Morpholine and thiomorpholine tachykinin receptor antagonists

  • US 6,048,859 A
  • Filed: 02/16/1999
  • Issued: 04/11/2000
  • Est. Priority Date: 06/29/1992
  • Status: Expired due to Term
First Claim
Patent Images

1. 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 5HT3 receptor antagonist in conjunction with a compound of the structural formula;

    ##STR19## or a pharmaceutically acceptable salt thereof, wherein;

    R1 is selected from the group consisting of;

    (1) hydrogen;

    (2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

    (a) hydroxy,(b) oxo,(c) C1-6 alkoxy,(d) phenyl-C1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo, wherein halo is fluoro, chloro, bromo or iodo,(h) --NR9 R10, wherein R9 and R10 are independently selected from;

    (i) hydrogen,(ii) C1-6 alkyl,(iii) hydroxy-C1-6 alkyl, and(iv) phenyl,(i) --NR9 COR10,(j) --NR9 CO2 R10,(k) --CONR9 R10,(l) --COR9,(m) --CO2 R9,(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) C1-6 alkyl, unsubstituted or substituted with halo, --CF3, --OCH3, or phenyl, (ii) C1-6 alkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) --SR9, (vii) halo, (viii) cyano, (ix) phenyl, (x) trifluoromethyl, (xi) --(CH2)m --NR9 R10, wherein m is 0, 1 or 2, (xii) --NR9 COR10, (xiii) --CONR9 R10, (xiv) --CO2 R9, and (xv) --(CH2)m --OR9 ;

    (3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (a) hydroxy,(b) oxo,(c) C1-6 alkoxy,(d) phenyl-C1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR9 R10,(i) --COR9,(j) --CO2 R9,(k) heterocycle;

    (4) C2-6 alkynyl;

    (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (a) hydroxy,(b) C1-6 alkoxy,(c) C1-6 alkyl,(d) C2-5 alkenyl,(e) halo,(f) --CN,(g) --NO2,(h) --CF3,(i) --(CH2)m --NR9 R10,(j) --NR9 COR10,(k) --NR9 CO2 R10,(l) --CONR9 R10,(m) --CO2 NR9 R10,(n) --COR9, and(o) --CO2 R9 ;

    R2 and R3 are independently selected from the group consisting of;

    (1) hydrogen,(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

    (a) hydroxy,(b) oxo,(c) C1-6 alkoxy,(d) phenyl-C1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR9 R10,(i) --NR9 COR10,(j) --NR9 CO2 R10,(k) --CONR9 R10,(l) --COR9, and(m) --CO2 R9 ;

    (3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (a) hydroxy,(b) oxo,(c) C1-6 alkoxy,(d) phenyl-C1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR9 R10,(i) --COR9, and(j) --CO2 R9 ;

    (4) C2-6 alkynyl;

    (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (a) hydroxy,(b) C1-6 alkoxy,(c) C1-6 alkyl,(d) C2-5 alkenyl,(e) halo,(f) --CN,(g) --NO2,(h) --CF3,(i) --(CH2)m --NR9 R10,(j) --NR9 COR10,(k) --NR9 CO2 R10,(l) --CONR9 R10,(m) --CO2 NR9 R10,(n) --COR9, and(o) --CO2 R9 ;

    R6, R7 and R8 are independently selected from the group consisting of;

    (1) hydrogen;

    (2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

    (a) hydroxy,(b) oxo,(c) C1-6 alkoxy,(d) phenyl-C1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --NR9 R10,(i) --NR9 COR10,(j) --NR9 CO2 R10,(k) --CONR9 R10,(l) --COR9, and(m) --CO2 R9 ;

    (3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (a) hydroxy,(b) oxo,(c) C1-6 alkoxy,(d) phenyl-C1-3 alkoxy,(e) phenyl,(f) --CN,(g) halo,(h) --CONR9 R10,(i) --COR9, and(j) --CO2 R9 ;

    (4) C2-6 alkynyl;

    (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (a) hydroxy,(b) C1-6 alkoxy,(c) C1-6 alkyl,(d) C2-5 alkenyl,(e) halo,(f) --CN,(g) --NO2,(h) --CF3,(i) --(CH2)m --NR9 R10,(j) --NR9 COR10,(k) --NR9 CO2 R10,(l) --CONR9 R10,(m) --CO2 NR9 R10,(n) --COR9, and(o) --CO2 R9 ;

    (6) halo,(7) --CN,(8) --CF3,(9) --NO2,(10) --SR14, wherein R14 is hydrogen or C1-5 alkyl,(11) --SOR14,(12) --SO2 R14,(13) NR9 COR10,(14) CONR9 COR10,(15) NR9 R10,(16) NR9 CO2 R10,(17) hydroxy,(18) C1-6 alkoxy,(19) COR9,(20) CO2 R9,(21) 2-pyridyl,(22) 3-pyridyl,(23) 4-pyridyl,(24) 5-tetrazolyl,(25) 2-oxazolyl, and(26) 2-thiazolyl;

    R11, R12 and R13 are independently selected from the definitions of R6, R7 and R8 ;

    X is selected from the group consisting of;

    (1) --O--,(2) --S--,(3) --SO--, and(4) --SO2 --;

    Y is selected from the group consisting of;

    (1) a single bond,(2) --O--,(3) --S--,(4) --CO--,(5) --CH2 --,(6) --CHR15 --, and(7) --CR15 R16 --, wherein R15 and R16 are independently selected from the group consisting of;

    (a) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

    (i) hydroxy,(ii) oxo,(iii) C1-6 alkoxy,(iv) phenyl-C1-3 alkoxy,(v) phenyl,(vi) --CN,(vii) halo,(viii) --NR9 R10,(ix) --NR9 COR10,(x) --NR9 CO2 R10,(xi) --CONR9 R10,(xii) --COR9, and(xiii) --CO2 R9 ;

    (b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

    (i) hydroxy,(ii) C1-6 alkoxy,(iii) C1-6 alkyl,(iv) C2-5 alkenyl,(v) halo,(vi) --CN,(vii) --NO2,(viii) --CF3,(ix) --(CH2)m --NR9 R10,(x) --NR9 COR10,(xi) --NR9 CO2 R10,(xii) --CONR9 R10,(xiii) --CO2 NR9 R10,(xiv) --COR9, and(xv) --CO2 R9 ;

    Z is hydrogen or C1-6 alkyl.

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