Methods of treating sleep disorders

• US 20050239838A1
• Filed: 04/25/2005
• Published: 10/27/2005
• Est. Priority Date: 04/23/2004
• Status: Active Grant

• Current Assignee: Hypnion, Inc. (Eli Lilly and Company)
• Original Assignee: Hypnion, Inc. (Eli Lilly and Company)
• Inventors: Hangauer, David, Edgar, Dale
• Granted Patent: US 7,524,864 B2
• Time in Patent Office: Days
• US Class Current: 514/319
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/452 Piperidinium derivatives pancuronium A61K31/58
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to novel antihistamines and methods of modulating sleep by administering a doxepin analog 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 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 the group consisting of 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, together with the carbon to which they are attached, 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 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 COOR₁₇.

7. 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.

8. 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.

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 COOR₁₇.

10. The method of claim 1, wherein Z is COOH, COOR₁₇, 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, C₁, C₂, C₃, C₄, C₅, C₆, C₇, or C₈ cycloalkyl.

11. The method of claim 1, wherein Z is COOH, COOR₁₇, 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, COOR₁₇, 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-R₈ are not hydrogen.

17. The method of claim 1, wherein at least one of R₁₃-R₁₄ is not hydrogen.

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

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

20. The method of claim 1, wherein the compound is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

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

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

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

24. 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.

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

26. The method of claim 1, wherein the subject is selected from the group consisting of humans, companion animals, farm animals, laboratory animals and wild animals.

27. The method of claim 26, wherein the subject is a human.

28. A compound according to Formula I

29. The compound of claim 28, wherein R₉ and R₁₀ and the carbon they are attached to are absent.

30. The compound of claim 28, 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.

31. The compound of claim 28, wherein Z is CO₂H or tetrazole.

32. The compound of claim 28, 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.

33. The compound of claim 28, 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.

34. The compound of claim 28, wherein the compound is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8.

35. The compound of claim 28, 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 COOR₁₇.

36. The compound of claim 28, wherein Z is COOH, COOR₁₇ 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.

37. The compound of claim 28, wherein Z is COOH, COOR₁₇ 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.

38. The compound of claim 28, wherein Z is COOH, COOR₁₇ 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.

39. The compound of claim 28, wherein Z is tetrazole and R₂ is not H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy.

40. The compound of claim 28, wherein Z is tetrazole and R₇ is not H, F, Cl, Br, I, or C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy.

41. The compound of claim 28, 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.

42. The compound of claim 28, further comprising a pharmaceutically acceptable excipient.

43. The compound of claim 28, wherein at least three of R₁-R₈ are not hydrogen.

44. The compound of claim 28, wherein at least one of R₁₃-R₁₄ is not hydrogen.

45. The method of claim 28, wherein at least one of R₃ and R₇ is not hydrogen.

46. The compound of claim 28, wherein R₉ and R₁₀ are each methyl.

47. The compound of claim 28, wherein R₁₁ and R₁₂ are each methyl.

48. The compound of claim 28, 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.

49. A compound selected from compounds 1, 2, 3, 4, 5, 6, 7, and 8.