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EP-4385571-B1 - A LYSYL OXIDASE-LIKE 2 INHIBITOR FOR USE IN TREATING PRIMARY MYELOFIBROSIS

EP4385571B1EP 4385571 B1EP4385571 B1EP 4385571B1EP-4385571-B1

Inventors

  • BAIN, GRETCHEN
  • EVANS, JILLIAN FRANCES
  • MACKENNA, DEIDRE A.
  • HUTCHINSON, JOHN HOWARD

Dates

Publication Date
20260506
Application Date
20170906

Claims (3)

  1. A compound for use in a method for treating a disease or condition in a mammal that would benefit from inhibition or reduction of LOXL2 activity, wherein the compound is a small molecule LOXL2 inhibitor that is at least 100 times more selective for inhibiting or binding to LOXL2 than for LOX; wherein the small molecule LOXL2 inhibitor is: ( R , R )-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof; and wherein the disease or condition is primary myelofibrosis.
  2. The compound for use according to claim 1, wherein ( R , R )- trans -(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt.
  3. The compound for use according to any one of claims 1-2, wherein: the mammal is a human.

Description

FIELD OF THE INVENTION Described herein are methods of using a lysyl oxidase-like 2 (LOXL2) inhibitor in the treatment or prevention of conditions, diseases, or disorders associated with LOXL2 activity. BACKGROUND OF THE INVENTION Lysyl oxidase like-2 (LOXL2) is an amine oxidase enzyme that catalyzes crosslinking of extracellular matrix proteins. LOXL2 is also involved in intracellular processes such as mediating epithelial-to-mesenchymal transition of cells. LOXL2 signaling is implicated in, for example, in fibrotic diseases and cancer. There is an unmet medical need for therapies that could provide benefit to patients with fibrotic diseases and cancer. US2014/120102 discloses an antibody specifically binding to LOXL2 for use in treating fibrotic diseases in particular of the liver, such as NASH, PSC and myelofibrosis. SUMMARY OF THE INVENTION Described herein is the use of a small molecule LOXL2 inhibitor in the treatment of disease or condition in a mammal that would benefit from inhibition or reduction of LOXL2 activity, wherein the small molecule LOXL2 inhibitor is more selective for inhibiting or binding to LOXL2 than for LOX. The present invention relates to a compound for use in a method for treating a disease or condition in a mammal that would benefit from inhibition or reduction of LOXL2 activity, wherein the compound is a small molecule LOXL2 inhibitor that is at least 100 times more selective for inhibiting or binding to LOXL2 than for LOX;wherein the small molecule LOXL2 inhibitor is: (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof, andwherein the disease or condition is primary myelofibrosis. In one embodiment (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt. In another embodiment the myelofibrosis is post polycythemia vera or post essential thrombocythemia myelofibrosis. In a further embodiment the mammal is a human. In some embodiments, the pharmaceutically acceptable salt of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is formed from (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone and an acid selected from the group consisting of hydrochloride acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, metaphosphoric acid, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. In some embodiments, the (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is is used as the mesylate salt, hydrochloride salt, sulfate salt, maleate salt, phosphate salt, L-tartrate salt, fumarate salt, succinate salt, citrate salt or acetate salt. In some embodiments, the (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is used as the mesylate salt. In some embodiments the hydrochloride salt of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is used. In some embodiments, the mesylate salt of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is used. Described herein is the compound (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone (Compound I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments the hydrochloride salt of Compound I is used (i.e. Compound 1). In s