Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-07-24
1993-12-14
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483275, A61K 31415, C07D23391
Patent
active
052703304
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a 2-nitroimidazole derivative, which is a novel substance useful as a radiosensitizer for hypoxic cells, a production process thereof, and a radiosensitizer containing the same as an active ingredient.
BACKGROUND ART
Cancers are difficult to cure even at the present day, and hence inflict great pains and economical losses on the world. Broadly speaking, a cancer is treated by three therapies of radiotherapy, chemotherapy and surgical therapy.
In the radiotherapy for the cancer among these, the presence of hypoxic cells in the tumor becomes the greatest problem. The hypoxic cells have high resistance to radioactive rays and are hence believed to be a serious cause of the refractoriness and/or the recurrence in the radiotherapy. On the other hand, no hypoxic cells exist in any normal tissues. Upon performing the radiotherapy for the cancer, it is therefore important to enhance the radiosensitivity of the hypoxic cells in the tumor.
In view of the foregoing circumstances, the present inventors carried out an extensive investigation with a view toward providing a medicament by which the radiosensitivity of normal cells is unchanged and only hypoxic cells are sensitized when radiotherapy is performed, i.e., a radiosensitizer for hypoxic cells (hereinafter referred to as "radiosensitizer"). As a result, it has been found that a 2-nitroimidazole derivative represented by the general formula (I) which will be described subsequently has a high radiosensitizing effect even in a low concentration and is also low in toxicity which has heretofore become the greatest problem, leading to completion of the present invention.
DISCLOSURE OF THE INVENTION
The present invention provides a 2-nitroimidazole derivative represented by the following general formula (I): ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 may be the same or different from each other and mean individually a hydrogen atom or an acyl group, and a production process thereof. The present invention further provides a radiosensitizer containing this derivative as an active ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
In the general formula (I) by which the compound according to this invention is represented, examples of the acyl groups indicated by R.sub.1, R.sub.2 and R.sub.3 include alkanoyl, alkenoyl or aroyl groups having 1-10 carbon atoms. The illustrative representatives of the compounds (1) according to this invention are as follows: 1-[(2',3'-dipropionoxy-1'-propionoxymethyl)propoxy]methyl-2-nitroimidazole ; 1-[(2',3'-dicrotonoxy-1'-crotonoxymethyl)propoxy]methyl-2-nitroimidazole; and
The compound (I) of this invention can be produced in accordance with, for example, the following reaction formula: ##STR3## wherein R.sub.1 ', R.sub.2 ' and R.sub.3 ' may be the same or different from each other and mean individually an acyl group, R.sub.4 denotes an acyl group, and X stands for a hydrogen atom or a trialkylsilyl group.
Namely, 1,2,4-triacyloxy-3-acyloxymethoxybutane (II) is reacted with 2-nitroimidazole or a trialkylsilyl-containing product thereof (III), thereby producing a compound (Ia) in which R.sub.1, R.sub.2 and R.sub.3 in the formula (I) are individually an acyl group. Further, the hydrolysis of the compound (Ia) produces a compound (Ib) in which R.sub.1, R.sub.2 and R.sub.3 in the formula (I) are individually a hydrogen atom.
In the above-described reaction formula, the reaction in the case where the compound (III) is 2-nitroimidazole is preferably carried out by melting the compound (II) and 2-nitroimidazole in the presence of a catalyst while reducing pressure. Various kinds of catalysts may be used as such a catalyst. For example, proton acids such as paratoluenesulfonic acid, methanesulfonic acid and trichloroacetic acid, and Lewis acids such as anhydrous zinc chloride, anhydrous aluminum chloride and anhydrous stannic chloride may be used. Among these, paratoluenesulfonic acid is the most effective catalyst owing to formation of little by-product. The proportions of the compound (II
REFERENCES:
patent: 4462992 (1984-07-01), Agrawal et al.
patent: 4945102 (1990-07-01), Suzuki et al.
Miyata Yoshiyuki
Mori Tomoyuki
Sakaguchi Masakazu
Suzuki Akira
Suzuki Toshimitsu
Lee Mary C.
Pola Chemical Industries Inc.
Powers Fiona T.
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