Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-27
2004-04-20
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S295000, C546S301000, C514S280000, C514S283000
Reexamination Certificate
active
06723853
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods of preparation of homocamptothecins and intermediates therefor and, particularly, to methods and intermediates for the enantioselective synthesis (20R)-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.
In general, camptothecins and homocamptothecins as illustrated in
FIG. 1
(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 frequently have one or more substituents in place of hydrogen in the A and/or B rings at carbons 7, 9, 10, and/or 11. These analogs 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).
Recently, Lavergne et al. have shown that expansion of the E-ring of camptothecin to produce a homocamptothecin (hcpt) enhances the solution stability of camptothecin while maintaining anticancer activity. U.S. Pat. No. 5,981,542; PCT International Patent Application No. PCT/FR00/00461; Lavergne, O., et al.,
J. Med. Chem.,
41, 5410-5419 (1998); and Lavergne, O., et al.,
Bioorg. Med. Chem. Lett.,
7, 2235-2238 (1997). Once again, many of the most important compounds in this class have one or more substituents on rings A and/or B. For example, 10,11-difluorohomocamptothecin is in early stage clinical trials.
7-Silyl camptothecins and 7-silyl homocamptothecins (sometimes referred to as silatecans and homosilatecans) are important classes of lipophilic camptothecin and homocamptothecin analogs, See, for example, a) Josien, H., et al.,
Bioorg. Med. Chem. Lett.,
7, 3189 (1997); b) Pollack, I. F.; et al.,
Cancer Research,
59, 4898 (1999); Bom, D., et al.,
Clinical Cancer Research,
5, 560 (1999); Bom, D., et al.,
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 mono-substituted analogs. For example, DB-67, or 7-tert-butyldimethylsilyl-10-hydroxycamptothecin, is highly active against cancer cells and tumors and possesses many favorable physical and pharmacological properties. Silatecans and homosilatecans in general 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.
Camptothecins, silatecans, homocamptothecins and homosilatecans (referred to herein generally as “camptothecins” and “homocamptothecins”) have been prepared using cascade radical annulation routes. See, for example, U.S. Pat. Nos. 6,136,978, 6,150,343, 6,207,832 and 6,211,371, Curran, D. P, et al.,
Angew. Chem., Int. Ed. Eng.,
34, 2683 (1995) and Josien, H., et al.,
Chem. Eur. J.,
4, 67 (1998). Those total synthetic routes are highly flexible and allow the preparation of a diverse array of, for example, silatecan and homosilatecan analogs by both traditional and parallel routes. In that regard, substantially any substituent can be placed on, for example, the A- or B-ring of the camptothecin structure using those synthetic routes.
The cascade radical annulation route to homocamptothecins and homosilatecans is summarized in
FIG. 2
a
. The key iodopyridone 12 is first N-propargylated with a propargyl bromide 13 and the resulting intermediate 14 is next reacted with an aryl isonitrile 15 under the conditions of cascade radical annulation. The substituent on the propargyl bromide (R
B
) becomes the B-ring substituent at C7 while the substituent(s) on the isonitrile (R
A
) become(s) the A-ring substituents. In this way, many different homocamptothecins and homosilatecans 16 can be made from a single key intermediate 12. In turn, 12 is made from
10
a
by the steps of iododesilylation and demethylation.
In the Lavergne route to homocamptothecins (
FIG. 2
b
), compound 11 is alkylated with a bromomethyl quinoline 17 followed by Heck type cyclization. Accordingly, compounds of the structures 10-12 and their relatives are crucial intermediates in the synthesis of homocamptothecins, homosilatecans, and analogs.
Unfortunately, current syntheses of compounds 10-12 are racemic synthesis, requiring subsequent resolution of the active enantiomer. These resolutions add extra steps and are wasteful because the undesired enantiomer (50% of the mixture) must be discarded.
It is thus very desirable to develop enantioselective synthetic routes and intermediate compounds for use therein for the synthesis of biologically active (20R)-homocamptothecins.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides generally methods of synthesis of compounds of the formula:
from readily available compounds of the formula (IV):
wherein R
1
is, for example, hydrogen, fluorine, chlorine or SiR
5
R
6
R
7
wherein R
5
, R
6
, and R
7
are independently the same or different an alkyl group (preferably a lower alkyl group) or an aryl group. R
2
is an alkyl group (preferably, a lower alkyl group). R
3
is a protecting group (for example, acetate, methoxymethyl or tert-butyldimethylsilyl). R
4
is an alkyl group (preferably, a lower alkyl group), an allyl group, a propargyl group or a benzyl group. X
4
is H, Cl, Br or I.
Preferred embodiments of the compound of formula (I) for use in the synthetic methods of the present invention include those in which R
1
is H or a trimethylsilyl group, R
2
is a lower alkyl group, R
3
is a methoxymethyl group, and R
4
is an ethyl group.
In one embodiment, a nucleophilic organometallic species of the formula (IVa):
is produced by converting X
4
of the compound of formula (IV) to a metal or a metal-containing group X
5
(referred to herein collectively as a “metal-containing group”—for example Li, CuCN, MgBr or MgI). The nucleophilic organometallic species is generated either by deprotonation (in the case that X
4
is H) or halogen metal exchange (in the case that X
4
is Cl, Br or I). If desirable, the initial metal-containing group can be exchanged for another by transmetallation. Preferred metals for metalation or transmetalation to generate nucleophiles have a Pauling electronegativity less than or equal to about 1.9, and more preferred metals have a Pauling electronegativity less than or equal to about 1.6. Examples of preferred metals include lithium, sodium, potassium, cesium, magnesium, titanium, chromium, zirconium, copper, and aluminum. Even more preferred metals are lithium, magnesium and copper.
The resultant nucleophilic species is reacted with a suitable electrophile to effect direct or indirect acylation to the compound of formula (I). One example of a direct acylation is the reaction of the nucleophile with an acid chloride R
4
C(O)Cl or with a so-called “Weinreb” amide having the formula R
4
C(O)N(Me)OMe. An example of an indirect acylation is the reaction of the nucleophile with an aldehyde having the formula R
4
CHO to effect hydroxyalkylation. The resultant alcohol is then oxidized to the compound of formula (I). Many methods for acylation of nucleophiles suitable for use in the present invention are known to those skilled in the art.
In another embodiment, the Stille coupling reaction is used to effect reaction of the compound of formula (IV) wherein X
4
is Cl, Br or
Curran Dennis P.
Gabarda Ana E.
Bartony & Hare, LLP
Chang Ceila
Coppins Janet L
University of Pittsburgh
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