Arglabin compounds and therapeutic uses thereof

Details Arglabin compounds and therapeutic uses thereof Arglabin compounds and therapeutic uses thereof

1998-10-07

2001-03-06

Richter, Johann (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C549S298000, C549S299000, C544S107000, C514S468000

Reexamination Certificate

active

06197767

ABSTRACT:

BACKGROUND OF THE INVENTION
Cancer is a leading cause of death in the United States and affects people worldwide. Surgery, radiation and chemotherapy are the most widely used therapeutic modalities. Chemotherapy agents create conditions within the cell that limit cell growth and replication. DNA synthesis may be inhibited by preventing purine biosynthesis, pyrimidine biosynthesis, the conversion of ribonucleotides to deoxyribonucleotides, antimetabolites, intercalation, or cross-links. RNA synthesis, for example, may be inhibited by antimetabolites. Protein synthesis may be inhibited, for example, by agents that deaminate asparagine. Additionally, agents that inhibit the function of microtubules can be used as chemotherapy agents.
Chemotherapy agents typically affect both neoplastic and rapidly proliferating cells of normal tissue such as bone marrow, hair follicles and intestinal epithelium. Anorexia, nausea, vomiting, diarrhea, suppression of bone marrow function and hair loss are some of the negative effects commonly associated with chemotherapy. Development of a chemotherapy agent that is an effective antitumor agent with minimal toxicity would be advantageous.
SUMMARY OF THE INVENTION
It has been discovered that arglabin and various derivatives of arglabin can function as effective chemotherapeutic agents, with fewer side-effects than typically follow from use of other chemotherapeutic agents.
In one aspect, the invention features compounds that suppress tumor growth in a mammal. These compounds are selected from the group represented by the following Formulas I, II, III, IV, V and VI:
wherein RR
1
is NHCH
2
Ph or N(CH
2
CH
2
)
2
O, RR
2
is NHCH
2
Ph, N(CH
2
CH
2
)
2
O, N(CH
3
)
2
, or a pharmaceutically acceptable salt thereof; and X is OH or Cl. These arglabin derivatives include dimethylaminoepoxyarglabin, dibromoarglabin, arglabin chlorohydrin, arborescine, benzylaminoarglabin, morpholine-aminoarglabin, benzylaminoepoxyarglabin, morpholine-aminoepoxyarglabin, epoxyarglabinchlorohydrin or pharmaceutically acceptable salts thereof.
The invention also features a method of suppressing tumor growth in a human diagnosed with a cancer. The method includes administering to the human an amount of arglabin or a derivative thereof effective to suppress tumor growth in the human. The method is useful for the treatment of a wide variety of cancers, including, for example, breast, colon, rectal, stomach, pancreatic, lung, liver, ovarian, pancreatic and esophageal cancer, leukemia, and lymphoma. The method is particularly useful for lung, liver and ovarian cancers. An effective amount of arglabin or a derivative thereof may be from about 40 mg to about 480 mg per day, preferably from about 175 mg to about 315 mg day, most preferably from about 240 mg to about 280 mg per day.
Arglabin derivatives that may be used with this method include, for example, dimethylaminoepoxyarglabin, dibromoarglabin, arglabin chlorohydrin, arborescine, benzylaminoarglabin, benzylaminoepoxyarglabin, morpholine-aminoarglabin, morpholine-aminoepoxyarglabin, epoxyarglabinchlorohydrin, anobin, epoxyarglabin, dichlorodihydroxyarglabin, dimethylaminoarglabin or pharmaceutically acceptable salts thereof.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.


REFERENCES:
patent: 5663196 (1997-09-01), Sari et al.
patent: 1188 (1993-12-01), None
patent: 1190 (1993-12-01), None
patent: 1186 (1993-12-01), None
patent: 1192 (1993-12-01), None
patent: N-931984 (1993-12-01), None
patent: 1185 (1993-12-01), None
patent: 1187 (1993-12-01), None
patent: 1189 (1993-12-01), None
patent: 909 (1994-06-01), None
patent: 1746674 (1992-03-01), None
Adekenov et al. Khim. Prir. Soedin. (1991), (1), 33-42. Reactions at the Double Bond and Epoxy of Arglabin.
Adekenov et al., “Reactions at the double bond and epoxy group of arglabin,” 547, 314: 548, 737, pp. 33-42, 1991.
S. M. Adekenov, M.N. Mukhametzhanov, A.D. Kagarlitsky, A.N. Kupriyanov, “A New Sesqiterpene Lactone fromArtemisia Glabella”, Khim. Prir. Soedin., 547.314, 655-56 (1982) (English Translation).
S.M. Adekenov, et al., The Chemistry of Sesquiterpene Lactones, Alma-Ata: Gylym (1990).
S.M. Adekenov et al., Khim. Prir. Soedin. 5, 655 (1982).
Barbacid, M., Ann. Rev. Biochem., vol. 56:, pp. 779-827 (1987).
Gibbs et al., Proc. Natl. Acad. Sci. USA, vol. 81, pp. 5704-5708 (Sep. 1984).
Jung. et al., Molecular and Cellular Biol., vol. 14, No. 6, pp. 3707-3718 (Jun. 1994).
Marom et al., J. Biol. Chem., vol. 270, No. 38, pp. 22263-22270 (1995).
Prendergast et al., Mol. Cell. Biol., vol. 14, No. 6, pp. 4193-4202 (Jun. 1994).
S. M. Adekenov, K.M. Turdybekov, K.A. Aituganov, S. V. Lindeman, Yu. T. Struchkov, and S. N. Shaltakov 1&bgr;, 10&agr;-Dihydroxyarglabin—A New Sesquiterpene Lactone fromArtemisia glabella, Chemistry of Natural Compounds, vol. 29, No. 6, 1993, pp. 735-739.
“The Merck Index,” Merck & Co., 1983, pp. 329, 394, 408, 599, 1427 and 1428.
Blanco et al., “A novel activity for a group of sesquiterpene lactones: inhibition of aromatase,” FEBS Letters vol. 409, No. 3, (1997) pp. 396-400.
Giordano et al., “The Gastric Cytoprotective Effect of Several Sesquiterpene Lactones,” Journal of Natural Products, vol. 53, No. 4. pp. 803-809, Jul.-Aug. 1990.
Guardia et al., “Mucus Synthesis and Sulfhydryl Groups in cytoprotection mediated by Dehydroleucodine, A Sesquiterpene Lactone,” Journal of Natural Products, vol. 57, No. 4. pp. 507-509, Apr. 1994.
Shears et al., Biochem. J., vol. 219, pp. 375-382 (1984).
Vogt et al., J. Biol. Chem., vol. 270 No. 2, pp. 660-664 (1995).
Adekenov et al., Fitoterpia, vol. LXVI, No. 2, pp. 142-146 (1995).
Bottex-Gauthier et al., Biotechnology Therapeutics, 4 (1&2), pp. 77-98 (1993).
Epstein et al., Proc. Natl. Acad. Sci. USA, vol. 88, pp. 9668-9670 (Nov. 1991).

Affiliated with

Also associated with

Rating

Arglabin compounds and therapeutic uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Arglabin compounds and therapeutic uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Arglabin compounds and therapeutic uses thereof will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2512621