Allosteric adenosine receptor modulators

Abstract

The present invention relates to compounds of formulas (IA) and (IB): the preparation thereof, pharmaceutical formulations thereof, and their use in medicine as allosteric adenosine receptor modulators for uses including protection against hypoxia and ischemia induced injury and treatment of adenosine-sensitive cardiac arrhythmias.

What is claimed is:  
     
         1 . A method for providing cardioprotection, neuroprotection, pain management, reduction of free fatty acids, triglycerides, or glucose levels, adjunct therapy in diabetes, treatment of GI disorders, treatment of glaucoma; treatment of sleep disorders; treatment of cardiac disarrythmias (peroxysmal supraventricular tachycardia, treatment of congestive heart failure or treatment of inflammation comprising administering to a patient in need of treatment thereof an effective amount to treat the disorder of a compound selected from a group consisting of compounds of formulas IA and IB:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is  
                     
 wherein R 2  is H, C(═O)R 8 ;  
 R 8  is H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl;  
 R 3  and R 4  are independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, alkoxy, alkylthio, or arylthio;  
 or if R 3  and R 4  are both alkoxy or alkylthio, may form a 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, or 1,3-dithian-2-yl group;  
 or together R 3  and R 4  may form a carbonyl oxygen;  
 R 5 , R 6 , and R 7  are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, hydroxy, nitro, amino, substituted amino, disubstituted amino, alkoxy, aryloxy, alkylthio, arylthio, sulfonamido, or substituted sulfonamido;  
 or together R 5  and R 6  or R 6  and R 7  may be CH═CH—CH═CH, such that they form a fused aromatic ring;  
 A and B are independently O, S, or N—R 8 ;  
 or A and B may independently represent a carbon-carbon single bond; m  
 and n are independently 0, 1, 2, or 3; 
 except that A and B cannot both represent a carbon-carbon single  
 bond when m and n are both 0; and  
 
 X is CH═CH, CH═N, N═CH, O, S, or N—R 8 .  
 
     
     
         2 . The method of  claim 1 , wherein the cardioprotection involves short term protection during surgical procedures selected from the group consisting of percutaneous angioplasty (PTDA), angioplasty, and cardiac surgeries.  
     
     
         3 . The method of  claim 1 , wherein the cardioprotection involves long term protection from myocardial infarction.  
     
     
         4 . The method of  claim 1 , wherein the neuroprotection involves stroke prevention, stroke treatment, or the treatment of epilepsy.  
     
     
         5 . The method of  claim 1 , wherein the pain management involves the treatment of diabetic neuropathy, post herpetic neuralgia or other forms of neuropathic pain.  
     
     
         6 . The method of  claim 5  wherein the treatment involves acute intravenous injection, chronic oral administration or chronic intravenous injection.  
     
     
         7 . The method of  claim 1 , wherein the treatment of diabetes includes the treatment of insulin and non-insulin dependent diabetes mellitus, the stimulation of insulin secretion from the pancreas, or the increase in tissue sensitivity to insulin.  
     
     
         8 . The method of  claim 1 , wherein the treatment of GI disorders involves treating a disorder selected from the group consisting of diarrhea, irritable bowel disease, irritable bowel syndrome, and incontinence.  
     
     
         9 . The method of  claim 1  wherein the compound is selected from compounds of formula (IA).  
     
     
         10 . The method of  claim 1  wherein the compound is selected from compounds of formula (IB).  
     
     
         11 . The method of  claim 1  wherein the compound is selected from the group comprising: 
 (2-Amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)-phenyl-methanone  
 (2-Amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-4,5-dihydrothieno[2,3-b]thiophen-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-furan-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-1-yl-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-naphthalen-1-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-naphthalen-1-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yi)-naphthalen-1-yl-methanone  
 N-[3-(Furan-2-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl]-acetamide  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yi)-furan-2-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-furan-2-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-furan-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-benzofuran-2-yl-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-benzofuran-2-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-benzofuran-2-yl-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yi)-pyridin-2-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-benzofuran-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-pyridin-2-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-pyridin-2-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-pyridin-2-yl-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-bromonaphtha-Ien-1-yl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl-(4-methoxynaphtha-Ien-1-yl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-iodonaphthalen-1-yl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-chloronaph-thalen-1-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-iodonaphthalen-1-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-methoxynaph-thalen-1-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chloronaphthalen-1-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-bromonaphthalen-1-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobe nzo[b]thiophen-3-yl)-naphthalen-2-yl-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-naphthalen-2-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-naphtha-Ien-2-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-naphthalen-2-yl-methanone  
 (2-Amino-6-spiro(1,4-dioxolan-2-yi)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-6-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chloro-phenyl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yi)-thiophen-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(5-bromothiophen-2-yl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(5-bromothio-phen-2-yl)-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-(5-bromothiophen-2-yl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-(5-bromothiophen-2-yl)-methanone  
 (2-Amino-4,5,6,7-tetra hydrobenzo[b]thiophen-3-yl)-(5-chlorothiophen-2-yl)-methanone  
 (2-Amino-5,6-dihydrocyclopenta[b]thiophen-3-yl)-(5-chlorothiophen-2-yl)-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-(5-chlorothiophen-2-yl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-(5-chloro-thiophen-2-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-thiophen-3-yl-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[blthiophen-3-yl)-thiophen-3-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-thiophen-3-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-thiophen-3-yl-methanone  
 [2-Amino-6-(4-methoxyphenyl)-4H-1,5,7-trithia-inden-3-yl]-napthalen-1-yl-methanone  
 [2-Amino-6-(4-methoxyphenyl)-4H-1,5,7-trithia-inden-3-yl]-(4-chloro-phenyl)-methanone  
 [2-Amino-6-(4-methoxyphenyl)-4H-1,5,7-trithia-inden-3-yl]-thiophen-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(9H-fluoren-2-yi)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(9H-fluoren-2-yl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-(9H-fluor-en-2-yl)-methanone  
 [2-Amino-6-[(methanesulfonyl)oxy]-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl]-(4-chlorophenyl)-methanone  
 [2-Amino-6-(4-chlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl]-naphthalen-2-yl-methanone  
 2-Amino-6-(4-fluorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl]-naphthalen-2-yi-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-2-yl-methanone  
 [2-Amino-6-(2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl]-naphthalen-2-yi-methanone  
 [2-Amino-6-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl]-naphthalen-2-yl-methanone  
 [2-Amino-6-(3,4,5-trimethoxybenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyri-din-3-yl]-naphthalen-2yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl]-thiophen-3-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetra hydrobenzo[b]thiophen-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetra hydrobenzo[b]thiophen-3-yl]-naphthalen-2-yl-methanone  
 [2-Amino-6-(4-nitrobenzyl)-4,5,6,7-tetra hydrobenzo[b]thiophen-3-yl]-naphthalen-2-yl-methanone  
 
     
     
         12 . A method for determining whether a compound is active at moderating adenosine receptors in a mammal, comprising performing competitive binding studies with the compound to be analyzed and a compound selected from a group consisting of compounds of formulas IA and IB:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is  
                     
 wherein R 2  is H, C(═O)R 8 ;  
 R 8  is H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl;  
 R 3  and R 4  are independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, alkoxy, alkylthio, or arylthio;  
 or if R 3  and R 4  are both alkoxy or alkylthio, may form a 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, or 1,3-dithian-2-yl group;  
 or together R 3  and R 4  may form a carbonyl oxygen;  
 R 5 , R 6 , and R 7  are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, hydroxy, nitro, amino, substituted amino, disubstituted amino, alkoxy, aryloxy, alkylthio, arylthio, sulfonamido, or substituted sulfonamido;  
 or together R 5  and R 6  or R 6  and R 7  may be CH═CH—CH═CH, such that they form a fused aromatic ring;  
 A and B are independently O, S, or N—R 8 ;  
 or A and B may independently represent a carbon-carbon single bond;  
 m and n are independently 0, 1, 2, or 3;  
 except that A and B cannot both represent a carbon-carbon single bond when m and n are both 0; and  
 X is CH═CH, CH═N, N═CH, O, S, or N—R 8 .  
 
     
     
         13 . The method of  claim 12  wherein the compound is selected from compounds of formula (IA).  
     
     
         14 . The method of  claim 12  wherein the compound is selected from compounds of formula (IB).  
     
     
         15 . The method of  claim 12  wherein the compound is selected from the group comprising: 
 (2-Amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yi)-phenyl-methanone  
 (2-Amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-4,5-dihydrothieno[2,3-b]thiophen-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-furan-2-yi-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yi)-thiophen-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-1-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-naphthalen-2-yl-methanone  
 (2-Amino-6-spiro(1,4-dioxolan-2-yi)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chlorophenyl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-6-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chloro-phenyl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-thiophen-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(5-bromothiophen-2-yi)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(5-bromothio-phen-2-yl)-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-(5-bromothiophen-2-yl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-(5-bromothiophen-2-yl)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(5-chlorothiophen-2-yl)-methanone  
 (2-Amino-5,6-dihydrocyclopenta[b]thiophen-3-yl)-(5-chlorothiophen-2-yl)-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-(5-chlorothiophen-2-yl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-(5-chloro-thiophen-2-yi)-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-thiophen-3-yi-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-3-yl-methanone  
 (2-Amino-4,5-dimethylthiophen-3-yl)-thiophen-3-yl-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-thiophen-3-yl-methanone  
 [2-Amino-6-(4-methoxyphenyl)-4H-1,5,7-trithia-inden-3-yl]-napthalen-1-yl-methanone  
 [2-Amino-6-(4-methoxyphenyl)-4H-1,5,7-trithia-inden-3-yl]-(4-chloro-phenyl)-methanone  
 [2-Amino-6-(4-methoxyphenyl)-4H-1,5,7-trithia-inden-3-yl]-thiophen-2-yl-methanone  
 (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(9H-fluoren-2-yl)-methanone  
 (2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(9H-fluoren-2-yl)-methanone  
 (2-Amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-(9H-fluor-en-2-yl)-methanone  
 [2-Amino-6-[(methanesulfonyl)oxy]-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl]-(4-chlorophenyl)-methanone  
 [2-Amino-6-(4-chlorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl]-naphthalen-2-yl-methanone