Synthesis of FR901464 and analogs with antitumor activity
View Patent ↗The present invention provides novel analogs of FR901464, as well as an improved methodology for preparing FR901464 and its analogs. These compounds display an anti-cancer activity and are candidates for therapies against a number of disease states associated with dysfunctional RNA splicing.
1. A compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof having Formula I:
wherein
R 1 and R 8 are independently selected from the group consisting of H, C 1-6 -alkyl, halo(C 1-6 -alkyl), C(O)R 11 , C(O)OR 11 , and C(O)NR 12 R 13 ,
wherein each R 11 is independently H, C 1-6 -alkyl, or halo(C 1-6 -alkyl), and
wherein R 12 and R 13 are selected independently from the group consisting of H, C 1-6 -alkyl, and halo(C 1-6 -alkyl);
or R 12 and R 13 , together with the nitrogen atom to which they are bound, form a heterocyclic or heterocyclic ring;
R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, C 1-6 -alkyl, and halo(C 1-6 -alkyl);
R 7 is selected from the group consisting of H, C 1-6 -alkyl and halo(C 1-6 -alkyl); and
R 9 and R 10 are independently selected from the group consisting of H, OH, C 1-6 -alkyl, and C 1-6 -alkyl substituted with one to three groups independently selected from halo, hydroxy, and C 1-6 -alkoxy;
R 14 and R 15 are selected independently from the group consisting of halo(C 1-6 -alkyl), C(O)R 11 , F, Cl, NO 2 , and B(OR 11 ) 2 , wherein R 11 is as defined above;
or R 14 and R 15 , together with the carbon atom to which they are bound, form an epoxide ring;
provided that when R 1 is C(O)CH 3 , R 2 , R 4 , and R 8 are hydrogen, and R 3 , R 5 , R 6 , R 7 , and R 9 are methyl, then R 10 is not hydrogen or OH.
2. The compound according to claim 1 having Formula Ib:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined in claim 1 .
3. The compound according to claim 2 wherein R 1 is C(O)R 11 and R 11 is C 1-6 -alkyl or halo(C 1-6 -alkyl).
4. The compound according to claim 3 wherein R 1 is C(O)CH 3 .
5. The compound according to claim 2 wherein at least one of R 2 , R 3 , R 5 , and R 6 is C 1-6 -alkyl.
6. The compound according to claim 5 wherein at least one of R 2 , R 3 , R 5 , and R 6 is CH 3 .
7. The compound according to claim 2 wherein R 4 is hydrogen.
8. The compound according to claim 2 wherein R 7 is CH 3 or CF 3 .
9. The compound according to claim 2 wherein at least one of R 9 and R 10 is independently selected from the group consisting of C 1-6 -alkyl and C 1-6 -alkyl substituted with one to three groups independently selected from halo, hydroxy, and C 1-6 -alkoxy.
10. The compound according to claim 9 wherein at least one of R 9 and R 10 is independently selected from the group consisting of CH 3 , CH 2 I, and CH 2 OH.
11. The compound according to claim 1 having Formula (Ic):
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined in claim 1 .
12. The compound according to claim 11 wherein R 1 is C(O)R 11 and R 11 is C 1-6 -alkyl or halo(C 1-6 -alkyl).
13. The compound according to claim 12 wherein R 1 is C(O)CH 3 .
14. The compound according to claim 11 wherein at least one of R 2 , R 3 , R 5 , and R 6 is C 1-6 -alkyl.
15. The compound according to claim 14 wherein at least one of R 2 , R 3 , R 5 , and R 6 is CH 3 .
16. The compound according to claim 11 wherein R 4 is hydrogen.
17. The compound according to claim 11 wherein R 7 is CH 3 or CF 3 .
18. The compound according to claim 1 that is selected from the group consisting of:
19. The compound according to claim 18 or a stereoisomer or pharmaceutically acceptable salt or ester thereof of Formula (IX):
20. A pharmaceutical composition comprising a compound according to claim 1 , a stereoisomer, or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
21. The composition according to claim 20 comprising a compound or pharmaceutically acceptable salt or ester thereof of Formula (IX):
22. A process for preparing a compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof having Formula I:
wherein
R 1 and R 8 are independently selected from the group consisting of H, Pg, C 1-6 -alkyl, halo(C 1-6 -alkyl), C(O)R 11 , C(O)OR 11 , and C(O)NR 12 R 13 ,
wherein each R 11 is independently H, C 1-6 -alkyl, or halo(C 1-6 -alkyl), and
wherein R 12 and R 13 are selected independently from the group consisting of H, C 1-6 -alkyl, and halo(C 1-6 -alkyl);
or R 12 and R 13 , together with the nitrogen atom to which they are bound, form a 5- to 6-membered heterocyclic or heteroaromatic ring;
R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, C 1-6 -alkyl, and halo(C 1-6 -alkyl);
R 7 is selected from the group consisting of H, C 1-6 -alkyl and halo(C 1-6 -alkyl); and
R 9 and R 10 are independently selected from the group consisting of H, OH, C 1-6 -alkyl, and C 1-6 -alkyl substituted with one to three groups independently selected from halo, hydroxy, C 1-6 -alkoxy, and OPg;
R 14 and R 15 are selected independently from the group consisting of halo(C 1-6 -alkyl), C(O)R 11 , F, Cl, NO 2 , and B(OR 11 ) 2 , wherein R 11 is as defined above;
or R 14 and R 15 , together with the carbon atom to which they are bound, form an epoxide ring; and
each Pg is independently a hydroxy protecting group;
said method comprising contacting a compound of Formula (II) wherein E, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above:
with a compound of Formula (III) wherein R 8 , R 9 , R 10 , R 14 , and R 15 are as defined above:
in the presence of an olefin metathesis catalyst to provide a compound of Formula I
provided that when R 1 is C(O)CH 3 ; R 2 , R 4 , and R 8 are hydrogen; R 3 , R 5 , R 6 , R 7 , and R 9 are methyl; and R 10 is OH, then the compound of Formula (III) is a compound of Formula (IIIa):
23. The process according to claim 22 , wherein the compound of Formula I is compound (IX):
24. A process for preparing compound, stereoisomer, or pharmaceutically acceptable salt or ester thereof having Formula I:
wherein
R 1 and R 8 are independently selected from the group consisting of H, Pg, C 1-6 -alkyl, halo(C 1-6 -alkyl), C(O)R 11 , C(O)OR 11 , and C(O)NR 12 R 13 ,
wherein each R 11 is independently H, C 1-6 -alkyl, or halo(C 1-6 -alkyl), and
wherein R 12 and R 13 are selected independently from the group consisting of H, C 1-6 -alkyl, and halo(C 1-6 -alkyl);
or R 12 and R 13 , together with the nitrogen atom to which they are bound, form a 5- to 6-membered heterocyclic or heteroaromatic ring;
R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, C 1-6 -alkyl, and halo(C 1-6 -alkyl);
R 7 is selected from the group consisting of H, C 1-6 -alkyl and halo(C 1-6 -alkyl); and
R 9 and R 10 are independently selected from the group consisting of H, OH, C 1-6 -alkyl, and C 1-6 -alkyl substituted with one to three groups independently selected from halo, hydroxy, C 1-6 -alkoxy, and OPg;
R 14 and R 15 are selected independently from the group consisting of halo(C 1-6 -alkyl), C(O)R 11 , F, Cl, NO 2 , and B(OR 11 ) 2 , wherein R 11 is as defined above;
or R 14 and R 15 , together with the carbon atom to which they are bound, form an epoxide ring;
said process comprising:
(a) contacting a compound of Formula (IVc), wherein R 9 , R 14 , and R 15 are as defined above and P 1 is a hydroxy protecting group, with an oxidizing agent to form a first compound of Formula (V) wherein R 9 , R 14 , and R 15 are as defined above, P 1 is a hydroxy protecting group, and P 2 is hydrogen:
(b) converting said first compound of Formula (V) wherein P 1 is a hydroxy protecting group and P 2 is hydrogen to a second compound of Formula (V) wherein P 1 and P 2 are hydroxy protecting groups;
(c) optionally converting said first or second compound of Formula (V) under cyclization conditions to a compound of Formula (III) wherein R 8 , R 9 , and R 10 are as defined herein:
(d) optionally converting said second compound of Formula (V) under oxidative conditions to a compound of Formula (VI) wherein R 9 , R 14 , and R 15 are as defined above, and P 1 and P 2 are hydroxy protecting groups; and converting the compound of Formula (VI) under cyclization conditions to a compound of Formula (III):
(e) contacting a compound of Formula (III) with a compound of Formula (II) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein:
in the presence of an olefin metathesis catalyst to form a compound of Formula I.
25. The process according to claim 24 , said process further comprising:
(a) contacting a compound of Formula (VII) with Ag—CC—CO 2 Me and Cp 2 ZrCl 2 to form a compound of Formula (VIII) wherein R 9 , R 14 , and R 15 are as defined in claim 24 :
(b) contacting a compound of Formula (VIII) with Red-Al to form a compound of Formula (IVa) wherein P 1 is hydrogen:
(c) converting a compound of Formula (IVa) wherein P 1 is hydrogen to a compound of Formula (IVa) wherein P 1 is a hydrogen protecting group;
(d) contacting a compound of Formula (IVa) wherein P 1 is a hydrogen protecting group with a reducing agent to form a compound of Formula (IVb) wherein P 1 is a hydrogen protecting group
(e) reacting a compound of Formula (IVb) wherein P 1 is a hydrogen protecting group with o-O 2 N-PhSeCN under selenide forming conditions to a compound of Formula (IVc:
26. The process according to claim 24 , wherein the compound of Formula I is compound (X):
27. The process according to claim 24 , wherein the compound of Formula I is compound (IX):
28. An intermediate compound having Formula (IV):
wherein
Y is selected from the group consisting of MeO 2 C—, o-O 2 N-PhSeCH 2 —, and HOCH 2 —;
R 9 is selected from the group consisting of C 1-6 -alkyl and C 1-6 -alkyl substituted with one to three groups independently selected from halo, hydroxy, C 1-6 -alkoxy, and OPg;
R 14 and R 15 are selected independently from the group consisting of halo(C 1-6 -alkyl), C(O)R 11 , F, Cl, NO 2 , and B(OR 11 2 , wherein each R 11 is independently H, C 1-6 -alkyl, or halo(C 1-6 -alkyl),
or R 14 and R 15 , together with the carbon atom to which they are bound, form an epoxide ring; and
P 1 and Pg are independently a hydroxy protecting group.
29. The intermediate compound according to claim 28 wherein P 1 is triethylsilyl and R 9 is C 1-6 -alkyl.
30. The intermediate compound according to claim 29 that is selected from the group consisting of:
31. The composition according to claim 20 comprising a compound or pharmaceutically acceptable salt of ester thereof of:
32. The process according to claim 22 , wherein the compound of Formula I is
33. The process according to claim 24 , wherein the compound of Formula I is