Use of benzopyranols to treat neurological disorders

Abstract

Benzopyran derivatives and analogs are disclosed as useful for the treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction.

1 . A method of treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction,  
       which comprises administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (A) or pharmaceutically acceptable salt or solvate thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 P is a ring system selected from the following:  
                     
  and the other variables are as defined below:  
                     in which either a and b together represent a bond or CH 2  or a and b together represent a carbonyl group, a group C═NOR F , CHOR F  or                          where R F  is hydrogen or C 1-6  alkyl; or                          in which either J is nitrogen and J a  is a lone pair of electrons, M is carbon and M a  is R 5 ; or    J is carbon and M is nitrogen and J a  and M a  are hydrogen; or                          in which Z is oxygen or CH 2 ;                          wherein:    
 either Y is N and R 2  is hydrogen, or Y is C—R 1 ; where: 
 either one of R 1  and R 2  is hydrogen and the other is selected from the class of hydrogen, C 3-8  cycloalkyl, C 1-6  alkyl optionally interrupted by oxygen or substituted by hydroxy, C 1-6  alkoxy or substituted aminocarbonyl, C 1-6  alkylcarbonyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyloxy, C 1-6  alkoxy, nitro, cyano, halo, trifluoromethyl, CF 3 S, or a group CF 3 -A-, where A is —CF 2 —, —CO—, —CH 2 —, CH(OH), SO 2 , SO, CH 2 —O, or CONH, or a group CF 2 H-A′- where A′ is oxygen, sulfur, SO, SO 2 , CF 2  or CFH; trifluoromethoxy, C 1-6  alkylsulfinyl, perfluoro C 2-6  alkylsulfonyl, C 1-6  alkylsulfonyl, C 1-6  alkoxysulfinyl, C 1-6  alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C 1-6  alkylcarbonylamino, C 1-6  alkoxycarbonylamino, C 1-6  alkyl-thiocarbonyl, C 1-6  alkoxy-thiocarbonyl, C 1-6  alkyl-thiocarbonyloxy, 1-mercapto C 2-7  alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C 1-6  alkyl groups, or C 1-6  alkylsulfinylamnnino, C 1-6  alkylsulfonylamino, C 1-6  alkoxysulfinylamino or C 1-6  alkoxysulfonylamino, or ethylenyl terminally substituted by C 1-6  alkylcarbonyl, nitro or cyano, or —C(C 1-6  alkyl)NOH or —C(C 1-6  alkyl)NNH 2 ,  
 or one of R 1  and R 2  is nitro, cyano or C 1-3  alkylcarbonyl and the other is halo, C 1-4  alkyl, methoxy or amino optionally substituted by one or two C 1-6  alkyl or by C 2-7  alkanoyl;  
 or R 1  and R 2  together are —(CH 2 ) 4 —; (CH 2 ) x CO (CH 2 ) y  where x is 0 to 3 and y is 0 to 3 with the proviso that x+y is at least 2x; or —CH═CH—CH═CH—; or form an optionally substituted triazole or oxadiazole ring, or together form a group CONR C CO where R C  is hydrogen, C 1-6  alkyl, aralkyl or heteroarylalkyl;  
 Z is N only when Y is C—R 1  or Z is C—R a  when Y is N or C—R 1 ; wherein R a  is hydrogen, halogen, nitro; C 1-4  alkylcarbonyl, C 1-4  alkyl; aryl C 1-4  alkyl, aryl C 1-4  alkenyl, heteroaryl C 1-4  alkyl or heteroaryl C 1-4  alkenyl,  
 R b  is hydrogen, halogen, nitro; C 1-4  alkylcarbonyl or C 1-4  alkyl; and in which any aryl or heteroaryl or alkyl moeity associated with R a  or R b  are optionally substituted;  
 one of R 3  and R 4  is hydrogen or C 1-4  alkyl and the other is C 1-4  alkyl, CF 3  or CH 2 X a  where X a  is fluoro, chloro, bromo, iodo, C 1-4  alkoxy, hydroxy, C 1-4  alkylcarbonyloxy, —S—C 1-4  alkyl, nitro, amino optionally substituted by one or two C 1-4  alkyl groups; cyano or C 1-4  alkoxycarbonyl  
 or R 3  and R 4  together are C 2-5  polymethylene optionally substituted by C 1-4  alkyl;  
 R 5  is C 1-6  alkylcarbonyloxy, benzoyloxy, ONO 2 , benzyloxy, phenyloxy or C 1-6  alkoxy and R 6  and R 9  are hydrogen or R 5  is hydroxy and R 6  and R 9  are independently hydrogen or C 1-2  alkyl;  
 R x  is (a)  
                     
  in which: 
 R 11  and R 12  are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, cyano, nitro, COR 13 , CONHR 13 , CONR 13 R 14  or halo where R 13  and R 14  are independently selected from hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl)-alkyl;  
 R 10  is hydrogen, alkyl, haloalkyl, cycloalkyl, O—R 15 , cyano, nitro, CF 3 , halo, S-alkyl, COR 15 , COOR 15 , NR 15 CO alkyl or OCO alkyl where R 15  is hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl)-alkyl; m is O or 1;  
 
  or (b) R x  is a R 8 —N—CO—R 7  group where 
 R 7  is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C 1-4  alkyl, cyano, azido, C 1-4  alkyl, C 1-4  alkoxy, trifluoromethoxy, trifluoromethyl; optionally substituted aryloxy or heteroaryloxy; C 1-4  alkoxy substituted by one or more halogens (excluding trifluoromethoxy); amino substituted by C 1-4  alkanoyl, aroyl aryl phenylsulfonyl or C 1-4  alkylsulfonyl; C 1-4  alkyl substituted by one or more halogens (excluding trifluoromethyl) or alkoxy; phenylsulfonyl C 1-4  alkyl sulfonyl, aminosulfonyl in which the amino group is optionally substituted by C 1-4  alkyl; CONH 2  in which the amino group is optionally substituted by C 1-4  alkyl;  
 R 8  is hydrogen; C 1-6  alkyl, OR 16  or NHCOR 17  wherein R 16  is hydrogen, C 1-6  alkyl, formyl, C 1-6  alkanoyl, aroyl or aryl-C 1-6  alkyl and R 17  is hydrogen, C 1-6  alkyl, C 1-6  alkoxy, mono or di C 1-6  alkyl amino, amino, amino-C 1-6  alkyl, hydroxy-C 1-6  alkyl, halo-C 1-6  alkyl, C 1-6  acyloxy-C 1-6  alkyl, C 1-6  alkoxycarbonyl-C 1-6 -alkyl, aryl or heteroaryl;  
 X is oxygen or NR 18  where R 18  is hydrogen or C 1-6  alkyl; and the R x  group is cis or trans to the R 5  group.  
 
 
 
     
     
         2 . A pharmaceutical composition for use in the treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea. schizophrenia, neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity) and temporomandibular joint dysfunction, which comprises a compound of formula (A) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.  
     
     
         3 . The use of a compound of formula (A) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits associated with ADS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity) and temporomandibular joint dysfunction.  
     
     
         4 . A method according to  claim 1 , for the treatment of trigeminal neuralgia.  
     
     
         5 . A composition according to  claim 2 , for the treatment of trigeminal neuralgia.  
     
     
         6 . A use according to  claim 3 , for the treatment of trigeminal neuralgia.  
     
     
         7 . A method according to  claim 1 , for the treatment of neuropathic pain.  
     
     
         8 . A composition according to  claim 2 , for the treatment of neuropathic pain.  
     
     
         9 . A use according to  claim 3 , for the treatment of neuropathic pain.  
     
     
         10 . A method according to  claim 1 ,  4  or  7 , in which the compound of formula (A) is trans-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol or cis-6-acetyl-4S-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol or trans-6-acetyl-4S-(3,5-difluorobenzoyl-amino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         11 . A composition according to  claim 2 ,  5  or  8 , in which the compound of formula (A) is trans-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol or cis-6-acetyl-4S-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol or trans-6-acetyl-4S-(3,5-difluorobenzoyl-amino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, or a pharmaceutically acceptable silt or solvate thereof.  
     
     
         12 . A use according to  claim 3 ,  6  or  9 , in which the compound of formula (A) is trans-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol or cis-6-acetyl-4S-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol or trans-6-acetyl-4S-(3,5-difluorobenzoyl-amino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, or a pharmaceutically acceptable salt or solvate thereof.