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

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- Number: US 4,400,385 A
- Document ID: US4400385A
- Status: Granted
- Kind: A
- Application number: 06/328,928
- Filed: 1981-12-09
- Granted: 1983-08-23
- Earliest claimed: 1976-05-17
- Assignees: Pfizer Inc.
- Inventors: Michael R. Johnson
- Web page: https://patentgrep.com/patent/US4400385A

## CPC

- C07D 213/30: Oxygen atoms
- C07C 17/16: of hydroxyl groups
- C07C 37/055: the substituted group being bound to oxygen, e.g. ether group
- C07C 45/45: by condensation
- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 221/12: Phenanthridines
- C07D 303/22: with monohydroxy compounds
- C07F 9/5456: {Arylalkanephosphonium compounds}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R.sub.0 is oxo; R.sub.5 is hydrogen or methyl; each of R.sub.4 and R.sub.6 is hydrogen or alkyl; R.sub.1 is hydrogen or alkanoyl; Z is --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n --; and W is phenyl or hydrogen.

### Claim 3 (depends on 2)

A compound according to claim 2 wherein R.sub.4 is .beta.-methyl; R.sub.1 is acetyl; each of R.sub.5 and R.sub.6 is hydrogen; Z is --O--(alk.sub.2).sub.n --; and W is phenyl.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein Z is --O--CH(CH.sub.3)(CH.sub.2).sub.3 --.

### Claim 5 (depends on 4)

The trans(6a,10a)diasteromer compound of claim 4.

### Claim 6 (depends on 4)

The cis(6a,10a)diastereomer compound of claim 4.

### Claim 7 (depends on 2)

A compound according to claim 2 wherein Z is --O--(alk.sub.2).sub.n -- and W is hydrogen.

### Claim 8 (depends on 7)

The compound according to claim 7 wherein R.sub.1 is acetyl; each of R.sub.4 and R.sub.5 is methyl; R.sub.6 is hydrogen; and Z is --OCH(CH.sub.3)(CH.sub.2).sub.5 --.

### Claim 9 (depends on 1)

A compound according to claim 1 wherein R.sub.0 is oxo; R.sub.1 is hydrogen or acetyl; each of R.sub.4, R.sub.5 and R.sub.6 is hydrogen or methyl; Z is -alkylene- and W is hydrogen or phenyl.

### Claim 10

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.

### Claim 11 (depends on 10)

A process according to claim 10 wherein R.sub.1 is acetyl; R.sub.5 is hydrogen or methyl; each of R.sub.4 and R.sub.6 is hydrogen or alkyl; Z is --O--(alk.sub.2).sub.m --; and W is hydrogen or phenyl.

### Claim 12 (depends on 11)

A process according to claim 11 wherein R.sub.4 is methyl; each of R.sub.5 and R.sub.6 is hydrogen; Z is --O--CH(CH.sub.3)(CH.sub.2).sub.3 -- and W is phenyl.

### Claim 13 (depends on 11)

A process according to claim 11 wherein the compound is the cis-(6a,10a)diastereomer.

### Claim 14 (depends on 11)

A process according to claim 11 wherein the compound is the trans(6a,10a) diastereomer.

### Claim 15

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.

### Claim 16 (depends on 15)

A pharmaceutical composition according to claim 15 wherein R.sub.1 is acetyl; R.sub.4 is methyl; each of R.sub.5 and R.sub.6 is hydrogen; Z is --O--(alk.sub.2).sub.n --; and W is hydrogen or phenyl.

### Claim 17 (depends on 16)

A pharmaceutical composition according to claim 16 wherein Z is --O--CH(CH.sub.3)(CH.sub.2).sub.3 --; W is phenyl; R.sub.4 is .beta.-methyl; and each of R.sub.5 and R.sub.6 is hydrogen.