Bisphosphonate derivatives, their preparations and uses

Abstract

The present invention relates to derivatives of 1-hydroxymethylene-1,1-bisphosphonic acid, the pharmaceutical compositions comprising them, and their application in therapeutics, particularly for the treatment of cancerous tumors. It is also directed to a methods of preparation of such derivatives.

1 - Bisphosphonate derivatives, wherein they are represented by the following formula (I) or (I′):  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3 , which are the same or different, each represent a hydrogen atom, an alkyl, aryl, acyloxyalkyl or heterocycle group, and R′ and R″, which are the same or different, each represent a hydrogen atom, an alkali metal or alkaline earth atom, 
 A represents a group with the formula —(CH 2 )n-R 4 ,  
 R 4  represents a hydrogen atom, an alkyl group, an aryl group, a heterocycle or a group with the formula —NR 5 R 6 ,  
 R 5  and R 6 , which are the same or different, represent a hydrogen atom or an alkyl group,  
 n is a whole number from 0 to 24 inclusive, with the exception of compounds represented by formula (i) in which R 1 , R 2  and R 3  simultaneously represent a hydrogen atom, and compounds represented by formula (I′) in which R′ and R″ simultaneously represent a hydrogen atom, their optical and geometrical isomers, their racemates, their salts, their hydrates and their mixtures:  
 
       
     
     
         2 - Derivatives according to  claim 1 , wherein at least two of the substituents R 1 , R 2  and R 3  are different from a hydrogen atom.  
     
     
         3 - Derivatives according to  claim 1 , wherein the substituents R 1 , R 2  and R 3 , which are different from a hydrogen atom, are identical.  
     
     
         4 - Derivatives according to  claim 1 , wherein R 1 , R 2  and R 3  represent a hydrogen atom or an alkyl group of C1-12, more particularly C1-6.  
     
     
         5 - Derivatives according to  claim 1 , wherein R1, R2 and R3 represent a methyl or ethyl group.  
     
     
         6 - Derivatives according to  claim 1 , wherein R′ and R″ represent an hydrogen atom or sodium, calcium or potassium atom.  
     
     
         7 - Derivatives according to  claim 1 , wherein A represents a group with the formula —(CH 2 )n-R 4 , in which R 4  is a C1-C6 alkyl group, a heterocycle group, a phenyl group, or a group with the formula —NR 5 R 6 , wherein R 5  and R 6 , which are the same or different, represent a hydrogen atom or a C1-6 alkyl group, in which n is advantageously a whole number from 1 to 6 inclusive, preferably from 1 to 3.  
     
     
         8 - Derivatives according to  claim 1 , wherein A is a group chosen from:  
       
         
           
           
               
               
           
         
       
     
     
         9 - Derivatives according to  claim 1 , wherein derivatives are of formula (I′) wherein A is the —CH2-C6H5 group.  
     
     
         10 - Method of preparation of compounds represented by formula (I), wherein it comprises the following steps: 
 contacting at least one acid halide represented by formula (II): ACOX, or one α-ketophosphonate represented by formula (III):                           with at least one silyl phosphite represented by formula (IV):   P[(OSialk 3 ) x ][OR 3 ] 3-x   (IV)    wherein R 1 , R 2  and R 3 , which are the same or different, represent an alkyl, aryl, acyloxyalkyl, or heterocycle group, 
 A being defined in one of the previous claims,  
 X represents a halogen atom, preferably chlorine,  
 alk is a C1-6 alkyl group,  
 x is equal to 2 or 3,  
 hydrolysis of the compounds obtained in the previous step.  
   
     
     
         11 - Method according to  claim 10 , wherein it comprises the following steps: 
 contacting at least one acid halide represented by formula (II): ACOX, with at least one phosphite represented by formula (V): P(OR1)(OR2)(OR), wherein R 1 , R 2  and R, which are the same or different, represent an alkyl, aryl, acyloxyalkyl, or heterocycle group, to form an α-ketophosphonate represented by formula (III),    contacting the a-ketophosphonate obtained in the previous step with at least one silyl phosphite represented by formula (IV) such as defined in the preceding claim,    hydrolysis of the compounds obtained in the previous step.    
     
     
         12 . Method according to  claim 11 , wherein the silyl phosphite is a compound represented by formula (IV) in which x is equal to 2.  
     
     
         13 . Method according to  claim 11 , wherein the silyl phosphite is a compound represented by formula (IV) in which x is equal to 3.  
     
     
         14 . Method according to  claim 10 , wherein at least one acid halide represented by formula (II): ACOX, is placed in contact with at least one silyl phosphite represented by formula (IV) in which x is equal to 2, then the product so obtained is placed in contact with at least one silyl phosphite represented by formula (IV) in which x is equal to 3.  
     
     
         15 . Method of preparation of compounds represented by formula (I′), wherein it comprises the following steps: an acid chloride of formula (II) ACOX is caused to react with a mixture of dimethylphosphite and trimethylphosphite, and then in a second step, the ester functions obtained in the previous step are hydrolyzed by acid hydrolysis, followed by a salification.  
     
     
         16 . Method according to  claim 15 , wherein the reaction of the first step is carried out in a solvent such as chloroform at a temperature below 30° C.  
     
     
         17 . Method according to  claim 15 , wherein the hydrolysis is carried out by dissolving the product obtained in the first step in concentrated hot hydrochloric acid.  
     
     
         18 . Pharmaceutical composition comprising, in a pharmaceutically acceptable support, at least one compound represented by formula (I) or (I′) such as defined in  claim 1 .  
     
     
         19 . Pharmaceutical composition for the treatment or prophylaxis of disorders characterized by abnormal calcium metabolism comprising, in a pharmaceutically acceptable support, at least one compound represented by formula (I) or (I′) as represented in  claim 1 , wherein R 1 , R 2  and R 3 , which are the same or different, each represent a hydrogen atom, an alkyl, aryl, acyloxyalkyl or heterocycle group, and R′ and R″, which are the same or different, each represent a hydrogen atom, an alkali metal or alkaline earth atom, 
 A represents a group with the formula —(CH 2 )n-R 4 ,  
 R 4  represents a hydrogen atom, an alkyl group, an aryl group, a heterocycle or a group with the formula —NR 5 R 6 ,  
 R 5  and R 6 , which are the same or different, represent a hydrogen atom or an alkyl group,  
 n is a whole number from 0 to 24 inclusive, their optical and geometrical isomers, their racemates, their salts, their hydrates and their mixtures.  
 
     
     
         20 . Pharmaceutical composition, for the treatment of malignant tumors, more specifically the treatment of malignant solid tumors, comprising, in a pharmaceutically acceptable support, at least one compound represented by formula (I) or (I′) as defined in  claim 19 .  
     
     
         21 . Pharmaceutical composition to partially or totally inhibit tumor angiogenesis, comprising, in a pharmaceutically acceptable support, at least one compound represented by formula (I) or (I′) as defined in  claim 19 .  
     
     
         22 . Pharmaceutical composition to treat viral or inflammatory hepatic diseases, comprising, in a pharmaceutically acceptable support, at least one compound represented by formula (I) or (I′) as defined in  claim 19 .  
     
     
         23 . Method of treatment or prophylaxis in the human or animal body by administering to a subject, in particular a mammal and more specifically a human being, in need of such treatment at least one compound of formula (I) or (I′) such as defined in  claim 1 .  
     
     
         24 . Method of treating a disorder characterized by abnormal calcium metabolism, such as cancers or osteoporosis, comprising administering to a subject, in particular a patient, in need of such treatment a therapeutically effective amount of at least one compound represented by formula (I) or (I′) as defined in  claim 1 , wherein R 1 , R 2  and R 3 , which are the same or different, each represent a hydrogen atom, an alkyl, aryl, acyloxyalkyl or heterocycle group, and R′ and R″, which are the same or different, each represent a hydrogen atom, an alkali metal or alkaline earth atom, 
 A represents a group with the formula —(CH 2 )n-R 4 ,  
 R 4  represents a hydrogen atom, an alkyl group, an aryl group, a heterocycle or a group with the formula —NR 5 R 6 ,  
 R 5  and R 6 , which are the same or different, represent a hydrogen atom or an alkyl group,  
 n is a whole number from 0 to 24 inclusive,  
 their optical and geometrical isomers, their racemates, their salts, their hydrates and their mixtures.  
 
     
     
         25 . Method for treating viral or inflammatory hepatic disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound represented by formula (I) or (I′) as defined above, wherein R 1 , R 2  and R 3 , which are the same or different, each represent a hydrogen atom, an alkyl, aryl, acyloxyalkyl or heterocycle group, and R′ and R″, which are the same or different, each represent a hydrogen atom, an alkali metal or alkaline earth atom, 
 A represents a group with the formula —(CH 2 )n-R 4 ,  
 R 4  represents a hydrogen atom, an alkyl group, an aryl group, a heterocycle or a group with the formula —NR 5 R 6 ,  
 R 5  and R 6 , which are the same or different, represent a hydrogen atom or an alkyl group,  
 n is a whole number from 0 to 24 inclusive,  
 their optical and geometrical isomers, their racemates, their salts, their hydrates and their mixtures.