2-ARYL pyrrologpyrimidines for A1 and A3 receptors

Abstract

This invention pertains to compounds which specifically inhibit the adenosine A 1 and A 3 receptors and the use of these compounds to treat a disease associated with A 3 adenosine receptor in a subject, comprising administering to the subject a therapeutically effective amount of the compounds.

1 - 6 . (canceled) 
   
   
       7 . A compound having the structure: 
     
       
         
         
             
             
         
       
     
   
   
       8 . A compound having the structure: 
     
       
         
         
             
             
         
       
     
   
   
       9 - 63 . (canceled) 
   
   
       64 . A compound having the structure: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is H or CH 3 ; 
 R 2  is 
 
     
       
         
         
             
             
         
       
       R 3  is 
     
     
       
         
         
             
             
         
       
       R 4  is H; 
       R 5  is H; 
       R 6  is H; and
 when R 1  is CH 3  and R 3  is 
 
     
     
       
         
         
             
             
         
       
       
         
           R 2  is 
         
       
     
     
       
         
         
             
             
         
       
       
         when R 1  is H and R 3  is 
       
     
     
       
         
         
             
             
         
       
       
         
           R 2  is 
         
       
     
     
       
         
         
             
             
         
       
       
         when R 1  is H and R 3  is 
       
     
     
       
         
         
             
             
         
       
       
         
           R 2  is 
         
       
     
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       65 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       66 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       67 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       68 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       69 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       70 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       71 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       72 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       73 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       74 . The compound of  claim 64 , having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       75 . A method for treating a disease associated with an A3 adenosine receptor in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the compound of any one of  claims 7 ,  8  or  64 - 74  so as to thereby treat the disease associated with the A3 adenosine receptor in the subject, wherein the disease associated with the A3 adenosine receptor is antidiuresis, myocardial ischemia, bronchoconstriction, asthma, glaucoma, retinopathy, ocular ischemia, macular degeneration, a respiratory disorder, inflammation of the eye, or whereby the disease associated with the A3 adenosine receptor is associated with mast cell degranulation or eosinophil activity. 
   
   
       76 . The method of  claim 75 , wherein the disease is glaucoma. 
   
   
       77 . The method of  claim 76 , further comprising administering to the subject a therapeutically effective amount of one or more compounds selected from the group consisting of beta adrenoceptor antagonists, alpha-2 adrenoceptor agonists, carbonic anhydrase inhibitors, cholinergic agonists, prostaglandins and prostaglandin receptor agonists, angiotensin converting enzyme (ACE) inhibitors, AMPA receptor antagonists, 5-HT agonists, angiogenesis inhibitors, NMDA antagonists, renin inhibitors, cannabinoid receptor agonists, angiotensin receptor antagonists, hydrochlorothiazide (HCTZ), somatostatin agonists, glucocorticoid antagonists, mast cell degranulation inhibitors, alpha-adrenergic receptor blockers, alpha-2 adrenoceptor antagonists, thromboxane A2 mimetics, protein kinase inhibitors, prostaglandin F derivatives, prostaglandin-2 alpha antagonists, dopamine D1 and 5-HT2 agonists, nitric-oxide-releasing agents, 5-HT 2 antagonists, cyclooxygenase inhibitors, inosine, dopamine D2 receptor and alpha 2 adrenoceptor agonists, dopamine D1 receptor antagonist and D2 receptor agonists, vasopressin receptor antagonists, endothelin antagonists, 1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) and related analogs and prodrugs, thyroid hormone receptor ligands, muscarinic M1 agonists, sodium channel blockers, mixed-action ion channel blockers, beta adrenoceptor antagonist and PGF2 alpha agonist combinations, guanylate cyclase activators, nitrovasodilators, endothelin receptor modulators, ethacrynic acid, other phenoxyacetic acid analogs, actin disrupters, calcium channel blockers and neuroprotective agents. 
   
   
       78 . The method of  claim 76 , further comprising administering to the subject a therapeutically effective amount of one or more compounds selected from the group consisting of beta adrenoceptor antagonists, alpha-2 adrenoceptor agonists, carbonic anhydrase inhibitors, cholinergic agonists and prostaglandin receptor agonists. 
   
   
       79 . The method of  claim 76 , further comprising administering to the subject a therapeutically effective amount of a prostaglandin agonist, β2 agonist, or a muniscrinic antagonist. 
   
   
       80 . A pharmaceutical composition comprising the compound of any one of  claims 7 ,  8  or  64 - 74  and a pharmaceutically acceptable carrier. 
   
   
       81 . The pharmaceutical composition of  claim 80 , wherein the pharmaceutical composition is an periocular, retrobulbar or intraocular injection formulation. 
   
   
       82 . A packaged pharmaceutical composition for treating a disease associated with an A3 adenosine receptor in a subject, comprising:
 (a) a container holding a therapeutically effective amount of the compound of any one of  claims 7 ,  8  or  64 - 74 ; and   (b) instructions for using the compound for treating the disease in a subject.   
   
   
       83 . A process of making a composition which comprises the compound of any one of  claims 7 ,  8  or  64 - 74 , comprising admixing the compound with a suitable carrier. 
   
   
       84 . A pharmaceutically acceptable salt of the compound of any one of  claims 7 ,  8  or  64 - 74 . 
   
   
       85 . The pharmaceutically acceptable salt of  claim 84 , wherein the pharmaceutically acceptable salt contains an anion selected from the group consisting of maleic, fumaric, tartaric, acetate, phosphate and mesylate.