LYSINE DEMETHYLASE INHIBITORS FOR MYELOPROLIFERATIVE DISORDERS

• US 20150232436A1
• Filed: 02/20/2014
• Published: 08/20/2015
• Est. Priority Date: 02/08/2011
• Status: Active Grant

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Oryzon Genomics, S.A.
• Inventors: Baker, Jonathan Alleman, Fyfe, Matthew Colin Thor, Martinell Pedemonte, Marc, Castro Palomino, Julio, Maes, Tamara
• Granted Patent: US 9,908,859 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/131 acyclic
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/164 of a carboxylic acid with an aminoalcohol, e.g. ceramides
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 295/195 Radicals derived from nitrogen analogues of carboxylic acids

Abstract

The invention relates to methods and compositions for the treatment or prevention of diseases and disorders associated with myeloproliferative disorders. In particular, the invention relates to an LSD 1 inhibitor for use in treating or preventing Philadelphia chromosome negative myeloproliferative disorders.

Claims

1-4. -4. (canceled)

5. A method of treating or preventing a Philadelphia chromosome negative myeloproliferative disease or disorder comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

7. The method of claim 5 wherein said Philadelphia chromosome negative myeloproliferative disease or disorder is essential thrombocythemia, polycythemia vera or myelofibrosis.

11. The method of claim 5 wherein said LSD1 inhibitor is a small molecule inhibitor of LSD1.

12. The method of claim 5 wherein said LSD1 inhibitor is a selective LSD1 inhibitor.

14. The method of claim 5 wherein said LSD1 inhibitor is an irreversible or a reversible amine oxidase inhibitor.

15. The method of claim 5 wherein said LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound, a phenelzine compound or a propargylamine compound.

16. The method of claim 5 wherein said LSD1 inhibitor is a 2-arylcyclopropan-1-amine compound or a 2-heteroarylcyclopropan-1-amine compound.

19. The method of claim 5 wherein said LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound of formula (I) or an enantiomer, a diastereomer or a mixture of stereoisomers (including a racemic mixture or diastereomer mixture) thereof, or a pharmaceutically acceptable salt or solvate thereof:

20. The method of claim 19 wherein R^a is —

H.

21. The method of claim 19 wherein A is aryl or heteroaryl and wherein A is unsubstituted or has 1 or 2 substituents A′

.

23. The the method of claim 21 wherein A is phenyl, pyridinyl, pyrimindinyl, thiophenyl, benzothiophenyl, pyrroyl, indolyl, furanyl, or thiazolyl, and wherein A is unsubstituted or has 1 or 2 substituents A′

.

33. The method of claim 19 wherein B is -L²-cyclyl, and further wherein the cyclyl moiety in said -L²-cyclyl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, —

CH₂—

CO—

NH₂, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea.

36. The method of claim 33 wherein the cyclyl moiety in said -L²-cyclyl is aryl or cycloalkyl.

37. The method of claim 33 wherein the cyclyl moiety in said -L²-cyclyl is heteroaryl or heterocycloalkyl.

41. The method of claim 33 wherein L² is —

(CH₂)_1-4—

, —

CH₂—

CO—

or a covalent bond.

49. The method of claim 19, wherein B is —

H.

50. The method claim 19, wherein B is -L²-CO—

NH₂, —

(CH₂)_1-4—

CO—

NH₂, -L-CO—

NR¹R², —

(CH₂)_1-4—

CO—

NR¹R², -L²-CO—

R³ or —

(CH₂)_1-4—

CO—

R³.

59. The method of claim 19 wherein the substituents on the cyclopropane ring are in trans configuration.

67. The method of claim 5 wherein said LSD1 inhibitor is to be administered in combination with an anti-myeloproliferative agent.

6. A method of treating or preventing a symptom of a Philadelphia chromosome negative myeloproliferative disease or disorder comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

8-10. -10. (canceled)

13. (canceled)

17-18. -18. (canceled)

22. (canceled)

24-32. -32. (canceled)

34-35. -35. (canceled)

38-40. -40. (canceled)

42-48. -48. (canceled)

51-58. -58. (canceled)

60-66. -66. (canceled)

68-73. -73. (canceled)