Preparation and uses of reactive oxygen species scavenger derivatives

1. A method of treating ischemia in a patient comprising administering to a patient in need of such treatment a therapeutically acceptable amount a compound of Formula (I)a or Formula (I)b, a pharmaceutically acceptable salt thereof, or an individual enantiomer or diastereomer thereof:

wherein,

z is 0 or 1;

L is absent; or L is selected from C 1 -C 10 alkyl, C 1 -C 10 alkoxyl, C 3-7 cycloalkyl, C 1 -C 10 alkylcycloalkyl, heterocycloalkyl, C 1 -C 10 alkylheterocycloalkyl, C 5-10 aryl, C 1 -C 10 alkylaryl, C 5-10 heteroaryl, and C 1 -C 10 alkylheteroaryl;

Q is selected from:

wherein,

n is an integer selected from 0 to 10;

each of R 1 and R 2 is independently selected from hydrogen and CH 3 ;

each of R 3 and R 4 is independently selected from hydrogen and C 1 -C 5 alkyl; and

each W is independently absent or is selected from O and S; or

i) when W is absent, then R 3 and R 4 , form the following structure:

 or

ii) when W is O, then OR 3 and OR 4 , together form the following structure:

 and

PEP is a peptidyl moiety having the following structure:

wherein,

each asterisk (*) independently denotes a chiral center in either an (S) or (R) configuration;

m is an integer selected from 0 to 10;

X 1 is selected from hydrogen, —C(═O)—O—R m , —S(O)—O—R m , —S(O 2 )—O—R m , —S(O 2 )—N—(R m ) 2 and —C(═O)—N—(R m ) 2 , where R m is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkylcycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 5 -C 10 aryl, C 1 -C 6 alkylaryl, C 5 -C 10 heteroaryl, and C 1 -C 6 alkylheteroaryl;

each of X 2 , X 3 and X 4 is independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 5 -C 6 aryl, C 1 -C 6 alkylaryl, heteroaryl, and C 1 -C 6 alkylheteroaryl;

A is absent, or A is selected from Ala, Leu, Ile, Phe, Met, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, His, Lys, Arg, Asp, Glu, and Val, each of which can be in either a D or L configuration; wherein the amino residue is either unprotected, or protected by a protecting group selected from Cbz and Fmoc; and

G is absent, or G is selected from —O—, —S—, —NH—, —NH—C(═O)—O—, —O—C(═O)—NH—, —NH—C(═O)—NH—, —NHSO 2 —, —SO—, —SO 2 —, and —NHC(═O)—.

2. The method of claim 1 , wherein L is C 1 -C 10 alkyl.

3. The method of claim 1 , wherein L is selected from C 5 -C 10 aryl and C 1 -C 10 alkylaryl.

4. The method of claim 1 , wherein L is selected from C 5 -C 10 heteroaryl, C 1 -C 10 alkylaryl, C 1 -C 10 alkylheteroaryl, and pyridine.

5. The method of claim 1 , wherein G is absent or G is selected from —NHC(═O)—, —NHC(═O)—O—, and —NHSO 2 —.

6. The method of claim 1 , wherein Q has the structure:

wherein,

each W is independently absent;

n is an integer from 1 to 3;

R 1 is selected from hydrogen and methyl; and

each R 3 is independently C 1-3 alkyl.

7. The compound according to claim 1 , wherein PEP has the structure:

wherein,

each asterisk (*) independently denotes a chiral center that can be either in an (S) or (R) configuration;

X 1 is selected from —C(═O)—O—R m , —S(O)—O—R m , —S(O 2 )—O—R m , —S(O 2 )—N—(R m ) 2 , and —C(═O)—N—(R m ) 2 , where R m is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkylcycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 5 -C 10 aryl, C 1 -C 6 alkylaryl, C 5 -C 10 heteroaryl, and C 1 -C 6 alkylheteroaryl;

each of X 2 , X 3 and X 4 is independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 5 -C 6 aryl, C 1 -C 6 alkylaryl, C 5 -C 6 heteroaryl, and C 1 -C 6 alkylheteroaryl; and

A is absent or A is selected from Ala, Leu, Ile, Phe, Met, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, His, Lys, Arg, Asp, Glu, and Val, each of which can be in either a D or L configuration; wherein the amino residue is either unprotected, or protected by a protecting group selected from Cbz and Fmoc.

8. The method of claim 7 , wherein A is absent or A is valine.

9. The method of claim 7 , wherein,

X 1 is absent, or X 1 is selected from Et-O—C(═O)—, i-Pr—O—C(═O)—, t-Bu-O—C(═O)—, and cyclopropyl-CH 2 —O—C(═O)—;

X 2 is selected from i-propyl-CH 2 —, cyclopropyl-CH 2 —, cyclopentyl-CH 2 —, and adamantyl-CH 2 —;

X 3 is selected from Ph-CH 2 — and Pyr-CH 2 —; and

X 4 is selected from i-propyl-CH 2 —, cyclopropyl-CH 2 —, and cyclopentyl-CH 2 —.

10. The method of claim 7 , wherein,

A is absent;

X 1 is selected from t-Bu-O—C(═O)—, cyclopropyl-CH 2 —O—C(═O)—, and ethyl-CH 2 —O—C(═O)—;

X 2 is i-propyl-CH 2 —;

X 3 is Ph-CH 2 —; and

X 4 is i-propyl-CH 2 —.

11. The method of claim 7 , wherein,

A is absent;

X 1 is t-Bu-O—C(═O)—;

X 2 is selected from i-propyl-CH 2 — and adamantyl-CH 2 —;

X 3 is Ph-CH 2 —; and

X 4 is selected from cyclopropyl-CH 2 —, cyclopentyl-CH 2 —, and i-propyl-CH 2 —.

12. The method of claim 7 , wherein,

A is valine;

X 1 is selected from t-Bu-O—C(═O)— and cyclopropyl-CH 2 —O—C(═O)—;

X 2 is selected from i-propyl-CH 2 — and adamantyl-CH 2 —;

X 3 is Ph-CH 2 —; and

X 4 is selected from i-propyl-CH 2 —, cyclopropyl-CH 2 —, and cyclopentyl-CH 2 —.

13. The method of claim 1 , wherein the compound is selected from:

a pharmaceutically acceptable of any of the foregoing.

14. The method of claim 1 , wherein the administering comprises administering a pharmaceutical composition comprising the compound of Formula (I)a, Formula (I)b, a combination thereof, a pharmaceutically acceptable salt thereof, or an individual enantiomer or diastereomer thereof.

15. The method of claim 1 , wherein the ischemia is associated with acute kidney injury.

16. The method of claim 1 , wherein the ischemia is associated with stroke.

17. The method of claim 1 , wherein the ischemia is associated with atherosclerosis.

18. The method of claim 1 , wherein the ischemia is associated with hypertensive cardiomyopathy.

19. The method of claim 1 , wherein the ischemia is associated with congestive heart failure.