Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-04-07
2001-04-03
Powers, Fiona T. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C548S126000, C549S399000, C564S184000
Reexamination Certificate
active
06211211
ABSTRACT:
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
European Published Patent Application No. 0126311 discloses substituted benzopyran compounds having blood pressure lowering activity, including 6-acetyl-trans-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.
Also 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-0 350 805 (Biersdorf), EP-A-0 277 611, EP-A-0 277612, EP-A-0 337 179 and EP-A-0 355 565 (Hoechst Aktiengesellschaft); EP-A-0 466 131 (Nissan Chemical Industries Ltd), EP-A-0339562 (Yoshitomi Pharmaceuticals) EP-A-415 065 (E. Merck) EP-A450415 (Squibb), EP-A-0482934, EP-A-0296975, JO-2004-791 and WO\89\07103 also describe certain benzopyran derivatives which are believed to 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 mentioned 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.
PCT/GB92/01045 (SmithKline Beecham plc; unpublished at the priority date), which describes certain fluorobenzoylamino benzopyrans, pyranopyridines and tetrahydronaphthalenes in which the 3 and 4 position substituents are trans to each other. These compounds are described as possessing inter alia anxiolytic and anti-convulsant activity.
It has now been surprisingly found that certain compounds of formula (I) (below) possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of epilepsy; and are also believed to have utility in the treatment or prevention of anxiety, mania, depression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse, Parkinson's Disease, psychosis, migraine with or without aura, cerebral ischaemia, Alzheimer's disease, schizophrenia, OCD, ie, obsessive compulsive disorders, panic disorders or aggression.
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
wherein:
P is a ring system selected from the following:
wherein;
and the other variables are as defined below:
in which either a and b together represent a bond or CH
2
or a and b together represent a carbonyl group, a group C═NOR
F
, CHOR
F
or
where R
F
is hydrogen or C
1-6
alkyl; or
in which either J is nitrogen and J
a
is a lone pair of electrons, M is carbon and M
a
is R
5
; or
J is carbon and M is nitrogen and J
a
and M
a
are hydrogen; or
in which Z is oxygen or CH
2
; and;
wherein:
either Y is N and R
2
is hydrogen, or Y is C—R
1
and where:
either one of R
1
and R
2
is hydrogen and the other is selected from the class of hydrogen, 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, sulphur, SO, SO
2
, CF
2
or CFH; trifluoromethoxy, C
1-6
alkylsulphinyl, perfluoro C
2-6
alkylsulphonyl, C
1-6
alkylsulphonyl, C
1-6
alkoxysulphinyl, C
1-6
alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, heteroarylsulphonyl 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 aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C
1-6
alkyl groups, or C
1-6
alkylsulphinylamino, C
1-6
alkylsulphonylamino,C
1-6
alkoxysulphinylamino or C
1-6
alkoxysulphonylamino, 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
, or one of R
1
and R
2
is nitro, cyano or C
1-3
alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C
1-6
alkyl or by C
2-7
alkanoyl; or R
1
and R
2
together are —(CH
2
)
4
— or —CH═CH—CH═CH—, or form an optionally substituted triazole or oxadiazole ring;
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
is hydrogen or C
1-2
alkyl and R
9
is hydrogen;
R
7
is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from a first group consisting of 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 and trifluoromethyl; and/or a second group consisting of optionally substituted aryloxy or heteroaryloxy;
C
1-4
alkoxy substituted by one or more halogens (excluding trifluoromethoxy);
amino substituted by C
1-4
alkanoyl, aroyl, aryl, phenylsulphonyl or C
1-4
alkylsulphonyl;
C
1-4
alkyl substituted by hydroxy, one or more halogens (excluding trifluoromethyl), or alkoxy or alkylcarbonyloxy;
phenylsulphonyl, C
1-4
alkyl sulphonyl, aminosulphonyl 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; with the proviso that the substituents on the heteroaryl or phenyl are not exclusively selected from the first group;
R
8
is hydrogen; C
1-6
alkyl, OR
9
or NHCOR
10
wherein R
9
is hydrogen, C
1-6
alkyl, formyl, C
1-6
alkanoyl, aroyl or aryl-C
1-6
alkyl and R
10
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;
the R
8
—N—CO—R
7
group being cis or trans to the R
5
group; and X is oxygen or NR
11
where R
11
is hydrogen or C
1-6
alkyl.
All C
1-6
alkyl or C
1-4
alkyl or alkyl containing groups in formula (I) are preferably selected from methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.
Suitable C
3-8
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Suitable halo substituents include fluoro, chloro and bromo.
Aryl whenever mentioned herein includes but is not limited to phenyl and naphthyl.
Heteroaryl whenever mentioned herein includes a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different. Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolyl. Preferred examples of such g
Chan Wai Ngor
Evans John Morris
Thompson Mervyn
Kinzig Charles M.
McCarthy Mary E.
Powers Fiona T.
SmithKline Beecham p.l.c.
Venetianer Stephen
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