JPH045003B2 - - Google Patents

Description

[Detailed description of the invention]

FIELD OF THE INVENTION This invention relates to anti-ulcer agents. PRIOR ART Many drugs are used for the treatment of ulcer diseases, and these drugs are mainly included in the group of so-called histamine- _H2 -receptor blockers, such as cimetidine and its derivatives, pirentzepine, etc. , and other derivatives included in the group of Anxiolyteix (S. Kobayashi et al.: Arzneim, Forsch. 31,
679, 1981), and is included in the group of intestinal anti-inflammatory agents, such as carbenoxolone [F. Tarnok:
Druga Exp. Clin. Ren. 5, 157, 1979] and proglumide [SE Miederer et al.:
drugs. Atropinium chloride, optionally also natural compounds, such as extracts from Glycyrrhiza Glabra or compounds in polyisoprenoid form (M. Mouukami et al.: Arzneim. Forsch. 31, 799,
(1981). In addition, local anesthetic oxesacaine [J. Seifert et al.: Proc.
Soc. Exp. Biol. Med. 109, 664, 1962] is used as an antacid suspension or mixed with procaine [F. Svec: Farmakodynamika
liekov I, Slorak Academy of Scieiice
Eratislava, 1953]. The disadvantage of the conventionally used compounds is that they have side effects, for example cimetidine and its derivatives damage the gastric mucosa [M. Guslandi: Int. J. Clin. Pharmakol. 18, 140,
1980), have an unfavorable effect on motility, and have weak or no antacid effect [V. Jirasek: Farmakotherap.zpravy no. 4,
43, 1980]. (Structure of the Invention) The above disadvantages are caused by the following formula of this invention: Trans-2-(1-pyrrolidinyl)cyclohexyl ester of 3-n-pentyloxycarbanylic acid represented by, or its salt with a pharmaceutically acceptable inorganic or organic acid as an active ingredient,
It is removed by an orally administered antiulcer agent containing a physiologically harmless carrier and/or an antacid component. (Specific explanation of composition) The active ingredient of the medicament of this invention, i.e. 3-n-
Trans-2- of pentyloxycarbanilic acid
(1-Pyrrolidinyl cis and hexyl ester, or its hydrochloride, is a known compound produced in connection with research on carbanilic acid derivatives with local anesthetic effect (Ciekoslovakia Patent No. 125666 and No. 126102).General It has membrane stabilizing effect, local anesthetic effect and antispasmodic effect, and maintaining its effect at low pH is important for its anti-ulcer effect.
And it is a proven prerequisite. The medicament of this invention exhibits a higher anti-ulcer effect than conventional medicaments under experimental ulcerative conditions caused by acute fatigue, and has a significant protective effect even after a single administration. This medicine has already known local anesthetic and antispasmodic effects (P. Svetsk et al.: Farm. obzor 45, 355, 1976). Nature, occurrence and development of local anesthetic effects in low PH media;
Connection, after-effects and storage, activity on the acidic side [S. Stolc et al.: Brat.Lek.Liaty70, 297,
1978], low acute toxicity immediately after oral administration, low side effects, and toxicity measured after one month of administration are sufficient to meet the requirements for the healing of gastric ulcers. The active ingredient of the medicament of this invention, namely 3-n-
Trans-2- of pentyloxycarbanilic acid
(1-pyrrolidinyl)cyclohexyl ester 1.0
mg/Kg and 10.0 mg/Kg were administered to Wistar rats, and 30 minutes later, acute fatigue due to swimming was initiated.
When given twice, the substance showed a significant protective effect as far as ulcer frequency, gastric lesion size and ulcer incidence index were concerned. Single administration of the active ingredient of the invention to rats under the above conditions at doses of 1.0 mg/Kg and 10 mg/Kg reduced the incidence of ulcers by 27% and 33%, respectively, compared to control animals; /Kg 5
and 10 repeated doses of 10 mg/Kg reduced the number of animals with ulcers by 30% and 37%, respectively. The average size of gastric lesions after single or repeated administration of the active ingredient of this invention was significantly smaller depending on the dose. Under the same experimental conditions,
Oxesacaine, used as a control, did not affect the size of the gastric lesions, but rather increased them. The active compounds of the invention substantially reduced the ulcerogenic index in comparative tests with oxesacaine, atropine and controls. in repeated administration
Only a dose of 10 mg/Kg was effective. In contrast, oxesacaine did not affect or increased the ulcerogenic index. Active compounds of this invention, antacids, combinations of active compounds of this invention with antacids (gel I) comprising aluminum phosphate and pectin, commercially available products containing active compounds of this invention and gels of aluminum hydroxide In experiments under the same conditions looking at the effect of the combination of the active compounds of the invention with Gel I and of the combination of magnesium hydroxide and oxesacaine, it was found that the combination of the active compounds of the invention with Gel I most strongly inhibited the formation of ulcers;
Reduced the size of gastric lesions by 73% and 73%, respectively.
78% inhibition was reached. 2mg/Kg each 5 times and 10 times
The combination was the most effective even after 5 repeated administrations of mg/Kg, reaching up to 80% inhibition. As a control, 5 ml of distilled water per kg of rat body weight was always administered. The effect of the combination was also most pronounced in the measurement of ulceration index values. In determining the acute toxicity of the active compounds of the invention, the following LD ₅₀ values (mg/Kg) were obtained:

[Table] In toxicity tests when doses of 0.1 mg/Kg, 1.0 mg/Kg and 10 mg/Kg were orally administered to urester rats for 1 month, no symptoms of toxic effects were observed in both behavior and body weight of the animals. He didn't appear. However, at the two highest doses, weight gain was in some cases lower than the average daily weight gain. There was no significant difference in % weight gain at the end of the experiment. In the analysis of the weights of the organs tested, the weights of the adrenals and kidneys increased only sporadically in response to the dose. Blood status did not show any signs of toxic effects; rather, red blood cell counts and hemoglobin levels were better at the end of the experiment than at the beginning. Biochemical parameters also do not show any signs of toxic effects. Most findings are indistinguishable from controls on histological examination. Vacuolar dystrophy and other types of dystrophy of a reversible nature that are expected to return to normal after removal of the inducing agent sometimes occur. Local irritation tests for intradermal and intramuscular administration did not show any abnormality or irritation effect. The medicaments of this invention may be prepared by dissolving a suitable salt of the active compound in water or other pharmaceutically acceptable liquid and semi-liquid carriers, or by dissolving the base of the active compound in a suitable solvent, especially an ether, if desired. and, with the addition of customary auxiliary compounds, can be formulated into solid pharmaceutical forms, for example tablets. In liquid medicines, the usual stabilizing additives may be added, such as phosphate buffers, emulsifiers (Solbimacrogel), suspension or emulsion stabilizers (e.g. cellulose esters, silicon dioxide hydrate, bentonite, etc.) In the case of solid pharmaceuticals, for example, starch, lactose, methyl cellulose, gelatin, dextran, magnesium stearate, microcrystalline cellulose, etc. can be added. Based on the expected daily dosage, the amount of base in the medicine should be in the range of 1 to 50 mg without destruction or decomposition. The starting active compounds of the invention are, as described above,
It can be produced by the method of Czechoslovakia Patents No. 125666 and No. 126102. The medicament of the invention can be administered to humans for one day in the usual dosage forms, e.g.
10-200 mg can be administered in several divided doses if desired. Similarly, the agents of the invention can be used as veterinary medicine, for example for inhibiting neurological damage to the gastric mucosa in commercial animals. The following examples are two specific examples of dosage forms of this invention. However, the scope of the present invention is not limited to the scope of this example. Example 1 Tablet with anti-ulcer effect 10 g of active compound are mixed with 10 g of lactose, 138 g of starch and moistened with the desired amount of starch aqueous gel. After the mixture is granulated and homogenized, 2 g of magnesium stearate are added and compressed into tablets with a diameter of about 5 mm and a weight of about 250 mg. One tablet corresponds to 10 mg of active compound. Tablets containing 5 mg of active ingredient can also be produced in a similar manner. Example 2 Anti-ulcer suspension 50 mg of active compound are dissolved in 20 ml of distilled or deionized water and this is mixed with a suspension prepared from 14.55 g of aluminum hydroxide and 4.90 g of magnesium hydroxide. Equalize. The suspension thus prepared contains 1 mg of active compound in 5 ml, 291
Contains mg aluminum hydroxide and 92 mg magnesium hydroxide.

Claims (1)

[Claims] 1 The following formula, Trans-2-(1-pyrrolidinyl)cyclohexyl ester of 3-n-pentyloxycarbanylic acid represented by, or its salt with a pharmaceutically acceptable inorganic or organic acid as an active ingredient,
An antiulcer agent comprising a physiologically harmless carrier and/or an antacid component.