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Claims for Patent: 6,214,865

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Claims for Patent: 6,214,865

Title: Macrocyclic analogs and methods of their use and preparation
Abstract:The invention provides halichondrin analogs having pharmaceutical activity, such as anticancer or antimitotic (mitosis-blocking) activity, and methods of identifying agents that induce a sustained mitotic block in a cell after transient exposure of the cell to the agents.
Inventor(s): Littlefield; Bruce A. (Andover, MA), Palme; Monica H. (San Jose, CA), Seletsky; Boris M. (Andover, MA), Towle; Murray J. (Auburn, NH), Yu; Melvin J. (Andover, MA), Zheng; Wanjun (Londonberry, NH)
Assignee: Eisai Co., Ltd. (Tokyo, JP)
Application Number:09/334,488
Patent Claims: 1. A compound having the formula: ##STR157##

wherein A is a C.sub.1-6 saturated or C.sub.2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having between 1 and 10 substituents, inclusive, independently selected from cyano, halo, azido, oxo, and Q.sub.1 ;

each Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2 R.sub.1, OSO.sub.2 R.sub.1, NR.sub.2 R.sub.1, NR.sub.2 (CO)R.sub.1, NR.sub.2 (CO)(CO)R.sub.1, NR.sub.4 (CO)NR.sub.2 R.sub.1, NR.sub.2 (CO)OR.sub.1, (CO)OR.sub.1, O(CO)R.sub.1, (CO)NR.sub.2 R.sub.1, and O(CO)NR.sub.2 R.sub.1 ;

each of R.sub.1, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl, C.sub.6-10 aryl, C.sub.6-10 haloaryl, C.sub.6-10 hydroxyaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6-10 aryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 aryl, C.sub.6-10 haloaryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 haloaryl, (C.sub.1-3 alkoxy-C.sub.6 aryl)-C.sub.1-3 alkyl, C.sub.2-9 heterocyclic radical, C.sub.2-9 heterocyclic radical-C.sub.1-6 alkyl, C.sub.2-9 heteroaryl, and C.sub.2-9 heteroaryl-C.sub.1-6 alkyl;

each of D and D' is independently selected from R.sub.3 and OR.sub.3, wherein R.sub.3 is H, C.sub.1-3 alkyl, or C.sub.1-3 haloalkyl;

n is 0 or 1;

E is R.sub.5 or OR.sub.5 ;

G is O, S, CH.sub.2, or NR.sub.6 ;

each of J and J' is independently H, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; or J and J' taken together are .dbd.CH.sub.2 or --O-(straight or branched C.sub.1-5 alkylene)-O--;

Q is C.sub.1-3 alkyl;

T is ethylene or ethenylene, optionally substituted with (CO)OR.sub.7, where R.sub.7 is H or C.sub.1-6 alkyl;

each of U and U' is independently H, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; or U and U' taken together are .dbd.CH.sub.2 or --O-(straight or branched C.sub.1-5 alkylene)-O--;

X is H or C.sub.1-6 alkoxy;

each of Y and Y' is independently H or C.sub.1-6 alkoxy; or Y and Y' taken together are .dbd.O, .dbd.CH.sub.2, or --O-(straight or branched C.sub.1-5 alkylene)-O--; and

each of Z and Z' is independently H or C.sub.1-6 alkoxy; or Z and Z' taken together are .dbd.O, .dbd.CH.sub.2, or --O-(straight or branched C.sub.1-5 alkylene)-O--;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1, wherein each of D and D' is independently selected from R.sub.3, C.sub.1-3 alkoxy, and C.sub.1-3 haloalkyloxy.

4. The compound of claim 1, wherein R.sub.5 is selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl, C.sub.6-10 aryl, C.sub.6-10 haloaryl, C.sub.6-10 hydroxyaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6-10 aryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 aryl, C.sub.6-10 haloaryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 haloaryl, (C.sub.1-3 alkoxy-C.sub.6 aryl)-C.sub.1-3 alkyl, C.sub.2-9 heterocyclic radical, C.sub.2-9 heterocyclic radical-C.sub.1-6 alkyl, C.sub.2-9 heteroaryl, and C.sub.2-9 heteroaryl-C.sub.1-6 alkyl.

5. The compound of claim 1, wherein A comprises a C.sub.1-6 saturated or C.sub.2-6 unsaturated hydrocarbon skeleton, said skeleton having at least one substituent selected from cyano, halo, azido, oxo, and Q.sub.1 ;

each Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2 R.sub.1, OSO.sub.2 R.sub.1, NR.sub.2 R.sub.1, NR.sub.2 (CO)R.sub.1, and O(CO)NR.sub.2 R.sub.1 ;

n is 0;

G is O;

J and J' taken together are .dbd.CH.sub.2 ;

Q is methyl;

T is ethylene;

U and U' taken together are .dbd.CH.sub.2 ;

X is H;

each of Y and Y' is H; and

Z and Z' taken together are .dbd.O or .dbd.CH.sub.2.

6. The compound of claim 1, wherein each Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2 R.sub.1, OSO.sub.2 R.sub.1, NH(CO)R.sub.1, NH(CO)(CO)R.sub.1, and O(CO)NHR.sub.1 ;

each R.sub.1 is independently selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6 aryl, C.sub.6 haloaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6 aryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 aryl, C.sub.6 haloaryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 haloaryl, (C.sub.1-3 alkoxy-C.sub.6 aryl)-C.sub.1-3 alkyl, C.sub.2-9 heterocyclic radical, C.sub.2-9 heteroaryl, and C.sub.2-9 heteroaryl-C.sub.1-6 alkyl;

one of D and D' is methyl or methoxy, and the other is H;

n is 0;

G is O;

J and J' taken together are .dbd.CH.sub.2 ;

Q is methyl;

T is ethylene;

U and U' taken together are .dbd.CH.sub.2 ;

X is H;

each of Y and Y' is H; and

Z and Z' taken together are .dbd.O.

7. The compound of claim 6, wherein A has at least one substituent selected from hydroxyl, amino, azido, halo, and oxo.

8. The compound of claim 7, wherein A comprises a saturated hydrocarbon skeleton having at least one substituent selected from hydroxyl, amino and azido.

9. The compound of claim 8, wherein A has at least two substituents independently selected from hydroxyl, amino, and azido.

10. The compound of claim 8, wherein A has at least two substituents independently selected from hydroxyl and amino.

11. The compound of claim 8, wherein A has at least one hydroxyl substituent and at least one amino substituent.

12. The compound of claim 8, wherein A has at least two hydroxyl substituents.

13. The compound of claim 8, wherein A comprises a C.sub.2-4 hydrocarbon skeleton.

14. The compound of claim 8, wherein A comprises a C.sub.3 hydrocarbon skeleton.

15. The compound of claim 13, wherein A has an (S)-hydroxyl on the carbon atom alpha to the carbon atom linking A to the ring containing G.

16. The compound of claim 6, wherein A comprises a C.sub.1-6 saturated hydrocarbon skeleton having at least one substituent selected from hydroxyl and cyano.

17. The compound of claim 6, wherein Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2 R.sub.1, and OSO.sub.2 R.sub.1 where each R.sub.1 is independently selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6 aryl, C.sub.6 haloaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6 aryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 aryl, C.sub.6 haloaryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 haloaryl, and (C.sub.1-3 alkoxy-C.sub.6 aryl)-C.sub.1-3 alkyl.

18. The compound of the following structure ##STR158##

19. The compound of the following structure ##STR159##

and pharmaceutically acceptable salts thereof.

20. A method for identifying an agent that induces a sustained mitotic block in a cell after transient exposure of said cell to said agent, said method comprising the steps of:

(a) incubating a first cell sample with a predetermined concentration of a test compound for a time interval between that sufficient to empty the G.sub.1 population and that equivalent to one cell cycle;

(b) substantially separating said test compound from said first cell sample;

(c) incubating said first sample in media free of said test compound for a time interval sufficient to allow at least 80% of the cells released from the mitotic block induced by a highly reversible mitotic inhibitor to complete mitosis and return to the G.sub.1 phase; and

(d) measuring the percentage of transiently-exposed cells from step (c) that have completed mitosis and returned to the G.sub.1 phase.

21. The method of claim 20, further comprising the steps of:

(e) incubating a second sample of cells with a concentration of said test compound less than or equal to that used in step (a) for a time interval between that sufficient to empty the G.sub.1 population and that equivalent to one cell cycle;

(f) measuring the percentage of cells from step (e) that have completed mitosis and have returned to the G.sub.1 phase; and

(g) determining the relative reversibility of said test compound by relating the measurement of step (d) and the measurement of step (f).
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