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US 5,998,434 AGranted
Composition for treating pain
AssigneeEli Lilly and Company
InventorsCharles H. Mitch, Harlan E. Shannon
Life of this patent
Estimating the term…
Abstract
The present invention provides a composition and method for treating pain using Selected Muscarinic Compounds and one or more compounds selected from the group consisting of Nonsteroidal Anti-inflammatory drugs, acetaminophen, opioids, and alpha-adrenergic compounds.
Claims41
A composition for treating pain comprising an analgesic dose of a First Compound selected from the group consisting of:
- ##STR40## wherein W is oxygen or sulphur;
- R is hydrogen, amino, halogen, NHR.sup.6, NR.sup.6 R.sup.7, R.sup.4, --OR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2 R.sup.4, C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl), --Z--C.sub.3-10 -cycloalkyl and --Z--C.sub.4-12 -(cycloalkylalkyl) wherein
- R.sup.4 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R is --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 or --S--R.sup.5 --Z--R.sup.4 wherein Z is oxygen or sulphur, R.sup.5 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y is a 5 or 6 membered heterocyclic group;
- and
- G is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR41## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ;
- R.sup.6 and R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl;
- or
- R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- R.sup.6' is hydrogen, C.sub.1-6 -alkyl;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- p is 0, 1 or 2;
- q is 1 or 2;
- r is 0, 1 or 2;
- ....... is a single or double bond;
- and ##STR42## wherein W' is oxygen or sulfur;
- R' is hydrogen, amino, halogen, NHR.sup.6', NR.sup.6' R.sup.7', R.sup.4', --OR.sup.4', --SR.sup.4', --SOR.sup.4', --SO.sub.2 R.sup.4', C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl), --Z'--C.sub.3-10 -cycloalkyl and --Z'--C.sub.4-12 -(cycloalkylalkyl) wherein R.sup.4' is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y', phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R' is --OR.sup.5' Y', --SR.sup.5' Y', OR.sup.5' --Z'--Y', --SR.sup.5' Z'Y', --O--R.sup.5' --Z--R.sup.4' or --S--R.sup.5' --Z'--R.sup.4' wherein Z' is oxygen or sulphur, R.sup.5' is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y' is a 5 or 6 membered heterocyclic group;
- and
- G' is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR43## or G' can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6' R.sup.7' ;
- R.sup.6' and R.sup.7' independently are hydrogen, C.sub.1-6 -alkyl;
- or
- R.sup.6' and R.sup.7' together with the nitrogen atom optionally form a 4- to 6-member ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6", CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- R.sup.6" is hydrogen, C.sub.1-15 -alkyl
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- p is 0, 1 or 2;
- q is 1 or 2;
- r is 0, 1 or 2;
- ....... is a single or double bond;
- or
- a pharmaceutically acceptable salt or solvate thereof;
- and one or more Synergistic Analgesics in a weight ratio of First Compound to Synergistic Analgesic of from about 1 to about 1000.
43 more elements
A method for treating pain comprising administering an analgesic dose of a composition comprising a a First Compound selected from the group consisting of:
- ##STR44## wherein W is oxygen or sulphur;
- R is hydrogen, amino, halogen, NHR.sup.6, NR.sup.6 R.sup.7, R.sup.4, --OR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2 R.sup.4, C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl) --Z--C.sub.3-10 -cycloalkyl and --Z--C.sub.4-12 -(cycloalkylalkyl) wherein R.sup.4 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R is --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 or --S--R.sup.5 --Z--R.sup.4 wherein Z is oxygen or sulphur, R.sup.5 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y is a 5 or 6 membered heterocyclic group;
- and
- G is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR45## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ;
- R.sup.6 and R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl;
- or
- R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- R.sup.6' is hydrogen, C.sub.1-6 -alkyl;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- p is 0, 1 or 2;
- q is 1 or 2;
- r is 0, 1 or 2;
- ...... is a single or double bond;
- and ##STR46## wherein W' is oxygen or sulfur;
- R' is hydrogen, amino, halogen, NHR6', NR.sup.6' R.sup.7', R.sup.4', --OR.sup.4', --SR.sup.4', --SOR.sup.4", --SO.sub.2 R.sup.4', C.sub.3-10 -cycloalkyl, C.sub.4- 12 -(cycloalkylalkyl), --Z'-C.sub.3-10 -cycloalkyl and --Z'-C.sub.4-12 -(cycloalkylalkyl) wherein R.sup.4' is C.sub.1-5 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y', phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R' is --OR.sup.5' Y', --SR.sup.5' Y', OR.sup.5' --Z'--Y', --SR.sup.5' Z'Y', --O--R.sup.5' --Z--R.sup.4' or --S--R.sup.5' --Z'--R.sup.4' wherein Z' is oxygen or sulphur, R.sup.5' is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y' is a 5 or 6 membered heterocyclic group;
- and
- G' is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR47## or G' can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.16 -alkyl wherein the substitution is --NR.sup.6' R.sup.7' ;
- R.sup.6' and R.sup.7' independently are hydrogen, C.sub.1-6 -alkyl;
- or
- R.sup.6' and R.sup.7' together with the nitrogen atom optionally form a 4- to 6-member ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6", CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- R.sup.6" is hydrogen, C.sub.1-15 -alkyl
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- p is 0, 1 or 2;
- q is 1 or 2;
- r is 0, 1 or 2;
- ....... is a single or double bond;
- or
- a pharmaceutically acceptable salt or solvate thereof;
- and one or more Synergistic Analgesics in a weight ratio of First Compound to Synergistic Analgesic of from about 1 to about 1000.
42 more elements
The use of a First Compound selected from the group consisting of:
- ##STR48## wherein W is oxygen or sulphur;
- R is hydrogen, amino, halogen, NHR.sup.6, NR.sup.6 R.sup.7, R.sup.4, --OR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2 R.sup.4, C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl) --Z--C.sub.3-10 -cycloalkyl and --Z--C.sub.4-12 -(cycloalkylalkyl) wherein
- R.sup.4 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R is --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 or --S--R.sup.5 --Z--R.sup.4 wherein Z is oxygen or sulphur, R.sup.5 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y is a 5 or 6 membered heterocyclic group;
- and
- G is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR49## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ;
- R.sup.6 and R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl;
- or
- R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- R.sup.6, is hydrogen, C.sub.1-6 -alkyl;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- p is 0, 1 or 2;
- q is 1 or 2;
- r is 0, 1 or 2;
- is a single or double bond;
- and ##STR50## wherein W' is oxygen or sulfur;
- R.sup.1 is hydrogen, amino, halogen, NHR6', NR.sup.6' R.sup.7", R.sup.4", --OR.sup.4', --SR.sup.4', --SOR.sup.4', --SO.sub.2 R.sup.4', C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl), --Z'--C.sub.3-10 -cycloalkyl and --Z'--C.sub.4-12 -(cycloalkylalkyl) wherein R.sup.4' is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y', phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.14 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ;
- or
- R' is --OR.sup.5' Y', --SR.sup.5' Y', OR.sup.5' --Z'--Y', --SR.sup.5' Z'Y', --O--R.sup.5' --Z--R.sup.4' or --S--R.sup.5 --Z'--R.sup.4' wherein Z' is oxygen or sulphur, R.sup.5' is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y' is a 5 or 6 membered heterocyclic group;
- and
- G' is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR51## or G' can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6' R.sup.7' ;
- R.sup.6' and R.sup.7' independently are hydrogen, C.sub.1-6 -alkyl;
- or
- R.sup.6' and R.sup.7' together with the nitrogen atom optionally form a 4- to 6-member ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- R.sup.6' is hydrogen, C.sub.1-15 -alkyl
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- p is 0, 1 or 2;
- q is 1 or 2;
- r is 0, 1 or 2;
- ....... is a single or double bond;
- or
- a pharmaceutically acceptable salt or solvate thereof;
- and
- one or more Synergistic Analgesics in a weight ratio of Compound to Synergistic Analgesic of from about 1 to about 1000 for the manufacture of a medicament for therapeutic application in the treatment of pain.
44 more elements
Dependencies are inferred from the claim text.