Claims for Patent: 5,691,336

Summary for Patent: 5,691,336

Title:	Morpholine compounds are prodrugs useful as 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, and emesis.
Inventor(s):	Conrad P. Dorn, Jeffrey J. Hale, Malcolm MacCoss, Sander G. Mills
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US08/525,870
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 5,691,336
Patent Claims:	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, and v) 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. 2. The compound of claim 1 wherein: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: ##STR17## 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+, (f) --CH(R4)--PO(O-)2 •D2+, (g) --CO--CH2 CH2 --CO2 - •M+, (h) --CH(CH3)--O--CO--R5, wherein R5 is selected from the group consisting of: ##STR18## and Y is --O--; Z is hydrogen or C1-4 alkyl. 3. The compound of claim 1 wherein Z is C1-4 alkyl. 4. the compound of claim 1 wherein Z is --CH3. 5. The compound of claim 1 wherein A is --CH2 -- or --CH(CH3)--. 6. The compound of claim 1 wherein --B is selected from the group consisting of: ##STR19## 7. The compound of claim 1 wherein --A--B is selected from the group consisting of: ##STR20## 8. The compound of claim 1 wherein X is selected from the group consisting of:(a) --PO(O-)2 •2M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, and (b) --PO(O-)2 •D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion. 9. The compound of claim 1 of the structural formula II: ##STR21## or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1 of the structural formula III: ##STR22## or a pharmaceutically acceptable salt thereof. 11. 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-(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; (3) 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; (4) 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; (5) 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; (6) 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;or a pharmaceutically acceptable salt thereof. 12. The compound of claim 11 wherein the pharmaceutically acceptable salt is the bis(N-methyl-D-glucamine) salt. 13. A compound which is selected from the group consisting of: ##STR23## wherein K+ is a pharmaceutically acceptable counterion. 14. A compound which is:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine;or a pharmaceutically acceptable salt thereof. 15. The compound of claim 14 wherein the pharmaceutically acceptable salt is the bis(N-methyl-D-glucamine) salt. 16. A compound which is2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine). 17. A compound which is: ##STR24## wherein K+ is a pharmaceutically acceptable counterion. 18. The compound of claim 17 wherein K+ is N-methyl-D-glucamine. 19. A compound which is: ##STR25## 20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound of claim 1. 21. The pharmaceutical composition of claim 20 wherein the pharmaceutically acceptable carrier comprises water. 22. The pharmaceutical composition of claim 20 wherein the pharmaceutically acceptable carrier comprises a physiologically acceptable saline solution. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound which is: ##STR26## 24. A method for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal which comprises the administration to the mammal of the compound of claim 1 in an amount that is effective for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in the mammal. 25. A method of treating or preventing pain or nociception which comprises the administration to the mammal of an effective amount of the compound of claim 1. 1. A compound of structural formula: ##STR14## 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 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 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, (j) --NR.sup.9 CO.sub.2 R.sup.10, (k) --CONR.sup.9 R.sup.10, (l) --COR.sup.9, and (m) --CO.sub.2 R.sup.9, (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, (i) --COR.sup.9, (j) --CO.sub.2 R.sup.9 ; (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 is 0, 1 or 2, (j) --NR.sup.9 COR.sup.10, (k) --NR.sup.9 CO.sub.2 R.sup.10, (l) --CONR.sup.9 R.sup.10, (m) --CO.sub.2 NR.sup.9 R.sup.10, (n) --COR.sup.9, and (o) --CO.sub.2 R.sup.9 ; or 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, (iv) halo, and v) trifluoromethyl; or 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, (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, (i) --NR.sup.9 COR.sup.10, (j) --NR.sup.9 CO.sub.2 R.sup.10, (k) --CONR.sup.9 R.sup.10, (l) --COR.sup.9, and (m) --CO.sub.2 R.sup.9 ; (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, (i) --COR.sup.9, and (j) --CO.sub.2 R.sup.9 ; (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, (j) --NR.sup.9 COR.sup.10, (k) --NR.sup.9 CO.sub.2 R.sup.10, (l) --CONR.sup.9 R.sup.10, (m) --CO.sub.2 NR.sup.9 R.sup.10, (n) --COR.sup.9, and (o) --CO.sub.2 R.sup.9 ; (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, (12) --SO.sub.2 R.sup.14, (13) NR.sup.9 COR.sup.10, (14) CONR.sup.9 COR.sup.10, (15) NR.sup.9 R.sup.10, (16) NR.sup.9 CO.sub.2 R.sup.10, (17) hydroxy, (18) C.sub.1-6 alkoxy, (19) COR.sup.9, (20) CO.sub.2 R.sup.9, (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, (i) --NR.sup.9 COR.sup.10, (j) --NR.sup.9 CO.sub.2 R.sup.10, (k) --CONR.sup.9 R.sup.10, (l) --COR.sup.9, and (m) --CO.sub.2 R.sup.9 ; (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, (i) --COR.sup.9, and (j) --CO.sub.2 R.sup.9 ; and (3) C.sub.2-6 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) 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, (viii) halo, (ix) cyano, (x) phenyl, (xi) trifluoromethyl, (xii) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, (xiii) --NR.sup.9 COR.sup.10, (xiv) --CONR.sup.9 R.sup.10, (xv) --CO.sub.2 R.sup.9, and (xvi) --(CH.sub.2).sub.m --OR.sup.9 ; p is 0 or 1; X is selected from: (a) --PO(OH)O.sup.- .cndot.M.sup.+, wherein M.sup.+ is a pharmaceutically acceptable monovalent counterion, (b) --PO(O.sup.-).sub.2 .cndot.2M.sup.+, (c) --PO(O.sup.-).sub.2 .cndot.D.sup.2+, wherein D.sup.2+ is a pharmaceutically acceptable divalent counterion, (d) --CH(R.sup.4)--PO(OH)O.sup.- .cndot.M.sup.+, wherein R.sup.4 is hydrogen or C.sub.1-3 alkyl, (e) --CH(R.sup.4)--PO(O.sup.-).sub.2 .cndot.2M.sup.+, (f) --CH(R.sup.4)--PO(O.sup.-).sub.2 .cndot.D.sup.2+, (g) --SO.sub.3.sup.- .cndot.M+, (h) --CH(R.sup.4)--SO.sub.3.sup.- .cndot.M.sup.+, (i) --CO--CH.sub.2 CH.sub.2 --CO.sub.2.sup.- .cndot.M.sup.+, (j) --CH(CH.sub.3)--O--CO--R.sup.5, wherein R.sup.5 is selected from the group consisting of: ##STR16## (k) hydrogen, with the proviso that if 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, (ix) --NR.sup.9 COR.sup.10, (x) --NR.sup.9 CO.sub.2 R.sup.10, (xi) --CONR.sup.9 R.sup.10, (xii) --COR.sup.9, and (xiii) --CO.sub.2 R.sup.9 ; (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, (x) --NR.sup.9 COR.sup.10, (xi) --NR.sup.9 CO.sub.2 R.sup.10, (xii) --CONR.sup.9 R.sup.10, (xiii) --CO.sub.2 NR.sup.9 R.sup.10, (xiv) --COR.sup.9, and (xv) --CO.sub.2 R.sup.9 ; Z is selected from: (1) hydrogen, (2) C.sub.1-6 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 --CHR.sup.15 --, then Z and R.sup.15 may be joined together to form a double bond between the two carbon atoms. 2. The compound of claim 1 wherein: 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: ##STR17## p is 0; X is selected from: (a) --PO(OH)O.sup.- .cndot.M.sup.+, wherein M.sup.+ is a pharmaceutically acceptable monovalent counterion, (b) --PO(O.sup.-).sub.2 .cndot.2M.sup.+, (c) --PO(O.sup.-).sub.2 .cndot.D.sup.2+, wherein D.sup.2+ is a pharmaceutically acceptable divalent counterion, (d) --CH(R.sup.4)--PO(OH)O.sup.- .cndot.M.sup.+, wherein R.sup.4 is hydrogen or methyl, (e) --CH(R.sup.4)--PO(O.sup.-).sub.2 .cndot.2M.sup.+, (f) --CH(R.sup.4)--PO(O.sup.-).sub.2 .cndot.D.sup.2+, (g) --CO--CH.sub.2 CH.sub.2 --CO.sub.2.sup.- .cndot.M.sup.+, (h) --CH(CH.sub.3)--O--CO--R.sup.5, wherein R.sup.5 is selected from the group consisting of: ##STR18## and Y is --O--; Z is hydrogen or C.sub.1-4 alkyl. 3. The compound of claim 1 wherein Z is C.sub.1-4 alkyl. 4. the compound of claim 1 wherein Z is --CH.sub.3. 5. The compound of claim 1 wherein A is --CH.sub.2 -- or --CH(CH.sub.3)--. 6. The compound of claim 1 wherein --B is selected from the group consisting of: ##STR19## 7. The compound of claim 1 wherein --A--B is selected from the group consisting of: ##STR20## 8. The compound of claim 1 wherein X is selected from the group consisting of: (a) --PO(O.sup.-).sub.2 .cndot.2M.sup.+, wherein M.sup.+ is a pharmaceutically acceptable monovalent counterion, and (b) --PO(O.sup.-).sub.2 .cndot.D.sup.2+, wherein D.sup.2+ is a pharmaceutically acceptable divalent counterion. 9. The compound of claim 1 of the structural formula II: ##STR21## or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1 of the structural formula III: ##STR22## or a pharmaceutically acceptable salt thereof. 11. 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-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phen yl-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine; (3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phen yl-4-(3-(1-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-(2-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)-pheny l-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine; (6) 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phen yl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof. 12. The compound of claim 11 wherein the pharmaceutically acceptable salt is the bis(N-methyl-D-glucamine) salt. 13. A compound which is selected from the group consisting of: ##STR23## wherein K.sup.+ is a pharmaceutically acceptable counterion. 14. A compound which is: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl -4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine; or a pharmaceutically acceptable salt thereof. 15. The compound of claim 14 wherein the pharmaceutically acceptable salt is the bis(N-methyl-D-glucamine) salt. 16. A compound which is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl -4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine). 17. A compound which is: ##STR24## wherein K.sup.+ is a pharmaceutically acceptable counterion. 18. The compound of claim 17 wherein K.sup.+ is N-methyl-D-glucamine. 19. A compound which is: ##STR25## 20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound of claim 1. 21. The pharmaceutical composition of claim 20 wherein the pharmaceutically acceptable carrier comprises water. 22. The pharmaceutical composition of claim 20 wherein the pharmaceutically acceptable carrier comprises a physiologically acceptable saline solution. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound which is: ##STR26## 24. A method for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal which comprises the administration to the mammal of the compound of claim 1 in an amount that is effective for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in the mammal. 25. A method of treating or preventing pain or nociception which comprises the administration to the mammal of an effective amount of the compound of claim 1.