JPH09216822A - Vascularization inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a low-toxic and safely usable vascularization inhibitor containing, as active ingredient, a specific compound excellent in vascularization- inhibitory activity. SOLUTION: This vascularization inhibitor contains, as active ingredient, 8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-carboxylic acid of formula I. The compound of formula I is obtained, for example, by oxidation of 8- hydroxy-3-hydroxymethyl-6-methoxy-1H-2-benzopyran-1-one of formula II with Jones reagent (chromic acrid-sulfuric acid-water). This inhibitor is applicable to prevention and/or treatment of vascularization involved in the proliferation and metastasis of malignant solid tumor, diabetic retinopathy, various chronic inflammations, psoriasis and corneal transplantation, and arteriosclerosis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a low toxicity angiogenesis inhibitor which is expected to be applied to various diseases.

[0002]

The compound of the present invention, 8-hydroxy-6-
Methoxy-1-oxo-1H-2-benzopyran-3-
Carboxylic acid is a known compound, but it is not known to have an angiogenesis inhibitory action. On the other hand, as substances that inhibit angiogenesis, protamine, a combination of heparin and cortisone acetate, fumagillin and its derivatives,
Interferon etc. have been reported. However, these angiogenesis inhibitors have problems such as weak inhibitory activity, lack of sustained activity, and side effects such as cytotoxicity, fever and bleeding.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides an angiogenesis inhibitor which is excellent in angiogenesis inhibitory action, has low toxicity, and can be used safely.

[0004]

Means for Solving the Problems The present inventors have earnestly studied the pharmacological activity of 8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-carboxylic acid. Has a strong angiogenesis inhibitory activity,
The present invention has been completed by finding out that the compound has few side effects. The present invention is an angiogenesis inhibitor containing 8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-carboxylic acid represented by the following formula (I) as an active ingredient.

[0005]

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The compound of the present invention is prepared by converting 8-hydroxy-3-hydroxymethyl-6-methoxy-1H-2-benzopyran-1-one represented by the formula (II) by Jones reagent (chromic acid-sulfuric acid-water). It can be produced by oxidation.

[0007]

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The reaction of the compound of formula (II) with Jones reagent is generally carried out in an inert organic solvent such as acetone, ethylmethylketone, diethylketone or the like at about room temperature or lower, preferably about 0-50. It can be carried out under relatively mild conditions of ℃. By this reaction, the hydroxymethyl group at the 3-position of the compound of formula (II), which is the starting material, is oxidized and converted into a carboxyl group.

8-hydroxy-3 represented by the formula (II), which is a starting material for synthesizing the compound of the present invention,
-Hydroxymethyl-6-methoxy-1H-2-benzopyran-1-one is a microorganism belonging to the genus Streptoverticillium and having the ability to produce the compound represented by the formula (II), for example, Streptoverticillium europium. Sidi Kum MI43-37F11 strain (FERM BP-2
It is obtained by culturing 783) in a nutrient medium and collecting from the culture solution (JP-A-3-2177). Further, this raw material compound is a 2-benzopyran derivative, for example, 3
-Benzyloxymethyl-6,8-dimethoxy-1H-
It can also be produced by reacting 2-benzopyran-1-one with boron tribromide under a nitrogen atmosphere (JP-A-4-112884).

The compound (I) of the present invention exhibits an inhibitory effect on tumor cell-induced angiogenesis in the dorsal subcutaneous method of mice, and diseases in which angiogenesis plays an important role, that is, growth and metastasis of malignant solid tumor, diabetes mellitus. It is expected to be applied to the prevention and treatment of diabetic retinopathy, various chronic inflammations, psoriasis, angiogenesis associated with corneal transplantation, and arteriosclerosis. In addition, it shows almost no toxicity and can be used effectively and safely.

The compound (I) of the present invention is useful as an angiogenesis inhibitor, and its pharmaceutical preparation includes known fillers, fillers, binders, humectants, disintegrants, disintegration inhibitors, and surfactants. It can be prepared by using a diluent such as a lubricant, or an excipient. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspension syrups, emulsions, granules, capsules, suppositories, injections Agents (solutions, suspensions, etc.).

In the case of molding in the form of tablets, a wide variety of known carriers can be used, and examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Agent,
Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, hydrogen carbonate Sodium, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, disintegrants such as starch and lactose, sucrose, cacao butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium salt base, lauryl Absorption promoters such as sodium sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, lubricants such as polyethylene glycol Examples are agents It can be.

Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, a film-coated tablet, a double tablet and a multi-layer tablet. When molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, excipients such as kaolin and talc, gum arabic powder, Examples thereof include tragacanth powder, gelatin, binders such as ethanol, and disintegrants such as laminaran agar powder.

In the case of molding in the form of suppositories, those conventionally known in this field can be widely used as carriers, such as polyethylene glycol, cocoa butter higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. You can

When prepared as an injection, it is preferable that the solution and suspension are sterilized and isotonic with blood. When the solution or suspension is molded into the form of a solution or suspension, it is used as a diluent. All those commonly used in the field can be used, and examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the formulation, and a usual solubilizing agent, buffer, soothing agent, etc. may be used. Good. For oral administration, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent or the like and other pharmaceuticals may be contained in the preparation as required.

The amount of the compound (I) of the present invention to be contained in the angiogenesis inhibitor of the present invention is not particularly limited and can be selected within a wide range, but it is usually solid such as tablets, granules and capsules. In the case of agents, it is 1 to 70% by weight, preferably 5 to 50% by weight of the total composition, and in the case of solutions such as solutions, injections and suspensions, it is 0.1 to 10% by weight.

The administration method of the compound (I) of the present invention is not particularly limited, and it is administered according to various preparation forms, age and sex of patients, other conditions, and degree of disease. For example, tablets, pills, solutions, suspension syrups, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. In the case of suppositories, they are administered rectally.

The dose of the compound (I) of the present invention is as follows:
The dose may be adjusted depending on the patient's age, sex, other conditions, degree of disease, etc., but is 0.3 to 300 mg / kg per day for oral administration, and 0.03 for parenteral administration.
-30 mg / kg is suitable.

Hereinafter, the effects of the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[0020]

【Example】

Example 1 Inhibitory Effect on Angiogenesis Using the Mouse Subcutaneous Method Using the mouse dorsal subcutaneous method, the inhibitory effect of the compound (I) of the present invention on tumor angiogenesis induced by mouse transplanted tumor S180 was examined. That is, 1 × 10 ⁷ S180 cells were injected into a chamber created by attaching a millipore filter having a pore size of 0.45 μm on both sides of the millipore. After closing the inlet, IC
The R type female mouse (9 to 10 weeks old) was transplanted into an air sack created subcutaneously on the back. A 0.5% carboxymethylcellulose solution of compound (I) and a solvent control was orally administered for 5 days from the day of transplantation. Five days after transplantation, the skin was peeled off, and an O-ring having the same shape as the ring and an inner diameter of 10 mm was placed on the skin-side chamber contact portion and observed under a stereomicroscope
Further photo was taken.

From the obtained photographs, the intensity of angiogenesis was scored in four stages of 0, 1, 2, 3 based on the number of bent blood vessels having a length of 3 mm or more, which is peculiar to tumor blood vessels. A score of 0 indicates that the number of tumor vessels is 0, and a score of 1 indicates that the number of tumor vessels is 1
Book, score 2 indicates that the number of tumor blood vessels is 2, and score 3 indicates that the number of tumor blood vessels is 3 or more. Table 1 shows the results. Compound (I) gives 100 mg of neovascularization induced by tumor cell S180 in the dorsal subcutaneous method of mice.
It was significantly suppressed by oral administration of 1 mg / kg.

[0022]

[Table 1]

Example 2 Subacute toxicity 100 mg / k of the compound (I) of the present invention was administered to 8 mice.
After oral administration for 40 days, there were no deceased individuals and no toxic symptoms were observed. The toxicity of the compound (I) of the present invention to warm-blooded animals is very low.

[0024]

INDUSTRIAL APPLICABILITY As described above, the compound (I) of the present invention
Is a particularly strong inhibitor of tumor cell-induced angiogenesis in the dorsal subcutaneous method of mice, and thus diseases in which angiogenesis plays an important role, namely malignant solid tumor growth and metastasis, diabetic retinopathy, various chronic inflammations, and psoriasis It is expected to be applied to prevention and treatment of angiogenesis associated with corneal transplantation and arteriosclerosis. Moreover, it is particularly excellent as an angiogenesis inhibitor in terms of toxicity and can be used effectively and safely.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 311/76 C07D 311/76

Claims (1)

[Claims] (1) Formula (1) An angiogenesis inhibitor comprising 8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-carboxylic acid represented by as an active ingredient.