Methods of treating a sleep disorder

• US 20060063754A1
• Filed: 09/21/2005
• Published: 03/23/2006
• Est. Priority Date: 09/21/2004
• Status: Abandoned Application

• Current Assignee: Hypnion, Inc.
• Original Assignee: Hypnion, Inc.
• Inventors: White, James F., Solomon, Michael, Hangauer, David, Edgar, Dale M., Shiosaki, Kazumi
• Application Number:
  US11/232,489
• Publication Number:
  US 20060063754A1
• Time in Patent Office: Days
• US Class Current: 514/211.130
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem

Abstract

The invention relates to methods of modulating sleep.

Claims

1. A method of modulating sleep in a subject, comprising administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof:

wherein A is

X is a hydrogen atom or a halogen atom;

Y is a methylene group, an oxygen atom, or a sulfur atom;

R¹ is a hydrogen atom or a lower alkyl group;

n is an integer of from 0 to 5;

and pharmaceutically acceptable salts thereof,

further wherein the compound has one or more of the following characteristics;

(i) an inhibition constant (Ks) with regard to H1 receptor binding of less than 500 nM;

(ii) a K_i with regard to off target binding to an off target selected from M1, M2, M3, D1, D2, α

1 and α

2 that is more than 5 times greater than the K_i with regard to the H1 receptor;

(iii) a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after said compound is administered to a subject;

(iv) a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation;

(v) a longest sleep bout that is greater than 13 minutes in duration;

(vi) net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of said compound to a subject;

(vii) an average sleep bout that is greater than 5 minutes at absolute peak;

(viii) administration of said compound to a subject does not produce appreciable amounts of rebound insomnia;

(ix) administration of said compound to a subject does not appreciably inhibit REM sleep; and

administration of said compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep.

2. The method of claim 1, wherein the compound has one or more of the following characteristics:

(i) an inhibition constant (K_i) with regard to H1 receptor binding of less than 300 nM;

(ii) a K_i with regard to off target binding to an off target selected from M1, M2, M3, D1, D2, α

1 and α

2 that is greater than 1 μ

M;

(iii) a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after said compound is administered to a subject;

(iv) a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation;

(v) a longest sleep bout that is greater than 13 minutes in duration;

(vi) net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of said compound to a subject;

(vii) an average sleep bout that is greater than 5 minutes at absolute peak;

(viii) administration of said compound to a subject does not produce appreciable amounts of rebound insomnia;

(ix) administration of said compound to a subject does not appreciably inhibit REM sleep; and

(x) administration of said compound to a subject does not disproportionately inhibit locomotor activity relative to the normal effects of sleep.

3. The method of claim 1, wherein the compound has one or more of the following characteristics:

(i) an inhibition constant (K_i) with regard to H1 receptor binding of less than 150 nM;

(ii) a K_i with regard to off target binding to an off target selected from M1, M2, and M3, that is greater than 10 μ

M;

(iii) a nonREM peak time value that is greater than 55% nonREM sleep per hour by the third hour after said compound is administered to a subject;

(iv) a cumulative total increase in nonREM sleep not less than 20 minutes for compound doses that produce maximum sleep consolidation;

(v) a longest sleep bout that is greater than 17 minutes in duration;

(vi) net longest sleep bout post treatment is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of said compound to a subject;

(vii) an average sleep bout that is greater than 6 minutes at absolute peak;

(viii) administration of said compound to a subject does not produce appreciable amounts of rebound insomnia;

(ix) administration of said compound to a subject does not appreciably inhibit REM sleep; and

(x) administration of said compound to a subject does not disproportionately inhibit locomotor activity or motor tone relative to the normal effects of sleep.

4. The method of claim 1, wherein A is

5. The method of claim 4, wherein Y is oxygen.

6. The method of claim 4, wherein Y is sulfur.

7. The method of claim 1, wherein n is 2 or 3.

8. The method of claim 1, wherein X is hydrogen.

9. The method of claim 4, wherein X is halogen.

10. The method of claim 9, wherein X is chloride.

11. The method of claim 1, wherein R¹ is hydrogen.

12. The method of claim 1, wherein the sleep modulation is selected from decreasing the time to sleep onset, increasing the average sleep bout length, and increasing the maximum sleep bout length.

13. The method of claim 1, wherein the sleep modulation treats a sleep disorder.

14. The method of claim 13, wherein the sleep disorder is selected from circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia.

15. The method of claim 1, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

16. The method of claim 1, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, is co-administered with one or more additional therapies.

17. The method of claim 1, wherein the subject is a human.

18. A method of modulating sleep in a subject, comprising administering a therapeutically effective amount of Compound I or Compound 2 to a subject in need thereof.

19. A method of modulating sleep in a subject, comprising administering a therapeutically effective amount of Compound 3 or Compound 4 to a subject in need thereof.