Bis{3-phenyl-1-[n-(3-pyridyl)carboxamido]-1,3-propandionato} cadmium, which has anti-flammatory activity

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely described is bis{3-phenyl-1-[N-(3-pyridyl)carboxamido]-1,3-propandionato}cadmium, which has anti-inflammatory activity, of formula: .

EFFECT: obtainin compound with high output, which has expressed anti-inflammatory activity and low toxicity.

1 cl, 1 tbl, 1 ex

 

The invention relates to the field of organic chemistry, new biologically active substances of class of complex compounds of heterylamides 4-aryl-2,4-dioxobutane acids, namely bis{3-phenyl-1-[N-(3-pyridyl)carboxamido]-1,3-propanedione}cadmium formula (1):

possessing anti-inflammatory activity, suggesting its use in medicine as a medicinal anti-inflammatory agents.

The closest analogue to the structure and action of the present compound is 3-pyridylamino 4-phenyl-2,4-dioxaborinane acid (2) [ALEXANDER Milyutin, Amirov LR, I. Krylov, Nazmitdinov FA, Novoselova G.N., Andrejchikov US, Call VA Synthesis, properties and biological activity of 3-pyridylamino 4-aryl-2-hydroxy-4-oxo-2-butenova (aroylpropionic) acids. Chem.-Pharm. J., 1996, No. 1, S. 32-35] formula:

Structural analogue of 2 has weak anti-inflammatory action, are insufficient for practical health care.

A benchmark comparison of selected sodium salt of 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (ortofen) (3) of the formula:

which is widely used in medical practice and is similar in action [Mashkovsky PPM Medicines. - 15-ed., Rev., the DSS. and extra - M.: OOO "New wave", 2005. - s].

Object of the invention is the finding in a series of complex compounds of heterylamides 4-aryl-2,4-dioxobutane acid substances with pronounced anti-inflammatory activity and low toxicity.

This object is achieved by obtaining bis{3-phenyl-1-[N-(2-pyridyl)carboxamido]-1,3-propanedione}cadmium (1), possessing anti-inflammatory activity.

The claimed compound 1 synthesized by the interaction of 3-pyridylamino 4-phenyl-2,4-dioxaborinane acid (2) with cadmium dichloride, when the reagent ratio 2:1 in the environment of ethyl alcohol at room temperature, followed by separation of the target product known methods according to the scheme:

Example 1 to obtain compound 1. To a suspension of 5.36 g (0.02 mol) of 3-pyridylamino 4-phenyl-2,4-dioxaborinane acid in 40 ml of ethyl alcohol was added a solution of 2.28 g (0.01 mol) CdCl2·2.5H2O in 25 ml of the same solvent, is stirred until complete dissolution of the reagent and incubated at room temperature for 12 hours. The precipitation is filtered off, washed with hot toluene and dried. Output 5,63 g (87%). So pl. 322-324°C. Found, %: C 55.73; N, 3.40; N, 8.71. With30H22N4O6Cd. Calculated, %: 55.69; N, 3.43; N, 8.65.

IR spectrum (Specord M80, vaseline oil, νcm-1): 3355 (NH), 1705 (CO NH), 1610, 1600, 1580 (C=O, C=C, C=N). An NMR spectrum1N (Bruker DRX 500, DMSO-d6GMDS, δ, ppm): 7.13-8.82 (m, 20N, 2C6H5, 2C5H4N, 2CH); 10.75 (ush. s, 2H, 2NH).

The claimed compound 1 is a light yellow crystalline substance, soluble in dimethyl sulfoxide and dimethylformamide, insoluble in chloroform, hexane and water.

Anti-inflammatory activity was studied in experiments on 30 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 for an hour before modeling acute carragenine inflammation. Carrageenophyte swelling caused subplantar injection of 0.1 ml of 1% solution of logogen in hind paw of the rat. About anti-inflammatory activity was assessed by the change in the severity of inflammation in the dynamics, which were recorded ecometrics after 1, 3 and 5 hours after modeling inflammation [Methodical recommendations for a pilot study of non-steroidal anti-inflammatory substances. The pharmacological Committee of the Ministry of health, USSR, Protocol No. 22, dated November 11, 1982, Moscow (1982)]. Control animals were injected equiano amount of 2% starch solution. Drug comparison served ortofen in the dose of 10 mg/kg the Results were processed statistically using Excel 2000 and presented in the table.

Acute toxicity (LD0 ) the claimed compound 1 was determined on 24 outbred mice of both sexes weighing 18-22 g intraperitoneal route of administration as a suspension in 2% starch solution on an Express method Webprotector [Prozorovsky V.B. have been, Prozorovsky BTW, Demchenko V. Pharmacology and toxicology, 1978, No. 4, S. 497-502].

Found that LD50connection 1 is 1500 mg/kg According to the classification of the toxicity of preparations of compound 1 belongs to the class of practically non-toxic substances [Izmerov IVAN, Sanotski I., Sidorov, K.K. Settings toxicometric industrial poisons. - M.: Medicine, 1977, s-197]. It is 20 times less toxic than ortofen.

As can be seen from the table, compound 1 showed a pronounced anti-inflammatory activity throughout the observation period, and at the peak of inflammation, it has almost the same ortofen. In addition, the effective dose ortofena is 0.14 his LD50and the claimed connection - 0,03 from his LD50, indicating that certain advantages of the connection 1 before ortofen in terms of its safety and effectiveness.

Thus, bis{3-phenyl-1-[N-(3-pyridyl)carboxamido]-1,3-propanedione}cadmium (1) more effective and less toxic in comparison with ortofen that makes it possible to use it to create a new medicinal drugs is s, possessing anti-inflammatory activity.

LITERATURE

1. Milutin AV, Amirov LR, I. Krylov, Nazmitdinov FA, Novoselova G.N., Andrejchikov US, Call VA Synthesis, properties and biological activity of 3-pyridylamino 4-aryl-2-hydroxy-4-oxo-2-butenova (aroylpropionic) acids // Chem.-Pharm. W. - 1996. No. 1, S. 32-35.

2. Mashkovsky PPM Medicines. - 15-ed., Rev., Corr. and extra - M.: OOO "New wave", 2005. - S.

3. Methodological guidelines for experimental study of non-steroidal anti-inflammatory substances. The pharmacological Committee of the Ministry of health, USSR, Protocol No. 22, dated November 11, 1982, Moscow (1982).

4. Prozorovskiy V.B. have been, Prozorovsky BTW, Demchenko V. rapid method for determination of the average effective dose and its error // Pharmacology and toxicology. - 1978. No. 4. - S-502.

5. Izmerov IVAN, Sanotski I., Sidorov, K.K. Settings toxicometric industrial poisons. - M.: Medicine, 1977. - S-197.

Bis{3-phenyl-1-[N-(3-pyridyl)carboxamido]-1,3-propanedione}cadmium formula:

possessing anti-inflammatory activity.



 

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18 cl, 12 ex, 4 tbl

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29 cl, 1 tbl, 94 ex

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