Novel urea derivatives, method for preparing same, use thereof as medicines, pharmaceutical compositions and novel use

Abstract

The invention relates to new products of formula (I): in which: Y represents oxygen or sulphur, Z represents C═CH2, CH—CH3 or CH2, R1 represents hydrogen, morpholinyl or the radical. In which the two nitrogen atoms are linear or form a cyclic radical, X represents carbonyl, alkylene or alkenylene, linear or branched, containing at most 6 carbon atoms optionally interrupted by oxygen or sulphur, R4, R5 and R6 represent hydrogen, a protective group of the nitrogen, alkyl, cycloalkyl, aryl and arylalkyl optionally substituted, R2 represents alkyl optionally substituted by aryl, heteroaryl or —NR4R5, R3 represents alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally substituted, these products being in all isomer forms and the salts, as medicaments.

1 ) Products of formula (I):  
       
         
           
           
               
               
           
         
       
       in which: 
 Y represents the oxygen or sulphur atom,  
 Z represents the divalent C═CH2, CH—CH3 or CH2 radical,  
 R1 represents a hydrogen atom, an optionally substituted morpholinyl radical or a diamine radical of formula:  
                     which represents: either a saturated:                          radical or an unsaturated:                          radical or the;                          radical in which the continuous arc indicates that the two nitrogen atoms form a monocyclic heterocyclic saturated or unsaturated optionally substituted radical constituted by at most 8 members, the nitrogen atoms being able to be or not able be consecutive on the ring thus formed,    X represents a carbonyl, linear or branched alkylene or alkenylene radical containing at most 6 carbon atoms optionally interrupted by one or more oxygen or sulphur atoms,    R4, R5 and R6, identical or different, are chosen from the hydrogen atom, the protective groups of the nitrogen atom, the linear or branched alkyl radicals containing at most 4 carbon atoms, cycloalkyl containing at most 6 members, aryl and arylalkyl radicals, all these alkyl, cycloalkyl, aryl and arylalkyl radicals being themselves optionally substituted,    
 R2 represents a linear or branched alkyl radical containing at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from the aryl or heteroaryl radicals themselves optionally substituted and the —NR4R5 radical in which R4 and R5, identical or different, have the meaning indicated above,  
 R3 represents a linear or branched alkyl radical containing at most 6 carbon atoms, cycloalkyl containing at most 12 members, aryl, heteroaryl, arylalkyl or heteroarylalkyl in which the alkyl radical is linear or branched containing at most 4 carbon atoms, all these radicals being optionally substituted,  
 it being understood that all the heterocyclic, morpholinyl, cycloalkyl, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl radicals indicated above as being optionally substituted, are optionally substituted by one or more identical or different radicals chosen from halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, cyano, free, salified or esterified carboxy radicals, the linear or branched alkyl, alkenyl, alkylthio or alkoxy radicals containing at most 4 carbon atoms, the —NR4R5, —NHR4, —COR4, —COOR4 and—CONHR4 radicals in which R4 has the meaning indicated above and the radicals with an acid function and acid isosteres,  
 all the aryl and arylalkyl radicals being moreover optionally substituted by a dioxol radical formed on two consecutive carbon atoms of the aryl radical considered,  
 said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I).  
 
     
     
         2 ) Products of formula (I) as defined in  claim 1  corresponding to formula (Ia):  
       
         
           
           
               
               
           
         
       
       in which: 
 Y represents the oxygen or sulphur atom,  
 Z represents the divalent C═CH2, CH—CH3 or CH2 radical,  
 R1a represents a hydrogen atom, an optionally substituted morpholinyl radical or a diaminated radical of formula:  
                     which represents either a saturated:                          radical or an unsaturated:                          radical or the:                          radical in which the continuous arc indicates that the two nitrogen atoms form a heterocyclic radical chosen from the imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, furazannyl, imidazolidinyl, delta-2-imidazolinyl, pyrazolidinyl, delta-3-pyrazolinyl, piperazinyl or also homopiperazinyl radicals, these heterocyclic radicals being optionally substituted by a free or esterified carboxy, phenyl, alkyl or phenylalkyl radical in which the alkyl radical is linear or branched containing at most 4 carbon atoms,    Xa represents a carbonyl, linear or branched alkylene or alkenylene radical containing at most 6 carbon atoms optionally interrupted by an oxygen or sulphur atom,    R4a, R5a and R6a, identical or different, are chosen from the hydrogen atom, the protective groups of the nitrogen atom, the linear or branched alkyl containing at most 4 carbon atoms, cycloalkyl containing at most 6 members, phenyl and phenylalkyl (benzyl and phenethyl) radicals, these alkyl, cycloalkyl, phenyl and phenylalkyl (benzyl and phenethyl)radicals being themselves optionally substituted,    
 R2a represents a linear or branched alkyl radical containing at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from the optionally substituted phenyl radical and the —NR4aR5a radical in which 
 R4a and R5a, identical or different, have the meaning indicated above,  
 
 R3a represents a linear or branched alkyl containing at most 6 carbon atoms, cycloalkyl containing 5 or 6 members, adamentyl, pyridinyl, quinolinyl, phenyl or phenylalkyl radical in which the alkyl radical is linear or branched containing at most 4 carbon atoms, all these radicals being optionally substituted,  
 it being understood that all the cycloalkyl, alkyl, phenyl and phenylalkyl radicals indicated above as being optionally substituted, are optionally substituted by one or more identical or different radicals chosen from the halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, cyano, free, salified or esterified carboxy radicals, the linear or branched alkyl, alkenyl, alkylthio or alkoxy radicals containing at most 4 carbon atoms and the —NR4aR5a radical in which R4a and R5a, identical or different, have the meaning indicated above,  
 all the phenyl and phenylalkyl radicals being moreover optionally substituted by a dioxol radical formed on two consecutive carbon atoms of the phenyl radical considered, said products of formula (Ia) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (Ia).  
 
     
     
         3 ) Products of formula (I) as defined in  claim 1  corresponding to the formula (Ib):  
       
         
           
           
               
               
           
         
       
       in which: 
 Y represents the oxygen or sulphur atom,  
 Z represents the divalent C═CH2 CH, —CH3 or CH2 radical,  
 R1b is as such or R1b represents a hydrogen atom or a piperazinyl or homopiperazinyl radical optionally substituted by a linear or branched alkyl radical containing at most 4 carbon atoms or a free or esterified carboxy radical, or R1b represents the  
                     radical in which Xb represents a carbonyl or alkylene radical, linear or branched, containing at most 6 carbon atoms,    R4b, R5b and R6b, identical or different, are chosen from the hydrogen atom; the carboxy radical esterified by a linear or branched alkyl radical containing at most 4 carbon atoms; the linear or branched alkyl radicals containing at most 4 carbon atoms; the cycloalkyl containing at most 6 members; phenyl; benzyl and phenethyl radicals; all these alkyl, cycloalkyl, phenyl, benzyl and phenethyl radicals being themselves optionally substituted by one or more identical or different radicals chosen from the halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, cyano, free, salified or esterified carboxy radicals, the linear or branched alkyl, alkenyl, alkylthio or alkoxy radicals containing at most 4 carbon atoms and the —NH2 radical in which the hydrogen atoms are optionally substituted by one or two linear or branched alkyl radicals containing at most 4 carbon atoms,    
 R2b represents a linear or branched alkyl radical containing at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from the optionally substituted phenyl radical and the —NH2 radical in which one or two hydrogen atoms are optionally substituted by one or two identical or different substituents chosen from the linear or branched alkyl radical containing at most 4 carbon atoms and the phenyl radical itself optionally substituted, all these phenyl radicals being optionally substituted by one or more radicals chosen from the halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, free, salified or esterified carboxy radicals and the linear or branched alkyl and alkoxy radicals containing at most 4 carbon atoms,  
 R3b represents a linear or branched alkyl containing at most 4 carbon atoms, cyclohexyl, cyclopentyl, adamentyl, phenyl or phenylalkyl radical in which the alkyl radical is linear or branched containing at most 4 carbon atoms and the phenyl radical is optionally substituted by one or more identical or different radicals chosen from the halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, cyano, free, salified or esterified carboxy radicals, the linear or branched alkyl, alkenyl, alkylthio and alkoxy radicals containing at most 4 carbon atoms and the —NH2 radical in which the hydrogen atoms are optionally substituted by one or two linear or branched alkyl radicals containing at most 4 carbon atoms,  
 all the phenyl, benzyl and phenethyl radicals being moreover optionally substituted by a dioxol radical formed on two consecutive carbon atoms of the phenyl radical considered, said products of formula (Ib) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (Ib).  
 
     
     
         4 ) Products of formula (I) as defined in  claim 1  corresponding to the formula (Ic):  
       
         
           
           
               
               
           
         
       
       in which: 
 Y represents the oxygen atom,  
 Z represents the divalent C═CH2 or CH—CH3 radical,  
 R1c is chosen from the hydrogen atom and the piperazinyl and homopiperazinyl radicals linked by a nitrogen atom and optionally substituted on their second nitrogen atom by a linear or branched alkyl radical containing at most 4 carbon atoms or a free or esterified carboxy radical (—COOtBu)), or R1c represents the  
                     radical in which Xc represents a carbonyl or alkylene radical, linear or branched, containing at most 4 carbon atoms,    R4c, R5c and R6c, identical or different, are chosen from the hydrogen atom; the carboxy radical esterified by a linear or branched alkyl radical containing at most 4 carbon atoms; the cyclohexyl radical optionally substituted by an NH2 radical in which the hydrogen atoms are optionally substituted by one or two linear or branched alkyl radicals containing at most 4 carbon atoms; the linear or branched alkyl radicals containing at most 4 carbon atoms; the phenyl radicals; benzyl and phenethyl radicals themselves optionally substituted by one or more identical or different radicals chosen from the halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, cyano, free, salified or esterified carboxy radicals, the linear or branched alkyl, alkenyl, alkylthio and alkoxy radicals containing at most 4 carbon atoms and the dioxol radical formed on two consecutive carbon atoms of the phenyl radical considered,    
 R2c represents a linear or branched alkyl radical containing at most 6 carbon atoms optionally substituted by one or two radicals chosen from the phenyl and NH2 radicals, the phenyl radicals themselves being optionally substituted by a phenyl, linear or branched alkyl or alkoxy radical containing at most 4 carbon atoms and the —NH2 radical being optionally substituted on the one or two hydrogen atoms by one or two radicals chosen from linear or branched alkyl containing at most 4 carbon atoms and phenyl itself optionally substituted by a linear or branched alkyl radical containing at most 4 carbon atoms,  
 R3c represents a linear or branched alkyl radical containing at most 4 carbon atoms, cyclohexyl, adamentyl, phenyl or phenylalkyl in which the alkyl radical contains at most 2 carbon atoms and the phenyl radical is optionally substituted by one or more identical or different radicals chosen from the halogen atoms, the hydroxyl, phenyl, phenoxy, trifluoromethyl, cyano, free, salified or esterified carboxy radical, the linear or branched alkyl, alkenyl, alkylthio or alkoxy radicals containing at most 4 carbon atoms and the dioxol radical formed on two consecutive carbon atoms of the phenyl radical considered,  
 said products of formula (Ic) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (Ic).  
 
     
     
         5 ) Process for the preparation of the products of formula (I), as defined in  claim 1 , characterized in that a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       in which B represents either R4′ which has the meaning indicated above for R4 in which the optional reactive functions are optionally protected by protective groups or RL which represents a remainder of a resin linked via a linker, for example via a carbamate bond, X, R5′ and R6′ have the meanings indicated in  claim 1  respectively for X, R5 and R6, in which the optional reactive functions are optionally protected by protective groups, is subjected to a reaction with a compound of formula (III): 
       Hal-CH2-Z1-CH2-Hal  (III) 
       in which Hal represents a halogen atom and Z1 represents the divalent C═CH2 or CH2 radical, in order to obtain the product of formula (IV):  
       
         
           
           
               
               
           
         
       
       in which B, X, Z1, R5′ and R6′ have the meanings indicated above, which product of formula (IV) is subjected to a reaction with a compound of formula (V): 
       R2′-NH2  (V) 
       in which R2′ has the meaning indicated in  claim 1  for R2, in which the optional reactive functions are optionally protected by protective groups, in order to obtain a product of formula (VI):  
       
         
           
           
               
               
           
         
       
       in which B, X, Z1, R2′, R5′ and R6′ have the meanings indicated above, which is subjected to a reaction with a compound of formula (VII): 
       Y═C═N—R3′  (VII) 
       in which R3′ has the meaning indicated in  claim 1  for R3, in which the optional reactive functions are optionally protected by protective groups and Y represents the oxygen or sulphur atom, in order to obtain a product of formula (VIII):  
       
         
           
           
               
               
           
         
       
       in which B, X, Y, Z1, R2′, R3′, R5′ and R6′ have the meanings indicated above, which product of formula (VIII) when B represents R4′ constitutes a product of formula (Ix1):  
       
         
           
           
               
               
           
         
       
       in which R1′ has the meaning indicated in  claim 1  for R1, in which the optional reactive functions are optionally protected by protective groups and R2′, R3′, Y and Z1 have the meanings indicated above, which product of formula (Ix1) when Z1 represents C═CH2, can be converted to the product of formula (Ix2):  
       
         
           
           
               
               
           
         
       
       in which R1′, R2′, R3′ and Y, have the meanings indicated above, which product of formula (VIII) when B represents a remainder of resin RL as defined above, can be subjected to a cleavage reaction in order to obtain a product of formula (Iy1):  
       
         
           
           
               
               
           
         
       
       in which X, Y, Z1, R2′, R3′, R5′ and R6′ have the meanings indicated above, which product of formula (Iy1) when Z1 represents C═CH2, can be converted to the product of formula (Iy2):  
       
         
           
           
               
               
           
         
       
       in which X, Y, R2′, R3′, R5′ and R6′ have the meanings indicated above, which product of formula (V) as defined above can also be reacted with the aldehyde of formula (IX): 
       CHO—CH(CH3)(CH3)  (IX) 
       in order to obtain a product of formula (X): 
       R2′-NH—CH2-CH(CH3)(CH3)  (X) 
       in which R2′ has the meaning indicated above, which product of formula (X) is reacted with the product of formula (VII) as defined above in order to obtain the product of formula (Iz):  
       
         
           
           
               
               
           
         
       
       in which R2′ and R3′ have the meanings indicated above, which products of formula e (VIII) in the form of (Ix1) and (Iy1) and products of formulae (Ix2), (Iy2) and (Iz) can be the products of formula (I) and which, in order to obtain products or other products of formula (I), can be subjected, if desired and if necessary, to the one or more of the following conversion reactions, in any order: 
 a) an esterification reaction of the acid function,  
 b) a saponification reaction of the ester function to an acid function,  
 c) an oxidation reaction of the alkylthio group to a corresponding sulphoxide or sulphone,  
 d) a conversion reaction of the ketone function to an oxime function,  
 e) a reduction reaction of the free or esterified carboxy function to an alcohol function,  
 f) a conversion reaction of the alkoxy function to a hydroxyl function, or also of the hydroxyl function to an alkoxy function,  
 g) an oxidation reaction of the alcohol function to an aldehyde, acid or ketone function,  
 h) a conversion reaction of the nitrile radical to tetrazolyl or also a conversion reaction of the amine radical to a carbamate or urea or also a conversion reaction of an amine to sulphonamide or carboxamide,  
 i) an elimination reaction of the protective groups which can be carried by the protected reactive functions,  
 j) a salification reaction by a mineral or organic acid or by a base in order to obtain the corresponding salt,  
 k) a resolution reaction of the racemic forms to resolved products,  
 said products of formula (I) thus obtained being in all possible racemic, enantiomeric and diastereoisomeric isomer forms.  
 
     
     
         6 ) Process for the preparation of the products of formula (IIR) corresponding to the formula (II) as defined in  claim 5  when B represents RL:  
       
         
           
           
               
               
           
         
       
       in which RL represents a resin remainder linked via a linker, X, R5′ and R6′ have the meanings indicated in  claim 1  for X, R5 and R6 respectively, in which the optional reactive functions are optionally protected by protective groups, characterized in that a resin r containing an NH2 group: 
       r-NH2 
       is subjected to a reaction with a linker l having a carboxy function and a benzyl alcohol: 
       COOH-l-OH 
       in order to obtain a product of formula (IX) having a free benzyl alcohol: 
       r-NH—CO-l-OH  (IX) 
       in which r and l have the meanings indicated above, which is reacted with 1-1 carbonylimidazole in order to obtain the product of formula (X):  
       
         
           
           
               
               
           
         
       
       in which r and l have the meanings indicated above, which is reacted with an amine of formula (XI):  
       
         
           
           
               
               
           
         
       
       in which R5′, X and R6′ have the meanings indicated above, in order to obtain the product of formula (IIR):  
       
         
           
           
               
               
           
         
       
       in which RL represents the  
       
         
           
           
               
               
           
         
       
       group with r and l as defined above.  
     
     
         7 ) As medicaments, the products of formula (I) as defined in  claims 1  to  4 , as well as the addition salts with pharmaceutically acceptable mineral and organic acids or with mineral and organic bases of said products of formula (I).  
     
     
         8 ) The pharmaceutical compositions containing at least one of the medicaments defined in  claim 7  as active ingredient.  
     
     
         9 ) Use of the products of formula (I) as defined in  claims 1  to  4  and/or their pharmaceutically acceptable salts for the preparation of medicaments intended for the treatment or the prevention of diseases or disorders linked to an abnormal physiological behaviour at the level of receptors of inorganic ions and in particular at the level of calcium receptors.  
     
     
         10 ) Use of the products of formula (I) as defined in  claims 1  to  4  and/or their pharmaceutically acceptable salts for the preparation of medicaments intended for the treatment or the prevention of bone metabolism diseases, cardiovascular diseases, cancers, neurodegenerative diseases, diseases of the immune system, infectious, inflammatory diseases, autoimmune diseases, hypercalcemia or hyperparathyroidism.  
     
     
         11 ) Use of the products of formula (I) as defined in  claims 1  to  4  and/or their pharmaceutically acceptable salts for the preparation of medicaments intended for the prevention or the treatment of bone metabolism diseases, cancers, neurodegenerative diseases, hypercalcemia or hyperparathyroidism.  
     
     
         12 ) Use of the products of formula (I) as defined in  claims 1  to  4  and/or their pharmaceutically acceptable salts for the preparation of medicaments intended for the prevention or the treatment of hypercalcemia or hyperparathyroidism.  
     
     
         13 ) Use of the products of formula (I) as defined in  claims 1  to  4  and/or their pharmaceutically acceptable salts for the preparation of medicaments intended for the prevention or the treatment of bone metabolism diseases.  
     
     
         14 ) Use of the products of formula (I) as defined in  claims 1  to  4  and/or their pharmaceutically acceptable salts for the preparation of medicaments intended for the prevention or the treatment of osteoporosis.