Condensed-hexacyclic compounds and a process therefor

Details Condensed-hexacyclic compounds and a process therefor Condensed-hexacyclic compounds and a process therefor

2001-06-11

2003-04-22

Kifle, Bruck (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S048000

Reexamination Certificate

active

06552197

ABSTRACT:

TECHNICAL FIELD
This invention relates to a camptothecin derivative having antitumor activities and an industrially advantageous preparation process therefor.
BACKGROUND ART
The compound represented by the following formula (4):
that is, [(1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]-indolizino[1,2-b]quinoline-10,13(9H,15H)-dione] or a salt thereof is a camptothecin derivative which exhibits excellent antitumor activities (Japanese Patent Laid-Open No. 87746/1994).
The conventional hydrochloride, sulfate, hydrobromide, nitrate or the like of the above compound are, however, accompanied by one or more disadvantages such as high hygroscopicity, low filterability and/or low solubility, leading to intractable handling property at industrial preparation.
Further, in order to convert any one of these inorganic salts into a pharmacologically-useful acid addition salt such as the tartrate, malonate or malate, it requires the conversion of the inorganic salt into the sparingly-soluble free compound prior to the formation of the desired salt. Such conventional salts thus require the extra step and in addition, the free compound had low solubility and cannot be handled easily. These conventional salts are therefore disadvantageous from the industrial viewpoint.
Upon preparation of Compound (4) according to the conventional procedure, an unnecessary stereoisomer is formed together with the target stereoisomer theoretically in equal amounts, lowering the yield of the desired compound. And further, to obtain the target stereoisomer, high-performance liquid chromatography should be used. So the target stereoisomer cannot be prepared advantageously in industry by the conventional preparation procedure.
An object of the present invention is therefore to provide a novel acid addition salt of a camptothecin derivative, said salt being free of hygroscopicity, having excellent filterability and solubility and being pharmacologically useful; and also an industrially advantageous preparation process therefor.
With the foregoing in view, the present inventors have conducted with an extensive investigation. As a result, it has been found that treatment of the compound represented by the below-described formula (2) with methanesulfonic acid allows isomerization upon removal of the amino-protecting group proceed so that the target isomer can be obtained in an improved yield; that the repetition of the above reaction makes it possible to convert an unnecessary isomer, which has remained after the separation of the necessary isomer, into the desired isomer; that the target product can be selectively collected easily by recrystallization while making use of the difference in solubility between the unnecessary isomer and the desired isomer; and that the methanesulfonate as the target product is useful as a pharmaceutical for the lack of hygroscopicity and good filterability and solubility, leading to the completion of the present invention.
DISCLOSURE OF THE INVENTION
The present invention therefore provides the methanesulfonate of a camptothecin derivative, said methanesulfonate being represented by the following formula (1):
or a hydrate thereof, and also a preparation process therefor.
The present invention also provides a pharmaceutical composition comprising the Compound (1) or a pharmaceutically-acceptable salt thereof.


REFERENCES:
patent: 4939255 (1990-07-01), Tagawa et al.
patent: 5061795 (1991-10-01), Tagawa et al.
patent: 5637770 (1997-06-01), Terasawa et al.
patent: 0 296 597 (1988-12-01), None
patent: 0 495 432 (1992-07-01), None
patent: 6-87746 (1994-03-01), None
Mitsui et al. (Jpn. J. Cancer Res. (1995), 86(8), 776-782) Abstract.*
Mitsui et al, 84thAnnual Meeting of the American Association of Cancer Research Poster No. 2510 Figures 1-3 (1993).

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