US 5,512,570 AGranted

Treatment of emesis with morpholine tachykinin receptor antagonists

AssigneeMerck & Co., Inc.

InventorsConrad P. Dorn, Malcolm MacCoss, Jeffrey J. Hale, Sander G. Mills

Life of this patent

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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.

Claims15

Dependent claims

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.

240 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/450,507Filed 25 May 1995 · division
Priority: 4 Mar 1994
Granted: 30 Apr 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 265/30
1,4-Oxazines; Hydrogenated 1,4-oxazines: not condensed with other rings
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics
A61P 3/00
Drugs for disorders of the metabolism

Family

Serial206,771Parent of this division · filed 4 Mar 1994
US 5,512,570 AThis patent

From the US filing history. Foreign family members aren’t listed.

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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.

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.

240 more elements

Facts

Application

08/450,507Filed 25 May 1995 · division

Priority

4 Mar 1994

Granted

30 Apr 1996

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 265/30
1,4-Oxazines; Hydrogenated 1,4-oxazines: not condensed with other rings
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics
A61P 3/00
Drugs for disorders of the metabolism