US 4,228,169 AGranted

1,9-Dihydroxyoctahydrobenzo[c]quinolines and 1-hydroxyhexahydrobenzo[c]quinoline-9(8H)-ones as antiemetic agents

AssigneePfizer Inc.

InventorsMichael R. Johnson, George M. Milne

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Abstract

1,9-Dihydroxyoctahydro[c]quinolines (I) and 1-hydroxyhexahydrobenzo[c]quinoline-9(8H)-ones (II), useful as antiemetic agents and derivatives thereof having the formulae ##STR1## wherein R is hydroxy or alkanoyloxy having from one to five carbon atoms; R.sub.1 is hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms or --CO--(CH.sub.2).sub.p --NR.sub.2 R.sub.3 wherein p is 0 or an integer from 1 to 4; each of R.sub.2 and R.sub.3 when taken individually is hydrogen or alkyl having from one to four carbon atoms; R.sub.2 and R.sub.3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring (piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group); R.sub.4 is hydrogen, alkyl having from 1 to 6 carbon atoms and --(CH.sub.2).sub.z --C.sub.6 H.sub.5 wherein z is an integer from 1 to 4; R.sub.5 is hydrogen, methyl or ethyl; R.sub.6 is hydrogen, --(CH.sub.2).sub.y --carbalkoxy having from 1 to 4 carbon atoms in the alkoxy group wherein y is 0 or an integer from 1 to 4; carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; --(CH.sub.2).sub.x --C.sub.6 H.sub.5 wherein x is an integer from 1 to 4; and --CO(CH.sub.2).sub.x-1 --C.sub.6 H.sub.5 ; Z is (a) alkylene having from one to nine carbon atoms; (b) --(alk.sub.1).sub.m --X--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not greater than 9; each of m and n is 0 or 1; X is O, S, SO or SO.sub.2 ; and W is hydrogen, methyl, ##STR2## wherein W.sub.1 is hydrogen, chloro or fluoro; pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is ##STR3## wherein W.sub.2 is hydrogen, chloro or fluoro; and pharmaceutically-acceptable acid addition salts of compounds of formulae I and II and the ketals of compounds of formula II wherein the ketal moiety has from two to four carbon atoms.

Claims27

Dependent claims

A process for the prevention and treatment of nausea in a mammal subject to said nausea which comprises administering to said mammal a compound in an amount effective to prevent nausea, said compound being selected from the group consisting of ##STR11## and the pharmaceutically acceptable acid addition salts thereof. wherein R is selected from the group consisting of hydroxy and alkanoyloxy having from one to five carbon atoms;

R.sub.1 is selected from the group consisting of hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms and --CO--(CH.sub.2).sub.p --NR.sub.2 R.sub.3 wherein p is 0 or an integer from 1 to 4;
each of R.sub.2 and R.sub.3 when taken individually is selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms;
R.sub.2 and R.sub.3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group;
R.sub.4 is selected from the group consisting of hydrogen, alkyl having from 1 to 6 carbon atoms and --(CH.sub.2).sub.z --C.sub.6 H.sub.5 wherein z is an integer from 1 to 4;
R.sub.5 is selected from the group consisting of hydrogen, methyl and ethyl;
R.sub.6 is selected from the group consisting of hydrogen, --(CH.sub.2).sub.y -carbalkoxy having from one to four carbon atoms in the alkoxy group and wherein y is 0 or an integer from 1 to 4, carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms and --(CH.sub.2).sub.x --C.sub.6 H.sub.5 wherein x is an integer from 1 to 4;
and CO(CH.sub.2).sub.x-1 --C.sub.6 H.sub.5 ;
Z is selected from the group consisting of
(a) alkylene having from one to nine carbon atoms;
(b) --(alk.sub.1).sub.m --X--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not greater than nine;
each of m and n is 0 or 1;
X is selected from the group consisting of O, S, SO and SO.sub.2 ;
and
W is selected from the group consisting of hydrogen, methyl, pyridyl, piperidyl, ##STR12## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR13## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR14## a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5;
with the proviso that the sum of a and b is not greater than 5.

13 more elements

##STR15## and the pharmaceutically acceptable acid addition salts thereof wherein R.sub.1 is selected from the group consisting of hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms and --CO--(CH.sub.2).sub.p --NR.sub.2 R.sub.3 wherein p is 0 or an integer from 1 to 4;
each of R.sub.2 and R.sub.3 when taken individually is selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms;
R.sub.2 and R.sub.3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group;
R.sub.4 is selected from the group consisting of hydrogen, alkyl having from 1 to 6 carbon atoms and --(CH.sub.2).sub.z --C.sub.6 H.sub.5 wherein z is an integer from 1 to 4;
R.sub.5 is selected from the group consisting of hydrogen, methyl and ethyl;
R.sub.6 is selected from the group consisting of hydrogen, --(CH.sub.2).sub.y -carbalkoxy having from one to four carbon atoms in the alkoxy group and wherein y is 0 or an integer from 1 to 4;
carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms;
--(CH.sub.2).sub.x --C.sub.6 H.sub.5 wherein x is an integer from 1 to 4;
and --CO(CH.sub.2).sub.x-1 --C.sub.6 H.sub.5 ;
Z is selected from the group consisting of
(a) alkylene having from one to nine carbon atoms;
(b) --(alk.sub.1).sub.m --X--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not greater than nine;
each of m and n is 0 or 1;
X is selected from the group consisting of O, S, SO and SO.sub.2 ;
and
W is selected from the group consisting of hydrogen, methyl, pyridyl, piperidyl, ##STR16## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR17## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR18## a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5;
with the proviso that the sum of a and b is not greater than 5.

15 more elements

Dependencies are inferred from the claim text.