Cyclic dipeptides and azetidinone compounds and their use in treating CNS injury and neurodegenerative disorders

1. A method of treating a neurodegenerative disorder in a subject comprising administering to said subject in need of such treatment an effective amount of a compound having the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

n is an integer from 0 to 3;

X is selected from the group consisting of —S—, —O—, —NR— and CH 2 —;

R 1 and R 2 are each independently selected from the group consisting of —H, —OR, —SR, —NRR, —NO 2 , CN, —C(O)OR, —C(O)NRR, —C(NR)NRR, trihalomethyl, halogen, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, substituted (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, substituted (C 2 -C 6 ) alkynyl, (C 5 -C 20 ) aryl, substituted (C 5 -C 20 ) aryl, 5-20 membered heteroaryl, substituted 5-20 membered heteroaryl, (C 6 -C 26 ) alkaryl, substituted (C 6 -C 26 ) alkaryl, 6-26 membered alk-heteroaryl and substituted 6-26 membered alk-heteroaryl,

or R 1 and R 2 taken together are —CH 2 —(CH 2 ) m —CH 2 —, where m is an integer from 0 to 6;

each alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alk-heteroaryl substitutent is independently selected from the group consisting of —OR, —SR, —NRR, —CN, —NO 2 , —C(O)OR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, halogen and trihalomethyl; and

each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 5 -C 20 ) aryl, 5-20 membered heteroaryl, (C 6 -C 26 ) alkaryl and 6-26 membered alk-heteroaryl.

2. The method of claim 1 , wherein both carbons at positions 3 and 6 of the bicyclic 2,5-diketopiperazine ring are in the S configuration.

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

4. The method of claim 1 , wherein n is 1.

5. The method of claim 1 , wherein said compound is selected from the group consisting of:

6. The method of claim 1 in which said compound has the following structure:

7. The method of claim 1 , wherein R 1 is H.

8. The method of claim 7 , wherein n is an integer from 1 to 3;

X is —S—, —O—, —NH— or —CH 2 —;

R 2 is —CH 2 —R 5 , —CH 2 —R 5 or —CH 2 —CH 2 —CH 2 —R 5 ;

R 5 is phenyl, imidazolyl other than imidazol-2-yl, indolyl other than indol-3-yl,

—SR 6 , —OR 6 or —NHR 6 ; and

R 6 is —H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —C(NH)NH 2 or —C(S)NH 2 .

9. The method of claim 7 , wherein n is an integer from 1 to 3;

X is —S—, —O—, —NH— or —CH 2 —;

R 2 is —H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl or —(CH 2 ) g —CH 2 —R 7 ;

g is an integer from 0 to 5;

R 7 is —OR 8 , —SR 8 , —NR 8 R 8 , —CH(OR 8 )—CH 3 , —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 8 , —SC(NH)NH 2 , —NH—C(NH)NH 2 , —NH—C(S)NH 2 , phenyl, hydroxyphenyl, imidazolyl, indolyl; and

R 8 is —H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl.

10. The method of claim 7 , wherein n is an integer from 1 to 3;

X is —S—, —O—, —NH— or —CH 2 —; and

R 1 and R 2 taken together are —CH 2 —(CH 2 ) b — where b is an integer from 0 to 6.

11. The method of claim 1 wherein said compound has the formula:

wherein

X is —CH 2 —;

n is 1;

R 1 is H;

R 2 is (CH 2 ) q R 18 ,

q is 0, 1, 2, 3 or 4; and

R 18 is di-t-butylhydroxyphenyl.

12. The method of claim 11 wherein R 18 is 3,5-di-t-butyl-4hydroxy phenyl.

13. The method of claim 12 wherein q is 1.

14. The method of claim 11 wherein said compound has the formula:

wherein

X is —CH 2 —;

n is 1;

R 1 is H, and

R 2 is (CH 2 ) q R 18 ;

q is 0, 1, 2, 3, or 4; and

R 18 is di-t-butylhydroxyphenyl.

15. The method of claim 14 wherein R 18 is 3,5-di-t-butyl-4-hydroxyphenyl.

16. The method of claim 15 wherein q is 1.

17. The method of claim 8 wherein R 6 is t-butyl.

18. The method of claim 1 wherein the neurodegenerative disorder is Alzheimer's disease.

19. The method according to claim 18 wherein the compound is

20. The method according to claim 1 wherein the compound is

21. A compound of the formula

or a pharmaceutically acceptable salt or hydrate thereof.