5-chloro-2-pyridylamino-4-nitro-n-(carboxymethyl)anthranilic acid, exhibiting anti-inflammatory activity

 

(57) Abstract:

Usage: in medicine as anti-inflammatory drugs. The essence of the invention: 5-chloro-2-pyridylamino-4-nitro-N-(carboxymethyl)-Anthranilic acid, exhibiting anti-inflammatory activity. BF C12H8O3N3Cl , So pl. 162-163C, yield 79%. Reagent 1: 5-chloro-2-pyridylamino 2-chloro-4-nitrobenzoic acid. Reagent 2: glycine. Reaction conditions: dimethylformamide, sodium carbonate. table 4.

The invention relates to new biologically active compound, specifically to 5-chloro-2-pyridylamino 4-nitro-N - (carboxymethyl) Anthranilic acid of formula I exhibiting anti-inflammatory activity

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Having the mentioned properties, a new connection can be used in medical practice as anti-inflammatory agents.

The closest structural analogue of the action, showing anti-inflammatory activity is voltaren (II)

However, voltaren has a number of side effects, the main of which is ulzerogennoe action.

In this regard, the search for new chemical substances possessing anti-inflammatory activity is relevant prabhudeva high anti-inflammatory activity and low toxicity.

Synthesis of compound I is carried out in two stages

Getting 5-chloro-2-pyridylamine 2-chloro-4-nitrobenzoic acid by amidation of the acid chloride of 2-chloro-4-NIT - robinsonii acid 2-amino-5-chloropyridine.

The condensation of the resulting amide with glycine in the medium of dimethylformamide according to the scheme

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P R I m e R 1. Synthesis of 5-chloropyridine 2-chloro-4-nitrobenzoic acid.

4,06 g (0.02 mol) of 2-chloro-4-nitrobenzoic acid, 6 ml of thionyl chloride, 25 ml of benzene is heated on a water bath for 40 min, distilled under reduced pressure created by the water jet pump, the excess thionyl chloride, sulfur dioxide and hydrogen chloride. The obtained acid chloride was dissolved in 20 ml of dry dioxane and added dropwise to 2,08 g (0.03 mol) of 5-chloro-2-aminopyridine dissolved in 15 ml of dry dioxane with addition of 0.02 mol of triethylamine and leave for the day.

The resulting material is diluted with water, acidified with HCl (1:1) to pH 5. The precipitation is filtered off and dried. Yield 79% (4,56 g). Crystallized from ethanol. Tpl.162-163aboutC.

Calculated, %: C 51,91; H 2,90; N 15,13; Cl 12,76

C12H8O3N3Cl

Found,%: C 51,82; H 2,73; N 14,92; Cl 12,89.

Synthesis of 5-chloro-2-pyridylamine 4-nitro-N - (Carbo is 10 ml of dimethylformamide was added 0.75 g (0.01 mol) of glycine and 2.8 g (0.02 mol) of potassium carbonate. Heated at 140aboutC for 4 hours Sucked. The filtrate is diluted with water and acidified with HCl (1:1) to pH 5. Yield 57% (1.98 g). Crystallized from ethanol. MP. 137-138aboutC. Compound I crystalline substance beige color, soluble in ethanol, dimethylformamide, alkali solutions.

Calculated,%: C 47,95; H 3,16; N 15,97; Cl 11,10.

C14H11N4O5Cl.

Found,%: C 47,72; H 3,22; N 15,76; Cl 11,38.

IR spectrum (cm-1): SIMC=O.- 1435;ACCC=Othem.- 1580; - 1310, - 1530;NH- 1550;-S-CL- 775;-CO-NH-R- 3400.

P R I m m e R 2. The study of the pharmacological actions: anti-inflammatory activity and acute toxicity.

Anti-inflammatory activity was studied on the model carragenine edema in mice (Yakovlev, L. C., Supanet I. A., 1987).

Swelling caused white mice weighing 16-18 g the introduction of a 1% solution carragenine subcutaneously in the right hind leg at the rate of 0.05 ml per animal. The test substance and the comparison drug voltaren is administered orally 1 h before the introduction of carragenine. Every four hours the animals were scored, amputated hind legs at the level of the hip joint and weighed. On the extent of otakucenter and was determined by the ability of a substance to inhibit an inflammatory response in the experimental animals compared with controls. The test substance was administered in three doses: 0.1, 1 and 5 mg/kg It was possible to calculate the ED50and its confidence limits (Haji J. I., 1965). ED50the dose that causes in a group of experimental animals anti-inflammatory effect, equal to 50%. This value is also quantitative pharmacological characterization of biologically active substances. The results of the study anti-inflammatory activity are presented in table.1.

To calculate the ED50and its confidence limits used method I. I. of Haga (1965), as an anti-inflammatory activity not considered in the alternative, and in graded form. Graphic by finding the dose ED50and its confidence interval. The latter are represented in the table.4.

Acute toxicity of compound I was evaluated in mice weighing 15 grams in a single oral administration according to the method Pastushenko T. C. et al. (1985). First raised a number of preliminary experiments. Each dose was tested on two mice. The results are shown in table.2.

To obtain the final result were selected by the method of the following doses: 708 mg/kg, single dose up the scale - 668 mg/kg and a dose of down - 750 mg/kg the result of nogeneral find the right dose LD50with the condence interval. Thus, for compound I LD50= 765 (697-833) mg/kg According to the classification of the toxicity of chemicals K. K. Sidorov (1973) compound I refers to little toxic compounds.

The final results that characterize the anti-inflammatory activity and acute toxicity of compound I are shown in table.4.

Studies have shown that the connection I activity is superior to the comparator drug voltaren 5.7 times, and the breadth of therapeutic action in 12 times.

Thus, 5-chloro-2-pyridylamino 4-nitro-N - (carboxymethyl) Anthranilic acid is a highly active and low-toxic compound, greatly exceeds voltaren.

5-Chloro-2-pyridylamino - 4-nitro-N - (carboxymethyl)Anthranilic acid formula

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exhibiting anti-inflammatory activity.

 

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20 cl, 1 tbl, 86 ex

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15 cl, 7 tbl, 56 ex

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25 cl, 29 ex

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EFFECT: valuable medicinal properties of compound.

1 cl, 1 tbl, 1 ex

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