RU2364592C1 - N-[2-(5-ethyl-1,3,4-thiadiazolyl)]amide of 2-(2-hydroxyphenyl)-2-oxoethane acid, possessing anti-inflammatory and analgesic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: claimed invention relates to N-[2-(5-ethyl-1,3,4-thiadiazolyl)]amide of 2-(2-hydroxyphenyl)-2-oxoethane acid, which has anti-inflammatory and analgesic activity, of formula:

.

EFFECT: compound has low toxicity.

1 tbl

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of N-heterylamides of 2- (2-hydroxyphenyl) -2-oxoethanoic acid, namely to N- [2- (5-ethyl-1,3,4-thiadiazolyl) ] amide of 2- (2-hydroxyphenyl) -2-oxoethanoic acid (1) of the formula

possessing anti-inflammatory and analgesic activity, which suggests its use in medicine as a medicinal anti-inflammatory and analgesic. The closest analogue in structure and action to the claimed compound is N- (2-thiazolyl) amide 2- (2-hydroxyphenyl) -2-oxoethanoic acid [Pulina N.A., Yushkov V.V., Zalesov V.V., Mokin P .A., Odegova T.F., Syropyatov B.Ya., Yatsenko K.V. Search for biologically active compounds among derivatives of o-hydroxyphenylglyoxalic acid // Pharmacy. - 2007. - No. 5. - S.35-37] formulas

Structural analogue 2 has a weak anti-inflammatory and analgesic effect, insufficient for practical health care.

The sodium salt of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid (diclofenac) (3) of the formula was chosen as the reference standard

which is widely used in medical practice and is an analogue in action [Mashkovsky M.D. Medicines - 15th ed., Rev., Rev. and add. - M .: New Wave LLC, 2005. - P.170].

The objective of the invention is to search for a series of N-heterylamides of 2- (2-hydroxyphenyl) -2-oxoethanoic acid substances with pronounced anti-inflammatory and analgesic activity and low toxicity.

The problem is achieved by obtaining N- [2- (5-ethyl-1,3,4-thiadiazolyl)] amide 2- (2-hydroxyphenyl) -2-oxoethanoic acid (1), which has anti-inflammatory and analgesic activity. The claimed compound 1 is synthesized by the interaction of 2,3-dihydrobenzo [b] furan-2,3-dione with 2-amino-5-ethyl-1,3,4-thiadiazole in anhydrous chloroform at room temperature, followed by isolation of the target product by known methods according to the scheme:

Compound 1 was prepared. A suspension of 1.29 g (0.01 mol) of 2-amino-5-ethyl- was added to a solution of 1.48 g (0.01 mol) of 2,3-dihydrobenzo [b] furan-2,3-dione in 30 ml of anhydrous chloroform. 1,3,4-thiadiazole in 25 ml of the same solvent and stirred at room temperature for one hour. The reaction mixture was cooled to 0 ° C, the precipitate was filtered off and recrystallized from dioxane. Yield 2.08 g (75%). Mp 172-173 ° C. Found,%: C 52.12; H 4.09; N, 15.18. C ₁₂ H ₁₁ N ₃ O ₃ S. Calculated,%: C 51.98; H 4.00; N 15.15.

IR spectrum (Specord M80, liquid paraffin, ν, cm ^-1 ): 3205 ( NH CO), 1695 ( CO NH), 1640, 1610, 1580 (C ² = O, C = C, C = N). ¹ H NMR spectrum (Bruker DRX 500, DMSO-d ₆ , HMDS, δ, ppm): 1.31 t (3H, CH ₃ , J 7.4 Hz), 2.97 k (2H, CH ₂ , J 7.4 Hz), 6.81-7.67 m (4H, C ₆ H ₄ ), 10.74 s (1H, NH), 12.85 br.s (1H, OH).

The resulting compound 1 is a light yellow crystalline substance, soluble in toluene, dimethyl sulfoxide, insoluble in water and alkanes.

Anti-inflammatory activity was studied in experiments on 30 white outbred rats of both sexes weighing 220-260 g. Compound 1 was administered orally at a dose of 50 mg / kg as a suspension in 2% starch solution an hour before modeling acute carrageenin inflammation. Carrageenin edema was caused by subplant implantation of 0.1 ml of a 1% phlogogen solution in the hind paw of a rat. Anti-inflammatory activity was judged by the change in the severity of inflammation in dynamics, which was recorded oncometrically 1, 3, and 5 hours after modeling inflammation [Methodological recommendations for the experimental study of non-steroidal anti-inflammatory substances, pharmacological committee of the USSR Ministry of Health, protocol No. 22 of November 11, 1982. - Moscow, 1982]. Equivolume amount of 2% starch solution was administered to control animals. The comparison drug was diclofenac at a dose of 10 mg / kg. The results were statistically processed using Excel 2003 and presented in the table.

The analgesic activity of compound 1 was studied on 12 white mice males weighing 20-25 g by the method of thermal irritation [N.B. Eddy, D. Leimbach // Pharmacology and Toxicology. - 1960. - No. 4. - S.311-315]. Test compound 1 was administered orally at a dose of 50 mg / kg in suspension in a 2% starch solution 1 hour before placing the animals on a hot plate. An indicator of pain sensitivity was the length of time the mice stay on the plate until the onset of the defensive reflex - licking the paws. Equivolume amount of 2% starch solution was administered to control animals. The comparison drug was diclofenac at a dose of 10 mg / kg. The results were statistically processed using Excel 2003 and presented in the table.

Acute toxicity (LD ₅₀ ) of the claimed compound 1 was determined on 24 white mongrel mice of both sexes weighing 18-22 g with an intraperitoneal route of administration in the form of a suspension in a 2% starch solution according to the express method B. B. Prozorovsky [Prozorovsky VB, Prozorovskaya M.P., Demchenko V.I. // Pharmacology and toxicology. - 1978. - No. 4. - S.497-502]. It was found that the LD _{50 of} compound 1 is 1500 mg / kg. According to the classification of drug toxicity, 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 20 times less toxic than diclofenac.

Table Anti-inflammatory, analgesic activity and acute toxicity of compound 1 Compound Dose mg / kg LD ₅₀ mg / kg % inhibition of carrageenin edema Latent period of the defensive reflex, s 1 hour 3 hours 5 o'clock The control - - 0,0 ± 0,0 0,0 ± 0,0 0,0 ± 0,0 10.0 ± 0.5 one fifty 1500

Diclofenac 10 74

^* = p <0.05, ^** = p <0.01, ^*** = p <0.001 1 - compared to control; 2 - compared with diclofenac.

As can be seen from the table, compound 1 showed a pronounced anti-inflammatory activity during the entire observation period, and at the peak of inflammation it is practically not inferior to diclofenac. In addition, compound 1 showed significant analgesic activity at the level of the reference standard. It should be noted that the effective dose of diclofenac is 0.14 from its LD ₅₀ , and the claimed compound is 0.03 from its LD ₅₀ , which indicates certain advantages of compound 1 over diclofenac in terms of its safety and effectiveness.

Thus, N- [2- (5-ethyl-1,3,4-thiadiazolyl)] amide 2- (2-hydroxyphenyl) -2-oxoethanoic acid (1) is more effective and less toxic compared to diclofenac, which makes it is possible to use it to create new drugs with anti-inflammatory and analgesic activity.

LITERATURE

1. Pulina N.A., Yushkov V.V., Zalesov V.V., Mokin P.A., Odegova T.F., Syropyatov B.Ya., Yatsenko K.V. Search for biologically active compounds among derivatives of o-hydroxyphenylglyoxalic acid // Pharmacy. - 2007. - No. 5. - S. 35-37.

2. Mashkovsky M.D. Medicines - 15th ed., Rev., Rev. and add. - M .: New Wave LLC, 2005. - P.170.

3. Guidelines for the experimental study of non-steroidal anti-inflammatory substances, Pharmacological Committee of the Ministry of Health of the USSR, protocol No. 22 of November 11, 1982. - Moscow, 1982.

4. N.B. Eddie, D. Leimbach // Pharmacology and Toxicology. - 1960. - No. 4. - S. 311-315.

5. Prozorovsky V. B., Prozorovskaya M. P., Demchenko V. I. // Pharmacology and toxicology. - 1978. - No. 4. - S.497-502.

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

Claims (1)

N- [2- (5-ethyl-1,3,4-thiadiazolyl)] amide 2- (2-hydroxyphenyl) -2-oxoethanoic acid of the formula:

possessing anti-inflammatory and analgesic activity.