DE3804433A1 - Arylamides of alpha -hexamethyleneiminocarboxylic acids and their hydrochlorides - Google Patents

Abstract

The present invention relates to novel chemical compounds, to be precise arylamides of alpha -hexamethyleneiminocarboxylic acids and their hydrochlorides of the following general formula: <IMAGE> in which R is H, CH3, C2H5, n-C3H7; R' is H or CH3; and X is absent or is HCl. The compounds according to the invention have a prolonged local anaesthetic action and can be used in medicine.

Description

The present invention relates to organic chemistry and relates in particular to new compounds, arylamides of α- hexamethyleneiminocarboxylic acids and their hydrochlorides which have a local anesthetic activity. The compounds mentioned can be used in medicine as local anesthetic agents with prolonged action.

Known are various compounds which have a local anesthetic activity and in medicine as a local anesthetic agents such as procaine (procaine) - β -Diethylaminoethylester the Paraaminobenzoesäure- hydrochloride; Cocaine methyl ether of benzoylekgonin hydrochloride; Pyromecain-2,4,6-trimethylanilide-1-butyl-pyrrolidine-2-carboxylic acid hydrochloride; Trimecain (mesocaine) - α -diethyleneamino-2,4,6-trimethylacetanilide hydrochloride; Lidocaine (xylocaine) - a -diethylamino-2,6-dimethylacetanilide hydrochloride; Marcain (Bulivacaine) -2,6-xylidide-N-butyl- α -piperidine carboxylic acid hydrochloride and others are used (M. Finster, H. Pedersen, "Uptake Distribution and Excretion of Local Anesthetics by the Foetus an Newborn", 1984 (Sweden), p. 90-94; Acta phamacol. Et toxicol, 1977, 41, 432-443). The above-mentioned agents (except for the Marcain) have an insufficient duration of the anesthetic effect. Several of them (cocaine and novocaine) can cause allergic and other undesirable reactions. The Marcain has a prolonged effect, but also a higher toxicity compared to all the preparations listed above. The compounds of the invention are new.

The invention has for its object new connections to develop a high local anesthetic Activity, long duration, comprehensive Range of therapeutic effects and low toxicity exhibit.  

The object was achieved in that new compounds, arylamides of α- hexamethyleneiminocarboxylic acids and their hydrochlorides of the general formula:

are provided wherein R = H, CH₃, C₂H₅, n-C₃H₇; R ′ = H, CH₃; X - missing or HCl.

These compounds have high local anesthetic activity. The following compounds are particularly active: Mesidide of α- hexamethylene iminopropionic acid hydrochloride with the following formula:

and mesidide of α- hexamethyleneiminobutyric acid hydrochloride with the following formula:

The compounds according to the invention, arylamides of α- hexamethyleneiminobutyric acids, are crystalline substances; are readily soluble in ethyl ether, benzene, toluene, chloroform, alcohol and are insoluble in water. Their structure was verified by the information from the elementary analysis, by the physico-chemical characteristics and by chemical properties. In the IR spectra there are absorption bands of the carbonyl ν (C = O) amide 1642 cm ^-1 - 1687 cm ^-1 and NH groups of the amide character ν 3101 cm ^-1 - 3278 cm ^-1 . The structure of the substances obtained is also confirmed by their ability to form salts by acid addition, which indicates the presence of a major nitrogen atom in the compounds mentioned. Arylamides of a -Hexamethyleniminocarbonsäure- hydrochlorides provide white, high melting crystalline substances which are soluble in water and in a physiological solution and insoluble in ether, chloroform, and aromatic hydrocarbons. Their structure is confirmed by the information from the elementary analysis and results from the structure of the starting aryl amides of α- hexamethyleneiminocarboxylic acids.

The activity of the compounds according to the invention has been investigated in animal experiments.

Pharmacological studies of the invention Connections were made in comparison to etalon preparations by: with surface anesthesia with cocaine, Pyromecain and dicaine; in line and infiltration anesthesia with novocaine, trimecain, lidocaine and marcaine.

Used as criteria of anesthetic activity the time when anesthesia begins to work, their depth (change in electrical stimulus threshold) and duration of anesthesia.

The line anesthesia was examined with the help the method of pain sensation.

It was found in the experiment that the inventive Compounds with a concentration of 1% lead anesthesia is very active. The experiments were carried out on rabbits weighing 2.5 to 3 kg carried out. The average activity information achieved out of 5 attempts with the standard error of Average sizes are shown in Table 1. The Depth of the anesthetic effect of the compounds according to the invention is given in percent (the change in  Threshold of pain sensitivity around 1 V is compared for control conditionally accepted for 20% anesthesia).

Table I

Comparative activity of the line anesthesia of the hydrochlorides of arylamides of a- hexamethyleneiminocarboxylic acids, novocaine, trimecain, lidocaine, marcaine

From the information provided it can be seen that the Compounds according to the invention the line anesthesia in 1.2 to 2 minutes evoke their depth in 30 minutes is equal to 100% and the duration of the anesthetic effect 5 to 7 hours, which means that the invention Connections after the onset of action, according to the depth and duration of the effect, the novocaine by Exceed 1.5 to 7 times, 2 to 2.5 times longer act as trimecain and lidocaine and the Marcain not inferior.

The infiltration anesthesia was performed using the method examined the sensitivity to pain. The results showed that the substances according to the invention in a concentration 1% sustained infiltration anesthesia cause.

The experiments were carried out on rabbits weighing 2.5 to 3 kg performed. The average figures achieved the activity from 5 attempts with a standard error the average size is shown in Table 2. The depth of the anesthetic effect is in percent specified (the change in sensitivity to pain around 5 V compared to the control was conditional for 20% Anesthesia accepted).  

Table 2

Comparative activity of the arylamides of α- hexamethyleneiminocarboxylic acid hydrochloride, novocaine, trimecain, lidocaine and marcaine in infiltration anesthesia

Infiltration anesthesia occurs in rabbits in 3 to 6 minutes after the implementation of the solutions substances according to the invention, the depth of anesthesia reached in 30 minutes after the introduction of each Fabric 60 to 100%.

Work according to the duration of the anesthetic effect the compounds of the invention 3 to 5 times  longer than novocaine and 1.2 to 1.8 times longer as Trimecain and Lidokain, but is inferior to Marcain (by 1.5 to 2.5 times).

Examination of the ability of the invention Connections to cause surface anesthesia has been performed on rabbits using the Regn´ method. In the Table 3 gives average activity data from 8 experiments with the standard error of the average size for 1% solutions.

Table 3

Comparative activity of the compounds according to the invention, the arylamides of α- hexamethyleneiminocarboxylic acid hydrochloride, cocaine, dikain, pyromecain, trimecain, lidocaine and marcaine, in surface anesthesia

It was found that all of the compounds of the invention are active in surface anesthesia.

Hydrochloride of the mesidides of α- hexamethylene imino acetic acid, α- hexamethylene iminopropionic acid and α- hexamethylene iminobutyric acid cause a rapidly occurring, practically immediately after the application of the substance, deep (Regn´ index is 1300) and persistent (over 1.5 hours) anesthesia .

According to the depth of effect, the inventive ones outperform Connections the cocaine, trimecain and lidocaine by 2 to 2.3 times, the Marcain by 1.2 times and don't step behind those with this type of anesthetic highly active preparations such as dicain and pyromecain.

Exceed after the duration of the anesthetic effect the compounds of the invention all etalon preparations by 1.3 to 2.8 times.

The compounds of the invention are relatively few toxic and have no local irritant effect on eye tissue of a rabbit. The attempts to investigate Acute toxicity was assessed in mice weighing 20 to 22 g performed with intra-abdominal insertion. Table 4 shows average data from 6 experiments with a standard error of average size compared to the toxicity data for preparations cited with local anesthetic effect, which is currently  are used in medicine.

Table 4

Acute toxicity of the inventive arylamides of a -Hexamethyleniminocarbonsäuren hydrochloride, cocaine, Dicain, Pyromecain, trimecaine, lidocaine and marcaine

The particularly active compounds, mesidide of α- hexa methyleniminopropionic acid hydrochloride and mesidide of α- hexamethylene iminobutyric acid hydrochloride, were additionally used in line anesthesia in 0.5% and 0.25% concentration and in surface anesthesia in 0.5% Concentration examined. The acute toxicity of these compounds was determined in mice when introduced subcutaneously (Table 7). The results of the tests are shown in Tables 5, 6 and 7.

It was found that the activity of the above connections in the line and in the Surface anesthesia in 0.5% and 0.25% concentration the solutions are maintained. Here outperform the compounds of the invention in Line anesthesia in its duration of action the trimecain and Marcain, they call for surface anesthesia deeper anesthesia than cocaine and marcaine, but are somewhat weaker than dicain and pyromecain.

Approaching mice during subcutaneous introduction the acute toxicity of the highly active fiction moderate compounds of the toxicity of pyromecain, Tri mecains and lidocaine and is 3.5 to 5.5 times lower than Marcain and Dicain.

Thus, the pharmacological Investigations that the compounds of the invention a pronounced local anesthetic activity in upper surface, line and infiltration anesthesia sen by taking advantage of the well-known prep guess, cocaine and novocaine, through the quick on occurs through the depth and a particularly persistent Differentiate effect; they excel after the effects takes trimecain and lidocaine. The invention Connections stand practically in their activity Mercain does not follow, but is less toxic.

Table 5

Activity in line anesthesia

Table 6

Surface anesthesia activity

Table 7

Acute toxicity of the compounds according to the invention

The process for the preparation of the arylamides of α- hexamethyleneiminocarboxylic acids and their hydrochlorides is carried out as follows. The amination of α- chloro and α- bromocarboxylic acids with hexamethyleneimine is carried out according to the following scheme:

where Hal = Cl or Br; R is H, CH₃, C₂H₅, n-C₃H₇; R '= H, CH₃.

When the corresponding arylamides of the α- halocarboxylic acids are boiled with an excess of hexamethyleneimine in an organic solvent, the end products are obtained in a yield of 65 to 83% of theory. Aromatic hydrocarbons, preferably ethyl alcohol, toluene or xylene, can be used as solvents. The process time depends on the boiling point of the solvent and the structure of the starting aryl amides.

The arylamides of the α- hexamethyleneiminocarboxylic acid hydrochlorides are prepared by reacting the arylamides of the α- hexamethyleneiminocarboxylic acids with a hydrogen chloride solution in organic solvents (ether, acetone, chloroform). The yield of end products is from 62 to 87% of theory.

To better explain the present invention The following are examples for the production of the registered Connections listed.

example 1

A mixture of 8.2 g (0.038 mol) of meside of chloroacetic acid and 11.3 g (0.114 mol) of hexamethyleneimine in 60 ml of dry toluene is boiled for 10 hours. The precipitate is filtered off, the filtrate is washed with water, dried with anhydrous magnesium sulfate and evaporated. The yield of the end product, meside of α -hexamethyleneiminoacetic acid, is 8.8 g (83% of theory). The melting point is 74 to 75 ° C (from hexane), IR spectrum (in oil): ν (C = O) (amide) 1661 cm ^-1 , ν NH (amide) 3278 cm ^-1 .

Found%: C 74.45; H 10.00; N 10.23; C₁₇H₂₆N₂O. Calculated%: C 74.40; H 9.55; N 10.21.

Example 2

A solution of 8.8 g of meside of α- hexamethyleneiminoacetic acid in 60 ml of dry chloroform is added to a 5% solution of the hydrogen chloride in isopropyl alcohol until a pH ∼ 2 is reached. The precipitate is filtered off and washed with chloroform. The yield of the end product, meside of the α- hexamethyleneiminoacetic acid hydrochloride, is 8 g (80% of theory). The melting point is 185 to 186 ° C (from isopropyl alcohol). IR spectrum (in oil): ν (C = O) (amide) 1687 cm ^-1 , ν NH (amide) 3101 cm ^-1 .

Found%: N 9.00; Cl 11.48; C₁₇H₂₇ClN₂O. Calculated%: N 9.01; Cl 11.40.

Example 3

The process is carried out as in Example 1. A mixture of 5.4 g (0.02 mol) of mesidide of α- bromopropionic acid and 5.9 g (0.06 mol) of hexamethyleneimine is taken and the mixture is boiled in toluene for 3 hours. The yield of the final product, mesidide of α- hexamethyleneiminopropionic acid, was 4.5 g (79.8% of theory). The melting point is 107.5 to 108.5 ° C (from 70% ethyl alcohol). IR spectrum (in oil): ν (C = O) (amide) 1649 cm ^-1 , ν NH (amide) 3228 cm ^-1 .

Found%: C 75.17; H 9.86; N 10.07; C₁₈H₂₈N₂O. Calculated%: C 74.96; H 9.78; N 9.71.

Example 4

The ether saturated with hydrogen chloride is added to a solution of 2.88 g of meside of α- hexamethyleneiminopropionic acid in 30 ml of dry acetone until a pH of ∼ 2 is achieved. The reaction mixture is left to stand in the refrigerator for 1 hour. The precipitate is filtered off and washed with acetone. The yield of the end product, mesidide of the α- hexamethyleneiminopropionic acid hydrochloride, is 2.7 g (83.3% of theory). The melting point is 218 to 220 ° C (from isopropanol). IR spectrum (in oil): ν (C = O) (amide) 1681 cm ^-1 , ν NH (amide) 3106 cm ^-1 .

Found% Cl 10.99; C₁₈H₂₉ClN₂O. Calculates% Cl 10.91.

Example 5

A mixture of 10.81 g (0.04 mol) of 2,6-xylidide of α- bromobutyric acid and 11.9 g (0.12 mol) of hexamethyleneimine is boiled in 150 ml of o-xylene for 10 hours. After cooling, the reaction mixture is washed with water. The solvent is evaporated, the remaining oil crystallizes on standing out. The yield of the final product, 2,6-xylidide of α- hexamethyleneiminobutyric acid, is 7.5 g (65.1% of theory). The melting point is 129 to 131 ° C (from 80% ethyl alcohol). IR spectrum (in oil): ν (C = O) (amide) 1644 cm ^-1 ; ν NH (amide) 3240 cm ^-1 .

Found%: C 75.11; H 9.75; N 9.80; C₁₈H₂₈N₂O. Calculated%: C 74.95; H 9.78; N 9.71.

Example 6

4 g of 2,6-xylide of α- hexamethyleneiminobutyric acid are obtained analogously to Example 4, 2,6-xylidide of α- hexamethyleneiminobutyric acid hydrochloride in an amount of 3.3 g (71% of theory). The melting point is 231 to 233 ° C (from absolute alcohol). IR spectrum (in oil): ν (C = O) (amide) 1678 cm ^-1 ; ν NH (amide) 3176 cm ^-1 .

Found%: Cl 10.96; C₁₈H₂₉ClN₂O. Calculated%: Cl 10.91.

Example 7

From 11.36 g (0.04 mol) of a Mesidid -Brombuttersäure and 11.9 g (0.12 mol) of hexamethyleneimine is obtained as in Example 5, 8.6 g (71% of theory) of α Mesidid -Hexamethyleniminobuttersäure. The melting point is 108-110 ° C (from 80% ethyl alcohol). IR spectrum (in oil): ν (C = O) (amide) 1642 cm ^-1 ; ν NH (amide) 3249 cm ^-1 .

Found%: C 75.38; H 9.97; N 9.32; C₁₉H₃₀N₂O. Calculated%: C 75.45; H 10.00; N 9.26.

Example 8

Similar to Example 3, 2.5 g (74.5% of theory) of mesidide of α- hexamethyleneiminobutyric acid hydrochloride are obtained from 3 g of meside of α- hexamethyleneiminobutyric acid. The melting point is 232 to 234 ° C (from absolute alcohol). IR spectrum (in oil): ν (C = O) (amide) 1681 cm ^-1 ; ν NH (amide) 3180 cm ^-1 .

Found%: Cl 10.44; C₁₉H₃₁ClN₂O. Calculated%: Cl 10.46.

Example 9

Analogously to Example 5, from 9.55 g (0.032 mol) of mesidide of α- bromvaleric acid and 6.5 g (0.066 mol) of hexamethyleneimine, 7.6 g (75% of theory) of mesidide of α- hexamethyleneiminovaleric acid are obtained. The melting point is 120 to 122 ° C (from 70% ethyl alcohol). IR spectrum (in oil): ν (C = O) (amide) 1668 cm ^-1 ; ν NH (amide) 3170 cm ^-1 .

Found%: C 76.21; H 10.15; N 8.90. C₂₀H₃₂N₂O. Calculated%: C 75.90; H 10.19; N 8.85.

Example 10

Similarly to Example 4 is obtained from 4.3 g of a Mesidid -Hexamethyleniminovaleriansäure 4 g (87% of theory) of α Mesidid -Hexamethyleniminovaleriansäure hydrochloride. The melting point is 188 to 190 ° C (from absolute alcohol). IR spectrum (in oil): n (C = O) (amide) 1672 cm ^-1 ; ν NH (amide) 3158 cm ^-1 .

Found%: Cl 10.01; C₂₀H₃₃ClN₂O. Calculated%: Cl 10.04.

Claims (3)

1. Arylamides of α- hexamethyleneiminocarboxylic acids and their hydrochlorides of the general formula: wherein R = H, CH₃, C₂H₅, n-C₃H₇; R ′ = H, CH₃; X - missing or HCl. 2. Mesidide of α- hexamethyleneiminopropionic acid hydrochloride of the following formula: 3. Mesidide of α- hexamethyleneiminobutyric acid hydrochloride of the following formula: