# US 4,391,827 A · 3-(2-Hydroxy-4-(substituted)phenyl)-cycloalkanone and cycloalkanol analgesic agents and intermediates therefor

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- Number: US 4,391,827 A
- Document ID: US4391827A
- Status: Granted
- Kind: A
- Application number: 06/286,809
- Filed: 1981-07-27
- Granted: 1983-07-05
- Earliest claimed: 1977-09-13
- Assignees: Pfizer Inc.
- Inventors: Charles A. Harbert; Michael R. Johnson; Lawrence S. Melvin, Jr.
- Web page: https://patentgrep.com/patent/US4391827A

## CPC

- C07D 317/72: spiro-condensed with carbocyclic rings
- C07C 37/002: {by transformation of a functional group, e.g. oxo, carboxyl}
- C07C 37/055: the substituted group being bound to oxygen, e.g. ether group
- C07C 37/0555: {being esterified hydroxy groups}
- C07C 39/17: containing other rings in addition to the six-membered aromatic rings {, e.g. cyclohexylphenol}
- C07C 39/23: polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
- C07C 39/42: containing six-membered aromatic rings and other rings
- C07C 41/26: by introduction of hydroxy or O-metal groups
- C07C 41/48: Preparation of compounds having [IMAGE cpc-sch-C07C-0958.gif] groups
- C07C 41/56: by condensation of aldehydes, paraformaldehyde, or ketones
- C07C 43/23: containing hydroxy or O-metal groups
- C07C 49/255: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 49/747: containing six-membered aromatic rings
- C07C 49/753: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 403/02: having side-chains containing only carbon and hydrogen atoms
- C07F 9/117: with cycloaliphatic alcohols
- C07C 2601/14: The ring being saturated
- C07C 2601/16: the ring being unsaturated
- C07C 2601/18: with a ring being at least seven-membered
- 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

Cycloalkanones, cycloalkanols and unsaturated analogs thereof, each of which has at the 3-position a 2-hydroxy-4-substituted phenyl group wherein the 4-position substituent is alkyl which can have an oxygen atom as part of the chain, or aralkyl which can have an oxygen atom as part of the alkyl chain, their use for pharmacological and medicinal purposes, intermediates therefor and processes for their preparation.

## Claims

### Claim 1

A compound selected from the group consisting of those having the formula ##STR42## wherein R is selected from the group consisting of saturated and unsaturated cycloalkyl moieties selected from the group consisting of ##STR43## wherein A when taken alone is hydrogen;
B when taken alone is selected from the group consisting of hydroxy, hydroxymethyl and alkanoyloxy having from one to five carbon atoms;
A and B when taken together are selected from the group consisting of oxo and alkylenedioxy having from two to four carbon atoms
R.sub.1 is selected from the group consisting of hydrogen, alkanoyl having from one to five carbon atoms, P(O)(OH).sub.2 and mono- and disodium and potassium salts thereof, --CO(CH.sub.2).sub.2 COOH and the sodium and potassium salts thereof, and --CO(CH.sub.2).sub.p NR.sub.5 R.sub.6 wherein p is an integer from 1 to 4, each of R.sub.5 and R.sub.6 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.2 is selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, alkenyl having from three to six carbon atoms and phenylalkyl having from one to two carbon atoms in the alkyl moiety;
R.sub.3 is hydrogen;
R.sub.4 is selected from the group consisting of hydrogen and alkyl having from one to six carbon atoms;
Z is selected from the group consisting of
(a) alkylene having from four to eleven carbon atoms; and
(b) --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to eleven carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than four or greater than eleven; and at least one of m and n is 1;
W is selected from the group consisting of hydrogen, pyridyl and ##STR44## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
with the provisos that when W is hydrogen, B is other than hydroxy, Z is alkylene having from seven to eleven carbon atoms or --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to eleven carbon atoms with the further proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than seven or greater than eleven carbon atoms; and when W is ##STR45## or pyridyl, Z is alkylene having from four to seven carbon atoms or --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to seven carbon atoms with the further proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than four or greater than seven carbon atoms;
and the pharmaceutically acceptable acid addition salts of those compounds wherein R.sub.1 is --CO(CH.sub.2).sub.p NR.sub.5 R.sub.6 and/or W is pyridyl.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R is a saturated cycloalkyl moiety; A and B taken together are oxo and Z is alkylene.

### Claim 3 (depends on 2)

A compound according to claim 2 wherein each of R.sub.3 and R.sub.4 is hydrogen, R.sub.2 is alkenyl, and R.sub.1 is hydrogen or benzyl.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein R is formula II-B.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein Z is --C(CH.sub.3).sub.2 (CH.sub.2).sub.6 --.

### Claim 6 (depends on 5)

A compound according to claim 5 wherein R.sub.2 is 2-propenyl.

### Claim 7 (depends on 6)

The compound according to claim 6 wherein R.sub.1 is benzyl, said compound being 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohexanone.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R is a saturated cycloalkyl moiety.

### Claim 9 (depends on 1)

A compound according to claim 1 wherein B is hydroxy, R.sub.1 is hydrogen, Z is (alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- and W is ##STR46##

### Claim 10 (depends on 9)

A compound according to claim 9 wherein Z is --O--(alk.sub.2)-- wherein (alk.sub.2) has from 4 to 5 carbon atoms and W is phenyl.

### Claim 11 (depends on 10)

The compound according to claim 10 wherein Z is --O--CH(CH.sub.3)(CH.sub.2).sub.3 --, R is I-B and each of R.sub.2 and R.sub.4 is hydrogen, said compound being 3-[2-hydroxy-4-(2-(5-phenylpentyloxy)phenyl)]cyclohexanol.

### Claim 12 (depends on 2)

A compound according to claim 2 wherein Z is alkylene; each of R.sub.2, and R.sub.4 is hydrogen.

### Claim 13 (depends on 12)

The compound according to claim 12 wherein R is II-B; Z is --C(CH.sub.3).sub.2 (CH.sub.2).sub.6, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohexanone.

### Claim 14 (depends on 12)

The compound according to claim 12 wherein R is II-C; Z is --C(CH.sub.3).sub.2 (CH.sub.2).sub.6, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cycloheptanone.

### Claim 15 (depends on 2)

A compound according to claim 2 wherein R.sub.2 is methyl, Z is alkylene; R.sub.4 is hydrogen, and R is II-B or II-C.

### Claim 16 (depends on 15)

The compound according to claim 15 wherein R is II-C; Z is C(CH.sub.3).sub.2 (CH.sub.2).sub.6, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-methylcycloheptanone.

### Claim 17 (depends on 1)

A compound according to claim 1 wherein R is a saturated cycloalkyl moiety; A and B taken together are oxo; Z is --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- and W is ##STR47##

### Claim 18 (depends on 17)

A compound according to claim 17 wherein Z is --O--(alk.sub.2)-- and each of R.sub.1, W.sub.1, R.sub.2 and R.sub.4 is hydrogen.

### Claim 19 (depends on 18)

The compound according to claim 18 wherein R is II-B; Z is --O--CH(CH.sub.3)(CH.sub.2).sub.3 --, said compound being 3-[2-hydroxy-4-(2-(5-phenylpentyloxy)phenyl)]cyclohexanone.

### Claim 20 (depends on 18)

The compound according to claim 18 wherein R is II-C; Z is --O--CH(CH.sub.3)(CH.sub.2).sub.3 --, said compound being 3-[2-hydroxy-4-(2-(5-phenylpentyloxy)phenyl)]cycloheptanone.

### Claim 21

A pharmaceutical composition in unit dosage form comprising a pharmaceutically acceptable carrier or diluent and an analgesic, tranquilizer, sedative, antiaxiety or anticonvulsant effective amount of a compound selected from the group consisting of those having the formula ##STR48## wherein R is selected from the group consisting of saturated and unsaturated cycloalkyl moieties selected from the group consisting of ##STR49## wherein A when taken alone is hydrogen;
B when taken alone is selected from the group consisting of hydroxy, hydroxymethyl and alkanoyloxy having from one to five carbon atoms;
A and B when taken together are selected from the group consisting of oxo and alkylenedioxy having from two to four carbon atoms
R.sub.1 is selected from the group consisting of hydrogen, alkanoyl having from one to five carbon atoms, P(O)(OH).sub.2 and mono- and disodium and potassium salts thereof, --CO(CH.sub.2).sub.2 COOH and the sodium and potassium salts thereof, and --CO(CH.sub.2).sub.p NR.sub.5 R.sub.6 wherein p is an integer from 1 to 4, each of R.sub.5 and R.sub.6 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.2 is selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, alkenyl having from three to six carbon atoms and phenylalkyl having from one to two carbon atoms in the alkyl moiety;
R.sub.3 is hydrogen;
R.sub.4 is selected from the group consisting of hydrogen and alkyl having from one to six carbon atoms;
Z is selected from the group consisting of
(a) alkylene having from four to eleven carbon atoms; and
(b) --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to eleven carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than four or greater than eleven; and at least one of m and n is 1;
W is selected from the group consisting of hydrogen, pyridyl and ##STR50## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
with the provisos that when W is hydrogen, Z is alkylene having from seven to eleven carbon atoms or --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to eleven carbon atoms with the further proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than seven or greater than eleven carbon atoms; and when W is ##STR51## or pyridyl, Z is alkylene having from four to seven carbon atoms or --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to seven carbon atoms with the further proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than four or greater than seven carbon atoms;
and the pharmaceutically acceptable acid addition salts of those compounds wherein R.sub.1 is --CO(CH.sub.2).sub.p NR.sub.5 R.sub.6 and/or W is pyridyl.

### Claim 22 (depends on 21)

A pharmaceutical composition according to claim 21 wherein R is a saturated cycloalkyl moiety.

### Claim 23 (depends on 22)

A pharmaceutical composition according to claim 22 wherein each of R.sub.1, R.sub.4 and W is hydrogen; R.sub.2 is hydrogen or alkyl; and Z is alkylene.

### Claim 24 (depends on 23)

A pharmaceutical composition according to claim 23 wherein R is I-B or I-C; A is hydrogen and B is hydroxy.

### Claim 25 (depends on 24)

A pharmaceutical composition according to claim 24 wherein R is I-B, Z is C(CH.sub.3).sub.2 (CH.sub.2).sub.6 and R.sub.2 is hydrogen, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol.

### Claim 26 (depends on 24)

A pharmaceutical composition according to claim 24 wherein R is I-C, Z is C(CH.sub.3).sub.2 (CH.sub.2).sub.6 and R.sub.2 is methyl, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-methylcycloheptanol.

### Claim 27 (depends on 21)

A pharmaceutical composition according to claim 21 wherein A and B taken together are oxo; and R is a saturated cycloalkyl moiety.

### Claim 28 (depends on 27)

A pharmaceutical composition according to claim 27 wherein R is I-B or I-C; each of R.sub.1, R.sub.4 and W is hydrogen; R.sub.2 is hydrogen or alkyl, and Z is alkylene.

### Claim 29 (depends on 28)

A pharmaceutical composition according to claim 28 wherein R is I-B, R.sub.2 is methyl, and Z is --C(CH.sub.3).sub.2 (CH.sub.2).sub.6, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-methylcyclohexanone.

### Claim 30 (depends on 28)

A pharmaceutical composition according to claim 28 wherein R is I-C; R.sub.2 is hydrogen, and Z is C(CH.sub.3).sub.2 (CH.sub.2).sub.6, said compound being 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cycloheptanone.

### Claim 31

A method 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 ##STR52## wherein R is selected from the group consisting of saturated cycloalkyl moieties selected from the group consisting of ##STR53## wherein A when taken alone is hydrogen;
B when taken alone is selected from the group consisting of hydroxy, hydroxymethyl and alkanoyloxy having from one to five carbon atoms;
A and B when taken together are selected from the group consisting of oxo and alkylenedioxy having from two to four carbon atoms;
R.sub.1 is selected from the group consisting of hydrogen, alkanoyl having from one to five carbon atoms, P(O)(OH).sub.2 and mono- and disodium and potassium salts thereof, --CO(CH.sub.2).sub.2 COOH and the sodium and potassium salts thereof, and --CO(CH.sub.2).sub.p NR.sub.5 R.sub.6 wherein p is an integer from 1 to 4, each of R.sub.5 and R.sub.6 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.2 is selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, alkenyl having from three to six carbon atoms and phenylalkyl having from one to two carbon atoms in the alkyl moiety;
R.sub.3 is hydrogen,
R.sub.4 is selected from the group consisting of hydrogen and alkyl having from one to six carbon atoms;
Z is selected from the group consisting of
(a) alkylene having from four to eleven carbon atoms; and
(b) --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to eleven carbon atoms; each of m and n is 0 or 1; with the provisos that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than four or greater than eleven; and at least one of m and n is 1;
W is selected from the group consisting of hydrogen, pyridyl and ##STR54## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
with the proviso that when W is hydrogen, Z is alkylene having from seven to eleven carbon atoms or --(alk.sub.1).sub.m --O--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to eleven carbon atoms with the further proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than seven or greater than eleven carbon atoms; and
when W is ##STR55## or pyridyl, Z is alkylene having from four to seven carbon atoms or --(alk.sub.1)--O--(alk.sub.2)-- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to seven carbon atoms with the further proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not less than four or greater than seven carbon atoms;
and the pharmaceutically acceptable acid addition salts of those compounds wherein R.sub.1 is --CO(CH.sub.2).sub.p NR.sub.5 R.sub.6 and/or W is pyridyl.

### Claim 32 (depends on 31)

The method according to claim 31 wherein the compound is 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-n-propylcyclohexanol.

### Claim 33 (depends on 31)

The method according to claim 31 wherein the compound is 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohexanol.

### Claim 34 (depends on 31)

The method according to claim 31 wherein the compound is 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol.

### Claim 35 (depends on 31)

The method according to claim 31 wherein the compound is 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-methylcyclohexanol.

### Claim 36 (depends on 31)

The method according to claim 31 wherein the compound is 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cycloheptanone.