Quetiapine analogs and methods of use thereof

• US 20060094705A1
• Filed: 09/21/2005
• Published: 05/04/2006
• Est. Priority Date: 10/29/2004
• Status: Active Grant

• Current Assignee: Hypnion, Inc.
• Original Assignee: Hypnion, Inc.
• Inventors: White, James, Solomon, Michael, Hangauer, David, Edgar, Dale, Shiosaki, Kazumi
• Granted Patent: US 7,563,785 B2
• Time in Patent Office: Days
• US Class Current: 514/211.13
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 281/14 [b, e]-condensed
• CPC Class Codes: C07D 281/16 [b, f]-condensed
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to novel compounds and methods of using them for 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:

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 H 1 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 R₆ is not hydrogen or halogen.

5. The method of claim 4, wherein R₁-R₅ and R₇-R₈ are each hydrogen.

6. The method of claim 1, wherein at least one of R₁-R₈ is a non-hydrogen substituent and the remaining R₁-R₈ are hydrogen.

7. The method of claim 1, wherein at least two of R₁-R₈ are non-hydrogen substituents, and the remaining R₁-R₈ are hydrogen.

8. The method of claim 1, wherein at least three of R₁-R₈ are non-hydrogen substituents, and the remaining R₁-R₈ are hydrogen.

9. The method of claim 6, wherein the at least one non-hydrogen R₁-R₈ is independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

10. The method of claim 7;

wherein the at least 2 non-hydrogen R₁-R₈ are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

11. The method of claim 8, wherein the at least 3 non-hydrogen R₁-R₈ are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

12. The method of claim 1, wherein R₉ and R₁₀ and the carbon to which they are attached are absent.

13. The method of claim 1, wherein R₁₁ and R₁₂ are each methyl.

14. The method of claim 1, wherein R₁₁ and R₁₂ are each ethyl.

15. The method of claim 1, wherein R₁₁ and R₁₂, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7.

16. The method of claim 15, wherein the spiro ring is a cyclopropyl ring.

17. The method of claim 1, wherein the compound is selected from 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.

18. 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.

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

20. The method of claim 19, wherein the sleep disorder is selected from circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia.

21. 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.

22. The method of claim 11, wherein the subject is a human.

23. A compound of Formula I:

24. The compound of claim 23, wherein R₆ is not hydrogen or halogen.

25. The compound of claim 24, wherein R₆ is methyl, methoxymethylene, methoxy or hydroxy.

26. The compound of claim 25, wherein R₁-R₅ and R₇-R₈ are each hydrogen.

27. The compound of claim 23, wherein at least one of R₁-R₈ is a non-hydrogen substituent and the remaining R₁-R₈ are hydrogen.

28. The compound of claim 23, wherein at least two of R₁-R₈ are non-hydrogen substituents, and the remaining R₁-R₈ are hydrogen.

29. The compound of claim 23, wherein at least three of R₁-R₈ are non-hydrogen substituents, and the remaining R₁-R₈ are hydrogen.

30. The compound of claim 27, wherein the at least one non-hydrogen R₁-R₈ are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

31. The compound of claim 28, wherein the at least two non-hydrogen R₁-R₈ are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

32. The compound of claim 29, wherein the at least three non-hydrogen R₁-R₈ are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

33. The compound of claim 23, wherein R₉ and R₁₀ together with the carbon to which they are attached are absent.

34. The compound of claim 23, wherein R₁ and R₁₂ are each methyl.

35. The compound of claim 23, wherein R₁₁ and R₁₂ are each ethyl.

36. The compound of claim 23, wherein R₁ and R₁₂, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7.

37. The compound of claim 23, wherein the spiro ring is a cyclopropyl ring.

38. The compound of claim 23, wherein the compound is selected from 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

39. A compound selected from Compound 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.