CS208960B1 - 1-methyl-2-diethylaminoethylester of 2-heptyl-oxycarbanilic acid and method of its production - Google Patents

Description

The present invention relates to 2-heptyloxycarbamic acid 1-methyl-2-diethylaminoethyl ester of formula (I).

and salts thereof with pharmaceutically acceptable inorganic and organic acids, in particular hydrochloric acid. The invention also relates to processes for preparing the ester of formula I.

This substance is characterized by extremely high local anesthetic activity and relatively low acute toxicity. The following table shows the results of testing its efficacy as the hydrochloride compared to cocaine and procaine as standards and the acute toxicity value of LD ₅₀ in mice by subcutaneous administration.

In monitoring the local anesthetic effect on the rat sciatic nerve in vitro at pH 7.2, the compound of formula I is 185 times more potent than the procaine standard and 50 times more potent than the trimecain standard. By lowering the pH of the external environment to 6.0, the compound of formula I is 1575 times more potent than the procaine standard and 525 times more potent than the trimecain standard. The onset of action of the compound of formula I is at equally effective concentrations at pH compared to standards

7.2 slower but equally fast at pH 6.0. A characteristic of the compound of formula I is the long-lasting local anesthetic activity; at pH 6.0 it is 5.8 times more effective than at pH 7.2, while the efficiency of the procaine standard is 0.7 times less under the same conditions and the tximecaine standard 0.5 times less.

The 2-heptyloxycarbamic acid 1-methyl-2-diethylaminoethyl ester of formula I can be prepared according to the invention in several simple ways; for example by reacting

(a) a compound of formula (II);

Relative anesthesia LD ₅₀ surface infiltration mg / kg sc

Substance of Formula I 251 ·. » 416 600 Procaine - 1 630 Cocaine 1 - 125

wherein Y represents a halogen atom, preferably chlorine, with 1-methyl-2-diethylaminoethanol, used in the form of an alkali metal alcoholate, preferably sodium;

b) o-heptyloxyaniline with a compound of formula III,

Y— COO ·

CH - CH ² - N ' ² ' CH ² / A (III) ^C 2 ^H 5 wherein Y denotes the same as in formula II; (c) a compound of formula IV;

CH "

I ³

NHCOO - CH - CH - Y (IV)

^OC 7 ^H 15 wherein Y denotes the same as in formula II, with diethylamine, in an inert inert solvent such as an aromatic hydrocarbon, preferably benzene, at the boiling point of the reaction mixture, whereupon the ester obtained in base form is converted by neutralization with inorganic or organic acid in the corresponding salt.

d) a compound of formula V, (V)

Y-COO-CH-CH ₂ -Y in which Y is the same as in Formula II, first with o-heptyloxyoxyaniline, then the product of this reaction in the form of a water-washed and dried solution in the solvent used is further reacted with diethylamine.

In carrying out the processes of the invention, the reaction takes place between the starting components in an inert organic solvent, preferably benzene or toluene, and, depending on their reactivity, either under cooling, at room temperature or at the boiling point of the reaction mixture. After completion of the reaction, the reaction mixture is most often treated by washing with water, the organic solvent is evaporated and the crude base ester residue is purified by conversion to salt and alkalization and extraction into an organic, water-immiscible solvent. From this solution, the basic ester can be converted directly into the desired salt and further purified by crystallization from an organic solvent, preferably acetone or a solvent mixture. Salts with inorganic acids suitable for the preparation of dosage forms are, for example, hydrochloride, hydrobromide, sulphate or phosphate, and optionally salts with organic acids, for example methanesulphonate, tartrate, citrate, maleic, fumaran and the like.

The starting materials for the preparation of 1-methyl-2-diethylaminoethyl ester of o-heptyloxycarbanilic acid of the formula I are both commercially available compounds o-aminophenol and heptyl halides and substances prepared analogously to the methods previously described in the literature.

Further details of the individual preparation methods are given in the following examples:

Example 1

11.5 g of sodium are dissolved in 66 g of 1-methyl-2-diethylaminoethanol and 200 ml of menzene are added to the solution. This solution was slowly added to a solution of 21.9 g of 2-heptyloxyphenylcarbamic acid chloride in 200 ml of benzene with stirring and cooling. After the heat evolution had ceased, the reaction mixture was boiled for an additional 1 hour, cooled to room temperature and filtered. Benzene and excess alcohol were distilled off from the filtrate and the residue was dissolved in dilute hydrochloric acid. The solution is shaken several times with ether and the base is separated from the separated aqueous phase by alkalization with ammonia and taken up in ether. After drying, the filtered ethereal solution is evaporated or the hydrochloride precipitates from this solution by addition of an equivalent amount of ethereal hydrogen chloride solution, which melts at 92-94 ° C after crystallization from acetone.

Salts with organic acids: fumarate has m.p. 98-100 ° C and the oxalate has m.p. Mp 74-77 ° C.

Example 2

To a solution of 41.4 g of 2-heptyloxyaniline in 200 ml of benzene is added a solution of 19.4 g of 1-methyl-2-diethylaminoethyl chloroformate in 200 ml of benzene while cooling at not more than 20 ° C. After completion of the self-heating the mixture is boiled for a further 5 hours. After cooling, o-heptyloxyaniline hydrochloride was filtered off. The solvent was distilled off from the benzene filtrate after washing with water and the crude ester base obtained as a slurry was treated as in Example 1.

Example 3

To a solution of 32.8 g of 2-chloropropyl o-heptyloxycarbamic acid ester in 200 ml of benzene was added 14.6 diethylamine, the mixture was boiled for 5 hours, washed with water after cooling, filtered and evaporated. The residue is treated as in Example 1.

Example 4

To a solution of 41.4 g of o-heptyloxaniline in 500 ml of benzene was added, with stirring and cooling, a solution of 15.1 g of 2-chloropropyl chloroformate in 300 ml of benzene. After the heat evolution had ceased, the precipitated o-heptyloxyaniline hydrochloride was filtered off, washed with benzene and the benzene filtrate with water. The dried and filtered benzene solution was mixed at room temperature with 14.6 g of diethylamine and boiled for 5 hours. After cooling and washing with water, benzene is distilled off and the residue is treated as in Example 1.

Claims (4)

SUBJECT 1. 2-Heptyloxycarbamic acid 1-methyl-2-diethylaminoethyl ester of the formula I CH, OF THE INVENTION NHCOO - / ^C 2 ^H 5 I \ ₅ (I) wherein Y has the same meaning as in formula II in an inert organic solvent such as an aromatic hydrocarbon, preferably benzene, first at a temperature of 20 ° C, after completion of self-generation of heat and at the boiling temperature of the reaction mixture, whereupon the ester obtained in the form of a base is converted by neutralization with an inorganic or organic acid into the corresponding salt. 4. A process according to claim 1, wherein the compound of formula (IV) and its salts are reacted with pharmaceutically acceptable inorganic and organic acids, in particular hydrochloric acid. 2. A process for the preparation of 1-methyl-2-diethylaminoethyl ester of 2-heptyloxycarbanilic acid of the formula I according to claim 1, which comprises reacting a compound of the formula II: NHCOO- -CH CH - ^Y-C 7 ^H 15 in which Y is halogen, preferably chlorine, is reacted with l-methyl-2-diethylaminoethanol, used in the form of an alkali metal, preferably sodium, in an inert organic solvent such as % of an aromatic hydrocarbon, preferably benzene, at the boiling point of the reaction mixture, whereupon the ester obtained in base form is converted by neutralization with an inorganic or organic acid into the corresponding salt. 3. A process for the preparation of 1-methyl-2-diethylaminoethyl ester of 2-heptyloxycarbanilic acid of the formula I according to claim 1, characterized in that o-heptyloxyaniline is reacted with a compound of the formula III in which Y stands for formula II; diethylamine, in an inert organic solvent such as an aromatic hydrocarbon, preferably benzene, at the boiling point of the reaction mixture, whereupon the ester obtained in base form is converted by neutralization with an inorganic or organic acid to the corresponding salt. 5. A process for the preparation of a 1-methyl-2-diethylaminoethyl ester of the formula (I) according to claim 1, which comprises reacting a compound of formula (V): Y - COO - CH - CH - Y (V) I 4 CH, ( ^ΙΠ > / 25 Y-COO-CH-CH-n; ^{1 2} \ CH. ^C 2 ^H 5 in which Y denotes the same as in formula II, first with o-heptyloxaniline in an inert organic solvent such as an aromatic hydrocarbon, preferably benzene, the product of this reaction in the form of a water washed and dried solution is reacted with diethylamine at the boiling point of the reaction mixture, whereupon the ester obtained in base form is converted by neutralization with an inorganic or organic acid into the corresponding salt.