Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-28
2004-12-28
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S018000, C514S278000
Reexamination Certificate
active
06835736
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to discorhabdin compounds and compositions which have useful therapeutic properties. More particularly, the invention provides discorhabdin compounds having antitumor activities, pharmaceutical compositions comprising such compounds, methods for the preparation of the compounds, and compositions and methods of their use.
BACKGROUND OF INVENTION
Various tumor and cancer related diseases afflict animals, including humans. The term “tumor” refers to abnormal masses of new tissue growth which is discordant with the the tissue of origin or of the host's body as a whole. Tumors inflict animals with a variety of disorders and conditions, including various forms of cancer. The seriousness of cancer is well known, e.g. cancer is second only to heart and vascular diseases as a cause of death in man. Cancer is common in a variety of animals, and the prevention and control of the growth of tumors is important to man.
Considerable research and resources have been devoted to oncology and anticancer measures, including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling unwanted cellular proliferation, further anticancer methods and chemical compositions are needed.
It has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activities. For example, the diterpene commonly known as paclitaxel (Taxol®), isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978
] Cancer Treat. Rep
. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [19791
] Nature
(London) 22:665-667). Taxol® is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995
] N. Engl. J. Med
. 332:1004-1014). See also, e.g. U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine life has been the source for the discovery of compounds having varied biological activities. Some of the United States patents which have issued for such inventions are as follows: U.S. Pat. No. 4,548,814 for didemnins, having antiviral activity, were isolated from a marine tunicate; U.S. Pat. No. 4,729,996 discloses compounds, having antitumor properties, that were isolated from marine sponges
Teichaxinella morchella
and
Ptilocaulis walpersi
; U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp.; and U.S. Pat. No. 4,737,510 discloses compounds, having antiviral and antibacterial properties, isolated from the Caribbean sponge
Agelas coniferin.
A number of publications disclose organic compounds derived from marine sponges including Scheuer, P. J. (ed.)
Marine Natural Products, Chemical and Biological Perspectives
, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985)
J. Am. Chem. Soc
. 107:4796-4798; Minale, L. et al. (1976)
Fortschr. Chem. org. Naturst
. 33:1-72; Faulkner, D. J. (2002)
Natural Products Reports
19:1-48; Gunasekera, S. P., M. Gunasekera, R. E. Longley and G. K. Schulte (1990) “Discodernolide: A new bioactive polyhydroxy lactone from the marine sponge
Discodermia dissoluta” J. Org. Chem
., 55:4912-4915 [correction (1991)
J. Org. Chem
. 56:1346]; Hung, Deborah T., Jenne B. Nerenberg, Stuart Schreiber (1994) “Distinct binding and cellular properties of synthetic (+)- and (−) discodermolides”
Chemistry and Biology
1:67-71; Hung, Deborah T., Jie Cheng, Stuart Schreiber (1996) (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks Taxol binding and results in mitotic arrest”
Chemistry and Biology
3:287-293; Nerenberg, Jennie B., Deborah T. Hung, Patricia K. Somers, Stuart L. Schreiber (1993) “Total synthesis of immunosuppressive agent (−)-discodemolide”
J. Amer. Chem. Soc
. 115:12621-12622; Smith III, Amos B., Yuping Qiu, David R. Jones, Karoru Kobayashi (1995) “Total synthesis of (−) discodernolide”
J. Amer. Chem. Soc
. 117:12011-12012; Harried, Scott H., Ge Yang, Marcus A. Strawn, David C. Myles (1997) “Total synthesis of (−)-discodermolide: an application of a chelation-controlled alkylation reaction”
J. Org. Chem
. 62:6098-6099; Balachandran, R., ter Haar, E., Welsh, M. J., Grant, S. G., and Day, B. W. (1998) “The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells-preliminary comparisons to paclitaxel.”
Anticancer Drugs
9: 67-76 and references cited therein. U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp. (International Patent Application No. WO 9824429; Kowalski, R. J., P. Giannakakou, S. P. Gunasekera et al. (1997)
Mol. Pharmacol
52:613-622; ter Haar, E., R. J. Kowalski, E. Hamelet al. (1996)
Biochemistry
35:243-250; Stafford, J. A. and M. M. Mehrotra (1995)
Chemtract: Org. Chem
. 8:41-47; and U.S. Pat. No. 5,789,605.
Discorhabdin compounds have been produced from marine sponges as disclosed in U.S. Pat. Nos. 4,731,366; 4,874,767; and 6,057,333 and have been discussed in various publications including: Perry, N. B. et al. (1986)
J. Org. Chem
. 51:5476; Blunt, J. W. et al. (1987)
J. Nat. Prod
. 50:290; Munro, M. H. G. et al. (1987)
Bioorganic Marine Chemistry
, Scheuer, P. J., Ed., Verlag Chemie: Heidelberg, Vol. 1, Chapter 4; Kobayashi,
J. et al
. (1987)
Tetrahedron Letters
28:4939; Perry, N. B. et al. (1988)
Tetrahedron Letters
44:1727; Perry, N. B. et al. (1988)
J. Org. Chem
. 53:4127; and Cheng et al. (1988)
J. Org. Chem
. 53:4610.
The previously known discorhabdins (A→R), have an iminoquinone and a spiro-enone or spiro-dienone system, and are believed to be formed by the combination of a molecule of substituted tyrosine and a molecule of tryptamine.
The present invention, utilizing sponges as a source material, provides the art with new biologically active compounds and new pharmaceutical compositions useful for the control of unwanted cellular proliferation as antitumor agents. The present invention has added to the arsenal of phrmaceutical compounds by the discovery of novel compounds isolatable from extracts of marine sponges of the family Desmacididae.
BRIEF SUMMARY
The subject invention provides discorhabdin compounds having advantageous biological activities. Specifically, in one embodiment, the discorhabdin compounds and compositions of the subject invention can be used in the treatment of an animal (including humans) hosting cancer cells, including, for example, inhibiting the growth of tumor cells in a mammalian host. More particularly, the subject compounds can be used for inhibiting in a human the growth of tumor cells, including cancer cells of the pancreas, breast, colon, CNS, ovarian, renal, prostrate, lung, leukemia and melanoma cells.
Also provided according to the subject invention are compositions containing the biologically active discorhabdin compounds, as well as methods for the preparation and use of the compounds and compositions.
Other advantages and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.
REFERENCES:
patent: 4206221 (1980-06-01), Miller et al.
patent: 4548814 (1985-10-01), Rinehart, Jr.
patent: 4729996 (1988-03-01), Wright et al.
patent: 4731366 (1988-03-01), Munro et al.
patent: 4737510 (19
Gunasekera Sarath P.
Longley Ross E.
Pomponi Shirley A.
Wright Amy E.
Desai Rita
Harbor Branch Oceanographic Institution Inc.
Saliwanchik Lloyd & Saliwanchik
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