4-methylanilide-n-n-propylpyrrolidine-2-carboxylic acid borate, having anthelminthic activity

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound 4-methylanilide-N-n-propylpyrrolidine-2-carboxylic acid borate of formula:

, having anthelminthic activity. The compound is obtained through bromination of 5-chlorovaleric acid with subsequent conversion thereof into an acid chloride using thionyl chloride, further amination with 4-methylaniline and then ring closure with n-propylamine in 4-methylanilide-N-n-propylpyrrolidine-2-carboxylic acid and reaction of the latter with boric acid.

EFFECT: high activity of the compound.

1 tbl


The claimed connection relates to the field of organic chemistry class arylamido azacyclopentadecan acids, namely new biologically active 4-methylaniline-N-n-propylpyrrolidine-2-carboxylic acid borate (I) of the formula:

which can be used as an anthelminthic drug drug.

As standards anthelminthic action used a well-known drugs Pyrantel and levamisole [Mashkovsky PPM Medicines. - 15-ed., Rev., Corr. and supplementary): RIA "New wave": the Publisher Merenkov, 2008. - 1206 S.: ill.].

The aim of the invention is to obtain a new previously undescribed 4-methylaniline-N-n-propylpyrrolidine-2-carboxylic acid borate having anthelmintic activity. This goal is achieved by the synthesized δ is haralanova acid, followed by its translation into the acid chloride with chloride tonila, further aminating 4-methyl-aniline production and then cyclization with n-Propylamine 4-methylaniline-N-n-propylpyrrolidine-2-carboxylic acid and the interaction of the latter with boric acid according to the scheme:

Synthesis of base 4-methylaniline-N-n-propylpyrrolidine-2-carboxylic acid made by well-known methods [Lihosherstov A.M., Pryanishnikova HT., Lebedev, A.S., and other Azacycloheptane XIX. Synthesis and an anaesthetic activity of some Mezhidov pyrrolidinecarbonyl-2 acid. // Chem-Pharm. J., 1976, Vol.7, p.36-40.].

Borat 4-methylaniline-N-n-propylpyrrolidine-2-carboxylic acid

Mixed 0.04 mol of 4-methylaniline N-propylpyrrolidine-2-carboxylic acid in 15 ml of ethanol and 0.08 mol of boric acid in ethyl alcohol (in sufficient quantity to dissolve when heated). Then was placed in a round bottom flask of 100 ml with a reflux condenser and heated on a water bath for 15 minutes After evaporation of the solvent precipitated residue, which is recrystallized twice from acetonitrile. The yield was 56%, TPL 196-198°C, the decomposition of 310°C.

The inventive compound is a white crystalline substance or plate white color, soluble in ethanol, DMF, with water forms an emulsion milky white, not soluble in acetone, hexane, diethyl ether. The NMR spectrum1N (BS-567A, (100 MHz) in CDCl3internal standard - GMDS) of compound (I) include: a triplet of three protons metal group through radical at the nitrogen heteroatom when 0,890 ppm, multiplet two protons of methylene group through radical at the nitrogen heteroatom when 1,475-1,707 ppm, multiplet four protons of two methylene groups pyrolidine cycle when 1,929-2,244 ppm, a singlet of three ol the tones of a methyl group to the aromatic ring at 2,244 ppm, multiplet three methylene protons and CH-groups pyrolidine cycle and two protons of methylene group have various substituent at the nitrogen heteroatom at 2,800-4,072 ppm, multiplet four protons of the aromatic ring in the area 6,242-7,438 ppm, a singlet proton-NH-group at 9,386 ppm, a singlet proton boric acid at 10,258 ppm

Study of biological activity

Anthelmintic activity was studied on earth (rain) worms (Lumbricus terresrtis) according to the method of Nikolaev M.P. (1941): in a 0.5% aqueous solution of tested compound was placed earthworms and recorded the time of death. As standards of comparison used a 0.5% aqueous solutions of Pyrantel (as pamoate) and levamisole.

Acute toxicity when administered orally (p/o) was determined by nonlinear white mice of both sexes weighing 18-24 g test substance and the Comparators was introduced through the mouth using a probe in the form of aqueous solution or suspension (for Pyrantel of pamoate, because it is not soluble in water) at a rate of 0.1 ml / 10 g weight of the animal in increasing doses. The results were processed by Prozorovsky calculation of the median lethal dose (LD50) at P≤0,05 [Prozorovsky CENTURIES, Prozorovsky BTW, Demchenko V.M. Pharmacol. toxicol., Vol 41, No. 4, s-502, 1978.]. The results of anthelmintic activity and acute toxicity of the compounds I, the feast of the body and levamisole are presented in table 1.

Table 1
ConnectionThe lifespan of worms, minP1in comparison with PyrantelP2in comparison with
LD50p/o, mg/kg
Pyrantel537,50±8,664470 (2983-5815)
Levamisole20,2±2,08282 (159-419)
I10,9±1,24<0,001<0,0015150 (3616-6920)

As can be seen from the table, the inventive compound of formula (I) 18.3 times is less toxic in comparison with levamisole and significantly greater in anthelminthic activity of 1.85 times. In addition, the compound of formula (I) toxicity is comparable to the toxicity of Pyrantel (a drug with low toxicity), but significantly greater in anthelmintic action in 49.3 times.

Thus, 4-methylaniline-N-n-about iparralde-2-carboxylic acid borate exhibits more pronounced anthelminthic effect at equal or lesser toxicity, what Pyrantel and levamisole. Therefore, the claimed compound (I) can be used in medicine as an anthelmintic drug.

4-methylaniline-N-n-propylpyrrolidine-2-carboxylic acid Borat

having anthelmintic activity.


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8 tbl, 2 ex, 2 cl

Acid complex // 2442578

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26 cl, 2 dwg, 1 tbl, 4, ex

FIELD: medicine.

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2 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

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2 cl, 2 ex

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2 ex

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2 ex, 1 tbl

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2 ex

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2 ex

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34 cl, 6 tbl, 2 ex

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1 tbl, 2 ex

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3 ex, 1 tbl

FIELD: medicine.

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5 ex

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1 ex

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2 cl, 14 ex

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3 ex, 3 tbl