NO120959B - - Google Patents

Description

Process for the preparation of 3-N-lower alkyl or 3-N, N-dilower alkylaniino-isocamphane compounds.

The present invention relates to a

process for the preparation of 3-N-lower alkyl or 3-N,N-dilower alkyl-amino-isocamphane compounds of the general formula

in which R, denotes hydrogen or a lower alkyl group. The invention includes

also production of addition salts with

acids or quaternary ammonium salts of

compounds with this general formula.

The compounds obtained by the process according to the invention are valuable ganglion blocking agents.

The characteristic main feature of

the invention is to react an iso-camphane compound with the general formula

(in which R 1 has the meaning given above, and R 1 denotes an acyl group)

with a reducing agent and possibly over-

leads the formed N-monoalkyl or N,N-dialkyl compounds to respectively addition salts with acids and to cationic ammonium compounds.

The reduction is preferably carried out in an anhydrous, non-reactive solvent such as ethyl ether with a reducing agent consisting of an aluminum hydride, in particular an alkali metal aluminum hydride, such as e.g. lithium aluminum hydride or sodium aluminum hydride. When carrying out the reduction, the aluminum hydride should be present in an amount equivalent to about 2 mol of hydride per moles of starting material. Thus, the reduction can conveniently be carried out by dissolving lithium aluminum hydride in ethyl ether, adding to the resulting solution a solution of 3-(N-acylamino)- or 3-(N-acylalkylamino)-isocamphane in anhydrous ether and then heating the resulting mixture under reflux cooling for about 4-6 hours. The reduction of the starting material (the acyl amide compound) is then essentially complete.

The mono- or di-alkylamino compound thus formed is conveniently recovered by adding water to the reaction mixture, filtering the solution obtained and evaporating the filtrate to a small volume. When an N-monoalkyl compound is formed, this is preferably isolated in the form of the corresponding hydrochloride by adding a saturated solution of hydrochloric acid in ether to the evaporated solution. This precipitates the hydrochloride of 3-(N-alkylamino)-iso-camphane in crystalline form and can be separated and dried.

The N-formylamino compounds that can be used as starting material in the process according to the invention can be prepared as indicated in patent no. 99 610. The other N-acylamino and N-acyl-alkyl-amino compounds that can be used as starting material can be prepared by react the corresponding amino compounds with an acylating agent which is a derivab of a lower aliphatic carboxylic acid, such as e.g. acetyl chloride, in the presence of a base, or with glacial acetic acid. Preferably, however, an anhydride of an acid is used as mentioned, in the presence of a small amount of sulfuric acid.

Examples of suitable starting materials can be mentioned N-formyl-, N-acetyl-, N-propionyl-, N-butyroyl-, N-caproyl-, N-capryl-, N-isopropionyl- and N-isobutyroyl -amino compounds, as well as the corresponding N-alkyl-N-acyl-substituted compounds.

The obtained N-monoalkyl compounds can be transferred in the usual way to the corresponding addition salts with acids, such as e.g. the hydrochlorides, by reaction with the corresponding acid, e.g. hydrochloric acid, dissolved in ether to a saturated solution. In the same way, the corresponding hydrobromide, hydroiodide, sulphate, phosphate, citrate, tartrate etc. can be prepared.

The obtained N-dialkyl compounds can — likewise in the usual way — be transferred to the corresponding quaternary ammonium salts, e.g. by reaction with alkyl halides such as methyl iodide, or with alkyl sulphates, in alcoholic solution containing an alkali metal alcoholate, e.g. in ethanol containing sodium ethylate.

In the following, some embodiments of the invention are described as examples.

Example 1.

Preparation of dl-3-(N-methylamino)

isocamphane.

4.23 liters of anhydrous ether in a 12 liter three-necked flask equipped with a stirrer, reflux condenser and dropping funnel is quickly added 78 g (2.05 mol) of lithium aluminum hydride. The mixture is heated under reflux with stirring until all the hydride is dissolved, which requires several hours.

A solution of 168 g (0.92 mol) of dl-(N-formylamino)isocamphane in 1.81 liters of anhydrous ether is added with stirring to the mixture over the course of one hour. The solution is heated under reflux for approx. 6 hours, after which it is cooled carefully and 347 ml of water are added with continued stirring while gaseous hydrogen is added. Stirring is continued until the precipitate becomes powdery. It is filtered off using suction and washed with ether (total amount approx. 2 litres). The filtrate and the washing liquid are mixed and evaporated to a volume of 1.6 litres. The concentrate containing dl-3-(N-methylamino)isocamphane is washed once with approx. 350 ml of water and dried over anhydrous sodium sulphate. The dried ether concentrate is cooled in an ice bath and a cold, saturated solution of hydrogen chloride in ether is added slowly and with stirring until the mixture shows an acidic reaction to Congo red. This includes approx. 440 ml of anhydrous ether, saturated with HCl gas at 0° C. After complete precipitation, the white crystalline dl-3-(N-methylamino)isocamphane hydrochloride is filtered off and washed with anhydrous ether (approx. 1 liter) until it becomes neutral. The dl-3-(N-methylamino)isocamphane hydrochloride is dried in air at room temperature. It melts with cleavage at 249° C. Yield 156.5 g.

dl-3-(N-methylamino)isocamphane hydrochloride (156.5 g) is dissolved in 1.5 liters of boiling isopropanol and the solution is allowed to stand at room temperature for approx. 2 days to reach complete crystallization. After filtration, the product is washed with a little cold isopropanol (2 x 70 ml) and dried in the air at room temperature. 104 g of product is obtained which melts at 249° C during cleavage.

Example 2.

Preparation of dl-3-(N-ethylamino)-isocamphane.

A solution of 4.0 g of once crystallized dl-3-acetamido-isocamphane in 90 ml of anhydrous ether is added over 25 minutes with stirring to a solution of 1.75 g (0.046 mol) of lithium aluminum hydride in 100 ml of absolute ether. After heating under reflux cooling for 3 hours, carefully add 8.3 ml of water while slowly cooling and vigorously stirring. The granular white precipitate is filtered off and washed with ether. The ether extracts are washed with 2 x 50 ml of water and dried over anhydrous sodium sulfate. The ether extract is evaporated to a small volume, and while cooling, a solution of HC1 in ether is added until a pH value of approx. 3. The white precipitate thus obtained is filtered off by suction, washed with ether until it is free of HC1 and dried in the air. The dl-3-(N-ethylamino)isocamphane hydrochloride with boiling isopropanol (225 ml) gave pure 3-(N-ethylamino)isocamphane hydrochloride, m.p. 260—1° C (during decomposition).

Analysis: Calcd for Cr2H24Cl (217.78): C, 66.18; H, 11.11; N, 6.43; Cl, 16.28 Found: C, 66.04; H, 11.16; N, 6.16; Cl, 16,12

Starting from the corresponding N-ethyl-dl-3-acetamido-isocamphane, the corresponding 3-(N,N-diethyl-amino)-isocamphane is obtained in the same way.

Example 3.

Preparation of dl-3-(N-n-butyl-amino) isocamph an

A solution of 2.62 g (0.069 mol) of lithium aluminum hydride in 150 ml of absolute ether is added with stirring to 7.0 g (0.031 mol) of di-3-(N-butyrylamino) isocamphane dissolved in 60 ml of dry ether. After heating the solution under reflux overnight, 13 ml of mannitol are added, and the powdery metal hydroxide-containing mixture obtained is filtered and washed with ether. The ether extract is washed with water (3 x 50 ml), dried over anhydrous MgSO 4 and concentrated to a volume of approx. 30 ml. The hydrochloride is then precipitated by adding a solution of HC1 in ether (approx. 8 ml pH value 3). The compound is then filtered off and washed with ether until it is free of acid. By recrystallization of the product from 400 ml of methyl isobutyl ketone, pure dl-3-(N-n-butylamino)-isocamphane hydrochloride is obtained which melts at 212.5-213.5°C.

Analysis: Calculated for CI4H27N.HC1

(245.83): C, 68.40; H, 11.48; N, 5.70; Cl, 14.43 Found: C, 68.75; H, 11.72; N, 5.96; Cl, 14.1

Example 4.

Preparation of dl-3-(N-3,3-dimethyl-butylamino) isocamph an

To a mixture of 6.1 g (0.16 mol) of lithium aluminum hydride and 350 ml of absolute ether is added 6.77 g (0.027 mol) of dl-3-(N-3,3-dimethylbutyrylamino) isocamphane, dissolved in 80 ml of ether. After heating under reflux cooling for approx. After 19 hours, the mixture is decomposed by the gradual addition of 30 ml of water. The inorganic salt is filtered off and washed with ether. The filtrate is washed with water (3 x 100 ml) and dried over magnesium sulphate. After evaporation to a small volume, the hydrochloride salt is precipitated by adding a cold, saturated solution of hydrogen chloride in ether (approx. 10 ml) until the mixture becomes acidic to Congo red. The precipitate consisting of dl-3-(N-3,3-dimethylbutylamino) isocamphane is filtered off and washed with ether. After recrystallization from hot methyl isobutyl ketone, the product melts at 233-4° C with cleavage.

Analysis: Calcd for ClBH.,,N.HCl (273.89): C, 70.16; H, 11.78; N, 512;

Found: C, 70.25; H, 11.86; N, 5.31.

Example 5.

Preparation of d-3-(N-methylamino)-isocamphane and 1-3-(N-methylamino)-isocamphane.

A cold solution of 25.0 g of dl-3-(N-methylamino)-isocamphane hydrochloride in 200 ml of water is added to 50 ml of 2.5 N sodium hydroxide solution. The free base is extracted with 2 portions of ether, each of 100 ml. The ether extract is dried over sodium sulphate and 21.0 g of free amine is obtained.

A solution of this amine (21.0 g) in 210 ml of acetone is mixed with a solution of 26.5 g of d-camphorsulfonic acid in 200 ml of acetone. After standing for 2 hours at room temperature, the precipitated crystalline substance is filtered off. This is d-3-(N-methylamino)-isocamphane-d-camphor sulphonate which melts at 213-214° C and has a specific rotation angle [a]25 = _|_ 31.2° (C = 2% in absolute ethanol ) After recrystallization of the compound, the specific rotation and melting point of the compound remained unchanged. The d-(3-N-methylamino)isocamphor anhydrochloride is prepared by treating the d-camphor sulfonic acid salt with an equivalent amount of 2.5 N sodium hydroxide solution, extracting the free base with ether, and treating the ether extract with a solution of HCl in ether. After two recrystallizations from isopropanol, d-3-(N-methylamino)-isocamphane hydrochloride has a specific twist angle [a]25 = 20.6 (C-1.57 in chloroform) and melts at 262-264° C during decomposition.

1-3-(N-methylamino)-isocamph an-d-camphor sulphonate can be recovered from the mother liquor from which the d-form was recovered by evaporating this mother liquor under reduced pressure. By transferring this salt to the free base and treating this with a solution of HCl in ether, 1-3-(N-methylamino) isocamph anhydrochloride is obtained which can be further purified by recrystallization

from isopropanol. The connection then has one

specific turning angle of approx. 20°.

The N-alkyl derivatives of 3-amino-isocamphane and the acid salts thereof as well as those

quaternary ammonium salts of the tertiary

amines are new chemical compounds with

valuable pharmacological properties. Thus, 3-(N-methylamino) isocamph has been shown

itself to be a valuable ganglion blocker

medium. This connection prevents the transmission of nerve impulses both through them

sympathetic and parasympathetic centers in it

autonomic nervous system. Furthermore, the connection has been shown to be approx. 2 times as active as hexamethionium bromide, calculated

on mg per kg body weight, and is active for a considerably longer time than hexamethionium bromide. This has been found in experiments on dogs that have been anesthetized, and with bilaterally severed vagus nerves, using

(1) stimulation of the peripheral end of

the severed vagus nerve, (2) blocking of

the carotid artery as well as (3) reaction to the injection of nicotine as a ganglion blocker

medium.

Claims (3)

1. Process for the preparation of 3-N-lower alkyl or 3-N,N-di-lower alkylamino-isocamphane compounds with ganglion-blocking action and with the general formula (in which R denotes a lower alkyl group or hydrogen or salts thereof), characterized by reacting an iso-camphane compound with the general formula (in which Rn has the above meaning, and R2 denotes an acyl radical) with a reducing agent and optionally transfer the formed N-monoalkyl or N,N-dialkyl compounds to respectively addition salts with acids and to quaternary ammonium salts. 2. Method according to claim 1, characterized in that lithium aluminum hydride is used as reducing agent. 3. Process according to claim 1 or 2, characterized in that 3-(N-formylamino)-isocamphane, 3-(N-acetylamino)-isocamphane or 3-(N-ethyl-N-acetylamino) is used as starting material )-isocamphane.