Antimitotic eleuthesides

• US 20040266700A1
• Filed: 04/07/2004
• Published: 12/30/2004
• Est. Priority Date: 06/22/2001
• Status: Active Grant

• Current Assignee: University of British Columbia
• Original Assignee: University of British Columbia
• Inventors: Britton, Robert A., Roberge, Michel, De Silva, E. Dilip, Andersen, Raymond J
• Granted Patent: US 7,067,494 B2
• Time in Patent Office: Days
• US Class Current: 514/28
• CPC Class Codes: C07H 15/26 Acyclic or carbocyclic radicals, substituted by hetero rings
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms

Abstract

This invention provides analogs of eleutherobin and the eleuthesides modified at the C-11 position or comprising an epoxide functionality from C-11 to C-12. C-11 to C-12 is an ideal location for conjugating functional moieties to the eleutherobin pharmacophore without significant loss of antimitotic activity. Moieties that may be conjugated at C-11 include those intended to increase the solubility of the pharmacophore, to facilitate drug formulation, or to facilitate in vivo delivery or targeting.

Claims

1. A compound or pharmaceutically acceptable salt thereof, wherein the compound is of formula I or II:

2. A compound of claim 1, wherein R¹ and R² are H and R³ is acyl.

3. A compound of claim 1, wherein one of R¹ and R² is H, and the other of R¹ and R² is acyl and, R³ is H.

4. A compound of claim 1, wherein one or more of R¹-R⁴ is acetyl.

5. A compound of claim 2 or 3, wherein acyl is acetyl.

6. A compound of claim 1, wherein one or more of R¹-R⁴ is a C₂-C₅ straight-chain or branched alkyl.

7. A compound of any one of claims 1-6, wherein R⁴ is selected from the group consisting of:

H, ethyl, propyl, butyl and pentyl.

8. A compound of claim 1, wherein R¹ and R³ are H;

R² is acyl; and

, R⁴ is methyl.

9. A compound of claim 8, wherein R² is acetyl.

10. A compound of any one of claims 1-9, wherein the compound is of formula I and X is a moiety comprising a component selected from the group consisting of:

a pharmaceutically acceptable polymer, a peptide, a lipid and a polysaccharide.

11. A compound of any one of claims 1-9, wherein the compound is of formula I and, X is selected from the group consisting of:

—

CH₂OR, —

COR, —

COY, —

C(OR)R, —

CRCR₂, and, —

CH₂W;

R is selected from the group consisting of;

H;

a linear, branched, or cyclic, saturated or unsaturated alkyl group containing one to ten carbons optionally substituted with Z;

an aromatic group optionally substituted with Z; and

, arylalkyl (ArR*) in which an alkyl group (R*) is a linear, branched, or cyclic, and saturated or unsaturated containing one to ten carbons optionally substituted with Z and an aryl group (Ar) optionally substituted with Z;

Z is selected from the group consisting of;

—

OH, —

OR, —

O₂CR, —

SH, —

SR, —

SOCR, —

NH₂, —

NHR, —

NHR₂, —

NHCOR, —

NRCOR, —

I, —

Br, —

Cl, —

F, —

CN, —

CO₂H, —

CO₂R, —

CHO, —

COR, —

CONH₂, —

CONHR, —

CONR₂, —

COSH, —

COSR, —

NO₂, —

SO₃H, —

SOR, and —

SO₂R;

Y is selected from the group consisting of;

—

OH, —

NH₂, —

NHR, —

NR₂, —

SH, —

SR and —

OR;

W is selected from the group consisting of;

R, F, Cl, Br, I, —

OSO₃R, —

SO₃R, —

OPO₃R₂, —

PO₃R₂, —

SR, —

SOR, —

SO₂R, —

NR₂, —

NOR, and —

NR₃⁺;

with each R being the same or different, and wherein for R* and for R when comprising an alkyl, —

CH₂—

may be replaced by —

O₂S or NR, and CH may be replaced by N.

12. A compound of claim 11, wherein R is:

H;

or, a linear, branched or cyclic, saturated or unsaturated alkyl group; and

, Y is selected from the group consisting of;

OH, NH₂, NHR, NHR₂ and OR.

13. A compound of claim 11, wherein R is H or a C₁-C₆ branched or straight chain alkyl.

14. A compound of claim 11, wherein X is selected from the group consisting of:

—

COH;

—

COOH;

—

CNH₂;

—

CNHR;

—

CNR₂; and

, —

COR.

15. A compound of claim 14, wherein R is a C₁-C₆ branched or straight chain alkyl.

16. A compound of claim 11, wherein X is —

CH₂OH.

17. A compound of any one of claims 1-9, wherein the compound is of formula II.

18. A compound of claim 17, wherein the epoxide at C-11 is in a β

configuration.

19. A pharmaceutical preparation comprising a compound or pharmaceutically acceptable salt of any one of claims 1-18 and a pharmaceutically acceptable carrier or diluent.