Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-11
2004-08-03
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S145000
Reexamination Certificate
active
06770657
ABSTRACT:
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
Prior art document U.S. Pat. No. 4,022,900 (Marion Laboratories Inc.) discloses benzamido-1,2,3,4-tetrahydroisoquinolines having anti-hypertensive properties. Prior art documents International Application Publication Numbers WO 97/48683, WO98/41507, WO 98/41508, WO 97/48683, WO 99/21836 and WO 99/31068 (SmithKline Beecham) disclose isoquinolinyl benzamide derivatives and their use as anticonvulsants.
It has now been surprisingly found that carboxamide 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 ischaernia, 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 trigerminal 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).
Accordingly, in a first aspect, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
wherein:
Q is a monocyclic or bicyclic aryl or heteroaryl ring;
R
1
is hydrogen;
R
2
is hydrogen or up to three substituents selected from halogen, NO
2
, CN, N
3
, CF
3
O—, CF
3
S—, CF
3
SO
2
—, CF
3
CO—, C
1-6
alkyl, C
1-6
alkenyl, C
1-6
alkynyl, C
1-6
perfluoroalkyl, C
3-6
cycloalkyl, C
3-6
cycloalkyl-C
1-4
alkyl-, C
1-6
alkylO—, C
1-6
akylCO—, C
3-6
cycloalkylO—, C
3-6
cycloalkylCO—,C
3-6
cycloalkyl-C
1-4
alkylO—, C
3-6
cycloalkyl-C
1-4
alkylCO—,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
NCO—, (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;
X is halogen, C
1-6
alkoxy, C
1-6
alkyl, or C
1-6
perfluoroalkyl, and;
Y is hydrogen, halogen, C
1-6
alkoxy, C
1-6
alkyl, or C
1-6
perfluoroalkyl; with the proviso that the following compounds are excluded:
N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, and;
N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide.
The compounds of this invention are typically (tetrahydroisoquinolin-7-yl) carboxamides.
The ring system Q is typically unsubstituted or substituted phenyl or unsubstituted or substituted thiophenol. When two R
2
groups form a carbocyclic ring, this is typically a 5-7-membered ring, and Q may be a naphthalene, indane, or indanone ring system.
Alkyl groups of formula (I), including alkyl groups that are part of other moieties such as alkoxy or acyl, may be straight or branched chain. Phenyl groups in R
2
, including phenyl groups that are part of other moieties, may be substituted independently with one or more groups selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, or C
1-6
alkylcarbonyl. Suitable C
3-6
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.
A suitable group of compounds of this invention consists of compounds of formula (IA):
another suitable group of compounds consists of compounds of formula (IB):
wherein R
1
, R
2
, X, and Y are as hereinbefore defined.
A suitable group of compounds of formula (I) are those wherein;
R
1
is hydrogen;
R
2
is hydrogen or one or more of the following groups; methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl, or two R
2
groups form a benzene, cyclopentane or cyclopentanone ring;
X is chloro, bromo, iodo, fluoro C
1-6
perfluoroalkyl, and;
Y is hydrogen, halogen, C
1-6
alkoxy, C
1-6
alkyl, or , C
1-6
perfluoroalkyl.
A preferred group of compounds of formula (I) are those wherein:
R
1
is hydrogen;
R
2
is hydrogen or one or more of the following groups; methyl, ethyl, iso-propyl, n-butyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, phenoxy, acetoxy, nitro, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, trifluoromethyl, pentafluoroethyl, azido, trifluoromethoxy;
X is iodo, chloro, bromo or trifluoromethyl, and;
Y is hydrogen, chloro, bromo, iodo or trifluoromethyl.
The following compounds are examples of compounds of formula (I), but do not limit the invention in any way:
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxy benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethylbenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-trifluoromethyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxy benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxy benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-trifluoromethyl benzamide
N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propoxybenzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl benzamide
N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxy-3-trifluoromethyl benzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-trifluoromethyl benzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(5-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide
N-(5-Trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide
Harling John David
Thompson Mervyn
Davis Zinna Northington
Hall Linda E.
Kinzig Charles M.
Smithkline Beecham p.l.c.
Venetianer Stephen A.
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