Pharmaceutical aminophosphonic acid derivatives

Abstract

Aminophosphonates alpha substituted by phenol groups, of formula (I) have lipoprotein(a) lowering activity.

1 . A compound of structure (I):  
       
         
           
           
               
               
           
         
       
       in which: 
 X 1  and X 2 , which may be the same or different, are H, a straight or branched C (1-8) alkyl or C (1-8) alkoxy group, a hydroxy group or a nitro group;  
 X 3  is H, a C (1-4) alkyl group, X 3 O and one of the two other substituents X 1  or X 2  may form a C (1-4) alkylidene dioxy ring;  
 R 1  and R 2 , which may be the same or different, are H, a straight or branched C (1-6) alkyl group;  
 B is CH 2 , CH 2 -CH 2  or CH═CH;  
 n is zero or 1;  
 Z is H, or a straight or branched C (1-8) alkyl group;  
 m is 0 or an integer from 1 to 5; and  
 Y 1 , Y 2 , Y 3  and Y 4 , which may be the same or different, are H, a straight or branched C ( 1-8) alkyl or C (1-8) alkoxy group, a cyano, trifluoromethyl, nitro, hydroxy, hydroxymethyl, C (1-4) alkoxymethyl, amino, C (1-4) alkylamino, C (1-4) dialkylamino group, a halogen atom (F, Cl, Br, I), or any two adjacent Y 1 , Y 2 , Y 3  and Y 4  may form an optionally substituted C (1-6) alkylidene or C (1-4) alkylidenedioxy ring, with the proviso that at least two of the Y 1 , Y 2 , Y 3  and Y 4  groups are not H;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound as claimed in  claim 1  in which X 1  is H, hydroxy, C (1-4) alkyl or C (1-4) alkoxy.  
     
     
         3 . A compound as claimed in  claim 1  or  2  in which X 2  is C (1-4) alkyl or C (1-4) alkoxy.  
     
     
         4 . A compound as claimed in any one of  claims 1  to  3  in which X 1  and X 2  is each C (1-4) alkyl or C (1-4) alkoxy; or or one of X 1  and X 2  is C (1-4) alkyl and the other is C (1-4) alkoxy or C (1-3) alkyl; or X 1  is hydroxy and X 2  is C (1-4) alkyl or C (1-4) alkoxy.  
     
     
         5 . A compound as claimed in any one of  claims 1  to  4  in which X 1  and X 2  are methoxy and methoxy, methoxy and methyl, ethoxy and methyl, methyl or t-butyl and methyl, ethoxy and ethoxy, hydroxy and methyl, and hydroxy and methoxy, respectively.  
     
     
         6 . A compound as claimed in any one of  claims 1  to  5  in which X 3  is hydrogen or methyl.  
     
     
         7 . A compound as claimed in any one of  claims 1  to  6  in which (B) n  is a direct bond.  
     
     
         8 . A compound as claimed in any one of  claims 1  to  7  in which Z is hydrogen.  
     
     
         9 . A compound as claimed in any one of  claims 1  to  8  in which Y 1  and Y 2  is each methyl and Y 3  and Y 4  is each hydrogen..  
     
     
         10 . A compound as claimed in  claim 9  in which Y 1  and Y 2  are 2,6-substituents of the pyridyl ring.  
     
     
         11 . A compound as claimed in any one of  claims 1  to  10  in which the pyridyl ring is attached by the ring carbon β- to the nitrogen (⅗-pyridyl).  
     
     
         12 . A compound as claimed in any one of  claims 1  to  10  in which m is zero.  
     
     
         13 . A compound of formula (I) as defined in  claim 1  selected from: 
 diethyl α-(4-hydroxy-3,5-dimethoxyphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 diethyl α-(4-hydroxy-3,5-dimethylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 diethyl α-(3-tert-butyl-4-hydroxy-3-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 diethyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 diisopropyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[4-(2,6-di-tert-butylpicolyl)]-aminomethylphosphonate;  
 diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[4-(3-hydroxy-5-hydroxymethyl-2-methylpicolyl)]-aminomethylphosphonate;  
 diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[5-(3,4-O-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methylpicolyl)]-aminomethylphosphonate;  
 diethyl α-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-[5-(3-hydroxy-4-hydroxymethyl-2-methylpicolyl)]-aminomethylphosphonate;  
 diethyl α-(3,4-dimethoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;  
 diisopropylα-(3,4-dimethoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;  
 diethyl α-(3-hydroxy-4-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;  
 diisopropyl α-(3-hydroxy-4-methoxy-5-methylphenyl)- N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;  
 diethyl α-(4,5-dimethoxy-3-hydroxyphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;  
 diisopropyl α-(4,5-dimethoxy-3-hydroxyphenyl)-N-[3-(2,6-dimethylpyridyl)]-amino-methylphosphonate;  
 diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dichloropyridyl)]-amino-methylphosphonate;  
 diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dichloropyridyl)]-amino-methylphosphonate; and  
 diethyl α-(3,5-dimethoxy-4-hydroxyphenyl)-N-[3-(2,6-dimethoxypyridyl)]-amino-methylphosphonate; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         14 . A compound of formula (I) as defined in  claim 1  selected from: 
 diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 (+)diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 (-)diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate; or  
 a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt.  
 
     
     
         15 . A compound of formula (I) as defined in  claim 1  selected from: 
 diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate;  
 (+)diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate; and  
 (−)diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2,6-dimethylpyridyl)]-aminomethylphosphonate; or  
 a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt.  
 
     
     
         16 . A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1  and a pharmaceutically acceptable excipient thereof.  
     
     
         17 . A compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in therapy.  
     
     
         18 . The use of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in decreasing plasma and tissue lipoprotein(a) levels.  
     
     
         19 . A use of a compound of formula (I) as claimed in  claim 18 , for the manufacture of a medicament for the treatment of thrombosis by decreasing plasma lipoprotein(a) levels.  
     
     
         20 . A use of a compound of formula (I) as claimed in  claim 18 , for the manufacture of a medicament for the treatment of restenosis following angioplasty by decreasing plasma lipoprotein(a) levels.  
     
     
         21 . A use of a compound of formula (I) as claimed in  claim 18 , for the manufacture of a medicament for the treatment of atherosclerosis by decreasing plasma lipoprotein(a) levels.  
     
     
         22 . A method of treating a disease associated with elevated plasma and tissue lipoprotein(a) levels which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         23 . A process for preparing a compound of formula (I) as defined in  claim 1  which process comprises: 
 (a) for compounds of formula (I) in which Z is hydrogen, treating an imine of formula (II):  
                     
 in which X 1 , X 2 , X 3 , B, n, m, Y 1 , Y 2 , Y 3  and Y 4  are as defined in  claim 1;  with a dialkyl phosphite of formula (III):  
 H—PO(OR 1 )(OR 2 )  (III) in which R 1  and R 2  are as defined in  claim 1;  or a trialkyl silyl or metal derivative thereof;    
 (b) reacting together equimolar amounts of an aldehyde of formula (IV):  
                     in which X 1 , X 2 , X 3 , B and n are as defined in  claim 1;     an amine of formula (V):                        in which Z, m, Y 1 , Y 2 , Y 3  and Y 4  are as previously defined; and a dialkyl phosphite of formula (III; or      
 (c) for compounds of formula (I) in which m is not zero, treating a compound of formula (VI)  
                     in which X 1 , X 2 , X 3 , B and n are as defined in  claim 1 , with an aldehyde of formula (VII):                        in which m is an integer from 1 to 5 and Y 1 , Y 2 , Y 3  and Y 4  are as defined in  claim 1;  under reductive amination conditions.