Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-16
2000-08-29
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546146, 51421301, 514412, 540593, 548503, C07D21704, A61K 3147
Patent
active
061109347
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
U.S. Pat. No. 4,022,900 (Marion), FR-A-2004748 (Marion) and DE-A-2101691 (Marion) disclose benzamido-tetrahydroisoquinolines having anti-hypertensive and vasodilator properties, including the compound 5-(2,4,5-trimethoxy-benzamido)-2-methyl-1,2,3,4-tetrahydroisoquinolin, which can also be expressed as 2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.
It as now been surprisingly found that benzamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention 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, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof: ##STR1## where n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5;
R.sup.1 is C.sub.1-6 alkylO-;
R.sup.2 is hydrogen, halogen, CN, N.sub.3, trifluoromethyldiazirinyl, CF.sub.3, CF.sub.3 O--, CF.sub.3 S--, CF.sub.3 CO--, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-, C.sub.1-6 alkylO-, C.sub.1-6 alkylCO-, C.sub.3-6 cycloalkylCO-, C.sub.3-6 cycloalkyl-C.sub.1-4 alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C.sub.1-4 alkyl-, C.sub.1-6 alkylS-, C.sub.1-6 alkylSO.sub.2 --, (C.sub.1-4 alkyl).sub.2 NSO.sub.2 -- or (C.sub.1-4 alkyl)NHSO.sub.2 --;
R.sup.3 is hydrogen, halogen, NO.sub.2, CN, N.sub.3, trifluoromethyldiazirinyl, C.sub.1-6 alkylO-, C.sub.1-6 alkylS-, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-, C.sub.1-6 alkenyl, C.sub.1-6 alkynyl, CF.sub.3 CO--, C.sub.1-6 alkylCO-, C.sub.3-6 cycloalkylCO-, C.sub.3-6 cycloalkyl-C.sub.1-4 alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C.sub.1-4 alkyl-, or --NR.sup.5 R.sup.6 were R.sup.5 is hydrogen or C.sub.1-4 alkyl, and R.sup.6 is hydrogen, C.sub.1-4 alkyl, --CHO, --CO.sub.2 C.sub.1-4 alkyl or --COC.sub.1-4 alkyl;
R.sup.4 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, or C.sub.1-6 alkynyl; 2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.
The compounds of this invention are typically (tetrahydroisoquinolin-5-yl)benzamides, (tetrahydroisoquinolin-6-yl)benzamides, (tetrahydroisoquinolin-7-yl)benzamides or (tetrahydroisoquinolin-8-yl)benzamides, especially (tetrahydroisoquinolin-7-yl)benzamides, and most suitably (tetrahydroisoquinolin-5-yl)benzamides; or (dihydroisoindol-4-yl)benzamides; or (tetrahydro-3-benzazepin-6-yl)benzamides.
In the formula (I), R.sup.1 alkoxy groups are typically based on straight chain alkyl groups, but in general alkyl groups may be straight chain or branched. Aromatic rings, especially the aromatic ring in the bicyclic heterocyclic moiety in formula (I) and phenyl groups, including phenyl groups that are part of other moieties, in R.sup.2 and R.sup.3 may optionally be substituted with one or more independently selected halogen or C.sub.1-6 alkyl, C.sub.1-6
REFERENCES:
patent: 4022900 (1977-05-01), Mathison
Mathison, et al., "Synthesis and Hypotensive Properties of Tetrahydroisoquinolines", (1973), Journal of Medicinal Chemistry, vol. 18, No. 4, pp. 332-336.
Harling John David
Orlek Barry Sidney
Thompson Mervyn
Davis Zinna Northington
Hall Linda E.
Kinzig Charles M.
SmithKline Beecham p.l.c.
Venetianer Stephen A.
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