Synthesis of silyl camptothecins and silyl homocamptothecins

Details Synthesis of silyl camptothecins and silyl homocamptothecins Synthesis of silyl camptothecins and silyl homocamptothecins

2001-04-12

2002-04-16

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S048000

Reexamination Certificate

active

06372906

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the synthesis of silyl camptothecins and silyl homocamptothecins and, particularly, to synthesis of silyl camptothecins and silyl homocamptothecins via a semisynthetic route from camptothecins and homocamptothecins.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
The structure of camptothecin 1a and homocamptothecin 10a are illustrated in FIG.
1
. The core structure of the camptothecin class of molecules has five fused rings, A-E. Standard substituents include hydroxyl and ethyl at C20, and other positions of the camptothecin ring core can also be substituted. Homocamptothecin has the same A-D rings as camptothecin, but the E-ring contains an additional methylene group (C20a). The A-B ring system of the camptothecin and homocamptothecin is a quinoline, and this part of the ring system is especially important since substituents in the quinoline part of the molecule often impart useful properties, as detailed below.
In general, camptothecins and homocamptothecins (sometimes referred to generally herein as camptothecins or the camptothecin family) are DNA topoisomerase I inhibitors useful, for example, as anticancer drugs. Analogs of the natural product camptothecin are among the most important classes of compounds available for treatment of solid tumors. Topotecan (tpt) and CPT-11 were the first two members in the camptothecin family to gain United States Food and Drug Administration full approval status (topotecan in 1996 as second-line therapy for advanced epithelial ovarian cancer, topotecan again in 1998 for the treatment of small cell lung cancer, CPT-11 in 1998 as first-line therapy for colon cancer).
Lavergne et al. have shown that expansion of the E-ring of camptothecin to produce a “homocamptothecin” enhances the solution stability of camptothecin while maintaining anticancer activity. Lavergne, O., Lesueur-Ginot, L., Rodas, F. P., Kasprzyk, P. G., Pommier, J., Demarquay, D., Prevost, G., Ulibarri, G., Rolland, A., Schiano-Liberatore, A.-M., Harnett, J., Pons, D., Camara, J., Bigg, D., “Homocamptothecins: Synthesis and Antitumor Activity of Novel E-Ring Modified Camptothecin Analogs”, J. Med. Chem., 41, 5410-5419 (1998); and Lavergne, O., Lesueur-Ginot, L., Rodas, F. P., and Bigg, D., “An E-Ring Modified Camptothecin With Potent Antiproliferative and Topoisomerase I Inhibitory Activities,” Bioorg. Med. Chem. Lett. 7, 2235-2238 (1997). The modification to the E-ring in the studies of Lavergne et al. involved insertion of a methylene spacer between the carbon bearing the 20-OH functionality and the carboxyl group of the naturally occurring six-membered &agr;-hydroxylactone of camptothecin. Incorporation of the new 7-membered &bgr;-hydroxylactone ring into camptothecin has been found to improve the solution stability of the agent. Despite the structural similarity to camptothecins, homocamptothecins behave very differently under physiological conditions. In general, standard camptothecin analogs are dynamic drugs because their lactone rings open rapidly and reversibly under physiological conditions. Typically, the lactone rings of homocamptothecins open comparatively slowly and irreversibly.
7-Silyl camptothecins 2 and 7-silyl homocamptothecins 11 (sometimes referred to as silatecans and homosilatecans) as illustrated in
FIG. 1
are important classes of lipophilic camptothecin analogs, See, for example, a) Josien, H.; Bom, D.; Curran, D. P.; Zheng, Y.-H.; Chou, T.-C. Bioorg
Med. Chem. Lett
., 7, 3189 (1997); b) Pollack, I. F.; Erff, M.; Bom, D.; Burke, T. G.; Strode, J. T.; Curran, D. P.
Cancer Research
, 59, 4898 (1999); Bom, D.; Du, W.; Garbarda, A.; Curran, D. P.; Chavan, A. J.; Kruszewski, S.; Zimmer, S. G.; Fraley, K. A.; Bingcang, A. L.; Wallace, V. P.; Tromberg, B. J.; Burke, T. G.
Clinical Cancer Research
, 5, 560 (1999); Bom, D.; Curran, D. P.; Chavan, A. J.; Kruszewski, S.; Zimmer, S. G.; Fraley, K. A.; Burke, T. G.
J. Med. Chem
., 42, 3018 (1999). Many of the most interesting silatecans and homosilatecans contain one or more additional substituents (for example, hydroxy or amino) in the A ring, and the combination of these substituents can provide significant improvements over either of the corresponding the mono-substituted analogs. For example, 7-tert-butyldimethylsilyl-10-hydroxy camptothecin 2a (DB-67), is currently in late stages of preclinical development. DB-67 and other silatecans and homosilatecans show a number of attractive features including high activity against a broad spectrum of solid tumors, low binding to blood proteins, resistance to lactone opening, high lipophilicity, and potential oral availability among others.
DB-67 and other silatecans and homosilatecans have been prepared by total synthesis using the cascade radical annulation routes. See, for example, U.S. patent application Ser. Nos. 09/007,872, 09/212,178 and 09/209,019, U.S. Pat. Nos. 6,150,343 and 6,136,978, Curran, D. P.; Ko, S. B.; Josien, H.
Angew. Chem., Int. Ed. Eng
, 34, 2683 (1995) and Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P.
Chem. Eur. J
., 4, 67 (1998). Those total synthetic routes are highly flexible and allow the preparation of a diverse array of silatecan and homosilatecan analogs by both traditional and parallel routes. However, the total synthesis of silatecans and homosilatecans via cascade radical annulation can require thirteen or more steps and proceeds in about 2% overall yield.
It is very desirable to develop improved synthetic routes for producing silyl camptothecins and silyl homocamptothecins.
SUMMARY OF THE INVENTION
The present invention provides semisynthetic routes to the synthesis of silyl camptothecins and silyl homocamptothecins from camptothecins and homocamptothecins by addition of silyl radicals thereto.
In one aspect, the present invention provides a method of synthesizing a compound having the formula
in racemic form, enantiomerically enriched form or enantiomerically pure form, the method including generally the step of reacting a compound having the formula
with a silyl radical precursor under conditions to generate a silyl radical. SiR
1
R
2
R
3
wherein R
1
, R
2
and R
3
are, for example, independently the same or different a C
1-10
alkyl group, a C
2-10
alkenyl group, a C
2-10
alkynyl group, an aryl group, —(CH
2
)
m
R
11
, or SiR
12
R
13
R
14
, wherein m is an integer within the range of 1 through 10 and R
11
is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, Cl, F, a cyano group, —SR
c
or a nitro group, and wherein R
12
, R
13
and R
14
are independently the same or different an alkyl group or an aryl group. Preferably R
1
, R
2
and R
3
are independently the same or different an alkyl group or an aryl group.
R
4
and R
5
are, for example, independently the same or different hydrogen, —C(O)R
f
wherein R
f
is an alkyl group, an alkoxy group, an amino group or a hydroxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, —OC(O)OR
d
, wherein R
d
is an alkyl group, —OC(O)NR
a
R
b
wherein R
a
and R
b
are independently the same or different, H, —C(O)R
f
, an alkyl group or an aryl group, Cl, F, a hydroxy group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an amino group, —SR
c
, wherein R
c
is hydrogen, —C(O)R
f
, an alkyl group or an aryl group; or R
4
and R
5
together form a chain of three or four members selected from the group of CH, CH
2
, O, S, NH, or NR
15
, wherein R
15
is a C
1
-C
6
alkyl group. R
4
and R
5
together can, for example, form a group of the formula —O(CH
2
)
j
O— wherein j represents the integer 1 or 2.
R
6
is, for example, H, Cl, F, a nitro group, an amino group, a hydroxy group, or a cyano group; or R
5
and R
6
together form a

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