Morpholine compounds are prodrugs useful as tachykinin receptor antagonists

CAFC
  • US 5,691,336 A
  • Filed: 09/08/1995
  • Issued: 11/25/1997
  • Est. Priority Date: 03/04/1994
  • Status: Expired due to Term
First Claim
Patent Images

1. A compound of structural formula:

  • ##STR14## or a pharmaceutically acceptable salt thereof, wherein;

    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, 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, 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,(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, wherein m is 0, 1 or 2,(j) --NR9 COR10,(k) --NR9 CO2 R10,(l) --CONR9 R10,(m) --CO2 NR9 R10,(n) --COR9, and(o) --CO2 R9 ;

    or the groups R2 and R3 are 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) C1-6 alkyl,(ii) C1-6 alkoxy,(iii) --NR9 R10,(iv) halo, andv) trifluoromethyl;

    or the groups R2 and R3 are joined together to form a heterocyclic ring selected from the group consisting of;

    (a) pyrrolidinyl,(b) piperidinyl,(c) pyrrolyl,(d) pyridinyl,(e) imidazolyl,(f) furanyl,(g) oxazolyl,(h) thienyl, and(i) thiazolyl,and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from;

    (i) C1-6 alkyl,(ii) oxo,(iii) C1-6 alkoxy,(iv) --NR9 R10,(v) halo, and(vi) trifluoromethyl;

    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, or --OX;

    A is selected from the group consisting of;

    (1) 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,(i) --NR9 COR10,(j) --NR9 CO2 R10,(k) --CONR9 R10,(l) --COR9, and(m) --CO2 R9 ;

    (2) 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 ; and

    (3) C2-6 alkynyl;

    B is a heterocycle, wherein the heterocycle is selected from the group consisting of;

    ##STR15## and wherein the heterocycle is substituted in addition to --X with one or more substituent(s) selected from;

    (i) hydrogen;

    (ii) C1-6 alkyl, unsubstituted or substituted with halo, --CF3, --OCH3, or phenyl,(iii) C1-6 alkoxy,(iv) oxo,(v) hydroxy,(vi) thioxo,(vii) --SR9,(viii) halo,(ix) cyano,(x) phenyl,(xi) trifluoromethyl,(xii) --(CH2)m --NR9 R10,(xiii) --NR9 COR10,(xiv) --CONR9 R10,(xv) --CO2 R9, and(xvi) --(CH2)m --OR9 ;

    p is 0 or 1;

    X is selected from;

    (a) --PO(OH)O-

    M+, wherein M+ is a pharmaceutically acceptable monovalent counterion,(b) --PO(O-)2

    2M+,(c) --PO(O-)2

    D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion,(d) --CH(R4)--PO(OH)O-

    M+, wherein R4 is hydrogen or C1-3 alkyl,(e) --CH(R4)--PO(O-)2

    2M+,(f) --CH(R4)--PO(O-)2

    D2+,(g) --SO3-

    M+,(h) --CH(R4)--SO3-

    M+,(i) --CO--CH2 CH2 --CO2-

    M+,(j) --CH(CH3)--O--CO--R5, wherein R5 is selected from the group consisting of;

    ##STR16## (k) hydrogen, with the proviso that if p is 0 and none of R11, R12 or R13 are --OX, then X is other than hydrogen;

    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 selected from;

    (1) hydrogen,(2) C1-6 alkyl, and(3) hydroxy, with the proviso that if Y is --O--, then Z is other than hydroxy, and with the further proviso that if Y is --CHR15 --, then Z and R15 may be joined together to form a double bond between the two carbon atoms.

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