Organophosphorous Compounds for the Activation of Gamma/Delta T Cells

Abstract

The present invention describes organophosphorus compounds of general formula (I) their preparation and their uses in the activation of gamma/delta T-cells, in the screening of GcpE and LytB enzyme inhibitors and in the prophylaxis and treatment of diseases in humans and animals.

1 . A method for the treatment of a human or animal disease comprising the administration of a compound of formula (I) to a human or animal having a disease, wherein said compound of formula (I) is: 
       
         
           
           
               
               
           
         
         in which R 1  is selected from the group consisting of a methyl radical, a formyl radical, substituted or unsubstituted hydroxymethyl radicals and C 0 H 2 R 31 , R 31  being selected from the group consisting of OH, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate and it being impossible for R 31  and R 2  to be present in the molecule simultaneously, R 33  is selected from the group consisting of hydrogen, OH, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate, 
         R 3  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having 1 to 26 carbon atoms, substituted or unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl having 1 to 26 carbon atoms, substituted or unsubstituted alkynyl having 1 to 26 carbon atoms, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radicals, substituted or unsubstituted phosphate, a silyl, a nucleoside, a nucleoside monophosphate, diphosphate or triphosphate, a deoxynucleoside, a cation of an organic or inorganic base, a cation of an organic or inorganic base wherein the metal is from main group I, II or III of the Periodic Table, ammonium, substituted ammonium, ammonium compounds derived from ethylenediamine or amino acids, and OR 34 , wherein R 34  is defined in the same way as R 3 , X 2  is defined in the same way as X 1  if a ring is formed between X 2  and C 1  of X 2  is selected from the group consisting of —OR 6 , 
       
       
         
           
           
               
               
           
         
         R 7  and R 8  being defined in the same way as R 34 , and 
       
       
         
           
           
               
               
           
         
         R 4  being defined in the same way as R 3 , Z 1  being defined in the same way as X 1 , and X 3  being defined in the same way as X 1  if it forms a ring with C 1  and, if it does not form a ring with C 1 , being a group 
       
       
         
           
           
               
               
           
         
         R 5  being defined in the same way as R 3 , and Z 2  and X 4 , which forms a ring with C 1 , being defined in the same way as X 1 , 
         R 2  is selected from the group consisting of hydrogen, OH, alkoxy, phenoxy, benzyloxy, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate, and 
         X 1  can be oxygen or 
       
       
         
           
           
               
               
           
         
         Y 1  and Y 2 , which can be identical or different, being selected from the group consisting of H. OH, halogen, an amino radical, a C 1-9 -alkoxy radical and a C 1-9 -alkylthio radical, or together forming an oxo group, 
         and it being possible for a double bond to be present between C 0  and C 1  or C 1  and C 2  or C 2  and C 3 . 
       
     
     
         2 . The method according to  claim 1 , wherein said compound has formula (II): 
       
         
           
           
               
               
           
         
         in which a single or double bond is present between C 2  and C 3 , R 1  is selected from the group consisting of a methyl radical, a formyl radical and substituted or unsubstituted hydroxymethyl radicals, R 2  is selected from the group consisting of hydrogen, hydroxyl, alkoxy, phenoxy and benzyloxy radicals, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate, X 1  is oxygen or a group 
       
       
         
           
           
               
               
           
         
         Y 1  and Y 2 , which can be identical or different, being selected from the group consisting of H, OH, halogen, amino, a C 1-9 -alkoxy radical and a C 1-9 -alkylthio radical, or together forming an oxo group, R 3  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having 1 to 26 carbon atoms, substituted or unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl having 1 to 26 carbon atoms, substituted or unsubstituted alkynyl having 1 to 26 carbon atoms, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radicals, substituted or unsubstituted phosphate, a silyl, a nucleoside, a nucleoside monophosphate, diphosphate or triphosphate, a deoxynucleoside, a cation of an organic or inorganic base, especially a metal of main group I, II or III of the Periodic Table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, X 2  is defined in the same way as X 1  if a ring is formed between X 2  and C 1 , and otherwise is 
       
       
         
           
           
               
               
           
         
         R 4  being defined in the same way as R 3 , Z 1  being defined in the same way as X 1 , and X 3  being defined in the same way as X 1  if it forms a ring with C 1  and, if it does not form a ring with C 1 , being a group 
       
       
         
           
           
               
               
           
         
         R 5  being defined in the same way as R 3 , and Z 2  and X 4 , which forms a ring with C 1 , being defined in the same way as X 1 . 
       
     
     
         3 . The method according to  claim 2 , wherein said compound is of formula (IIA): 
       
         
           
           
               
               
           
         
         in which C 2  and C 3  are joined together by either a single bond or a double bond, R 1  is a methyl group or a substituted or unsubstituted hydroxymethyl group, R 2  is selected from the group consisting of hydrogen, OH, a substituted or unsubstituted phosphate and a substituted or unsubstituted pyrophosphate, X 1  and X 2  are selected from the group consisting of O, CHF, CHCl, CFCl, CH 2 , CF 2  and CCl 2 , and R 3  is selected from the group consisting of hydrogen, substituted or unsubstituted phosphate, a nucleoside, a nucleoside monophosphate, diphosphate or triphosphate, a deoxynucleoside, a cation of an organic or inorganic base, a cation of an organic or inorganic base wherein the metal is from main group I, II or III of the Periodic Table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids. 
       
     
     
         4 . The method according to  claim 2 , wherein said compound is of formula (IIB): 
       
         
           
           
               
               
           
         
         in which C 2  and C 3  are joined together by either a single bond or a double bond, R 1  is a methyl group or a substituted or unsubstituted hydroxymethyl group, R 2  is H if R 1  is a substituted or unsubstituted hydroxymethyl, and is OH, a substituted or unsubstituted phosphate or a substituted or unsubstituted pyrophosphate if R 1  is a methyl radical, X 1 , X 2  and X 3  are selected from the group consisting of O, CHF, CHCl, CFCl, CH 2 , CF 2  and CCl 2 , and R 3  and R 4  are selected from the group consisting of hydrogen, substituted or unsubstituted phosphate, a nucleoside, a nucleoside monophosphate, diphosphate or triphosphate, a deoxynucleoside, a cation of an organic or inorganic base, a cation of an organic or inorganic base wherein the metal is from main group I, II or III of the Periodic Table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids. 
       
     
     
         5 . The method according to  claim 2 , wherein said compound is of formula (IIC): 
       
         
           
           
               
               
           
         
         in which there can be a single or double bond between C 2  and C 3 , R 1  is a methyl group or a substituted or unsubstituted hydroxymethyl group, R 2  is H, OH, a substituted or unsubstituted phosphate or a substituted or unsubstituted pyrophosphate, X 1 , X 2 , X 3  and X 4  are selected from the group consisting of O, CHF, CHCl, CFCl, CH 2 , CF 2  and CCl 2 , and R 3 , R 4  and R 5  are selected from the group consisting of hydrogen, substituted or unsubstituted phosphate, a nucleoside, a nucleoside monophosphate, diphosphate or triphosphate, a deoxynucleoside, a cation of an organic or inorganic base, a cation of an organic or inorganic base wherein the metal is from main group I. II or III of the Periodic Table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids. 
       
     
     
         6 . The method according to  claim 3 , wherein X 1 , X 2 , X 3  and X 4  are oxygen. 
     
     
         7 . The method according to  claim 3 , wherein R 1  is a substituted or unsubstituted hydroxymethyl radical, hydroxymethyl, or a hydroxymethyl radical substituted by phosphate, diphosphate or nucleoside diphosphate, and R 2 =H. 
     
     
         8 . The method according to  claim 3 , wherein R 1  is a methyl radical and R 2  is OH, a substituted or unsubstituted phosphate, a substituted pyrophosphate, or a nucleoside diphosphate. 
     
     
         9 . The method according to  claim 5 , wherein said compounds are: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 1 , wherein said compound is of formula III: 
       
         
           
           
               
               
           
         
         in which R 31  and R 2 , which cannot be present in the molecule simultaneously, are selected from the group consisting of OH, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate, a double bond being formed between C 1  and C 2  if R 31  is present in the molecule and a double bond being formed between C 0  and C 1  if R 2  is present in the molecule, R 33  is selected from the group consisting of hydrogen, OH, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate, R 34  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl having 1 to 26 carbon atoms, substituted or unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl having 1 to 26 carbon atoms, substituted or unsubstituted alkynyl having 1 to 26 carbon atoms, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radicals, substituted or unsubstituted phosphate, a silyl, a nucleoside, a deoxynucleoside, a nucleoside monophosphate, diphosphate or triphosphate, a cation of an organic or inorganic base, a cation of an organic or inorganic base wherein the metal is from main group I, II or III of the Periodic Table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, X 2  is either —OR 6 , R 6  being defined analogously to R 34 , or can be 
       
       
         
           
           
               
               
           
         
         R 7  and R 8  being defined in the same way as R 4 , and X 1 , X 32  and X 33 , which can be identical or different, can be oxygen or a group 
       
       
         
           
           
               
               
           
         
         Y and Z, which can be identical or different, being selected from the group consisting of H, OH, halogen, amino, C 1-9 -alkoxy and C 1-9 -alkylthio, or together forming an oxo group. 
       
     
     
         11 . The method according to  claim 10 , wherein said compound is of formula (IIIA): 
       
         
           
           
               
               
           
         
         in which R 31  and R 2 , which cannot be present in the molecule simultaneously, are selected from the group consisting of OH, substituted or unsubstituted phosphate and substituted or unsubstituted pyrophosphate, a double bond being formed between C 1  and C 2  if R 31  is present in the molecule and a double bond being formed analogously between C 0  and C 1  if R 2  is present in the molecule, R 34 , R 7  and R 8 , which can be identical or different, are as defined in  claim 1  and X 1 , X 32  and X 33 , which can be identical or different, are likewise as defined in  claim 10 . 
       
     
     
         12 . The method according to  claim 11 , wherein R 31 =OH and C 0  and C 1  are joined by a double bond. 
     
     
         13 . The method according to  claim 11 , wherein R 2 =OH and C 1  and C 2  are joined by a double bond. 
     
     
         14 . The method according to  claim 10 , wherein either R 34  or R 6  or R 7  or R 8  is a substituted or unsubstituted phosphate radical. 
     
     
         15 . The method according to  claim 10 , wherein either R 31  or R 2  or X 2  is a substituted or unsubstituted phosphate radical. 
     
     
         16 . The method according to  claim 10 , wherein R 34 , R 6 , R 7  and R 8 , which can be identical or different, are hydrogen, a cation of a metal of main group I, II or III of the Periodic Table, or substituted or unsubstituted ammonium. 
     
     
         17 . The method according to  claim 10 , wherein X 1  and X 32 =O. 
     
     
         18 . The method according to  claim 10 , wherein X 1 =CYZ, X 32 =O and X 33 =CYZ, Y and Z being as defined in  claim 10 . 
     
     
         19 . The method according to  claim 10 , wherein X 1 =O, X 32 =CYZ and X 33 =O, Y and Z being as defined in  claim 10 . 
     
     
         20 . The method according to  claim 10 , wherein X 1 , X 32  and X 33 , which can be identical or different, are selected from the group consisting of CH 2 , CHF, CHCl, CFCl, CCl 2  and CF 2 . 
     
     
         21 . The method according to  claim 10 , wherein said compound is selected from the following group: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . The method according to  claim 1 , wherein said treatment or prophylaxis is of immune, autoimmune, respiratory diseases or allergies in humans. 
     
     
         23 . The method according to  claim 22 , wherein the disease is selected from the group consisting of asthma, Crohn's disease, ulcerative colitis, multiple sclerosis, bone disease, especially osteoporosis, and chronic bronchitis, as well as rheumatoid arthritis, Hashimoto's thyroiditis, myasthenia gravis, lupus erythematosus, diabetes mellitus, primary biliary cirrhosis, active chronic hepatitis, adrenalitis/Addison's disease, polymyositis, dermatomyositis, autoimmune haemolytic anaemia, myocarditis and pericarditis, scleroderma, uveitis, phacouveitis, sympathetic ophthalmia, pemphigus vulgaris, pemphigoid, pernicious anaemia, autoimmune atrophic gastritis, bronchitis, diseases caused by viruses, bacteria and parasites, benign and malignant tumours, hepatitis C virus infections, and helicobacter eradication therapy on ulcers of the gastrointestinal tract.