Cannabinoid receptor modulator

Abstract

A cannabinoid receptor modulator containing a compound represented by Formula (I 0 ) wherein, X is an oxygen atom, etc., R 0 is an optionally substituted acylamino group, ring A 0 is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof.

1 . A cannabinoid receptor modulator containing a compound represented by Formula (I 0 ) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an optionally substituted acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted membered heterocycle, or a salt thereof or a prodrug thereof. 
     
     
         2 . The modulator as described in  claim 1  wherein the compound represented by Formula (I 0 ) or a salt thereof or a prodrug thereof is a compound represented by Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 1 , R 2 , R 3  and R 4  are independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted mercapto group or an optionally substituted amino group, or R 2  and R 3  may be taken together to form a bond, or R 1  and R 2  may be taken with the adjacent carbon atom to form an optionally substituted ring, Y is —CO—, —SO—, or —SO 2 —, R 5  is a hydrogen atom or an optionally substituted hydrocarbon group, R 6  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group, or R 5  and R 6  may be taken with the adjacent carbon atom or sulfur atom and nitrogen atom to form an optionally substituted ring, and ring A is a benzene ring which may further have a substituent in addition to a group represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein, each symbol has the same meaning as described above, or a salt thereof or a prodrug thereof. 
     
     
         3 . The modulator as described in  claim 2  wherein R 1  and R 2  are a hydrogen atom. 
     
     
         4 . The modulator as described in  claim 2  wherein R 1  and R 2  are respectively a hydrogen atom or a C 1-4  alkyl group, provided that R 1  and R 2  are not a hydrogen atom at the same time. 
     
     
         5 . The modulator as described in  claim 1  wherein the compound represented by Formula (I 0 ) or the salt thereof is a cannabinoid receptor agonist. 
     
     
         6 . The modulator as described in  claim 5  wherein cannabinoid receptor is type 1 cannabinoid receptor. 
     
     
         7 . The modulator as described in  claim 1  wherein the compound represented by Formula (I 0 ) or the salt thereof is a cannabinoid receptor antagonist. 
     
     
         8 . The modulator as described in  claim 7  wherein the cannabinoid receptor is type 1 cannabinoid receptor. 
     
     
         9 . The modulator as described in  claim 1  wherein the compound represented by Formula (I 0 ) or a salt thereof is type 2 cannabinoid receptor agonist. 
     
     
         10 . The modulator as described in  claim 1  which is an agent of preventing, treating or pain-relieving acute cerebrovascular disorders, spinal damage, head injury, multiple sclerosis, glaucoma, depression, vomit, arthritis or asthma. 
     
     
         11 . The modulator as described in  claim 1  which is an agent of preventing or treating memory disorders, psychiatric diseases, obesity, mental diseases, anxiety, depression, drug-dependency, Alzheimer's dementia or Parkinson's disease, or an aid for smoking cessation. 
     
     
         12 . The modulator as described in  claim 1  which is an agent of preventing or treating multiple sclerosis, neurodegenerative diseases, irritable bowel syndrome, Crohn's Disease, reflux oesophagitis, COPD, psoriasis, autoimmune diseases, graft rejection, allergic diseases, neuropathic pain, hepatitis virus or hypertension, or an agent of regulating immunity. 
     
     
         13 . A compound represented by Formula (I′) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 1  and R 2  are independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted mercapto group or an optionally substituted amino group, or R 1  and R 2  may be taken with the adjacent carbon atom to form an optionally substituted ring, R 3′  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted mercapto group or an optionally substituted amino group, R 4′  is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, Y is —CO—, —SO—, or —SO 2 —, R 5  is a hydrogen atom or an optionally substituted hydrocarbon group, R 6′  is an optionally substituted hydrocarbon group (provided that both of R 1  and R 2  are not a hydrogen atom, R 6′  has no benzene ring), an optionally substituted hydroxyl group or an optionally substituted amino group, and ring A′ is a benzene ring which may have further substituent in addition to a group represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein, each symbol has the same meaning as described above, or a salt thereof. 
     
     
         14 . The compound as described in  claim 13  wherein R 1  and R 2  are independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted mercapto group or an optionally substituted amino group. 
     
     
         15 . The compound as described in  claim 13  wherein R 1  and R 2  are a hydrogen atom. 
     
     
         16 . The compound as described in  claim 13  wherein R 1  and R 2  are respectively a hydrogen atom or a C 1 - 4  alkyl group, provided that R 1  and R 2  are not a hydrogen atom at the same time. 
     
     
         17 . The compound as described in  claim 13  wherein R 3′  is a hydrogen atom. 
     
     
         18 . The compound as described in  claim 13  wherein R 4′  is an optionally substituted C 6 - 14  aryl group or an optionally substituted 5 to 14-membered heterocyclic group. 
     
     
         19 . The compound as described in  claim 13  wherein R 4′  is an optionally substituted phenyl group. 
     
     
         20 . The compound as described in  claim 19  wherein R 4′  is a phenyl group which may be substituted with an optionally substituted C 1-4  alkyl group or an optionally substituted C 1-4  alkoxy group. 
     
     
         21 . The compound as described in  claim 13  wherein Y is —CO—. 
     
     
         22 . The compound as described in  claim 13  wherein R 5  is a hydrogen atom. 
     
     
         23 . The compound as described in  claim 13  wherein X is an oxygen atom. 
     
     
         24 . The compound as described in  claim 13  wherein 5-position of the fused-heterocycle in Formula (I′) is substituted by a group represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein, each symbol has the same meaning as described above. 
     
     
         25 . The compound as described in  claim 24  wherein 7-position of the fused-heterocycle in Formula (I′) is further substituted by an optionally substituted C 6-14  aryl-C 1 - 4  alkyl group. 
     
     
         26 . The compound as described in  claim 25  wherein the optionally substituted C 6-14  aryl-C 1 - 4  alkyl group is an optionally substituted benzyl group. 
     
     
         27 . The compound as described in  claim 13  wherein ring A′ is a benzene ring which may further have 1 to 3 substituents selected from an optionally substituted C 1-6  alkyl group, an optionally substituted C 6-12  aryl group, an optionally substituted 5- or 6-membered heterocyclic group and an acyl group in addition to a group represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein, each symbol has the same meaning as described above. 
     
     
         28 . The compound as described in  claim 27  wherein 7-position of the fused-heterocycle in Formula (I 0 ) is substituted by an optionally substituted C 1 - 4  alkyl group, an optionally substituted C 6-12  aryl group, an optionally substituted 5- or 6-membered heterocyclic group, or an acyl group. 
     
     
         29 . The compound as described in  claim 27  wherein 7-position of the fused-heterocycle in Formula (I 0 ) is substituted by an phenyl group, a furanyl group, a thienyl group, a pyridyl group, an acetyl group, a propionyl group, a butyryl group, or a benzoyl group, which may be substituted, respectively. 
     
     
         30 . (+)-N-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,
 N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   (+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   (+)-N-(tert-butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea,   N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(7-(3-dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(3-hydroxypropyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea,   N-((4-isopropyl-3-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1′-cyclopentan)-5-yl)-3,3-dimethylbutanamide,   N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(7-(6-fluoropyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(7-(3-furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,   N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide, or   N-(7-ethoxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide.   
     
     
         31 . A prodrug of the compound as described in  claim 13 . 
     
     
         32 . A drug, comprising the compound as described in  claim 13  or a prodrug thereof. 
     
     
         33 . A method of preventing, treating, or pain-relieving acute cerebrovascular disorders, spinal damage, head injury, multiple sclerosis, glaucoma, depression, vomit, arthritis or asthma, comprising administering an effective amount of a compound represented by Formula (I 0 ) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof to a subject in need of such treatment. 
     
     
         34 . A method of preventing or treating memory disorders, psychiatric diseases, obesity, mental diseases, anxiety, depression, drug-dependency, Alzheimer's dementia or Parkinson's disease, or a method of aiding smoking cessation, which is characterized by administering an 
       
         
           
           
               
               
           
         
       
       effective amount of a compound represented by Formula (I o )
 wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof to a subject in need of such treatment. 
 
     
     
         35 . A method of preventing or treating multiple sclerosis, neurodegenerative diseases, irritable bowel syndrome, Crohn's Disease, reflux oesophagitis, COPD, psoriasis, autoimmune diseases, graft rejection, allergic diseases, neuropathic pain, hepatitis virus or hypertension, or a method of regulating immunity, which is characterized by administering an effective amount of a compound represented by Formula (I 0 ) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof to a subject in need of such treatment. 
     
     
         36 . Use of a compound represented by Formula (I 0 ) 
       
         
           
           
               
               
           
         
         wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof, for manufacturing an agent of preventing or treating acute cerebrovascular disorders, spinal damage, head injury, multiple sclerosis, glaucoma, depression, vomit, arthritis or asthma; or for manufacturing an analgesic agent. 
       
     
     
         37 . Use of a compound represented by Formula (I 0 ) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof, for manufacturing an agent of preventing or treating memory disorders, psychiatric diseases, obesity, mental diseases, anxiety, depression, drug-dependency, Alzheimer's dementia or Parkinson's disease, or an aid for smoking cessation. 
     
     
         38 . Use of a compound represented by Formula (I 0 ) 
       
         
           
           
               
               
           
         
       
       wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 0  is an acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof, for manufacturing an agent of preventing or treating multiple sclerosis, neurodegenerative diseases, irritable bowel syndrome, Crohn's Disease, reflux oesophagitis, COPD, psoriasis, autoimmune diseases, graft rejection, allergic diseases, neuropathic pain, hepatitis virus or hypertension, or an agent of regulating immunity. 
     
     
         39 . A method of preparing a compound represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein, each symbol has the same meaning as described below, or a salt thereof, comprising reacting a compound 
       
         
           
           
               
               
           
         
       
       represented by the following formula
 wherein, X is an oxygen atom, an optionally substituted sulfur atom or an optionally substituted imino group, R 1 , R 2 , R 3  and R 4  are independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted mercapto group or an optionally substituted amino group, or R 2  and R 3  may be taken together to form a bond, or R 1  and R 2  may be taken with the adjacent carbon atom to form an optionally substituted ring, 
 R 5  is a hydrogen atom or an optionally substituted hydrocarbon group, R 6  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group, or R 5  and R 6  may be taken with the adjacent carbon atom or sulfur atom and nitrogen atom to form an optionally substituted ring, and 
 ring A is a benzene ring which may have further substituent in addition to a group represented by Formula —NHR 5  (wherein, each symbol has the same meaning as described above), or a salt thereof with, R 6 YL, (R 6 Y) 2 O or R 6 N═Y, wherein, L is a leaving group, and Y is —CO—, —SO—, or —SO 2 —. 
 
     
     
         40 . (+)-N-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         41 . N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         42 . (+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         43 . (+)-N-(tert-butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea or a salt thereof. 
     
     
         44 . N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         45 . N-(7-(3-dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         46 . N-(3-hydroxypropyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea or a salt thereof. 
     
     
         47 . N-((4-isopropyl-3-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         48 . N-(7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         49 . N-(3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         50 . N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1′-cyclopentan)-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         51 . N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         52 . N-(7-(6-fluoropyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         53 . N-(7-(3-furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         54 . N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof. 
     
     
         55 . N-(7-ethoxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide or a salt thereof.