Indole derivatives as 5HT.sub.1 -like agonists

Details Indole derivatives as 5HT.sub.1 -like agonists Indole derivatives as 5HT.sub.1 -like agonists

1997-04-03

1998-06-23

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514414, 546201, 548468, C07D40314, C07D40514, A61K 3140, A61K 31445

Patent

active

057706115

DESCRIPTION:

BRIEF SUMMARY
This is the national stage under 35 U.S.C. 371 of application no. PCT/EP95/03884 filed Sep. 29, 1995.
The present invention relates to indole derivatives which act on 5-hydroxytryptamine (5-HT) receptors.
More particularly the present invention relates to 3,5-disubstituted indoles which are selective agonists at the "5-HT.sub.1 -like" subtype of the 5-hydroxytryptamine receptor. Such "5-HT.sub.1 -like" receptors are present in the carotid vascular bed and their activation causes vasoconstriction with a consequent reduction in carotid blood flow. Compounds which have "5-HT-like" agonist activity are therefore useful in the treatment of medical conditions which are thought to result from excessive dilation of the carotid bed, such as migraine, cluster headache, chronic paroxysmal hemicrania and headache associated with vascular disorders. Certain compounds of the present invention are also agonists at central 5-HT.sub.1 receptors and are therefore useful for the treatment of depression, anxiety, eating disorders, obesity, drug abuse and emesis.
The present invention provides compounds of formula: ##STR2## and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates (including hydrates) of either entity, wherein R.sup.1 is ##STR3## R.sup.2 is R.sup.3 R.sup.4 C(OH)A; V is C.dbd.O or CH.sub.2 ; -C.sub.4 alkyl; or, together with the carbon atom to which they are attached, form a 4- or 5-membered carbocyclic ring; -C.sub.4)alkyl; n is 1 and V is CH.sub.2 then W is O.
In the above definition, unless otherwise indicated, alkyl groups having three or more carbon atoms and alkanoyl groups having four or more carbon atoms may be straight chain or branched chain.
The compounds of formula (I) may contain one or more asymmetric centres and thus can exist as stereoisomers, i.e. as enantiomers or as diastereoisomers, and the invention includes both the separated individual stereoisomers as well as mixtures thereof.
The preferred stereoisomers are those compounds of formula (IA) which possess the R-configuration at the 2-position of the pyrrolidine ring, as represented by formula (IA): ##STR4##
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
The pharmaceutically acceptable salts of compounds of formula (I) are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids, or with organo-sulphonic acids. For a review of suitable pharmaceutical salts, see J. Pharm. Sci., 1977, 66, 1-19.
A preferred group of compounds of formula (I) is that wherein W is NR.sup.5 ; R.sup.3 and R.sup.4 are both methyl; R.sup.5 is H, benzyl, COCH.sub.3 or SO.sub.2 CH.sub.3 ; A is ethylene; m is 0 or 1; and n is 0.
A more preferred group of compounds of formula (I) is that wherein W is NR.sup.5 ; R.sup.3 and R.sup.4 are both methyl; R.sup.5 is benzyl or SO.sub.2 CH.sub.3 ; A is ethylene; m is 1; and n is 0.
Particularly preferred individual compounds of the invention include: roxy-3-methyl-1-butyl)-1H-indole ethyl)-2(R)-pyrrolidinylmethyl!-1H-indole; acceptable solvates (including hydrates) of either entity.
In another aspect, the present invention provides processes for the preparation of compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates (including hydrates) of either entity, as illustrated below. It will be appreciated by persons skilled in the art that, within the various processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps. It will also be appreciated that various standard transformations within certain compounds of formula (I) will provide

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