Doxepin analogs and methods of use thereof

• US 20050256165A1
• Filed: 04/25/2005
• Published: 11/17/2005
• Est. Priority Date: 12/10/2003
• Status: Active Grant

• Current Assignee: Hypnion, Inc.
• Original Assignee: Hypnion, Inc.
• Inventors: White, James F., Hangauer, David G., Solomon, Michael, Edgar, Dale M.
• Granted Patent: US 7,482,460 B2
• Time in Patent Office: Days
• US Class Current: 514/320
• CPC Class Codes: A61K 31/452 Piperidinium derivatives pancuronium A61K31/58
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Abstract

The invention relates to novel doxepin analog compounds and methods of modulating sleep by administering such compounds, or a pharmaceutically effective salt thereof.

Claims

1. A method of modulating sleep in a subject, comprising administering a therapeutically effective amount of a compound having the formula of Formula I

2. The method of claim 1, wherein the compound has at least one 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.

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

4. 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, 4, 5, 6, or 7.

5. The method of claim 1, wherein Z is CO₂H or tetrazole.

6. The method of claim 1, wherein Z is CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl, CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, S(O)₂NHCO-alkyl, S(O)₂NHCO-cycloalkyl, S(O)₂NHCO-heteroalkyl, S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl, CONHS(O)₂N-cycloalkyl, CONHS(O)₂N-heteroalkyl, CONHS(O)₂N-aryl, CONHS(O)₂N-heteroaryl, SO₃H, SO₂H, S(O)NHCO-alkyl, S(O)NHCO-aryl, or S(O)NHCO-heteroaryl.

7. The method of claim 1, wherein Z is CONHS(O)₂-alkyl, wherein alkyl is C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

8. The method of claim 1, wherein the compound is selected from 47a, 47b, 47c, 47d, 47sm, 47se, 47sc, 47scm, 49a, 49b, 49c, 49d, 49sm, 49se, 49sc, 49scm, 10a, 10b, 10c, 10d, 37, 38a, 38b, 39c, 39d, 39sm, 39se, 39sc, 39scm, 4a, 4b, 4c, 4d, 4sm, 4se, 4sc, 4scm, 50a, 50b, 50c, 50d, 50sm, 50se, 50sc, and 50scm.

9. The method of claim 1, wherein at least one of R₁-R₈, R₁₃-R₁₄ and at least one of R₉-R₁₀, R₁₁-R₁₂ are not hydrogen, when Z is COOH or COOR₁₃.

10. The method of claim 1, wherein Z is COOH, COOR₁₃, or tetrazole, and R₂ is not H, F, Cl, Br, I, CH₃, C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

11. The method of claim 1, wherein Z is COOH, COOR₁₃, or tetrazole, and R₇ is not H, F, Cl, Br, I, CH₃, C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

12. The method of claim 1, wherein Z is COOH, COOR₁₃, or tetrazole, and neither of R₂ and R₇ is H, F, Cl, Br, I, CH₃, C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

13. The method of claim 1, wherein Z is tetrazole and R₂ is not H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅ or C₆ alkoxy.

14. The method of claim 1, wherein Z is tetrazole and R₇ is not H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅ or C₆ alkoxy.

15. The method of claim 1, wherein Z is tetrazole and neither of R₂ and R₇ is H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅ or C₆ alkoxy.

16. The method of claim 1, wherein at least three of R₁, R₂, R₃, R₄, R₅, R₆, R₇, or R₈ are not hydrogen.

17. The method of claim 1, wherein R₉ and R₁₀ are each methyl.

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

19. The method of claim 1, wherein R₁₁ and R₁₂ and the carbon to which they are attached are connected to form a spiro ring of size 3, 4, 5, 6, or 7.

20. 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.

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

22. The method of claim 21 wherein the sleep disorder is selected from circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia.

23. 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.

24. The method of claim 1, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is co-administered with at least one additional therapy.

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

26. A compound according to Formula I

27. The compound of claim 26, wherein R₉ and R₁₀ and the carbon they are attached to are absent.

28. The compound of claim 26, wherein R₁₁ and R₁₂, together with the carbon to which they are attached, are connected to form a spiro ring of size 3, 4, 5, 6, or 7.

29. The compound of claim 26, wherein Z is CO₂H or tetrazole.

30. The compound of claim 26, wherein Z is CONHS(O)₂-alkyl, CONHS(O)₂-cycloalkyl, CONHS(O)₂-heteroalkyl, CONHS(O)₂-aryl, CONHS(O)₂-heteroaryl, S(O)₂NHCO-alkyl, S(O)₂NHCO-cycloalkyl, S(O)₂NHCO-heteroalkyl, S(O)₂NHCO-aryl, S(O)₂NHCO-heteroaryl, CONHS(O)₂N-alkyl, CONHS(O)₂N-cycloalkyl, CONHS(O)₂N-heteroalkyl, CONHS(O)₂N-aryl, CONHS(O)₂N-heteroaryl, SO₃H, SO₂H, S(O)NHCO-alkyl, S(O)NHCO-aryl, or S(O)NHCO-heteroaryl.

31. The compound of claim 26, wherein Z is CONHS(O)₂-alkyl, wherein alkyl is C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

32. The compound of claim 26, wherein the compound is selected from 7a, 47b, 47c, 47d, 47sm, 47se, 47sc, 47scm, 49a, 49b, 49c, 49d, 49sm, 49se, 49sc, 49scm, 10a, 10b, 10c, 10d, 37, 38a, 38b, 39c, 39d, 39sm, 39se, 39sc, 39scm, 4a, 4b, 4c, 4d, 4sm, 4se, 4sc, 4scm, 50a, 50b, 50c, 50d, 50sm, 50se, 50sc, and 50scm.

33. The compound of claim 26, wherein at least one of R₁-R₈, R₁₃-R₁₄ and at least one of R₉-R₁₀, R₁₁-R₁₂ are not hydrogen, when Z is COOH or COOR₁₃.

34. The compound of claim 26, wherein at least three of R₁-R₈ are not hydrogen.

35. The compound of claim 26, wherein at least one of R₃ and R₇ is not hydrogen.

36. The compound of claim 26, wherein R₉ and R₁₀ are each methyl.

37. The compound of claim 26, wherein R₁₁ and R₁₂ are each methyl.

38. The compound of claim 26, wherein R₁₁ and R₁₂ and the carbon to which they are attached are connected to form a spiro ring of size 3, 4, 5, 6, or 7.

39. The compound of claim 26, wherein Z is COOH, COOR₁₃ or tetrazole, and R₂ is not H, F, Cl, Br, I, CH₃, C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

40. The compound of claim 26, wherein Z is COOH, COOR₁₃ or tetrazole and R₇ is not H, F, Cl, Br, I, CH₃, C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

41. The compound of claim 26, wherein Z is COOH, COOR₁₃ or tetrazole, and neither of R₂ and R₇ is H, F, Cl, Br, I, CH₃, C₂, C₃, C₄, C₅ or C₆ straight chain alkyl, C₃, C₄, C₅ or C₆ branched alkyl, or C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

42. The compound of claim 26, wherein Z is tetrazole and R₂ is not H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy.

43. The compound of claim 26, wherein Z is tetrazole and R₇ is not H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy.

44. The compound of claim 26, wherein Z is tetrazole and neither of R₂ and R₇ is H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy.

45. The compound of claim 26, further comprising a pharmaceutically acceptable excipient.