Bridged bicyclic compounds and their derivatives as neuroprotective agents and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10759735-B2
Application number	US-201916245587-A
Country	US
Kind code	B2
Filing date	Jan 11, 2019
Priority date	Mar 14, 2018
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

Neuroprotective compounds for reducing neurological damage due to cellular stress in an individual are of Formula 1:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof, wherein: Ar=aryl; Y=aryl substituent (ortho, meta, or para) selected from the group consisting of: alkyl, alkyloxy, alkylamino, R 5 R 6 N, and halo; X═O, N, or S; R═H, alkyl, aryl, OH, alkyloxy, aryloxy, NH 2 , alkylamino, R 5 R 6 N, or arylamino; R 1 and R 2 =alkylcarbonyl, arylcarbonyl, alkyl, or H, individually; R 3 =arylCH═CH, alkylCH═CH, alkyl; R 4 ═H, alkyl, or aryl; and R 5 and R 6 =alkyl, individually. Methods of reducing neurological damage due to cellular stress in an individual include administering to the individual during or after the cellular stress a neuroprotective compound of Formula I in a therapeutically effective amount to restore synaptic function during or after the cellular stress.

First claim

What is claimed is:

1. A compound of Formula 1:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ar is aryl;
Y is an ortho, meta, or para aryl substituent selected from the group consisting of alkyl, alkyloxy, alkylamino, NR 5 R 6 , and halo;
X is O, S, or NH bonded to R 1 or R 2 ;
R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH 2 , alkylamino, NR 5 R 6 , or arylamino;
R 1 and R 2 are alkylcarbonyl, arylcarbonyl, alkyl, or H, individually;
R 3 is arylCH=CH, a 1 kylCH=CH, or alkyl;
R 4 is H, alkyl, or aryl; and
R 5 and R 6 are alkyl, individually.

2. The compound of claim 1 , wherein:
alkyl is a saturated hydrocarbon moiety containing up to six carbons at any of Y, R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 .

3. The compound of claim 1 , having the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , having the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , having the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , having the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , having the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

8. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

9. The composition of claim 8 , wherein the compound has the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

10. The composition of claim 8 , wherein the compound has the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

11. The composition of claim 8 , wherein the compound has the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

12. The composition of claim 8 , wherein the compound has the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

13. The composition of claim 9 , wherein the compound has the formula:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt thereof.

14. A method of reducing neurological damage due to cellular stress in an individual comprising administering to the individual during or after the cellular stress a compound according to claim 1 or a composition according to claim 8 in a therapeutically effective amount to restore synaptic function during or after the cellular stress, wherein the cellular stress is anoxia or oxidative stress.

15. The method of claim 14 , wherein the cellular stress is caused by at least one selected from the group consisting of migraine, Alzheimer's disease, traumatic brain injury, heart attack and stroke.

16. The method of claim 14 , wherein the cellular stress is acute oxidative stress.

17. The method of claim 14 , wherein administering the compound or composition to the individual increases time until synaptic failure.

18. The method of claim 14 , further comprising detecting a state or condition of cellular stress in the individual prior to administering to the individual during or after the cellular stress a compound according to claim 1 or a composition according to claim 8 .

19. A compound of Formula 1:

or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ar is 5- or 6- membered heteroaryl;
Y is an ortho, meta, or para heteroaryl substituent selected from the group consisting of alkyl, alkyloxy, alkylamino, NR 5 R 6 , and halo;
X is O, S, or NH bonded to R 1 or R 2 ;
R is H, alkyl, heteroaryl, OH, alkyloxy, heteroaryloxy, NH 2 , alkylamino, NR 5 R 6 , or heteroarylamino;
R 1 and R 2 are alkylcarbonyl, heteroarylcarbonyl, alkyl, or H, individually;
R 3 is heteroarylCH=CH, a 1 kylCH=CH, or alkyl;
R 4 is H, alkyl, or heteroaryl; and
R 5 and R 6 are alkyl, individually.

Assignees

• Florida Atlantic Univ Board Of Trustees

Inventors

• Lepore Salvatore D
• Dawson-Scully Kenneth
• St Germain Elijah J
• Maki Samantha L
• Bollinger Wesley L
• Sial Nadia K

Classifications

• C07C62/34

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C2602/44

  the bicyclo ring system containing eight carbon atoms · CPC title

• C07C69/18

  of trihydroxylic compounds · CPC title

• C07C67/03

  by reacting an ester group with a hydroxy group · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title