JPS6310701B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the formula [] The present invention relates to a novel thiazole derivative represented by, a method for producing the same, and an anti-peptic ulcer agent containing this derivative as an active ingredient. The novel thiazole derivative of the present invention (hereinafter abbreviated as "the present compound") has an excellent anti-peptic ulcer effect and is low in toxicity, so it is useful for gastric and duodenal ulcers. Furthermore, the present compound has a mild blood pressure lowering effect, a sedative effect on the central nervous system, and has no undesirable central nervous system effects such as motor nerve suppressing effect, so it can also be used as a blood pressure lowering agent or tranquilizer. Peptic ulcers are ulcers formed when weakened portions of the gastric and intestinal mucosa collapse under the action of aggressive factors such as hydrochloric acid and pepsin. Mild cases can be cured in 3 to 4 months with hospitalization, but severe cases can cause bleeding and perforation, becoming chronic. The cause of this disease is believed to be abnormalities in the autonomic nervous system caused by physical and mental stress, abnormalities in mucosal blood flow, etc., but since the internal organs themselves are complexly controlled by neurohormones, the etiology cannot be explained as one-dimensional. It is practically impossible to interpret it. As anti-ulcer agents, sodium hydrogen carbonate, aluminum salts, magnesium salts, etc. have long been used to neutralize acids as attack factors. However, these agents only temporarily neutralize acid and alleviate pain, but do not promote essential healing of ulcers. In recent years, a variety of anti-ulcer agents have been developed based on the assumed causes of ulcers, such as autonomic nerve suppressants, so-called anticholinergic agents, tissue repair agents, and blood flow improving agents. However, it is difficult to say that either of these drugs is fully satisfactory in terms of efficacy or side effects. The first problem in the development of antiulcer agents is the screening system. Many conventional anti-ulcer agents have been evaluated for their preventive effects on acute ulcers such as pyloric ligation ulcer, aspirin ulcer, and intomesacin ulcer. However, sufficient evidence has not yet been provided as to how much the results from these ulcer models reflect the therapeutic effects of human ulcers. In view of these points, the present inventors screened a large number of compounds using an animal chronic ulcer model, which is said to be the closest to human ulcers, and found that the present compound shown in the above formula [] was extremely excellent. The present invention was achieved based on the discovery that it exhibits medicinal efficacy. The present invention will be explained in detail below. This compound can be produced by the following method. That is, 3,4,5-trimethoxythiobenzamide is heated with an equimolar to slightly excessive amount of 3-haloacetylacetone in an inert solvent such as benzene, toluene, or xylene for 1 to 10 hours. The reaction temperature is preferably 50 to 150°C, but usually the boiling point of the solvent used may be used. The reaction formula is as follows: On the other hand, 3,4,5-trimethoxythiobenzamide can be easily produced by reacting 3,4,5-trimethoxybenzamide with phosphorus pentasulfide. Therefore, in the above reaction, 3,4,5-trimethoxythiobenzamide was used instead of 3,4,5-trimethoxythiobenzamide.
-A mixture of trimethoxybenzamide and phosphorus pentasulfide may be used. Reaction formula: After the completion of these reactions, when the reaction solution is cooled, crystals will precipitate, which can be collected and recrystallized with a solvent such as ethanol or methanol to obtain the desired product. In addition, in the above-mentioned crystallization separation step, a phenomenon was observed in which it was relatively difficult to crystallize and separate the present compound from the reaction mixture. As a result of intensive studies to improve this point, we found that from an industrial production standpoint, the present compound can be crystallized and separated very effectively by extracting the reaction solution with an acid, particularly diluted hydrochloric acid, and neutralizing the diluted hydrochloric acid layer. was discovered. The physical properties of the compound thus obtained are as follows: 1 Melting point 128-129°C 2 Elemental analysis theoretical value (%): C: 58.63, H: 5.54, N: 4.56, S :10.42 Actual value (%): C: 58.59, H: 5.56, N: 4.57, S: 10.45 3 The infrared absorption spectrum is as shown in Figure 1. 4 The mass spectrum is as shown in Figure 2. Next, the pharmacological effects and mode of use of this compound will be shown. (1) To summarize some of the anti-ulcer effects of this compound, for example, in a test using rats whose pylorus was ligated by the method of Shay et al. The rate is
The efficacy of this compound was 85%, and was approximately 11% superior to that of the commercially available anti-ulcer agent gefalnate, which was used as a control, at the same dose. Furthermore, the rat acetic acid ulcer method is considered to be the most similar experimental model to human peptic ulcers (Okabe, 1971).
This compound also showed an ulcer healing rate of 80% when administered at 100 mg/Kg, which was higher than 20% of the above commercially available anti-ulcer agents.
%. This experimental model makes ulcers more difficult to cure than the cautery ulcer method (SKoryna, 1958) and the clamping cortisone method (Umehara, 1965), which are frequently used as screening methods for peptic ulcer therapeutics.
It has received worldwide recognition because it does not heal spontaneously and the histopathological changes in the ulcer area are similar to human chronic ulcers. We further evaluated this compound using methods that have been commonly used to screen for clinically effective anti-ulcer agents, such as the stress ulcer method and the aspirin ulcer method. It was found to be more effective than anti-ulcer drugs. (2) In toxicity tests using rats and mice, the LD ₅₀ for oral administration was 5 g/Kg or more, and for intravenous administration
_LD50 was 1.5g/Kg or more. Furthermore, mice were fed with feed containing the present compound for 3 months, during which time general symptoms, body weight changes, and feed intake were observed. The intake amount of this compound at this time was 200 mg/Kg, but no difference from the control group was observed in all test items. After breeding, the mice were sacrificed and the liver, kidneys,
Major organs, including the heart and spleen, were observed, and tissue specimens were prepared and examined under a microscope. In addition, blood and urine were collected at the time of slaughter and biochemical tests were performed, but no abnormal findings due to this compound were observed in these tests. In this way, this compound is extremely safe,
It can be safely used as an anti-peptic ulcer agent in humans. (3) The clinical dose of this compound is 60 mg per person per day.
mg to 6000 mg, preferably 100 mg to 3000 mg. The administration method may be oral or injection, but oral administration is preferred in view of the possibility of long-term administration. The compounds are also miscible with excipients, surfactants, binders, and lubricants. Moreover, the dosage form and prescription are not limited in any way, but one example of formulation is as follows. That is, the present compound was finely ground to a size of 1 to 50 microns, mixed with commonly used excipients such as starch and lactose, and a thickening agent made from sodium carboxymethyl cellulose, gum arabic, starch, etc. was added and kneaded. Afterwards, it is formed into granules using an extrusion granulator, dried and sieved to obtain oral granules. The compound usually contains 0.1 to 90wt in the agent.
%, preferably 1 to 60 wt%. Next, the present invention will be explained in more detail with reference to Examples. Example 1 2-(3,4,5-trimethoxyphenyl)-
Synthesis of 4-methyl-5-acetylthiazole 3,4,5-trimethoxythiobenzamide
22.7 g (0.1 mol) and 16.0 g (0.12 mol) of monochloroacetylacetone are dissolved in 200 ml of benzene and heated under reflux for 3 hours. After cooling, the precipitated crystals were collected and recrystallized from methanol. Yield: 24.5 g (yield 79.8%) Pale yellow needle crystals Melting point: 128-129°C [Elemental synthesis value] C ₁₅ H ₁₇ O ₄ SN as C H N S Theoretical value 58.63 5.54 4.56 10.42 Actual value 58.59 5.56 4.57 10.45 Example 2 2-(3,4,5-trimethoxyphenyl)-
Synthesis of 4-methyl-5-acetylthiazole 3,4,5-trimethoxybenzamide 21.1g
(0.1 mol) and monochloroacetylacetone 16.0g
(0.12 mol), and 4.4 g (0.02 mol) of phosphorus pentasulfide
was added to 250 ml of benzene and heated under reflux for 5 hours. Although the coolant was left to stand, no crystallization was observed. Example 3 Crystallization Separation Method The reaction solution obtained in Example 2 was shaken with 100 ml of 10% hydrochloric acid, and the hydrochloric acid layer was taken and neutralized with 10% NaOH to precipitate crystals. The precipitated crystals are collected and recrystallized from methanol. Yield 20.8g (yield 67.8
%), melting point 128-129°C Example 4 Anti-ulcer effect Effect of this compound on pylorus ligation ulcer Male rats weighing 180-200 g, 10 rats per group were treated for 48 hours.
After fasting Shay et al; (Gastroenterology
The pyloric region of the stomach was ligated under ether anesthesia according to the method of 5.43.1945). Immediately after ligation, the drug was suspended in physiological saline and injected intraperitoneally. The control group was injected with physiological saline. After 15 hours of fasting and water deprivation, the animals were killed with ether and the stomachs were removed and observed under a dissecting microscope. The vertical and horizontal lengths of the developed ulcer were measured, and the sum of their products (mm ² ) was expressed as the ulcer coefficient. [Table] Example 5 Anti-ulcer effect Effect of the compound of the present invention on acetic acid ulcer Using male rats weighing 240 to 260 g and 15 rats per group, Okabe et al. (Amer. J. Rlg. Dis. 16 , 277, 1977) According to the method described above, a metal circular frame was placed on the serosa 5 to 7 mm from the pylorus of the duodenum under ether anesthesia, and 0.06 ml of glacial acetic acid was poured into it. After 30 seconds, the acetic acid solution was removed and the frame was placed. Removed. The drug was suspended in physiological saline and orally administered three times a day for 10 consecutive days starting from the third day after surgery. After the administration, the rats were killed with ether, and the duodenum was removed and observed under a dissecting microscope. The vertical and horizontal lengths of the developed ulcer were measured, and their product (mm ² ) was expressed as the ulcer coefficient. [Table] Example 6 Production of granules for oral administration 200 g of the present compound was pulverized, 800 g of corn starch was added thereto and stirred, then 80 ml of water in which 3 g of sodium carboxymethylcellulose was dissolved was added and kneaded, followed by extrusion. After molding into granules using a granulator, they are dried at 60 to 80°C and sized to produce granules.

[Brief explanation of the drawing]

Attached Figure 1 shows the infrared absorption spectrum of the thiazole derivative of the present invention, and Figure 2 shows its mass spectrum.
It is a spectrum diagram.

Claims (1)

[Claims] 1 Formula [] 2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole represented by 2 formula [] 3,4,5-trimethoxythiobenzamide and the formula [] (However, X represents a halogen atom) 2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole characterized by heating and reacting with 3-haloacetylacetone represented by Production method. 3. The method according to claim 2, wherein the heating reaction is carried out at a temperature of 50 to 150°C. 4 formula [] 3,4,5-trimethoxybenzamide and the formula [] (However, X represents a halogen atom) 2- characterized by reacting with 3-haloacetylacetone and phosphorus pentasulfide represented by
A method for producing (3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole. 5 formula [] An anti-peptic ulcer agent characterized by containing 2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole as an active ingredient.