Analgesic 1-oxa-, aza- and thia-spirocyclic compounds
AssigneeThe Upjohn Company
InventorLester J. Kaplan
Life of this patent
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Abstract
Mono-Oxa-, thiaspirocyclic-benzene-acetamide and -benzamide compounds of the formula ##STR1## wherein p, n, m, A, E, R, R.sub.1, R.sub.2, X, Y and Z are as defined in the specification, e.g., (.+-.)-(5.alpha.,7.alpha.,9.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidi nyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide, and the pharmacologically acceptable salts thereof, are useful as analgesic compounds having low physical dependence liability, compared to morphine and methodone, and low dysphoria side effects. Some of these compounds have potent analgesic activity when administered orally, and some have low CNS sedative side effects. Pharmaceutical compositions and methods for using these compounds as analgesics are disclosed. Processes for preparing this class of compounds are also disclosed.
Claims26
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.sub.2).sub.q where q is a whole number integer 0 to 4 or --CH(CH.sub.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.sub.1 to C.sub.3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C.sub.1 to C.sub.3 -alkoxycarbonyl, C.sub.1 to C.sub.3 -alkanoyloxy, C.sub.1 to C.sub.3 -carboxyacylamino (--NHC(.dbd.O)R.sub.4 where R.sub.4 is hydrogen or C.sub.1 to C.sub.2 -alkyl);
- R is hydrogen or C.sub.1 to C.sub.3 -alkyl;
- R.sub.1 and R.sub.2, taken separately, are each hydrogen, C.sub.1 to C.sub.3 -alkyl or allyl;
- R.sub.1 and R.sub.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.sub.2).sub.q where q is 1, R is methyl, R.sub.1 and R.sub.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 (5.alpha.,7.alpha.,8.beta.), 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
A composition useful in pharmaceutically effective dosage unit form for alleviating pain in warm blooded animals which comprises a compound of
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.sub.2).sub.q where q is a whole number integer 1 to 4 or --CH(CH.sub.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.sub.1 to C.sub.3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C.sub.1 to C.sub.3 -alkoxycarbonyl, C.sub.1 to C.sub.3 -alkanoyloxy, C.sub.1 to C.sub.3 -carboxyacylamino (--NHC(.dbd.O)R.sub.4 where R.sub.4 is hydrogen or C.sub.1 to C.sub.2 -alkyl);
- R is hydrogen or C.sub.1 to C.sub.3 -alkyl;
- R.sub.1 and R.sub.2, taken separately, are each hydrogen, C.sub.1 to C.sub.3 -alkyl or allyl;
- R.sub.1 and R.sub.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.sub.2).sub.q where q is 1, R is methyl, R.sub.1 and R.sub.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 (5.alpha.,7.alpha.,8.beta.), 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.
A compound selected from the group consisting of
- (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspir o[4.5]dec-8-yl]benzenepropanamide,
- (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspir o[4.5]dec-8-yl]benzenebutanamide,
- (.+-.)-(5.xi.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) -1-thiaspiro[4.5]dec-8-yl]benzeneacetamide,
- (.+-.)-(5.xi.-7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-th iaspiro[4.5]dec-8-yl]benzamide,
- (.+-.)-(5.xi.-7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl) -1-thiaspirot[4.5]dec-7-yl]benzeneacetamide, and
- (.+-.)-(5.xi.-7.alpha.,8.beta.)-4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1-th iaspiro[4.5]dec-7-yl]benzamide,
- or a pharmacologically acceptable salt thereof.
Dependencies are inferred from the claim text.