JPH02169520A - Microcirculation improving agent - Google Patents

Abstract

NEW MATERIAL:4-(5'-Nitroxypentylamino)-6,7,8-trimethoxyquinazoline expressed by the formula. USE:A microcirculation improving agent useful for remedy of thrombosis. PREPARATION:A commercial methyl-3,4,5-trianthranylate used as a raw material is reacted with formamide to give a quinazolinone derivative, which is then reacted with a mixture of phosphorus oxychloride and oxygen at 4 position is replaced by halogen such as chlorine to afford a halide. The halide is then reacted with 5-aminopentanol and Na2CO3 in isopropyl alcohol, etc., and halogen at 4 position is replaced to give 4-(5-hydroxypenthylamino)quinazoline, which is then reacted with fuming nitric acid in a solvent such as glacial acetic acid to esterify hydroxyl group and provide the compound expressed by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a microcirculation improving agent useful for treating myocardial infarction, cerebral thrombosis, and the like.

[Prior Art and Problems] Microvessels respond sensitively to changes in blood viscosity and red blood cell deformability. Therefore, when blood viscosity increases and red blood cell deformability decreases, thrombotic diseases such as myocardial infarction and cerebral thrombosis are more likely to occur. Therefore, improving microcirculation by reducing blood viscosity and increasing red blood cell deformability is considered to be effective in the treatment of thrombotic diseases, and the development of therapeutic drugs for these thrombotic diseases is currently being pursued in many ways. The development of more useful drugs has been desired.

[Means for Solving the Problems] The present inventors have conducted intensive research in order to develop a drug useful for the treatment of thrombotic diseases, and as a result, they have found that a compound represented by the following formula has an excellent microcirculation improving effect. The present invention has been completed based on the discovery that the present invention has the following properties. That is, the present invention is a microcirculation improving agent (hereinafter referred to as the drug of the present invention) containing the compound represented by (hereinafter referred to as the compound of the formula) as an active ingredient.

A compound of formula can be obtained, for example, as follows.

(2) Using commercially available methyl-3,4,5-trimethoxyanthranilate as a raw material, it is reacted with formamide to obtain a quinazolinone derivative.

(2) A mixture of the derivative and phosphorus oxychloride is reacted, and oxygen at the 4-position is replaced with a halogen such as chlorine to obtain a halide.

■Nuclear halide, 5-aminopentanol, and sodium carbonate are reacted in a solvent such as isopropyl alcohol, and the 4-position halogen is replaced with a 5-hydroxypentylamino group to form 4-(5'-hydroxypendelamino). Get Quinazoline.

(2) React the core compound with fuming nitric acid in a solvent such as glacial acetic acid to convert the hydroxyl group into a nitric acid ester to obtain the compound of the formula.

The compound of the formula may also be used as a pharmacologically acceptable salt, specific examples of which include salts with dicarboxylic acids such as maleic acid.

A specific example of the production of the compound of the formula is shown below.

Specific example 1 Methyl-3,4,5-)rimethquin anthranilar) 4
A mixture of 8.39 and 160 dj of formamide was refluxed for 3 hours. After cooling, it was poured into 600 d of water ice, and the precipitated yellow precipitate was collected by filtration, washed with water, and air-dried.
．． 7.8-trimethoxyquinazolin-4-(3H)-one was obtained.

Then 6.7.8-trimethquine quinazoline-4(3H)
- 20 g of a mixture of 509 and 250 g of phosphorus oxychloride
Refluxed for minutes. After cooling in a water bath, it was poured into 1250 y of water. Further, this cold aqueous solution was gradually poured into ammonia water ('a ammonia water 750I/!i-water 75 (Ml), and the precipitated gray precipitate was collected by filtration, washed with water, and then dissolved in chloroform.The chloroform solution was washed with water. After drying, treating with activated carbon, and concentrating, petroleum ether was added, and the precipitated pale yellow precipitate was collected by filtration to obtain 41.39 of 4-chloro-6,7,8-trimethoxyquinazoline.

Then 4-chloro-6,7,8-trimethoxyquinazoline 12.739, sodium carbonate 7.429.5 aminopentanol 5.679 and isopropyl alcohol 3
The mixture of 00d was refluxed for 4 hours.

The mixture was filtered when ripe, and the solid obtained by concentrating the filtrate was dissolved again in isopropyl alcohol 1207d to remove insoluble matter. The filtrate was left to stand, the precipitated crystals were collected, and 4-(5'
-Hydroxypentylamino)-6°7.8-trimethoxyquinazoline 12.169 was obtained.

Next, 7.339% of the quinazoline was dissolved in 35% of glacial acetic acid, and this solution was added dropwise to a mixture of 14.27% of acetic anhydride and 4.7% of fuming nitric acid with stirring. This mixture was mixed with 1:1 of acetic acid and sodium acetate.
It was added to solution a and extracted with ethyl acetate. The edyl acetate layer was washed, dried over anhydrous magnesium sulfate, the solvent was distilled off, and recrystallized from methanol to obtain a compound of the formula 4-(5'-nitroxypentylamino)-6,7,
8 trimethoxyquinazoline was obtained.

[Pharmacology] The production of acceptable salts can be carried out by common salt production methods used in the production of ordinary pharmaceuticals. For example, when using maleic acid, it can be obtained by reacting maleic acid with the compound obtained in Example 1 in an organic solvent such as ethanol, and further recrystallizing from an organic solvent such as methanol.

A specific example of the production of maleate salt will be shown.

Specific Example 2 The compound obtained in Specific Example 1 and 3.08 g of maleic acid were dissolved in a solution of 257 ethanol by heating, and after cooling, the solvent was distilled off. The residue was washed with cold ethanol and recrystallized from methanol to give the maleate salt of the formula compound (melting point: 100-102°C).

[Effects of the Invention] The fact that the drug of the present invention has a microcirculation-improving effect will be explained with reference to experimental examples.

Experimental example! Eight-week-old SD male rats [body weight 250-3009, purchased from Nippon Talea Co., Ltd.] were fasted overnight, and 30 zg/kg of the compound obtained in Example 2 was dissolved in physiological saline and orally administered, The control group received only physiological saline. Three hours later, the abdomen was opened under ether anesthesia, blood was collected from the abdominal aorta with a disposable syringe for 8 days, and blood viscosity and red blood cell deformability were immediately measured. Blood viscosity was measured using a rotational viscometer CBIO-RHEO using a cone plate with 48 cones.
The shear rate was 7.
50°18.75, 37.50, 75.00, 150.
00 and 375.00/see.

The results are shown in Table 1.

Table 1 Experimental Example 2 For the blood collected in Experimental Example 1, polycarbonate membrane
As a result of investigating the effect on red blood cell deformability using the passage time of ne) as an index, the passage time of the control group was 10.87.
seconds, whereas the blood transit time of rats to which the compound obtained in Example 2 was administered was 6.79 seconds.

From the above results, it was confirmed that the compound obtained in Example 2 had an effect of lowering blood viscosity and an effect of increasing red blood cell deformability.

When an acute toxicity test of the compound of the formula, which is the active ingredient of the drug of the present invention, was conducted using ddY male mice, L D
s. was 2.24g/&9, and it was confirmed that the toxicity was very low.

Next, the dosage and formulation of compounds of formula will be described.

The compounds of the formula can be administered to animals and humans neat or with conventional pharmaceutical carriers.

The dosage form is not particularly limited and may be selected and used as required, including tablets, capsules, granules, fine granules,
Examples include oral preparations such as powders, parenteral preparations such as injections, and suppositories.

In order to exert the desired effect as an oral agent, it is usually necessary for an adult to take 30 to 700 ml of the compound of the formula in divided doses several times a day, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take it. Oral preparations are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, inorganic salts, and the like.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sugar fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the formula can also be administered as suspensions, emulsions, syrups, and elixirs, various of which may contain flavoring and coloring agents.

In order to exert the desired effect as a parenteral agent, it is usually necessary for adults to administer the compound of formula 5 to 45R9 per day by intravenous injection or intravenous drip, although this will vary depending on the age, weight, and severity of the disease of the patient. Note: Subcutaneous and intramuscular injections are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. I can do it. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

Example 1 ■Corn starch 24.99■Crystalline cellulose 1509 ■Carboxymethylcellulose calcium 2.09 ■Light anhydrous silicic acid 0.29■Magnesium stearate 0.49 Compound of formula 75 Total 50.0g Prepare ■～■ according to the above recipe. The mixture was mixed uniformly and compressed using a key press to obtain a portion of 20019 tablets.

These tablets contain the compound of the formula 30M9 and are taken by adults in 1 to 23 tablets per day in several doses.

Example 2 ■Crystalline cellulose 80.5g■Magnesium stearate 0.59■Carboxymethyl cellulose calcium 4.09 grams 150 total 100. 09 According to the above recipe, mix ■, ■, and a part of ■ uniformly, compression mold, crush, add the remaining amount of ■ and ■, mix, and compression mold with a key press to make a portion of 200R9 tablets were obtained.

This tablet-tablet contains the compound of the formula 3ON9 and is taken by adults in 1 to 23 tablets per day in several divided doses.

Example 3 ■ Crystalline cellulose 30.59 ■ lO% hydroxypropyl cellulose ethanol solution 50.09 ■ Carboxymethyl cellulose calcium 4.09 ■ Magnesium stearate 0.59 ■ Compound of formula 15.09 total 100.09 ■ According to the above recipe , ■ and ■ are homogeneously mixed, and the mixture is made into a paste using a conventional method, and then granulated using an extrusion granulator, dried and crushed. 200 R9 tablets were obtained.

This tablet-tablet contains 30 Mg of the compound of the formula, and adults should take 1 to 23 tablets per day in several doses.

Example 4 ■ Corn starch 39.99 ■ Magnenium stearate 0.4 g ■ Carboxymethylcellulose calcium 2.09 ■ Light silicic anhydride 0.29 ■ Compound of formula
7.59 total 50.09 According to the above recipe, ■ to ■ were uniformly mixed, compression molded using a compression molding machine, crushed using a crusher, and sieved to obtain granules.

1 g of this granule contains 150 Rg of the compound of formula, and adults should take 0.2 to 4.69 g of the compound in several doses per day.

Example 5 ■ Crystalline cellulose 249 ■ 10% hydroxypropyl cellulose ethanol solution 189 Compound of formula 8 g Total 50 g According to the above recipe, ■ to ■ were mixed uniformly and made into a paste. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

This granule 19 contains compound 160Q of the formula, and is taken by adults in 0.2 to 4.39 doses per day in several doses.

Example 6 ■Corn starch 41.5g■Light silicic anhydride 0.29■Compound of formula
8.39 total 50.09 Mix ■～■ uniformly according to the above recipe, 20019
was filled into a No. 2 capsule.

This capsule contains a compound of the formula 33.2M
9, and adults should take 1 to 21 capsules a day in several doses.

Example 7 ■ Distilled water for injection Tihui ■ Glucose 200 Q ■ Compound of formula 20 ~ Total amount 5 d After dissolving ■ and ■ in distilled water for injection, inject into a ampule of 5- and diluted at 1 21 'C. The mixture was autoclaved for a minute to obtain an injection.

Claims (1)

[Claims] formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A microcirculation improving agent containing the compound represented by as an active ingredient.