UA135630U - 2 - ((5 - ((2,5-DIMETHOXYPHENYL) AMINO) -1,3,4-THIADIAZOL-2-YL) THIO) -N- (NAPHTHYLEN-1-YL) ACETAMIDE EXPRESSING A DIURETIC ACTIVE - Google Patents

Abstract

2 - ((5 - ((2,5-Dimethoxyphenyl) amino) -1,3,4-thiadiazol-2-yl) thio) -N- (naphthylen-1-yl) acetamide of formula:, which exhibits diuretic activity.

Description

The useful model belongs to the chemical and pharmaceutical industry, namely to the synthesis of new biologically active substances based on 1,3,4-thiadiazole and can be used as a medicinal substance in the creation of medicinal products with diuretic activity.

Due to the unique pharmacological activity of 1,3,4-thiadiazole derivatives, there is a large arsenal of medicines of this series on the pharmaceutical market. The search for biologically active substances with predictable activity is most often carried out in the class of chemical compounds where substances with a certain direction of action have already been found. In medical practice, substances containing a 1,3,4-thiadiazole fragment are currently widely used as diuretics, namely: 2-acetylamino-1,3,4-thiadiazole-5-sulfamide (Acetazolamide, Diakarb) and its 3 - (M-methyl) iminoform (Methazolamide) (1, 2, ZI.

The useful model is based on the task of obtaining a new biologically active compound based on 1,3,4-thiadiazole, which exhibits diuretic activity. The task is solved by the synthesis of 2-(5-(2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylene-1-ylluacetamide of formula I:

Her o - -e her 0 o / Y, which exhibits diuretic activity.

The claimed compound is obtained by the interaction of 2,5-dimethoxyphenylamino-1,3,4-thiadiazole (ZH)-2-thione (preliminarily obtained by cyclization of M-(2,5-dimethoxyphenyl)thiosemicarbazide and carbon disulfide in the presence of ammonium salt 2 in the reaction medium ,5-dimercaptothiadiazole) with naphthylamide of chloroacetic acid during short-term heating of the initial components in equimolar ratios in a water-ethanol medium in the presence of an equimolar amount of KOH according to the scheme:

M--M

Н ШЧИ А r что У DMF Что и и и Фф кон с8., з -- М M с.нЬон 759 ий -- ф' т -и---- 1

Sunday, Sunday, at 2 Kc! 4

M-M

Zh. r pri - zhk N dol osn, 5 .

The yield of the substance is 69 95. 2-(5-(2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylen-1-yl)uacetamide is a compound, which is a white crystalline substance with a melting point of 138-140 "С, which is soluble in methanol, ethanol, DMF and insoluble in water.

The structure of the synthesized compound was proven by H NMR spectroscopy, elemental analysis, purity was confirmed by thin-layer chromatography.

A useful model is illustrated by examples.

Example 1. Preparation of 2-(5-(2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylen-1-yl)acetamide. 0.01 mol (2.28 g) of M-(2,5-dimethoxyphenyl)thiosemicarbazide is dissolved in DMF in the presence of 60 ml of the ammonium salt of 2,5-dimercaptothiadiazole in an apparatus equipped with a stirrer, a dropper, a reflux condenser and a gas outlet. 6.0 mL (0.1 mol) of carbon disulfide was added from a dropper at 40 "C for 4 hours. The reaction mixture was then heated to 75 "C under reflux for 1 hour. The process was monitored by TLC. The reaction mixture was cooled, the solid product was filtered off without additional purification. 0.015 mol (0.84 g) of potassium hydroxide is added to a solution of 0.01 mol (2.66 g) of 2,5-dimethoxyphenylamino-1,3,4-thiadiazole (ZH)-2-thione in 50 ml of ethanol with stirring. After that, pour in a solution of 0.01 mol (2.19 g) of naphthylamide of chloroacetic acid 4 in 30 ml of ethanol. Crystallized from ethanol.

Output 3.1 g (69 95), Tpl. 138-140 "C, M.m. 449,551.

Gross formula: Cg2NhoMaOz5".

Calculated: M, 95 12.38; 5, 95 14,17.

Found: M, Fo 12.39; 5, 90 14,18.

"H NMR spectrum, ppm: 10.10 (1Н, с, SOMN); 9.60 (1Н, с, МНРИ); 3.75 (6Н, с, 2x Osn»); 6.45 (1Н , c, AgH); 6.85 (1H, c, AgH); 7.4-7.5 (ZH, m, AgH); 7.85 (2H, c, AgH); 8.15 (2H, c , АН); 4.2 (2Н, с,

ZON).

Example 2. Study of the diuretic activity of 2-((5-(2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylen-1-yl)acetamide was performed on rats males with a body weight of 160-220 g. Rats, according to current norms, underwent acclimatization during the day in the room for conducting experiments. The keeping of the animals complied with the current rules on devices, equipment and maintenance of vivariums. The animals received standard food, in accordance with the current norms. The air temperature in the room was 21-24 "С, humidity no more than 60-65 95

I4.

When studying the pharmacological action of 2-(5-(2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylen-1-yl)yaoacetamide, animals were injected intragastrically immediately before harvesting urine in a dose of 5 mg/kg. Previously, the substance was suspended with distilled water and administered at the rate of 10 ml/kg. The intact control group was injected with the solvent distilled water in the appropriate amount.

The diuretic effect was evaluated by the ability to change urine output in the experimental group of animals in comparison with the intact control group and was calculated per 100 g of the animal's body weight; calculation was made according to the formula: 7

IT animals

Mvidn. - with ' - . where, - relative volume of urine, ml/100 g;

Cut off the volume of urine that was allocated by each animal during the period of time, ml;

IT animal: - body weight of the animal, g.

Mathematical statistics methods were used to evaluate the research results.

The amount of urine that was allocated by the control group of animals (which did not receive the studied compounds) was taken as 100 Ob.

Analysis of variance (AMOMA) and the Newman-Keuls method were used to compare samples subject to normal distribution. Analysis of the reliability of differences between samples that are subject to normal distribution will be carried out according to the Kruskal method

Wallis and the Mann-Whitney criterion (5, 61.

In intact control animals, during the first hour of testing, 0.32 ml of urine was collected per 100 g of the animal's weight, during further testing, diuresis was reduced by half. The diuretic effect of 2-((5- ((2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylen-1-yl)yauacetamide increased 1.8 times during the first and second hours of the experiment. Research and analysis of the obtained experimental data was carried out in comparison with the reference drug Hypothiazid, which has a pronounced saluretic effect (table).

Table

Diuretic effect of 2-((5-(2,5-dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylene-1-ylluacetamide after a single intragastric administration to rats, p-5

Intact control /- | 0.3224006 | 055003 | 0465008 sh 11111111 | bmoik | 0.5340.057 | 03050037 | 08350087

Note:

1. - the differences are significant relative to the control pathology group, (Newman-Keuls criterion, rae0.05); 2. - the differences are significant relative to the comparison drug group (Newman-Keuls test, p:0.05).

The claimed compound can be obtained in the conditions of a chemical-pharmaceutical enterprise using available technology without the use of toxic reagents. This allows predicting the possibility of its use in medical practice for the treatment of diseases accompanied by a decrease in diuresis and in the complex treatment of arterial hypertension.

Sources of information: 1. Mashkovsky, M.D. Medicines. Ed. 15th, revised, ex. and additional - M.: Novaya Volna, 2005. - 1200 p. 2. Diakarb (Electronic resource: Instructions for medical use of the drug. - Access mode: Per://to2dos5.Kiem. chalikimiem. rpr?ia-13719. 3. Acetazolamide. (Electronic resource): Instructions for medical use of the drug. -

Access mode: perz:/Lymly. rpagtepsusioredia.sot.cha/aplisive/2933/aseitagoiatia. 4. Modei, N.sch. (2002). The abomination of dissomegu apa emaitsayop: rpaptasoiodisa! azzaubz SPARIEG C:

Asiimiu op shhipagu gasi: 317-348. IBVM 3-540-42396-6 Zrgipdeg-Mepayad Vepip NeideIregd Mem/ Mogk. 5. Mispiga, Misnav! 9. (2006). Tne soogaipaie-itee arrgoasi yu Ipeag todei!v. Satbgidde bepev ip eiaiiviiisaI apa Rgobabiiviiis Maipetaiiiisv5. Satbrgidde: Satbrgidde Opimegeyu Rgezv5, year of chemistry--199.

IBM 978-0-521-86842-6. MA 2283455. b. Bryptii, 9.0. (2003). "Op She pi! aiviirshiop oi She KgtyvzKa!-UMaiyiv viaiyyviis". come on! oh

Mopragateiis 5iaiiviisv. 15 (6): 685-691. doi:10.1080/10485250310001634719.

Claims (1)

USEFUL MODEL FORMULA 2-(5-(2,5-Dimethoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)-M-(naphthylene-1-ylluacetamide of the formula: M--M nm Z tru (c) It shows diuretic activity.