Details for Patent: 5,780,467

Title:	Morpholine compounds are prodrugs useful as tachykinin receptor antagonists
Abstract:	Substituted heterocycles of the general structural formula: ##STR1## are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, and emesis.
Inventor(s):	Dorn; Conrad P. (Plainfield, NJ), Hale; Jeffrey J. (Westfield, NJ), Maccoss; Malcolm (Freehold, NJ), Mills; Sander G. (Woodbridge, NJ)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Filing Date:	Aug 08, 1997
Application Number:	08/907,738
Claims:	1. A method for the treatment or prevention of a condition selected from the group consisting of: diabetic neuropathy; peripheral neuropathy; AIDS related neuropathy; chemotherapy-induced neuropathy; neuralgia; depression; anxiety; psychosis; schizophrenia; pruritis; rhinitis; ulcerative colitis; irritable bowel syndrome; incontinence; cystic fibrosis; and rheumatoid arthritis, in a mammal in need thereof which comprises the administration to the mammal of an effective amount of 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.-.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.sup.-.M+, (h) --CH(R.sup.4)--SO.sub.3.sup.-.M.sup.+, (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: ##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 method of claim 1 wherein the compound: 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.-.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.+, (f) --CH(R.sup.4)--PO(O.sup.-).sub.2.D.sup.2+, (g) --CO--CH.sub.2 CH.sub.2 --CO.sub.2.sup.-.M.sup.+, (h) --CH(CH.sub.3)--O--CO--R.sup.5, wherein R.sup.5 is selected from the group consisting of: ##STR18## Y is --O--; Z is hydrogen or C.sub.1-4 alkyl. 3. The method of claim 1 wherein the compound Z is C.sub.1-4 alkyl. 4. The method of claim 1 wherein the compound Z is --CH.sub.3. 5. The method of claim 1 wherein the compound A is --CH.sub.2 -- or --CH(CH.sub.3)--. 6. The method of claim 1 wherein the compound --B is selected from the group consisting of: ##STR19## 7. The method of claim 1 wherein the compound --A--B is selected from the group consisting of: ##STR20## 8. The method of claim 1 wherein the compound 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, and (b) --PO(O.sup.-).sub.2.D.sup.2+, wherein D.sup.2+ is a pharmaceutically acceptable divalent counterion. 9. The method of claim 1 wherein the compound is of the structural formula II: ##STR21## or a pharmaceutically acceptable salt thereof. 10. The method of claim 1 wherein the compound is of the structural formula III: ##STR22## or a pharmaceutically acceptable salt thereof. 11. The method of claim 1 wherein the compound is selected from the group consisting of: (1) 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; (2) 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; (3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phen yl-4-(3-(2-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)-phen yl-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)-methyl)morpholine; (5) 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 method of claim 1 wherein the compound is present as the bis(N-methyl-D-glucamine) salt. 13. The method of claim 1 wherein the compound is selected from the group consisting of: ##STR23## wherein K.sup.+ is a pharmaceutically acceptable counterion. 14. A method for the treatment or prevention of a condition selected from the group consisting of: diabetic neuropathy; peripheral neuropathy; AIDS related neuropathy; chemotherapy-induced neuropathy; neuralgia; depression; anxiety; psychosis; schizophrenia; pruritis; rhinitis; ulcerative colitis; irritable bowel syndrome; incontinence; cystic fibrosis; and rheumatoid arthritis, in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound which is: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)pheny l-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methyl-morpholine; or a pharmaceutically acceptable salt thereof. 15. The method of claim 14 wherein the compound is present as the bis(N-methyl-D-glucamine) salt. 16. The method of claim 14 wherein the compound 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 method for the treatment or prevention of a condition selected from the group consisting of: diabetic neuropathy; peripheral neuropathy; AIDS related neuropathy; chemotherapy-induced neuropathy; neuralgia; depression; anxiety; psychosis; schizophrenia; pruritis; rhinitis; ulcerative colitis; irritable bowel syndrome; incontinence; cystic fibrosis; and rheumatoid arthritis, in a mammal in need thereof which comprises the administration to the mammal of an effective amount of a compound which is: ##STR24## wherein K.sup.+ 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. The method of claim 17 wherein the compound is: ##STR25##