Phosphorylated A2A Receptor Agonists

Abstract

A phosphorylated A 2A receptor agonist providing agonist properties on the A 2A receptor after dephosphorylation the phosphorylated A 2A receptor agonist comprises a ribosyl moiety and a purine moiety and being phosphorylated at the 5 ′-position of the ribose moiety except adenosine monophosphate (AMP), adenosine diphosphate (ADP) or adenosine triphosphate (ATP), a medicament containing the compound of the invention including ADP and the use of the compound of the invention including ATP and ADP for several medical indications e. g. inflammatory events. In particular, compounds of formula (I) are also disclosed.

1 . An A 2A  receptor agonist which comprises a ribosyl moiety and a purine moiety, wherein said agonist exerts agonist activity on an A 2A  receptor after dephosphorylation, and wherein said agonist is phosphorylated at the 5′-position of the ribosyl moiety, wherein said agonist is not selected from the group consisting of adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP). 
     
     
         2 . The phosphorylated A 2A  receptor agonist of  claim 1  of the formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         A and B independently are CH or N, 
         Y is selected from the group consisting of NH, O, S, C═O, and CH 2 ; 
         R 1  is selected from the group consisting of hydrogen, (C 1 -C 5 ) alkyl, alkenyl and alkoxy; 
         X is selected from the group consisting of O, S, NH, C═O, C═S, O(CH 2 ) 1-3 , N(CH 2 ) 1-3 , NH(CH 2 ) 1-3 , S(CH 2 ) 1-3 , NHN═N, NHN═NCH 2 ; C(O)—(CH 2 ) 1-3 , C(S)—(CH 2 ) 1-3 , C═N═N, C≡C, C≡C—(CH 2 ) 1-3 ; 
         R 2 , R 3  independently are OR5, NR 5 R 6 , SR 5 ,
 wherein R 5  and R 6  are independently hydrogen or lower alkyl such as selected from the group consisting of Me, Et, nProp, iProp, nBu, sekBu, tertBu; alkoxy, alkylamino, C 1 -C 3  alkylthio; 
 
         R 4  is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 10  alkyl, unsubstituted or substituted C 1 -C 10  alkenyl, unsubstituted or substituted C 1 -C 10  alkynyl, unsubstituted or substituted C 3 -C 8  cycloalkyl, unsubstituted or substituted C 1 -C 10  alkoxy, unsubstituted or substituted C 3 -C 8  cycloalkoxy, an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring,
 wherein 1 to 3 ring atoms independently are nitrogen, oxygen or sulfur, 
 
         —OR, —C(O)R, —C(O)OR, —C(O)NRR′, —NRR′, —S(O) 2 R, —S(O) 2 OR, and —S(O) 2 NRR′
 wherein R and R′ independently are (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkenyl residues, and 
 
         or physiologically acceptable salts thereof such as sodium, selected from the group consisting of sodium, potassium, ammonium, triethylammonium, trimethylammonium, and other substituted ammonium salts. 
       
     
     
         3 . The phosphorylated A 2A  receptor agonist of  claim 2  of the formula (I), wherein
 A and B are CH;   Y is O;   R 1  is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 10  alkyl, unsubstituted or substituted C 1 -C 10  alkenyl, unsubstituted or substituted C 1 -C 10  alkynyl, unsubstituted or substituted C 3 -C 8  cycloalkyl, unsubstituted or substituted C 1 -C 10  alkoxy, unsubstituted or substituted C 3 -C 8  cycloalkoxy, unsubstituted or substituted C 6 -C 14  aryl, an unsubstituted or substituted 5- to 10-membered heteroaryl,
 wherein 1 to 4 ring atoms independently are nitrogen, oxygen or sulfur, 
   an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring,
 wherein 1 to 3 ring atoms independently are nitrogen, oxygen or sulfur, 
   —OR, —C(O)R, —C(O)OR, —C(O)NRR′, —NRR′, —S(O) 2 R, —S(O) 2 OR,
 wherein R and R′ independently are (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkenyl residues; 
   X is selected from the group consisting of O, S, NH, C═O, C═S, O(CH 2 ) 1-3  N(CH 2 ) 1-3 , NH(CH 2 ) 1-3 , S(CH 2 ) 1-3 , NHN═N, NHN═NCH 2 ; C(O)—(CH 2 ) 1-3 , C(S)—(CH 2 ) 1-3 , C═N═N, C≡C, and C≡C—(CH 2 ) 1-3 ,   R 2 , R 3  independently are OR 5 , NR 5 R 6 , SR 5 ,
 wherein R 5  and R 6  independently are hydrogen; or lower alkyl selected from the group consisting of Me, Et, nProp, iProp, nBu, sekBu, and tertBu; 
   R 4  is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 10  alkyl, unsubstituted or substituted C 1 -C 10  alkenyl, unsubstituted or substituted C 1 -C 10  alkynyl, unsubstituted or substituted C 3 -C 8  cycloalkyl, unsubstituted or substituted C 1 -C 10  alkoxy, unsubstituted or substituted C 3 -C8 cycloalkoxy, unsubstituted or substituted C 6 -C 14  aryl, an unsubstituted or substituted 5- to 10-membered heteroaryl,
 wherein 1 to 4 ring atoms independently are nitrogen, oxygen or sulfur, 
   an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring,
 wherein 1 to 3 ring atoms independently are nitrogen, oxygen or sulfur, 
   —OR, —C(O)R, —C(O)OR, —C(O)NRR′, —NRR′, —S(O) 2 R, —S(O) 2 OR, and —S(O) 2 NRR′
 wherein R and R′ independently are (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkenyl residues, 
   or physiologically acceptable salts thereof selected from the group consisting of sodium, potassium, ammonium, triethylammonium, trimethylammonium, and other substituted ammonium salts.   
     
     
         4 . The phosphorylated A 2A  receptor agonist of  claim 3 , wherein X is S. 
     
     
         5 . The phosphorylated A 2A -receptor agonist of  claim 4 , selected from the group consisting of
 2-(Cyclohexylthio)adenosine-5′-monophosphate;   2-(Cyclohexylmethylthio)adenosine-5′-monophosphate;   2-(Cyclohexylethylthio)adenosine-5′-monophosphate;   2-(Propylthio)adenosine-5′-monophosphate;   2-(Allylthio)adenosine-5′-monophosphate;   2-(Hexylthio)adenosine-5′-monophosphate;   2-(Cyclopentylmethylthio)adenosine-5′-monophosphate;   2-(Benzylthio)adenosine-5′-monophosphate; and   2-(Phenylethylthio)adenosine-5′-monophosphate.   
     
     
         6 . A pharmaceutical composition comprising a phosphorylated A 2A  receptor agonist, wherein said agonist exerts agonist activity on an A 2A  receptor after dephosphorylation, and wherein said agonist is not adenosine triphosphate (ATP). 
     
     
         7 . A pharmaceutical composition comprising the phosphorylated A 2A  receptor agonist of any one of  claims 2  to  5 . 
     
     
         8 . A method for treatment of disease related with or caused by acute or chronic inflammatory, hypotensive, psychotic, or asthmatic events, comprising administering, to a patient in need thereof, the pharmaceutical composition of  claim 6 . 
     
     
         9 . The to method of  claim 8 , wherein the inflammatory event is selected from the group consisting of arteriosclerosis, arthritis, Crohn's disease, traumatic spinal cord injury, restenosis of arteries and combinations thereof. 
     
     
         10 . A method for identifying a phosphorylated A 2A  receptor agonist comprising the steps of:
 a) providing an A 2A  receptor containing entity,   b) adding an established A 2A  receptor agonist to said entity, and   c) (i) determining the degree of competition of a putative A 2A  receptor agonist with the established A 2A  receptor agonist, or
 (ii) determining the degree of binding of a putative A 2A  receptor agonist to said entity; and 
   d) determining in a functional assay whether an identified A 2A  receptor agonist is able to elicit the physiological response of an A 2A  receptor agonist.   
     
     
         11 . The method of  claim 10 , wherein the degree of binding of the putative A 2A  receptor agonist to said entity is a dissociation constant K D  between the putative A 2A  receptor agonist and an A 2A  receptor. 
     
     
         12 . The method of  claim 11 , wherein the degree of competition between the putative A 2A  receptor agonist and an established A 2A  receptor agonist is the EC 50  value. 
     
     
         13 . The method of  claim 12 , wherein the physiological response of an identified A 2A  receptor agonist is validated by an animal model. 
     
     
         14 . A method for treating inflammation caused by an immune response to transplanted tissue, comprising the administration, to a patient in need thereof, an effective amount of an A 2A  adenosine receptor agonist. 
     
     
         15 . The method of  claim 14 , wherein immune response is a transplant rejection, or graft versus host disease. 
     
     
         16 . The method of  claim 15 , wherein immune response is a transplant rejection. 
     
     
         17 . The method of  claim 14 , wherein the transplantation comprises an organ, tissue or cell transplantation. 
     
     
         18 . The method of  claim 17 , wherein the cells are bone marrow, skin, or pancreatic islets. 
     
     
         19 . The method of  claim 18 , wherein the cells are pancreatic islets. 
     
     
         20 . The method of  claim 19 , wherein the organ is a cornea, kidney, lung, liver, or heart.