ETM-775 metabolite of ecteinascidin 743

Details ETM-775 metabolite of ecteinascidin 743 ETM-775 metabolite of ecteinascidin 743

1999-05-11

2001-11-13

Gitomer, Ralph (Department: 1623)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving oxidoreductase

C514S250000, C544S233000

Reexamination Certificate

active

06316214

ABSTRACT:

BACKGROUND OF THE INVENTION
The ecteinascidins (herein abbreviated Et or Et's) are exceedingly potent antitumor agents isolated from the marine tunicate
Ecteinascidia turbinata.
In particular, Et's 729, 743 and 722 have demonstrated promising efficacy in vivo, including activity against P388 murine leukemia, B16 melanoma, Lewis lung carcinoma, and several human tumor xenograft models in mice.
The isolation and characterization of natural Et 743 is taught in U.S. Pat. No. 5,089,273 which is hereby incorporated herein by reference. The preparation of synthetic Et 743 is taught in U.S. Pat. No. 5,721,362, which is hereby incorporated herein by reference.
The antitumor activities of ecteinascidin compounds, particularly Et 729 and Et 743 are well documented in the scientific literature. See for example, Goldwasser et al.,
Proceedings of the American Association for Cancer Research,
39: 598 (1998); Kuffel et al.,
Proceedings of the American Association for Cancer Research,
38: 596 (1997); Moore et al.,
Proceedings of the American Association for Cancer Research,
38: 314 (1997); Mirsalis et al.,
Proceedings of the American Association for Cancer Research,
38: 309 (1997); Reid et al.,
Cancer Chemotherapy and Pharmacology,
38: 329-334 (1996); Faircloth et al.,
European Journal of Cancer,
32A, Supp. 1, pp. S5 (1996); Garcia-Rocha et al.,
British Journal of Cancer,
73: 875-883 (1996); Eckhardt et al.,
Proceedings of the American Association for Cancer Research,
37: 409 (1996); Hendriks et al.,
Proceedings of the American Association for Cancer Research,
37: 389 (1996); the disclosures of which are hereby incorporated herein by reference.
Ecteinascidin 743 (Et 743) has the following structure:
In view of the impressive antitumor activities of this class of compounds, the search continues for related structures that may possess equal or higher levels of antitumor activity. The present invention, which is directed to the isolation and characterization of natural metabolites of Et 743, is a result of these continued studies.
SUMMARY OF THE INVENTION
The purification and structure elucidation of several products of the metabolism of Et 743 by human cytochrome CYP3A4 have been accomplished. These compounds are abbreviated herein as “ETM” followed by a numeric value which represents the approximate molecular weight.
For example, ETM 305 and ETM 775 were isolated from a metabolic mixture obtained from a biochemical study performed by the Analytical Chemistry Department at PharmaMar, Spain. A similar metabolic study carried out by the Mayo Clinic led to the identification of ETM 204. The structures of these ecteinascidin metabolites are as follows:


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