(BIS)UREA AND (BIS)THIOREA COMPOUNDS AS EIPGENIC MODULATORS OF LYSINE-SPECIFIC DEMETHYLASE 1 AND METHODS OF TREATING DISORDERS

• US 20120322877A1
• Filed: 08/18/2010
• Published: 12/20/2012
• Est. Priority Date: 08/18/2009
• Status: Active Grant

• Current Assignee: Patrick M. Woster
• Original Assignee: Patrick M. Woster
• Inventors: Casero, Robert A., Woster, Patrick M.
• Granted Patent: US 9,708,255 B2
• Time in Patent Office: Days
• US Class Current: 514/586
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 275/14 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/28 having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 335/08 of a saturated carbon skeleton
• CPC Class Codes: C07C 335/12 the carbon skeleton containing six-membered aromatic rings
• 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 provides for novel (bis)urea and (bis)thiourea 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 I or Formula II:

2. The compound of claim 1, wherein each R is independently H, —

C₁-C₈ alkyl, —

C₆-C₂₀ aralkyl, or —

C₃-C₁₂ aryl;

each of which is optionally substituted.

3. The compound of claim 1, wherein each R′

is independently H, —

C₁-C₈ alkyl, —

C₆-C₂₀ aralkyl, or —

C₃-C₁₂ aryl;

each of which is optionally substituted.

4. The compound of claim 1, wherein m and p are 1.

5. The compound of claim 1, wherein the compound is a compound of formula I-a, I-b, I-c, or I-d:

6. The compound of claim 5, wherein each R is independently H, methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, benzyl, ethyl phenyl, propyl phenyl, or naphthyl, each of which is optionally substituted.

7. The compound of claim 6, wherein each R is independently H, methyl, ethyl, propyl, phenyl, benzyl, 3,3-diphenylpropyl, 2,2-diphenylethyl, or diphenylmethyl.

8. The compound of claim 5, wherein each R₁, R₂, R₃, R₄, R₅, and R₆ are H.

9. The compound of claim 5, wherein each R₇, R₈, and R₉ are H.

10. The compound of claim 5, wherein each n is independently 1, 2, 3, 4, 5, or 6.

11. The compound of claim 1, wherein the compound is a compound of formula II-a, II-b, II-c, or II-d:

12. The compound of claim 11, wherein each R is independently H, methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, benzyl, ethyl phenyl, propyl phenyl, or naphthyl, each of which is optionally substituted.

13. The compound of claim 11, wherein each R is independently H, methyl, ethyl, propyl, phenyl, benzyl, 3,3-diphenylpropyl, 2,2-diphenylethyl, or diphenylmethyl.

14. The compound of claim 11, wherein each R₁, R₂, R₃, R₄, R₅, and R₆ are H.

15. The compound of claim 11, wherein each R₇, R₈, and R₉ are H.

16. The compound of claim 11, wherein each n is independently 1, 2, 3, 4, 5, or 6.

17. The compound of claim 1, wherein the compound is selected from a compound of Table 1.

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

19. 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 claim 1, or a pharmaceutically acceptable salt, ester or hydrate thereof.

20. 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 claim 1, or a pharmaceutically acceptable salt, ester or hydrate thereof.

21. The method of claim 19, wherein the disease or disorder is selected from:

tumor, cancer, 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.

22. The method of claim 21, wherein the disease or disorder is cancer.

23. The method of claim 22, wherein the disease or disorder is ocular cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, corpus uteri, ovary cancer, prostate cancer, testicular cancer, renal cancer, brain/cns cancer, throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing'"'"'s Sarcoma, Kaposi'"'"'s Sarcoma, basal cell carinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangiomas, and lymphangiogenesis.

24. 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 claim 1;

wherein said compound is identified in a screening assay.

27. A method of treating tumor, cancer, or neoplasia in a subject, the method comprising the step of administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

28. The method of claim 27, wherein the compound inhibits LSD1 to thereby treat the tumor, cancer, or neoplasia.

29. The method of claim 19, further comprising an additional therapeutic agent.

32. The method of method of claim 19, wherein the step of administering the compound comprises administering the compound orally, topically, parentally, intravenously or intramuscularly.

33. The method of claim 32, wherein the step of administering the compound comprises administering the compound in a dosage of between about 0.1 and 120 mg/kg/day.

34. The method of claim 33, wherein the step of administering the compound comprises administering the compound in a dosage of less than about 500 mg/day.

35. The method of claim 19, wherein the subject is a human.

36. 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.

25-26. -26. (canceled)

30-31. -31. (canceled)