A. H. Robins Company, Incorporated

Syntex (u.s.a.) Inc.

William L Smith

Robin D Clark

Klaus K Weinhardt

Richard M Eglen

Jacob Berger

Reevis S Alphin

Joseph M Muchowski

Harry R Munson, Jr

Lina C Teng

Robert F Boswell

John Wesley Ward

Lennox B Turnbull

Pershottam P Mathur

Stephen C Bearekman

The present invention is directed to 5-HT.sub.3 receptor antagonist compounds of formula I: ##STR1## in which the dashed line denotes an optional double bond;

Tricyclic 5-HT.sub.3 receptor antagonists

Compounds of Formula I: ##STR1## in which Z is CH.sub.2 or C.dbd.O;

Tricyclic compounds acting at serotonin receptor subtypes

.alpha.-Oxoacetamides of the formula R.sup.1 C(O)C(O)NR.sup.2 R.sup.3 in which R.sup.1 is optionally substituted phenyl, 1-indolyl, 2,3-dihydro-1-indolyl, 1-benzimidazolidinonyl, 3-benzofuranyl, 3-benzothiophenyl, 3-indolyl, and 1,2-alkano-3-indolyl; R.sup.2 is selected from: ##STR1## and R.sup.3 is selected from hydrogen or lower alkyl; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.

Serotonergic alpha-oxoacetamides

A pharmaceutical method for improving memory or correcting memory deficiency is disclosed, utilizing compounds having the formula: ##STR1## wherein n.sup.1, n.sup.2, n.sup.3, and n.sup.4 =0 to 3; R.sup.1, R.sup.2, R.sup.3 , and R.sup.4 =H, loweralkyl or phenyl; R.sup.5 =H or loweralkyl; X=0 or S; Ar=phenyl, substituted phenyl, pyridinyl, furanyl, thienyl, methoxy-1H-benzotriazolyl, indolinyl, methoxyindolinyl, methoxypyrimidinyl, amino-methoxypyrimadinyl, 1,3-benzodioxolyl, or naphthalenyl; the optical isomers; and the pharmaceutically acceptable acid addition salts, hydrates and alcoholates thereof. The dosage effective for this use is from about 10 to 1000 nanograms/kg.

Method of enhancing memory or correcting memory deficiency with

A method for the treatment of emesis in a mammal, which method comprises administering to said mammal an emesis inhibiting amount of a compound which depletes serotonin in the brain of mammals; among which are compounds having the formula: ##STR1## wherein, R is selected from hydrogen, loweralkyl, trifluoromethyl, carboxyl, or loweralkoxycarbonyl; R.sup.1 and R.sup.2 are hydrogen or loweralkyl; Z is trifluoromethyl or halogen; the optical isomers and pharmaceutically acceptable salts thereof; two of the preferred compounds of the invention are fenfluramine and norfenfluramine.

Method of treating nausea and vomiting with certain

A method of controlling emesis caused by anticancer drugs with 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamide-N-oxides having the formula: ##STR1## wherein R.sub.1 is loweralkyl, and R.sub.2 is selected from the group consisting of hydrogen, halo, 4,5-benzo, methylsulfonyl, loweralkoxy or Am and n is 1 or 2, and the pharmaceutically acceptable acid addition salts thereof is disclosed.

Method of using

A method of controlling emesis caused by non-platinum anti-cancer drugs with 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides having the formula ##STR1## wherein X is oxygen or sulfur; R.sub.1 is loweralkyl; and R.sub.2 is selected from the group consisting of hydrogen, halo, 4,5-benzo, methylsulfonyl, loweralkoxy or Am and n is 1 or 2, and the pharmaceutically acceptable acid addition salts thereof is disclosed.

2-alkoxy-N-(1-azabicyclo(2.2.2)oct-3-yl) benzamides and thiobenzamides

Pharmaceutical compositions comprised of aryloxy-N-(aminoalkyl)-1-pyrrolidine and piperidine carboxamides and carbothioamides are provided of the formula: ##STR1## wherein Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, phenyl, substituted phenyl wherein the substituents are selected from lower alkyl of from 1 to 8 carbon atoms, lower alkyloxy of from 1 to 8 carbon atoms, halogen and trifluoromethyl; m and n are 1 or 2 but are never 2 at the same time; p is 1, 2, 3 or 4; R is selected from hydrogen or lower alkyl of from 1 to 3 carbon atoms; R.sup.1 and R.sup.2 are selected from hydrogen, lower alkyl of from 1 to 8 carbon atoms, phenyl, phenyl lower alkyl of from 7 to 9 carbon atoms, and cycloalkyl of from 3 to 8 carbon atoms, and R.sup.1 and R.sup.2 taken together with the adjacent atom may form a heterocyclic residue selected from 4-morpholino, 1-pyrrolidino, 1-piperidino, 1-piperazino and 4-lower alkyl piperazin-1-yl; X is oxygen or sulfur; and the pharmaceutically acceptable acid addition salts thereof having antiarrhythmic activity.

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Sunnyvale, CA, United States of America

William L Smith