RU1831338C - Medicine with anti-ulcer activity - Google Patents

Abstract

The invention relates to medicine and relates to the use of the compounds - (quinucyldyl-3) -di- (thienyl-2) carbinol and its pharmaceutically acceptable salts, for example, hydrochloride, as anti-ulcer drugs. Previously, these compounds are described as biologically active compounds having an antihistamine. antiserotonin and antiallergic activity. 1 ill., 3 tablets

Description

The invention relates to medicine and relates to the use of the compounds: (quinuclide-di-3) -di- {thienyl-2) carbinol of the formula I

ffS-c-O

iTi s

N OH s

U

and its pharmaceutically acceptable salts, for example, its hydrochloride (I), as new drugs with antisecretory and antiulcer effects.

Compounds I and II have previously been described as biologically active substances having antihistamine, antiserotonin and antiallergic activity.

In the USSR, peptic ulcer disease occurs in 2-3% of the adult population and to date, despite the increase in the number of new drugs, the traditional complex therapy of this disease in our country is not perfect enough, which creates the need to find more reliable means for treating peptic ulcer disease. Basically, the traditional complex therapy of gastric ulcer and duodenal ulcer includes anticholinergics (atropine, metacin, plastifillin); buffering antacids (phospholugel almagel); combined preparations Dvikalin, Roter); anti-inflammatory drugs that enhance the repair of the mucous membrane (trichopolum, oxyferriscorbone, gastroparm, methyluracil, steroid hormones, sea buckthorn oil, aloe, retabolil, etc.). However, as a rule, they are not effective enough and cause unwanted side effects. In recent years, abroad, there have been a number of drugs intended for the pathogenetic treatment of ulcer disease - antagonists of Ng-histamine receptors (renitidine, cimetidine), prostaglandins

(L

WITH

00 CJ

Oj

s

00

Gj

type E (enprostil), inhibitors of the K + / H-ATPase enzyme (omeprazole), etc. The listed drugs are not manufactured in our country.

At present, it is believed that Ngreceptor antagonists are the most effective anti-ulcer drugs that should be widely used in medical practice, and cimetidine remains the reference drug among them. Cimetidine is a strong inhibitor of gastric secretion, it suppresses the stimulating effect of such exo - gene pathogens of secretion as pentagastrin. histamine. From the point of view of anti-ulcer treatment, the ability of cimetidine to inhibit basal secretion is important. Endoscopic monitoring of treatment results with cimetidine om showed that healing of gastroduodenal ulcers within 3-4 weeks was noted in cases.

However, the therapeutic efficacy of cimetidine is combined with serious side effects. Thus, one of the disadvantages of cimetidine and other Na-histamine receptor blockers is withdrawal syndrome, which is manifested in that. that after stopping their intake, the secretion of acid by the stomach increases above the initial level, and this leads to an exacerbation of the disease.

As can be seen from the above, further improvement of existing ones, and the synthesis of new pharmacological agents continues to be an urgent task for the time being.

The purpose of the invention is a new agent with antisecretory and anti-ulcer properties.

This goal is achieved by the use of (quinuclidyl-3) -di- {thienyl-2) carbinol or its pharmaceutically acceptable salts, for example, hydrochloride, as drugs having antisecretory and anti-ulcer action.

(Quinuclidyl-3) -di- {hyenyl-2) carbinol- (compound I) is a white or yellowish-yellow crystalline powder insoluble in water, soluble in alcohols, chloroform, acetone, acids; molecular weight 305.47; melting point 215-218 ° C with decomposition.

The use of (quinuclidyl-3} -di-thienyl-2) carbinol in the form of pharmaceutically acceptable salts, for example, hydrochloride, having better than base physicochemical properties (greater

stability, better solubility in water} allows to enhance the anti-ulcer and antisecretory effect of the above base, not due to a change in the basic

pharmacological effect, and by improving bioavailability (increasing absorption from the gastrointestinal tract or other places of administration). Such a salt is (carbo nuclidyl-3-di- {thienyl-2) carbinol hydrochloride (compound I).

The hydrochloride of (quinuclidyl-3) -di- (thienyl-2) carbinol is a white or white, creamy-tinted crystalline powder; odorless, non-hygroscopic; very slightly soluble in water, 95 ° ethanol, practically insoluble in chloroform, acetone, ether. Molecular weight 341.928; melting point

0 252 ° C with decomposition.

A study of the pharmacological activity of compound I and its hydrochloride.

A study of the pharmacological activity of these compounds was carried out

5 in comparison with cimetidine, a well-known foreign anti-ulcer drug.

The study of antiulcer activity.

The study of anti-ulcer activity was carried out on male rats weighing 160-180 tons and male mice 20-22 g on different models of gastric ulcers caused by the administration of 300 mg / kg of histamine intraperitoneally; the introduction of intraperitoneal

5 10 mg / animal serotonin; the introduction of intraperitoneal 2.5 mg / kg reserpine; oral administration of 50 mg / kg voltaren: intraperitoneal administration of 40 mg / kg indomethacin; the introduction of 1 ml of absolute ethanol inside; stress exposure (immobilization + cold).

The results of a study of antiulcer activity are presented in Table 1.

5 It can be seen from Table 1 that compounds I and II have a dose-dependent antiulcer effect on the gastric ulcer model induced by the administration of histamine. The ED50 of compound l is 13 mg / kg orally, and

0 EDBO of compound II was 6.4 mg / kg orally, while EDbo of cimetidine was 35 mg / kg orally.

Thus, compounds I and II in this case are 3-5 times superior to cytimetine dyne.

In a model of gastric ulcers caused by administration of serotonin in rats, compounds 1 and II also exceeded cimetidine by more than 35 times. The Eso of Compound t is 36.8 mg / kg orally, the ED of Compound II is 27 mg / kg

by mouth, cimetidine at a dose of 100 mg / kg by mouth reduces the formation of ulcers by only 30%.

Compounds I and II at doses of 5.25.50 mg / kg inside rats have a pronounced anti-ulcer effect (ED of compound I is 5.3 mg / kg, ED of compound II is 2 mg / kg) in the model of gastric ulcers caused by the administration of voltaren and significantly (5-14 times) superior to cimetidine (ED50 28 mg / kg).

The claimed compounds I and II, when administered orally at doses of 5.10.25.50,100 mg / kg, provide a dose-dependent warning of the formation of stomach ulcers in rats after administration of absolute ethanol (I ml to the stomach). The EDU of compound I is 13 mg / kg orally, the EDU of compound II is 8 mg / kg orally. Under similar conditions, cimetidine is ineffective. According to published data, cimetidine at a dose of 400 mg / kg orally does not prevent the development of ulcerative lesions of the gastric mucosa in rats after ethanol administration.

In experiments in mice, the claimed compound II, when administered orally at doses of 10.25.50.00 mg / kg, prevents the formation of gastric ulcers caused by the administration of indomethacin. and significantly (12 times) superior to cimetidine.

By the method of Barnaulova O.D. et al. We studied in mice the effect of compounds I and II at doses of 10.25.50.100 mg / kg when administered orally to gastric ulcers caused by intraperitoneal administration of reserpine (2.5 mg / kg).

It was found that compounds I and II dose-dependently prevent the formation of gastric ulcers (Eso of compound I is 33 mg / kg, EDbO of compound II is 23 mg / kg), cimetidine under similar conditions is not very effective (even at a dose of 100 mg / kg) .

At doses of 5.10.25 mg / kg inward, Compounds I and II protect the gastric mucosa in rats from damage caused by stress exposure (immobilization combined with cold) (Compound I EDbO is 23 mg / kg; Compound I - 16 mg / kg ) According to the well-known data, during immobilization stress in rats, EDso cimetidine is 200 mg / kg orally.

Thus, a comparison of the activity of the claimed compounds I and If and the known drug cimetidine (in parallel experiments and according to published data) allows us to conclude that the claimed compounds I and II are superior in anti-ulcer activity to cimetidine and have a wider spectrum of link action, i.e. have an effect with ethanol, indomethacin, reserpine and stress ulcers, when the effect of cimetidine is insufficient.

The study of antisecretory activity

the claimed preparations.

The study of antisecretory activity of the claimed drugs was carried out on male rats weighing 160-180 g according to the Sha method and on non-anesthetized dogs

0 weighing 12.5-17 kg with a fistula of the stomach.

It can be seen from Table 2 that compounds I and II at doses of 10.25.50.00 mg / kg orally reduce the amount of gastric secretion and the content of free hydrochloric acid in it. In similar experiments, cimeti5 dyne exhibits high antisecretory activity, but is 2–3 times less than claimed drug II and drug I,

If the drug at a dose of 100 mg / kg inside inhibits rat secretion, stimulated by subcutaneous administration of histamine (2.5 mg / kg) and carbacholine (0.25 mg / kg), and is not inferior in activity to cimetidine in this case (Table. )

5 At a dose of 10 mg / kg, oral drug II has a strong inhibitory effect (80%) on gastric secretion, stimulated by subcutaneous administration of pentaastrin (4 μg / kg) in non-narcotic

0 dogs (see drawing). Pentagastrin was administered 1 hour after the administration of the claimed compound.

Study of acute toxicity of the claimed drugs.

5 Acute toxicity (LDI) was determined in male rats weighing 100-120 when administered orally and was calculated by the Lichfield-Wilcoxon method, LDI of the claimed drug was 1–530 mg / kg, drug II - 470

0 mg / kg, according to known data, LDu of cimetidine when administered to rats is greater than 1000 mg.

According to the classification of toxicity of chemicals, the claimed drugs can

5 classified as moderately toxic compounds, cimetidine in this classification belongs to the class of low toxic substances.

Thus, for the first time in the series of quinuclidylcarbinols, medicinal

0 agents that exhibit high antiulcer activity in experiments on different models of gastric ulcers significantly exceed cimetidine in the effectiveness and spectrum of this action. They are

5 have a pronounced effect on gastric secretion, reduce the volume and content of free hydrochloric acid.

Doses in which the prescribed drugs have an antiulcer effect are 5-10 times lower than those required for suppression

secretion. This suggests that they do not have the withdrawal syndrome that occurs when cimetidine is discontinued and exacerbates the disease as a result of increased secretion. Consequently, the claimed drugs, pharmacological properties trial, can be used for the treatment of gastroduodenal ulcers, in case of hyperecid gastritis, as well as in other conditions requiring a decrease in the acidity of gastric juice.

Claims (1)

The claims An anti-ulcer agent, characterized in that it is (quinuclidyl-3) - di- {thienyl-2) carbinol of the formula 10 N OH  Lj or its hydrochloride. The study of anti-ulcer activity of the claimed drugs I and II and the well-known drug cimetidine 3fijЈ - the dose at which the drug prevents the formation of gastric ulcers by 50% .- - according to the literature Table 1 table 2 The effect of the inventive preparations I and II and the well-known drug cimetidine when administered orally on the indicators of gastric secretion in rats (10 animals in each group). Table3 The effect of the claimed drug II and the known drug cimetidine with the introduction by mouth at a dose of 100 mg / kg per stomach stimulated by histamine and carbacholine secretion in rats (12 animals in each group). m50 twenty YU ABOUT Control Proposed Compound G P -t, - J -.-, - t / 5 30 fS 60 75 nTime, min Lentagaslrm