JP3077046B2 - New quinazoline derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel quinazoline derivative useful as a drug having an excellent antiulcer activity. It also relates to a tyrosinase activity inhibitor and an external preparation for skin as a whitening cosmetic.

[0002]

BACKGROUND OF THE INVENTION With respect to quinazoline derivatives, 4-substituted-
2-piperazinylquinazoline derivatives are described in Chem. Ph
arm. Bull. 38 (3) 681-7 (19
90) and Chem. Pharm. Bull. 38
(5) 1286-1129 (1990) describes its antispasmodic and arousal effects, and 2-aralkylsulfinyl 4 (3H) quinazolinone derivatives are disclosed in JP-A-63-30.
No. 1873 has already reported on its anti-ulcer action.

However, it has not yet been known that a quinazoline derivative having a halogen group or a lower alkoxy group at the 4-position as shown in the present invention has antiulcer activity. No studies have been made on tyrosinase activity inhibitors or skin external preparations as whitening cosmetics.

[0004]

Cimetidine [0005] Current anti-ulcer agents mainstream are aggressive factors inhibitors, ranitidine, is a histamine H ₂ receptor antagonists such as famotidine, ulcer recurrence after discontinuation dosing to these And anti-androgenic action,
Side effects such as inhibition of liver metabolic enzyme activity have been reported. In recent years, as the same aggressive factor inhibitor, a benzimidazole derivative has been found to inhibit the enzyme [H ⁺ + K ⁺ ] ATPase activity in gastric juice and suppress gastric acid secretion, and is being developed as an anti-ulcer agent. . Omeprazole, which has been developed as a new type of anti-ulcer drug called this proton pump inhibitor, has a strong [H ⁺ + K ⁺ ] AT
Although it is reported that it has a Pase inhibitory activity (Japanese Patent Application Laid-Open No. 54-141783, British Medical Journal 287, page 12, 1983), it is hard to say that it is a sufficient drug in terms of safety and the like. The biosynthesis of melanin present in the human skin is said to be carried out in the pigment cells through the action of tyrosinase, where tylosin is changed to dopaquinone after dopa, and via 5,6-dihydroxyindole and the like. If the amount of melanin biosynthesized in such a process is excessive, the melanin is colored black, and its uneven distribution is regarded as spots or freckles. Accordingly, an object of the present invention is to provide a highly safe anti-ulcer agent having a remarkable inhibitory action on gastric acid secretion and having few side effects, and a novel quinazoline derivative as an inhibitor against tyrosinase which greatly affects melanin biosynthesis, and a novel quinazoline derivative thereof. An object of the present invention is to provide an acid addition salt.

[0005]

Means for Solving the Problems General formula (1)

Embedded image (Wherein, X is a halogen atom, a lower alkoxy group, m is an integer of 0 to 2, A is a phenyl group, an anilino group, or
Nitro group, lower alkylamino group, lower alkoxy group,
A phenyl group substituted at any position with a halogen atom, or
Or lower alkyl group, lower alkoxy group, halogen atom
Which means a pyridyl group substituted at any position ) and an acid addition salt thereof useful as a pharmaceutical. The general formula (1) will be specifically described. Halogen atoms are fluorine, chlorine,
Bromine and iodine, a lower alkoxy group is a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group,
n- butoxy, iso- butoxy group, a number 1-6 alkoxy group having a carbon such as a tert- butoxy group, lower alk
A killamino group is a dimethylamino group or a diethylamino group
And so on.

The addition salts of pharmaceutically acceptable acids are 1
It consists of equivalents or two equivalents of acid. Suitable salts include, but are not limited to, hydrochloric acid, sulfuric acid,
Inorganic acids such as nitric acid and phosphoric acid, and maleic acid, fumaric acid,
Organic acids such as oxalic acid, succinic acid, malonic acid, lactic acid and citric acid.

When the compound represented by the general formula (I) or an acid addition salt thereof is used as a medicament, it may be used in the form of tablets, powders, capsules, injections, suppositories and the like as it is or together with excipients known per se. Can be stably administered orally or parenterally. The dose is appropriately determined depending on the individual case in consideration of the symptoms, the age of the administration subject, the sex, etc. Usually, when orally administered as a therapeutic agent for gastric / duodenal ulcer or acute gastritis, the general formula The compound represented by (I) or an acid addition salt thereof is used in a single dose of 1-2.
It is convenient to administer about 00 mg / kg about 1 to 3 times a day.

Next, a method for producing the compound of the present invention will be described. The compounds of the present invention can be obtained in good yields by the methods described below, but the scope of the present invention is not limited thereto.

Manufacturing method 1

Embedded image (In the formula, Hal represents a halogen atom such as chlorine, fluorine, or bromine, and A and m have the same meanings as described above.) General formula (II)
Using a halogenating agent such as phosphorus oxychloride or phosphorus pentabromide in the absence of a solvent or in a solvent of 20 to 1
Compound (Ia) can be obtained by reacting at 50 ° C. for several minutes to several hours. Further, if necessary, compound (Ia) can be prepared by using an oxidizing agent such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide or the like, and halogenating hydrocarbon such as carbon tetrachloride, dichloromethane or chloroform. The compound (Ib) can be obtained by reacting at −40 ° C. to 100 ° C. in various solvents for several minutes to several hours.

Manufacturing method 2

Embedded image (In the formula, R represents a lower alkoxy group, Hal., A, and m have the same meanings as described above.) The compound represented by the general formula (Ia) obtained by the above-mentioned production method 1 is used together with methanol, ethanol, propanol, The compound (Ic) can be obtained by reacting a lower alcohol with 20 to 120 ° C. for 1 to 24 hours in various solvents in the presence of a base such as sodium hydride. Further, if necessary, compound (Id) can be obtained by a method similar to the oxidation method in Production Method 1 described above.

The starting compound represented by the general formula (II) can be prepared by a generally known method (JP-A-63-30187).
No. 3) can be easily synthesized.

[0012]

The present invention will be described more specifically with reference to the following examples. Of course, the present invention is not limited to only these examples.

Example 1 2- (2-dimethylaminobenzylthio) -4-chloroquinazoline 2- (2-dimethylaminobenzylthio)-
4g of 4 (3H) -quinazolinone and 6m of phosphorus oxychloride
was refluxed for 30 minutes, and the reaction product was poured into 200 ml of ice water, neutralized with an aqueous sodium hydroxide solution, extracted with chloroform, washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (developing solvent, chloroform), and recrystallized from isopropyl ether to obtain 2.9 g of 2- (2-dimethylaminobenzylthio) -4-chloroquinazoline.

Melting point 51-53 ° C Elemental analysis C₁₇H₁₆ClN 3S calculated value C: 61.90 H: 4.89 N: 1
2.74 Found C: 61.57 H: 4.83 N: 1
2.66

Example 2 2- (2-Dimethylaminobenzylthio) -4-methoxy-quinazoline 2 g of 2- (2-dimethylaminobenzylthio) -4-chloro-quinazoline and 0.3 of methanol
g was added to 15 ml of dimethylformamide, and 0.36 g of sodium hydride was further added under ice-cooling, followed by stirring at room temperature for 15 hours. After completion of the reaction, 10 ml of water and hydrochloric acid were added to adjust the pH to 4, followed by extraction with chloroform, washing with water,
After drying, the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (developing solvent, chloroform) and distilled under reduced pressure to obtain 0.64 g of 2- (2-dimethylaminobenzylthio) -4-methoxy-quinazoline.

Boiling point: 215 to 220 ° C./0.1 mmH
g Elemental analysis C₁₈H₁₉N 3OS calculated value C: 66.43 H: 5.88 N: 1
2.91 found C: 66.28 H: 5.75 N: 1
2.98

Example 3 2- (2-dimethylaminobenzylsulfinyl) -4
2.9 g of -chloro-quinazoline 2- (2-dimethylaminobenzylthio) -4-chloro-quinazoline was dissolved in 150 ml of dichloromethane, 1.8 g of m-chloroperbenzoic acid was added under ice cooling, and the mixture was stirred for 1 hour. . The reaction solution was washed with an aqueous sodium hydrogen carbonate solution, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: chloroform: methanol = 30:
Separation and purification in 1) and recrystallization from isopropyl ether gave 0.45 g of 2- (2-dimethylaminobenzylsulfinyl) -4-chloro-quinazoline.
I got

Melting point 114-117 ° C Elemental analysis C₁₇H₁₆ClN 3OS calculated value C: 59.04 H: 4.66 N: 1
2.15 Found C: 58.94 H: 4.59 N: 1
1.90

Examples 4 to 26 According to the methods of Examples 1 to 3, compounds represented by the general formula (I) were synthesized. Table 1 below shows the substituents in the general formula (I) and the melting points of the obtained compounds.

[0020]

[Table 1]

[0021]

[0022]

[0023]

According to various pharmacological experiments on anti-ulcer, the compound of the present invention has a remarkable inhibitory effect on gastric acid secretion, has been found to be safe with few side effects, and is very useful as an anti-ulcer agent. I can say.

The compound of the present invention has been found to significantly inhibit tyrosinase activity, which greatly affects melanin biosynthesis, and can be expected to be used as a whitening cosmetic.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ identification code FI A61K 31/517 A61K 31/517 A61P 17/00 A61P 17/00 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 239/72-239/96 C07D 401/12 A61K 7/00 A61K 31/517 A61P 17/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (1) In the formula, X represents a halogen atom, a lower alkoxy group, and m represents 0
A represents a phenyl group, an anilino group, or
Toro, lower alkylamino, lower alkoxy, c
A phenyl group substituted at any position with a logen atom, or
Is a lower alkyl group, a lower alkoxy group, or a halogen atom
A quinazoline derivative represented by a pyridyl group substituted at an arbitrary position ), and an acid addition salt thereof useful as a medicament.