NL8204126A - PROCESS FOR PREPARING A PHARMACEUTICAL PREPARATION WITH A LOCAL ANESTHETIC EFFECT CONTAINING A DIALYLAMINO-2 ', 6'-ACETOXYLIDIDE AND / OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND THE PREPARED PROPERTY OF THESE PREPARED THEREFORE THEREFORE DIALKYLAMINO-2 ', 6'ACETOXYLIDIDS AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS. - Google Patents

Description

«4 *

A process for the preparation of a pharmaceutical composition with a local anesthetic effect containing a dialkylamino-2 ', 6'-acetoxy-lidide and / or a pharmaceutically acceptable salt thereof, as well as the formed pharmaceutical preparations obtained by this process and a process for preparing dialkylamino-2 ', 6'-acetoxylidides and the pharmaceutically acceptable salts thereof.

The invention relates to a method for preparing a pharmaceutical composition with local anesthetic effect by applying a dialkylamino-2 ', 6'-aceto-xylidide and / or a pharmaceutically acceptable salt thereof in a dosage form suitable for therapeutic purposes. and to the formed pharmaceutical preparations with local anesthetic activity obtained by this method. Such a method and the resulting pharmaceutical preparations obtained therewith are known from US Pat. No. 3,542,850. This patent describes compounds of formula Ivan the formula sheet wherein R 1 is a lower alkenyl, lower alkynyl, mercapto lower alkyl, hydroxy low alkyl, acyloxymethyl, benzylthio lower alkyl, lower alkoxycarbonyl, carbamoyl or an amido-substituted lower alkyl, lower alkyl disulfide group, i.e. a reactive or functional group, and Rg and Rg represent, inter alia, a lower alkyl group.

It has now been found that the new compounds of formula 1, and / or the pharmaceutically acceptable salts thereof, wherein R 1 represents a propyl or butyl group and & 2 represent a methyl, ethyl, propyl and / or butyl group or wherein R 2 and together form a tetramethylene group, where the number of carbon atoms in R 1, R 2 and R 2 is at least 6 in total, exert a longer or more potent local anesthetic activity, cause only an acceptably low tissue irritation and an acceptably low possess acute toxicity.

The invention is therefore directed to a method of preparing a pharmaceutical composition with local anesthetic activity by bringing one or a number of the above-defined compounds, and / or the pharmaceutically acceptable salts thereof, into a dosage form suitable for therapeutic purposes. and shaped pharmaceutical preparations having local anesthetic activity obtained on the orider 10 by the application of this method. Preferably 2-diethylamino-2f, 6-n-valeroxylidide, 2-dimethylamino-2 ', 6'-caproylxylidide or 2-pyrrolidino-2', 6'-n-valeroxylidide, and / or a pharmaceutically acceptable salt of that, please.

Since the compounds of the invention have an asymmetric carbon atom, they can exist in both racemic and optically active form. It will be clear that optically active isomers of the compounds of the invention having a local anesthetic effect are also within the scope of the invention.

Two acylxylidide compounds with local anesthetic activity which are commercially available are the Nn-butylpipecolyl-2,6-xylidide or bupivacaine of the formula 5 sold under the name "Marcaine" and the diethylaminoaceto- sold under the name "Xylocaine". 2,6-xylidide or 10-diethylamino-2,6-dimethylacetanilide or lidocaxne of formula 6. Although "Marcaine" is a long-acting local anesthetic, it has the drawback of irritating to the tissue. "Xylocaine", on the other hand, does not irritate the tissue, but again has the drawback that it does not exert a long-lasting effect.

Other local anesthetics commercially available include the a-propylamino-propiono-2-boluidide or prilocaine sold under the name "Citanest", the a-pyrrolidinoaceto-8204126 sold under the names "Endocaine" and "Dynacaine". * 9 3 2,6-xylidide or pyrrocaine and the N-methylpipecolyl-2,6-xylidide or mepivacaine sold under the name "Carbocaine".

These local anesthetics, however, have a short-term effect.

Examples of compounds according to the invention are: 2-diethylamino-2 ', 6'-n-valeroxylidide, which may also be referred to as 2-n-propy1-2-diethylamino-2', 6'-acetoxyxylidide, of the formula 1 wherein Rj represents the n-propyl group and-I & 2 and Rg represents the ethyl group, 2-dimethylamino-2f, 6'-caproylxylidide, which may also be called 2-n-butyl-2-dimethylamino-2 ', 6'-acetoxylidide, of formula 1 wherein R 1 represents the n-butyl group and R 2 and R 9 represent a methyl group and 2-pyrrolidino-2?, 61-n-valeroxylidide, which may also be 2-n-propyl-2-pyrrolidino-2r, 6'-acetoxylidide mentioned, of formula 1, wherein R 1 * n-propyl and R 2 and R 8 form the fetramethylene group.

The compounds according to the invention can be prepared in a manner customary for the synthesis of analogous compounds, for example according to reaction scheme A, wherein Rj, Rg and Rg have the same meanings as before and X is a bromine or chlorine atom, or according to reaction scheme B, wherein Rj, R2, Rg and X have the same meanings as before. In the reaction according to scheme A, the bromine atom of the compound of the formula II can also be converted into an iodine atom before the compound is used in the second reaction step.

In the reaction according to scheme B, other halogenating agents, for example NaJ, can be used instead of KJ.

As an alkylating agent, for example, (^ 2 ^ 5 ^ 2 ^ 4 and ^ can be used

The racemic compounds can be cleaved into their optically active d and 1 isomers by treatment with 1 and d-weistoic acid.

The compounds of the invention can be used as local anesthetics in a conventional manner and using conventional 8204126 to 4 doses.

The bases can be easily used in the form of solutions of their pharmaceutically acceptable salts, for example, the hydrochloride tartrates and citrates.

Parenteral solutions can be administered peridural, subarachnoidal or by infiltration. Solutions, jellies, ointments and sprays prepared from the bases or their pharmaceutically acceptable salts can be applied topically to mucous membranes and the damaged, e.g. abraded, black.

The compounds can be used in concentrations of 0.25 - 2% and in doses of 75 - 300 mg.

However, the concentrations and doses are not limited to these ranges, but must be determined individually, taking into account factors such as the age and body weight of the patient, the clinical indication and the route of administration.

The invention is further illustrated by the following examples: 20

Example I

This example describes the preparation of 2-diethylamino-2 ', 6'-n-valeroxylidide according to rectification scheme A.

2-Bromo2T, 6f-n-valeroxylidide of formula 2, wherein R 1 represents a propyl group and Y represents a bromine atom.

2,6-xylidine (0.347 mol) and glacial acetic acid (310 ml) were mixed together in a 2 liter bottle. The mixture was cooled to 12 ° C and 2-bromo-n-valeryl chloride (0.349 mol) was added quickly. After rapid mixing, a pre-cooled (5 ° C) solution of sodium acetate trihydrate (85 g) in water (340 ml) was immediately added and the mixture was shaken for about 30 minutes. The solid was filtered and washed carefully and repeatedly with water until the filtrate was free of bromide. After drying 8204126 5 Μ in a desiccator over potassium hydroxide flakes, the solid (0.345 mol) melted at 189-190.5 ° C. After recrystallization from 95% ethanol, the melting point of the colorless crystals was 190-190.5 ° C.

5 Yield: 65-78%.

Calcd for C 18 G BrNO: C 54.9%; H 6.38%; Br 28.1%. Found: C 54.9%; H 6.33%; Br 28.2%.

2-Diethylamino-2 *, 61-n-valeroxylidide.

A mixture of 2-bromo-2 *, 6'-n-valeroxylidide (0.176 mol), diethylamine with foxmule 3, in which Rj and Rg represent an ethyl group (0.528 mol) and benzene (125ml) was placed in a pressure vessel and Heated at 100 ° C for 35 hours. After cooling, the dark brown content was filtered off and the solid (23.2 g diethyl ammonium bromide) carefully washed with benzene. The filtrate was extracted with 4N hydrochloric acid (3 x 50ml) and the acid extract was washed with ether (3 x 50ml) and made basic with 7N sodium hydroxide in the presence of ether (100ml) with cooling and stirring.

After two more extractions with ether (2 x 50 ml), the combined ether extracts were dried (Na 2 SO 4) and the ether was evaporated, leaving 16.5 g of a residue. The hydrochloride was prepared in the residue by dissolving it in ether and adding an ethereal hydrogen chloride solution. The hydrochloride was recrystallized twice with absolute ethanol / ether (3: 5), mp 205 - 206 ° C.

Calculated for C17 H21 ClN2 O: C 65.3%; H 9.34%; N 8.95%

Found: C 65.2%; H 9.49%; N 9.15%.

Gas chromatography of the salt gave only a clear peak.

I.R. (KBr disc, hydrochloride): 3170 (mw, NH amide); 2968 and 2930 (m, CH3 and CH2); 2560 (m, NH +); 1677 (s, amide I); 1593 (w, pH); 1528 (s, amide II); 1472 and 1433 (MS); 1230 (mw, amide III); 775 (m, 3 adjacent Ph-hydrogen-35 atoms outside the plane).

8204126 6 »'* ο

Example II

This example describes the preparation of 2-dimethylamino-2 ', 6'-caproylxylidide according to reaction scheme A.

2-Bromo-2 *, 61-caproylxylidide of formula 2, wherein R 1 represents a butyl group and Y represents a bromine atom.

A mixture of 2,6-xylidine (0.125 mol) and glacial acetic acid (115 ml) was cooled to 10 ° C in a 1 liter bottle, after which 2-bromo-caproyl bromide (0.136 mol) was added and mixed quickly. This was followed as soon as possible by a cool (50 ° C) solution of sodium acetate trihydrate (45 g) in water (190 ml). The mixture was shaken for 45 minutes and filtered. The precipitate was carefully and repeatedly washed with water until free of bromide-15 ions. It was then dried in a desiccator over potassium hydroxide flakes and recrystallized twice from methanol / water (about 15: 1); melting point 167-169 ° C. Yield; 67%. This material was sufficiently pure for the next reaction. The pure compound (a further recrystallization) had a melting point of 168.5-169 ° C.

Calcd for C 20 g BrNO: C 56.4%; H 6.76%; Br 26.8%.

Found s C 56.2%; H 6.40%; Br 25.9%.

2-Dimethylamino-21,61-caproylxylidide 25 A mixture of 2-6 ^ 0 ^ -21,6'-caproylxylidide (0.119 mol), dimethylamine of formula 3, wherein R2 represents a methyl group (0.356 mol) and benzene (177 ml) was heated in a pressure vessel at 100 ° C for 22 hours. After cooling, the reaction mixture was filtered. The weight of the dimethylammonium bromide obtained indicated that 97% of the bromine compound had been converted. The filtrate was extracted with 4N hydrochloric acid (1 x 50 + 2 x 25ml) and the acidic solution was adjusted to pH 11 with 7N sodium hydroxide and extracted with ether (3 x 50ml). The combined ether extracts were dried (Na 2 SO 4) and evaporated in vacuo. The residue obtained was hereid the hydrochloride with an ethereal hydrochloric acid solution (8204126).

t

This was recrystallized twice from absolute alcohol / ether (1: 8) to give colorless crystals (0.0992 mol) which melted at 193.5-194.5 ° C.

5 Calculated for C 1/2 / Cl 2 O: C 64.3%; H 9.10%; N 9.37%; Cl 11.9%,

Found: C 64.2%; H 9.04%; N 9.52%; Cl 12.0%.

I.R. (KBr disc, hydrochloride): 3185 (m, amide NH); 2950 and 2920 (ms-m, CH 2 and CH 2); 2450 (ms, NH +); 1682 (s, ami de I); 1591 (w, Ph); 1530 (s, amide II); 1470 (s); 1236 (mw, I * 10 amide III); 776 (m, 3 adjacent PH hydrogen atoms out of plane).

Example III

This example describes the preparation of 2-pyrrolidino-2,6,6-n-valeroxylidide according to reaction scheme A.

2-iodo-2 *, 6'-n-valeroxylidide (of formula 2, wherein R 1 represents propyl group and Y iodine).

A mixture of 2-bromo-2 ', 6'-n-valeroxylidide 20 (of formula 2, wherein R 1 represents a propyl group and Y represents a bromine atom) (0.137 mol), potassium iodide (0.274 mol) and dry methanol (375 ml) refluxed under stirring for 3 hours. After cooling, 1 liter of water was added to the yellow-colored reaction mixture and it was left under stirring for 15 minutes. The precipitate was filtered off, washed repeatedly with water until the filtrate was free of halides, and dried. After recrystallization from 95% ethanol, it melted at 196.5 - 197.5 ° C; yield 0.105 mol of a product which was sufficiently pure for the next step of the synthesis. Another recrystallization brought the melting point to 197-198 ° C.

Calcd for C 21 H 21 JNO: C 47.1; H 5.48; J 38.3 Found: C 47.3; H 5.36; J 38.2.

8204126 8 w-2-Pyrrolidlno-2T, 6T-valeroxylidide.

A mixture of 2-iodo-21,61-n-valeroxylidide (0.0754 mol), pyrrolidine (of formula 3, wherein R2 and R1 together form a tetramethylene group) (0.226 mol) and benzene 5 (65 mol) heated in a pressure vessel for 24 n at 100 ° C. After cooling, the benzene and excess pyrrolidine were evaporated in vacuo. The residue was stirred with water (150 ml) for 30 minutes and filtered. To the filtrate was added 7 N sodium hydroxide (pH 11) with stirring and after 30 minutes the solid base was filtered off, carefully and repeatedly washed with water and dried in vacuo. The crude base (14 g) was recrystallized from nitrous ethanol to a constant melting point (126-127.5 ° C), yield 4.9 g. 2.7 g were obtained from the mother liquors. Total yield: 37%.

Calculated for C 17 H 26 N 2 O: C 74.4%; H 9.55%; N 10.2%.

Found: C 74.1%; H 9.66%; N 10y4%.

I.R. (KBr 1 disc, base): 3210 (s, NH amide); 2933 (s), 2915 (ms) (CH3 and CH2); 1645 (s, amide I); 1593 (w, PH); 1529 (s, amide II); 1478 and 1465 (ms); 770 (s, 3 adjacent Ph-20 hydrogen atoms out of the plane).

Example IV

One example describes pharmaceutical preparations.

Solutions containing 0.25, 0.50, 0.75 and 1.0% diethylamino-21.6 * n-valeroxylidine hydrochloride without added vasoconstrictor. pH 3.5 - 4.5.

_Quantity (g) ^ Component 0.25% 0.50% 0.75% 1.0%

Diethylamino-2, 6'-n-valeroxydide hydrochloride 2.50 5.00 7.50 10.00

Sodium chloride USP XVIII 8.53 8.07 7.70 7.10

Salt salt, 2N as necessary to adjust pH 35 Sodium hydroxide, 2N as necessary to adjust pH

Water for injection, USP XVIII supplemental to 1000 ml.

8204126 £ 9 *

Example V

One example describes pharmaceutical preparations.

Solutions containing 0.25, 0.50, 0.75 and 1.0% 2-diethylamino-21,6r-n-valeroxylidide hydrochloride with adrenaline 1: 200,000. pH 3.5 ~ 4.5.

_ Quantity (g) _

Component 0.25% 0.50% 0.75% 1.0% 10 2-Diethylamino-2 ', 6'-n-valoxylidide.hydrochloride 2.50 5.00 7.50 10.00

Sodium chloride, USP XVIII 8.53 8.07 7.70 7.10

Adrenaline, USP XVIII 0.0050 0.0050 0.0050 0.0050

Sodium metabisulphite 0.50 0.50 0.50 0.50 J5 Sodium hydroxide, 2N as necessary to adjust pH

Hydrochloric acid, 2N as necessary to adjust pH water for injection, USP XVIII additionally up to 1000 ml.

20

Capital letters shown in the tables below have the following meanings: A is 2-diethylamino-2,6-n-valeroxylidide.

B is 2-dimethylamino-2 ', 6'-caproylxylidide.

^ · V

C is 2-pyrrolidino-2t, 6 * -n-valeroxylidide.

X is the known compound N-n-butylpipecolyl-2,6-xylidide, i.e. bupivacaine or "Marcaine" of formula 5.

Y is the known compound, Diefahylaminoaceto-2,6-xylidide, i.e. Lidocaine or "Xylocaine" of Formula 6.

Z is the known compound a- (diethylamino) -n-butyromesidide of formula 7.

8204126

I 10 t

Tables A through C contain comparative data on the duration of action of different local anesthetic compounds, while Table D includes comparative data on the acute toxicity of different local anesthetic compounds.

TABLE A

10 Blocking sciatic nerves in the rat

Duration in minutes ± standard deviation% Cone.

as base_A B X_Y_Z

15 0.125 117 + 11 96 ± 23 121 + 32 - 101 ± 15 0.25 123 ± 19 117 + 11 175 ± 16 102 ± 15 114 + 14 0.5 140 + 12 126 + 13 212 + 34 123 + 10 118+ 15 1.0 179 + 27 146 + 19 213 162 + 39 126 + 21 VW 20 2.0 268 + 36 280 + 42 - 185 + 23 146 + 18

All solutions contain 1: 100,000 adrenaline.

25x: The study method is described in Truant, A.P., Arch.

Int. Pharmacodyn. 115, 483-497 (1958).

: Some animals exhibited blockage longer than 12 hours.

8204126 11 *

TAB E L B

Peridural anesthesia in the guinea pig. Duration of blocking of support of weight 5 in minutes + standard deviation.

% Cone.

base _A_2_Y_ 0.25 39 + 7 38 + 7 10 10 0.5 55 + 7 59 + 12 14 + 2 1.0 68 + 5 89 + 8 21 +6

All Solutions contain]: 100,000 adrenaline.

15 X: Research method described in Tan and Snow,

Am. J. Yet. Kes. 39, 487 (1968). Brie animals died 5 minutes after the injection and one animal did not experience the blockage.

20

I A B E L C

X

Peridural anesthesia in the dog Duration of blocking weight support in minutes 25% Cone.

base_A_X_Y_ 0.5 304 1.0 417 30 2.0 - - 137

All solutions contain 1: 100,000 adrenaline.

oc X.

35: In adult male beagles, a cannula 8204126 - 12 was surgically implanted into a lumbar vertebra so that solution (5 ml) of the agent can be introduced into the peridural space.

After administration of solutions of the local anesthetics, the animals were intermittently examined for the duration of the motor block (weight support).

T A B E L D

10 Acute toxicity in female mice - LD ^ q and 95% confidence limits according to Fieller: mg / kg as base

Intraperitoneal Intravenous 15 A 51 (41 - 58) B - 11.3 (9.2 - 13.9) X 40 (28 - 56) 6.4 (5.5 - 7.3) Y 102 (73 - 142) ) 25 (22 - 33) Z 93 (81-110) 9.4 (8.3-10.6) 20

The solutions do not contain adrenaline.

The LD ^ Q values and the 95% confidence limits according to Fieller were calculated using the "Minimum Logit Chi Square" method of Berkson, J.Am.Stat.Assoc.

48, 565 (1953).

The values in the previous tables show that the compounds of the invention generally have a longer local anesthetic activity, especially at concentrations of 1 or 2%, than the related homologous compounds Y and Z, while still having a have satisfactorily low toxicity.

8204126

Claims (6)

1, A method of preparing a pharmaceutical composition having a local anesthetic effect by applying a dialkylamino-2 ', 6'-acetoxylidide and / or a pharmaceutically acceptable salt thereof in a dosage form suitable for therapeutic purposes, characterized in that, that as dialkylamino-2 ', 6'-acetoxylidide one or a number of compounds of formula 1, wherein R 1 represents a propyl or butyl group and E 2 and represent a methyl, ethyl, propyl and / or butyl group or wherein R 2 and R 1 together form a tetramethylene-10 group, wherein the number of carbon atoms in R 1, R 2 and R 1 is at least 6 in total. 2 * Process according to claim 1, characterized in that 2-diethylamino-2, 6'-valeroxylidide is used. 15 3. Process according to claim 1, characterized in that 2-dimethylamino-2, 6-eaproylxylidide is used. 4. Process according to claim 1, characterized in that 2'-pyrrolidino-2,6,6-valeroxylidide is used. 5. Formed pharmaceutical preparations with lp-pole anesthetic effect obtained by a method according to claim 1. 25 6. Process for preparing a dialkyl-amino-2 ', 6'-acetoxylidide or a pharmaceutically acceptable salt thereof in a manner customary for analogous compounds, characterized in that a compound of formula 1, wherein R 1, and R have the meanings set forth in claim 1, or prepare a pharmaceutically acceptable salt thereof. & 8204126