Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-16
2001-08-14
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S310000, C546S140000, C546S143000
Reexamination Certificate
active
06274594
ABSTRACT:
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
WO96/39382 (Fujisawa) discloses the preparation of N-heterocyclyl-ureas as 5-HT antagonists, including the compound N-(1-methyl-1H-indol-5-yl)-N′-(1,2,3,4-tetrahydro-7-isoquinolinyl)-urea.
It has now been surprisingly found that heterocyclyl-N-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 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, panic disorders and/or aggression.
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
where P and Q are each independently a bond, methylene or ethylene such the ring structure Z is a five or six membered ring,
R
1
is hydrogen or C
1-6
alkyl,
R
2
is hydrogen or up to four substituents independently selected from halogen,
CF
3
, NO
2
, CN, N
3
, C
1-6
alkylO—, C
1-6
alkylS—, C
1-6
alkyl, C
3-6
cycloalkyl,
C
3-6
cycloalkyl-C
1-4
alkyl-, C
1-6
alkenyl, C
1-6
alkynyl, CF
3
CO—, CF
3
O,
C
1-6
alkylCO—, C
3-6
cycloalkylCO—, C
3-6
cycloalkyl-C
1-4
alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C
1-4
alkyl-,
or —NR
4
R
5
where
R
4
is hydrogen or C
1-4
alkyl, and
R
5
is hydrogen, C
1-4
alkyl, —CHO, —CO
2
C
1-4
alkyl or —COC
1-4
alkyl.
R
3
is hydrogen or up to two C
1-6
alkyl groups.
The ring structure Z is a five or six-membered saturated ring, optionally substituted by one or two C
1-6
alkyl groups, including gem-dialkyl substitution, typically such that compounds of this invention are tetrahydroisoquinoline, tetrahydroquinoline or dihydroindole N-carboxamides.
The left hand side tetrahydroisoquinolinyl moiety is typically tetrahydroisoquinolin-5-yl or tetrahydroisoquinolin-7-yl.
The benzene ring fused to ring structure Z may be substituted by up to four, preferably 2 or 1, non-hydrogen R
2
groups.
In the formula (I), alkyl groups, including alkyl groups that are part of another moiety, may be straight chain or branched. Aromatic rings, such as 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
2
may optionally be substituted with one or more independently selected halogen or 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 formula (I) have substituents selected from:
R
1
as hydrogen, methyl, ethyl or propyl,
R
2
as hydrogen, methyl, ethyl, n-butyl, phenyl, iso-propyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, phenoxy, benzyloxy, bromo, chloro, iodo, fluoro, nitro, cyano, acetyl, pivaloyl, iso-butyroyl, benzoyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, amino, acetylamino, methylthio, n-propylsulfonyl, isopropylsulfonyl or dimethylsulfamoyl.
R
3
as hydrogen or methyl.
Examples of compounds of formula (I) are:
2,3-dihydroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amide
3,4-dihydro-1H-isoquinoline-2-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
3,4-dihydro-2H-quinoline-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dihydro-5-methylthio-6-trifluoromethyl-indole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amide
2,3-dihydro-6-methoxyindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dihydro-4-methoxyindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dihydro-4,5,6,7-tetrafluoroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amide
2,3-dihydro-5-fluoroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dihydro-5-nitroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dihydro-6-nitroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dihydro-5-methoxy-6-trifluoromethylindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amide
3,3-dimethyl-2,3-dihydroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dimethyl-2,3-dihydroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
2,3-dimethyl-2,3-dihydroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)amide
3,3-dimethyl—5-fluoro-2,3-dihydroindole-1-carboxylic acid (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amide.
When synthesised, these compounds may be in salt form, such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
The above-listed compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, nasal, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to
Coulton Steven
Porter Roderick Alan
Thompson Mervyn
King William T.
Kinzig Charles M.
Seaman D. Margaret
Simon Soma G.
SmithKline Beecham p.l.c.
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