Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-10-20
1997-03-04
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514415, 514419, 514323, 514339, 514210, 546 20, 5462774, 548466, 548492, 548493, 548494, 548511, A61K 31405, C07D40104, C07D40106
Patent
active
056079605
DESCRIPTION:
BRIEF SUMMARY
This applicaiton is a 371 of PCT/EP 94/01121 filed Apr. 11, 1994.
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.sub.1 -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.
WO-A-92/06973 discloses a series of 3,5-disubstituted indoles having utilities similar to those of the present invention and which are related to compounds of formula (IA), vide infra, but which contain structurally distinct 5-substitutents.
J. Med. Chem., 1963, 6, 719 relates, inter alia, to the synthesis, and antiserotonin and hypotensive properties, of certain 5-acyltryptamines, whilst J. Med. Chem., 1979, 22, 428 reports the serotonin receptor binding affinities of various tryptamine analogues. In addition, the effects of some tryptamine analogues on brain monoamines are described in Neuropharmacology, 1972, 11, 373 (Chem. Abs., 1972, 77, 83394v).
The present invention provides compounds of formula: ##STR1## pharmaceutically acceptable salts thereof, and pharmaceutically acceptable-solvates (including hydrates) of either entity, wherein R.sup.1 is ##STR2## or CH.sub.2 CH.sub.2 NR.sup.3 R.sup.4 (E);
R.sup.2 is R.sup.5 R.sup.6 C(OH)A or R.sup.7 COA;
R.sup.3 is H; C.sub.1 -C.sub.6 alkyl; (R.sup.8 CO) C.sub.1 -C.sub.3 alkylene; (R.sup.9 O.sub.2 C) C.sub.1 -C.sub.3 alkylene; (R.sup.10 R.sup.11 NOC) C.sub.1 -C.sub.6 alkylene; (R.sup.10 R.sup.11 NO.sub.2 S) C.sub.1 -C.sub.3 alkylene; [R.sup.8 S(O).sub.m ]C.sub.1 -C.sub.3 alkylene; (R.sup.12 O) C.sub.2 -C.sub.4 alkylene; (R.sup.13 NH) C.sub.2 -C.sub.4 alkylene; (C.sub.3 -C.sub.7 cycloalkyl) C.sub.1 -C.sub.3 alkylene; (aryl) C.sub.1 -C.sub.3 alkylene; (heteroaryl) C.sub.1 -C.sub.3 alkylene; C.sub.3 -C.sub.7 cycloalkyl optionally substituted with HO; C.sub.3 -C.sub.6 alkenyl optionally substituted with aryl; C.sub.5 -C.sub.7 cycloalkenyl; or C.sub.3 -C.sub.6 alkynyl;
R.sup.4 is H or C.sub.1 -C.sub.6 alkyl;
R.sup.5 and R.sup.6 are each independently selected from H; C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.4 perfluoroalkyl; and C.sub.3 -C.sub.7 cycloalkyl; or, together with the carbon atom to which they are attached, form a 3- to 7-membered carbocyclic ring which optionally incorporates a double bond or a heteroatom linkage selected from O, S(O).sub.m, NH, N(C.sub.1 -C.sub.4 alkyl), and N(C.sub.1 -C.sub.5 alkanoyl);
R.sup.7 and R.sup.8 are each independently selected from C.sub.1 -C.sub.6 alkyl; (C.sub.3 -C.sub.7 cycloalkyl) C.sub.1 -C.sub.3 alkylene; (aryl) C.sub.1 -C.sub.3 alkylene; C.sub.3 -C.sub.7 cycloalkyl; and aryl;
R.sup.9 is C.sub.1 -C.sub.6 alkyl; (C.sub.3 -C.sub.7 cycloalkyl) C.sub.1 -C.sub.3 alkylene; (aryl) C.sub.1 -C.sub.3 alkylene; or C.sub.3 -C.sub.7 cycloalkyl;
R.sup.10 and R.sup.11 are each independently selected from H; C.sub.1 -C.sub.6 alkyl; (R.sup.14 R.sup.15 NOC) C.sub.1 -C.sub.3 alkylene; (R.sup.16 O) C.sub.2 -C.sub.4 alkylene; (C.sub.3 -C.sub.7 cycloalkyl) C.sub.1 -C.sub.3 alkylene; (aryl) C.sub.1 -C.sub.3 alkylene; and C.sub.3 -C.sub.7 cycloalkyl; or, together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring which optionally incorporates a further heteroatom linkage selected from O, S(O).sub.m, NH, N(C.sub.1 -C.sub.4 alkyl), and N(C.sub.1 -C.sub.5 alkanoyl);
R.sup.12 is H; C.sub.1 -C.su
REFERENCES:
M. Von Strandtmann, et al., J. Med. Chem., 6 (1963), pp. 719-725.
R. A. Glennon, J. Med. Chem., 22(4), pp. 428-432 (1979).
Chem Ab. 77 (13), B. E. Leonard, et al., Neuropharm, 11 (3), pp. 373-384 (1972).
A. Agarwal, et al., J. Med. Chem., 36 (25), pp. 4006-4014 (1993).
Fuller Jr. Grover F.
Ginsburg Paul H.
McKane Joseph
Pfizer Inc.
Richardson Peter C.
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