RU2549572C2 - 2-(5-ethyl-1,3,4-thiadiazolyl)amide of 2-(4-bromophenyl)-4-oxo-4-phenyl-2-butenoic acid, having analgesic effect - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, novel biologically active substances of the class of N-hetarylamides of 4-aryl-2,4-dioxobutanoic acids, and specifically to 2-(5-ethyl-1,3,4-thiadiazolyl)amide of 2-(4-bromophenyl)-4-oxo-4-phenyl-2-butenoic acid. The compound is obtained by reacting 4-bromophenyl-5-aryl-3-imino-3H-furan-2-one with 2-amino-5-ethyl-1,3,4-thiadiazole with equimolar ratio of reactants in a medium of anhydrous toluene while boiling, followed by separation of the end product.

EFFECT: obtaining compounds having analgesic effect, as well as low toxicity

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Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of N-hetarylamides of 4-aryl-2,4-dioxobutanoic acids, namely to 2- (5-ethyl-1,3,4-thiadiazolyl) amide 2- (4 -bromophenyl) -4-oxo-4-phenyl-2-butenoic acid (1) of the formula:

possessing analgesic activity, which suggests its use in medicine as an analgesic drug.

The closest analogue in structure and action to the claimed compound is 2- (5-ethyl-1,3,4-thiadiazolyl) amide 2-hydroxy-4-oxo-4-phenyl-2-butenoic acid (2) [Pulina N.A. , Zalesov V.V., Yushkov V.V., Mokin P.A., Sobin F.V. et al. Synthesis and biological activity of salts of heterocyclic amines and heterylamides based on 4-aryl-2,4-dioxobutanoic acids // Problems of Biological, Medical and Pharmaceutical Chemistry. - 2008. - No. 2. - S.37-40] formulas:

Structural analogue 2 has a weak analgesic activity, insufficient for practical health care.

Reference standards selected:

1) an analgesic drug metamizole sodium (1-phenyl-2,3-dimethyl-4-methylaminopyrazolone-5-N-methanesulfonate sodium) (3), widely used in medical practice and is an analogue in action [Mashkovsky M.D. Medicines - 16th ed., Rev., Rev. and add. - M .: New wave: Publisher Umerenkov, 2010. - S.164-165].

2) the non-steroidal anti-inflammatory drug diclofenac (sodium salt of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid) (4), which is widely used in medical practice and is analogous in action [Mashkovsky M.D. Medicines - 16th ed., Rev., Rev. and add. - M .: New wave: Publisher Umerenkov, 2010. - S.176-177].

The objective of the invention is to search for a series of derivatives of N-hetarylamides of 4-aryl-2,4-dioxobutanoic acids substances with a pronounced analgesic effect and low toxicity.

The problem is achieved by obtaining 2- (5-ethyl-1,3,4-thiadiazolyl) amide 2- (4-bromophenyl) -4-oxo-4-phenyl-2-butenoic acid (1), which has analgesic activity.

The claimed compound 1 is synthesized by the interaction of 4-bromophenyl-5-aryl-3-imino-3H-furan-2-one (5) with 2-amino-5-ethyl-1,3,4-thiadiazole at an equimolar ratio of reactants in anhydrous medium toluene when boiling the reaction mixture, followed by isolation of the target product by known methods according to the scheme:

A compounding example 1: A suspension of 1.29 is added to a suspension of 3.28 g (0.01 mol) of 4-bromophenyl-5-aryl-3-imino-3H-furan-2-one (2) in 50 ml of anhydrous toluene g (0.01 mol) of 2-amino-5-ethyl-1,3,4-thiadiazole in 35 ml of anhydrous toluene and the solution is boiled for 3 hours. The reaction mixture was cooled to room temperature, the precipitate formed was filtered off, recrystallized from acetonitrile and dried. Yield 3.74 g (84%). Mp 152-154 ° C. Found,%: C 51.41; H 3.36; Br 18.09; N, 12.68. C ₁₉ H ₁₅ BrN ₄ O ₂ S. Calculated,%: C 51.48; H 3.41; Br 18.02; N, 12.64. IR spectrum (Specord M80, liquid paraffin, ν, cm ^-1 ): 3148 ( NH CO), 1691 ( CO NH), 1608, 1595 (C ⁴ = O, C = C, C = N). ¹ H NMR spectrum (Mercury-300BB, DMSO-d ₆ , GMDS, δ, ppm): 1.33 t (3H, CH ₃ ), 3.05 k (2H, CH ₂ ), 6.40 s (1H, = CH) 7.09-7.64 m (9H, C ₆ H ₅ , C ₆ H ₄ Br), 8.81 s (1H, NH), 11.87 s (1H, NH).

The inventive compound 1 is a yellow crystalline substance soluble in acetonitrile, toluene, dioxane, acetone, insoluble in water and hexane.

The analgesic activity of compound 1 was studied on white nonlinear mice weighing 18-22 g by the method of thermal irritation [V.V. Gatsura. Methods of primary pharmacological studies of biologically active substances. - M .: Medicine, 1974. - 39 p.]. Test compound 1 was administered intraperitoneally at a dose of 50 mg / kg in suspension in a 2% starch solution 30 minutes before the animals were placed on a hot plate. The latent period (in seconds) from placing the mouse on the “hot plate” to the first signs of a defensive reaction (pulling or licking paws, vertical stance) served as a criterion of pain irritation. Equivolume amount of 2% starch solution was administered to control animals. The reference drug was metamizole sodium at a dose of 93 mg / kg (ED ₅₀ ), as well as diclofenac at a dose of 10 mg / kg (ED ₅₀ ). The results were statistically processed using MS Excel, 2003 and are presented in table 1.

Acute toxicity (DL ₅₀ ) of the claimed compound 1 was determined on white non-linear mice of both sexes weighing 16-18 g with a single intraperitoneal injection. The animals were monitored for 10 days, recording the behavior, intensity and nature of motor activity, the presence and nature of seizures, coordination of movements, skeletal muscle tone, reactions to tactile, sound and light stimuli, the frequency and depth of respiratory movements, heart rate, state hair and skin integument, coloration of visible mucous membranes, water and food intake, weight change [Guide to the experimental (preclinical) study of new pharmacological substances / Po the general editorship of Corresponding Member of the Academy of Medical Sciences, Professor RW Khabrieva. - 2nd ed., Revised. and add. - M .: OJSC "Publishing house" Medicine ", 2005. - P.41-54]. It was found that the DL _{50 of} compound 1 is 1350 mg / kg. According to the classification of toxicity of drugs, compound 1 belongs to the class of practically non-toxic substances [Izmerov I.F., Sanotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons. - M .: Medicine, 1977. - S.196-197]. It is 3.8 times less toxic than metamizole sodium, and 18.2 times less toxic than diclofenac.

In the course of the studies (see table), it was found that compound 1 exhibits pronounced analgesic activity. So, after 120 minutes after administration, it exceeds the activity of metamizole sodium by 1.84 times and diclofenac by 1.33 times. Given the values of acute toxicity, compound 1 has certain advantages over metamizole sodium and diclofenac in terms of its safety and effectiveness.

Table Analgesic activity and acute toxicity of compound 1 Compound DL ₅₀ , mg / kg Latent period of the defensive reflex, s (after 120 min) The control - 10.60 ± 1.09 one 1350 32.80 ± 2.77 ^{*** 1 ** 2 * 3} Metamizole sodium 350 17.33 ± 2.02 ^{** 1} Diclofenac 74 26.2 ± 0.61 ^{*** 1} * = p <0.05, ** = p <0.01, *** = p <0.001; 1 - compared to control; 2 - compared with metamizole sodium; 3 - compared with diclofenac

Thus, 2- (5-ethyl-1,3,4-thiadiazolyl) amide of 2- (4-bromophenyl) -4-oxo-4-phenyl-2-butenoic acid (1) exhibits a higher analgesic activity compared to structural analogue and standards of comparison, and is also practically non-toxic, which makes it possible to use it to create new drugs with analgesic activity.

Literature

1. Pulina N.A., Zalesov V.V., Yushkov V.V., Mokin P.A., Sobin F.V. et al. Synthesis and biological activity of salts of heterocyclic amines and heterylamides based on 4-aryl-2,4-dioxobutanoic acids // Problems of Biological, Medical and Pharmaceutical Chemistry. - 2008. - No. 2. - S. 37-40.

2. Mashkovsky M.D. Medicines - 16th ed., Rev., Rev. and add. - M .: New wave: Publisher Umerenkov, 2010. - S.164-165, 176-177.

3. V.V. Gatsura. Methods of primary pharmacological studies of biologically active substances. - M .: Medicine, 1974. - 39 p.

4. Guidance on the experimental (preclinical) study of new pharmacological substances / Under the general editorship of the corresponding member of RAMS, Professor R.U. Khabrieva. - 2nd ed., Revised. and add. - M .: OJSC "Publishing house" Medicine ", 2005. - P.41-54.

5. Izmerov I.F., Sanotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons. - M .: Medicine, 1977. - S.196-197.

Claims (1)

2- (4-bromophenyl) -4-oxo-4-phenyl-2-butenoic acid 2- (5-ethyl-1,3,4-thiadiazolyl) amide of the formula

,
possessing analgesic activity.