CS269021B1 - Carbanic acid esters and methods for their preparation - Google Patents

Abstract

The solution relates to carbanilic acid esters of the general formula I, namely 1-[2-[2-butyloxycarbaniloyloxycycloheptyl]methyl]piperidinium chloride and (2-[2-butyloxycarbaniloyloxy]bornan-3-ylmethyl]diethylammonium chloride and a method for preparing these compounds by reacting 2-butyloxyphenylisocyanate with a compound selected from the group consisting of 2-piperidinomethylcycloheptanol and 3-diethylaminomethyl-2-bornanol in toluene at the boiling point of this solvent for 12 h.

Description

The invention relates to carbanilic acid esters of the general formula I o-ch,/ch ₂ / ₂ ch ₃

where R means or

(la) (lb) and the method of preparation of these esters of carbanilic acid. Some compounds from the group of esters of carbanilic acid are characterized by high local anesthetic activity /Carbizocaine, Heptacaine, Pentacaine/ and in some cases also by antidysrhythmic and anti-leukemia activity. The compounds that are the subject of the invention are new substances, not yet described in the chemical literature. These compounds have been found to have extremely high, previously unknown local anesthetic effects on the body. For comparison, we present in Table 1 the indices of local anesthetic activity and toxicity of the prepared esters of carbanilic acid and the structurally close highly active compound Carbizocaine, the values of which are taken from the work Tůmová I., Svec P. Drugs txptl. clin.Res. 12,845 /1985/. The examples show the compounds that are the subject of the invention, as well as the method of their preparation together with the characterization of these compounds. In addition to the samples, the results of elemental analysis, Rp values /Thin layers of Silufol UF 366, silica gel, developing system cyclohexane - benzene - diethylamine /45: 11: 3/, detection under UF radiation/, IC spectral characteristics /chloroform, V ⁱⁿ cm ^- ^/ and NMR spectral characteristics /chemical shift </” in ppm/ are also given. .

To determine the local anesthetic activity, a method was used, the principle of which is to determine the equieffective concentration of the substance and the standard. The index of local anesthetic activity for surface application was determined on the rabbit cornea, the standard cocaine-2 -3 chloride, c = 10 mol.co and the index of local anesthetic activity for infiltration application was determined on the goat back of guinea pigs, the standard procaine chloride c = 2.10 mol.dm . The acute toxicity of LO-θ / ⁱⁿ mg.kg”^/ was determined on mice by subcutaneous application.

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

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Table 1. Local anesthetic activity and toxicity of prepared esters of carbanilic acid and the structurally related Carblzocaine.

Fabric Local anesthetic activity index Toxicity infiltration anesthesia superficial anesthesia /mg.kg ^-1 /

Carbizocaine 416,251 380 I and/ 232,709 100 I b/ 25,568 100 Next the examples illustrate, but do not limit, the method about the preparation of the night- biologically active carbanilic acid esters according to the invention.

Example 1

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

The liquid residue is dissolved in 20 cm of ether and this solution is extracted twice in a separatory funnel into 150 cm of 5% 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]J piperidinium chloride is obtained in a yield of 64% of theory. Colorless crystals m.p. 167 - 169 °C, Rp = 0.27 and 0.44 (two spots, a mixture of two cis- and trans- isomers).

Analysis for C ₂₄ ^H 3gN2 ⁰ 3Cl /Mry 439.04/ calculated: 75.57% C, 11.83% H, 5.87% N, found: 75.39% C, 12.03% H, 5.80% N; IC - spectral characteristics 7 /NH/ 3427, V /^-h/ 2448, V /C=0/ 1725, V /C=C/ 1604, cf /CNH/ 1520. j'H NMR spectral characteristics CH ₃ /alkoxy group/ 1.02, CH ₂ 0 4.07, NH-CO 7.27, NH 12.00. Indices of local anesthetic activity 232 /for infiltration application/ 709 /for surface application, lo _5O = 100.

Example 2

A mixture of 0.0091 mol of 3-diethylaminomethyl-2-bornanol, 0.0090 mol of 2-butyloxyphenylisocyanate and 15 cm of anhydrous toluene is heated under reflux for 12 h, with the exclusion of atmospheric moisture. After cooling, 15 cm of hexane is added to the mixture and the precipitated solid (symmetrically substituted urea) is filtered off. The unreacted starting compounds are distilled off from the filtrate under atmospheric pressure, and finally under reduced pressure. The liquid residue is dissolved in 20 cm of ether and this solution is extracted twice into 200 cm of 5% hydrochloric acid in a separatory funnel. The aqueous layer is separated, filtered through a folded filter and 10% aqueous sodium hydroxide solution is added in portions with stirring and cooling so that the temperature of the mixture does not exceed 20°C to pH= 9. The separated oil is extracted three times into ether. The ether layer is dried over anhydrous sodium carbonate and after filtration the ether is distilled off. Residual moisture is removed by azeotropic distillation of the oily residue with toluene. The oil obtained is dissolved in 15 cm of anhydrous ether and ethereal hydrogen chloride solution is added to the turbidity so that the temperature of the mixture does not exceed 0°C. The separated solid is filtered off and purified by crystallization from butanone. £2-(2-butyloxycarbaniloyloxy)bornan-3-ylmethyl) diethylammonium chloride (11) is obtained in a yield of 69% of theory. Colorless crystals mp 152 - 154°Cj Analysis for C ₂₈ H ₄₃ N ₂ 0 ₂ Cl /Mr · 467.19/ calculated: 66.84% C, 9.30% H, 6.00% N, found 66.29% C, 9.34% H, 5.70% Nj IC - spectral characteristics V /NH/ 3424, V /$-H/ 2448.7/0=0/ 1726, Ý /C«C/ 1603, cT /CNH/ 1517. NMR spectral characteristics CH ₂ 0 4.08, NH-CO 7.26, 11.80.

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Indices of local anesthetic activity 25 /for infiltration application/ 56Θ /for surface application/, LDgg« 100.

Claims (4)

TRANSFER OF THE INVENTION 1. Carbanilic acid esters of general formula I 0-CH2/ _CH2 / _2CH3 or _group R-O-CO-HN (I) 2. 1 - 2-(Butyloxycarbaniloyloxycycloheptyl/methyl) piperidinium chloride 3. [2-/2-butyloxycarbaniloyloxy/bornan-3-ylmethyl] diethylammonium chloride 4. A method for preparing carbanilic acid esters according to item i, characterized in that 2-butyloxyphenyl isocyanate is reacted with a compound selected from the group consisting of 2-piperidinomethylcycloheptanol or 3-diethylaminomethyl-2-bornanol in toluene at the boiling point of this solvent for 12 h.