Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-07-18
1996-07-02
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
560264, C07D23391, C07D23394, C07C 6963, C07C 6976, A61K 31415
Patent
active
055323804
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP 93/01519 filed Oct. 20, 1993.
FIELD OF TECHNOLOGY
The present invention relates to an optically active 2-nitroimidazole derivative which is useful as a drug used along with radiotherapy of cancers, a radiosensitizer comprising the same as an effective component, a process for preparing the same, and an intermediate for the preparation of this derivative.
BACKGROUND ART
A 2-nitroimidazole derivative represented by the following formula (5) exhibits an action of promoting radiosensitivity of hypoxic cells existing in cancers. Because it has the excellent radiosensitivity and is highly safe, this compound is known to be useful as a drug used along with radiotherapy of cancer (Japanese Patent Application Laid-open (kokai) No. 223258/1991). ##STR2##
A process of the following reaction scheme is known for preparing the 2-nitroimidazole derivative (5). ##STR3##
This process comprises a step of selectively acylating three hydroxy groups, two primary hydroxy groups and one secondary hydroxy group, among four hydroxy groups in erythritol which is a raw material compound. It is essential to react erythritol at a low temperature in order to differentiate the reactivities of the primary hydroxy group and the secondary hydroxy group. But at such a low temperature, a large amount of solvent is required, because this raw material is scarcely soluble. Further, because the reaction product from this step is a mixture containing tetra-, tri-, di- and mono-acylated compounds, and unreacted compound, purification by column chromatography or the like is indispensable in order to selectively obtain the target triacylated compound. The low yield of this step results in the decrease in the overall yield of the process. In addition, expensive raw materials such as D-erythritol and L-erythritol must be used in order to produce the optically active 2-nitroimidazole derivative.
The 2-nitroimidazole derivative (5) has two asymmetric carbon atoms. Isolation of the optical isomers is so difficult that there have been no reports on the successful isolation of these isomers. Furthermore, nothing have been known at all about the pharmaceutical activities of these optical isomers.
An object of the present invention is therefore to provide optical isomers of 2-nitroimidazole derivative (5) and a drug comprising the same as an effective components.
Other objects of the present invention is to provide a novel process for the preparation of the 2-nitroimidazole derivative (5) and an intermediate for preparing this compound.
DISCLOSURE OF THE INVENTION
In view of this situation, the present inventors have undertaken extensive studies, and found that 2-nitroimidazole derivative and its optical isomers can be obtained at a high yield and industrial advantage, by using tartaric acid diester which is an inexpensive compound as a raw material and by producing an intermediate compound, 2-halomethoxy-1,3,4-triacyloxybutane, by the ring-opening reaction of a dioxolane compound. This finding has led to the completion of the present invention.
Specifically, the present invention provides optically active 2-nitroimidazole derivatives of the following formulas (1) to (4) and a radiosensitizer comprising one of these derivatives as an effective component. ##STR4##
Furthermore, the present invention relates to a process for the preparation of the 2-nitroimidazole derivative according to the following reaction scheme, ##STR5## wherein R.sup.1, R.sup.2, and R.sup.3 may be the same or different and each individually represents an aliphatic group or an aromatic group, and X represents a halogen atom; and to an intermediate for the 2-nitroimidazole derivative.
Specifically, the present invention relates to a process for preparing 2-halomethoxy-1,3,4-triacyloxybutane derivative (11) comprising reacting 1,3-dioxolane derivative (9), which is easily obtained from tartaric acid diester (6), and acyl halide (10).
Further, the present invention relates to a process for preparing 2-nitroimidazole derivative (12), which comprise
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Nishio Azuma
Suzuki Toshimitsu
Higel Floyd D.
Pola Chemical Industries Inc.
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