FR2532306A1 - BASIC ACETANILIDES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THE SAME - Google Patents

Abstract

NEW BASIC ACETANILIDES OF FORMULA III (CF DRAWING IN BOPI) IN WHICH: R IS A HYDROGEN OR ALKYL RADICAL POSSIBLY SUBSTITUTED, R IS A HALOGEN RADICAL, ALCOXY POSSIBLY SUBSTITUTED, ALKYLTHIO POSSIBLY ALKYLTHIO, POSSIBLY SUBSTITUTED, OR SUBSTITUTED ALKYLTHIO, NOW ALKYLTHIO, NOW SUBSTROUTINE, OR THEN ALKYLTHIO R AND R MAY BE THE SAME OR DIFFERENT, AND R IS A BASIC RADICAL, AND THEIR SALTS USE IN PHARMACOLOGY. THESE NEW COMPOUNDS ARE PREFERABLY USED AS LOCAL ANESTHESICS AND AS ANTI-ARRHYTHMICS.

Description

Basic acetanilides, process for their preparation

and drugs containing it.

  The present invention relates to acetanilines

  new basics, a process for their preparation and drugs containing them. The present invention aims at novel compounds which can be used for example as local anesthetics and as anti-arrhythmic agents and which are less toxic and more effective than the

known compounds.

  Another object of the present invention is to provide processes for the preparation of these novel compounds which are simple to implement and economically advantageous. These aims are achieved with the novel basic acetanilides of the invention of formula III R 1 R

/ Y X NH-J-CH-R III

  R 4 in which R is a hydrogen radical or an optionally substituted alkyl, R 4 is a halogen radical, optionally substituted alkoxy, optionally substituted alkylthio,

  nitro, amino or optionally substituted alkylamino

  killed, propionyl or trifluoromethyl, R 1 and R

  be identical or different, and R 5 is a basic radical,

  and their salts for use in pharmacology.

  The process of the invention for the preparation of novel basic acetanilides of formula III R 1

-CH 2-R 5

III R 4

  in which R 1, R 4 and R 5 have the indi-

  above and their salts for use in pharmaco-

  The invention is characterized in that an aniline of formula I in which R 1 and R are as defined above is reacted with a halogenated compound of formula II ## STR2 ## wherein

  X is a hydroxyl group, an ester radical, a halogen,

  an amide radical or an anhydride radical or other suitable starting group, and Hal is a halogen atom or another group of

  appropriate share, with cooling or at room temperature

  ambient temperature, in a solvent and in the presence of a base, to obtain a compound of formula IV

R 1

NH-CO-CH 2-Hal IV

4 IV

R 1 4

  in which R 1, R and Hal have the indicated meaning

  above, these compounds are then reacted in an inert solvent and at elevated temperature with

  an amine yielding the radical R 5, and optionally converting

  the compounds obtained in their salts

in pharmacology.

  Intermediate products of

  mule IV as follows: halogenated fatty acids or suitable derivatives are

  their esters, halides (e.g.

  acid or bromide), amides or anhydrides on a

  aniline, with cooling or at ambient temperature

  biante, in a solvent, for example acetone, acid

  acetic acid, ethyl acetate, chloroform, and in

  this of a base such as sodium carbonate, carbona

  potassium, sodium bicarbonate or potassium

  sium, sodium acetate, or in aqueous buffer with

  sodium acetate The halogeno-halogenated

  acetanilides of general formula IV with an amine in an inert solvent, preferably benzene, and

at high temperature.

  Acetanilides of general formula III can also be prepared without isolating the intermediate product.

  formula IV, adding, after hydrogenation,

  alkanoylation, the appropriate amine in an inert solvent.

  high boiling point, for example toluene or

  xylene, to the reaction mixture and heating.

  Compounds of general formula III in

  which R is an amino can be prepared by reducing

  from the acetanilides of formula III corresponding to

  in which R is a nitro.

  Acetanilides of formula III in which R is a halogen can be prepared either from

  described above from the corresponding anilides

  respondent, either by Sandmeyer's reaction to

  acetanilides in which R 4 is an amino.

  Here we mean by radical radical a radical

  any one containing at least one basic nitrogen atom.

  In the process of the invention, it is also possible to use catalysts. Those skilled in the art can easily determine the temperatures and the reaction times which are suitable. It is usual to work at normal atmospheric pressure, but a lower pressure than the normal one. normal is not excluded or

  The novel compounds of formula III of the invention

  are administered in the usual way for

  known compounds of similar application.

  The preferred embodiments stand out

  examples which follow are also

  some of the starting materials and products

new medias.

  With isolation of the intermediate product of formula IV

EXAMPLE 1

  To a mixture of 53 g (0.35 mole) of 2-ethoxy-6-methyl-aniline in 525 ml of absolute acetone and 7 g of sodium bicarbonate is added dropwise over one hour, while cooling with ice-cream. 46 g (0.4 mole) of chloroacetyl chloride, followed by shaking a

  hour at room temperature We suck the salt half

  and washes it with acetone. The volume of the

  filtrate to the water pump, add to the

  of and one sucks the separated crystals of chloro-2

  2'-ethoxy-6'-methyl-acetanilide, m.p.

149 C.

EXAMPLE 2

  Using 2-methyl-6-aniline aniline instead of 2-ethoxy-6-methyl-aniline and proceeding

  as in Example 1, 2-chloromethyl is obtained.

  2 'nitro-6' acetanilide, m.p. 140-141.5 ° C.

amination

EXAMPLE 1

  To 10.25 g (0.045 mole) of 2-chloro-2-ethoxy

  6-methylacetanilide in 100 ml of benzene is added.

  10 g (0.136 mole) of diethylamine are added and

  reflux the mixture for 6 hours after cooling

  The diethylamine hydrochloride salt is removed, washed with benzene and the volume of the filtrate is reduced under water suction. To the residue is added water and ether, the base is extracted from the ether phase. in 5% hydrochloric acid, the acidic aqueous solution is basified and stirred with ether After drying and evaporation of the ether, the residue is dissolved in ethanol and added dropwise with cooling, ethereal hydrochloric acid, and there is obtained 2-diethylamino-ethoxy-2'-methyl-6 'acetanilide hydrochloride,

melting point 107-109 C.

EXAMPLE 2

  Using piperidine instead of di-

  ethylamine and proceeding as in Example 1,

  2-piperidino-2'-ethoxy-6-methyl-acetyl acetate is obtained.

  nilide, melting point 79-80 C, and the

  base in hydrochloride, mp 192-193 C.

EXAMPLE 3

  Using pyrrolidine instead of diethylamine and proceeding as in Example 1,

  obtains 2-pyrrolidinethoxy-2'-methyl-6-acetanitrile

  lide, melting point 60.5-62 C, which is converted into

  hydrochloride, mp 180-181.5 ° C.

EXAMPLE 4

  Starting with 2-chloro-2'-methyl-6'-nitroacetanilide and diethylamine and proceeding as

  in Example 1, there is obtained 2-diethylamino-methyl

  2 'nitro-6' acetanilide, m.p. 60-61 ° C, and its hydrochloride, mp 166-1680 ° C.

EXAMPLE 5

  Using piperidine instead of di-

  ethylamine and proceeding as in Example 1, there is obtained 2-piperidino-2'-methyl-6'-nitroacetanilide, melting point 72-73 C, and its hydrochloride point

192-194C fusion

EXAMPLE 6

  Starting with 2-chloro-2-trifluoromethylacetanilide and diethylamine and proceeding as

  in Example 1, the dihydrochloride of

  2-ethylamino-2-trifluoromethylacetanilide, point of

melting 160.1 C.

EXAMPLE 7

  By using pyrrolidine instead of di-

  ethylamine and proceeding as in Examples 1

  and 6, there is obtained 2-pyrrolidino hydrochloride

  2-fluoromethyl acetanilide, mp 229.4 ° C.

EXAMPLE 8

  Starting with 2-chloropropionyl-2 'acetaniline

  of and of pyrrolidine and proceeding as in Example 1, we obtain the hydrochloride of pyrrolidino-2

propionyl-2 'acetanilide.

EXAMPLE 9

  Starting from 2-chloro-2-methyl-6'-propionylacetanilide and pyrrolidine and proceeding as

  in Example 1, pyrrolidine hydrochloride is obtained

  lidino-2-methyl-2 'propionyl 76' acetanilide, point of

192.6 C. fusion

  The 2-methylpropionyl-6-aniline used is prepared

  As starting material from 2-amino-3-methylbenzonitrile was prepared as follows. Ethyl magnesium bromide was prepared from magnesium (6.3 g, 0.26 moles) and magnesium (25.5 g). ethyl bromide in 130 ml of absolute ether and heated for 30 minutes in a water bath Then, a solution consisting of 6.65 g (0.05 mole) of 2-amino-2 3-methylbenzonitrile

  in 100 ml of absolute ether and boil the mixture

  After 15 hours at reflux with stirring After cooling

  The mixture is poured into ice (110 g) and a solution of 15.6 g of ammonium chloride in 67 ml of water is added. The ether phase is separated and the aqueous phase is stirred with ether. The two ether phases are distilled from the ether and the residue is boiled for 30 minutes.

  9.5 ml of water and 11.2 ml of concentrated hydrochloric acid

  After cooling, the mixture is stirred with ether, the aqueous phase is basified and the mixture is extracted with ether. After drying and evaporation of the ether, there is obtained 2-methylpropionyl-6-aniline, which is

  characterized in the form of hydrochloride, point of

191.2 C.

EXAMPLE 10

  To 10.9 g (0.05 mol) of 2-chloro-2'-chloro-6'-methyl-acetanilide in 30 ml of absolute toluene, 12.75 g (0.15 mol) of cyclopentylamine in 50 ml of toluene are added. and boil 6 hours to

  reflux After cooling, the chlorhy-

  Separated cyclopentylamine dearate, the volume of the filtrate is reduced and the residue is added with water and ether. The ether phase is extracted and a solution of 5% hydrochloric acid is added.

  separates by crystallization the cyclopenyl hydrochloride

  tylamino-2-chloro-2 'methyl-6' acetanilide, point of

melting 209.7 C.

  The base was prepared, mp 76.8 ° C,

from 1 g of hydrochloride.

EXAMPLE 11

  By adding 2-chloro-2-chloro-6-methyl-acetanilide cyclopropylamine in benzene, heating for 10 hours at 100 C in an autoclave with

  inner lining of glass and, after cooling

  By following the procedure of Example 1, 2-cyclopropylamino-2-chlorohydrochloride is obtained.

  6-methyl-acetanilide, m.p.

  B Without isolation of the intermediate product of formula IV

EXAMPLE 1

  To 18.6 g (0.1 mole) of 2-bromo-6-methyl-6-methyl

  in 150 ml of absolute acetone and 20 g of bicarbonate.

  sodium chloride, 12 g (0.11 mol) of chloroacetyl chloride are added dropwise over one hour, while cooling with ice, and the mixture is then stirred for 30 minutes at room temperature. 22 g (0.degree. 3 mol) of diethylamine in 50 ml of toluene and boiled for 6 hours at reflux.

as in A, example 1.

  Diethylamino-2 hydrochloride is obtained

  2'-bromo-6-methylacetanilide, m.p.

174 C.

  a) The same diethylamino-2 can be prepared

  2'-bromo-6-methylacetanilide from diethylamine

  No. 2-amino-2'-methyl-6-acetanilide by the Sandmeyer reaction as follows: 11.75 g (0.05 mole) of 2-diethylamino-2-amino-6-methyl-amine are cooled in an ice-bath acetanilide in 30 ml of 48% hydrobromic acid and is diazotized at -5 ° C. for 30 minutes with 3.45 g of sodium nitrite in 20 ml of water (starch paper control)

  iodine), then stirred for 40 minutes at -5 ° C.

  the suspension to a mixture heated at 70 ° C. with 4 g of CuBr in 20 ml of 48% hydrobromic acid and

  stirring for 2 hours at this temperature After cooling

  The mixture is stirred with ether and the acid solution is made alkaline and extracted with ether. After drying and evaporation of the ether, the residue is dissolved in

  ethanol and transform it with hydrochloric acid

  ethereal gene in hydrochloride, which is identical to

  as shown in Example 1, melting point 172-

1740 C.

  Reduction of 2-diethylamino and 2-piperidino-2-methyl-6-nitroacetanilide

EXAMPLE 1

  a) To 25 g (0.094 mol) of 2-diethylamino-2-methyl-6'-nitroacetanilide in 500 ml of concentrated hydrochloric acid, 100 g of tin (II) chloride are added in one hour with stirring. The mixture is heated for 30 minutes in a boiling water bath and, after cooling, basified with 35% sodium hydroxide solution while cooling with ice and

  extracted with ether After washing, drying and evaporation

  ether, 2-ethyl-2-diethylamino is obtained.

  2-methyl-6'-acetanilide, mp 105-106.5 ° C, which is converted with ethereal hydrogen chloride to dihydrochloride, mp 182 ° -184 ° C. b) The same diethylamino-2 is also obtained

  2'-Amino-6-methylacetanilide as follows.

  To a mixture of 300 mg of Pd-C in 60 ml of water flushed with a nitrogen stream, 4.8 g of sodium boron hydride in 90 ml of water are added. Then, dropwise is added dropwise. in 30 minutes the solution consisting of 15.9 g (0.06 mol) of 2-diethylamino-2-methyl-6'-nitroacetanilide in 150 ml of methanol and then stirring for a further 20 minutes is filtered, the volume of the water-jet filtrate, water is added and the separated crystals are aspirated,

melting point 105-106.5 C.

EXAMPLE 2

  2-piperidino-2-amino-2'-methyl-6'-acetanilide, melting point 169-170 ° C., is prepared by proceeding

  as in Example lb, except that the heat is

  before the filtration, because the product is not very soluble in cold methanol The base is dissolved in ethanol and transformed with acid

  ethereal hydrochloric acid to dihydrochloride,

259-260 C.

Claims (8)

  1 Basic Acetanilides of Formula III R V NH-C-CH-R III R 4 in which   R 1 is a radical hydrogen or alkyl possible-   substituted, R is a halogen radical, optionally substituted alkoxy, optionally substituted alkylthio,   nitro, amino or optionally substituted alkylamino   killed, propionyl or trifluoromethyl, R and R 4 may be the same or different, and R is a basic radical,   and their salts for use in pharmacology.   2 Basic acetanilides according to the claim   1, characterized by the fact that in the   Formula III, R 1 is hydrogen or methyl, R 4 is chloro, bromo, trihalognomethyl, R is chloro, bromo, trihalomethyl, I 2 preferably trifluoromethyl, ethoxy, nitro, amino or propionyl, and   R 5 is a diethylamino, piperidino, pyrrolidine radical   no, cyclopropylamino or cyclopentylamino.   3 Basic acetanilides according to claim 1 or 2, characterized in that the   salts of the compounds of the formula III are hydrochloric   tures, hydrobromides, fumarates, maleates, hydrogen fumarates or hydrogen maleates.   Process for the preparation of basic acetanilides of formula III R 1 -R III = <NH-C-CH 2 -R 5 R 4 1 4 5   in which R 1, R and R have the indicated significance   in claim 1, and their salts   sands in pharmacology, characterized in that an aniline of formula I R 1 is reacted / \ NH 2 I   in which R and R 4 have the meaning indicated in claim 1, with a halogenated compound of formula II X C O -CH 2 -Hal II in which   X is a hydroxyl group, an ester radical, a halogeno   an amide radical or an anhydride radical or other suitable starting group, and   Hal is a halogen atom or another group of   appropriate part, with cooling or at room temperature,   in a solvent and in the presence of a base, to obtain a compound of formula IV R 1 / X \ NH-CO-CH 2-Hal IV R 4 - 1 4   in which R 1, R and Hal have the indicated meaning   above, these compounds are then reacted in an inert solvent and at elevated temperature with a yielding amine.   the redical R, and we eventually transform the   obtained in their salts which can be used in pharmaco- logie -   Process according to Claim 4, characterized in 6   rised by the fact that   mule II acid chlorides or acid bromides.   6 Drug, characterized by the fact that   contains at least one compound of formula III. 253-2306   Medicament according to claim 6,   terized by the fact that it is a local anesthetic.   Medicament according to claim 6,   terized by the fact that it is an anti-arrhythmic.