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Claims for Patent: 5,512,570

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Claims for Patent: 5,512,570

Title: Treatment of emesis with morpholine tachykinin receptor antagonists
Abstract:Substituted heterocycles of the structural formula: ##STR1## are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, emesis and nausea.
Inventor(s): Dorn; Conrad P. (Plainfield, NJ), MacCoss; Malcolm (Freehold, NJ), Hale; Jeffrey J. (Westfield, NJ), Mills; Sander G. (Woodbridge, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:08/450,507
Patent Claims: 1. A method for the treatment or prevention of emesis in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound of the formula I: ##STR11## or a pharmaceutically acceptable salt thereof, wherein: 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 ed 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, 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 de fined 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, alternatively, the groups R.sup.2 and R.sup.3 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) 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, alternatively, the groups R.sup.2 and R.sup.3 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) 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:

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,

(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, or -OX;

A is selected from the group consisting of:

(1) 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 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;

(2) 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, and

(j) -CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; and

(3) C.sub.2-6 alkynyl;

B is a heterocycle, wherein the heterocycle is selected from the group consisting of: ##STR12## and wherein the heterocycle is substituted in addition to -X with one or more substituent(s) selected from:

(i) hydrogen;

(ii) C.sub.1-6 alkyl, unsubstituted or substituted with halo. -CF.sub.3, -OCH.sub.3, or phenyl,

(iii) C.sub.1-6 alkoxy,

(iv) OXO,

(v) hydroxy,

(vi) thioxo,

(vii)-SR.sup.9, wherein R.sup.9 is as defined above,

(viii) halo,

(ix) cyano,

(x) phenyl,

(xi) trifluoromethyl,

(xii) -(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,

(xiii) -NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,

(xiv) -CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,

(xv) -CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, and

(xvi) -(CH.sub.2).sub.m -OR.sup.9, wherein m and R.sup.9 are as defined above;

p is 0 or 1;

X is selected from:

(a) -PO(OH)O-. M.sup.+, wherein M.sup.+ is a pharmaceutically acceptable monovalent counterion,

(b) -PO(O.sup.-).sub.2.2M.sup.+,

(c) -PO(O.sup.-).sub.2.D.sup.2 +, wherein D.sup.2+ is a pharmaceutically acceptable divalent counterion,

(d) -CH(R.sup.4)-PO(OH)O-.sup.-. M.sup.+, wherein R.sup.4 is hydrogen or C.sub.1-3 alkyl,

(e) -CH(R.sup.4)-PO(O.sup.-).sub.2.2M.sup.+,

(f) -CH(R.sup.4)-PO(O.sup.-).sub.2.D.sup.2+,

(g) -SO.sub.3 -.M.sup.+,

(h) -CH(R.sup.4)-SO.sub.3 -.M.sup.30 ,

(i) -CO-CH.sub.2 CH.sub.2 -CO.sub.2 -.M.sup.+,

(j)-CH(CH.sub.3)-O-CO-R.sup.5, wherein R.sup.5 is selected from the group consisting of: ##STR13## (k) hydrogen, with the proviso that is p is 0 and none of R.sup.11, R.sup.12 or R.sup.13 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) -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.1-6 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 are optionally joined together to form a double bond.

2. The method of claim 1 wherein the compound of formula I:

R.sup.2 and R.sup.3 are independently selected from the group consisting of:

(1) hydrogen,

(2) C.sub.1-6 alkyl,

(3) C.sub.2-6 alkenyl, and

(4) phenyl;

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,

(3) fluoro,

(4) chloro,

(5) bromo,

(6) iodo, and

(7) -CF.sub.3 ;

R.sup.11, R.sup.12 and R.sup.13 are independently selected from the group consisting of:

(1) fluoro,

(2) chloro,

(3) bromo, and

(4) iodo;

A is unsubstituted C.sub.1-6 alkyl;

B is selected from the group consisting of: ##STR14## p is 0; X is selected from:

(a) -PO(OH)O.sup.-.M.sup.+, wherein M.sup.+ is a pharmaceutically acceptable monovalent counterion.

(b) -PO(O.sup.-).sub.2.2M.sup.+,

(c) -PO(O.sup.-).sub.2.D.sup.2+, wherein D.sup.2+ is a pharmaceutically acceptable divalent counterion,

(d) -CH(R.sup.4)-PO(OH)O.sup.-.M.sup.+, wherein R.sup.4 is hydrogen or methyl,

(e) -CH(R.sup.4)-PO(O.sup.-).sub.2.2M.sup.+, wherein R.sup.4 is hydrogen or methyl,

(f) -CH(R.sup.4)-PO(O.sup.-).sub.2.D.sup.2+, wherein R.sup.4 is hydrogen or methyl,

(i) -CO-CH.sub.2 CH.sub.2 -CO.sub.2.sup.-.M.sup.+,

(j) -CH(CH.sub.3)-O-CO-R.sup.5, wherein R.sup.5 is selected from the group consisting of: ##STR15## Y is -O-; Z is hydrogen or C.sub.1-4 alkyl.

3. The method of claim 1 wherein the compound of formula I:

Z is C.sub.1-4 alkyl.

4. The method of claim 1 wherein the compound of formula I:

Z is -CH.sub.3.

5. The method of claim 1 wherein the compound of formula I:

A is -CH.sub.2 - or -CH(CH.sub.3)-.

6. The method of claim 1 wherein the compound of formula I:

-B is selected from the group consisting of: ##STR16##

7. The method of claim 1 wherein the compound of formula I:

-A-B is selected from the group consisting of: ##STR17##

8. The method of claim 1 wherein the compound of formula I:

-A-B is selected from the group consisting of: ##STR18##

9. The method of claim 1 wherein the compound of formula I:

X is selected from the group consisting of:

(a) -PO(O.sup.-).sub.2.2M.sup.+, wherein M.sup.+ is a pharmaceutically acceptable monovalent counterion,

(b) -PO(O.sup.-).sub.2.2D.sup.2+, wherein D.sup.2+ is a pharmaceutically acceptable monovalent counterion,

(c) -CH(CH.sub.3)-O-CO-CH.sub.2 CH.sub.2 -NH.sub.3.sup.+. M.sup.-, and

(d) -CH(CH.sub.3)-O-CO-CH.sub.2 CH.sub.2 -NH.sub.2.sup.+ -(CH.sub.2 CH.sub.2 -OH).M.sup.-.

10. The method of claim 1 wherein the compound of formula I is of the structural formula II: ##STR19## or a pharmaceutically acceptable salt thereof, wherein R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.11, R.sup.12, R.sup.13, A, B and Z are as defined in claim 1.

11. The method of claim 1 wherein the compound of formula I is of the structural formula III: ##STR20## or a pharmaceutically acceptable salt thereof, wherein R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.11, R.sup.12, R.sup.13, A, B and Z are as defined in claim 1.

12. A method for the treatment or prevention of emesis in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound which is selected from the group consisting of:

(1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1 ,2,4-triazolo)-methyl)morpholine N-oxide;

(2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarb onyloxy-1-ethyl)5-oxo-1 H-1,2,4-triazolo)-methyl)morpholine;

(3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro) )-phenyl-4-(3-(4-monophosphoryl-5-oxo-1 H-1,2,4-triazolo )-methyl)morpholine;

(4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phe nyl-4-(3-(1-monophosphoryl-5-oxo-1 H-1,2,4-triazolo)-methyl)morpholine;

(5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phe nyl-4-(3-(2-monophosphoryl-5-oxo-1 H-1,2,4-triazolo) methyl) morpholine;

(6) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phe nyl-4-(3-(5-oxyphosphoryl-1 H-1,2,4-triazolo)-methyl morpholine;

(7)2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-p henyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)-methyl)morpholine;

or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 wherein the compound is present as the bis(N-methyl-D-glucamine) salt.

14. A method for the treatment or prevention of emesis in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound which is selected from the group consisting of: ##STR21## wherein K.sup.+ is a pharmaceutically acceptable counterion.

15. The method of claim 14 wherein the compound K.sup.+ is N-methyl-D-glucamine.
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