Neutrophil inflammation inhibitor and uses thereof

10654,848

16/185017

November 09, 2018

Disclosed herein are compounds of formula (I), and pharmaceutical compositions comprising the same. The compounds of formula (I) are neutrophilic inflammation inhibitors, thus, they are useful for treatment and/or prophylaxis of inflammatory diseases and/or disorders associated with abnormal activation of neutrophils, such as ARDS, ALI, COPD, lung fibrosis, chronic bronchitis, pulmonary emphysema, α-1 anti-trypsin deficiency, cystic fibrosis, idiopathic pulmonary fibrosis, liver injury, steatohepatitis, liver fibrosis, damages caused by ischemia and reperfusion, myocardial infarction, shock, stroke, and organ transplantation, ulcerative cholitis, vasculitis, SLE, sepsis, SIRS, arthritis, psoriasis, atopic dermatitis, and inflammatory skin diseases. [chemical expression included]

Chang Gung University of Science and Technology (Taoyuan, TW)

Chang Gung University of Science and Technology (Taoyuan, TW), Chang Gung University (Taoyuan, TW), Kaohsiung Medical University (Kaohsiung, TW)

1. A compound of formula (I), a salt, or a solvate thereof: [chemical expression included] wherein, X is N or O; R 1 is alkyl or nil, in which R 1 is nil when X is O, and R 1 is alkyl when X is N; R 2 , R 3 , R 4 , and R 5 are independently H, hydroxyl, sulfhydryl, halogen, alkyl, haloalkyl, —OR 6 , —SR 6 , —(C═O)R 6 , or —COOH; and R 6 is alkyl or haloalykl.

2. The compound of claim 1 , wherein X is N; R 1 is methyl; R 2 , R 3 , and R 5 are independently H; and R 4 is hydroxyl.

3. A pharmaceutical composition comprising a compound of formula (I), a salt, or a solvent thereof, [chemical expression included] wherein, X is N or O; R 1 is alkyl or nil, in which R 1 is nil when X is O, and R 1 is alkyl when X is N; R 2 , R 3 , R 4 , and R 5 are independently H, hydroxyl, sulfhydryl, halogen, alkyl, haloalkyl, —OR 6 , —SR 6 , —(C═O)R 6 , or —COOH; and R 6 is alkyl or haloalkyl; and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition of claim 3 , wherein in the compound of formula (I), X is N; R 1 is methyl; R 2 , R 3 , and R 5 are independently H; and R 4 is hydroxyl.

5. A method for treating an inflammatory disease and/or disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I), a salt, or a solvate thereof, [chemical expression included] wherein, X is N or O; R 1 is alkyl or nil, in which R 1 is nil when X is P, and R 1 is alkyl when X is N; R 2 , R 3 , R 4 , and R 5 are independently H, hydroxyl, sulfhydryl, halogen, alkyl, —OR 6 , —SR 6 , —(C═O)R 6 , or —COOH; and R 6 is alkyl optionally substituted with at least one halogen.

6. The method of claim 5 , wherein in the compound of formula (I), X is N; R 1 is methyl; R 2 , R 3 , and R 5 are independently H; and R 4 is hydroxyl.

7. The method of claim 5 , wherein the inflammatory disease and/or disorder is selected from the group consisting of acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic Obstructive Pulmonary Disease (COPD), lung fibrosis, liver injury, steatohepatitis, liver fibrosis, ischemia-reperfusion injury, myocardial infarction, shock, stroke, and organ transplantation, vasculitis, systemic lupus erythematosus (SLE), sepsis, systemic inflammatory response syndrome (SIRS), arthritis, psoriasis, atopic dermatitis, and inflammatory skin diseases.

8. The method of claim 7 , wherein the inflammatory disease and/or disorder is ALI.

9. The method of claim 7 , wherein the inflammatory disease and/or disorder is ARDS.

10. The method of claim 7 , wherein the inflammatory disease and/or disorder is psoriasis.

11. The method of claim 5 , wherein the compound of formula (I) is administered to the subject in the amount of 0.001-100 mg/Kg.

12. The method of claim 5 , wherein the subject is a human.

2018/0214426 August 2018 Chen
WO-2016191576 December 2016

edspgr.10654848