Analgesic 1-oxa-, aza- and thia-spirocyclic compounds

Claim 2

A compound of the formula wherein p is a whole number integer 0, 1 or 2 and n is a whole number integer 1, 2, or 3, so that the resulting cycloaliphatic ring containing them has six (6) carbon atoms; m is 3 or 4; A is a single chemical bond (-), --(CH 2 ) q where q is a whole number integer 0 to 4 or --CH(CH 3 )--; X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C 1 to C 3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C 1 to C 3 -alkoxycarbonyl, C 1 to C 3 -alkanoyloxy, C 1 to C 3 -carboxyacylamino (--NHC(═O)R 4 where R 4 is hydrogen or C 1 to C 2 -alkyl); R is hydrogen or C 1 to C 3 -alkyl; R 1 and R 2 , taken separately, are each hydrogen, C 1 to C 3 -alkyl or allyl; R 1 and R 2 , taken together with the nitrogen to which they are bonded complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl; E is oxygen or sulfur; Z is selected from the group consisting of oxygen, bivalent sulfur and sulfinyl; provided that when p is 2, n is 1, m is 3, A is --(CH 2 ) q where q is 1, R is methyl, R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a pyrrolidinyl ring, E is oxygen, Z is oxygen, and the relative stereochemistry is (5α,7α,8β), then X and Y taken together on the phenyl ring cannot be chlorine on the 2- and 4-positions of the phenyl ring, or a

Claim 3

A compound according to claim 1 wherein p is 1 or 2, n is 1 or 2; m is 3 or 4; A is --(CH 2 ) q where q is a whole number integer of from 0 to 1; X and Y are independently hydrogen or a halogen having an atomic number of from 9 to 35; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl; E is oxygen; Z is oxygen,

Claim 4

A compound according to claim 2 which is 3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzen

Claim 5

A compound according to claim 2 wherein the compound is 4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzamide,

Claim 6

A compound according to claim 2 which is 3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-7-yl]benzen

Claim 7

A compound according to claim 2 wherein the compound is (+)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]be

Claim 8

A compound according to claim 2 where the compund is (-)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]be

Claim 9

A compound according to claim 1 wherein p is 0; n is 3; m is 3 or 4; A is --(CH 2 ) q where q is a whole number integer of from 0 to 4; X and Y are independently hydrogen or a halogen having an atomic number of from 9 to 35; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl; E is oxygen; Z is oxygen;

Claim 10

A compound according to claim 8 wherein the compound is 3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-6-yl]benzen

Claim 11

A compound according to claim 2 wherein the compound is 1-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide,

Claim 12

A compound according to claim 2 wherein the compound is 4-chloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneace

Claim 13

A compound according to claim 2 wherein the compound is 4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacet

Claim 14

A compound according to claim 1 wherein p is 1 or 2; n is 1 or 2; m is 3 or 4; A is --(CH 2 ) q where q is a whole number integer of from 1 to 4; X and Y are independently selected from the group consisting of hydrogen and methoxy R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl, E is oxygen; Z is oxygen,

Claim 15

A compound according to claim 13 where the compound is 4-methoxy-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneac

Claim 16

A compound according to claim 1 wherein p is 1 or 2; n is 1 or 2; m is 3; A is --(CH 2 ) q --where q is a whole number integer of from 1 to 4; X and Y are independently selected from the group consisting of hydrogen and C 1 to C 3 -alkyl; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl; E is oxygen; Z is oxygen;

Claim 17

A compound according to claim 15 wherein the compound is 4, N-dimethyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide.

Claim 18

A composition useful in pharmaceutically effective dosage unit form for alleviating pain in warm blooded animals which comprises a compound of

Claim 19

A composition useful in pharmaceutically effective dosage unit form for alleviating pain in warm blooded animals which comprises a compound of

Claim 20

A composition of claim 17 wherein the compound of claim 1 is a compound of the formula ##STR11## wherein p is 1 or 2, n is 1 or 2; m is 3 or 4; A is --(CH 2 ) q where q is a whole number integer of from 0 to 1; X and Y are independently hydrogen or a halogen having an atomic number of from 9 to 35; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl; E is oxygen; Z is oxygen; or a pharmacologically acceptable salt thereof.

Claim 21

A composition of claim 1 wherein the compound of claim 1 is 3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide, or a pharmacologically acceptable salt thereof.

Claim 22

A method for alleviating pain in a warm blooded animal which comprises administering to an animal suffering pain an effective amount of a compound of claim 1 in a pharmaceutically dosage unit form.

Claim 23

A method according to claim 20 wherein the compound of claim 1 is a compound of claim 3.

Claim 24

A compound of the formula ##STR12## wherein p is a whole number integer 0, 1, 2, 3 or 4 and n is a whole number integer 0, 1, 2, 3 or 4, so that the resulting cycloaliphatic ring containing them has 5, 6 or 7 carbon atoms; m is 3 or 4; A is a single chemical bond (--), --(CH 2 ) q where q is a whole number integer 1 to 4 or --CH(CH 3 )--; X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C 1 to C 3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C 1 to C 3 -alkoxycarbonyl, C 1 to C 3 -alkanoyloxy, C 1 to C 3 -carboxyacylamino (--NHC(═O)R 4 where R 4 is hydrogen or C 1 to C 2 -alkyl); R is hydrogen or C 1 to C 3 -alkyl; R 1 and R 2 , taken separately, are each hydrogen, C 1 to C 3 -alkyl or allyl; R 1 and R 2 , taken together with the nitrogen to which they are bonded complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, pyrrolyl, 3-pyrrolinyl, 3-azabicyclo[3.1.0]-hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl; E is oxygen or sulfur; Z is selected from the group consisting of oxygen, bivalent sulfur, and sulfinyl; provided that when p is 2, n is 1, m is 3, A is --(CH 2 ) q where q is 1, R is methyl, R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a pyrrolidinyl ring, E is oxygen, Z is oxygen, and the relative stereochemistry (5α,7α,8β), then X and Y taken together on the phenyl ring cannot be chlorine on the 2-and 4-positions of the phenyl ring; or a pharmacologically acceptable salt thereof.

Claim 25

A compound of the formula ##STR12## wherein p is a whole number integer 0, 1, 2, 3 or 4 and n is a whole number integer 0, 1, 2, 3 or 4, so that the resulting cycloaliphatic ring containing them has 5, 6 or 7 carbon atoms; m is 3 or 4; A is a single chemical bond (--), --(CH 2 ) q where q is a whole number integer 1 to 4 or --CH(CH 3 )--; X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C 1 to C 3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C 1 to C 3 -alkoxycarbonyl, C 1 to C 3 -alkanoyloxy, C 1 to C 3 -carboxyacylamino (--NHC(═O)R 4 where R 4 is hydrogen or C 1 to C 2 -alkyl); R is hydrogen or C 1 to C 3 -alkyl; R 1 and R 2 , taken separately, are each hydrogen, C 1 to C 3 -alkyl or allyl; R 1 and R 2 , taken together with the nitrogen to which they are bonded complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, pyrrolyl, 3-pyrrolinyl, 3-azabicyclo[3.1.0]-hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl; E is oxygen or sulfur; Z is selected from the group consisting of oxygen, bivalent sulfur, and sulfinyl; provided that when p is 2, n is 1, m is 3, A is --(CH 2 ) q where q is 1, R is methyl, R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete a pyrrolidinyl ring, E is oxygen, Z is oxygen, and the relative stereochemistry (5α,7α,8β), then X and Y taken together on the phenyl ring cannot be chlorine on the 2-and 4-positions of the phenyl ring; or a pharmacologically acceptable salt thereof.

Claim 26

A compound according to claim 3 which is (5α,7α,8β)-(±)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide methanesulfonate.

Claim 27

A compound selected from the group consisting of (±)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenepropanamide, (±)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenebutanamide, (±)-(5ξ,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, (±)-(5ξ-7α,8β)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzamide, (±)-(5ξ-7α,8β)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspirot[4.5]dec-7-yl]benzeneacetamide, and (±)-(5ξ-7α,8β)-4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-7-yl]benzamide, or a pharmacologically acceptable salt thereof.

Claim 28

A compound selected from the group consisting of (±)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenepropanamide, (±)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzenebutanamide, (±)-(5ξ,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, (±)-(5ξ-7α,8β)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzamide, (±)-(5ξ-7α,8β)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspirot[4.5]dec-7-yl]benzeneacetamide, and (±)-(5ξ-7α,8β)-4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-7-yl]benzamide, or a pharmacologically acceptable salt thereof.

Claim 29

A composition useful in pharmaceutically effective dosage unit form for alleviating pain in warm-blooded animals which comprises a compound of claim 22 in combination with a pharmaceutically acceptable carrier.

Claim 30

A method for alleviating pain in a warm-blooded animal which comprises administering to an animal suffering pain an effective amount of a compound of claim 22 in a pharmaceutically acceptable dosage unit form.