Phosphonates useful as modulators of t $g(g)9$g(d)2 lymphocyte activity

Abstract

The invention concerns novel phosphonate derivatives, preparation method, use thereof as ligands modulating T γ9δ2 lymphocyte activity and pharmaceutical compositions comprising them.

1 . Use of a compound complying with formula (I) below,  
     
       
         
         
             
             
         
       
       said compound being characterised in that A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated at C 1 -C 50 , said alkyl group may comprise one or more aromatic groups, it may comprise one or more ether bridges, one or more functions selected from: a carboxylic acid, an ester, an amide, a nitrile, a hydroxyl, an aldehyde, a ketone, a halogen, an amine, a thiol, a thio-ketone, an episulphide, a selenol, a seleno-ketone, a sulphide, a sulphone, a sulphoxide, it may comprise one or more heterocycles,  
       n is an integer ranging from 1 to 4,  
       X represents a group selected from the hydrogen atom and a pharmaceutical acceptable organic or mineral cationic group,  
       B represents a group selected from:  
       
         
           
           
               
               
           
         
       
       X and  
       wherein X and A have the same signification as above, for preparation of a medicinal product modulating γ9δ2 T lymphocyte proliferation.  
     
   
   
       2 . Use of a compound according to formula (I) as defined in  claim 1  in an in vitro biological test as a γ9δ2 T lymphocyte proliferation stimulant.  
   
   
       3 . Use of a compound according to formula (I) as defined in  claim 1  in an in vitro biological test as a γ9δ2 T lymphocyte proliferation inhibitor.  
   
   
       4 . Use according to  claim 1  of a compound according to formula (I) for the preparation of a formulation intended for the prevention or treatment of a condition inducing γ9δ2 T lymphocyte activation.  
   
   
       5 . Use according to  claim 1  of a compound complying with formula (I) for the preparation of a formulation intended for the prevention or treatment of an infectious disease, such as those caused by viruses, protozoa agents.  
   
   
       6 . Use according to  claim 1  of a compound complying with formula (I) for the preparation of a formulation intended for the prevention or treatment of a chromic inflammatory disease.  
   
   
       7 . Use according to any of  claims 1  to  6 , characterised in that A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group in C 1 -C 50  comprising at least one double bond  
     
       
         
         
             
             
         
       
     
   
   
       8 . Use according to any of  claims 1  to  7 , characterised in that A comprises 3 to 25 carbon atoms.  
   
   
       9 . Use according to any of  claims 1  to  8 , characterised in that A represents a linear, ramified or cyclic alkyl group in C 1 -C 50  comprising at least one α-halohydrine group according to formula (II) below, wherein Y represents an atom selected from fluorine, chlorine, iodine and bromine:  
     
       
         
         
             
             
         
       
     
   
   
       10 . Use according to any of  claims 1  to  9  above, characterised in that A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated in C 1 -C 50  comprising at least one epoxide group.  
   
   
       11 . Use according to any of  claims 1  to  10  above, characterised in that A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated in C 1 -C 50  comprising at least one tertiary alcohol group.  
   
   
       12 . Use according to any of  claims 1  to  11  above, characterised in that A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated in C 1 -C 50  comprising at least one α-diol group.  
   
   
       13 . Use according to any of  claims 1  to  12  above, characterised in that A represents a linear, ramified or cyclic alkyl group in C 1 -C 50  comprising at least one aldehyde group or α-hydroxyaldehyde group.  
   
   
       14 . Use according to any of  claims 1  to  13  above, characterised in that A comprises at least one ether bridge.  
   
   
       15 . Use according to any of  claims 1  to  14  above, characterised in that X +  is selected from H + , Na + , NH 4   + , K + , Li + , (CH 3 CH 2 ) 3 NH +  or an enzyme-labile ester function.  
   
   
       16 . Compound complying with formula (I) according to  claim 1 , characterised in that n=1 and B represents:  
     
       
         
         
             
             
         
       
     
   
   
       17 . Compound complying with formula (I) according to  claim 1 , characterised in that it belongs to the following list: 
 (E)1-pyrophosphonobuta-1,3-diene    (E)1-pyrophosphonopenta-1,3-diene    (E)1-pyrophosphono-4-methylpenta-1,3-diene    (E,E)1-pyrophosphono-4,8-dimethylnona-1,3,7-triene    (E,E,E)1-pyrophosphono-4,8,12-trimethyltrideca-1,3,7,11-tetraene    (E,E)1-triphosphono-4,8-dimethylnona-1,3,7-triene    4-triphosphono-2-methylbutene    α,β-di-[3-methylpent-3-enyl]-pyrophosphonate    α,γ-di-[3-methylbut-2-enyl]-triphosphonate    α,β-di-[3-methylbut-2-enyl]-pyrophosphonate    allyl pyrophosphonate    allyl triphosphonate    α,γ-di-allyl-triphosphonate    α,β-di-allyl-pyrophosphonate    4-phosphono-2-methylbutene    (E,E)4-[(5′-pyrophosphono-6′-methyl-penta-2′,4′-dienyloxymethyl)-phenyl]-phenyl-methanone    (E,E)4-[(5′-triphosphono-6′-methyl-penta-2′,41-dienyloxymethyl)-phenyl]-phenyl-methanone    [4-(9′-pyrophosphono-2′,6′,8′-dimethyl-nona-2′,6′,8′-trienyloxymethyl)-phenyl]-phenyl-methanone    ([4-(9′-triphosphono-2′,6′-dimethyl-nona-2′,6′,81-trienyloxymethyl)-phenyl]-phenyl-methanone    5-pyrophosphono-2-methylpentene    5-triphosphono-2-methylpentene    α,γ-di-[4-methylbut-4-enyl]-triphosphonate    5-pyrophosphono-2-methylpent-2-ene    5-triphosphono-2-methylpent-2-ene    α,γ-di-[4-methylbut-4-enyl]-triphosphonate    9-pyrophosphono-2,6-dimetylnona-2,6-diene    9-triphosphono-2,6-dimetylnona-2,6-diene    α,γ-di-[4,8-dimethylnona-2,6-dienyl]-triphosphonate    5-phosphono-2-methylpentene    5-phosphono-2-methylpent-2-ene    4-pyrophosphono-2-methylbutene    4-methyl-2-oxa-pent-4-enyloxymethylpyro-phosphonate    4-methyl-2-oxa-pent-4-enyloxymethyltri-phosphonate    α,β-di-[4-methyl-2-oxa-pent-4-enyloxymethyl]-pyrophosphonate    α,γ-di-[4-methyl-2-oxa-pent-4-enyloxymethyl]-triphosphonate    4-methyl-2-oxa-pent-4-enyloxymethylphosphonate.    
   
   
       18 . Compound complying with formula (I) according to  claim 1 , characterised in that A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated in C 1 -C 50  comprising at least one tertiary alcohol group.  
   
   
       19 . Compound complying with formula (I) according to  claim 1 , characterised in that A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated in C 1 -C 50  comprising at least one α-diol group.  
   
   
       20 . Compound complying with formula (I) according to  claim 1 , characterised in that A represents a linear, ramified or cyclic alkyl group in C 1 -C 50  comprising at least one aldehyde group or α-hydroxyaldehyde group.  
   
   
       21 . Pharmaceutical formulation characterised in that it comprises, in addition to a pharmaceutically acceptable excipient, at least one compound according to any of  claims 16  to  20 .  
   
   
       22 . Formulation according to  claim 21 , for use thereof as a medicinal product.  
   
   
       23 . Formulation according to  claim 20  or  claim 21 , characterised in that it is intended to prevent or treat an infectious disease.  
   
   
       24 . Formulation according to  claim 23 , characterised in that it is intended to prevent or treat a disease induced by an infectious agent selected from: human immunodeficiency virus, simian immunodeficiency virus, herpes simplex virus, human herpes virus-6 or vaccinia.  
   
   
       25 . Formulation according to  claim 21  or  claim 22 , characterised in that it is intended to prevent or treat a chronic inflammatory disease.  
   
   
       26 . Formulation according to  claim 25 , characterised in that it is intended to prevent or treat a condition selected from: systemic lupus erythematosus, multiple sclerosis, rheumatoid polyarthritis, Behcet's disease, allogenic transplant rejection, chronic autoimmune hepatitis, polymyositosis, inflammatory colon diseases.  
   
   
       27 . In vitro diagnostic kit for a condition inducing γ9δ2 T lymphocyte activation, characterised in that it comprises at least one compound according to  claims 16  to  20 .  
   
   
       28 . In vitro diagnostic kit for a condition inducing γ9δ2 T lymphocyte inhibition, characterised in that it comprises at least one compound according to  claims 16  to  20 .  
   
   
       29 . In vitro diagnostic kit for an infectious disease, such as those caused by viruses, bacteria, protozoa agents, characterised in that it comprises at least one compound according to  claims 16  to  20 .  
   
   
       30 . In vitro diagnostic kit for a chronic inflammatory disease, characterised in that it comprises at least one compound according to  claims 16  to  20 .