Non-catalytic substrate-selective, p38α-specific MAPK inhibitors with endothelial-stabilizing and anti-inflammatory activity, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11357781-B2
Application number	US-202117231598-A
Country	US
Kind code	B2
Filing date	Apr 15, 2021
Priority date	Jun 23, 2016
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

Compounds that inhibit p38α MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.

First claim

It is claimed:

1. A method of treating an inflammatory disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein,
R 5 is selected from SO 2 , —CH(OH)—, and —N(CH 3 )—; and
L 1 is selected from —CH 2 —, —C(CH 3 ) 2 —, and —C(CH 2 CH 2 )—,

wherein the inflammatory disease is selected from rheumatoid arthritis, a cardiovascular disease, multiple sclerosis, inflammatory bowel disease, multiple sclerosis, inflammatory bowel diseases, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, and acute lung injury.

2. The method of claim 1 , wherein L 1 is —CH 2 —.

3. The method of claim 1 , wherein L 1 is —C(CH 3 ) 2 —.

4. The method of claim 1 , wherein L 1 is —C(CH 2 CH 2 )—.

5. The method of claim 1 , wherein the compound is 4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof:

6. The method of claim 1 , wherein the compound is 4-chloro-N-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof:

7. The method of claim 1 , wherein the compound is 4-chloro-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof:

8. The method of claim 1 , wherein the disease is acute respiratory distress syndrome.

9. The method of claim 1 , wherein administering comprises administering a pharmaceutical composition comprising the compound.

10. The method of claim 1 , wherein administering comprises administering an oral dosage form comprising the compound.

11. The method of claim 10 , wherein the oral dosage form comprises a controlled-release oral dosage form, a sustained-release oral dosage form, or an extended release oral dosage form.

12. The method of claim 1 , wherein administering comprises orally administering.

13. The method of claim 1 , wherein administering comprises administering from 0.1 mg/kg to 200 mg/kg of the compound.

14. A method of treating an inflammatory disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein,
R 5 is —O—; and
L 1 is selected from —CH 2 —, —C(CH 3 ) 2 —, and —C(CH 2 CH 2 )—,

wherein the inflammatory disease is selected from rheumatoid arthritis, a cardiovascular disease, multiple sclerosis, inflammatory bowel disease, multiple sclerosis, inflammatory bowel diseases, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, and acute lung injury.

15. The method of claim 14 , wherein the disease is acute respiratory distress syndrome.

16. The method of claim 14 , wherein administering comprises administering a pharmaceutical composition comprising the compound.

17. The method of claim 14 , wherein administering comprises administering an oral dosage form comprising the compound.

18. The method of claim 17 , wherein the oral dosage form comprises a controlled-release oral dosage form, a sustained-release oral dosage form, or an extended release oral dosage form.

19. The method of claim 14 , wherein administering comprises orally administering.

20. The method of claim 14 , wherein administering comprises administering from 0.1 mg/kg to 200 mg/kg of the compound.

21. The method of claim 14 , wherein the compound is 4-chloro-N-(4-(morpholinomethyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof:

Assignees

• Univ Maryland
• Us Veterans Affairs

Inventors

• Shapiro Paul S
• Mackerell Jr Alexander D
• Hasday Jeffrey D

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K31/5375 Primary

  1,4-Oxazines, e.g. morpholine · CPC title

• C07D213/81

  Amides; Imides · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title