US 4,400,385 A · 9-Hydroxyoctahydrobenzo [c]quinolines, analgesic compositions containing them and processes for producing analgesia with them

Abstract

1,9-Dihydroxyoctahydrobenzo[c]quinolines (I), 1-hydroxyhexahydrobenzo[c]quinoline-9 (8H)-ones (II), and 1-hydroxy-tetrahydrobenzo[c]quinolines (IV) useful as CNS agents, especially as analgesics and tranquilizers, as hypotensives, as agents for the treatment of glaucoma and as diuretics; intermediates therefor (III) and derivatives thereof having the formulae ##STR1## wherein R is hydroxy, alkanoyloxy having from one to five carbon atoms and hydroxymethyl; 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 ; R.sub.O is oxo, methylene or alkylenedioxy having from two to four carbon atoms; R' is R or R.sub.0 ; 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 0, 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, II and IV and the ketals of compounds of formulae II, III and IV wherein the ketal moiety has from two to four carbon atoms.

Claims17

Dependent claims

A compound having the formula:

##STR73## 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 wherein 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 ;
R.sub.0 is selected from the group consisting of oxo, methylene and alkylenedioxy having from two or four carbon atoms;
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, ##STR74## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR75## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR76## 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.

16 more elements

A process for producing analgesia in a mammal which comprises administering to the mammal an analgesic producing quantity of a compound selected from the group consisting of those having the formula ##STR77## and the pharmaceutically acceptable acid addition salts thereof, wherein

R.sub.1 is selected from the group consisting of hydrogen, 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 ;
R.sub.0 is selected from the group consisting of oxo, alkylenedioxy having from two to four carbon atoms and methylene;
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, ##STR78## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR79## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR80## 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.

14 more elements

A pharmaceutical composition in unit dosage form suitable for use as an analgesic, comprising a pharmaceutical carrier and, as active ingredient, from 0.01 to 50 mg. of a compound selected from the group consisting of those having the formula ##STR81## and the pharmaceutically-acceptable acid addition salts thereof, wherein

R.sub.1 is selected from the group consisting of hydrogen, 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 ;
R.sub.0 is selected from the group consisting of oxo;
alkylenedioxy having from two to four carbon atoms and methylene;
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, ##STR82## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR83## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR84## 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.

9-Hydroxyoctahydrobenzo [c]quinolines, analgesic compositions containing them and processes for producing analgesia with them

Life of this patent

9-Hydroxyoctahydrobenzo [c]quinolines, analgesic compositions containing them and processes for producing analgesia with them

Life of this patent

Abstract

Claims17