Patent ID: 6048859
Filing Date: 2000-04-11
Classification: A61K,A61P,C07D,Y10S

Abstract:
A method for the prevention or treatment of emesis in a mammal in need thereof which comprises the administration to the mammal of an effective amount of: a 5HT.sub.3 receptor antagonist in conjunction with a compound of the structural formula: ##STR19## 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, wherein halo is fluoro, chloro, bromo or iodo,(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,(j) --NR.sup.9 CO.sub.2 R.sup.10,(k) --CONR.sup.9 R.sup.10,(l) --COR.sup.9,(m) --CO.sub.2 R.sup.9,(n) heterocycle, wherein the heterocycle is selected from the group consisting of:(A) benzimidazolyl,(B) benzofuranyl,(C) benzothiophenyl,(D) benzoxazolyl,(E) furanyl,(F) imidazolyl,(G) indolyl,(H) isooxazolyl,(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) piperazinyl,(AA) piperidinyl,(AB) pyrrolidinyl,(AC) tetrahydrofuranyl, and(AD) tetrahydrothienyl,and wherein the heterocycle 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,(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,(xii) --NR.sup.9 COR.sup.10,(xiii) --CONR.sup.9 R.sup.10,(xiv) --CO.sub.2 R.sup.9, and(xv) --(CH.sub.2).sub.m --OR.sup.9 ;(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,(i) --COR.sup.9,(j) --CO.sub.2 R.sup.9,(k) heterocycle;(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,(j) --NR.sup.9 COR.sup.10,(k) --NR.sup.9 CO.sub.2 R.sup.10,(l) --CONR.sup.9 R.sup.10,(m) --CO.sub.2 NR.sup.9 R.sup.10,(n) --COR.sup.9, and(o) --CO.sub.2 R.sup.9 ;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,(i) --NR.sup.9 COR.sup.10,(j) --NR.sup.9 CO.sub.2 R.sup.10,(k) --CONR.sup.9 R.sup.10,(l) --COR.sup.9, and(m) --CO.sub.2 R.sup.9 ;(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,(i) --COR.sup.9, and(j) --CO.sub.2 R.sup.9 ;(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,(j) --NR.sup.9 COR.sup.10,(k) --NR.sup.9 CO.sub.2 R.sup.10,(l) --CONR.sup.9 R.sup.10,(m) --CO.sub.2 NR.sup.9 R.sup.10,(n) --COR.sup.9, and(o) --CO.sub.2 R.sup.9 ;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,(i) --NR.sup.9 COR.sup.10,(j) --NR.sup.9 CO.sub.2 R.sup.10,(k) --CONR.sup.9 R.sup.10,(l) --COR.sup.9, and(m) --CO.sub.2 R.sup.9 ;(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,(i) --COR.sup.9, and(j) --CO.sub.2 R.sup.9 ;(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,(j) --NR.sup.9 COR.sup.10,(k) --NR.sup.9 CO.sub.2 R.sup.10,(l) --CONR.sup.9 R.sup.10,(m) --CO.sub.2 NR.sup.9 R.sup.10,(n) --COR.sup.9, and(o) --CO.sub.2 R.sup.9 ;(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,(12) --SO.sub.2 R.sup.14,(13) NR.sup.9 COR.sup.10,(14) CONR.sup.9 COR.sup.10,(15) NR.sup.9 R.sup.10,(16) NR.sup.9 CO.sub.2 R.sup.10,(17) hydroxy,(18) C.sub.1-6 alkoxy,(19) COR.sup.9,(20) CO.sub.2 R.sup.9,(21) 2-pyridyl,(22) 3-pyridyl,(23) 4-pyridyl,(24) 5-tetrazolyl,(25) 2-oxazolyl, and(26) 2-thiazolyl;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 ;X is selected from the group consisting of:(1) --O--,(2) --S--,(3) --SO--, and(4) --SO.sub.2 --;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,(ix) --NR.sup.9 COR.sup.10,(x) --NR.sup.9 CO.sub.2 R.sup.10,(xi) --CONR.sup.9 R.sup.10,(xii) --COR.sup.9, and(xiii) --CO.sub.2 R.sup.9 ;(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,(x) --NR.sup.9 COR.sup.10,(xi) --NR.sup.9 CO.sub.2 R.sup.10,(xii) --CONR.sup.9 R.sup.10,(xiii) --CO.sub.2 NR.sup.9 R.sup.10,(xiv) --COR.sup.9, and(xv) --CO.sub.2 R.sup.9 ;Z is hydrogen or C.sub.1-6 alkyl.