NO880604L - ARYLAMIDES OF ALFA-HEXAMETHYLENIMINOCARBOXYL ACIDS AND HYDROCHLORIDES THEREOF, AND THE PROCEDURE FOR THEIR PREPARATION. - Google Patents

Description

The present invention relates to new compounds, namely arylamides of α-hexamethyleneiminocarboxylic acids and hydrochlorides thereof, which possess a local anesthetic activity.

Various compounds are known which possess local anesthetic activity, and which are used in medicine as local anesthetic agents, such as novocaine (procaine)-3-diethylaminoethylparaaminobenzoate hydrochloride; cocaine methyl ester of benzoylecgonine hydrochloride; pyromecaine-2,4,6-trimethyl-anilide-1-butylpyrrolidinecarboxylic-2-acid hydrochloride; tr i-mecanine (mesocaine)-2-diethylamino-2,4,6-trimethylacetanilide hydrochloride; lidocaine (xylokaline)-cx-diethylamino-2,6-dimethyl-acetanilide hydrochloride marcaine (bupivacaine)-2,6-xylidide-N-butyl-a-pyridinecarboxylic acid hydrochloride, etc. (M. Finster, H. Pederse, "Uptake Distribution and Excretion of Local Anesthetic by the Foetus and Newborn" 1984 (Sweden), pages 90-94; Acta Pharmacol. et Toxicol., 1977, 41, 432-443). The above-mentioned preparations (with the exception of marcaine) have an anesthetic effect of insufficient duration. Many of them (cocaine, novocaine) can cause allergic and other unwanted reactions. Markain has a longer-lasting effect, but is more toxic than other of the above preparations.

The compounds proposed in the present invention are new and have not been described in the literature.

The main purpose of the invention lies in the provision of new compounds which possess high anesthetic activity, prolonged effect, broad spectrum of therapeutic effect and low toxicity.

The purpose is achieved according to the invention by providing new compounds, namely arylamides of cx-hexamethyleneiminocarboxylic acids and hydrochlorides thereof with the general formula:

where R =H, CH3, C2H5, n-C3H7;

R' = H, CH 3 ;

X = absent or is HC1.

These compounds have high local anesthetic activity. The most active among the compounds are α-hexamethyleneimino-propionic acid mesidide hydrochloride with the formula: and cx-hexamethyleneiminobutyric acid mesidide hydrochloride id with the formula:

The relevant compounds, namely arylamides of α-hexamethyleneiminocarboxylic acids are crystals which are easily soluble in ether, benzene, toluene, chloroform, alcohol and insoluble in water. Their structure has been shown by elemental analysis, through physicochemical properties, and chemical properties. IR spectra have the absorption bands for carbonyl v (C=0) of the amide type 1642-1687 cm-<1> and NH group of the amide type v 3101-3278 cm-<1>. The structure of the compounds produced is also confirmed through their ability to give acid addition salts, which indicates the presence of a base nitrogen atom in the compounds. Hydrochlorides of arylamides of α-hexamethyleneiminocarboxylic acids are white low-melting crystalline compounds which are soluble in water and in a physiological solution and insoluble in ether, chloroform and aromatic hydrocarbons. Their structure is confirmed by elemental analysis and follows from the structure of the parent arylamides of α-hexamethyleneiminocarboxylic acids.

The activity of the relevant compounds has been studied experimentally on animals.

Pharmacological studies of the compounds were carried out in comparison with reference preparations, namely with cocaine, pyromecaine and dicaine for the purpose of surface anaesthesia, and with novocaine, trimecaine, lidocaine and marcaine for conduction and infiltration anaesthesia.

As criteria for anesthetic activity, the time period before the anesthetic effect was observed (the time for onset of anesthesia), the depth of anesthesia (the change in the threshold value for electrical irritation) and the duration of anesthesia were used.

Conduction anesthesia was studied using the "pain" method.

The experiments have shown that . the proposed compounds in 11% concentration are very active for conduction anaesthesia. Tests were carried out with rabbits weighing 2.5-3.0 kg. In Table 1, average activity data for 5 trials are given with a standard error of the mean value. The depth of the anesthetic effect for the relevant compounds is given in % (a change in the threshold value for pain sensitivity of 1 V compared to the control experiment was under certain conditions set to 20% anesthesia). The table shows that the proposed compounds cause conduction anesthesia within 1.2-2.0 min.; the depth of anesthesia is 100$ during 30 min., and the duration of the anesthetic effect is 5-7 hours, i.e. they are superior to novocaine, i.e. 1.5-7 times with regard to the onset of anesthesia, — depth and duration of the anesthetic effect, they work 2-2.5 times longer than trimocaine and lidocaine, and are no worse than marcaine.

Infiltration anesthesia was studied using the "pain" method. The results have shown that the compounds produced according to the invention in a concentration of 1% cause prolonged infiltration anaesthesia.

The experiments were carried out with rabbits weighing 2.5-3.0 kg. Table 2 indicates average data for activity obtained in 5 trials with a standard error of the mean value. The depth of the anesthetic effect is given in % (a change in pain sensitivity of 5 V compared to the control experiment was under certain conditions indicated as 20$ anesthesia). Infiltration anesthesia in rabbits begins 3-5 min. after injection of solutions of the proposed compounds: depth of anesthesia reaches 60-100$ within 30 min. after the administration of the preparation. The duration of the anesthetic effect of the proposed compounds exceeds 3-5 times that of novocaine, 1.2-1.8 times that of trimocaine and lidocaine, and is somewhat shorter than the duration of marcaine (1.5-2.5) times ).

The ability of the proposed compounds to cause surface anesthesia was studied using the Regné method. Table 3 provides mean activity data for 8 experimental trials with a standard error of the mean for 1$ solutions.

It has been shown that all the compounds prepared according to the invention are active with regard to surface anesthesia.

Hydrochlorides of a-hexamethyleneiminoacetic acid, a-hexa-methyleneiminopropionic acid and cx-hexamethyleneiminobutyric acid mesidide cause rapid (almost immediately after the introduction of the compound) deep (Regné index is 1300) and long-lasting (more than 1.5 hours) anesthesia.

The depth of anesthesia caused by the compounds in question exceeds 2.0-2.3 times that of cocaine, trimocaine and lidocaine, 11.2 times that of marcaine, and is not less than the depth of anesthesia caused by dicaine and pyromocaine, which are very effective for this type of anesthesia.

The duration of the anesthetic effect for the proposed compounds exceeds 1.3-2.5 times that of all the reference preparations.

The proposed compounds have relatively low toxicity, and cause no local irritation in the rabbit's eye tissue. Acute toxicity was studied in mice weighing 20-22 g by intra-abdominal administration. Table 4 illustrates average data for 6 trials with a standard error for the average value compared to data for the preparations that possess a local anesthetic effect used in medicine.

The most active compounds, namely ot-hexamethyleneimino-propionic acid mesidide hydrochloride and cx-hexamethyleneiminobutyric acid mesidide hydrochloride, were further studied for conduction anesthesia at a concentration of 0.5 and 0.25$ and for surface anesthesia at a concentration of 0.5$. The acute toxicity of these compounds was determined in mice by subcutaneous administration (Table 7). The results from the tests are shown in tables 5, 6, 7.

It has been shown that a high activity of the above compounds is maintained for both conduction and surface anesthesia in 0.5$ and 0.25$ solutions. The duration of the anesthetic effect of the proposed compounds in conduction anesthesia exceeds that of trimocaine and marcaine; the compounds produced according to the invention cause deeper anesthesia than cocaine and marcaine, and are somewhat weaker than dicaine and pyromecaine.

When administered subcutaneously to mice, it turns out that the acute toxicity of the highly active compounds described here is close to that of pyromecaine, trimecaine.. and lidocaine and is 3.5-5.5 times lower than the toxicity of marcaine and dicaine.

The pharmacological studies have thus shown that the proposed compounds possess significant local anesthetic activity with regard to surface, conduction and infiltration anaesthesia, as they are superior to such known compounds as cocaine and novocaine in terms of rapid action, depth and especially duration of the anesthetic effect; the duration of effect exceeds that of trimecaine and lidocaine. The compounds produced according to the invention have almost the same activity as marcaine, but are significantly less toxic. The proposed compounds are prepared by amination of α-chloro- and α-bromocarboxylic acids with hexamethyleneimine in the reaction:

where Hal = Cl or Br;

R = H, CH3, C<2H>5,n-C3H7;'

R' = H, CH 3 .

Refluxing the corresponding arylamines of cx-halocarboxylic acids with excess hexamethylene imide in an organic solvent gives the desired products in yields of 65-83$ of the theoretical. Aromatic hydrocarbons can be used as solvents. The duration of the process depends on the boiling point of the solvent and on the structure of the arylamide starting materials.

Hydrochlorides of α-hexamethyleneiminocarboxylic acid arylamides are prepared by reacting α-hexamethyleneiminocarboxylic acid arylamides with a hydrogen chloride solution in organic solvents (ether, acetone, chloroform). Yield of the desired products is 62-87$ of the theoretical.

In order to better understand the present invention, specific examples of the preparation of the compounds in question are given below.

Example 1

A mixture of chloroacetic acid mesidide (8.2 g; 0.038 mol) and hexamethyleneimine (11.3; 0.114 mol) in 60 ml of dry toluene is refluxed for 10 hours. The precipitate is filtered, the filtrate is washed with water, dried with anhydrous magnesium sulphate and evaporated. The yield of the desired product, namely α-hexamethyleneiminoacetic acid mesidide, is 8.8 g (83% of the theoretical). Temp. 74-75°C (from hexane). IR spectrum in oil: v (C=0) (amide) 1661 cm-<1>, v NH (amide) 3278 cm-<1>.

Found $: C 74.45; H 10.00; N 10.23; C17H26N20. Calculated: C 74.40; H -9.55; N 10,21

Example 2

A solution (5$) of hydrogen chloride in isopropyl alcohol is added to a solution of 8.8 g of α-hexamethyleneiminoacetic acid messide in 60 ml of dry chloroform up to pH~2. The precipitate is filtered and washed with chloroform. The yield of the desired product, namely α-hexamethyleneiminoacetic acid mesidide hydrochloride is 8 g (80$ of the theoretical). Temp. 185-186°C (from isopropyl alcohol). IR spectrum (in oil): v (C=0) (amide) 1687 cm-<1>, v NH (amide) 3101 cm-<1>.

Found $: N 9.00; Cl 11.48; C17<H>27CIN20.

Calculated $: N 9.01; Cl 11.40

Example 3

The procedure is carried out by following the method described in example 1. A mixture of cx-bromopropionic acid mesidide (5.4 g; 0.02 mol) and hexamethyleneimine (5.9 g; 0.06 mol) is refluxed in toluene for 3 hours. The yield of the desired product, namely α-hexamethyleneiminopropionic acid mesidide Br 4.5 g (79.8% of the theoretical). Temp. 107.5-108.5°C (from 70$ ethyl alcohol). IR spectrum in oil (in oil): v (C=0) (amide) 1649 cm"<1>, v NH (amide) 3228 cm-<1>.

Found $: C 75.17; H 9.86; N 10.07. C18<H>28N20.

Calculated $: C 74.96; H 9.78; N 9.71.

Example 4

Ether saturated with hydrogen chloride is added to a solution of 2.88 g of α-hexamethyleneiminopropionic acid mesidide in 30 ml of dry acetone up to pH~2. The reaction mixture is kept in a refrigerator for 1 hour. The precipitate is filtered and washed with acetone. The yield of the desired product, namely α-hexmethylene-imino-propionic acid mesidine hydrochloride, is 2.7 g (83.3% of the theoretical). Temp. 218-2220°C (from isopropanol). IR spectrum (in oil): v (C=0) (amide) 1681 cm-<1>), v NH (amide) 3106 cm-<1>.

Found $: Cl 10.99. C18<H>29CIN20

Calculated $: Cl 10.91.

Example 5

A mixture of α-bromobutyric acid-2,6-xylidide (10.81 g; 0.04 mol) and mexamethyleneimine (11.9; 0.12 mol) is refluxed in 150 ml of o-xylene for 10 hours. After cooling, the reaction mass is washed with water, and the solvent is evaporated. The remaining oil is crystallized. The yield of the desired product, namely α-hexamethyleneiminobutyric acid-2,6-xylidide, is 7.5 g (65.1$). Temp. 129-131°C (from 80$ ethyl alcohol). IR spectrum (1 oil): v (C=0) (amide) 1644 cm-<1>; v NH (amide) 3240 cm"1.

Found $: C 75.11; H 9.75; N 9.80; C18<H>28N20.

Calculated $: C 74 , 95 ; H 9.78; N 9 .71.

Example 6

α-Hexamethyleneiminobutyric acid-2,6-xylidide hydrochloride in a yield of 3.3 (71$) is prepared by following the method described in Example 4 from 4 g of α-hexamethyleneiminobutyric acid-2,6-xylidide. Temp. 231-233°C (from absolute alcohol). IR spectrum (in oil): v (C=0) (amide) 1678 cm-<1>; v NH (amide) 3176 cm-<1>.

Found $: Cl 10.96. C18<H>2gCIN20.

Calculated $: Cl 10.91

Example 7

α-Hexamethyleneiminobutyric acid mesidide (8.6 g; 71%) is prepared from α-bromobutyric acid mesidide (11.36 g; 0.04 mol) and hexamethylene imine (11.9 g; 0.12 mol) by following the method described in Example 5. Temp. 108-110°C (from 80$ ethyl alcohol). IR spectrum (in oil): v (C=0) (amide) 1642 cm-<1>; v NH (amide) 3249 cm-1.

Found $: C 75.38; H 9.97; N 9.32; Cig<H>30<N>20.

Calculated $: C 75 .45; H 10 , 00 ; N 9 , 26

Example 8

α-hexamethyleneiminobutyric acid mesidide hydrochloride (2.5 g; 73.5) is prepared from 3 g of α-hexamethyleneiminobutyric acid by following the method described in example 4. M.p. 232-234°C (from absolute alcohol). IR spectrum (in oil): v (C=0) (amide) 1681 cm-<1>, v (NH) (amide) 3180 cm-<1>.

Found $: Cl 10.44. C19<H>31CIN20.

Calculated $: Cl 10.46

Example 9

cx-hexamethyleneiminovaleric acid messide (7.6 g; 75$) is prepared from α-bromovaleric acid messide (9.55 g; 0.032 mol) and hexamethyleneimine (6.5 g; 0.066 mol) by following the method described in Example 5. M.p. 120-122°C (from 70$ ethyl alcohol).. IR spectrum (in oil): v (C=0) (amide) 1668, v NH (amide) 3170 cm"<1>.

Found $: C 76.21; H 10.15; N 8.90. C20H32H20.

Estimated $: C 75.90; H 10.19; N 8.85.

Example 10

α-hexamethyleneiminovaleric acid mesidide hydrochloride (4 g; 87$) is prepared from 4.3 g of cx-hexamethyleneiminovaleric acid mesidyl by following the method described in Example 4. M.p. 188-190°C (from absolute alcohol). IR spectrum (oil): v (C=0) (amide) 1672 cm-<1>, v (NH) (amide) 3158 cm-<1>.

Found $: Cl 10.00. C20<H>33C1N20.

Calculated $: Cl 10.04.

Claims (4)

1. Arylamides of cx-hexamethyleneiminocarboxylic acids and hydrochlorides thereof, characterized by the general formula: where R = H, CH3 , C2 H5 , n-C3 H7 ; R' = H, CH 3 ; X is absent or is HC1. 2. Compound according to claim 1, characterized in that it consists of α-hexamethyleneimino-propionic acid mesidine hydrochloride with the formula: 3. Compound according to claim 1, characterized in that it consists of cx-hexamethyleneiminobutyric acid mesidine hydrochloride with the formula: 4. Process for producing the compounds according to claims 1-3, essentially as described and exemplified herein.