Substituted isoquinoline derivatives and their use as...

Details Substituted isoquinoline derivatives and their use as... Substituted isoquinoline derivatives and their use as...

2000-06-15

2001-06-19

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...

C546S143000

Reexamination Certificate

active

06248754

ABSTRACT:

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) discloses benzamido-etrahydroisoquinolines having anti-hypertensive and vasodilator properties.
WO97/48683 (SmithKline Beecham) discloses that benzamide compounds of formula (A) below possess anticonvulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, and related depression disorders.
where n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5;
R
1
is C
1-6
allylO—;
R
2
is hydrogen, halogen, CN, N
3
, trifluoromethyldiazirinyl, CF
3
, CF
3
O—, CF
3
S—, CF
3
CO—, C
1-6
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkyl-C
1-4
alkyl-, C
1-6
alkylO—, 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-, C
1-6
alkylS—, C
1-6
alkylSO
2
—, (C
1-4
alkyl)
2
NSO
2
— or (C
1-4
alkyl)NHSO
2
—;
R
3
is hydrogen, halogen, NO
2
, CN, N
3
, trifluoromethyldiazirinyl, 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—, 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
5
R
6
where R
5
is hydrogen or C
1-4
alkyl, and
R
6
is hydrogen, C
1-4
alkyl, —CHO, —CO
2
C
1-4
alkyl or —COC
1-4
alkyl;
R
4
is hydrogen, C
1-6
alkyl, C
1-6
alkenyl, or C
1-6
alkynyl;
and also 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-methoxy-4-trifluoromethyldiazirinylbenzamide, N-(5-iodo-1,2,3,4tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinyl-benzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethyldiazirinyl-benzamide and N-(8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide.
It has now been surprisingly found that tetrahydroisoquinolinyl-carboxamide compounds of formula (I) below possess anti-convulsant activity and are believed to be useful in the for 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).
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically 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 C
1-6
alkylSO
2
—,
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
CO—, tifluoromethyldiazirinyl, 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
alkylCO—, 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, CONH
2
, CF
3
SO
2
, C
1-6
alkenyl, C
1-6
alkynyl or C
1-6
hydroxyalkyl; 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 halogen, C
1-6
alkoxy, C
1-6
alkyl, C
2-6
alkenyl optionally substituted by phenyl.
When compounds of the present invention possess chiral centres and as such may exist in different enantiomeric forms, the present invention extends to each enantiomeric form and mixtures thereof including diastereoisomers and racemates. Alkenyl compounds exist as geometric isomers and the present invention extends to each isomeric form and mixtures thereof.
The ring system Q is typically optionally substituted phenyl or optionally substituted thiophenyl. When two R
2
groups form a carbocyclic ring, this is typically a 5-7 membered ring, so that Q may be a naphthalene or an indane or indanone ring system.
In the formula (I), alkyl groups, including alkyl groups that are part of other moieties, such as alkoxy or acyl, may be straight chain or branched. 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.
One suitable group of compounds of this invention are of formula (IA)
and another suitable group are of formula (IB)
A suitable group of compounds of formula (I) have
R
1
as hydrogen, methyl, ethyl, propyl, hydroxyethyl, formyl, acetyl, trifluoroacetyl or methanesulfonyl,
R
2
as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, methoxy, ethoxy, isopropoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, propionyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, tifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, trifluoromethyldiazirinyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl, CF
3
SO
2
;
or two groups R
2
form a benzene, cyclopentane or cyclopentanone ring;
X as methyl, ethyl, chloro, bromo, iodo, fluoro, phenylethenyl.
A preferred group of compounds of formula (I) have
R
1
as hydrogen, methyl, hydroxyethyl, formyl or trifluoroacetyl.
R
2
as hydrogen or one or more of methyl, ethyl, iso-propyl, methoxy, ethoxy, isopropoxy, acetyl, propionyl, pivaloyl, cyano, bromo, chloro, fluoro, iodo, trifluoromethyl.
X as methyl, ethyl, chloro or bromo.
In a special class of compounds of formula (I), suitable for use as mechanistic probes, R
2
groups are photolabile groups, such as N
3
, benzoyl and trifluoromethyldiazirinyl. Also radiolabels such as
125
I can be incorporated at R, and
3
H can be located at suitable positions.
Examples of compounds of formula (I) are:
N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
N-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl

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