LYSINE DEMETHYLASE INHIBITORS FOR THROMBOSIS AND CARDIOVASCULAR DISEASES

• US 20140296255A1
• Filed: 05/21/2012
• Published: 10/02/2014
• Est. Priority Date: 05/19/2011
• Status: Abandoned Application

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Oryzon Genomics, S.A.
• Inventors: Martinell Pedemonte, Marc, Maes, Tamara
• Application Number:
  US14/118,330
• Publication Number:
  US 20140296255A1
• Time in Patent Office: Days
• US Class Current: 514/255.01
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The invention relates to methods and compositions for the treatment or prevention of thrombosis, thrombus formation, a thrombotic event or complication, or a cardiovascular disease or event. In particular, the invention relates to an LSD inhibitor such as a 2-cyclylcyclopropan-1-amine derivative, a phenelzine derivative and a propargylamine derivative, for use in treating or preventing thrombosis, thrombus formation, a thrombotic event or complication, or a cardiovascular disease or event.

Claims

1-4. -4. (canceled)

5. A method of treating or preventing thrombosis, thrombus formation, a thrombotic event or complication or a cardiovascular disease or event, comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

7. The method of claim 5 wherein said thrombosis, thrombus formation, thrombotic event or complication or cardiovascular disease or event is selected from venous thrombosis, deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, Budd-Chiari syndrome, Paget-Schroetter disease, cerebral venous sinus thrombosis, arterial thrombosis, myocardial infarction, coronary heart disease, coronary artery disease, cardiac surgery, need for coronary revascularization, peripheral artery disease, a pulmonary circulatory disease, pulmonary embolism, a cerebrovascular disease, stroke, graft occlusion or failure, heart failure, hypertension, peripheral bypass graft surgery, coronary artery bypass (CABG) surgery, an adverse clinical outcome after CABG surgery, failure after CABG surgery, failure or adverse outcome after angioplasty, internal mammary artery graft failure, vein graft failure, autologous vein grafts, vein graft occlusion, and or vein graft occlusion due to thrombosis.

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

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

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

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

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

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

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

H.

22. The method of claim 20 wherein A is aryl or heteroaryl and wherein A is unsubstituted or has 1 or 2 substituents A′

.

24. The method of claim 22 wherein A is phenyl, pyridinyl, pyrimidinyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, furanyl, or thiazolyl, and wherein A is unsubstituted or has 1 or 2 substituents A′

.

34. The method of claim 20 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, amino, alkylamino, hydroxyl, nitro, —

CH₂—

CO—

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

37. The method of claim 34 wherein the cyclyl moiety in said -L²-cyclyl is aryl or cycloalkyl.

38. The method of claim 34 wherein the cyclyl moiety in said -L²-cyclyl is heteroaryl or heterocycloalkyl.

42. The method of claim 34 wherein L² is —

(CH₂)_1-4—

, —

CH₂—

CO—

, or a covalent bond.

50. The method of claim 20, wherein B is —

H.

51. The method of claim 20, wherein B is -L²-CO—

NH₂, —

(CH₂)_1-4—

CO—

NH₂, -L²-CO—

NR¹R², —

(CH₂)_1-4—

CO—

NR¹R², -L²-CO—

R³, or —

(CH₂)_1-4—

CO—

R³.

60. The method of claim 20 wherein the substituents on the cyclopropane ring are in trans configuration.

6. A method of treating or preventing a symptom of thrombosis, thrombus formation, a thrombotic event or complication or a cardiovascular disease or event, comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

8-10. -10. (canceled)

11. A method of reducing or preventing the risk of thrombosis, thrombus formation, a thrombotic event or complication or a cardiovascular disease or event, wherein said thrombosis, thrombus formation, thrombotic event or complication, or cardiovascular disease or event is associated with or caused by inflammatory diseases, infections, acute blood loss, haemolytic anaemias, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) and similar medical procedures, tissue damage from accident, microsurgery, angioplasty or trauma, medications, cancer chemotherapy, cancer, polycythemia vera or myeloproliferative disorders, diabetes, celiac disease, renal disorders or splenectomy, comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

14. (canceled)

18-19. -19. (canceled)

23. (canceled)

25-33. -33. (canceled)

35-36. -36. (canceled)

39-41. -41. (canceled)

43-49. -49. (canceled)

52-59. -59. (canceled)

61-72. -72. (canceled)