Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-06-27
1995-12-12
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548466, A61K 31405, C07D40304
Patent
active
054750202
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage of PCT/EP93/00074, filed Jan. 12, 1993
and now WO93/10487, published Jul. 22, 1993.
This invention relates to indole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use, in particular to compounds and compositions of use in the treatment of migraine.
It has been suggested that the pain of migraine may be associated with excessive dilatation of the cranial vasculature and known treatments for migraine include the administration of compounds having vasoconstrictor properties such as ergotamine. However, ergotamine is a non-selective vasoconstrictor which constricts blood vessels throughout the body and has undesirable and potentially dangerous side effects. Migraine may also be treated by administering an analgesic usually in combination with an antiemetic but such treatments are of limited value.
More recently, indole derivatives which are selective 5HT.sub.1 -like receptor angonists and which exhibit selective vasoconstrictor activity have been described in the art as useful in the treatment of migraine.
We have now found a novel group of indole derivatives which exhibit 5HT.sub.1 -like receptor agaonist activity and selective vasoconstriction.
Thus, the present invention provides a compound of formula (I): ##STR2## wherein R.sub.0 represents a hydrogen atom or a C.sub.1-3 alkyl group;
R.sub.1 represents a group R.sub.4 CONH--, R.sub.4 R.sub.5 NSO.sub.2 --, R.sub.4 SO.sub.2 NH-- or R.sub.4 R.sub.5 NCO-- (where R.sub.4 represents a hydrogen atom or a C.sub.1-6 alkyl group, provided that R.sub.4 does not represent a hydrogen atom when R.sub.1 represents R.sub.4 SO.sub.2 NH--, and R.sub.5 represents a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl or phen (C.sub.1-3)alkyl group in which the phenyl ring is optionally substituted by a halogen atom or a C.sub.1-4 alkoxy, hydroxy or C.sub.1-3 alkyl group); R.sub.2 represents a hydrogen atom or a C.sub.-3 alkyl, C.sub.3-6 alkenyl, phenyl or phen(C.sub.1-3)alkyl group; R.sub.3 represents a hydrogen atom, a C.sub.1-3 alkyl group or a group --CO.sub.2 R.sub.6, --COR.sub.6, --COCO.sub.2 R.sub.6 or --CONHR.sub.6 where R.sub.6 represents a hydrogen atom or a C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, aryl or ar(C.sub.1-4)alkyl group in which the aryl group may be unsubstituted or substituted by a halogen atom or a C.sub.1-4 alkoxy, C.sub.1-4 alkyl or hydroxy group (provided that when R.sub.3 represents --CO.sub.2 R.sub.6, R.sub.6 is other than hydrogen);
As used herein an alkyl group either as such or as part of a phenalkyl, alkoxy or alkoxycarbonyl group may be a straight chain or branched chain alkyl group, for example a methyl, ethyl, or prop-2-yl group. A C.sub.1-6 alkyl group is conveniently C.sub.1-3 alkyl such as methyl. A C.sub.3-7 cycloalkyl group may be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
When R.sub.5 represents a substituted or unsubstituted phen (C.sub.1-3)alkyl group, the alkyl moiety of the group is preferably methyl.
A halogen substitutent may be a fluorine, chlorine, bromine or iodine atom. A C.sub.1-4 alkoxy group may be, for example, a methoxy or ethoxy group.
An aryl group, either as such or as part of an ar(C.sub.1-4)alkyl group is preferably phenyl. Where R.sub.2 and/or R.sub.6 represents an alkenyl group it will be understood that no double bond may be adjacent to the nitrogen atom. An alkenyl group may for example be a 2-propenyl or butenyl group.
In one preferred class of compounds of formula (I), R.sub.1 represents a group R.sub.4 CONH--.
In another preferred class of compounds of formula (I), R.sub.1 represents a group R.sub.4 R.sub.5 NSO.sub.2 --, for example CH.sub.3 NHSO.sub.2 --.
Another preferred class of compounds of formula (I) is that in which R.sub.1 represents a group R.sub.4 SO.sub.2 NH--.
In a further preferred class of compounds of formula (I), R.sub.1 represents a group R.sub.4 R.sub.5 NCO--, for example H.sub.2 NCO--.
In the compounds of formula (I) R.sub.
REFERENCES:
patent: 3506683 (1970-04-01), Anthony et al.
Johnson Martin R.
North Peter C.
Glaxo Group Limited
Haley Jacqueline
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