Small molecule inhibitors of the mitochondrial permeability transition pore (mtPTP)

Patent metadata

Field	Value
Publication number	US-10865181-B2
Application number	US-201515524595-A
Country	US
Kind code	B2
Filing date	Nov 4, 2015
Priority date	Nov 5, 2014
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

The present technology relates to compounds of any one of Formula I, II, IIa, III, IV, and/or V as described herein and their tautomers and/or pharmaceutically acceptable salts, compositions, and methods of uses thereof.

First claim

What is claimed is:

1. A compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is O;
W 1 is N;
Z 1 , Z 2 , and Z 3 are each independently CH, C—R 9 , or N;
m is 1;
G 1 is C═O;
R 1 is

R 2 , R 4 , R 5 , and R 9 are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, heterocyclyl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two adjacent R 4 , R 5 , and R 9 together form an aryl, heteroaryl, or heterocyclyl ring;
R 3 is hydrogen, alkyl, cycloalkyl, alkenyl, or alkynyl; and
R 21 is F or Cl.

2. The compound of claim 1 , wherein R 2 , R 4 , R 5 , and R 9 are independently at each occurrence hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, cyano, carboxyl, carboxyl ester, acyl, formyl, C 3 -C 7 heteroaryl, or C 3 -C 7 heterocyclyl, or two adjacent R 4 , R 5 , and R 9 together form an aryl, heteroaryl, or heterocyclyl ring.

3. The compound of claim 2 , wherein Z 1 is CH.

4. The compound of claim 1 , wherein Z 1 is CH.

5. The compound of claim 1 , wherein the compound is a compound of Formula-IIa:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

7. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

8. The composition of claim 7 , wherein the compound is a compound of Formula-IIa:

or a pharmaceutically acceptable salt thereof.

9. A composition comprising a compound of claim 6 and a pharmaceutically acceptable excipient.

10. A method for treating a disease in a subject having said disease, wherein the method comprises administering an effective amount of a compound of claim 1 to the subject, wherein the disease is multiple sclerosis, amyotropic lateral sclerosis, ischemic reperfusion injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-induced hypoglycemia, cerebral ischemia, brain damage from epilepsy or experimental trauma, Bethlem myopathy, pancreatitis, hepatitis, type II diabetes, diabetic retinopathy, muscular dystrophy, traumatic brain injury, heart infarction, or stroke.

11. The method of claim 10 , wherein the compound is a compound of Formula-IIa:

or a pharmaceutically acceptable salt thereof.

12. A method for inhibiting a mitochondrial permeability transition pore, wherein the method comprises contacting a cell with an effective amount of a compound of claim 1 .

13. A method for treating a condition in a subject having said condition, wherein the method comprises administering to a patient an effective amount of a compound of claim 1 ; and the condition in the subject is mediated by [Ca 2+ ] dysregulation or an accumulation of a reactive oxygen species.

Assignees

• Univ Kansas
• Univ Oregon Health & Science

Inventors

• Roy Sudeshna
• Bernardi Paolo
• Forte Michael
• Schoenen Frank
• Sileikyte Justina

Classifications

• A61K31/42

  Oxazoles · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D203/04

  not condensed with other rings · CPC title

• C07D211/14

  with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom · CPC title