with the nitrogen to which they are bound, a heteroaryl group;  
 R 40  has one of the significances given for R 30 ;  
 R 41  has one of the significances given for R 31  or is —O—CO—C 1-8 alkyl;  
 either each of X and Y is H or X and Y form together  
                     
 each of R 50 , independently is H; C 1-8 alkyl; C 3-7 cycloalkyl; aryl; C 3-7 cycloalkyl-C 1-4 alkyl; aryl-C 1-4 alkyl; heteroaryl; heteroaryl-C 1-4 alkyl; C 1-4 alkyl-carbonyl; aryl-carbonyl; heteroaryl-carbonyl; aryl-C 1-4 alkyl-carbonyl or heteroaryl-C 1-4 alkyl-carbonyl, and  
 each of R 51 , independently is H; C 1-4 alkyl; hydroxy-C 1-4 alkyl; amino-C 1-4 alkyl; C 1-4 alkoxy-C 1-4 alkyl; C 1-4 alkoxy-carbonyl-C 1-4 alkyl wherein C 1-4 alkoxy is optionally substituted by amino, C 1-4 alkyl-amino or di-(C 1-4 alkyl)-amino; HOOC-C 1-4 alkyl; or R 23 R 24 N—CO—C 1-4 alkyl wherein R 23  is H, C 1-4 alkyl, hydroxy-C 1-4 alkyl, polyhydroxy-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-4 alkylamino-C 1-4 alkyl, di-(C 1-4 alkyl)amino-C 1-4 alkyl or aryl-C 1-4 alkyl and R 24  is H, C 1-4 alkyl or hydroxy-C 1-4 alkyl,  
 at least one of R 50  and R 51  being other than H.  
 
     
     
         3 . A compound according to  claim 2  wherein R 3  is a radical of formula (a); 
 R 30  being benzyl or naphthyl-methyl wherein the phenyl or naphthyl ring is optionally substituted by OH, C 1-4 alkoxy, hydroxy-C 1-4 alkoxy or hydroxy-C 1-4 alkyl, or morpholino, pyridyl, indolyl or quinolyl; and  
 R 31  being OH, C 1-4 alkoxy, hydroxy-C 1-4 alkoxy, C 1-4 alkoxy-carbonyl-C 1-4 alkoxy or HOOC-C 1-4 alkoxy.  
 
     
     
         4 . A compound according to  claim 2  wherein R 3  is a radical of formula (c 1 ) or (C 2 ) wherein X and Y form together —CO—; 
 R 50  being benzyl or naphthyl-methyl wherein the phenyl or naphthyl ring is optionally substituted by OH, C 1-4 alkoxy, hydroxy-C 1-4 alkoxy or hydroxy-C 1-4 alkyl; and  
 R 51  being hydroxy-C 1-4 alkyl; amino-C 1-4 alkyl; C 1-4 alkoxy-C 1-4 alkyl; C 1-4 alkoxy-carbonyl-C 1-4 alkyl; HOOC-C 1-4 alkyl; or R 23 R 24 N—CO—C 1-4 alkyl wherein R 23  and R 24  are as defined in  claim 2 .  
 
     
     
         5 . A compound according to  claim 1  which is (S)-2-methyl-butyric acid (S)-(3R,7S,8aR)-8-{(S)-2-[(4R,6R)-3-(4-hydroxy-3-methoxy-benzyl)-4-methylcarbamoylmethyl-2-oxo-[1,3]oxazinan-6-yl]-ethyl}3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester or (S)-2-methyl-butyric acid (1S,3R,7S,8S,8aR)-8-{2-[(2S,4R)-4-hydroxy-1-(5-hydroxymethyl-6-methoxy-naphthalen-2-ylmethyl)-6oxo-pipeddin-2-yl]-ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl ester.  
     
     
         6 . A compound according to any one of  claims 1  to  5 , in free form or in pharmaceutically acceptable salt form, for use as a pharmaceutical.  
     
     
         7 . A pharmaceutical composition comprising a compound of formula I according to any one of  claims 1  to  5 , in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutically aceptable diluent or carrier therefor.  
     
     
         8 . A pharmaceutical composition according to  claim 7 , for use in combination with at least one pharmaceutical composition comprising an immunosuppressant, immunomodulatory or anti-inflammatory drug.  
     
     
         9 . A method for preventing or treating disorders or diseases mediated by LFA-1/ICAM1 interactions in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I according to any one of  claims 1  to  5  or a pharmaceutically acceptable salt thereof.