CS269021B1 - Esters of carbanilic acid and method of their preparation - Google Patents

Abstract

The solution relates to carbanilic esters of formula I, and tol 1- [2- (2-Butyloxycarbaniloyloxycycloheptyl) methyl] piperidinium chloride and (2- (2-butyloxycarbaniloyloxy) boron-3-ylmethyl) diethylammonium chloride and a method of preparation of these compounds by reaction of 2-butyloxyphenyl isocyanate with a compound selected from the group comprising 2-piperidinomethylcycloheptanol and 3-diethylaminomethyl-2-bornanol in toluene at the boiling point of the solvent for 12 h.

Description

CS 269021 31 1/1 /

BACKGROUND OF THE INVENTION The present invention relates to carbanilic acid esters of the formula I-O-CH 2 / CH 2 / CH 3 R-O-CO-HN- wherein R is cn 2 -h

Cl (Ia) or ©

Ch2-N / C2h5 / 2 (Ib)

C1 and the method of making these carbanilic acid esters. Some compounds of the carbanilic acid ester groups are characterized by high local anesthetic activity (Carbizocaine, Heptacaine, Pentacain) and in some cases also by anti-arrhythmic and antileacous activity, The compounds of the invention are novel substances not previously described in chemical literature. . These compounds have been found to have extremely high, hitherto unknown, local anesthetic effects on the body. For comparison, Table 1 shows the local anesthetic activity and toxicity of the prepared carbanilic acid esters and the structurally close high-potency compound Carbizocaine, the values of which are presented in Tůmová I., Švec P. Drugs txptl. clin.Res. 12,845 (1985). In the examples, the compounds of the invention as well as the methods for their preparation are described together with the characterization of these compounds. In addition to the extracts, the results of elementary element analysis,

Values / Thin Films Silufol Ur 356, silica gel, cyclohexane-benzene-diethylamine / 45: 11: 3 /, detection under UF radiation / IC spectral characteristics are also listed 1 T p ristics / chloroform, V in cm and 1 H NMR spectral characteristics / chemical shift of 2 ppm /.

To determine the local anesthetic activity, a method was used, the principle of which is to detect the effective concentration of the substance and the standard. Topical topical anesthetic activity index was measured on the cornea of the rabbit, cocaine standard -2-3 chloride, c = 10 mol.co, and local anesthetic activity index for intiltration - -2 - 3 cii was found on the skin of the guinea pig back , standard procainium chloride c = 2.10 mol.dm. The acute toxicity of LO-θ / in mg.kg-1 was determined in mice by subcutaneous administration.

The process for preparing carbanilic esters is characterized in that 2-butyloxyphenyl isocyanate is reacted with a compound selected from the group consisting of 2-piperidinomethylcyclo-heptane and 3-diethylaminomethyl-2-bornanol in toluene at the boiling point of this solvent for 12 hours.

Table 1. Local anesthetic activity and toxicity of prepared carbalinic and structurally close carbizocaine esters.

Local anesthetic activity index infiltration.anesthesia superficial anesthesia

Toxicity / mg.kg-1 /

Carbizocaine 416 I a / 232 I b / 25 251 709 568 380 100 100

The following examples illustrate, but do not limit, the preparation of the novel biologically active carbanilic acid esters of the present invention. Example 1

A mixture of 2-piperidinomethylcycloheptanol (0.0091 mol), 2-butyloxyphenylisocyanate (0.0090 mol) and toluene (15 cm) was heated under reflux for 12 h, avoiding atmospheric moisture. After cooling, 15 cm of hexane are added to the mixture and the precipitated solid / symmetrically substituted urea is filtered off. The solvent and unreacted starting materials are distilled off from the filtrate under atmospheric, low-vacuum under reduced pressure. 3

The liquid residue is dissolved in 20 cm @ 3 of ether and this solution is extracted twice in a separatory funnel to 150 cm @ 3 of 5% strength hydrochloric acid. The precipitated solid is filtered off, washed with a small volume of water and purified by crystallization from water. 1- [2- (2-Butyloxycarbaniloyloxycycloheptyl) methyl] piperidinium chloride is obtained in a yield of 54% of theory. Colorless crystals, m.p. 167-169 ° C, Rp = 0.27 and 0.44 / two spots, a mixture of cis- and trans-.

N, 5.87. Found: C, 75.39; H, 12.03; N, 5.80. Found: C, 75.57; - spectral characteristics / NH / 3427, V / $ Ή / 2448, V / 0 = 0/1725, 7/0 = 0/1604, cf / CNH / 1520. * Η NMR spectral characteristics of CH3 / alkoxy / 1 , 02, CH 2 O 4.07, NH-CO 7.27, NH 12.00. Local anesthetic activity indices 232 (in infiltration) (709) at topical application, lo5O = 100. Example 2

The mixture of 0.0091 mol of 3-diethylaminomethyl-2-bornanoic acid, 0.0090 mol of 2-butyloxyphenylisocyanate and 15 cm @ 3 of anhydrous toluene was heated under reflux for 12 h, avoiding atmospheric humidity. After cooling, 15 cm of hexane are added to the mixture and the precipitated solid / symmetrically substituted urea is filtered off. Unreacted starting materials are distilled off from the filtrate at atmospheric, under reduced pressure. Liquid zvy-3 shock to dissolve! in 20 cm @ 3 of ether and this solution in a separatory funnel twice extracted into 200 cm @ 3 of 5% hydrochloric acid. The aqueous layer was separated, filtered through a padded filter, and 10% aqueous sodium hydroxide solution was added portionwise with stirring and cooling, so that the temperature of the mixture did not exceed 20 ° C to pH = 9. Extracted oil was extracted three times into ether. Dry the ether layer. ether is distilled over anhydrous sodium carbonate and filtered. Moisture residues are removed by azeotropic distillation of the oily residue with toluene. The oil obtained is dissolved in 15 cm @ 3 of anhydrous ether and ethereal hydrochloric acid solution is added to the mixture so that the temperature of the mixture does not exceed 0 DEG C. The precipitated solid is filtered off and purified by crystallization from butanone. There was obtained 2- (2-butyloxycarbaniloyloxy) boron-3-ylmethyl] diethylammonium chloride (11) in a yield of 69% of theory. Colorless crystals, m.p. 152-154 ° C Analysis for C 26 H 43 N 2 O 2 Cl / M · r. 457.19 / calculated! % H, 9.64; N, 6.00; % C, 9.34%, N, 5.70% IC, spectral characteristics P / NH / 3424, p / $ - H / 2448.7 / 0 = 0/1726, Ý / 0 = 0/1603 1 H NMR spectral characteristics CH 3 O 4.08, NH-CO 7.26, $ 4 11.80.

Claims (2)

CS 268021 81 3 Indices of local anesthetic activity 25 / for infiltration application / 558 / for surface application /, LD5q “100. P R E O Μ E T OUT 1. Carbanilic acid esters of the general formula I R-O-CO-HN · O-CHg / CH2 / gCH3 (o) (I) wherein R is CH2-V / H ' Cl 2. 1- {2- [2- (Butyloxycarbaniloyloxy) cycloheptyl] methyl] piperidinium chloride 3. [2- (2-Butyloxycarbaniloyloxy) boron-3-ylmethyl] diethylammonium chloride 4. A process for the preparation of carbanilic esters according to claim 1, wherein the 2-butyloxyphenyl isocyanate is reacted with a compound selected from the group consisting of 2-piperidinomethylcycloheptanol or 3-diethylaminomethyl-2-bornanoic acid in the thiol to boil the solvent for 12 hours.