Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-09-21
1996-03-26
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514323, 514414, 548402, 548405, 548406, 548466, 548469, 546 2, 546 9, 546 13, 546 14, 546192, 546193, 546194, 546201, 546273, 544225, 544226, 544229, 544238, 544297, 544298, 544322, 544331, 544333, 544405, A61K 3144, C07D20904, C07D21304
Patent
active
055020658
DESCRIPTION:
BRIEF SUMMARY
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 and drug abuse.
The present invention provides compounds of the formula: ##STR2## and pharmaceutically acceptable salts thereof, wherein R is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl or thienyl, all of which may be optionally substituted by halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or a group of the formula: -C.sub.7 cycloalkenyl, C.sub.3 -C.sub.6 alkenyl or C.sub.1 -C.sub.6 alkynyl, said alkyl group being optionally substituted by C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloalkyloxy, OH, C.sub.1 -C.sub.6 alkoxy, CONR.sup.3 R.sup.4, SO.sub.2 NR.sup.3 R.sup.4, COR.sup.5, SOR.sup.5, SO.sub.2 R.sup.5, CO.sub.2 R.sup.6, aryl, aryloxy, aryl(C.sub.1 -C.sub.6)alkoxy or heteroaryl, said alkenyl group being optionally substituted by aryl and said cycloalkyl group being optionally substituted by OH; the cycloalkyl and cycloalkenyl groups being optionally linked to the N-atom by a C.sub.1 -C.sub.2 alkylene moiety; CONR.sup.3 R.sup.4, SO.sub.2 NR.sup.3 R.sup.4, NHCOR.sup.7, NHCONR.sup.3 R.sup.4, NHSO.sub.2 R.sup.7, NHSO.sub.2 NR.sup.3 R.sup.4, OH or CN; -C.sub.7 cycloalkyl and C.sub.1 -C.sub.6 alkyl, said alkyl group being optionally substituted by C.sub.3 -C.sub.7 cycloalkyl or aryl, or R.sup.3 and R.sup.4 taken together represent C.sub.3 -C.sub.6 alkylene optionally interrupted by O, S(O).sub.n, NH or N(C.sub.1 -C.sub.6 alkyl); -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkylene, aryl(C.sub.1 -C.sub.6)alkylene, or aryl; aryl(C.sub.1 -C.sub.6)alkylene; C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or halo; and pyrazinyl, furyl, thienyl, pyrrolyl, thiazolyl or oxazolyl. alkynyl groups having four or more carbon atoms, can be straight- or branched-chain. being preferably at the 3- or 4-position of the ring.
A preferred groups of compounds of formula (I) is that wherein R.sup.1 is (R.sup.5 CO)C.sub.1 -C.sub.2 alkylene; (R.sup. O.sub.2 C)C.sub.1 -C.sub.2 alkylene; (R.sup.3 R.sup.4 NOC)C.sub.1 -C.sub.2 alkylene; R.sup.3 R.sup.4 NO.sub.2 SCH.sub.2 CH.sub.2 ; R.sup.3 NSO.sub.2 C.sub.1 -C.sub.2 alkylene; R.sup.3 SOC.sub.1 -C.sub.2 alkylene; R.sup.3 SO.sub.2 C.sub.1 -C.sub.2 alkylene; (R.sup.5 O)C.sub.2 -C.sub.3 alkylene; (C.sub.3 -C.sub.7 cycloalkyl)CH.sub.2 ; (phenyl)C.sub.1 -C.sub.2 alkylene; (pyridyl)C.sub.1 -C.sub.2 alkylene; C.sub.5 -C.sub.6 cycloalkyl optionally substituted with HO; C.sub.3 -C.sub.5 alkenyl optionally substituted with phenyl; or cyclohexenyl;
Preferably R.sup.1 is C.sub.1 -C.sub.6 alkyl. Most preferably it is H or CH.sub.3.
Preferably R.sup.3 and R.sup.4 are either each independently selected from H and C.sub.1 -C.sub.4 alkyl, or R.sup.3 and R.sup.4 taken together represent C.sub.3 -C.sub.6 alkylene interrupted by O.
Most preferably R.sup.3 and R.sup.4 are either each independently selected from H, or C.sub.1 -C.sub.4 alkyl, or R.sup.3 and R.sup.4 taken together with the nitrogen atom to which they are attached represent morpholino.
Preferably R.sup.7 is methyl, ethyl or n-propyl.
Preferably X is a direct link or methylene.
Preferably m is 1.
In a further aspect, therefore, the invention provides compounds of formula (I) wherein: optionally subst
REFERENCES:
CA119:249833a Indole . . . Antagonist, Macor et al. p. 970, 1993.
A. R. Martin, et al., QSAR Studies of 5-Substituted-3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indoles at Serotonin Binding Sites, 8th Camerino--Noordwijkerhout Symposium, Sep. 8-12, 1991.
A. R. Martin, et al., Preparation of 5-Substituted Indoles via Halogen-Metal Exchange and Palladium Catlayzed Cross Coupling Strategies, 13th International Congress of Heterocyclic Chemisty, Aug. 11-16, 1991.
Y. Yang, et al., Heterocycles, 34 (b), 1169 (1992), Synthesis of Some 5-Substituted Indoles.
Brown Alan D.
Dickinson Roger P.
Wythes Martin J.
Fuller Jr. Grover F.
Ginsburg Paul H.
McKane Joseph K.
Pfizer Inc.
Richardson Peter C.
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