Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-08
2001-04-17
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S427000, C548S469000, C548S494000, C548S511000, C548S516000
Reexamination Certificate
active
06218419
ABSTRACT:
FIELD OF THE INVENTION
The subject invention pertains to novel compounds which can be used as anti-inflammatory, immunomodulatory, neuroprotective, and anti-cancer agents, and to compositions containing such compounds as active ingredients. More particularly, the invention concerns novel biologically active tryptamine-derived aminoquinone and aminoiminoquinone alkaloid compounds, pharmaceutical compositions containing these compounds, uses thereof, and methods of producing the compounds.
BACKGROUND OF THE INVENTION
The prevention and control of inflammation is of prime importance to the maintenance of human and animal health, and much research has been devoted to development of compounds having anti-inflammatory properties. Certain methods and chemical compositions have been developed which aid in inhibiting or controlling inflammation, but additional anti-inflammatory methods and compositions are needed.
Also of great importance to the maintenance of good health is the control of pathological cellular proliferation such as that which occurs in the case of cancer. Considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and anti-cancer compositions are needed.
A further area of great significance in human and animal health care is immunomodulation. Immunomodulator compounds and compositions, are useful for modulating or regulating immunological functions in animals. Immunomodulators may be immunostimulants for building up immunities to, or initiate healing from, certain diseases and disorders. Conversely, immunomodulators may be immunoinhibitors or immunosuppressors for preventing undesirable immune reactions of the body to foreign materials, or to prevent or ameliorate autoimmune reactions or diseases.
Immunomodulators have been found to be useful for treating systemic autoimmune diseases, such as lupus erythematosus and diabetes, as well as immunodeficiency diseases. Further, immunomodulators may be useful for immunotherapy of cancer or to prevent rejections of foreign organs or other tissues in transplants, e.g., kidney, heart, or bone marrow.
Various immunomodulator compounds have been discovered, including FK506, muramylic acid dipeptide derivatives, levamisole, niridazole, oxysuran, flagyl, interferons, interleukins, leukotrienes, corticosteroids, and cyclosporins. Many of these compounds have been found, however, to have undesirable side effects and/or high toxicity. New immunomodulator compounds are therefore needed to provide a wider range of immunomodulator function for specific areas with a minimum of undesirable side effects.
It has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activities. Marine sponges have proved to be such a source, and a number of publications have issued disclosing organic compounds derived from marine sponges. Such publications include Scheuer, P. J., Ed. (1978-1983)
Marine Natural Products, Chemical and Biological Perspectives,
Academic Press, New York; Faulkner,D. (1998)
J. Nat. Prod. Rep.
15:113-158;(1997)
J. Nat. Prod. Rep.
14:259-302; (1996)
J. Nat. Prod. Rep.
13:75-125; (1995)
J. Nat. Prod. Rep.
12:223-269; (1994)
J. Nat. Prod. Rep.
11:355-394;(1993)
J. Nat. Prod. Rep.
10:497-539;(1992)
J. Nat. Prod. Rep.
9:323-364; (1991)
J. Nat. Prod. Rep.
8:97-147; (1990)
J. Nat. Prod. Rep.
7:269-309; (1988)
J. Nat. Prod. Rep.
5:613-663; (1987)
J. Nat. Prod. Rep.
4:539-576;(1986)
J. Nat. Prod. Rep.
3:1-33;(1984)
J. Nat. Prod. Rep.
1:551-598;and Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985)
J. Am. Chem. Soc.
107:4796-4798.
Utilizing sponges as a source material and supplemented by novel synthetic production methods, new classes of biologically active compounds and new pharmaceutical compositions have been provided to the art. However, as noted above, there is a great need for additional compounds useful in treating a variety of pathological conditions.
BRIEF SUMMARY OF THE INVENTION
The subject invention concerns tryptamine-derived aminoiminoquinone and aminoquinone alkaloid compounds. Specifically exemplified herein are secobatzellines A and B, as well as compositions containing these compounds. Further aspects of the subject invention pertain to methods of preparation and use of the compounds.
In one preferred embodiment the compounds of the subject invention are useful as inhibitors of biologically important enzymes associated with inflammatory and neurodegenerative processes. The ability of the compounds of the subject invention to inhibit caspase (CPP32) makes these compounds useful in the treatment of a variety of chronic and acute inflammatory diseases including, but not limited to, pancreatitis, rheumatoid arthritis, osteoarthritis, asthma, inflammatory bowel disease, psoriasis and in certain neurological disorders such as Alzheimer's disease.
In a second preferred embodiment, compounds of the subject invention can be used to inhibit pathological cellular proliferation such as that which is associated with cancer. In a further embodiment, the compounds of the subject invention have been found to be useful in immune modulation and, more specifically, immune suppression.
Secobatzelline A (aminoiminoquinone alkaloid) has some structural similarities to the previously known isobatzellines A-D, a class of compounds which has a carbon skeleton of pyrrolo[4,3,2,-de] quinoline derived aminoiminoquinone. However, secobatzelline A possesses an unusual pyrroloaminoiminoquinone with a secoquinoline skeleton system not previously reported from a natural source. Secobatzelline A has shown strong biological activity against the CPP32 enzyme with an IC
50
value of 0.02 &mgr;g/ml and significant anti-cancer activity against P388 murine leukemia (IC
50
=0.06 &mgr;g/ml) and A549 human lung adenocarcinoma (IC
50
=0.04 &mgr;g/ml). Secobatzellines A and B can be isolated from marine sponges of the genus Batzella as described herein.
REFERENCES:
patent: 3265698 (1966-08-01), Allen, Jr. et al.
patent: 5028613 (1991-07-01), Sun et al.
patent: WO 97/23456 (1977-07-01), None
patent: 9816502 (1998-04-01), None
Sun, Hao H., Shinichi Sakemi, Neal Burres, Peter McCarthy (1990) “Isobatzillines A, B, C, and D. Cytotoxic and Antifungal Pyrroloquinoline Alkaloids from the Marine SponeBatzellasp.”J. Org. Chem.55:4964-4966.
Stierle, Donald B. and D. John Faulkner (1991) “Two New Pyrroloquinoline Alkaloids From The SponeDamiriasp.”Journal of Natural Products54(4):1131-1133.
Radisky, Derek C., Evette S. Radisky, Louis R. Barrows, Brent R. Copp, Robert A. Kramer, Chris M. Ireland (1993) “Novel Cytotoxic Topoisomerase II Inhibiting Pyrroloiminoquinones from Fijian Sponges of the Genus Zyzzya”J. Am. Chem. Soc.115(5):1632-1638.
Sakemi, Shinichi and Hao H. Sun (1989) “Batzellines A, B, and C. Novel Pyrroloquinoline Alkaloids From the SpongeBatzellaSp.”Tetrahedron Lett.302:2517-2520.
Faulkner, D. (1998)J. Nat. Prod. Rep.15:113-158.
Faulkner, D. (1997)J. Nat. Prod. Rep.14:259-302.
Faulkner, D. (1996)J. Nat. Prod. Rep.13:75-125.
Faulkner, D. (1995)J. Nat. Prod. Rep.12:223-269.
Faulkner, D. (1994)J. Nat. Prod. Rep.11:355-394.
Faulkner, D. (1993)J. Nat. Prod. Rep.10:497-539.
Faulkner, D. (1992)J. Nat. Prod. Rep.9:323-364.
Faulkner, D. (1991)J. Nat. Prod. Rep.8:97-147.
Faulkner, D. (1990)J. Nat. Prod. Rep.7:269-309.
Faulkner, D. (1988)J. Nat. Prod. Rep.5:613-663.
Faulkner, D. (1987)J. Nat. Prod. Rep.4:539-576.
Faulkner, D. (1986)J. Nat. Prod. Rep.3:1-33.
Faulkner, D. (1984)J. Nat. Prod. Rep.1:551-598.
Scheuer, P.D., ed. (1978-1983) InMarine Natural Products, Chemical and Biological Perspectives,Academic Press, New York (see entire book, copy not enclosed).
Uemura, D., K. Takahashi, T. Yamamoto et al. (1985) Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine SpongeJ. Am. Chem. Soc.107:4796
Gunasekera Sarath P.
Longley Ross E.
McCarthy Peter J.
Pomponi Shirley A.
Wright Amy E.
Harbor Branch Oceanographic Institution Inc.
Oswecki Jane C.
Saliwanchik Lloyd & Saliwanchik
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