Patent ID: 6180624
Filing Date: 2001-01-30
Classification: A61K,A61P

Abstract:
A method for the treatment or prevention of pain or nociception in a patient in need thereof which comprises administering to the patient an effective amount of a tachykinin antagonist and an opioid analgesic wherein the tachykinin antagonist is a compound of formula (I): ##STR37##or a pharmaceutically acceptable salt thereof, wherein:R.sup.1 is selected from the group consisting of:(1) hydrogen;(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl-C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently selected from:(i) hydrogen,(ii) C.sub.1-6 alkyl,(iii) hydroxy-C.sub.1-6 alkyl, and(iv) phenyl,(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --COR.sup.9, wherein R.sup.9 is as defined above,(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above,(n) heterocycle, wherein the heterocycle is selected from the group consisting of:(A) benzimidazolyl,(B) benzofuranyl,(C) benzthiophenyl,(D) benzoxazolyl,(E) furanyl,(F) imidazolyl,(G) indolyl,(H) isoxazolyl,(I) isothiazolyl,(J) oxadiazolyl,(K) oxazolyl,(L) pyrazinyl,(M) pyrazolyl,(N) pyridyl,(O) pyrimidyl,(P) pyrrolyl,(Q) quinolyl,(R) tetrazolyl,(S) thiadiazolyl,(T) thiazolyl,(U) thienyl,(V) triazolyl,(W) azetidinyl,(X) 1,4-dioxanyl,(Y) hexahydroazepinyl,(Z) oxanyl,(AA) piperazinyl,(AB) piperidinyl,(AC) pyrrolidinyl,(AD) tetrahydrofuranyl, and(AE) tetrahydrothienyl,and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from:(i) C.sub.1-6 alkyl, unsubstituted or substituted with halo, --CF.sub.3, --OCH.sub.3, or phenyl,(ii) C.sub.1-6 alkoxy,(iii) oxo,(iv) hydroxy,(v) thioxo,(vi) --SR.sup.9, wherein R.sup.9 is as defined above,(vii) halo,(viii) cyano,(ix) phenyl,(x) trifluoromethyl,(xi) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m is 0, 1 or 2, and R.sup.9 and R.sup.10 are as defined above,(xii) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xiii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xiv) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, and(xv) --(CH.sub.2).sub.m --OR.sup.9, wherein m and R.sup.9 are as defined above;(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl-C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --COR.sup.9, wherein R.sup.9 is as defined above,(k) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above,(k) heterocycle, wherein the heterocycle is as defined above;(4) C.sub.2-6 alkynyl;(5) phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) C.sub.1-6 alkoxy,(c) C.sub.1-6 alkyl,(d) C.sub.2-5 alkenyl,(e) halo,(f) --CN,(g) --NO.sub.2,(h) --CF.sub.3,(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(n) --COR.sup.9, wherein R.sup.9 is as defined above,(o) --C.sub.2 R.sup.9, wherein R.sup.9 is as defined above;R.sup.2 and R.sup.3 are independently selected from the group consisting of:(1) hydrogen;(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl-C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --COR.sup.9, wherein R.sup.9 is as defined above, and(m) --C(2 R.sup.9, wherein R.sup.9 is as defined above;(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are as defined above,(i) --COR.sup.9, wherein R.sup.9 is as defined above,(l) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(4) C.sub.2-6 alkynyl;(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) C.sub.1-6 alkoxy,(c) C.sub.1-6 alkyl,(d) C.sub.2-5 alkenyl,(e) halo,(f) --CN,(g) --NO.sub.2,(h) --CF.sub.3,(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(n) --COR.sup.9, wherein R.sup.9 is as defined above,(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;and the groups R.sup.1 and R.sup.2 may be joined together to form a heterocyclic ring selected from the group consisting of:(a) pyrrolidinyl,(b) piperidinyl,(c) pyrrolyl,(d) pyridinyl,(e) imidazolyl,(f) oxazolyl, and(g) thiazolyl,and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:(i) C.sub.1-6 alkyl,(ii) oxo,(iii) C.sub.1-b 6 alkoxy,(iv) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(v) halo, and(vi) trifluoromethyl;and the groups R.sup.2 and R.sup.3 may be joined together to form a carbocyclic ring selected from the group consisting of:(a) cyclopentyl,(b) cyclohexyl,(c) phenyl,and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:(i) C.sub.1-6 alkyl,(ii) C.sub.1-6 alkoxy,(iii) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(iv) halo, and(v) trifluoromethyl;and the groups R.sup.2 and R.sup.3 may be joined together to form a heterocyclic ring selected from the group consisting of:(a) pyrrolidinyl,(b) piperidinyl,(c) phenyl,(d) pyridinyl,(e) imidazolyl,(f) furanyl,(g) oxazolyl,(h) thienyl, and(i) thiazolyl,and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituent selected from:(i) C.sub.1-6 alkyl,(ii) oxo,(iii) C.sub.1-6 alkoxy,(iv) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(v) halo, and(vi) trifluoromethyl;X is selected from the group consisting of:(1) --O--,(2) --S--,(3) --SO--, and(4) --SO.sub.2 --;R.sup.4 is selected from the group consisting of:(1) ##STR38##(2) --Y--C.sub.1-8 alkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --COR.sup.9, wherein R.sup.9 is as defined above,(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(3) --Y--C.sub.2-6 alkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --COR.sup.9, wherein R.sup.9 is as defined above,(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above,(4) --O(CO)--phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R.sup.6, R.sup.7 and R.sup.8 ;R.sup.5 is selected from the group consisting of:(1) phenyl, unsubstituted or substituted with one or more of R.sup.11, R.sup.12 and R.sup.13 ;(2) C.sub.1-8 alkyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --COR.sup.9, wherein R.sup.9 is as defined above,(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --COR.sup.9, wherein R.sup.9 is as defined above,(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(4) heterocycle, wherein the heterocycle is as defined above;R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of:(1) hydrogen;(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --COR.sup.9, wherein R.sup.9 is as defined above, and(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) oxo,(c) C.sub.1-6 alkoxy,(d) phenyl--C.sub.1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are as defined above,(i) --COR.sup.9 wherein R.sup.9 is as defined above,(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(4) C.sub.2-6 alkynyl;(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(a) hydroxy,(b) C.sub.1-6 alkoxy,(c) C.sub.1-6 alkyl,(d) C.sub.2-5 alkenyl,(e) halo,(f) --CN,(g) --NO.sub.2,(h) --CF.sub.3,(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 are as defined above,(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(n) --COR.sup.9, wherein R.sup.9 is as defined above;(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(6) halo,(7) --CN,(8) --CF.sub.3,(9) --NO.sub.2,(10) --SR.sup.14, wherein R.sup.14 is hydrogen or C.sub.1-5 alkyl,(11) --SOR.sup.14, wherein R.sup.14 is as defined above,(12) --SO.sub.2 R.sup.14, wherein R.sup.14 is as defined above,(13) NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(14) CONR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(15) NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(16) NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(17) hydroxy,(18) C.sub.1-6 alkoxy,(19) COR.sup.9, wherein R.sup.9 is as defined above,(20) CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above,R.sup.11, R .sup.12 and R.sup.13 are independently selected from the definitions of R.sup.6, R.sup.7 and R .sup.8 ;Y is selected from the group consisting of:(1) a single bond,(2) --O--,(3) --S--,(4) --CO--,(5) --CH.sub.2 --,(6) --CHR.sup.15 --, and(7) --CR.sup.15 R.sup.16 --, wherein R.sup.15 and R.sup.16 are independently selected from the group consisting of:(a) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:(i) hydroxy,(ii) oxo,(iii) C.sub.1-6 alkoxy,(iv) phenyl--C.sub.1-3 alkoxy,(v) phenyl,(vi) --CN,(vii) halo,(viii) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(ix) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(x) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xi) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xii) --COR.sup.9, wherein R.sup.9 is as defined above, and(xiii) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:(i) hydroxy,(ii) C.sub.1-6 alkoxy,(iii) C.sub.1-6 alkyl,(iv) C.sub.2-5 alkenyl,(v) halo,(vi) --CN,(vii) --NO.sub.2,(viii) --CF.sub.3,(ix) --(CH.sub.2).sub.m--NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 are as defined above,(x) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xi) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xiii) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,(xiv) --COR.sup.9, wherein R.sup.9 is as defined above, and(xv) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;Z is selected from:(1) hydrogen,(2) C.sub.1-4 alkyl, and(3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, or if Y is --CHR.sup.15 --, then Z and R.sup.15 may be joined together to form a double bond.