Prevention or treatment of insomnia with a neurokinin-1 receptor antagonist

• US 6,525,073 B2
• Filed: 10/16/2001
• Issued: 02/25/2003
• Est. Priority Date: 07/17/1996
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Waldstreicher, Joanne, Mendel, Carl M.
• Primary Examiner(s): Jarvis, William R. A.
• Assistant Examiner(s): KIM, VICKIE Y
• Application Number:
  US09/978,292
• Publication Number:
  US 20020035059A1
• Time in Patent Office: 497 Days
• Field of Search: 514/255, 514/323, 514/337, 514/364, 514/381
• US Class Current: 514/337
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A tachykinin antagonist is useful, alone or in conjunction with other agents, for altering circadian rhythmicity and alleviating circadian rhythm disorders and for enhancing and improving the quality of sleep.

Claims

1. A method for the treatment of insomnia selected from primary insomnia, circadian rhythm-related insomnia, insomnia associated with depression, insomnia associated with an emotional disorder and insomnia associated with a mood disorder, in a human in need thereof which comprises administering to the human an effective amount of a CNS-penetrating neurokinin-1 receptor antagonist.

2. The method of claim 1 wherein the insomnia is primary insomnia.

3. The method of claim 1 wherein the insomnia is circadian rhythm-related insomnia.

4. The method of claim 1 wherein the insomnia is insomnia associated with depression.

5. The method of claim 1 wherein the insomnia is insomnia associated with an emotional disorder.

6. The method of claim 1 wherein the insomnia is insomnia associated with a mood disorder.

7. The method of claim 1 wherein the human is an elderly human.

8. The method of claim 1 wherein the neurokinin-1 receptor antagonist is an orally active neurokinin-1 receptor antagonist.

9. The method of claim 8 wherein the neurokinin-1 receptor antagonist is a non-peptidal neurokinin-1 receptor antagonist.

10. The method of claim 1 wherein the neurokinin-1 receptor antagonist is administered in conjunction with melatonin or a compound which suppresses or stimulates melatonin production.

11. The method of claim 1 wherein the neurokinin-1 receptor antagonist is selected from group consisting of:

(2R*,4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine;

[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine;

[5-(5-methyl-tetrazol-1-yl)-benzofuran-7-ylmethyl]-(2S-phenyl-piperidin-3S-yl)-amine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-((dimethylamino-methyl)-1,2,3-triazol-4-yl)methyl)-3-(S)-(4-fluorophenyl)morpholine;

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;

(2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(3aS ,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol;

(+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)-acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane;

and pharmaceutically acceptable salts thereof.

12. The method of claim 1 wherein the neurokinin-1 receptor antagonist is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine.

13. A method for the prevention of insomnia in a human in need thereof who is predisposed to insomnia, wherein the insomnia is selected from primary insomnia, circadian rhythm-related insomnia, insomnia associated with depression, insomnia associated with an emotional disorder and insomnia associated with a mood disorder, which comprises administering to the human an effective amount of a CNS-penetrating neurokinin-1 receptor antagonist.

14. The method of claim 13 wherein the insomnia is primary insomnia.

15. The method of claim 13 wherein the insomnia is circadian rhythm-related insomnia.

16. The method of claim 13 wherein the insomnia is insomnia associated with depression.

17. The method of claim 13 wherein the insomnia is insomnia associated with an emotional disorder.

18. The method of claim 13 wherein the insomnia is insomnia associated with a mood disorder.

19. The method of claim 13 wherein the human is an elderly human.

20. The method of claim 13 wherein the neurokinin-1 receptor antagonist is an orally active neurokinin-1 receptor antagonist.

21. The method of claim 20 wherein the neurokinin-1 receptor antagonist is a non-peptidal neurokinin-1 receptor antagonist.

22. The method of claim 13 wherein the neurokinin-1 receptor antagonist is selected from group consisting of:

(2R*,4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine;

[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine;

[5-(5-methyl-tetrazol-1-yl)-benzofuran-7-ylmethyl]-(2S-phenyl-piperidin-3S-yl)-amine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-((dimethylamino-methyl)-1,2,3-triazol-4-yl)methyl)-3-(S)-(4-fluorophenyl)morpholine;

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;

(2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(3aS ,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol;

(+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)-acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane;

and pharmaceutically acceptable salts thereof.

23. The method of claim 13 wherein the neurokinin-1 receptor antagonist is 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine.