LYSINE DEMETHYLASE INHIBITORS FOR INFLAMMATORY DISEASES OR CONDITIONS

• US 20140329833A1
• Filed: 05/21/2012
• Published: 11/06/2014
• Est. Priority Date: 05/19/2011
• Status: Abandoned Application

• Current Assignee: Oryzon Genomics, S.A.
• Original Assignee: Oryzon Genomics, S.A.
• Inventors: Maes, Tamara, Martinell Pedemonte, Marc, Castro-Palomino Laria, Julio
• Application Number:
  US14/118,323
• Publication Number:
  US 20140329833A1
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• 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
• CPC Class Codes: C07C 215/64 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 237/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• 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 295/192 from aromatic carboxylic acids

Abstract

The invention relates to methods and compositions for the treatment or prevention of inflammation and inflammatory diseases or conditions. In particular, the invention relates to an LSD1 inhibitor, such as a 2-cyclylcylopropan-1-amine derivative, a phenelzine derivative and a propargylamine derivative, for use in treating or preventing inflammation and inflammatory diseases or conditions.

Claims

1-4. -4. (canceled)

5. A method of treating or preventing inflammation or an inflammatory disease or condition, comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

7. The method of claim 5 wherein said inflammation or inflammatory disease or condition is selected from atherosclerosis, a respiratory inflammatory disorder, respiratory distress syndrome, asthma, COPD, bronchial hyperresponsiveness, bronchoconstriction, airway inflammation, airway remodeling, cystic fibrosis, chronic inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, a chronic skin inflammatory disease, psoriasis, atopic dermatitis, mesangial glomerulonephritis, Kawasaki disease, disseminated intravascular inflammation, Caffey disease, TRAP syndrome, allergic vasculitis, arthritis, vasculitis, coronary artery disease, carotid artery disease, transplant vasculopathy, rheumatoid arthritis, hepatic cirrhosis, and nephritis.

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

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

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

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

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

21. 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 thereof, or a pharmaceutically acceptable salt or solvate thereof:

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

H.

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

.

25. The method of claim 23 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′

.

35. The method of claim 21 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.

38. The method of claim 35 wherein the cyclyl moiety in said -L²-cyclyl is aryl or cycloalkyl.

39. The method of claim 35 wherein the cyclyl moiety in said -L²-cyclyl is heteroaryl or heterocycloalkyl.

43. The method of claim 35 wherein L² is —

(CH₂)_1-4—

, —

CH₂—

CO—

or a covalent bond.

51. The method of claim 21, wherein B is —

H.

52. The method of claim 21, 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.

61. The method of claim 21 wherein the substituents on the cyclopropane ring are in trans configuration.

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

6. A method of treating or preventing a symptom of inflammation or an inflammatory disease or condition, comprising administering to an individual a therapeutically effective amount of a LSD1 inhibitor.

8-12. -12. (canceled)

15. (canceled)

19-20. -20. (canceled)

24. (canceled)

26-34. -34. (canceled)

36-37. -37. (canceled)

40-42. -42. (canceled)

44-50. -50. (canceled)

53-60. -60. (canceled)

62-68. -68. (canceled)

70-71. -71. (canceled)