Substituted isoquinoline derivatives and their use as anticonvulsants and in the treatment and/or prophylaxis of other neurological disorders

摘要

Compounds of formula (I), and pharmaceutically acceptable salts thereof for the manufacture of a medicament; where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R1 s hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCO-, formyl, CF3CO- or C1-6alkylSO2-, R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl-, C1-6alkylO-, C1-6alkylCO-, C3-6cycloalkylO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylO-, C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS-, C1-6alkylSO2-, (C1-4alkyl)2NSO2-, (C1-4alkyl)NHSO2-, (C1-4alkyl)2NCO-, (C1-4alkyl)NHCO- or CONH2; or -NR3R4 where R3 is hydrogen or C1-4alkyl, and R4 is hydrogen, C1-4alkyl, formyl, -CO2C1-4alkyl or -COC1-4alkyl; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and X is hydrogen, halogen, C1-6alkoxy, C1-6alkyl, amino or trifluoroacetylamino, but when X is hydrogen excluding compounds in which R2 is 2-alkoxy and when X is hydrogen 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-methoxy benzamide, 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-methoxy-4-trifluoromethyldiazirinylbenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-5-trifluoromethyldiazirinyl benzamide, N-(7-iodo-1,2,3,4,-tetrahydroisoquinolin-5-yl) -2-methoxy-5-trifluoromethyldiazirinylbenzamide et N-(8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -4-t-butyl-2-methoxybenzamide, are useful inter alia 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).