Class of Gamma Delta T Cells Activators and Use Thereof

Abstract

The present invention relates to a new class of compounds having γδ T cells activating properties referred to herein as angelyl or tiglyl phosphoesters, compositions comprising any of these compounds and methods for regulating an immune response in a subject comprising the step of administering these compounds.

1 . A method of treating a disease caused or associated with the presence of pathological cells which are sensitive of γδ T cell lysis, comprising administering a composition comprising a compound according to formula: 
     
       
         
         
             
             
         
       
       wherein Cat +  represents one or more cation, that can be the same or different, selected from proton(s), organic cation(s) or mineral cation(s); 
       m is an integer from 1 to 3; 
       B is O, NH, or any other group capable of being hydrolyzed; 
       A is O, NH, CHF, CF 2  or CH 2 , or any other isosteric group; 
       W is C—R 6  or N; 
       R 7  is a (C 1 -C 3 )alkyl group or any other isosteric group such as CF 3 ; 
       R 3 , R 4 , and R 6  identical or different, are a hydrogen or a (C 1 -C 3 )alky group; 
       R 5  is an (C 2 -C 3 )acyl, an aldehyde, an (C 1 -C 3 )alcohol, or an (C 2 -C 3 )ester; and, 
       Y═O − Cat + , a C 1 -C 3  alky group, a group -A-R, wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C 1 -C 50  hydrocarbon group, optionally interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl or an alkynyl which can be substituted by one or several substituents selected from the group consisting of: an alkyl, an alkylenyl, an alkylnyl, an epoxyalkyl, an aryl, an heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (—COOH), an ester, an amine, an amino group (—NH 2 ), an amide (—CONH 2 ), an imine, a nitrile, an hydroxyl (—OH), a aldehyde group (—CHO), an halogen, an halogenoalkyl, a thiol (—SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof. 
     
   
   
       2 . The method according to  claim 1 , wherein said disease is a cancer, an autoimmune disease or an allergic disease. 
   
   
       3 . The method according to  claim 2 , wherein said cancer is selected from the group consisting of melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head and neck cancer, bladder cancer, renal cancer, brain cancer, gastric cancer, lung cancer, colorectal cancer, prostate cancer and breast cancer. 
   
   
       4 . The method according to  claim 2 , wherein said autoimmune disease is selected from diabetes, multiple sclerosis and rheumatoid arthritis. 
   
   
       5 . The method according to  claim 2 , wherein said allergic disease is selected from asthma and airway hyperresponsiveness. 
   
   
       6 . The method according to  claim 1 , wherein said compound is administered conjointly with a cytokine. 
   
   
       7 . The method according to  claim 7 , wherein said cytokine is IL-2. 
   
   
       8 . A method of regulating the activity of γδ T cells in a human subject, said method comprising the steps of administering, in at least one treatment, a therapeutically effective amount of a compound of formula 
     
       
         
         
             
             
         
       
       wherein Cat +  represents one or more cation, that can be the same or different, selected from proton(s), organic cation(s) or mineral cation(s); 
       m is an integer from 1 to 3; 
       B is O, NH, or any other group capable of being hydrolyzed; 
       A is O, NH, CHF, CF 2  or CH 2 , or any other isosteric group; 
       W is C—R 6  or N; 
       R 7  is a (C 1 -C 3 )alkyl group or any other isosteric group such as CF 3 ; 
       R 3 , R 4 , and R 6  identical or different, are a hydrogen or a (C 1 -C 3 )alky group; 
       R 5  is an (C 2 -C 3 )acyl, an aldehyde, an (C 1 -C 3 )alcohol, or an (C 2 -C 3 )ester; and, 
       Y═O − Cat + , a C 1 -C 3  alky group, a group -A-R, wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C 1 -C 50  hydrocarbon group, optionally interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl or an alkynyl which can be substituted by one or several substituents selected from the group consisting of: an alkyl, an alkylenyl, an alkylnyl, an epoxyalkyl, an aryl, an heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (—COOH), an ester, an amine, an amino group (—NH 2 ), an amide (—CONH 2 ), an imine, a nitrite, an hydroxyl (—OH), a aldehyde group (—CHO), an halogen, an halogenoalkyl, a thiol (—SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof, optionally together with a pharmaceutically acceptable carrier. 
     
   
   
       9 . The method according to  claim 8 , wherein said compound is administered in a dosage between about 1 μg/kg and 1.2 g/kg. 
   
   
       10 . The method according to  claim 8 , wherein said compound is administered in a dosage between about 10 μg/kg and 1.2 g/kg. 
   
   
       11 . The method according to  claim 1 , wherein said compound is administered in a dosage between about 2 μg/kg and 100 mg/kg. 
   
   
       12 . The method according to  claim 8 , wherein said compound is administered conjointly with a cytokine. 
   
   
       13 . The method according to  claim 12 , wherein said cytokine is IL-2. 
   
   
       14 . The method according to  claim 8 , wherein said compound is administered in a dosage between about 1 μg/kg and 1.2 g/kg. 
   
   
       15 . The method according to  claim 8 , wherein said compound is administered in a dosage between about 10 μg/kg and 1.2 g/kg. 
   
   
       16 . The method according to  claim 8 , wherein said compound is administered in a dosage between about 2 μg/kg and 100 mg/kg. 
   
   
       17 . A composition comprising a compound of formula 
     
       
         
         
             
             
         
       
       wherein Cat +  represents one or more cation, that can be the same or different, selected from proton(s), organic cation(s) or mineral cation(s); 
       m is an integer from 1 to 3; 
       B is O, NH, or any other group capable of being hydrolyzed; 
       A is O, NH, CHF, CF 2  or CH 2 , or any other isosteric group; 
       W is C—R 6  or N; 
       R 7  is a (C 1 -C 3 )alkyl group or any other isosteric group such as CF 3 ; 
       R 3 , R 4 , and R 6  identical or different, are a hydrogen or a (C 1 -C 3 )alky group; 
       R 5  is an (C 2 -C 3 )acyl, an aldehyde, an (C 1 -C 3 )alcohol, or an (C 2 -C 3 )ester; and, 
       Y═O − Cat + , a C 1 -C 3  alky group, a group -A-R, wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C 1 -C 50  hydrocarbon group, optionally interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl or an alkynyl which can be substituted by one or several substituents selected from the group consisting of: an alkyl, an alkylenyl, an alkylnyl, an epoxyalkyl, an aryl, an heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (—COOH), an ester, an amine, an amino group (—NH 2 ), an amide (—CONH 2 ), an imine, a nitrile, an hydroxyl (—OH), a aldehyde group (—CHO), an halogen, an halogenoalkyl, a thiol (—SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof, wherein said composition prevents or is a treatment against a tumor, and optionally an antigen 
     
   
   
       18 . The composition according to  claim 17 , wherein said antigen is selected from  Mycobacterium bovis ; a tumoral antigen; an inactivated or attenuated pathogen, microorganism or parasite; an enriched or purified polypeptide; a lipid; a polysaccharide; a glycoprotein; a glycolipid; or a nucleic acid antigen.