Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-02-17
2001-04-10
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S510000
Reexamination Certificate
active
06214814
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the use of betulinic acid and its derivatives for the inhibition and/or prevention or cancer growth. The invention also relates to novel betulinic acid derivatives useful for the inhibition of tumor/cancer cells and a process for the preparation of the derivatives. The invention also relates to the antileukemic, and anti-lymphoma activity of the betulinic acid derivatives, and the use of the derivatives for the treatment of prostate, ovarian and lung cancer.
BACKGROUND AND PRIOR ART REFERENCES TO THE INVENTION
Under the auspices of a National Cooperative Natural Product Drug Discovery Group supported by the National Cancer Institute, the potential antitumor activity of approximately 2500 extracts derived from globally collected plants was evaluated in a panel of enzyme based assays and in a battery of cultured human tumor cell lines. One such extract, prepared from the stem bark of
Ziziphus mauritiana
Lam. (Rhamnaceae), displayed selective cytotoxicity against cultured human melanoma cells (Nature Medicine, Vo. 1 (10), 1995, WO 96/29068). As a result of bioactivity guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with a thymic mice carrying human melanomas, tumor growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumor activity was mediated by the induction of apoptosis.
A number of triterpenoids, including betulinic acid, have several known medical applications, including use as anticancer drugs. Anderson et al., in WO 95/04526, have discussed the derivatives of triterpenoids which have been used in cancer therapy, including their activity against polyamines which are required by cells to grow at an optimal rate. Some of these triterpenoids have been found to interfere with enzymatic synthesis of polyamines required for optimal cell growth, and thus inhibit the growth of cancer cells, particularly by inhibiting ornithine decarboxylase (Yasukawa, K. et al., Oncology 48: 72-76, 1991), The anti-cancer activity of betulinic acid and some derivatives has been demonstrated using mouse sarcoma 180 cells implanted subcutaneously in nude mice (JP 87,301,580). Choi et al have shown that betulinic acid 3-monoacetate, and betulinic acid methyl ester exhibit ED
50
values of 10.5 and 6.8 &mgr;g/ml, respectively, against p388 lymphocytic leukemia cells (Choi, Y-H et al., Planta Medical vol. XLVII, pages 511-513, 1988).
Derivatives having ED
50
values greater than 4.0 &mgr;g/ml are considered not to have any significant anticancer activity. Table 1 indicates anticancer activity (ED
50
values) of a number of betulinic acid derivatives.
SUMMARY OF THE INVENTION
The present invention provides betulinic acid derivatives, compositions comprising betulinic acid derivatives, use of the betulinic acid derivatives for killing or inhibiting multiplication of cancer cells, a process for the synthesis of the derivatives of betulinic acid and testing the bio-activity of the derivatives using cultured human leukemia (MOLT-4, Jurkat E6.1, HL60, CEM.CM3), lymphoma cells (BRISTOL-8, U937), prostate cancer cells (DU 145), lung cancer cells (A 549) and ovarian cancer cells (PA-1) as the monitor.
In a preferred embodiment, a pharmaceutically acceptable carrier, diluent, or solvent is used. The invention also provides a method of treatment for humans, mammals, or other animals suffering from cancer or other tumors. The method may suitably comprise administering a therapeutically effective dose of the derivative in a pharmaceutical composition so as to kill or inhibit the multiplication of cancer or tumor cells. The method of treatment of the present invention is particularly useful in the treatment of leukemias and lymphomas, and in general in the treatment of prostate, ovarian and lung cancer.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a method and composition for inhibiting tumor growth and, particularly, for inhibiting the growth of leukemias and lymphomas and for inhibiting the growth of prostate, ovarian and lung cancer using betulinic acid, one or more betulinic acid derivatives or a combination thereof.
A further object of the invention is to provide a treatment method using at least one betulinic acid derivative to prevent the growth of cancerous cells, preferably the betulinic acid derivative is administered systematically.
A still further object of the invention is to provide betulinic acid derivatives and a process for producing such derivatives.
Yet another object of the invention is to provide pharmaceutical formulations containing betulinic acid derivatives alone or in combination.
Still another object of the invention is to overcome the problem of high toxicity associated with standard chemotherapeutic agents by using a natural product-derived compound, e.g., betulinic acid derivatives.
Yet another object of the invention is to overcome the problem of insufficient availability associated with synthetic anticancer agents by using synthetic derivatives of betulinic acid.
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Hashimoto et al., Bioorg. Med. Chem., vol. 5(12), 1997, pp. 2133-2143, 1994.*
Fujioka et al., Journal of Natural Products, vol. 57(2), pp. 243-247, 1994.*
Hashimoto et al, Bioorg. Med. Chem., vol. 5(12), pp. 2133-2143, 1997.*
Konoshima et al., Journal of Natural Products, vol. 50(6), pp. 1167-1170, 1987.
Ahmed Siddiqui Mohammad Jamshed
Jaggi Manu
Khanna Achla B.
Ramadoss Sunder
Badio Barbara P.
Dabur Research Foundation
Ladas & Parry
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