JPH0419967B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for peptic ulcers containing dipyrubicin triureide as an active ingredient. The etiology of peptic ulcers cannot necessarily be interpreted uniformly and is thought to occur as a result of several factors closely interrelated; It is believed that the main cause is an imbalance of factors. Conventionally, therapeutic agents for peptic ulcers act on any of the above-mentioned ulcerogenic factors. In other words, drugs aimed at suppressing aggressive factors include antacids, antipepsin drugs, anticholinergic drugs, antigastrin drugs, and antihistamine _H2 drugs, while drugs aimed at enhancing defensive factors include is a gastrointestinal mucosal repair promoter. Specific examples of the former drugs include dimetidine, suralfate, urogastrone, aluminum hydroxide gel, valetamate bromide, butyl scopolamine bromide, and specific examples of the latter drugs include aldioxa, gephalnate, L-glutamine, etc. can be mentioned. Cimetidine, a drug that suppresses aggressive factors, requires a large dose and has side effects on the endocrine system due to its anti-androgien effect and prolactin-elevating effect, while anticholinergic drugs may cause dry mouth, difficulty urinating, and worsening of internal disorders. Side effects of antacids include constipation and other side effects, which are not always satisfactory. Although protective factor-enhancing drugs have relatively few side effects and are easy to use, they are still not sufficient to rapidly and significantly suppress peptic ulcer disease. Especially,
Since no satisfactory therapeutic agents for intractable ulcers have yet been found, the emergence of effective therapeutic agents in this field is particularly desired. In view of the above circumstances, the present inventors have conducted various studies and have already discovered that 5-lower alkylalantoins and their aluminum salts have excellent therapeutic effects on peptic ulcers, and have filed a patent application. Based on this knowledge, in the course of further investigation, it was newly discovered that dipirvic triureide has an excellent therapeutic effect on peptic ulcers, and as a result of further research, the present invention was completed. The drug of the present invention is a therapeutic agent for peptic ulcers containing dipirubitric triureide as an active ingredient, and an object of the present invention is to provide a therapeutic agent having such medical value. Dipyruvic triureide, which is the active ingredient of the drug of the present invention, is a compound represented by the following chemical formula (). This compound has been described in the literature [J.Amer.Chem.
Soc.), Vol. 47, p. 255 (1925);
This is a known compound obtained by the method described in Bull.Chem.Soc.Japan, Vol. 39, p. 1559 (1966). is not known at all. Compared to other compounds that have peptic ulcer therapeutic effects such as 5-lower alkylalantoins, this compound is industrially very easy to use (specifically, in short steps, high yield, and low cost). It is a stable compound produced. Furthermore, although this compound is normally contained in the therapeutic agent of the present invention in a free state (including its hydrated form), it may be used in the form of its salt because it has a ureido group, and such salts As, alkali metals such as sodium and potassium,
Examples include salts with alkaline earth metals such as calcium and magnesium, metals such as aluminum, or their hydroxides or halides. The active ingredient of the therapeutic agent of the present invention, dipyrvictriureide, may be administered as it is, but if desired, it can be formulated into a suitable dosage form along with carriers or adjuvants and other active substances.
The above-mentioned carriers or adjuvants include organic or inorganic substances that are suitable for oral, parenteral or topical administration and do not react with dipyruvial triureide or its salts, such as solubilizing agents or solubilizing agents, emulsifying or suspending agents. These agents are selected from those that have functions such as oxidizing agents, stabilizers/excipients, binders, disintegrants, lubricants, and preservatives.More specifically, water, oils and fats (vegetable oils, mineral oils, animal oils, glycerin esters of fatty acids, etc.), alkylene glycols, alcohols, higher fatty acids,
Examples include carbohydrates (cellulose, starch, lactose, sucrose, mannitol, etc.), proteins (gelatin, peptides, etc.), talc, surfactants, etc. Dosage forms for oral administration include tablets,
Capsules, pills, granules, fine granules, powders, liquids, syrups, etc. are used as dosage forms for parenteral administration, such as intramuscular injections, and dosage forms for topical administration include: Examples include suppositories, injections, oral preparations, and skin application preparations. Preparations having these dosage forms can be manufactured by methods known per se. Furthermore, examples of the above-mentioned other active substances include absorption enhancers, sustained release agents, and known peptic ulcer therapeutic agents as described above. The therapeutic agent of the present invention is administered to humans, and the administration method thereof can be similar to that of known peptic ulcer therapeutic agents.
Oral administration, buccal administration, etc. are particularly preferred. The dosage of the therapeutic agent of the present invention is usually 0.03 to
The amount is about 5 g/day, preferably about 0.05 g to 3 g/day, and these doses are preferably administered in divided doses 2 to 5 times a day, but the dose for individual patients depends on many variables, For example, the dosage may be increased or decreased as appropriate depending on the patient's weight, age and health condition, administration method, administration interval, presence or absence of other drugs used concomitantly, severity of disease, etc. The therapeutic agents of the present invention include those used for the prevention and treatment of peptic ulcers. For prophylactic purposes, it is used when peptic ulcers are suspected or suspected, and to prevent flare-ups or relapses (particularly after discontinuing the use of antihistamine _H2 drugs). For therapeutic purposes, it is effectively used for mild or severe peptic ulcers caused by various factors, acute or chronic peptic ulcers, etc., and is particularly difficult to treat in the past. It is expected that it will also be effectively used for intractable ulcers. In the above-mentioned prevention or treatment, the therapeutic agent of the present invention is usually used alone, but other peptic ulcer therapeutic agents may be added or used in combination if desired. As shown in the experimental examples described below, the therapeutic agent of the present invention has superior effects compared to conventional drugs. Note that dipyrubicin triureide is a compound with extremely low toxicity and can be used safely. Synthesis example: Dissolve 2.1 parts of urea in excess concentrated hydrochloric acid, then add 1 part of pyruvic acid and leave at room temperature for 60 hours. The resulting solid was recrystallized from dilute ammonia water and acetic acid to obtain 1.6 parts (80%) of dipyrubicut triureide as colorless crystals with a decomposition point of 300°C or higher. Nuclear magnetic _{resonance spectrum} : δ (DMSO- _d6 ) 1.33 (singlet, _CH3 ), 6.62, 7.90 and _10.27 (each singlet, NH) Elemental analysis ( _C9H12N6O5・_2H2O ) Calculation Value: C, 33.75; H, 5.03; N, 26.24 Experimental value: C, 34.10; H, 4.58; N, 26.39 Thin layer chromatography: Rf value = 0.50 (Developing solvent n-butanol: dioxane: water =
4:1:2, using a silica gel plate and developing color with tert-butyl hypochlorite. Example 1 (granules and capsules) Dipirvic triureide 100 parts, lactose 2.5
part, crystalline cellulose 10 parts, carboxymethyl cellulose/calcium 10 parts, corn starch
Granules were produced using 100 parts of dextrin and 10 parts of dextrin according to a known method (for example, the method described in the general rules for formulations of the 10th edition of the Japanese Pharmacopoeia). In addition, hard capsules were obtained by encapsulating this product in gelatin capsules. Example 2 (Tablet) Dipirvic triureide was prepared using 50 parts of dipyruvic triureide, 70 parts of magnesium aluminate metasilicate, 70 parts of corn starch, 10 parts of dextrin, and 2 parts of magnesium stearate according to a known method.
Tablets were prepared containing 50 mg of dipirvic triureide per tablet. Furthermore, this product was coated with a coating agent consisting of sucrose, talc, tragacanth, and starch by a conventional method to obtain sugar-coated tablets. Experimental Example 1 (Effect on aspirin gastric disorder) <Experimental method> ddY male mice (5 weeks old, 1
Group of 6 animals, body weight 22-26 g)
triureide or aldioxa) is suspended in 1% gum arabic, and the volume of the dose is per 10 g of body weight.
0.05 ml of aspirin and 100 mg/Kg of aspirin were orally administered. 3.5 hours after the above administration, 0.2 ml/mouse of 1% trypan blue was administered into the tail vein, and 30 minutes later, the mice were sacrificed and their stomachs were removed. The removed stomach was incised along the greater curvature and the gastric mucosa was ``erosed''.
The length of the sample was measured under a stereomicroscope, and the sum of the lengths was calculated to determine the degree of gastric disorder. In addition, 0.05 ml/(10 g body weight) of 1% gum arabic containing no specimen was administered to the control group. <Results>

[Table] Ureide
Ardioxa 1.0 18.5 31.0

Claims (1)

[Claims] 1 Dipyruvic A peptic ulcer treatment containing triureide as an active ingredient.