Taxoid derivatives and process for producing the same

Details Taxoid derivatives and process for producing the same Taxoid derivatives and process for producing the same

2000-04-07

2001-10-23

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S510000, C549S414000

Reexamination Certificate

active

06306893

ABSTRACT:

TECHNICAL FIELD
The present invention relates to taxoid derivatives and process for producing the same and more particularly to taxoid derivatives having improved physiological activity and solubility in water by linking galactose or mannose to any one of paclitaxel, docetaxel and 10-deacetyl-baccatin III through a spacer, and process for producing the same.
TECHNICAL BACKGROUND
Paclitaxel is a diterpene compound isolated from the bark of a yew tree of North American growth (Taxus brevifolia) [M. C. Wani et al.: J. Am. Chem. Soc., 93, 2325 (1971)] andis apotent antitumor agent having improving effect against tumors that cannot be cured by conventional chemical therapy. The mechanism by which taxol controls a tumor is specific; it causes excessive formation of a microtubule to inhibit mitosis in contrast to many conventional antitumor agents that inhibit the formation of a microtubule, which is a major component of a spindle, mitotic apparatus.
Although paclitaxel is an important antitumor agent, it is low solubility in water and hence its application as a therapeutic drug is limited. Accordingly, studies on improvement of its solubility by use of a solubilizing agent or converting it into derivatives have been made intensively. However, no satisfactory solution has been found yet. For example, currently paclitaxel is administered together with “Cremophor”, a solubilizing agent. This is performed by administering 1 liter over 6 hours every 2 weeks, which is practiced for 4 cycles, and imposes the patient with a heavy burden [Eric K. Rowinsky et al.: CANCER RESEARCH, 49, 4640 (1989)] and in addition has the problem that the solubilizing agent has side effects.
Also, docetaxel has been developed as a paclitaxel derivative having improved solubility. The solubility in water of docetaxel is only 35 times as high as taxol [I. Ringel et al.: J. Natl. Cancer Inst., 83, 288 (1991)], and is not so much improved.
To improve the solubility of paclitaxel, introduction of various functional groups to a side chain or nucleus of taxol has been tried. However, improvement of solubility was observed on some compounds of such derivatives but none has been reported that has increased physiological activity.
No report has been made on sugar derivatives of paclitaxel only one exception is the report on the existence of a compound consisting of paclitaxel and xylose attached thereto naturally through an ether bond [H. Lataste et al.: Proc. Natl. Acad. Sci. USA, 81, 4090 (1984)].
Chemical glycosylation of paclitaxel includes many known methods as described in, for example, “Experimental Chemistry Course 26, Organic Synthesis VIII, Chapter 3, 4th Edition, edited by Japan Chemical Society”, any of which methods must use a heavy metal or strong Lewis acid. However, since paclitaxel and docetaxel have an oxetane skeleton, which is unstable to acids, and a basic skeleton having high stereo hindrance, conventional chemical glycosylation process does not proceed efficiently. On the other hand, glycosylation with an enzyme results in failure of obtaining the target compound because of very low solubility in water of paclitaxel and docetaxel.
Furthermore, 10-deacetyl-baccatin III extracted from a yew tree of North American growth (Taxus brevifolia) like paclitaxel is a precursor of docetaxel, so that development of a method for producing hydrophilic taxoid derivatives can be expected by use of this substance.
DISCLOSURE OF THE INVENTION
Under the circumstances, an object of the present invention is to develop derivatives of paclitaxel, etc. having improved solubility and physiological activity and provide an effective therapeutic drug for tumors that imposes less burden on patients.
The present inventors have made intensive research with view to developing derivatives of paclitaxel and as a result found that there can be obtained paclitaxel derivatives that consists of paclitaxel, and galactose or mannose linked thereto via an ester bond through a spacer and that the resulting derivatives show improved solubility in water and physiological activity. The present invention has been accomplished based on this discovery. Also, as for docetaxel and 10-deacetyl-baccatin III described above, the present inventors have established methods for preparing taxoid derivatives in which galactose or mannose is linked via an ester bond in a similar manner.
That is, the present invention relates to taxoid derivatives comprising any one of paclitaxel, docetaxel and 10-deacetyl-baccatin III to which galactose or mannose is linked through a spacer, to methods for producing the same and to their use.


REFERENCES:
patent: 4857653 (1989-08-01), Colin et al.
patent: 5767297 (1998-06-01), Mandai et al.
patent: 781778 A1 (1997-07-01), None
patent: 9-241293 (1997-09-01), None

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