Isopropylated 2-(4-chloroanilino)cinchoninic acid, exhibiting anti-inflammatory and analgesic activity

 

(57) Abstract:

Isopropylated 2-(4-chloroanilino)cinchoninic acid of the formula I can be used in medicine as anti-inflammatory and analgesic funds. 1 PL.

The invention relates to new biologically active compounds, namely isopropylamino 2-(4-chloroanilino)cinchoninic acid of the formula:

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possessing anti-inflammatory and analgesic activity, suggesting the possibility of its use in medicine as a drug for the treatment of inflammatory processes.

The closest analogue to the structure of the claimed compounds is 2- (2,4-dimethylaniline)Tikhonova acid, which exhibits anti-inflammatory activity [1] (Yanborisova O. A., Konshina T. M., Employees, Y. M., Zaks, A. S., Konshin M. E., Synthesis and antiinflammatory activity of 2-allamericanheroes acids and amides of 1,2-dihydro-2-oxazinone acid, Chem.-Pharm. zhurn., 1995, T. 29, N 6, S. 32-33).

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In medical practice widely used anti-inflammatory medication may also fuse [2] (Mashkovsky, M. D., Medicines, M, Medicine, 1985, T. 1, S. 198), which has taken us the plants is search in a series of amides of 2-substituted cinchoninic acid compounds, having a high anti-inflammatory and analgesic activity with low toxicity.

This goal is achieved by the synthesis of Isopropylamine 2-(4-chloroanilino)cinchoninic acid interaction Isopropylamine 2-horseshoebay acid [3] (Mikhalev A. I., M. Zueva Century, Sachs A. S. Synthesis and anti-inflammatory activity of substituted amides 2-horseshoebay acid, Dept. in VINITI, 1996, N 2433-B96) with 4-Chloroaniline according to the following scheme:

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An example of obtaining the claimed compounds.

The solution 2,48 g (0.01 mol) of Isopropylamine 2-horseshoebay acid and 1.28 g (0.01 mol) of 4-Chloroaniline in 10 ml of DMF is boiled for 4 h, cooled, poured into 50 ml of water, neutralized with 10 % sodium carbonate solution. The precipitate is filtered off and recrystallized from dioxane. Yield 3.0 g (88%).

So pl., 250 - 252oC. C19H18CIN3O.

Found, % : C 67,20; H 5,42; N 12,31.

Calculated, % : C 67,15; N. Of 5.34; N 12,37.

IR-spectrum (UR - 20) vaseline oil, cm-1: 1640 (CO), 3400 (NH). PMR-spectrum (Fourier spectrometer NMR firm Tesla BS-587A, DMSO-d6, GMDS, , M. D. ): 9,63 s (1H, NH), 8.58 in d (1H, NH-amide), 7,0-8,06 m (9H, ArH) 4.1 m (1H, CH) and 1.15 (6H, 2CH3).

The compound obtained is when Suche connection stable.

The claimed compound was examined for the presence of anti-inflammatory and analgesic actions.

Acute toxicity of the compounds and ortofena studied on white mice by the method of [4] (Prozorovsky Century B., a Practical guide for rapid determination of the average effective doses and concentrations of biologically active substances, S.-Petersburg, SPE-Science, 1992, S. 42) intraperitoneal injection, and found that LD50for the claimed compound is 631 mg/kg, and ortofena - 132 mg/kg

Anti-inflammatory activity (PVA) has been studied in outbred rats weighing 160-190 g test substance was administered intraperitoneally in the form of a suspension in water with tween-80) for 1 h prior to the introduction of carragenine. Increase inflamed foot was evaluated ecometrics after 3 and 5 h after injection of 0.1 ml of 1% solution carragenine and calculated the percentage inhibition of edema compared to the control [5] (Trinus F. P., B. Klebanov M., Kondratyuk C. I. Methodological guidance on experimental (preclinical) study of non-steroidal anti-inflammatory pharmacological substances. M., the Ministry of health of the USSR, 1983, p. 16).

It is established that isopropylated 2-(4-chloroanilino)cinchoninic acid intraperitoneal call for the development carragenine edema during all periods of observation. The difference between the PKA of the claimed compounds at a dose of 10 mg/kg and activity ortofena in the same dose statistically insignificant. ED50compounds, calculated graphically equal to 8 mg/kg and corresponds to the ED50ortofena calculated for the same route of administration [6] (Subev R. F., Mashkovsky M. D., Schwartz, J., Pokryshkin Century. And. Comparative pharmacological activity of modern non-steroidal anti-inflammatory drugs, Chem. Pharm. zhurn., 1986, T. 20, No. 1, S. 33-39). The analyzed connection manifests PVA at a dose of 25 mg/kg and the oral route of administration and causes inhibition of edema after 3 h of 38.2% and 5 h by 42.6%.

The positive difference between the claimed compounds from used in medicine anti - inflammatory drugs-ortofena is a large amount of therapeutic index of PVA, which are respectively 79,0 and 16.5, i.e., therapeutic index of the claimed compounds is 4.8 times higher than ortofena.

To characterize the analgesic activity of the used test acetic cramps" in mice caused by intraperitoneal introduction of 0.25 ml of a 0.75% solution of acetic acid by counting the number of "cramps" within 10 minutes [7] C. A. Winter, E. A. Risley and G. W. Nuss // Proc. Soc. Exp. Biol. (New York), -1962. -Vol.111. -P. 544-547).

And the Oia irritating agent.

The experimental results were processed statistically with the calculation of the criterion of validation [8] (Belenky, M. L., Elements of quantitative evaluation of the pharmacological effect, 2nd ed., Leningrad, Medgiz, 1963, S. 81 - 106).

On the analgetic action of the studied compound at a dose of 25 mg/kg (table). several inferior activity ortofena in the same dose.

Sources of information

1. Yanborisova O. A., Konshina T. M., Employees, Y. M., Zaks, A. S., Konshin M. E., Synthesis and antiinflammatory activity of 2-allamericanheroes acids and amides of 1,2-dihydro-2-oxazinone acid, Chem.-Pharm. zhurn., 1995, T. 29, N 6, S. 32-33.

2. Mashkovsky, M. D., Medicines. Medicine, Moscow, 1985, T. 1, S. 198.

3. Mikhalev A. I., M. Zueva Century, Sachs A. S., Synthesis and anti-inflammatory activity of substituted amides 2 - horseshoebay acid, Dept. in VINITI, 1996, N 2433-B96.

4. Prozorovskiy Century B., a Practical guide for rapid determination of the average effective doses and concentrations of biologically active substances, SPE-Science, S. - Petersburg, 1992, S. 42.

5. Trinus F. P., B. Klebanov M., Kondratyuk Century. And., guidance on experimental (preclinical) study of the non-steroidal protivovospalitelnye Century. And., Comparative pharmacological activity of modern non-steroidal anti-inflammatory drugs, Chem.-Pharm.zhurn., 1986, T. 20, No. 1, S. 33-39.

7. C. A. Winter, E. A. Risley And G. W. Nuss // Proc.Soc.Exp.Biol. (New York), -1962. -Vol.111.-P. 544-547.

8. Belenky, M. L. , Elements of quantitative evaluation of the pharmacological effect, 2nd ed., Leningrad, Medgiz, 1963, S. 81-106.0

Isopropylated 2-(4-chloroanilino)cinchoninic acid formula

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exhibiting anti-inflammatory and analgesic activity.

 

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