DK144063B - METHOD OF ANALOGUE FOR THE PREPARATION OF N- (TERT.AMINOALKYL) -2-ALKYNYLOXYBENZAMIDES OR ACID ADDITION SALTS OR QUATERNARY AMMONIUM SALTS. - Google Patents

Description

(11) PRESENTATION 1 44063 (61) Appendix to Patent No. 124944 DENMARK im-Cl. 'C 07 C 103/82 c 07 0 295/12 § (21) Application No 2889/68 (22) Filed on 19. June 1953 (24) Race day 19 · Jun. 1968 (44) The application presented and the petition published on 30 November. 1981

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority baked from it

20. thun. 1967, 111225, FR

Sep 5 1967, 120062, FR

(71) SCIENTIFIQUES AND INDUSTRIALS OF L 'ILE-DE-FRANCE, Paris, FR.

(72) Inventor: Michel Leon Thominet, FR.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Patent Office.

(54) Analogous process for the preparation of N- (tert-aminoalkyl) -2-alkynyloxybenzamides or acid addition salts or quaternary ammonium salts thereof.

Patent No. 124,944 relates to an analogous process for the preparation of substituted 2-arylalkyloxybenzamides of the general formula:

C0-NH- (CH2) n-A

z — k —w

Y

2 m063 wherein A means dialkylamino having 1-5 carbon atoms in the alkyl moiety, morpholino, piperidino, pyrrolidyl or N-alkyl pyrrolidyl having 1-5 carbon atoms in the alkyl moiety, X, ¥ and Z means hydrogen or halogen, Y means hydrogen or amino, and n and k are each 1 or 2, or acid addition salts or quaternary ammonium salts thereof, and the characteristic of the main patent is that a 2-arylalkyloxy-benzoic acid derivative of the formula:

CO-B

Z-- ¥ '-'

Y

wherein B represents a labile group consisting of a chlorine atom or an alkoxy group having 1 to 5 carbon atoms and γ, X, Y, Z and k having the meaning given above are reacted with a diamine of the formula:

H2N - (CH2) n - A

wherein A and n are as defined above and the compound formed, if desired, is transferred into an acid addition salt or a quaternary ammonium salt.

The 2-arylalkyloxy compounds disclosed in the main patent exhibit considerable local anesthetic effect, which is surprising since the homologous 2-alkyloxy compounds are potent antiemetics, as are also the homologous 2-alkenyloxy compounds not previously reported as being local anesthetic. active. The said homologous compounds are described in Danish Patent No. 14,563,106,557 and British Patent No. 994,023.

It has now been found that the compounds of the general formula I which differ substantially only from the compounds prepared according to the main patent in that the substituent at the 2-position is a 2-propargyloxy group also exhibits local anesthetic effect, which must be considered too surprising in view of the previously reported effects for the above-mentioned homologous alkyl and alkenyloxy compounds.

The invention therefore relates to an analogous method according to patent no.

124,944 for the preparation of compounds of the general formula (i) as claimed in the process which are characterized by reaction between the corresponding 2-substituted benzoic acid chloride of the general formula (XI) as claimed and a suitable diamine of the general formula NH 2 ( CH 2) 2 NR R, wherein R and R have the meaning set forth in the claim, whereupon, if desired, the final product is transferred into a pharmacologically acceptable acid addition salt or quaternary ammonium salt.

The process according to the invention is further illustrated by the following examples:

Example 1 N- (Diethylaminoethyl) -2-propargyloxy-3,5-dibromobenzamide.

28.6 g of thionyl chloride and 13.5 g of 2-propargyloxy-3,5-dibromobenzoic acid are placed in a 250 ml. flask equipped with a reflux condenser. The mixture is heated in a water bath at 40 ° C until the reagents have dissolved completely (2 hours). It is cooled and the rest of the acid (13.5 g) is added. The mixture is heated to 40 ° C and then to 70 ° C to completely dissolve reagent sera (1 1/2 hours). Excess thionyl chloride is then removed under vacuum. 28 g of 2-propargyloxy-3,5-dibromobenzoyl chloride are obtained.

9.2 g of .beta.-diethylaminoethylamine in 30 ml of anhydrous methyl ethyl ketone are introduced into a 1 liter flask equipped with a stirrer, thermometer and separatory funnel. 28 g of the acid chloride dissolved in 80 ml of methyl ethyl ketone is then added dropwise, keeping the temperature at 5 - 10 ° C. Mixtures are kept under stirring for 1/2 hour at 10 ° C and then left at ambient temperature for 2-3 hours. The solution is then dissolved in 200 ml of water. Methyl ethyl ketone is removed under vacuum. The solution is treated with charcoal, filtered and the base is precipitated with the calculated amount of sodium hydroxide. The precipitate is filtered off, washed with water and dried at 40 ° C.

15 g of N- (diethylaminoethyl) -2-propargyloxy-3,5-dibromo-benzamide are obtained (yield 43.5%) · (mp: 54-55 ° C).

Example 2 N- (Diethylamino ethyl) -2-propargyloxy-3,5-dichlorobenzamide.

195 g of 2-propargyloxy-3,5-dichlorobenzoic acid, 284 g of thionyl chloride and a few drops of dimethylformanide are introduced into a 2 liter flask equipped with a stirrer, thermometer and reflux. The mixture is heated slightly on a water bath at 40 ° C until the reagents are completely dissolved. After 1 1/2 hours, the reaction is complete and unreacted thionyl chloride is completely evaporated under vacuum. 210 g of 2-propargyloxy-3,5-dichlorobenzoyl chloride are obtained (yield: 100%), which is dissolved in 500 ml of methyl ethyl ether. 92.3 g of N, N-diethylaminoethylamine dissolved in 200 ml of methyl ethyl ketone are introduced into a 2 L flask equipped with a stirrer, thermometer and separating funnel. The acid chloride solution prepared above is then added and the temperature is maintained at 0 - 5 ° C. The mixture is then kept at a temperature of 5 - 10 ° C with stirring for 1/2 hour and then at ambient temperature for 1 hour. The resulting crystals are dried without heating, washed repeatedly with methyl ethyl ketone and then dried at 50 ° C. The resulting product is dissolved in boiling acetone, which is added to activated charcoal, and filtered in hot state. The solution is cooled to 0 ° C and after two hours the crystals formed are dried without heating, washed in ice-cold acetone and then dried at 50 ° C.

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170 g of N- (diethylaminoethyl) -2-propargyloxy-3,5-dichloro-henzamide are obtained. (Yield: 56%). (Mp: 110 ° - 111 ° C).

Example 3 N- (The thylaminoethyl) -2-propargyloxy-3,5-dibromobenzamide bromomethylate.

15.5 g of N- (diethylaminoethyl) -2-propargyloxy-3,5-dibromobenzamide are dissolved in 15 ml of acetone. 10 g of methyl bromide dissolved in 20 ml of acetone are added. The mixture is left for 24 hours. Extensive crystallization takes place. The crystallized material is dried at ambient temperature. 16 g of N- (diethylaminoethyl) -2-pro-pargyloxy-3,5-dibromobenzamide bromomethylate are obtained. (Mp: 110 ° C).

Example 4 N- (Diethylaminoethyl) -2-propargyloxy-3,5-dichlorobenzamide bromomethylate 24.5 g of N- (diethylaminoethyl) -2-propargyloxy-3,5-dichlorobenzamide are dissolved in 50 ml of acetone. 16 g of methyl bromide dissolved in 32 ml of acetone are added. N- (diethylaminoethyl) -2-propargyloxy-3,5-dichlorobenzamide bromomethylate is immediately crystallized. The mixture is left for 24 hours. It is dried without heating and washed on an ice-cold acetone filter and dried at ambient temperature. (Mp: 155 ° C).

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Example 5 N- (morpholinoethyl) -2-propargyloxy-3,5-dichlorobenzamide hydrochloride In a 250 ml flask provided with a sealed stirrer and a cooling tube, 24.5 g of 2-propargyloxy-3,5-dichlorobenzoic acid and 49 ml of thionyl are mixed. -chloride with three drops of dimethylformamide.

The mixture is heated to 50-60 ° C for one hour and excess thionyl chloride is distilled off under vacuum.

In another 250 ml flask equipped with stirrer, thermometer and separatory funnel, dissolve 13 g of morpholinoethylamine in 24 ml of anhydrous methyl ethyl ketone and cool to 5 ° C. Then 25.3 g of the acid chloride obtained above is introduced dropwise while maintaining the temperature at 5-10 ° C. Crystallization takes place. Stirring is continued for one hour while the temperature is allowed to reach 20 ° C. After extraction and leaching of the crystals with ice-cold methyl ethyl ketone, 27 g of N- (morpholinoethyl) -2-propargyloxy-3,5-dichloro-benzamide hydrochloride are obtained, m.p. 165 ° C.

Example 6 N-piperidinoethyl-2-nronargyloxy-5-fluorobenzamide oxalate In a 250 ml flask equipped with mechanical stirrer, thermometer and separatory funnel, 10 g of piperidinoethylamine are cooled to 0 ° C. A solution of 15 g of 2-propargyloxy-5-fluoro-benzoyl chloride in 50 ml of methyl ethyl ketone is added dropwise. After solution, add 200 ml of water and 10 ml of ammonia (d = 0.89). The oil formed is extracted three times with 200 ml of ether. The ether extracts are dried over magnesium sulfate and filtered. After dissolving 10 g in 20 ml ether, the product is added dropwise to an oxalic acid solution (4.5 g in 300 ml ether). N-piperidinoethyl-2-pro-pargyloxy-5-fluorobenzamide oxalate is crystallized. After extraction, washing with ether and drying, 4.5 g of crystal are obtained with m.p. 173 ° C.

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Pharmacological effects:

Acute toxicity

The compounds of this invention have a low toxicity, as shown in the table below, which compares LD 50 for known local anesthetics to mice: LD50 (mg / kg)

Connection Connection in base form

IV IP SC PO

Ex. 2 27.4-31 91.2-93 233-226 283-30

Ex. 1 14 76-81 108 162-182

Procaine 42.9 182 450 987

Tetracaine 6.3 51 29 334

Xylocaine 19.4 111 166 454

Ex.2 according to the main patent 15 96 186 640

Local anesthetic effects:

The local anesthetic properties of the subject compounds are shown by the following various tests: 1) Local surface anesthesia is determined by the Regnier method, which includes studies on the suppression of oculopalpebral reflex in rabbits as explained in the main patent in comparison with cocaine.

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The experiments showed that the compounds of the present invention were more potent than cocaine, as can be seen from the table which shows efficacious equivalent concentrations: Equivalent.

Compound Concentration of cocaine 1 0.1% 1.6% 2. 0.5% 0.71% g 2) Small blood vessel anesthesia was induced by Intramuscular administration of the compound to be tested in theca in the sciatic nerve of rats further explained in the main patent in comparison with xylocarn.

^ __

Connection Wife. mg / ml Anesthesia (mg / ml base)

Experiment No. 1

Ex. 2 3 77% 1.21 1.5 57% _ 0.75 70 _

Ex. 1 3 67% 1.5 57% 1.06 0.75 43% (after 60 min.) 8 73 $

Xylocaine 4 63 $ 2.03 2 40%

Experiment No. 2 -p, -1 4 87%

Ex. 1 2 53% 1.2 1 53% (after 60 minutes) 8 73%

Xylocaine 4 53 90 2.7 2 43% (after 30 minutes) 10 144063

From these results, one can deduce the local anesthetic effect of the two compounds in relation to Xylocaine, further listing the results of the compound of Example 3.

Connection Activity Index

Example 2 1.9

Example 1 2.2-2.25

Example 3 1.9 - 2.3

Xylocaine 1 3) Investigation of infiltration anesthesia is performed analogously to the main patent by intradermal injection into the skin of the back of a guinea pig in comparison with procaine.

Connection Wife. Number of needle% ED, -0 ms / 2 - (mg / ml) plug for 30 min. anesthesia base

Example 2 2 30.6 85 1 17 47 0.79 0.5 10.3 29

Procine 5 26.3 73 2.5 18.45 51 2.3 1.25 12.05 33 1.0 - ™ 25 0.625 0.7 1

Example 1 0.25 - 25

It can be seen from the table that the compound of Example 2 is substantially more active than procaine, while the compound of Example 1 at a concentration of 0.25% has the same effect as 1% procaine.