SMALL MOLECULES AS EPIGENETIC MODULATORS OF LYSINE-SPECIFIC DEMETHYLASE 1 AND METHODS OF TREATING DISORDERS

• US 20140011857A1
• Filed: 09/12/2011
• Published: 01/09/2014
• Est. Priority Date: 09/10/2010
• Status: Active Grant

• Current Assignee: Patrick M. Woster, Progen Pharmaceuticals Limited, Robert A. Casero
• Original Assignee: Johns Hopkins University
• Inventors: Casero, Robert A., Bytheway, Ian, Woster, Patrick M.
• Granted Patent: US 9,527,805 B2
• Time in Patent Office: Days
• US Class Current: 514/417
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 211/53 having the nitrogen atom of at least one of the amino groups further bound to a hydrocarbon radical substituted by amino groups
• CPC Class Codes: C07C 237/16 the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07C 259/14 having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 335/12 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide

Abstract

The invention provides for novel compounds which are inhibitors of lysine-specific demethylase 1 (LSD1). Such compounds may be used to treat disorders, including cancer.

Claims

1. A compound of formula II,

2. The compound of claim 1, wherein Y is (i)

3. The compound of claim 2, wherein J is O.

4. The compound of claim 2, wherein q is 1.

5. The compound of claim 2, wherein R₃ is nitro, hydroxy, thio, C(O)NR_AR_B, or C(O)OR_A.

6. The compound of claim 5, wherein R₃ is nitro, hydroxy, thio, C(O)NH₂, or C(O)OEt.

7. The compound of claim 1, wherein Y is —

NH₂.

8. The compound of claim 7, wherein J is absent, and the carbon to which J is attached is —

CH₂—

.

9. The compound of claim 7, wherein q is 3 or 4.

10. The compound of claim 7, wherein R₃ is nitro, hydroxy, thio, C(O)NR_AR_B, or C(O)OR_A.

11. The compound of claim 7, wherein R₄ is haloalkyl, nitro, hydroxy, thio, C(O)NR_AR_B, or C(O)OR_A.

12. The compound of claim 7, wherein R₅ is haloalkyl, nitro, hydroxy, thio, C(O)NR_AR_B, or C(O)OR_A.

13. The compound of claim 1, of formula II-A,

15. The compound of claim 1, of formula II-B,

19. The compound of claim 1, selected from the following:

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof thereof, in combination with a pharmaceutically acceptable carrier or excipient.

60. A kit comprising an effective amount of a compound of claim 1 in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to a LSD1-related disease.

14. (canceled)

16-18. -18. (canceled)

21. (canceled)

22. A method of treating a disease or disorder associated with lysine-specific demethylase 1 (LSD1) in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula I, formula II, or formula III,

24. The method of claim 22, wherein the disease or disorder is selected from:

tumor, cancer, blood disorder, neoplasia, skin disorders, neovascularization, inflammatory and arthritic diseases, retinoblastoma, cystoid macular edema (CME), exudative age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, or ocular inflammatory disorders.

23. A method of treating a disease or disorder associated with lysine-specific demethylase 1 (LSD1) in a subject, wherein the subject is identified as being in need of a LSD1 inhibitor, the method comprising the step of administering to the subject an effective amount of a compound of formula I, formula II, or formula III,

25-28. -28. (canceled)

29. A method of inhibiting or reducing lysine-specific demethylase 1 (LSD1) in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula I, formula II, or formula III,

30-31. -31. (canceled)

32. A method of treating tumor, cancer, blood disorder or neoplasia in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula I, formula II, or formula III,

33. The method of claim 32, wherein the compound inhibits LSD1 to thereby treat the tumor, cancer, blood disorder or neoplasia.

34-59. -59. (canceled)