NO137501B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF LOCAL ANESTHETICALLY EFFECTIVE COMPOUNDS. - Google Patents

Description

The present invention relates to the production of local

anesthetic active compounds of the type tertiary-alkylamino-

lower acyl xylidide with a long duration of action.

Two commercially available local anesthetic agents

bonds of the acyl xylidide type are N-n-butylpipecolyl-2,6-

xylidine or bupivacaine having the structural formula:

and diethylaminoaceto-2, 6-xylidide or u)-diethylamino-2, 6-dimethyl-

acetanilide or lidocaine, which has the structural formula:

Bupivacaine is a long-acting local anesthetic, but

has the disadvantage that it is more tissue irritating than lidocaine,

and lycocain is not a tissue irritant, but has the disadvantage that it is not a long-acting local anaesthetic.

From Norwegian patent no. 135934 it is known that local

esthetically effective compounds with a structure that is

related to the structure of the compounds being prepared

according to the present invention.

Other commercially available local anesthetics are ct-propylaminopropio-2-toluidide or prilocaine; α-pyrrolidino-aceto-2,6-xylidide; and N-methylpipecolyl-2,6-xylidide or mepivacaine. However, these local anesthetics are short-acting.

The purpose of the present invention is therefore to provide compounds which have an unusually long-acting local anesthetic effect or high local anesthetic activity, while also having a low degree of tissue irritation and satisfactorily low acute toxicity.

The local anesthetic compounds produced according to the present invention are tertiary alkylamino-acetoxylidides with the formula:

and pharmaceutically acceptable salts thereof, where R<1> is -CH2CH3 or -CH2CH2CH3, i.e. 2-(N-ethyl-tert.amylamino)-2',61 -

acetoxylidide:

and 2-(N-n-propyl-tert.-amylamino)-2<1>,6<1->acetoxylidide:

and pharmaceutically acceptable salts thereof.

According to the present invention, the compounds of formula I are prepared by

(a) a compound of the formula:

where X is Cl, Br or I, is reacted with a compound of the formula:

where R<1> is - CR^ CR^ or -CH2CH2CH3, to form a compound of formula I, or

(b) a compound of the formula:

where R 2 is -CH2CH3, -CH2CH2CH3, or

N-alkylated

for the formation of a compound of formula I,

after which the thus obtained compound of formula I is, if desired, transferred to a pharmaceutically acceptable salt.

Procedures (a) and (b) are further illustrated by the following reaction schemes:

Method (a)

Instead of the iodo-acetylxylidide, a corresponding chlorine or bromine compound can be used as starting material, and in such a case a suitable alkali metal iodide or quaternary ammonium iodide is used to promote the reaction.

Method (b)

Instead of diethyl sulfate, other ethylating agents such as ethyl iodide and ethyl bromide can be used.

The starting material can be produced in the following way:

Instead of chloroacetylxylidide, corresponding bromine or iodine compounds can be used - Instead of Nal can. Kl or a suitable quaternary ammonium iodide is used.

If, instead of the chloro or bromoacetyl xylidide, iodoacetyl xylidide is used as starting material, it is not necessary to use alkali metal iodide or quaternary iodide.

Method (b)

The reaction is preferably carried out with a suitable acid absorbing agent. Instead of n-propyl iodide, n-propyl bromide can be used.

Preparation of the secondary amines, N-ethyl-tert.-amylamine and N-n-propyl-tert.-amylamine, used as starting materials

These compounds, which are intermediate products in the production of the local anesthetic compounds,

can be produced as follows:

By using CH3CHO instead of CH3CH2CHO, a corresponding N-ethyl derivative is obtained.. Compounds A and B produced according to the invention can be used as local anesthetics in a conventional manner using conventional doses thereof. The bases can be used in a conventional manner in the form of solutions of their pharmaceutically acceptable salts, e.g. hydrochlorides, tartrates bg citrates. Compounds A and B provide anesthesia with a long duration. The connections can e.g. used in surgery when anesthesia of longer duration is desired. However, due to the ability to vary the concentration and dose of the agent, it is possible to achieve satisfactory anesthesia outside the range indicated above with both groups of agents.

The invention is further illustrated with the following examples.

Example 1

Preparation according to method (b) of 2-(N-ethyl-tert.-amylamino)-2', 6'-acetoxylidide of 2-(tert.-amylamino)-2', 6'-acetoxylidide..

2-(tert.-amylamino)-2',6'-acetoxylidide - To 400 ml of anhydrous benzene was added 18.9 g (0.0956 mol) 2-chloro-2',6<1->acetoxylidide, 20 g (0.2295 mol) of tert.-amylamine and 1 g of sodium iodide. The reaction mixture was kept at 100°C for 36 hours in an autoclave. A precipitate was collected and discarded. From the filtrate, the solvent was evaporated and the yellow, oily residue was dissolved in ether, whereby undissolved material was collected and discarded. After drying (Na 2 SO 4 ), the ether was evaporated in vacuo leaving an oily liquid which was taken up in dilute hydrochloric acid (final pH 2). The acidic aqueous phase was washed several times with ether basified to pH 9 using concentrated ammonia, and the precipitated base was extracted with ether (4x100 mL). The ether extract was dried (Na 2 SO 4 ) and evaporated in vacuo. This gave a yellow, oily residue which was vacuum distilled (b.p. 150°C, 0.05 mm) and on cooling gave 16.6 g of white solid, m.p. 54-55°C. (The hydrochloride was also prepared and recrystallized from acetonitrile,

m.p. 209-211°C.)

Calculated analysis for: ^i5H24<N>2<0:> C' 72'54'H' 9'74»

N, 11.28. Found: C, 72.32; H, 9.98; N, 11.34. IR spectrum (KBr plate, hydrochloride) 3150-3129 (m-s; amide, NH stretching); 2710 (s), 2620 (m), 2580 (m), 2440 (m) and 2417 (m-w) (NH<+->stretching); 1665 (s; amide I), 1590 (m-w; aromatic), 1542 (s; amide II), 1393 and 1375 (s-m; methyl CH bending), 775 (s-m;

3 nearby aromatic H out of plane) cm 1. 2-( N- ethyl- tert.- amylamino)- 2', 6'- acetoxylidide - To - 46.52 g (0.3017 mol) diethyl sulfate was added 10, 7 g (0.0431 mol) of 2-(tert.-amylamino)-2',6<1->acetoxylidide and the mixture held for 4 hours and 20 minutes at 100°C. After cooling, the reaction mixture was taken up in hydrochloric acid (final pH 2). The mixture was washed with ether and the aqueous solution made basic to pH 9 using concentrated ammonia, after which the solution was extracted with ether (5x75 ml). The combined ether extracts were dried (Na 2 SO 4 ) and the ether removed in vacuo to give a white solid residue. The residue was recrystallized three times from ethanol/H 2 O and this gave a yield of 37.1% of a white, crystalline material, m.p. 111.5-113.5°C. Calculated analysis for C17<H>2<gN>2<0:> C, 73.87; H, 10.21; N. 10,14. Found: C, 73.94; H, 9.94; N, 10,21. IR spectrum (KBr plate, base) 3262 (s; amide, NH 2 stretching), 1655 (s; amide I), 1590 (w; aromatic), 1498 (s; amide II)' 1385 and 1375 (w; methyl CH bending), 766 (s; 3 nearby aromatic H out of plane) cm .

Example 2

Preparation according to method (a) of 2-(N-n-propyl-tert.-amylamino) 2', 6'-acetoxylidide of N-n-propyl-tert.-amylamine.

N-n-propyl-tert.-amylamine - A suspension of 1.0 g of 10% palladium on charcoal in 100 ml of absolute alcohol was shaken with hydrogen until the absorption of hydrogen stopped. To the catalyst mixture was added 30 g (0.3442 mol) of tert-amylamine and then a solution of 18 g (0.3098 mol) of propionaldehyde in 50 ml of absolute alcohol. All of the above ingredients were cooled in an ice bath before mixing. After warming to room temperature, the reaction mixture was shaken with hydrogen at an initial pressure of 4.2 kg/cm 2 for 10 hours.

During this time, the theoretical amount of hydrogen was absorbed. The catalyst was separated by filtration and washed with ethanol and 40 ml of concentrated hydrochloric acid was added to the combined filtrate. The solution was dried by evaporation in vacuo. The dried product was dissolved in 250 ml of distilled water and 160 g of 50% sodium hydroxide was added slowly with cooling to liberate amines. The mixture was extracted with ether (3x200 mL)

and the combined ether extracts dried over anhydrous sodium sulfate. The dried extract was distilled through a 300 mm column packed with ID glass coils. The yield was 26.7 g (66.7%) N-n-propyl-tert.-amylamine, b.p. 136.5-137.5°C (atmospheric pressure),

22

n ^ 1.4106.

Calculated Assay-for CQH, nN: C, 74.34; H, 14.82; <3N, 10.84. Found: C, 74.76; H, 15.16; N, 10.96.

2-(N-n-propyl-tert..-amylamino)-2',6'-acetoxylidide. - That was 150 ml of benzene. added- 10 g (0.0346 mol) 2-iodo-2',6'-acetoxylidide and 11.18 g, (0.0865 mol) N-n-propyl-tert.-amylamine. The reaction mixture was refluxed for 29 hours. After cooling, was benzene, and unreacted. amine driven off. in. vacuum. The remaining semi-solid material was treated with anhydrous ether. Undissolved material was filtered off and discarded and the ether evaporated in vacuo. The. yellow waxy material was recrystallized twice from ethanol/water and twice from acetone/water. This gave a yield of 49.4% white crystalline material,

m.p. 96.5-97.5°C.

Calculated analysis for C18<H>3Q<N>2<0:> C, 74.43; H. 10.41; N, 9.65. Found: C, 74.4; H, 10.35; N, 9.59. IR (KBr plate, base) 3240 (m; amide, NH stretching), 1665 (s; amide I), 1495 (s; amide II.) , 1385 and 1370 (w; methyl CH bending) , 766 ( s; 3 nearby aromatic H out of plane) cm ^. A hydrochloride was prepared from the base. It was obtained as a stable monohydrate melting at 181.2-182.8°C.

Calculated analysis for ClgH31ClN20. H 2 O: H 2 O, 5.22. Found: (Karl Fischer) H20, 5.21.

Example 3

Preparation according to method (b) of 2-(N-ethyl-tert.-amylamino)-2', 6'-acetoxylidide.

A mixture of 0.170 mol of 2-(tert.-amylamino)-2',6'-acetoxylidide (cf. Example 1), 0.187 mol of ethyl bromide, 0.085 mol of potassium carbonate and 300 ml of methyl ethyl ketone was refluxed with mechanical stirring for 36 hours. After evaporation of low-boiling components, the residue was dissolved in dilute hydrochloric acid,

and filtered after which the acidic solution was extracted twice with ether. The ether extract was discarded and the water phase made alkaline by adding concentrated ammonia to pH 9-10. after which it was extracted several times with ether. This extract was dried and after filtration the ether was removed in vacuo. The residue was recrystallized from ethanol/water.

Example 4

Preparation according to method (a) of 2-(N-n-propyl-tert.-amylamino)-2', 6'-acetoxylidide.

In a similar manner to the preparation of 2-(tert.-amylamino)-2',6'-acetoxylidide in example 1, 2-chloro-21,61-acetoxylidide was reacted with N-n-propyl-tert.-amylamine in the presence of sodium iodide to form 2-(N-n-propyl-tert.-amylamino)-21,61-acetoxylidide. The reaction mixture was prepared as described in Example 2 for this compound.

Example 5

Preparation of the starting material N-n-propyl-tert.-amylamine

A mixture of 2 moles of tert.-amylamine and 1 mole of bromopropane was refluxed for 6 hours. The reaction mixture was cooled and kept at +4°C for 1 hour. After filtration, the filtrate was fractionated by column distillation and the colorless, clear fraction, boiling between 136-138°C, was collected.

Pharmacological trials

In the tables given below, the following code descriptions are used: A stands for 2-(N-ethyl-tert.-amylamino)-2<1>,6'-acetoxylidide B stands for 2-(N-n-propyl-tert .-amylamino)-2<1>,6'-acetoxylidide X stands for the previously known compound N-n-butyl- pipecolyl-2,6-xylidide, i.e. bupivacaine, Y stands for the previously known compound diethyl aminoaceto-2,6-xylidide, i.e. lidocaine. Tables 1,2 and 3 contain comparative data with respect to the duration of these local anesthetic compounds, Table 4 contains comparative data with respect to the effect on the action potential of an exposed sciatic nerve from a frog for some of these local anesthetic compounds, while Table 5 contains comparative data with respect to the acute toxicity of the local anesthetic compounds. Table 6 contains data from experiments regarding epidural anesthesia in dogs for compound B.

Adrenaline 1:100,000 was used in all solutions

The values for duration are mean values and the intervals for the trial values are indicated in parentheses.

Method: Fully developed male beagle dogs were prepared surgically by inserting a cannula into a lumbar vertebra so that the drug solutions could be administered into the epidural space. After administration of local anesthetic solutions, the animals were examined at intervals with regard to the duration of pain loss in the scrotal area and in the toes of the hind legs. Response to and attention to pain stimuli in the scrotal area is a test of anesthetic blockade in spinal cord roots L3-4 and Sl-2-3. These roots are the furthest away from the injection point (L6) and therefore least exposed to being affected by the anesthetic agent. Return of the pain response in the scrotum is often the first sign of recovery and suggests that the anesthesia of at least L4 anterior and S2 posterior is gone.

The results set out in Table 4 with regard to studies of the sciatic nerve from frogs were obtained using the following method, essentially according to A.P. Truant, Archives Inter-nationales de Pharmacodynamie et de Therapie Belgium 115: 483-497

(1958): Sciatic nerve trunks from Rana pipiens were prepared by cutting the nerve between its roots in the spinal cord and the ankle and by placing it on silver-silver chloride electrodes so that stimulation and recording could be carried out during the application of the test compounds and during the recycling period. Tasaki Ringers solution was used as a bath and for each blocking and recovery the drug solution and the recovery solution had the same pH value. The irritation propensity of the compounds was determined according to the method indicated by A.P. Truant, Arch. Int. Pharmacodyn. 115: 483-497 (1958). At the concentrations of clinical significance, compounds A and B were no more irritating than bupivacaine at a concentration of 0.5%.

The experimental method that was used for the studies of

acute toxicity listed in Table 5 was as follows:

Sexually mature female animals were used.

The animals were divided into groups of 10 and dosed with drug solution or vehicle. After dosing, the animals were observed at intervals for several hours with regard to obvious effects and deaths. Surviving animals were grouped according to dose level and monitored daily for the duration of the studies to determine whether or not delayed death would occur.

LD^Q values and 95% Fieller confidence limits (or

95% approximate limits) were calculated according to Berkson's Minimum Logit Chi Square Method, J. Am. State. Assoc. 4_8: 565 (1953).

The compounds A and B produced according to the invention have an unusually long-acting local anesthetic effect and high local anesthetic activity, satisfactorily low tissue irritation and satisfactorily low acute toxicity compared to bupivacaine (compound X).

In general, the compounds produced according to the invention will be used in a 0.25-2 percent water solution. with or without the addition of a vasoconstrictor in infiltration anaesthesia, peridural and subarachnoid anaesthesia. However, the application is not limited to this concentration range and the dose and concentration that is used most in each particular case is determined with regard to such factors as the age and body weight of the patient as well as the route of administration and the clinical requirements of anaesthesia.

The compounds produced according to the invention can also be applied locally to mucous membranes and damaged skin, i.e. skin damaged by mechanical impact, in the form of solutions, ointments, jellies or aerosols. Examples of suitable pharmaceutical preparations that can be used as local anaesthetics,

is indicated in table 7, where compound B is used as active ingredient. Similar preparations in which the compound A is used as active ingredient can be prepared in a known manner, possibly with a change in the amount of NaCl to achieve isotonicity.

As mentioned, Norwegian patent no. 135934 deals with locally, anesthetically active compounds and these have the general formula:

1 2 3

where R is ethyl, propyl, butyl, R and R are methyl, ethyl, propyl, butyl and tetramethylene, and where R^, R and R together contain 6 carbon atoms or more.

The compounds produced according to the present invention as well as the compounds in Norwegian patent 135934 are local anesthetics with a long-acting effect. Structurally, however, the compounds in the present invention differ from the compounds in the aforementioned application in two important respects: 1. The alkylene chain between the NHCO group and the amino group is

-CH9-, while the corresponding group in the compounds in Norwegian patent 11

135934 is always a branched group -CHR - where R is ethyl, propyl or butyl.

2. In the compounds of the present invention, one of

the substituents on the amino group always a tertiary amyl group, i.e. a branched alkyl group with 5 carbon atoms. In the compounds in the aforementioned Norwegian patent, no compound containing a branched alkyl group on the terminal nitrogen atom is exemplified.

A comparison between the local anesthetic effect of the compounds in the present invention, see table 1," and the corresponding effect of the compounds in the aforementioned Norwegian patent, see table 1, therein shows that the compounds in the present invention, despite the large differences in chemical structure, shows a pharmacological effect with regard to the duration of blockade of the sciatic nerve in rats, which is as good or better than the effect of the compounds in Norwegian patent 135934..

Claims (1)

Analogous methods for the preparation of local anesthetic active compounds with the formula: and pharmaceutically acceptable salts thereof, where R<1> is -CH2CH3 or -CH2CH2CH3, characterized in that a) a compound with the formula: where X is Cl, Br or I, is reacted with a compound of the formula: where R1 is -CH2CH3 or -CH2CH2CH3, to form a compound of formula I, or b) a compound of the formula: N-alkylated to form a compound of formula I, after which, if desired, a compound of formula I thus obtained is transferred to is pharmaceutically acceptable salt.