JPH0580479B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to novel tetrazole derivatives. Prior Art The tetrazole derivative of the present invention is a novel compound that has not been described in any literature. DISCLOSURE OF THE INVENTION The present invention is based on the following general formula

It relates to a tetrazole derivative represented by the following formula: (wherein R ¹ represents a lower alkyl group, and n represents an integer of 1 or 2). In the above general formula 1, the lower alkyl group represented by R ¹ has 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl group, etc.
Mention may be made of straight-chain or branched alkyl groups. The compound of the present invention has a blood sugar lowering effect, a lipid lowering effect, an aldose reductase inhibitory effect, etc., and is useful as a medicine such as a diabetic agent and a cataract agent. The tetrazole derivative represented by the general formula (1) according to the present invention can be obtained by reacting an aldehyde derivative represented by the general formula (2) with a compound represented by the formula (3), for example, as shown in the following reaction scheme. can be manufactured. <Reaction process formula>

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[Chemical formula] (In the formula, R ¹ and n are the same as above.) The aldehyde derivative (2) is a conventional aldol condensation,
It is condensed with compound (3) under the conditions of Knevenagel condensation reaction to produce compound (1) of the present invention. These condensation reactions are well-known reactions, such as those listed in the Organic name reactions of the Merck Index 10th Edition.
reactions). Catalysts used in this condensation include water containing alkali metals or alkaline earth metals such as potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, and sodium acetate. Oxides, carbonates, alkoxides, their organic acid salts, amines such as methylamine, ethylamine, diethylane, triethylamine, aniline, nicotine, pyridine, piperidine, ammonia, and organic anhydrides such as acetic anhydride and propionic anhydride. used. The ratio of aldehyde derivative (2) and compound (3) to be used can be selected as appropriate, but it is generally preferable to use about 1.0 to 1.2 times mole of (3) to (2). The reaction is usually carried out under heating, and generally proceeds advantageously at the reflux temperature of the solvent. As the solvent, alcohols such as methanol and ethanol, ethers such as dioxane, acetic acid, etc. are used. The tetrazole derivative of the present invention produced by the above reaction can be easily isolated by conventional separation means such as recrystallization, column chromatography, etc. The present invention includes any geometric isomer of general formula (1). It also includes acid addition salts, alkali metal salts, alkaline earth metal salts, hydrates, etc. of general formula (1). The aldehyde derivative represented by the general formula (2) used as a raw material is a new compound, and can be produced, for example, by the method shown in the reaction scheme below. <Reaction equation>

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[Formula] (In the formula, R ¹ is the same as above. R ² means a lower alkyl group.) That is, the dienoic acid derivative (4) is converted into an ester derivative (5) with, for example, alkanol sulfuric acid, and this is converted into an ester derivative (5), for example, with diisobutyl Reduction with aluminum handlide gives alcohol derivative (6). Subsequently, the dienaldehyde derivative (7) can be obtained by oxidation, for example, with pyridinium chlorochromate. Furthermore, tetrazolylmethylrhodanine, which is represented by compound (3) as a raw material, is a new compound and can be produced, for example, by the method shown in the reaction scheme below. <Reaction equation>

embedded image That is, the tetrazolylmethylrhodanine compound (3) can be obtained by heating and refluxing the tetrazole derivative (8) and the dithioacetic acid derivative (9) in ethanol water in the presence of triethylamine. Next, the present invention will be specifically explained with reference to reference examples and examples. Reference example 1 4-(5-methylisoxazol-3-yl)-
2.3 g of 1,3-pentadienoic acid was added to 100 ml of methanol and 10 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 8 hours. After the reaction, most of the solvent was distilled off, ice water was added to the residual liquid, the precipitated crystals were collected, and recrystallized from methanol to give methyl 4-(5-methylisoxazol-3-yl) with a melting point of 113-114°C. )−
1,3-pentadienoate 2.1g (yield 84.7%)
I got it. Elemental analysis (as C ₁₀ H ₁₁ N ₁ O ₃ ) C H N Calculated value (%) 62.17 5.74 7.25 Actual value (%) 62.02 6.00 7.18 Reference example 2 Methyl 4-(5-methylisoxazole-3-
2.1 g of diisobutylaluminum hydride (2.1 g)-1,3-pentadienoate was dissolved in 50 ml of dichloromethane, and 24 ml of a 25% toluene solution of diisobutylaluminum hydride was added dropwise while cooling to below -70°C. 2 below -40℃ after dropping
The reaction was carried out for a period of time, and the excess reducing agent was decomposed with a methanol solution containing 10% water. The organic layer was separated and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off to give 4-(5-methylisoxazol-3-yl)-
1,3-pentadienol 1.3g (yield 72.4%)
I got it. MS spectrum (m/e): 165 (M ⁺ ). Nuclear magnetic resonance spectrum ( _CDCl3 ), δ (ppm): 1.95 (1H, t), 2.40 (3H, s), 4.27 (2H, t), 5.70-6.16 (1H, m), 6.11 (1H, s) , 6.20-6.90 (3H, m). Reference example 3 4-(5-methylisoxazol-3-yl)-
Dissolve 1.2 g of 1,3-pentadienol in 30 ml of dichloromethane and add pyridinium chlorochromate.
2.8 g was added at room temperature and stirred for 4 hours. After the reaction,
The organic layer was separated and concentrated. The residue was purified by column chromatography (developing solvent was chloroform) to obtain 0.35 g of 4-(5-methylisoxazol-3-yl)-1,3-pentadienal with a melting point of 134-135°C (yield: 29.5%). Elemental analysis (as C ₉ H ₉ N ₁ O ₂ ) C H N Calculated value (%) 66.25 5.56 8.58 Actual value (%) 65.90 5.31 8.51 Reference example 4 5 g of aminomethyltetrazole (compound (8)) was mixed with 50 ml of water and ethanol Into 100 ml of the mixed solution, 7 ml of triethylamine was added dropwise and dissolved. Then carboxymethyl trithiocarbonate (compound (9))
11.3 g was added and heated under reflux for 4 hours. After cooling the reaction, remove the precipitate and recrystallize it from water to obtain a melting point of 173°C.
8 g (yield 73.7%) of 3-(tetrazol-5-yl)methylrhodanine (compound (3)) was obtained. Elemental analysis (as C ₅ H ₅ N ₅ OS ₂ ) C H N Calculated value (%) 27.90 2.34 32.53 Actual value (%) 28.25 2.25 32.56 Example 1 3-Methyl-isoxazole-5-acrylaldehyde 0.25 g, 3- (tetrazol-5-yl)
Methylrhodanine 0.6g, anhydrous sodium acetate
Add 0.2g to 7ml of acetic acid, then add 0.3ml of acetic anhydride.
was added, and the mixture was heated and stirred for 1 hour. After the reaction, the precipitate was collected by filtration and recrystallized from acetic acid to obtain 5-[(3-methyl-5-isoxazole) with a melting point of 265-266°C (decomposition).
-1,3-propanediene]-3-(5-tetrazolylmethyl)rhodanine (compound 1) 0.28 g
(yield 45.6%). Example 2 Compounds 2 and 3 shown in Table 1 were synthesized in the same manner as in Example 1.

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Claims (1)

[Claims] 1. A tetrazone derivative represented by the general formula: (wherein R ¹ represents a lower alkyl group, and n represents 1 or 2).