Morpholine compounds are prodrugs useful as tachykinin receptor antagonists

• US 5,691,336 A
• Filed: 09/08/1995
• Issued: 11/25/1997
• Est. Priority Date: 03/04/1994
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Hale, Jeffrey J., Maccoss, Malcolm, Mills, Sander G., Dorn, Conrad P.
• Primary Examiner(s): Higel, Floyd D.
• Application Number:
  US08/525,870
• Time in Patent Office: 809 Days
• Field of Search: 544/132, 544/134, 544/139, 544/141, 544/143, 514/235.2, 514/235.5, 514/235.8, 514/233.5, 514/236.2
• US Class Current: 514/236.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: B60R 16/0373 Voice control in general G10L
• CPC Class Codes: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 265/32 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

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.

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) C_1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independently selected from;

(i) hydrogen,

(ii) C_1-6 alkyl,

(iii) hydroxy-C_1-6 alkyl, and

(iv) phenyl,

(i) --NR⁹ COR¹⁰,

(j) --NR⁹ CO₂ R¹⁰,

(k) --CONR⁹ R¹⁰,

(l) --COR⁹, and

(m) --CO₂ R⁹,

(3) C_2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰,

(i) --COR⁹,

(j) --CO₂ R⁹ ;

(4) C_2-6 alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

(a) hydroxy,

(b) C_1-6 alkoxy,

(c) C_1-6 alkyl,

(d) C_2-5 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) C_1-6 alkyl,

(ii) C_1-6 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) C_1-6 alkyl,

(ii) oxo,

(iii) C_1-6 alkoxy,

(iv) --NR⁹ R¹⁰,

(v) halo, and

(vi) trifluoromethyl;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of;

(1) hydrogen;

(2) C_1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 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) C_2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰,

(i) --COR⁹, and

(j) --CO₂ R⁹ ;

(4) C_2-6 alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

(a) hydroxy,

(b) C_1-6 alkoxy,

(c) C_1-6 alkyl,

(d) C_2-5 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 C_1-5 alkyl,

(11) --SOR¹⁴,

(12) --SO₂ R¹⁴,

(13) NR⁹ COR¹⁰,

(14) CONR⁹ COR¹⁰,

(15) NR⁹ R¹⁰,

(16) NR⁹ CO₂ R¹⁰,

(17) hydroxy,

(18) C_1-6 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) C_1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 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) C_2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰,

(i) --COR⁹, and

(j) --CO₂ R⁹ ; and

(3) C_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_1-6 alkyl, unsubstituted or substituted with halo, --CF₃, --OCH₃, or phenyl,

(iii) C_1-6 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 C_1-3 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) C_1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from;

(i) hydroxy,

(ii) oxo,

(iii) C_1-6 alkoxy,

(iv) phenyl-C_1-3 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) C_1-6 alkoxy,

(iii) C_1-6 alkyl,

(iv) C_2-5 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) C_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 --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) C_1-6 alkyl,

(3) C_2-6 alkenyl, and

(4) phenyl;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of;

(1) hydrogen,

(2) C_1-6 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 C_1-6 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 C_1-4 alkyl.

3. The compound of claim 1 wherein Z is C_1-4 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.

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.

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.

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 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⁺ is a pharmaceutically acceptable counterion.

18. The compound of claim 17 wherein K⁺ is N-methyl-D-glucamine.

19. A compound which is:

##STR25##

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound which is:

##STR26##