Adenosine Receptor Modulators for the Treatment of Circadian Rhythm Disorders

Abstract

The present invention relates to the use of adenosine receptor modulators to affect the circadian rhythm, in particular, to the use of such modulators for the treatment of circadian rhythm disorders. In particular, the invention relates to a composition comprising at least one selective adenosine receptor modulator, wherein said composition modulates two or three, but not all of adenosine receptor subtypes A 1 , A 2A , A 2B and/or A 3 for use in the treatment of circadian rhythm disorders or for modulating a biological clock.

1 . (canceled) 
     
     
         2 . A composition comprising at least one selective adenosine receptor modulator, wherein said composition modulates two or three, but not all of adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3  for use in the treatment of circadian rhythm disorders or for modulating a biological clock. 
     
     
         3 . The composition of  claim 2 , wherein said circadian rhythm disorder is a circadian rhythm dysfunction. 
     
     
         4 . A composition comprising at least one selective adenosine receptor modulator, wherein said composition modulates two or three, but not all of adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3  for use in circadian realignment. 
     
     
         5 . (canceled) 
     
     
         6 . A composition comprising at least one selective adenosine receptor modulator, wherein said composition modulates two or three but not all of adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3  for use in circadian realignment or adjustment by administration once a day. 
     
     
         7 . The composition of  claim 2 , wherein administration is at Circadian Time 4 to 8, preferably at Circadian Time 6, or administration is Circadian Time 14 to 18, preferably at Circadian Time 16. 
     
     
         8 . (canceled) 
     
     
         9 . The composition of  claim 2 , wherein said composition modulates A 1  and A 2A  and/or A 2B , preferably A 1  and A 2A . 
     
     
         10 . The composition of  claim 2 , wherein said composition comprises a single adenosine receptor modulator which selectively modulates two adenosine receptor subtypes, preferably A 1  and A 2A . 
     
     
         11 . The composition of  claim 2 , wherein the adenosine receptor modulator is an agonist, antagonist or inverse agonist of said adenosine receptor, preferably an antagonist or inverse agonist. 
     
     
         12 . (canceled) 
     
     
         13 . The composition of  claim 2 , wherein the adenosine receptor modulator is a small molecule, a peptide, a protein, an aptamer, a non-coding RNA, or an antibody or antibody fragment. 
     
     
         14 . The composition of  claim 2 , wherein the adenosine receptor modulator or selective adenosine receptor modulator is selected from:
 1-Deoxy-1-[6-[((3-Iodophenyl)methyl)amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide, N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide;   2-[[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide;   3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid;   2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one;   8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione;   4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol;   9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline;   3-[(4-amino-3-methylphenyl)methyl]-7-furan-2-yltriazolo[5,4-d]pyrimidin-5-amine;   2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine;   4-hydroxy-N-(4-methoxy-7-morpholinobenzo [d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide;   2-butyl-9-methyl-8-(triazol-2-yl)purin-6-amine; or   (6-Amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)butan-2-one.   
     
     
         15 . The composition of  claim 2 , wherein the specific adenosine receptor modulator has at least 30% affinity, or at least 40% affinity, or at least 50% affinity or more for one, two or three, but not all of the adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3 , wherein the specific adenosine receptor modulator has at least 60% affinity or more for one, two or three, but not all of the adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3 , preferably A 1  and A 2A . 
     
     
         16 . (canceled) 
     
     
         17 . The composition of  claim 2 , wherein the modulator results in an increase in Per1 or Per2 gene expression after administration to a subject, and
 wherein the increase in Per1 or Per2 gene expression is observed at least 2 to 6 hours after administration, or   wherein the increase in Per1 or Per2 gene expression is observed at least 4 hours after administration.   
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The composition of  claim 17 , wherein the increase in Per1 or Per2 gene expression is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% or more increase in expression compared to in a subject without the administration of the modulator. 
     
     
         21 . A pharmaceutical composition comprising the composition of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         22 . The adenosine receptor modulator or composition of  claim 2  wherein said circadian rhythm dysfunction occurs in peripheral tissues, or wherein said circadian rhythm dysfunction occurs in the cardiovascular system, lungs, heart, circulatory system, immune or lymphatic system, stomach, pancreas, liver, spleen, small or large intestine, reproductive tissues, kidneys, bladder or urinary system, muscle, bone marrow, skin, endocrine system or peripheral nervous system. 
     
     
         23 . (canceled) 
     
     
         24 . The composition of  claim 4 , wherein said composition modulates at least one of: A 1  and A 2A , A 1  A 2B , or A 1  and A 2A . 
     
     
         25 . The composition of  claim 4 , wherein said composition comprises a single adenosine receptor modulator which selectively modulates two adenosine receptor subtypes, preferably A 1  and A 2A . 
     
     
         26 . The composition of  claim 4 , wherein the adenosine receptor modulator is a small molecule, a peptide, a protein, an aptamer, a non-coding RNA, or an antibody or antibody fragment. 
     
     
         27 . The composition of  claim 4 , wherein the adenosine receptor modulator or selective adenosine receptor modulator is selected from:
 1-Deoxy-1-[6-[((3-Iodophenyl)methyl)amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide, N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide;   2-[[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide;   3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid;   2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one;   8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione;   4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol;   9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline;   3-[(4-amino-3-methylphenyl)methyl]-7-furan-2-yltriazolo[5,4-d]pyrimidin-5-amine;   2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine;   4-hydroxy-N-(4-methoxy-7-morpholinobenzo [d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide;   2-butyl-9-methyl-8-(triazol-2-yl)purin-6-amine; or   (6-Amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)butan-2-one.   
     
     
         28 . The composition of  claim 4 , wherein the specific adenosine receptor modulator has at least 30% affinity, or at least 40% affinity, or at least 50% affinity or more for one, two or three, but not all of the adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3 . 
     
     
         29 . The composition of  claim 4 , wherein the specific adenosine receptor modulator has at least 60% affinity or more for one, two or three, but not all of the adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3 , or A 1  and A 2A . 
     
     
         30 . The composition of  claim 4 , wherein the modulator results in an increase in Per1 or Per2 gene expression after administration to a subject, wherein the increase in Per1 or Per2 gene expression is observed at least 2 to 6 hours after administration, or wherein the increase in Per1 or Per2 gene expression is observed at least 4 hours after administration. 
     
     
         31 . The composition of  claim 30 , wherein the increase in Per1 or Per2 gene expression is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% or more increase in expression compared to in a subject without the administration of the modulator. 
     
     
         32 . The pharmaceutical composition comprising the composition of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         33 . The composition of  claim 6 , wherein said composition comprises a single adenosine receptor modulator which selectively modulates two adenosine receptor subtypes. 
     
     
         34 . The composition of  claim 6 , wherein said composition modulates at least one of: A 1  and A 2A  and/or A 2B , or preferably A 1  and A 2A . 
     
     
         35 . A composition of  claim 6 , wherein the adenosine receptor modulator is a small molecule, a peptide, a protein, an aptamer, a non-coding RNA, or an antibody or antibody fragment. 
     
     
         36 . The composition of  claim 6 , wherein the adenosine receptor modulator or selective adenosine receptor modulator is selected from:
 1-Deoxy-1-[6-[((3-Iodophenyl)methyl)amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuronamide, N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide;   2-[[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide;   3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid;   2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one;   8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione;   4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol;   9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline;   3-[(4-amino-3-methylphenyl)methyl]-7-furan-2-yltriazolo[5,4-d]pyrimidin-5-amine;   2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine;   4-hydroxy-N-(4-methoxy-7-morpholinobenzo [d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide;   2-butyl-9-methyl-8-(triazol-2-yl)purin-6-amine; or   (6-Amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)butan-2-one.   
     
     
         37 . The composition of  claim 6 , wherein the specific adenosine receptor modulator has at least 30% affinity, or at least 40% affinity, or at least 50% affinity or more for one, two or three, but not all of the adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3 . 
     
     
         38 . The composition of  claim 6 , wherein the specific adenosine receptor modulator has at least 60% affinity or more for one, two or three, but not all of the adenosine receptor subtypes A 1 , A 2A , A 2B  and/or A 3 , or preferably A 1  and A 2A . 
     
     
         39 . The composition of  claim 6 , wherein the modulator results in an increase in Per1 or Per2 gene expression after administration to a subject, wherein the increase in Per1 or Per2 gene expression is observed at least 2 to 6 hours after administration, or wherein the increase in Per1 or Per2 gene expression is observed at least 4 hours after administration. 
     
     
         40 . The composition of  claim 39 , wherein the increase in Per1 or Per2 gene expression is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% or more increase in expression compared to in a subject without the administration of the modulator. 
     
     
         41 . A pharmaceutical composition comprising the composition of  claim 6  and a pharmaceutically acceptable carrier.