Process of preparing camptothecin derivatives

Details Process of preparing camptothecin derivatives Process of preparing camptothecin derivatives

2000-01-05

2001-10-30

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S044000

Reexamination Certificate

active

06310207

ABSTRACT:

PRIOR FOREIGN APPLICATIONS
This application is a 35 USC §371 filing of PCT/KR98/00199, filed Jul. 8, 1998 and claims priority from Korean Patent Application Number 1997/31710, filed Jul. 9, 1997.
TECHNICAL FIELD
This invention relates to a process of manufacturing a camptothecin derivative expressed by the following general formula 1, or a pharmaceutically acceptable salt thereof:
wherein
Y and Z are the same or different and each represents a hydrogen atom, an C
1
~C
6
alkyl group, a C
1
~C
3
hydroxyalkyl group, or a general protecting group of amine such as benzyloxycarbonyl, benzyl, etc.;
R
1
is a hydrogen atom, an C
1
~C
6
alkyl group, or a hydroxy group;
R
2
and R
3
are the same or different and each represents a hydrogen atom or a hydroxy group, or they may be attached together to form a cyclic moiety, which is a methylenedioxy or an ethylenedioxy group;
R
4
is a hydrogen atom or an C
1
~C
6
alkyl group; and
R
5
is hydrogen, hydroxy, fluoro, chloro, bromo, iodo or amine.
BACKGROUND ART
Since the first isolation of camptothecin from the wood and bark of
Camptotheca acuminata
by Wall and co-workers [M. E. Wall et al.,
J. Am. Chem. Soc
., 88, 3888 (1966)], there had been many approaches to synthesize camptothecin. However, the development of camptothecin as an effective antineoplastic agent was unsuccessful due to its severe toxicity in the clinical trial in 1970. Thereafter, Liu et a reported in 1985 that camptothecin had a specific mode of action to inhibit topoisomerase I. Thus, considerable interest has focused on this compound.
Recently, various studies for the development of camptothecin derivatives have been proposed in order to reduce the toxicity of camptothecin and to further enhance its antineoplastic activities. Among these related studies, the clinical trial of CPT-11 (irinotecan) synthesized by Yakurt-Honsha Co. of Japan in 1986 showed that it exhibited excellent antineoplastic activities with less toxicity (Japanese Patent Laid Open Publication No. 64-61482) and followed by other pharmaceutical companies such as Smithkline Beecham (topotecan) and Glaxo (MDO-camptothecin and 9-amino camptothecin). Among them, CPT-11 and topotecan are launched.
On the other hand, the present inventors have reported the 7-aminoethyl camptothecin derivatives and manufacturing process thereof through the total synthesis, which have strong antitumor activity, weak toxicity, and broad safe region, in Korean Patent Application No. 95-269 and 96-248.
The above invention produces camptothecin derivatives that have strong antitumor activity. However, the procedure of manufacturing those is complex since the total synthesis is adopted and since intermediate material used is a new one. Consequently, there has been a strong need to develop a simple and convenient manufacturing process of camptothecin derivatives for mass production.
Accordingly, the inventors et al. have studied a convenient process by which camptothecin derivatives having excellent activities can be manufactured from a compound of general formula 2 such as (S)-7-methylcamptothecin [S. Sawada et al.,
Chem. Pharm. Bull
., 39 (1991) 2574~2580]. Thus, the present invention has been completed.
DISCLOSURE OF THE INVENTION
A process of manufacturing a camptothecin derivative or a pharmaceutically acceptable salt thereof is described in more detail as set forth hereunder, in accordance with the practice of this invention.
The process of manufacturing a camptothecin derivative or a pharmaceutically acceptable salt thereof, according to the present invention, is to produce the compound of general formula 1 through Mannich Reaction, that is, a compound of general formula 2 is reacted with an amine or salt thereof and with a formaldehyde source in the presence of acid (Scheme 1).
wherein
Y and Z are the same or different and each represents a hydrogen atom, an C
1
~C
6
alkyl group, a C
1
~C
3
hydroxyalkyl group, or a general protecting group of amine such as benzyloxycarbonyl, benzyl, etc.;
R
1
is a hydrogen atom, an C
1
~C
6
alkyl group, or a hydroxy group;
R
2
and R
3
are the same or different and each represents a hydrogen atom or a hydroxy group, or they may be attached together to form a cyclic moiety, which is a methylenedioxy or an ethylenedioxy group;
R
4
is a hydrogen atom or an C
1
~C
6
alkyl group; and
R
5
is hydrogen, hydroxy, fluoro, chloro, bromo, iodo or amine.
Preferably, R
1
, R
2
, R
3
, R
4
, R
5
and Y represent hydrogen atoms, and Z is isopropyl.
Examples of the said formaldehyde source comprise formalin solution, paraformaldehyde, trioxane, dimethyl sulfoxide, etc.
Examples of the said amine comprise primary or secondary amines such as methyl amine, ethyl amine, propyl amine, isopropyl amine, butyl amine, pentyl amine, hexyl amine, benzyl amine, isopropylbenzyl amine, dimethyl amine, diethyl amine, benzyloxycarbonyl amine, hydroxymethyl amine, hydroxyethyl amine, hydroxypropyl amine and the like.
In this reaction, examples of a reaction solvent comprise water, methanol, ethanol, dioxane, acetic acid, dimethylformamide, dimethyl sulfoxide and the like. Examples of the said acid comprise hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride, tin chloride and the like. And the reaction temperature is 20~150° C.
According to the present invention, pharmaceutically acceptable salts of compounds represented with general formula 1 are inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., or organic acid salts such as p-toluenesulfonate, acetate, methanesulfonate, trifluoromethanesulfonate, etc.


REFERENCES:
patent: 0 296 597 A2 (1988-12-01), None
patent: 0 471 358 A1 (1992-02-01), None
patent: 0 495 432 A1 (1992-07-01), None
patent: WO 96/21666 (1996-07-01), None
Sawada, S. et al., “Chemical Modification of an Antitumor Alkaloid Camptothecin: Synthesis and Antitumor Activity of 7-C-Substituted Camptothecins,”Chem Pharm. Bull., 39:274-80 (1991).
Wall, M.E. et al., “Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor fromCamptotheca acuminata,” J. Am. Chem. Soc, 88:3888-90 (1996).

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