Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-19
2002-05-28
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S399000, C549S405000
Reexamination Certificate
active
06395909
ABSTRACT:
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
EP-A-0 126 311, EP-A-0 376 524, EP-A-0 205 292, EP-A-0 250 077, EP-A-0 093 535, EP-A-0 150 202, EP-A-0 076 075 and WO/89/05808 (Beecham Group plc) describe certain benzopyran derivatives which possess anti-hypertensive activity.
EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group plc) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentined patent applications.
EP-A-0 139 992 (Beecham Group plc) describes certain benzopyran derivatives which have cis isomerism at position 3 and 4 which compounds are described as possessing anti-hypertensive activity.
EP-A-0 587 645, EP-A-0 673 373, EP-A-0 673 374, EP-A-0 673 248, EP-A-0 674 519, WO95/34545, WO95/34547 and WO95/34546 (SmithKline Beecham plc) describe groups of benzopyran compounds possessing inter alia anti-convulsant activity.
This invention is based on the finding that further benzopyran 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, multiple sclerosis (MS) and motor neurone disease, amyotrophic lateral sclerosis (ALS), ataxias, muscular rigidity (spasticity), and/or temporomandibular joint dysfunction.
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof:
in which
R
1
is C
1-6
alkylcarbonyl in which the alkyl group is substituted by OH;
R
2
is hydrogen or C
3-8
cycloalkyl, C
1-6
alkyl optionally interrupted by oxygen or substituted by hydroxy, C
1-6
alkoxy or substituted aminocarbonyl, C
1-6
alkylcarbonyl, C
1-6
alkoxycarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkoxy, nitro, cyano, halo, trifluoromethyl, CF
3
S, or a group CF
3
—A—, where A is —CF
2
—, —CO—, —CH
2
—, CH(OH), SO
2
, SO, CH
2
—O, or CONH, or a group CF
2
H—A′— where A′ is oxygen, sulfur, SO, SO
2
, CF
2
or CFH; trifluoromethoxy, C
1-6
alkylsulfinyl, perfluoro C
2-6
alkylsulfonyl, C
1-6
alkylsulfonyl, C
1-6
alkoxysulfinyl, C
1-6
alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C
1-6
alkylcarbonylamino, C
1-6
alkoxycarbonylamino, C
1-6
alkyl-thiocarbonyl, C
1-6
alkoxy-thiocarbonyl, C
1-6
alkyl-thiocarbonyloxy, 1-mercapto C
2-7
alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C
1-6
alkyl groups, or C
1-6
alkylsulfinylamino, C
1-6
alkylsulfonylamino, C
1-6
alkoxysulfinylamino or C
1-6
alkoxysulfonylamino, or ethylenyl terminally substituted by C
1-6
alkylcarbonyl, nitro or cyano, or —C(C
1-6
alkyl)NOH or —C(C
1-6
alkyl)NNH
2
,
R
a
is hydrogen, halogen, nitro; C
1-4
alkylcarbonyl, C
1-4
alkyl; aryl C
1-4
alkyl, aryl C
1-4
alkenyl, heteroaryl C
1-4
alkyl or heteroaryl C
1-4
alkenyl,
R
b
is hydrogen, halogen, nitro; C
1-4
alkylcarbonyl or C
1-4
alkyl; and in which any aryl or heteroaryl or alkyl moiety associated with R
a
or R
b
are optionally substituted;
one of R
3
and R
4
is hydrogen or C
1-4
alkyl and the other is C
1-4
alkyl, CF
3
or CH
2
X
a
where X
a
is fluoro, chloro, bromo, iodo, C
1-4
alkoxy, hydroxy, C
1-4
alkylcarbonyloxy, —S—C
1-4
alkyl, nitro, amino optionally substituted by one or two C
1-4
alkyl groups; cyano or C
1-4
alkoxycarbonyl;
or R
3
and R
4
together are C
2-5
polymethylene optionally substituted by C
1-4
alkyl;
R
5
is C
1-6
alkylcarbonyloxy, benzoyloxy, ONO
2
, benzyloxy, phenyloxy or C
1-6
alkoxy and R
6
and R
9
are hydrogen or R
5
is hydroxy and R
6
and R
9
are independently hydrogen or C
1-2
alkyl;
R
7
is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C
1-4
alkyl, cyano, azido, C
1-4
alkyl, C
1-4
alkoxy, trifluoromethoxy, trifluoromethyl; optionally substituted aryloxy or heteroaryloxy; C
1-4
alkoxy substituted by one or more halogens; amino substituted by C
1-4
alkanoyl, aroyl, aryl, phenylsulfonyl or C
1-4
alkylsulfonyl; C
1-4
alkyl substituted by one or more halogens or alkoxy; phenylsulfonyl C
1-4
alkyl sulfonyl, aminosulfonyl in which the amino group is optionally substituted by C
1-4
alkyl; CONH
2
in which the amino group is optionally substituted by C
1-4
alkyl;
R
8
is hydrogen; C
1-6
alkyl, OR
16
or NHCOR
17
wherein R
16
is hydrogen, C
1-6
alkyl, formyl, C
1-6
alkanoyl, aroyl or aryl-C
1-6
alkyl and R
17
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, mono or di C
1-6
alkyl amino, amino, amino-C-
1-6
alkyl, hydroxy-C
1-6
alkyl, halo-C
1-6
alkyl, C
1-6
acyloxy-C
1-6
alkyl, C
1-6
alkoxycarbonyl-C
1-6
-alkyl, aryl or heteroaryl;
or R
7
and R
8
together form a C
3-4
alkylene group;
and the R
8
—N—CO—R
7
group is cis or trans to the R
5
group.
A preferred group of compounds are of formula (IA)
i.e. R
2
, R
6
, R
8
, R
9
, R
a
and R
b
are hydrogen, R
5
is hydroxyl, R
3
and R
4
are both methyl, or one of R
3
and R
4
is methyl and the other of R
3
and R
4
is hydroxymethyl, and the R
7
CONH group is cis or trans to the R
5
hydroxyl group.
Preferably R
7
is phenyl or heteroaryl which may be optionally substituted by up to three substituents independently selected from:
bromo, chloro, fluoro, iodo, nitro, amino optionally substituted once or twice by C
1-4
alkyl, cyano, azido, C
1-4
alkyl, C
1-4
alkoxy, trifluoromethyl or trifluoromethoxy.
More preferably R
7
is phenyl substituted by one or two groups independently selected from chlorine and fluorine.
It should be appreciated that the compounds of formula (I) may have chiral carbon atoms at positions 2, 3 or 4 and therefore may exist as enantiomers. The present invention extends to each enantiomer and to mixtures thereof including racemates. It should further be appreciated that particular enantiomeric forms are preferred for different utilities, thus for utilities other than sub-arachnoid haemorrhage or neural shock the 3R, 4S and 3S, 4S enantiomers are preferred, however, for sub-arachnoid haemorrhage or neural shock the 3S, 4R and 3R, 4R enantiomers are preferred.
The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt thereof as hereinbefore defined which exists predominantly in the cis 3S, 4S or trans 3R, 4S enantiomeric form.
The term “exists predominantly in the 3S, 4S enantiomeric form” means that there is greater than 50% of the 3S, 4S enantiomer present compared to the 3R, 4R enantiomer. More preferably there is greater than 60% of the 3S, 4S enantiomer present, yet more preferably greater than 70% of the 3S, 4S enantiomer present, even more preferably greater than 80% of the 3S, 4S enantiomer present and more preferably still greater than 90% of the 3S, 4S enantiomer present. Most preferably there is
Bell David
Cox Peter J.
Thompson Mervyn
Turner Gillian
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