RU2643669C1 - 3-[3-(morpholine-4-yl)propyl]-2-[(2,2,3-trimethylcyclopent-3-ene-1-yl)methyl-1,3-thiazolidine-4-one with anti-ulcer and anti-inflammatory activity - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to a new 3-[3-(morpholine-4-yl)propyl]-2-[(2,2,3-trimethylcyclopent-3-ene-1-yl)methyl]-1,3-thiazolidine-4-one compound.

EFFECT: new compound with anti-ulcer and anti-inflammatory activity is obtained.

2 tbl, 3 ex

Description

The invention relates to the field of medical chemistry and pharmacology, namely to biologically active compounds with antiulcer and anti-inflammatory effects.

Stomach ulcer is one of the acute problems of modern medicine and is a chronic relapsing disease that develops as a result of an imbalance of protective and aggressive factors affecting the gastric mucosa, characterized by alternating periods of exacerbation and remission. According to the WHO, the maximum incidence occurs in the age period of 40-60 years, which causes a temporary, and sometimes permanent loss of working capacity by people, and as a result entails significant economic losses. Thus, the prevention and treatment of this disease are of exceptional importance in the health care system. A special group of patients suffering from gastric ulcer are people with chronic inflammatory diseases, such as rheumatoid arthritis, etc., who are forced to take non-steroidal anti-inflammatory drugs on an ongoing basis. It is known that drugs of this group inhibit the cyclooxygenase enzyme, which is responsible for the production of prostaglandins in the body. The latter, in addition to inflammatory processes, are also involved in the production of gastric mucus, therefore, the suppression of prostaglandin synthesis increases the vulnerability of the gastric mucosa to aggressive factors of digestive juice.

Known antiulcer agents represented 7 classes: the inhibitors of proton pump (omeprazole, etc.), Blockers of H ₂ histamine receptors (, ranitidine, famotidine, etc.), Synthetic prostaglandins (enprostil, misoprostol), stimulants mucus production (carbenoxolone), M anticholinergics (pirenzepine), gastrin receptor blockers (proglumide), and astringent gastroprotective agents such as sucralfate and bismuth tripotassium dicitrate [Mashkovsky MD Medicines T. 1. M.: The new wave. 2012]. All of the listed drugs, except the last group, affect the secretory function of the cells of the gastric mucosa, without exerting an anti-inflammatory effect. In this regard, it is interesting to search and develop new effective therapeutic agents and approaches to rational therapy, which would suggest both regulation of the balance of factors affecting the state of the gastric mucosa and the effect on the inflammatory process that arises in it.

The problem to which the invention is directed, is to search for new effective low-toxic drugs with antiulcer and anti-inflammatory activity.

The problem is solved by 3- [3- (morpholin-4-yl) propyl] -2 - [(2,2,3-trimethylcyclopent-3-en-1-yl) methyl] -1,3-thiazolidin-4-one (1), including its spatial isomers, including optically active forms

Compound (1) has not been previously described in the literature, it can be synthesized according to Scheme 1 by the reaction of campholenic aldehyde, aminoproyl amorpholine and thioglycolic acid in the presence of dicyclohexylcarbodiimide, using a solvent, usually tetrahydrofuran.

The study of the pharmacological activity of compound (1) included the determination of antiulcer and anti-inflammatory action of the substance. The antiulcer activity of the compound was studied on female rats weighing 180-220 g, divided into groups of 6 individuals. A gastric ulcer induced by a single oral administration of the substance non-steroidal anti-inflammatory drug indomethacin at a dose of 25 mg / kg [Derelanko M.G., Long G.T. Effect of corticosteroids on indomethacin-induced intestinal ulceration in the rat // Dig. Diseases and sci. - 1980. - Vol.25. - No. 11. - P. 830-838]. The reference drug was an omeprazole proton pump inhibitor at a dose of 100 mg / kg [Yamamoto O, Okada Y, Okabe S. Effects of a proton pump inhibitor, omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats // Dig. Diseases and sci. - 1984.-Vol. 29. - No. 11. - P. 394-401]. The degree of gastric damage was assessed by calculating ulcerative defects in the gastric mucosa of animals and was expressed as the Pauls index (PI). Antiulcer activity (PA) was determined as the ratio of the control group to the experimental group. It was found that the administration of the test substance at a dose of 100 mg / kg an hour before the administration of the ulcerogenic agent significantly reduces ulcer formation compared with the negative control group. The results of the study are presented in table 1, where antiulcer activity is indicated in relative units.

* - p <0.05 - significant difference from control

It was found that the antiulcer activity of compound 1 is comparable to the activity of the drug of comparison of omeprazole in a similar dose.

To study the anti-inflammatory activity, we used sexually mature male mice weighing 25-30 g, distributed in groups of 8 individuals. Experimental inflammation was modeled by introducing under the aponeurosis of the hind paw of animals a 0.01% histamine solution, which is a physiological inducer of inflammation [Trinus F.P., Mohort N.A., Klebanov B.M. Methods of screening and pharmacological study of anti-inflammatory, analgesic and antipyretic substances (guidelines). - Kiev, 1974. - 28 p.]. As a comparison drug, diclofenac sodium was orally administered to animals at a therapeutic dose of 10 mg / kg. Assessment of the severity of edema was carried out based on the difference in weight of the inflamed and intact paws of animals, expressed as a percentage. For statistical processing of the results, Student t-test was used, considering the differences significant at p <0.05. Anti-inflammatory activity was defined as the percentage reduction in inflammatory edema relative to control. The data are presented in table 2.

* - p <0.05 - significant difference from control

It was shown that the administration of compound 1 at a dose of 100 mg / kg inhibits the development of inflammatory edema compared with the control group by 46.4%. Thus, (1) in its anti-inflammatory activity is comparable to the comparison drug diclofenac sodium at a dose of 10 mg / kg. It should be noted that diclofenac as a non-steroidal anti-inflammatory drug induces ulceration of the gastric mucosa (UD ₅₀ = 48 mg / kg) [Guidelines for preclinical studies of drugs. Part One / Ed. Mironova A.N. - M .: Grif and K, 2012. - 944 p.], While (1) does not cause the formation of erosive-ulcerative lesions.

The invention is illustrated by the following examples.

Example 1 Synthesis of 3- [3- (morpholin-4-yl) propyl] -2 - [(2,2,3-trimethylcyclopent-3-en-1-yl) methyl] -1,3-thiazolidin-4-one (1 )

In a round bottom flask in an ice bath, 200 ml of THF were added, then 4 g (27.7 mmol) of N- (3-aminopropyl) morpholine; 6.3 g (41.4 mmol) of campholenaldehyde. After stirring for 30 minutes, 4.3 ml (61.9 mmol) of thioglycolic acid was added and stirred for another 15 minutes. 5.13 g (24.9 mmol) of dicyclohexylcarbodiimide were added and allowed to mix for 3 hours. The precipitated white precipitate was filtered. The filtrate was concentrated, dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase was separated and dried over calcined sodium sulfate. Then methylene chloride was distilled off, the product was purified by silica gel column chromatography. Eluent methylene chloride with a methanol gradient of up to 3% vol. Received 7.16 g (20.3 mmol) of compound 1 (73%). Colorless gummy substance. ¹ H NMR (CDCl ₃ , δ, ppm): 0.74 (s, 3H ¹² ), 0.96 (s, 3H ¹¹ ), 1.06 (m, 1H ¹⁴ ), 1.31 (m, 1H ^{14 '} ), 1.53 ( m, H ⁴ ), 1.90 (m, 1H ^{4 '} ). 1.58 (m, 3H ¹⁰ ), 1.67 (m, 1H ⁶ ), 2.24 (m, 1H ^{6 '} ), 1.77 (m, 1H ⁵ ), 2.33 (m, 4H ^16.18 ), 2.38 (m, 2H ¹⁵ ) , 3.09 (m, 1H ¹³ ), 3.71 (m, 1H ^{13 '} ), 3.44 (m, 1H ³ ), 3.55 (m, 1H ^3' ), 3.67 (m, 4H ^17.19 ), 4.60 (m, 1H ¹ ), 5.19 (m, 1H ⁷ ). ¹³ C NMR (CDCl ₃ , δ, ppm): 12.42 (C ¹⁰ ), 19.81 (C ¹² ), 24.02 (C ¹⁴ ), 25.19 (C ¹¹ ), 31.62 (C ³ ), 33.82 (C ⁶ ) , 36.61 (С ⁴ ), 40.81 (С ¹³ ), 46.00 (С ⁵ ), 46.91 (С ⁹ ), 53.50 (С ^16.18 ), 55.75 (С ¹⁵ ), 61.41 (С ¹ ), 66.72 (С ^{17, 19} ), 120.88 (C ⁷ ), 148.47 (C ⁸ ), 170.88 (C ² ). Found: m / z 352.2182 [M] + C ₁₉ H ₃₂ O ₂ N ₂ ³² S ₁ . Calculated: M = 352.2179.

Example 2 Study of antiulcer activity (1) . The study was carried out on sexually mature female Wistar rats weighing 180-220 g. Animals were obtained from the vivarium of the Institute of Cytology and Genetics SB RAS, all manipulations were performed in accordance with the rules and principles of humane treatment of animals. The experiments were carried out at the same time from 9 ⁰⁰ to 12 ⁰⁰ . For research, animals were divided into groups of 6 animals each. Omeprazole (Ozone, Russia) was used as a comparison drug for studying the anti-ulcerogenic effect. The compound was administered on an empty stomach intragastrically at a dose of 100 mg / kg. Animals of the comparison group were once administered omeprazole in a similar dose. An hour later, gastric ulcer was induced in all experimental animals by oral administration of indomethacin (Sigma-Aldrich, Italy) at a dose of 25 mg / kg. The number of ulcerative defects in the stomachs of rats was evaluated a day after all manipulations, the Pauls index (PI) was calculated by the formula

,

,

where A is the average number of ulcers, B is the percentage of animals with ulcers in the group. Antiulcer activity (PA) was determined as the ratio of the Pauls index in the control group to the index in the experimental group and expressed in relative units. The test substance is considered active if the PA is 2 or more units [E.P. Zueva, D.V. Reichart S.G. Krylova, T.G. Razina, E.N. Amosov, V.V. Will blow out. Medicinal plants in the treatment of gastric ulcer and duodenal ulcer. - Tomsk: Publishing house Tom. University, 2003. - 212 p.].

The experimental data are presented in table 1.

According to the results of the experiment, it was found that compound 1 has a high antiulcer activity in the indomethacin ulcer model.

Example 3 A study of anti-inflammatory activity (1). The anti-inflammatory activity of compound 1 was studied on sexually mature male mongrel mice weighing 25-30 g, obtained from the vivarium of the ICG SB RAS, on a model of inflammatory edema induced by histamine. Animals were divided into groups of 8 individuals. The test compound was administered to animals on an empty stomach intragastrically at a dose of 100 mg / kg. The animals of the comparison group were orally administered the drug Diclofenac (Ozone, Russia). An hour later, inflammatory edema was simulated by introducing 0.05 ml of a 0.01% histamine dihydrochloride solution (ICN Biomedicals, USA) under the hind paw aponeurosis. Five hours after the introduction of phlogogen, the mass difference of the inflamed and intact hind legs of the animals was estimated and the percentage of inflammatory edema (BO) was calculated using the following formula:

,

,

where M _B is the mass of the inflamed paw, M _K is the mass of the intact (control) paw.

Data processing was performed using the software package "Statistica 6.0". During processing, the average edema in each group and the standard error of the mean were determined. Student's t-test was used as a statistical criterion. The result was considered reliable at p <0.05. Anti-inflammatory activity was presented as a percentage reduction in edema compared to control. The experimental results are shown in table 2.

Thus, it was found that compound 1 at a dose of 100 mg / kg exerts a pronounced anti-inflammatory effect on histamine inflammation models, reducing inflammatory edema by 46.4%, while the activity of the reference drug administered at a therapeutic dose is 25.5%.

Claims (3)

3- [3- (morpholin-4-yl) propyl] -2 - [(2,2,3-trimethylcyclopent-3-en-1-yl) methyl] -1,3-thiazolidin-4-one of formula 1

, possessing antiulcer and anti-inflammatory activity.