Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-11
2001-09-18
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C514S458000
Reexamination Certificate
active
06291482
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel N-hydroxyurea derivative having a lipoxygenase inhibitory activity and a thromboxane synthase inhibitory activity and pharmaceutical composition containing the same.
BACKGROUND ART
In recent years, the role of chemical mediators in asthma and other allergic diseases has been rapidly elucidated. In addition to histamine, PAF, leukotrienes, thromboxane, etc. have become known. It has been shown that leukotrienes are biosynthesized by the activity of 5-lipoxygenase from arachidonic acid, and thromboxane A
2
is biosynthesized by thromboxane synthase after the catabolism with cyclooxygenase from arachidonic acid. Further, both leukotrienes and thromboxane A
2
have been found to be important chemical mediators in allergic reactions, which cause various diseases such as asthma, chronic obstructive pulmonary disease, psoriasis, enteritis, nephritis, ulcers, and ischemia. Therefore, if it were possible to inhibit the biosynthesis of both chemical mediators, a greater effect could be obtained in treating or alleviating the above diseases when compared with the inhibition of single mediator.
Recently, as compounds for inhibiting the biosynthesis of such two mediators, benzothiazole derivatives (see Japanese Unexamined Patent Publication (Kokai) No. 5-178855), quinone derivatives (see Japanese Unexamined Patent Publication (Kokai) No. 5-78321), imidazolylphenol derivatives (see Japanese Unexamined Patent Publication (Kokai) No. 6-9571), and N-hydroxyurea derivatives (see WO96/23772) have become known.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide compounds capable of inhibiting the biosynthesis of both leukotrienes and thromboxane A
2
, that is, novel compounds having both the dual inhibition against lipoxygenase and thromboxane synthase at the same time.
In accordance with the present invention, there are provided N-hydroxy-N-[6-(3-pyridylmethyl)-2H-1-benzopyran-3-ylmethyl]urea having the formula (I), and the salts thereof:
In accordance with the present invention, there is further provided a pharmaceutical composition comprising this N-hydroxy-N-[6-(3-pyridylmethyl)-2H-1-benzopyran-3-ylmethyl]urea or its pharmaceutically acceptable salts, or the hydrates or solvates thereof as an active component, in particular an antiallergic or anti-inflammatory drug, especially antiasthmatic.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors widely studied to accomplish the above objects of the present invention. As a result, it was found that, among the compounds, which are included in the general wide concept, but not specifically disclosed in, for example, Examples, of benzopyran derivatives having a lipoxygenase inhibitory activity (Japanese Unexamined Patent Publication No. 3-83979), there are compounds having not only a lipoxygenase inhibitory activity but also a thromboxane synthase inhibitory activity. Thus, the present invention was completed.
Note that all the compounds having a lipoxygenase inhibitory activity disclosed in Japanese Unexamined Patent Publication No. 3-83979 do not possess the inhibitory activity of the thromboxane synthase and the present compounds are remarkably excellent, when compared with those compounds, for the purpose of curing or relaxing various diseases mentioned above.
The present invention will now be explained in further detail.
As mentioned above, the present invention provides N-hydroxy-N-[6-(3-pyridylmethyl)-2H-1-benzopyran-3-ylmethyl]urea and the salts thereof. As such a salt, the pharmacologically acceptable salts are preferable. The typical examples are salts of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, bisulfuric acid, phosphoric acid, etc. and salts of an organic acid such as formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, citric acid, gluconic acid, lactic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. Furthermore, the present invention includes the hydrates and solvates of the above-mentioned N-hydroxyurea derivatives and the salts thereof.
The N-hydroxyurea derivative according to the present invention can be produced by, for example, the following reaction formula (1) composed of the reaction steps 1-4, provided that the other method can be use for the synthesis thereof.
The starting substances used in the above reaction steps are those commercially available or those which may be produced from the known compounds by the known methods.
Step 1
3-(3′-Formyl-4′-hydroxybenzyl)pyridine (ii) is reacted, under a heating condition, with acrolein in the presence of an appropriate base such as potassium carbonate or sodium carbonate in a solvent, which does not inhibit this reaction, such as tetrahydrofuran or 1,4-dioxane to give the aldehyde (iii).
Step 2
The aldehyde (iii) is reacted with hydroxylamine hydrochloride in the presence of a base such as pyridine, picoline or triethyl amine in an appropriate solvent such as methanol, ethanol or propanol, or without a solvent, to give the oxime (iv).
Step 3
The oxime (iv) is reduced with an appropriate reductant to form hydroxylamine (v). As the reductant, borohydrides such as sodium cyanoborohydride or borane-amine complexes such as borane-pyridine complex, borane-dimethylamine complex are used. The reaction can be carried out under an acidic condition, namely in the presence of an appropriate acid such as an inorganic acid (e.g., diluted hydrochloric acid, diluted sulfuric acid) or an organic acid (e.g., formic acid, acetic acid, trifluoroacetic acid), with or without using an appropriate solvent such as an alcohol (e.g., methanol, ethanol), a halomethane (e.g,, methylene chloride, chloroform), an ether (e.g., diethyl ether, tetrahydrofuran) to give the hydroxylamine (v).
Step 4
The hydroxylamine (v) is reacted with trimethylsilylisocyanate in a solvent, which does not inhibit this reaction, such as tetrahydrofuran, or is reacted with alkali cyanate such as potassium cyanate or sodium cyanate under an acidic condition such as, for example, a diluted hydrochloric acid or diluted sulfuric acid condition, to thereby give the desired N-hydroxyurea derivative (I). The N-hydroxyurea derivative (I) thus obtained can be preferably purified by known methods, alone or in any combination thereof, such as recrystallization, chromatography.
3-(3′-Formyl-4′-hydroxylbenzyl)pyridine (ii) to be used, as the starting compound, in step 1 is a known compound as disclosed in Japanese Unexamined Patent Publication No. 58-15972.
The compounds of the present invention may be administered by a suitable method of administration such as oral or non-oral administration when used as a drug for the treatment of allergic diseases or inflammatory diseases. As a form of oral administration, for example, tablets, granules, capsules, pills, powders, liquids, syrups, etc may be exemplified and, further, as a form of non-oral administration, injections, external application agents, inhalants, etc. may be exemplified. When preparing these medically administered compounds, the compound of the present invention or its pharmacologically acceptable salt may be prepared according to an ordinary method.
In the case of oral administration, the preparations can be prepared into the desired form using excipients such as lactose, glucose, corn starch, sucrose, a disintegrator such as calcium carboxymethylcellulose, hydroxypropylcellulose; a lubricant such as calcium stearate, magnesium stearate, talc, polyethylene glycol, hardened oil, a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, arabia gum, a humectant such as glycerin, ethylene glycol; and, in addition, surfactants, taste adjusters, etc., if necessary.
Further, in the case of a non-oral drug, a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragacanth gum may be used and solution adjuvants, buffer agents, pre
Kawahara Yoshikazu
Komatsu Toshiya
Ohmori Hiromasa
Takano Michika
Tsuzuki Mina
Christie Parker & Hale LLP
Jones Dwayne C.
Nikken Chemicals Co., Ltd
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