Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-07-02
2001-06-26
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S481000, C540S597000, C546S189000, C546S208000, C546S221000, C546S223000, C546S226000
Reexamination Certificate
active
06252079
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel intermediates in the synthesis of camptothecin and related compounds, and to methods of synthesis of irenotecan and related compounds via a 4+1 radical annulation.
BACKGROUND OF THE INVENTION
As part of an antitumor screening program, Wall and coworkers identified the novel pyrrolo [3,4-b] quinoline alkaloid (S)-camptothecin in 1966. Wall, M. E., et al.,
J. Am. Chem. Soc.,
88, 3888 (1966); Carte, B. K., et al.,
Tetrahedron,
46, 2747 (1990). The chemical formula of (S)-camptothecin is provided below.
This compound had been isolated from the extracts of the camptotheca acuminata tree. In addition to its novel structure, camptothecin has two other unusual features: its quinoline nitrogen is not very basic, and its &agr;-hydroxy lactone is quite reactive. For a few years, camptothecin appeared to be an exciting lead compound for cancer chemotherapy. However, initial medical excitement waned because of the relative insolubility of camptothecin. Moreover, clinical trials of a water-soluble sodium salt derived by opening the lactone of camptothecin were abandoned because of unpredictable toxicity problems. The sodium salt is considerably less potent than camptothecin and its activity is now thought to result from lactonization to reform camptothecin in vivo. These observations delayed preclinical and clinical research of camptothecin and its analogs for 20 years.
However, oncological and medicinal interest in camptothecin was reborn in the mid 80s when details about the unique mechanism of action of camptothecin and its analogs began to unfold. Camptothecin acts on DNA through the intermediacy of the enzyme topoisomerase I. See Kaufman, S. H., et al.,
J. Nat'l. Cancer Inst,
85, 271 (1993); Hsiang, Y. H., et al.,
J. Biol. Chem.
260, 14873 (1985); Hsiang, Y. H. and Liu, L. F.,
Cancer Res.,
48, 1722 (1988); Liu, L. F.,
Annu. Rev. Biochem.,
58, 351 (1989); “Chemotherapy: Topoisomerases as Targets,”
Lancet,
335, 82 (1990). The topoisomerases solve topological problems of DNA. Human topoisomerase I (100 kd) catalyzes the relaxation of supercoiled DNA by cleaving a single phosphodiester bond to form a temporary phosphoryl tyrosine diester. This intermediate is called the “cleavable complex.” The other end of the cleaved strand is free, and can “unwind” before the DNA chain is resealed by reverse of the original reaction. Topoisomerase I acts without cofactors, its reactions are fully reversible, and it is thought to be especially important for unwinding DNA (thermodynamically favorable) during replication. In contrast, topoisomerase II acts by cleaving and resealing (after strand passage) both strands of DNA, and its reactions are coupled with ATP hydrolysis.
There is now very strong evidence that camptothecin kills cells by binding to and stabilizing the covalent DNA-topoisomerase I complex in which one strand of DNA is broken (the cleavable complex). The progression from the ternary camptothecin/topoisomerase I/DNA complex to cell death is not well understood, and is the subject of intense investigation. Several lines of evidence (including the complete reversibility of ternary complex formation) indicate that the ternary complex does not simply tie up DNA, but itself actively initiates cell death. For this reason, camptothecin is often called a “topoisomerase poison.”
Until very recently, camptothecin and its close relatives were the only known topoisomerase I poisons. In contrast, there are now many known antitumor agents that are topoisomerase II poisons. These include large classes of intercalators like the acridines and anthracyclines that were originally thought to interact only with DNA. Such topoisomerase II poisons may be inherently less selective than camptothecin because their interactions with DNA do not require topoisomerase II. Important non-intercalative topoisomerase II poisons include members of the podophyllotoxin class.
Camptothecin is being touted as an unusually important lead in cancer chemotherapy because of its selectivity. The (potential) selective toxicity of camptothecin towards cancer cells emanates from two sources: 1) camptothecin is highly selective for the DNA/topoisomerase I cleavable complex, and 2) replicating cancer cells contain elevated levels of topoisomerase I (15-fold increases over normal cells have recently been measured).
New interest resulting from the identification of camptothecin's mechanism of action has initiated (i) structure-activity relationship studies and (ii) a new series of clinical trials. Recent tests in xenografts by Potmesil and coworkers were very promising. See Giovanella, B. C., et al.,
Science,
246, 1046 (1989). Racemic 9-aminocamptothecin was found to be very effective in treating mice carrying colon cancer xenografts. Indeed most of the mice in the study were cured by 9-aminocamptothecin at dose levels that were well tolerated. The improved efficacy of 9-aminocamptothecin compared to current drugs used in colon cancer chemotherapy (like 5-fluorouracil) was dramatic. 10,11-Methylenedioxycamptothecin also showed very good promise. The significance of these results is very high. Human colon cancer is a major problem in clinical oncology, and one in twenty-five Americans will develop this disease during their lifetime.
More recently, other close relatives (analogs) of camptothecin have also emerged as excellent candidates for chemotherapy against a variety of tumor types. In an attempt to overcome the problem of low solubility encountered earlier with camptothecin, most of such compounds are designed to be water-soluble. Several of these compounds are undergoing clinical trials. See Sinha, B. K.,
Drugs,
49, 11 (1995). Pommier, Y. et al.,
J. Natl. Cancer Inst.,
86, 836 (1994). Potmesil, M.
Cancer Res.,
54, 1431 (1994). Curran, D. P., “The Camptothecins: A Reborn Family of Antitumor Agents,”
J. of the Chinese Chem. Soc.,
40, 1-6 (1993), the disclosure of which is incorporated herein by reference. See also Sawada, S.,
Chem. Pharm. Bull.,
39, 1446 (1991); Giovanella, B. C., et al.,
Science
(Washington, D.C.), 246, 1046 (1989); Kingsbury, W. D., et al.;
Med. Chem.,
34, 98 (1991); Sawada, S., et al.;
Chem. Pharm. Bull.,
39, 1446 (1991), Nicholas, A. W., et al.
J. Med. Chem.
33, 972 (1991).
Such compounds, for example, include topotecan (often called TPT), currently undergoing phase III studies, and irinotecan (often called CPT-11), currently approved for sale in France, Japan and the U.S. See Abigerges, D., et al.,
J. Clin. Oncol.,
13, 210 (1995). Potmesil, M.,
Cancer Res.,
54, 1431 (1994). Miller, A. et al.,
J. Clin. Oncol.,
12, 2743 (1994). Fukuoka, M. et al.,
Canc. Chemotherap. Pharmacol.,
34, 105 (1994). Shimada, Y. et al.,
J. Clin. Oncol.,
11, 909 (1993). Another analog, 10,11-ethylenedioxy-7-(4-methylpyrazino)-camptothecin, has been recently introduced by Glaxo and is now in clinical trials. See Eur. Pat. Appl. EP 540,099 (Cl. C07D491/22), May 5, 1993, U.S. application Ser. No. 784,275, Oct. 29, 1991. Luzzio, M. J. et al.,
J. Med. Chem.,
38, 395 (1995). See also Wall, M. E. et al.,
J. Med. Chem.,
36, 2689 (1993). The results of these recent trials suggest that these compounds hold excellent promise for the clinical treatment of a number of types of refractory solid tumors.
Moreover, recent trials using new formulations have recently opened new opportunities for camptothecin derivatives previously dismissed for their poor water solubility. In this regard, it has been discovered that (i) (S)-camptothecin itself can be formulated in 20% interlipid, and (ii) this formulation is active both intramuscularly and orally. These treatments were found far superior to previous intravenous treatments. With this formulation, non-toxic doses of camptothecin suppressed growth and induced regression of cancer in thirteen human xenograft lines, including colon, lung, breast, stomach, ovary, and malignant melanoma. Camptothecin was more effective than any other clinical drug tested. See Giovanella, B. C. et al.
Bom David
Curran Dennis P.
Bartony & Hare
Berch Mark L.
University of Pittsburgh
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