3-(2-Hydroxy-4-(substituted)phenyl)-cycloalkanone and cycloalkanol analgesic agents and intermediates therefor

Claim 2

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 1 is selected from the group consisting of hydrogen, alkanoyl having from one to five carbon atoms, P(O)(OH) 2 and mono- and disodium and potassium salts thereof, --CO(CH 2 ) 2 COOH and the sodium and potassium salts thereof, and --CO(CH 2 ) p NR 5 R 6 wherein p is an integer from 1 to 4, each of R 5 and R 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 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 3 is hydrogen; R 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 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 1 ) plus (alk 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 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 2 ) is alkylene having from one to eleven carbon atoms with the further proviso that the summation of carbon atoms in (alk 1 ) plus (alk 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 2 ) is alkylene having from one to seven carbon atoms with the further proviso that the summation of carbon atoms in (alk 1 ) plus (alk 2 ) is not less than four or greater than seven carbon atoms; and the pharmaceutically acceptable acid addition salts of those compounds wherein R 1 is --CO(CH 2 ) p NR 5 R 6 and/or W is pyridyl.

Claim 3

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 4

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

Claim 5

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

Claim 6

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

Claim 7

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

Claim 8

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

Claim 9

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

Claim 10

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

Claim 11

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

Claim 12

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

Claim 13

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

Claim 14

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

Claim 15

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

Claim 16

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

Claim 17

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

Claim 18

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

Claim 19

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

Claim 20

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

Claim 21

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

Claim 22

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 1 is selected from the group consisting of hydrogen, alkanoyl having from one to five carbon atoms, P(O)(OH) 2 and mono- and disodium and potassium salts thereof, --CO(CH 2 ) 2 COOH and the sodium and potassium salts thereof, and --CO(CH 2 ) p NR 5 R 6 wherein p is an integer from 1 to 4, each of R 5 and R 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 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 3 is hydrogen; R 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 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 1 ) plus (alk 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 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 2 ) is alkylene having from one to eleven carbon atoms with the further proviso that the summation of carbon atoms in (alk 1 ) plus (alk 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 2 ) is alkylene having from one to seven carbon atoms with the further proviso that the summation of carbon atoms in (alk 1 ) plus (alk 2 ) is not less than four or greater than seven carbon atoms; and the pharmaceutically acceptable acid addition salts of those compounds wherein R 1 is --CO(CH 2 ) p NR 5 R 6 and/or W is pyridyl.

Claim 23

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 1 is selected from the group consisting of hydrogen, alkanoyl having from one to five carbon atoms, P(O)(OH) 2 and mono- and disodium and potassium salts thereof, --CO(CH 2 ) 2 COOH and the sodium and potassium salts thereof, and --CO(CH 2 ) p NR 5 R 6 wherein p is an integer from 1 to 4, each of R 5 and R 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 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 3 is hydrogen; R 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 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 1 ) plus (alk 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 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 2 ) is alkylene having from one to eleven carbon atoms with the further proviso that the summation of carbon atoms in (alk 1 ) plus (alk 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 1 ) m --O--(alk 2 ) n -- wherein each of (alk 1 ) and (alk 2 ) is alkylene having from one to seven carbon atoms with the further proviso that the summation of carbon atoms in (alk 1 ) plus (alk 2 ) is not less than four or greater than seven carbon atoms; and the pharmaceutically acceptable acid addition salts of those compounds wherein R 1 is --CO(CH 2 ) p NR 5 R 6 and/or W is pyridyl.

Claim 24

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

Claim 25

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

Claim 26

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

Claim 27

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

Claim 28

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

Claim 29

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

Claim 30

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

Claim 31

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

Claim 32

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

Claim 35

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

Claim 36

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

Claim 37

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

Claim 38

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

Claim 39

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