NON-CATALYTIC SUBSTRATE-SELECTIVE p38alpha-SPECIFIC MAPK INHIBITORS WITH ENDOTHELIAL-STABILIZING AND ANTI-INFLAMMATORY ACTIVITY, AND METHODS OF USE THEREOF

Patent metadata

Field	Value
Publication number	US-2023201211-A1
Application number	US-202318169785-A
Country	US
Kind code	A1
Filing date	Feb 15, 2023
Priority date	Jun 23, 2016
Publication date	Jun 29, 2023
Grant date	—

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

1 .- 40 . (canceled)

41 . A compound having the formula:

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

42 . The compound of claim 41 , wherein L 1 is —CH 2 —.

43 . The compound of claim 41 , wherein L 1 is —CH 2 CH 2 —.

44 . The compound of claim 41 , wherein R 5 is —SO 2 —.

45 . The compound of claim 41 , wherein R 5 is —CH(OH)—.

46 . The compound of claim 41 , wherein the compound is 4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide, having the structure:

or a pharmaceutically acceptable salt thereof.

47 . The compound of claim 41 , wherein the compound is 4-chloro-N-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)benzamide having the structure:

or a pharmaceutically acceptable salt thereof.

48 . A pharmaceutical composition comprising the compound of claim 41 .

49 . The pharmaceutical composition of claim 48 , wherein the pharmaceutical composition comprises an oral dosage form.

50 . 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 the compound of claim 41 , 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.

51 . The method of claim 50 , wherein administering comprises orally administering.

52 . A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 41 ,
wherein the disease is selected from rheumatoid arthritis, Alzheimer's diseases, psoriasis, atherosclerosis, pain, multiple sclerosis, and glomerulosclerosis.

53 . The method of claim 52 , wherein administering comprises orally administering.

54 . 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 the pharmaceutical composition of claim 48 ,
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.

55 . The method of claim 54 , wherein administering comprises orally administering.

56 . A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 48 ,
wherein the disease is selected from rheumatoid arthritis, Alzheimer's diseases, psoriasis, atherosclerosis, pain, multiple sclerosis, and glomerulosclerosis.

57 . The method of claim 56 , wherein administering comprises orally administering.

Assignees

• Univ Maryland
• Us Veterans Affairs

Inventors

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

Classifications

• A61P19/02

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

• A61P29/00

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

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61K31/54

  having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame · CPC title

• A61K31/5375 Primary

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