Claims for Patent: 5,716,942

Summary for Patent: 5,716,942

Title:	Treatment of migraine with morpholine tachykinin receptor antagonists
Abstract:	Substituted heterocycles of the general structural formula: are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, emesis and nausea.
Inventor(s):	Conrad P. Dorn, Malcolm MacCoss, Jeffrey J. Hale, Sander G. Mills
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US08/450,198
Patent Claims:	1. A method for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal in need thereof which comprises the administration to the mammal of a compound in an amount that is effective for antagonizing the effect of substance P at its receptor site in the mammal, wherein the compound is of the formula I: ##STR25## 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, wherein R9 and R10 are as defined above, (j) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (k) --CONR9 R10, wherein R9 and R10 are as defined above, (l) --COR9, wherein R9 is as defined above, and (m) --CO2 R9, wherein R9 is as defined above; (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 wherein R9 and R10 are as defined above, (i) --COR9 wherein R9 is as defined above, (j) --CO2 R9, wherein R9 is as defined above; (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, R9 and R10 are as defined above, (j) --NR9 COR10, wherein R9 and R10 are as defined above, (k) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (l) --CONR9 R10, wherein R9 and R10 are as defined above, (m) --CO2 NR9 R10, wherein R9 and R10 are as defined above, (n) --COR9, wherein R9 is as defined above; (o) --CO2 R9, wherein R9 is as defined above;and, alternatively, 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, wherein R9 and R10 are as defined above, (iv) halo, and (v) trifluoromethyl; and, alternatively, 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, wherein R9 and R10 are as defined above, (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, wherein R9 and R10 are as defined above, (i) --NR9 COR10, wherein R9 and R10 are as defined above, (j) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (k) --CONR9 R10, wherein R9 and R10 are as defined above, (l) --COR9, wherein R9 is as defined above, and (m) --CO2 R9, wherein R9 is as defined above; (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 wherein R9 and R10 are as defined above, (i) --COR9 wherein R9 is as defined above, (j) --CO2 R9, wherein R9 is as defined above; (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, R9 and R10 are as defined above, (j) --NR9 COR10, wherein R9 and R10 are as defined above, (k) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (l) --CONR9 R10, wherein R9 and R10 are as defined above, (m) --CO2 NR9 R10, wherein R9 and R10 are as defined above, (n) --COR9, wherein R9 is as defined above; (o) --CO2 R9, wherein R9 is as defined above; (6) halo, (7) --CN, (8) --CF3, (9) --NO2, (10) --SR14, wherein R14 is hydrogen or C1-5 alkyl, (11) --SOR14, wherein R14 is as defined above, (12) --SO2 R14, wherein R14 is as defined above, (13) NR9 COR10, wherein R9 and R10 are as defined above, (14) CONR9 COR10, wherein R9 and R10 are as defined above, (15) NR9 R10, wherein R9 and R10 are as defined above, (16) NR9 CO2 R10, wherein R9 and R10 are as defined above, (17) hydroxy, (18) C1-6 alkoxy, (19) COR9, wherein R9 is as defined above, (20) CO2 R9, wherein R9 is as defined above, (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, wherein R9 and R10 are as defined above, (i) --NR9 COR10, wherein R9 and R10 are as defined above, (j) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (k) --CONR9 R10, wherein R9 and R10 are as defined above, (l) --COR9, wherein R9 is as defined above, and (m) --CO2 R9, wherein R9 is as defined above; (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 wherein R9 are as defined above, (i) --COR9 wherein R9 is as defined above, and (j) --CO2 R9, wherein R9 is as defined above; and (3) C2-6 alkynyl; B is a heterocycle, wherein the heterocycle is selected from the group consisting of: ##STR26## 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, wherein R9 is as defined above, (viii) halo, (ix) cyano, (x) phenyl, (xi) trifluoromethyl, (xii) --(CH2)m --NR9 R10, wherein m is 0, 1 or 2, and R9 and R10 are as defined above, (xiii) --NR9 COR10, wherein R9 and R10 are as defined above, (xiv) --CONR9 R10, wherein R9 and R10 are as defined above, (xv) --CO2 R9, wherein R9 is as defined above, and (xvi) --(CH2)m --OR9, wherein m and R9 are as defined above; 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: ##STR27## (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, wherein R9 and R10 are as defined above, (ix) --NR9 COR10, wherein R9 and R10 are as defined above, (x) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (xi) --CONR9 R10, wherein R9 and R10 are as defined above, (xii) --COR9, wherein R9 is as defined above, and (xiii) --CO2 R9, wherein R9 is as defined above; (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, wherein m, R9 and R10 are as defined above, (x) --NR9 COR10, wherein R9 and R10 are as defined above, (xi) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (xii) --CONR9 R10, wherein R9 and R10 are as defined above, (xiii) --CO2 NR9 R10, wherein R9 and R10 are as defined above, (xiv) --COR9, wherein R9 is as defined above, and (xv) --CO2 R9, wherein R9 is as defined above; Z is selected from:(1) hydrogen, (2) C1-6 alkyl, and (3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, or if Y is --CHR15 --, then Z and R15 are optionally joined together to form a double bond. 2. A method of treating or preventing pain or nociception attributable to or associated with migraine in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound of the formula I: ##STR28## 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, wherein R9 and R10 are as defined above, (j) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (k) --CONR9 R10, wherein R9 and R10 are as defined above, (l) --COR9, wherein R9 is as defined above, and (m) --CO2 R9, wherein R9 is as defined above; (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 wherein R9 and R10 are as defined above, (i) --COR9 wherein R9 is as defined above, (j) --CO2 R9, wherein R9 is as defined above; (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, R9 and R10 are as defined above, (j) --NR9 COR10, wherein R9 and R10 are as defined above, (k) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (l) --CONR9 R10, wherein R9 and R10 are as defined above, (m) --CO2 NR9 R10, wherein R9 and R10 are as defined above, (n) --COR9, wherein R9 is as defined above; (o) --CO2 R9, wherein R9 is as defined above; and, alternatively, 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, wherein R9 and R10 are as defined above, (iv) halo, and (v) trifluoromethyl; and, alternatively, 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, wherein R9 and R10 are as defined above, (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, wherein R9 and R10 are as defined above, (i) --NR9 COR10, wherein R9 and R10 are as defined above, (j) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (k) --CONR9 R10, wherein R9 and R10 are as defined above, (l) --COR9, wherein R9 is as defined above, and (m) --CO2 R9, wherein R9 is as defined above; (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 wherein R9 and R10 are as defined above, (i) --COR9 wherein R9 is as defined above, (j) --CO2 R9, wherein R9 is as defined above; (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, R9 and R10 are as defined above, (j) --NR9 COR10, wherein R9 and R10 are as defined above, (k) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (l) --CONR9 R10, wherein R9 and R10 are as defined above, (m) --CO2 NR9 R10, wherein R9 and R10 are as defined above, (n) --COR9, wherein R9 is as defined above; (o) --CO2 R9, wherein R9 is as defined above; (6) halo, (7) --CN, (8) --CF3, (9) --NO2, (10) --SR14, wherein R14 is hydrogen or C1-5 alkyl, (11) --SOR14, wherein R14 is as defined above, (12) --SO2 R14, wherein R14 is as defined above, (13) NR9 COR10, wherein R9 and R10 are as defined above, (14) CONR9 COR10, wherein R9 and R10 are as defined above, (15) NR9 R10, wherein R9 and R10 are as defined above, (16) NR9 CO2 R10, wherein R9 and R10 are as defined above, (17) hydroxy, (18) C1-6 alkoxy, (19) COR9, wherein R9 is as defined above, (20) CO2 R9, wherein R9 is as defined above, (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, wherein R9 and R10 are as defined above, (i) --NR9 COR10, wherein R9 and R10 are as defined above, (j) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (k) --CONR9 R10, wherein R9 and R10 are as defined above, (l) --COR9, wherein R9 is as defined above, and (m) --CO2 R9, wherein R9 is as defined above; (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 wherein R9 and R10 are as defined above, (i) --COR9 wherein R9 is as defined above, and (j) --CO2 R9, wherein R9 is as defined above; and (3) C2-6 alkynyl; B is a heterocycle, wherein the heterocycle is selected from the group consisting of: ##STR29## 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, wherein R9 is as defined above, (viii) halo, (ix) cyano, (x) phenyl, (xi) trifluoromethyl, (xii) --(CH2)m --NR9 R10, wherein m is 0, 1 or 2, and R9 and R10 are as defined above, (xiii) --NR9 COR10, wherein R9 and R10 are as defined above, (xiv) --CONR9 R10, wherein R9 and R10 are as defined above, (xv) --CO2 R9, wherein R9 is as defined above, and (xvi) --(CH2)m --OR9, wherein m and R9 are as defined above; 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: ##STR30## (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, wherein R9 and R10 are as defined above, (ix) --NR9 COR10, wherein R9 and R10 are as defined above, (x) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (xi) --CONR9 R10, wherein R9 and R10 are as defined above, (xii) --COR9, wherein R9 is as defined above, and (xiii) --CO2 R9, wherein R9 is as defined above; (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, wherein m, R9 and R10 are as defined above, (x) --NR9 COR10, wherein R9 and R10 are as defined above, (xi) --NR9 CO2 R10, wherein R9 and R10 are as defined above, (xii) --CONR9 R10, wherein R9 and R10 are as defined above, (xiii) --CO2 NR9 R10, wherein R9 and R10 are as defined above, (xiv) --COR9, wherein R9 is as defined above, and (xv) --CO2 R9, wherein R9 is as defined above; Z is selected from:(1) hydrogen, (2) C1-6 alkyl, and (3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, or if Y is --CHR15 --, then Z and R15 are optionally joined together to form a double bond. 3. The method of claim 2 wherein the compound of formula I:R2 and R3 are independently selected from the group consisting of:(1) hydrogen, (2) C1-6 alkyl, (3) C2-6 alkenyl, and (4) phenyl; R6, R7 and R8 are independently selected from the group consisting of:(1) hydrogen, (2) C1-6 alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) --CF3 ; R11, R12 and R13 are independently selected from the group consisting of:(1) fluoro, (2) chloro, (3) bromo, and (4) iodo; A is unsubstituted C1-6 alkyl; B is selected from the group consisting of: ##STR31## p is 0; 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 methyl, (e) --CH(R4)--PO(O-)2 •2M+, wherein R4 is hydrogen or methyl, (f) --CH(R4)--PO(O-)2 •D2+, wherein R4 is hydrogen or methyl, (i) --CO--CH2 CH2 --CO2 - •M+, --CH(CH3)--O--CO--R5, wherein R5 is selected from the group consisting of: ##STR32## Y is --O--; Z is hydrogen or C1-4 alkyl. 4. The method of claim 2 wherein the compound of formula I:Z is C1-4 alkyl. 5. The method of claim 2 wherein the compound of formula I:Z is --CH3. 6. The method of claim 2 wherein the compound of formula I:A is --CH2 -- or --CH(CH3)--. 7. The method of claim 2 wherein the compound of formula I:--B is selected from the group consisting of: ##STR33## 8. The method of claim 2 wherein the compound of formula I:--A--B is selected from the group consisting of: ##STR34## 9. The method of claim 2 wherein the compound of formula I:--A--B is selected from the group consisting of: ##STR35## 10. The method of claim 2 wherein the compound of formula I:X is selected from the group consisting of:(a) --PO(O-)2 •2M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) --PO(O-)2 •D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion, (c) --CH(CH3)--O--CO--CH2 CH2 --NH3 + •M-, and (d) --CH(CH3)--O--CO--CH2 CH2 --NH2 + --(CH2 CH2 --OH)•M-. 11. The method of claim 2 wherein the compound of formula I is of the structural formula II: ##STR36## or a pharmaceutically acceptable salt thereof, wherein R2, R3, R6, R7, R8, R11, R12, R13, A, B and Z are as defined in claim 2. 12. The method of claim 2 wherein the compound of formula I is of the structural formula III: ##STR37## or a pharmaceutically acceptable salt thereof, wherein R2, R3, R6, R7, R8, R11, R12, R13, A, B, and Z are as defined in claim 2. 13. A method of treating or preventing pain or nociception attributable to or associated with migraine 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-(ethoxycarbonyloxy-1-ethyl)5-oxo-1H-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-1H-1,2,4-triazolo)methyl)morpholine; (4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine; (5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine; (6) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine; (7) 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;and a pharmaceutically acceptable salt thereof. 14. The method of claim 13 wherein the compound is present as the bis(N-methyl-D-glucamine) salt. 15. A method of treating or preventing pain or nociception attributable to or associated with migraine 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: ##STR38## wherein K+ is a pharmaceutically acceptable counterion. 16. The method of claim 15 wherein the compound is present as the bis(N-methyl-D-glucamine) salt. 17. A method of treating or preventing pain or nociception attributable to or associated with migraine in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound which is: ##STR39## wherein K+ is a pharmaceutically acceptable counterion. 18. The method of claim 17 wherein the compound is present as the bis(N-methyl-D-glucamine) salt. 19. A method for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal in need thereof which comprises the administration to the mammal of a compound in an amount that is effective for antagonizing the effect of substance P at its receptor site in the mammal, wherein the compound is: ##STR40## wherein K+ is a pharmaceutically acceptable counterion. 20. The method of claim 19 wherein the compound is present as the bis(N-methyl-D-glucamine) salt.