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Details for Patent: 5,780,467

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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##
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