Substituted isoquinoline derivatives and their use as anticonvulsants

Abstract

This invention relates to substituted isoquinoline derivatives and their use as anticonvulsants.

1 . A compound of formula (I) or a p eutially acceptable salt thereof:  
                   
       where Q is a monocyclic or bicyclic aryl or heteroaryl ring, 
 R 1  is hydrogen, C 1-6  alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), C 1-6 alkenyl, C 1-6 alkynyl C 1-6 alkylCO—, formyl, CF 3 CO— or  
 R 2  is hydrogen, hydroxy or up to three substituents selected from halogen, NO 2 , CN, N 3 , 
 CF 3 O—, CF 3 S—, CF 3 CO—, trifuoromethyldiaztinyl, C 1-6 alkyl, C 1-6 alknyl  
 C 1-6 alkynyl, C 1-6 perfluoroalkyl, C 3-6 -cycloalkyl,  
 C 3-6 -cycloalkyl-C 1-4 alkyl-, C 1-6 alkyl, C 1-6 alykCO—,  
 C 3-6 -cycloalkylO—, C 3-6 -cycloalkylCO—, C 3-6 -cycloalkyl-C 1-4 alkylO—,  
 C 3-6 -cycloalkyl-C 1-4 aklyCO—, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl-, C 1-6 alkylS—, C 1-6 alkylSO 2 —, (C 1-4 alkyl) 2 NSO 2 —,  
 (C 1-4 alkyl)NHSO 2 —, (C 1-4 alkyl) 2 NC—, (C 1-4 alkyl)NHCO— or CONH 2 ;  
 or —NR 3 R 4  where R 3  is hydrogen or C 1-4  alkyl, and  
 R 4  is hydrogen, C 1-4 alkyl, formyl, —CO 2 C 1-4 alkyl or —COC 1-4 alkyl;  
 or two R 2  groups together form a carbocyclic ring that is saturated or  
 unsaturated and unsubstituted or substituted by —OH or ═O; and  
 
 X is hydrogen, halogen, C 1-6  alkoxy, C 1-6  alkyl, amino or trifluoroacetylamino; but when X is hydrogen excluding compounds in which R 2  is 2-alkoxy and when X is halogen excluding the compounds N-(7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxyutrifluoromethyldiazirnylbenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethyldiazinyl benzamide and N-(8-fluoro-2-methyl-1,2,3,4-teydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide.  
 
     
     
         2 . A compound of formula (IA) or (lB):  
                   
       wherein R 1 , R 2  and X are as defined in    claim 1   .  
     
     
         3 . A compound selected from the group consisting of: 
 N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide    N-(2-meihyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlorobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-t-butylbenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxybenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenoxybenzarnide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-nitrobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylbenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylbenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenzanide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dichlorobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-bromobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methylbenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-nitrobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxybenzanide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-butylbenzamnide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-acetoxybenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-triuoromethylbenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-difluorobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dimethoxybenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-fluoro-4-trifluoromethyl benzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-nitrobenzarnide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-di-triuoromethylbenzamide    N-(2-methyl-1,2.3,4-tetrahydroisoquinolin-7-yl)-2,4-dichloro-5-fluorobenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-5-trifluoromethyl benzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromometoxybenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4,5-timethoxybenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethoxybenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-pivaloylbenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propoxybenzanide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-acetoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopentyloxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopropylmethoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-pymethoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-naphthamnide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-naphthalene-1-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzaraide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-tety-butoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4n-propoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzotriazole-5-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzothiazole-6-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydrobenzofuran-5-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylbenzimidazole-5-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoqiinolin-7-yl)-3-chloro-4-iso-propoxybenzaradie    N-(2-Methyl-1,2,3,4-tetrahydroisouinolin-7-yl)-3-bromo-4-ethoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifiuoromethyl benzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-iso-methoxybenzamide    N-(2-Methyl)-1,2,3,4-tetmhydroisoquinoln-7-yl)-3,5-dichlorothoxybenzamide    N-(2-Methyl)-1,2,3,4-tetydroisoquinoln-7-yl)-3,5-dichloroiso-propoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonylbenzamide    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromotert-butylbenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-bromo-5-methoxybeuzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl-4-fluoro-3-methoxybenzamide, hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-methylpyrazole-4-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylthiazole-4-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-methylisoxazole-3-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-tert-butylisoxazole-3-carboxamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyisoxazole-5-carboxamide hydrochloride    N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)indole-2-carboxamide.    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propylbenzamide, hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinohin-7-yl)-3-cyano-4iso-propylbenzamide, hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3fluoromethoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-n-propoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-ethoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-n-propoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylhbenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxy-3-trifluoromethyl benzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-methoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxy-3-trifluoromethyl benzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-tert-butylbenzamide, hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxybenzamide hydrochloride.    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methylbenzamide, hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propylbenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propyl-3-trifluoromethyl-benzamide hydrochloride    N-(2-Methy-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-trifluoromethylbenzamide hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propoxybenzamide hydrochloride    N-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methyl-3-methylsulfonyl-benzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-methylsulfonylbenzamide    N-(2-Methyl-1,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-iso-propylbenzamide    N-(2-Methyl-1,2,3,-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-methoxybenzamide    N-(2-Methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamnide, hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl-benzamide hydrochloride    N-(2-n-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide    N-(2-n-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide    N-(2-n-Propyl-1,2,3,4-tetrahydroisquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-butylbenzamnide hydrochloride    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-butyl-3-difluoromethyl-benzamide hydrochloride    N-(2-Ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromowethoxybenzamide    N-(2-Ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-fluoromethyl benzamide    N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide    N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl ben7amide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-ethoxy-3-methylsulfonyl-benzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman-6-carboxamide hydrochloride    N-(2-Formyl-1,2,3,-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide    N-(2-Hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide    N-(2-Hydroxyethyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylmethoxy-3-trifluoromethyl benzamide    N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4 -hydroxy-3-trifiuoromethyl benzamide    N-(2-Methoxyethyl-l1,2,3,4-tetrrydroisoquinolin-7-yl)-3-bromo-4-iso-propoxyber amide    N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide    N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide    N-5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, trifluoroacetate    N-(2-Methyl-5-trifluoroacetylamino-1,2,3,4-tetrahydroisoquinoin-7-yl)-3-bromoA4-methoxybenzamide    N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromoethoxybenzamide    N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromoethylbenzamide.    
     
     
         4 . A pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & 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 (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS) which comprises a compound according to any one of    claims 1    to    3   , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.  
     
     
         5 . A method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & 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 (MS) and motor neurone disease, ataxias, muscularigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound according to any one of    claims 1    to    3   , or a pharmaceutically acceptable salt or solvate thereof.  
     
     
         6 . Use of a compound according to any one of    claims 1    to    3   , or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders andlor aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-onvulsive agents, such as epilepsy including post-traumatic epilepsy, Partinson's disease, psychosis, migaaine, cerebral ischaemia, Alzheimers disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & 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 (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS).  
     
     
         7 . A process for the preparation of a compound according to any one of    claims 1    to    3   , which comprises reacting a compound of formula (II)  
                 
 
       where R 1A  is R 1  as defined for formula () or a group convertible to R 1  and X is as defmed in    claim 1    with a compound of formula (III)  
                 

 where Q is as defined in formula (I), Y is Cl or OH, and R 2A  groups are independently R 2  as defined for formula (I) or groups convertible to R 2 ,  
 and where required converting an R 1A  or R 2A  group to a R 1  or R 2  group,  
 converting one R 1  or R 2  group to another R 1  or R 2  group,  
 converting a salt product to the free base or another pharmaceutically acceptable salt, or  
 converting a free base product to a pharmaceutically acceptable salt.