Bryostatin analogues, synthetic methods and uses

1. A compound having the structure represented by a formula:

wherein:

R 3 is H′, or OH;

R 7 is absent or represents from 1 to 4 substituents on the ring to which it is attached, independently selected from: lower alkyl, hydroxyl, amino, alkoxyl, alkylamino, ═O, acylainino and acyloxy;

R 20 is H, OH, or -T-U—V—R′ where:

T is —O—, —S—, —N(H)— or —N(Me)-;

U is absent or is —C(O)—, —C(S)—, —S(O)— or —S(O) 2 —; and

V is absent or is —O—, —S—, —N(H)— or —N(Me)-, provided that V is absent when U is absent;

R 21 is ═CR 3 R b or R 21 represents independent moieties R 6 and R d where:

R a and R b are independently H, CO 2 R′, CONR a R d or R′;

R c and R d are independently H, alkyl, alkenyl, alkynyl or (CH 2 ) p CO 2 R′;

R 26 is H, OH or R′;

R′ is independently selected from: H, C 1 –C 10 alkyl, naphthyl, anthracyl, phenanthryl, alkenyl, alkynyl, heteroaryl, aralkyl and heteroaralkyl;

X is —CH 2 —, —O—, —S— or —N(R e )— where R e is COH, CO 2 R′ or SO 2 R′, Z is —O— or —N(H)—; p is 1, 2 or 3;

or a pharmaceutically acceptable salt thereof,

excluding the compounds of Formula 1998a where R 3 is H or OH and where R 20 is —O—C(O)—CH 3 , or —O—C(O)—(CH 2 ) 6 —CH 3

2. The compound or salt of claim 1 where:

R 7 is absent;

R 20 is H, OH, or -T-U—V—R′;

wherein T is —O—, U is —C(O)—, V is absent, and R′ is C 1 –C 10 alkyl or alkenyl,

R 21 is ═CHCO 2 -lower alkyl;

R 26 is H or C 1 –C 6 alkyl; and

X is —CH 2 — or —O—.

3. The compound or salt of claim 2 where:

R 3 is OH;

R 20 is H, OH, or

-T-U—V—R′; wherein T is —O—, U is —C(O)—, V is absent, and R′ is C 1 –C 10 alkyl or alkenyl.

4. The compound or salt of claim 3 where R 26 is H.

5. The compound of any one of claims 2 or 3 wherein R′ is ethyl, isopropyl, cyclopropyl, 2-butyl or cyclopentyl.

6. The compound of claims 1 , wherein R′ is ethyl, isopropyl, cyclopropyl, 2-butyl or cyclopentyl.

7. The compound of any one of claims 2 or 3 , wherein R′ is 2-pentenyl, 2,4-pentadienyl, 2-octenyl, 2,4,6-octatrienyl.

8. The compound of any one of claims 2 or 3 , wherein R′ is

CH 3 —CH 2 —CH 2 —CH═CH—CH═CH—.

9. The compound of claim 1 , wherein R′ is 2-pentenyl, 2,4-pentadienyl, 2-octenyl, 2,4,6-octatrienyl.

10. The compound of claim 1 , wherein R′ is CH 3 —CH 2 —CH 2 —CH═CH—CH═CH—.

11. The compound of claim 1 , having the stereochemical configuration represented by the formula:

12. The compound of claim 1 , having the stereochemical configuration represented by the formula:

13. A compound having the structure represented by a formula of the group:

wherein:

R 3 is H, or OH;

R 20 is H, OH, or -T-U—V—R′ where:

T is —O—, —S—, —N(H)— or —N(Me)-;

U is absent or is —O—, —C(S)—, —S(O)— or —S(O) 2 —; and

V is absent or is —O—, —S—, —N(H)— or —N(Me)-, provided that V is absent when U is absent;

R′ is independently selected from: H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

or a pharmaceutically acceptable salt thereof.

14. A compound of claim 1 having one or more of the stereochemical configurations represented by the corresponding formula of the group:

15. The compound or salt of any of claim 13 or 14 where:

R 20 is H, OH or -T-U—V—R′

wherein T is —O—, U is —C(O)—, V is absent, and R′ is alkyl or alkenyl.

16. The compound or salt of claim 15 where:

R 3 is OH;

R 20 is H, OH, or

-T-U—V—R′;

wherein T is —O—, U is —C(O)—, V is absent, and R′ is alkyl or alkenyl.

17. The compound of claim 13 or 14 , wherein R′ is ethyl, isopropyl, cyclopropyl, 2-butyl or cyclopentyl.

18. The compound of claim 13 or 14 , wherein R′ is 2-pentenyl, 2,4-pentadienyl, 2-octenyl, 2,4,6-octatrienyl.

19. The compound of claim 13 or 14 , wherein R′ is

CH 3 —CH 2 —CH 2 CH═CH—CH═CH—.