DE2751905C2 - - Google Patents

Description

The invention relates to aminoamides and their pharmacologically acceptable Acid addition salts, the preparation of these compounds and drugs with these compounds as the active ingredient dimethylaminoalkyl-3 ', 4'-dihaloanilide of the general formula III, its pharmacologically acceptable Acid addition salts, and the preparation of these compounds and the corresponding salts, and medicaments containing them.

The procedures for The compounds of formula III can be prepared using the following reaction schemes are explained:

Manufacturing process I or a)

Manufacturing process II or b)

In the above-mentioned manufacturing process, A 1 represents a residue of the formulas and A₂ is a residue of the formulas

- (CH₂) ₄ or - (CH₂) ₅ ·

Furthermore is X is a bromine atom or Chlorine atom and X ′ is a chlorine atom, bromine atom or iodine atom, and R represents an ethyl radical, a cyclopropyl radical or a vinyl residue.

Preferred compounds prepared in this way have the following general formula IIIA on in which

A rest of the formulas - (CH₂) ₂-; - (CH₂) ₃-; - (CH₂) ₄- and and X represents a bromine atom or chlorine atom.

Particularly preferred compounds according to the invention have the following general formula IIIB in which

A 'an ethylene radical of the formula -CH₂-CH₂- or one Trimethylene radical of the formula -CH₂-CH₂-CH₂-.

Connections that have a similar structure to that own according to the invention are described in US Pat 30 16 281. The ones mentioned there However, compounds act as analgesics, i.e. as pain relievers Means while the compounds of the invention in contrast, have antidepressant activity.

In US-PS 35 73 320 compounds with antidepressant activity of the following formula described, being in these compounds

Leg is sulfur atom or oxygen atom, R₂ for a radical of the formula

is in which
n is 2 or 3, R₄ denotes a hydrogen atom or an alkyl radical,
or the rest of the formula represents a morpholino, piperidino, pyrrolidino or piperazino radical, and R₃ is an alkyl or aryl radical or a similar radical.

In US-PS 32 34 276 and FR-PS 20 73 286 (see also Chem. Abstracts 77,88108) are also similar connections described, however they are used for other purposes.

The new according to the invention Substances with antidepressant activity are caused by the mentioned publications not suggested.

If the compounds according to the invention Manufacturing process I or II, then you proceed expediently as follows:

1 molar equivalent of a 3,4-dihaloaniline of the formula I. with about ½ mol equivalent to 1 mol equivalent of a dimethylaminoalkyl halide heated, taking the compounds of formula II. If you have a surplus the compound of formula I applies, then this represents that Base, which is used to trap the hydrogen halide serves, which is formed in the reaction. Subsequently the compound of formula II thus obtained is then acylated, for example by using an acid halide, for example an acid chloride or bromide of propionic acid, acrylic acid or the cyclopropanecarboxylic acid used, namely  preferably in the presence of a base. One can do the acylation but also with an appropriate acid anhydride, for example Propionic anhydride, perform, and also in in this case the corresponding connections are then obtained of formula IV.

When considering the manufacturing method according to the invention II or b) is carried out, the procedure is advantageously as follows: 1 mol equivalent of 3,4-dihaloaniline is heated with about 1 mole equivalent of N, N-dimethylamino-halobutyric acid amide or N, N-dimethylamino-halovaleramide, where the compounds of the formula mentioned are used in the reaction V receives. These compounds of formula V are then reduced, for example using a metal hydride, whereby the compounds of formula VI are obtained. Subsequently then acylated these compounds of formula VI to form the compounds of formula VII.

Examples of metal hydrides, with the help of Reduction step can be carried out are lithium aluminum hydride, Sodium cyanobrohydride, borane and diborane.

examples for pharmaceutically acceptable acid addition salts of the compounds of the formulas III, IIIA and IIIB are Hydrochloride, hydrobromide, Sulfates, malates, maleates, Tartrates, lactates, citrates, cyclohexanesulfamates and methanesulfonates. These salts can be made by connecting the Formula III with a stoichiometrically calculated amount of corresponding acid, for example in aqueous  Solution or ethereal solution, and finally the solvent evaporates.

The medicaments according to the invention are suitable to treat depression endogenous character and exogenous character.

The compounds of formula III were on their antidepressant efficacy according to usual test procedures tested, which are described in more detail below.

The main effectiveness of an antidepressant consists of the living being in depression normal function. One should be very precise distinguish between substances with an antidepressant effect and psychological stimulants, such as amphetamines, which lead to over-stimulation in a normal living being to lead.

Many different methods have been used so far and are still used to be an antidepressant To determine activity. These methods generally exist in determining the counteraction, i.e. the antagonism, against an agent with a depressive effect, such as Example reserpine or tetrabenazine, or in a synergistic Increase the toxicity of certain compounds, such as yohimbine or 3,4-dihydroxyphenylalanine, as well as a comparison of the effectiveness of the new Connections with other, already known connections with antidepressant effectiveness. It is not possible with one single test alone to determine if a new connection is or not an anti-depressant, but by various Tests you finally get an impact profile  from which one can see whether the agent in question is an antidepressant Possess effectiveness. A number of such Tests are now described below:

A) Hypothermic tests with oxotremorine, namely the 1- [4- (1-Pyrrolidinyl) -2-butinyl] -2-pyrrolidinone

The oxotremorine leads just like the apomorphine and the tetrabenazine to a hypothermic reaction, d. H. to a body temperature below the normal temperature in mice. This effect can be caused by anti-cholinergic Agents, i.e. anticholinergics, d. H. Pharmaceuticals through their Effect of cholinergic-powered success organ cells weakened react to nerve impulses, as well as by means with antidepressants Effectiveness can be blocked, such as with the help of atropine or imipramine.

Oxotremorine produces very strong hypothermia, reached a maximum 60 minutes after administration.

The working methodology is the following:
The compounds to be tested are injected intraperitoneally into 4 male Carworth Farm (CF 1) mice, and these mice are kept in plastic cages for 30 minutes. Subsequently, an amount of 1 mg per kg body weight of oxotremorine hydrochloride was injected subcutaneously and the mice were then placed in a refrigerator which was kept at a temperature of 19 ° C. A group of 4 mice of the above-mentioned type are injected with saline instead of the compound to be tested, and then 30 minutes later they are injected with oxotremorine hydrochloride and refrigerated in the same way. 30 minutes after the administration of oxotremorine, the body temperature of the mice is rectally determined using a thermistor sample. An increase of 2.2 ° C (4 ° F) in the body temperature of the treated mice, namely those to which both the oxotremorine and the compound to be tested were administered, compared to the mice for comparison purposes, to which only the oxotremorine was administered administered indicates that the compound tested has antidepressant activity.

B) Enhancement of those caused by yohimbine toxicity

The LD₅₀ of yohimbine hydrochloride in mice is 45 mg per kg body weight with intraperitoneal Administration. If you take yohimbine hydrochloride in a lot of 20 mg per kg body weight, then it works not lethal. If you start with an antidepressant Efficacy and then yohimbine hydrochloride administered, then the lethality is increased.

On 4 male mice (CF mice) with a body weight from 18 to 22 g was injected a lot of 20 mg per kg body weight of yohimbine hydrochloride in a saline solution administered by injection, namely in a chamber at 30 ° C. After 2 hours the Number of deaths determined. At this applied concentration of yohimbine hydrochloride is either at all no mouse or at most one mouse died.

If you take 30 minutes before the administration of the Yohimbine Hydrochlorides is a compound with antidepressant Effectiveness injected, then the lethality of the yohimbine elevated. If of the 4 mice three at a certain concentration of the connection to be tested then die the test results obtained in this way as a positive indicator for  viewed the antidepressant activity of the tested compound.

C) Apomorphine gnawing method

To a group of 4 male mice, namely CF₁ mice, which have a body weight of 18 to 22 g, the compound to be tested is intraperitoneally 1 hour before the subcutaneous injection of apomorphine hydrochloride in one Amount of 10 mg administered per kg. Then the mice become single put in plastic boxes and you observe their stereotypical Gnaw. If 3 or 4 of the mice do this behavior show, it is then determined that the connection in question is active in the applied dosage.

Those described in the examples below Compounds were tested and found to be Have efficacies that are the same or better than that of previously commercially available substances with antidepressant Efficacy, such as imipramine hydrochloride.

The pharmaceutical administration forms of the compounds of formula III and their salts, the subject of Invention are pharmaceutical formulations that include suitable for oral, parenteral or rectal administration such as tablets, powder packs, Pastilles, drages, capsules, solutions, suspensions, sterile injectable forms, suppositories, probes Compounds or formulations incorporated in wax. As examples of suitable diluents or carrier materials may be mentioned: carbohydrates, lactose, sucrose, Mannitol, proteins, lipoids, calcium phosphate, corn starch, stearic acid, Methyl cellulose. These materials  can either be used as carrier materials or for coating be used. Water or oils, such as coconut oil, Sesame oil, safflower oil, cottonseed oil and peanut oil can for the production of solutions or suspensions for the active ingredient. Artificial sweeteners, Colorants and flavoring agents can also be added.

The compounds can be used as antidepressants of formula III and the preferred compounds of the invention of formulas IIIA and IIIB, as well as their pharmacological acceptable acid addition salts used in dosages be in the range of 0.01 to 2 mg per kg of body weight lie, depending on the particular used Connection, weight, age and other condition of the individual or patient to be treated. Preferably dosages in the range of 0.05 to 1 mg per kg body weight applied, namely when one is to be administered orally or injectable preparations as used above have been described. With such doses can the depressive states of the patients are remedied.

In the treatment of depression in humans dosage units can be administered which are 1.0 to Contain 30 mg of the active compound, and these dosage units can be given one to four times a day, each according to the body weight, age and condition of the patient, and depending on the specific compound of formula III, to be applied. These dosage units can administered orally or by injection, subcutaneously or intravenously or intramuscularly, and it is too rectal administration possible.  

Those for the preparation of the compounds according to the invention of the formula III required 3,4-dihaloanilines, wherein the halogen atoms are chlorine atoms or bromine atoms known connections. In the same way they are with them chlorinated or brominated dimethylaminoalkanes to be reacted described in the literature.

When carrying out the method according to the invention the special 3,4-dihaloaniline of formula I with the special halogen-1 (N-dimethylamino) alkane or a Acid addition salt thereof in the presence of a base, either in the presence or in the absence a solvent or suspending agent. In this implementation the desired compounds of formula III are then obtained.

In a preferred embodiment of the invention The 3,4-dihaloanilines are combined in one process Ratio of 1 to 2 molar equivalents per molar equivalent of Halodialkylaminoalkane used in the form of the free base or used in the form of salts of the base. If the connections are used in the form of the salts, then the Addition of another basic compound is necessary to make the free Base to release. If you take the halogen-substituted aniline Formula I used in excess, then it serves as an additional Base. However, inorganic bases, such as sodium bicarbonate or potassium bicarbonate or Carbonates can be used as an additional base. If the reaction is carried out in the presence of solvents then preferred solvents are those which at a temperature of more than 85 ° C below Reflux conditions such as toluene, xylene, trimethylbenzenes, Ethylbenzene and dioxane. These solvents can  serve either as a solvent or as a suspending agent. The reaction is preferably carried out at a temperature which between 100 ° C and the boiling point of the optionally solvent or suspending agent present lies. The reaction time is under the conditions mentioned generally 1 to 5 days. Once the reaction ends is the product of formula II, which is an N, N-dimethyl N ′ - (3,4-dihalophenyl) alkanediamine, obtained in the usual way, for example by extraction of the diamine of the formula II in the form of the free base with an organic, with water insoluble solvents, such as ether, Benzene or toluene. Furthermore, the compound of formula II can also be obtained in the form of the salt, for example as hydrochloride, which is then acidified in an aqueous Phase is present. The compound of formula II can after usual working procedures can be cleaned, for example by additional extractions, by chromatography or by recrystallization. This compound can also act as a salt are obtained, for example in the form of the hydrochloride.

The compounds of formula II can in the usual Be acylated, for example by implementing the Compound of formula II with a corresponding active Acid derivative, for example an acid halide, such as the chloride, bromide or anhydride of propionic acid, acrylic acid or cyclopropanecarboxylic acid. As a special An example is propionic anhydride. If you have one Acyl halide used, then one should be convenient Base, such as triethylamine, methyldiethylamine or N- Methyl piperidine can be added. The implementation is generally with the acid halide and a Base or with the acid anhydride and generally a solvent, such as methylene chloride, chloroform,  Tetrahydrofuran or dioxane performed. The response time is in the range of 1 to 8 hours at room temperature. If you use propionic anhydride then you need one for 2 to 24 hours at a temperature in the range is from 75 to 100 ° C, and for this purpose in general a water bath or steam bath is used. As soon as the reaction is complete, the compound of formula III is isolated in the form of the free base or its acid addition salt, and by adding acid to the mixture and with water extracted. The product obtained can then be recrystallized can be further cleaned and there can be further extraction processes or chromatography methods can be used. The compounds of formula III or their acid addition salts can also be in the crystalline state in the form of solvates be isolated, for example with a certain amount of solvents such as water or ethanol. This solvent is physical bound and accordingly removable without an essential Change in the chemical structure in and of itself takes place.

The invention is now based on the following examples explained in more detail.

Example 1 a) Preparation of N, N-dimethyl-N ′ - (3,4-dichlorophenyl) - ethylenediamine and the corresponding dihydrochloride.

A solution of 71.7 g (0.44 mol) of the 3,4-dichloroaniline and 23.8 g (0.22 mol) of 1-chloro-2-dimethylaminoethane are heated on a boiling water bath for 72 hours. The 1-chloro-2-dimethylaminoethane used in the starting product is obtained from its acid addition salt with hydrochloric acid by neutralization and distillation. The mixture is then treated with 200 ml of a 20 percent aqueous sodium hydroxide solution and extracted with ether. The ethereal layer is then washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness. Then distilled under reduced pressure (boiling point 128 to 135 ° C at 0.1 mm Hg) while 50.6 g of a mixture of the 3,4-dichloroaniline and the desired product, namely the N, N-dimethyl-N ' - (3,4-dichlorophenyl) ethylenediamine. The mixture is chromatographed using 500 g of silica gel and eluted with chloroform in 1000 ml fractions. Fractions 1 to 11 contain 44.4 g of 3,4-dichloroaniline. A further elution with 3000 ml of chloroform containing 20% methanol gives 4.4 g of the N, N-dimethyl-N '- (3,4-dichlorophenyl) ethylenediamine in the form of an oil. The hydrochloride of N, N-dimethyl-N '- (3,4-dichlorophenyl) ethylenediamine is prepared by reacting the oil with an excess of an ethereal hydrochloric acid solution and this hydrochloride is then recrystallized from a mixture of methanol and ether, whereby 4.2 (6.2% of theory) on the dihydrochloride of N, N-dimethyl-N '- (3,4-dichlorophenyl) ethylenediamine, which gave a melting point of 151 to 153 ° C. The elementary analysis gave the following values:
calculated for C₁₀H₁₄CL₂N₂ · 2 HCl · ½ CH₃OH:
C 39.25; H 5.63; Cl 44.03; N 8.70;
found:
C 39.58; H 5.51; Cl 44.03; N 9.06.

If you get this product dihydrochloride, which is a methanol solvate, in vacuum for 72 hours heated long at 80 °, then you get the pure unsolvated Dihydrochloride.

This dihydrochloride is then mixed with aqueous sodium carbonate treated until it's about neutral, and the mixture is then extracted twice with ether and the ether evaporated, the free base, namely the N, N-dimethyl N '- (3,4-dichlorophenyl) ethylenediamine is obtained.

b) Preparation of N- [2- (dimethylamino) ethyl] -3 ′, 4′-dichloropropionanilide and his maleates

There are 2.60 g (0.028 mol) of propionyl chloride during over a period of 30 minutes to a solution of 2.84 g (0.028 mol) of triethylamine and 3.26 g (0.024 mol) N, N-Dimethyl-N '- (3,4-dichlorophenyl) ethylenediamine in 100 ml Given methylene chloride. After 4 hours, add 100 ml saturated aqueous sodium bicarbonate. The organic Layer is then washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and evaporated, giving a yellow oil. The acid addition salt with the maleic acid is then prepared by mixing with 1.62 g (0.014 mol) of maleic acid in a mixture of methanol and ether and then from a mixture of Ethanol and water recrystallized.

The elementary analysis gave the following results:
calculated for C₁₃H₁₈Cl₂N₂O C₄H₄O₄:
C 50.39; H 5.47; Cl 17.50; N 6.91;
found:
C 50; 15; H 5.46; Cl 17.56; N 6.82.

If you add the salt of maleic acid with aqueous Treated sodium hydroxide and extracted the mixture with ether and evaporates, then the ether layer provides the corresponding free base, namely N - [(2-dimethylamino) ethyl] - 3 ′, 4′-dichloropropionanilide.

If you take this free base with hydrochloric acid treated in ether, then you get the hydrochloride of N - [(2-dimethylamino) ethyl] -3 ′, 4′-dichloropropionanilides.

Example 2 a) Preparation of N, N-dimethyl-N ′ - (3,4-dichlorophenyl) trimethylene 1,3-diamine and its dihydrochloride

A mixture of 60.8 g (0.38 mol) of 3,4-dichloroaniline and 39.5 g (0.25 mol) of 1-chloro-3-dimethylaminopropane Hydrochloride and 53.0 g (0.50 mol) sodium carbonate in 250 ml Toluene is boiled under reflux conditions for 72 hours. Then there you add water and the organic layer that forms washed with water and with 10 percent hydrochloric acid shaken out. Then the separated acid phase washed with ether, with the addition of 40 percent sodium hydroxide solution made basic and extracted with ether. The obtained ether layer is with saturated sodium chloride solution washed, then over anhydrous magnesium sulfate dried and finally evaporated. You get it a crude oil, which is added to 100 g of silica gel in a sintered glass funnel  is chromatographed and eluted three times with 250 ml of chloroform and then with 700 ml of methanol. After evaporation of the methanol, 5.1 g of the N, N-Dimethyl-N ′ - (3,4-dichlorophenyl) trimethylene-1,3-diamine in Form of a brown oil. The hydrochloride is made by using an excess of ethereal hydrochloric acid treated and the product from methanol + ether recrystallized, 5.1 g of the dihydrochloride of N, N-Dimethyl-N ′ - (3,4-dichlorophenyl) trimethylene-1,3-diamines obtained, which has a melting point of 182 to 183 ° C.

The elementary analysis showed the following values:
calculated for C₁₁H₁₈Cl₂N₂ · 2 HCl:
C 41.27; H 5.67; Cl 44.31; N 8.75;
found:
C 41.63; H 5.74; Cl 43.92; N 8.73.

b) Preparation of the N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloropropionanilides and the corresponding hydrochloride.

A solution of 3.70 g (0.015 mol) of the after Process according to a) prepared N, N-dimethyl-N'- (3,4-dichlorophenyl) trimethylene-1,3-diamines and 20 ml propionic anhydride is heated on the boiling water bath overnight. Then add 100 ml of water and heat more For 30 minutes. The mixture is then cooled, under Use of a 20 percent aqueous sodium hydroxide solution made basic and extracted with ether. The ether layer is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then  evaporated to dryness to give a yellow oil. From this the hydrochloride is made by using it treated with an excess of ethereal hydrochloric acid and then the product from a mixture of Methanol and ether recrystallized. This gives 3.3 g of the hydrochloride of N - [(3-dimethylamino) propyl] -3 ′, 4′-dichloropropionanilides.

The elementary analysis gave the following results:
calculated for C₁₄H₂₀Cl₂N₂O · HCl:
C 49.50; H 6.23; Cl 31.31; N 8.25;
found:
C 49.59; H 6.31; Cl 31.61; N 8.52.

If the hydrochloride thus obtained with a treated aqueous sodium hydroxide solution, then with Extract ether and evaporate the ethereal layer to dryness, then you get the free base, namely the N- [3-dimethylamino) propyl] -3 ′, 4′-dichloropropionanilide.

Example 3 a) Preparation of N '- (3,4-dichlorophenyl) -N, N, 1-trimethylethylenediamine and N '- (3,4-dichlorophenyl) -N, N, 2-trimethylethylenediamine

A mixture of 16.2 g of 3,4-dichloroaniline as well 39.6 g (0.25 mol) of the hydrochloride of 2-chloro-1-dimethylaminopropanes and 26.5 g (0.25 mol) sodium carbonate, as well 21.1 g (0.25 mol) of sodium bicarbonate in 200 ml of toluene Heated on the boiling water bath for 72 hours. Then 250 ml of water are added to the reaction mixture and the mixture is separated  the organic phase. This is then evaporated in a vacuum, where 17 g of a mixture of the N ′, (3,4-dichlorophenyl) - N, N, 1-trimethylethylenediamine and the N ′ - (dichlorophenyl) -N, N, 2- trimethylätäthendiamin receives, this mixture also a contained a certain amount of unreacted starting material.

b) Preparation of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dichloropropionanilide and the corresponding hydrochloride

The one obtained by the method according to a) Mixture and 50 ml of propionic anhydride are 18 hours long heated on the boiling water bath. Then there 400 ml of water are added to the reaction mixture and the mixture is heated for another hour. The mixture is then under Use a 40 percent aqueous sodium hydroxide solution made basic and extracted with 500 ml ether. The ethereal extract is then washed with 200 ml of water and then you shake it out again by adding 200 ml an aqueous 10 percent hydrochloric acid solution was used. This second extract, the aqueous extract Phase, is washed with 250 ml of ether and then make the aqueous layer using a 40th percent aqueous sodium hydroxide solution basic and extracted with ether. The ether extracts obtained are included Washed 100 ml of saturated sodium chloride solution. Subsequently the ethereal layers over anhydrous magnesium sulfate dried and evaporated to dryness. Here remains an oily material that is created using 500 g of silica gel is chromatographed, using an eluent Ethyl acetate used. You get 200  Fractions of 20 ml each and contain the fractions 91 to 180 just a single component. These factions 91 up to 180 together give 6.5 g of a yellow after evaporation Oil. This oil is the free base, namely the N - [(2- Dimethylamino-1-methyl) ethyl] -3 ′, 4′-dichloroanilide.

The oil becomes ethereal with an excess Treated hydrochloric acid and the precipitated salt twice from a mixture of methanol and ether in one Volume ratio of 1:10 recrystallized. Thereby receives 5.6 g, corresponding to 16% of theory, of the hydrochloride des N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′-dichloropropionanilides, which has a melting point of 196-197 ° C.

The elementary analysis showed the following values:
calculated for C₁₄H₁₀N₂Cl₂O · HCl-H₂O:
C 47.10; H 5.87; N 7.84;
found:
C 47.45; H 5.99; N 7.91.

Example 4 Preparation of N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′- dichloropropionanilide

After in the procedure described in Example 3b elution of the free base from the chromatography column is complete, then continue using a Mixture of ethyl acetate and methanol in the ratio 9: 1 eluted. One collects fractions of 500 ml each. The Fractions 5 through 8 are combined and evaporated to give 2.2 g of a yellow oil  receives which the N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′- is dichloropropionanilide. This product is obtained then treated with 1 g oxalic acid in 20 ml methanol and 200 ml ether. It is then crystallized from a mixture of methanol + Ether and thereby receives 2.3 g (6% of theory) the oxalate of N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′-dichloropropionanilides, which has a melting point of 183 ° C.

The elementary analysis showed the following values:
calculated for C₁₄H₂₀N₂Cl₂O · C₂H₂O₄:
C 48.86; H 5.64; N 7.12; Cl 18.03;
found:
C 49.04; H 5.63; N 7.31; Cl 18.30.

This oxalate is mixed with aqueous sodium hydroxide solution treated and the aqueous mixture extracted with ether, the ether layer separated and with gaseous hydrogen chloride treated, using the hydrochloride salt of the N- [(2-Dimethylamino-2-methyl) ethyl] -3 ′, 4′-dichloropropionanilides receives.

Example 5 Preparation of N - [(3-Dimethylamino-2-methyl) propyl] - 3 ′, 4′-dichloropropionanilide a) Preparation of the N '- (3,4-dichlorophenyl) -N, N, 2-trimethylpropane-1,3-diamines

43 g (0.75 mol) of the hydrochloride of 1-chloro 2-methyl-3- (dimethylamino) propanes were mixed with 25 ml of a 40 percent aqueous sodium hydroxide solution in 250 ml ether  heated. 16 g (0.10 mol) of 3,4- Dichloraniline. The ether was then removed by distillation and the mixture on the boiling water bath for 72 hours heated. The mixture was then 200 ml a 20 percent aqueous sodium hydroxide solution and they were treated on the boiling water bath for 1 hour and then extracted using 250 ml of ether. The ether extracts were over anhydrous magnesium sulfate dried and then evaporated, leaving an oil received. The black oil thus obtained is suctioned off filtered through 200 g of silicon dioxide, with methylene chloride eluted until no more material was washed out could be. The filtrate thus obtained becomes dry evaporated, the N- (3,4-dichlorophenyl) -N, N, 2-trimethylpropane 1,3-diamine in the form of an orange colored oil receives.

b) Preparation of N - [(3-dimethylamino-2-methyl) propyl] - 3 ′, 4′-dichloropropionanilide

The orange colored oil that after the one described above Process step a) was obtained with 25 ml of propionic anhydride treated and it was heated on the boiling Water bath for 20 hours. Then you gave Add 100 ml of water to the reaction mixture. The mixture was then basic using a 40 percent aqueous sodium hydroxide solution put, extracted with 250 ml ether, the Extracts washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to dryness. The base was obtained, namely the N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′-dichloropropionanilide. The free base thus obtained is converted into the corresponding one Hydrochloride salt transferred by adding an excess  ethereal hydrogen chloride used. The connection was made then from a mixture of methanol + ether in volume ratio 1:12 recrystallized, and 2.8 g was obtained on the hydrochloride of N - [(3-dimethylamino-2-methyl) propyl] - 3 ′, 4′-dichloropropionanilides, which has a melting point of 209-210 ° C. The yield corresponded to 8% of theory.

The elementary analysis gave the following values:
calculated for C₁₅H₂₂N₂Cl₂O · HCl:
C 50.93; H 6.55; N 7.92; Cl 30.07;
found:
C 51.16; H 6.51; N 8.10; Cl 30.07.

Example 6 Preparation of N - [(2-dimethylamino) ethyl] -3 ′, 4′-dibromopropionanilide

In the manner described in Example 1a) Mixture of 3,4-dibromaniline and 1-chloro-2-dimethylaminoethane heated to 90 to 100 ° C for 72 hours, wherein which received N, N-dimethyl-N- (3,4-dibromophenyl) ethylenediamine.

In the manner described in Example 16, a solution of N, N-dimethyl-N '- (3,4-dibromophenyl) ethylenediamine and triethylamine added the propionyl chloride, where in this reaction, the product N- [2- (dimethylamino) ethyl] - 3 ', 4'-dibromopropionanilide obtained.

Example 7 Preparation of N- [3- (dimethylamino) propyl] -3 ′, 4′-dibromopropionanilide

According to the working procedure described in example 1a) a mixture of 3,4-dibromaniline and 1-chloro 3-dimethylaminopropane heated at 90 to 100 ° C for 72 hours, where the product is N, N-dimethyl-N ′ - (3,4-dibromophenyl) - trimethylene-1,3-diamine was obtained.

To a solution of N, N-dimethyl-N ′ - (3,4-dibromophenyl) Trimethylene-1,3-diamine and triethylamine are added the working method propionyl chloride described in Example 1b) and then receives the product N- [3- (dimethylamino) propyl] -3 ′, 4′-dibromopropionanilide.

Example 8 Preparation of N- [3- (dimethylamino) propyl] -3 ′, 4′-dibromocyclopropanecarboxanilide

According to the working procedure described in example 1a) The 3,4-dibromaniline and the hydrochloride of the 1-chloro-3-dimethylaminopropanes and sodium bicarbonate in Toluene heated, the product being N, N-dimethyl- (3,4- dibromophenyl) trimethylene diamine.

The diamine so produced was then blended with the chloride the cyclopropanecarboxylic acid in the presence of triethylamine implemented, in a similar manner to that in Example 1b) is described. You get the corresponding product N- [3- (Dimethylamino) propyl] -3 ′, 4′-dibromocyclopropanecarboxanilide.

When treating this anilide with hydrochloric acid in ether then the hydrochloride of the N- [3- (Dimethylaminopropyl)] - 3 ', 4'-dibromocyclopropanecarboxanilides.  

Example 9 Preparation of N- [2- (dimethylamino) ethyl] -3 ′, 4′-dichloroacrylanilide

According to the procedure described in Example 1a) 3,4-dichloroaniline, the hydrochloride of 1-chloro-2-dimethylaminoethane as well as sodium bicarbonate, and one received the product N, N-dimethyl-N ′ - (3,4-dichlorophenyl) ethylenediamine.

The diamine thus obtained was then treated with the acid chloride similar to acrylic acid in the presence of triethylamine Implemented as described in Example 1b). The product obtained is the corresponding N- [2- (dimethylamino) ethyl] - 3 ', 4'-dichloroacrylanilide.

When treating this anilide with hydrochloric acid the hydrochloride of N- [2- (Dimethylamino) ethyl] -3 ′, 4′-dichloroacrylanilides.

Example 10 Preparation of N - [(3-Dimethylamino-2-methyl) propyl] - 3 ′, 4′-dibromopropionanilide

According to the working procedure described in Example 5a) 3,4-Dibromaniline and the hydrochloride were combined des 1-chloro-2-methyl-3-dimethylaminopropanes and sodium hydroxide heated, the product being the N ′ - (3,4-dibromophenyl) - N, N, 2-trimethylpropylene-1,3-diamine was obtained.  

If this diamine is present with the propionyl chloride was treated in a similar way by triethylamine, as described in Example 1b), then is obtained as Product the corresponding N - [(3-dimethylamino-2-methyl) propyl] - 3 ′, 4′-dibromopropionanilide.

This anilide thus obtained was then added Hydrochloric acid treated in ether, using as a product the corresponding hydrochloride of N- [3- (dimethylamino- 2-methyl) propyl] -3 ′, 4′-dibromopropionanilides.

Example 11 Preparation of N - [(3-Dimethylamino-2-methyl) propyl] - 3 ′, 4′.dibromocyclopropanecarboxanilide

According to the procedure described in Example 3a) 3,4-dibromaniline, the hydrochloride of 3-chloro-2-methyl 1-dimethylaminopropanes and sodium carbonate in toluene heated together, the product being the N ′ - (3,4-dibromophenyl) - N, N, 2-trimethylpropane-1,3-diamine was obtained.

Then this diamine with the cyclopropanecarboxylic acid chloride in the presence of triethylamine in a similar way Implemented as described in Example 1b). Man received the product N - [(3-dimethylamino-2-methyl) - propyl] -3 ′, 4′-dibromocyclopropanecarboxanilide.

The anilide so produced was then treated with hydrochloric acid treated in ether, being a product the corresponding hydrochloride of N - [(3-dimethylamino-2- methyl) propyl] -3 ′, 4′-dibromocyclopropanecarboxanilides.  

Example 12 Preparation of N - [(3-Dimethylamino-2-methyl) propyl] - 3 ', 4'-dibromoacrylic anilide

According to the procedure described in Example 3a) 3,4-dibromaniline, the hydrochloride of 1-chloro-2-methyl 3-dimethylaminopropanes as well as sodium carbonate and sodium bicarbonate heated in toluene, the product being N- (3,4-dibromophenyl) - N, N, 2-trimethylpropane-1,3-diamine was obtained.

If you compare this diamine with the acrylic acid chloride in the presence of triethylamine in a similar manner implemented, as described in Example 1b), then obtained the product is N - [(3-dimethylamine-2-methyl) propyl] -3 ′, 4′- dibromoacrylic anilide.

The anilide so produced was then treated with hydrochloric acid treated in ether, the product being the Hydrochloride of N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′- received dibromoacrylanilides.

Example 13 Preparation of N- [2- (dimethylamino) ethyl] -3 ′, 4′-dichlor cyclopropanecarboxanilide

According to the manufacturing process described in Example 3a) 3,4-dichloroaniline, the hydrochloride of 1-chloro-2-dimethylaminoethane and sodium carbonate in toluene heated, and the product obtained was the corresponding N, N- Dimethyl-N ′ - (3,4-dichlorophenyl) ethylenediamine.  

This diamine thus obtained was then used the cyclopropanecarboxylic acid chloride in the presence of triethylamine implemented in a similar manner as described in Example 2 is. The product obtained was N - [(2-dimethylamino) ethyl] - 3 ′, 4′-dichlorocyclopropanecarboxanilide.

The anilide thus obtained was then treated with hydrochloric acid treated in ether, taking the appropriate Hydrochloride of N - [(2-dimethylamino) ethyl] -3 ′, 4′-dichlorocyclopropanecarboxanilides won.

Example 14 Preparation of N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloroacrylanilide

According to the working procedure described in example 2a) 3,4-dichloroaniline, the hydrochloride of 1- Chloro-3-dimethylaminopropanes and sodium carbonate in toluene heated together, the product being the N, N-dimethyl N '- (3,4-dichlorophenyl) propylene-1,3-diamine was obtained.

Then this diamine thus produced with the acrylic acid chloride in the presence of triethylamine heated in a similar manner as described in Example 1b) , the product being the corresponding N - [(3-dimethylamino) propyl] - 3 ', 4'-dichloroacrylanilide was obtained.

The anilide thus obtained was then treated with hydrochloric acid treated in ether and so in the corresponding Hydrochloride of N - [(3-dimethylamino) propyl] -3 ′, 4′-dichloroacrylanilides transferred.  

Example 15 Preparation of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dichloroacrylanilide and the corresponding hydrochloride and of N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′-dichloroacrylanilide and the corresponding hydrochloride

After a working procedure similar to that in example 3b) described method, was the mixture of compounds obtained by the process according to Example 3a) with the acrylic acid chloride in the presence of Triethylamine treated. Then water was added, the mixture made basic with sodium hydroxide and the aqueous Phase extracted with ether. The separated ethereal Extracts were washed with water and with 10 percent  Hydrochloric acid extracted. The hydrochloric acid Extracts were then washed with ether, the ether discarded and the watery one thus purified Solution made basic using sodium hydroxide. Then the basic solution was extracted again with ether, washed the ether layer and then to Evaporated dry. The product so obtained was on silica gel chromatographed, with ethyl acetate as the eluent has been used. The product obtained was N - [(2-dimethylamino 1-methyl) ethyl] -3 ′, 4′-dichloroacrylanilide.

The product so obtained then became ethereal Hydrochloric acid treated, taking the hydrochloride des N - [(2-dimethylamino-1-methyl) ethyl] -3,4-dichloroacrylanilide received.

The chromatography column was then used for recovery des N - [(2-dimethylamino-1-methyl) ethyl] -3,4-dichloroacrylanilide extraction performed further extracted, using a mixture of ethyl acetate + Methanol. The extract obtained the N- [(2-Dimethylamino-2-methyl) ethyl] -3 ′, 4′-dichloroacrylanilide. This product was then made using an ethereal Solution of hydrochloric acid in the corresponding hydrochloride converted.

Example 16 Preparation of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dichlorocyclopropanecarboxanilide, the hydrochloride of this compound and of N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′- dichlorocyclopropanecarboxanilide and the corresponding hydrochloride

According to the working procedure described in example 3b) was the mixture of the compounds that after the in Example 3a) was obtained with the Acid chloride of cyclopropanecarboxylic acid and triethylamine treated. Then water was added, the mixture made basic with sodium hydroxide and extracted with ether. The ethereal extracts were washed with water and then extracted with 10 percent hydrochloric acid. The hydrochloric acid extracts thus obtained were washed with ether, discarded ether layers and then the obtained aqueous solution using Sodium hydroxide made basic and extracted again with ether. The separated ether layers were initially with Washed water, then evaporated to dryness and the residue chromatographed on silica gel, using as eluent Ethyl acetate was used. One eluted from the column the N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dichlorocyclopropanecarboxanilide.

The connection thus obtained became ethereal Hydrochloric acid treated, taking the hydrochloride des N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′-dichlorocyclopropanecarboxane-ilides could win.

The one remaining after the extraction described above Silica gel column is then further extracted by as a mixture of ethyl acetate and methanol Eluent used. The N - [(2-dimethylamino- 2-methyl) ethyl] -3 ′, 4′-dichlorocyclopropanecarboxanilide. This product can be converted into the corresponding hydrochloride by using an ethereal solution of Hydrochloric acid treated.  

Example 17 Preparation of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dibromopropionanilide and the hydrochloride of this compound and also of N - [(2-dimethylamino-2-methyl) ethyl] - 3 ', 4'-dibromopropionanilide and the corresponding hydrochloride. a) Preparation of a mixture of N ′ - (3,4-dibromophenyl) -N, N, 1- trimethylethylenediamine and N '- (3,4-dibromophenyl) -N, N, 2-trimethylethylenediamine

According to the Arbeitsver driving was a mixture of 3,4-dibromaniline and that Hydrochloride of 2-chloro-1-dimethylaminopropanes and sodium carbonate and sodium bicarbonate in toluene for 72 hours heated on the boiling water bath. Then What water added to the mixture, and the organic phase removed separates and then evaporated to dryness, being a Pro produces a mixture of the N- (3,4-dibromophenyl) -N, N, 1-trime ethyl ethylenediamine and the N- (3,4-dibromophenyl) -N, N, 2-trimethyl received ethylenediamine.

b) According to the procedure described in Example 3b) the mixture of the compounds which according to a) was obtained with the anhydride Treated propionic acid. Then you put water to, the mixture was made using sodium hydroxide basic and extracted them with ether. The severed essential extracts were washed with water and then with 10% hydrochloric acid extracted. The so won Hydrochloric acid extracts were then made with ether washed, the ether layers discarded and the aqueous Solution was then made using sodium hydroxide made basic and extracted again with ether. After this Wash the ethereal solution and evaporate the residue chromatographed on silica gel, using as eluent Ethyl acetate is used. You win from the Eluate the N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′-dibromopropionanilide.

Then the compound thus obtained treated with ethereal hydrochloric acid, whereby one the product is the hydrochloride of N - [(2-dimethylamino-1-methyl) - ethyl] -3 ′, 4′-dibromopropionanilides was obtained.

The silica gel column remaining after the first extraction is then mixed with a mixture of ethyl acetate and methanol further extracted, whereby the N - [(2-dimethylamino- 2-methyl) ethyl] -3 ', 4'-dibromopropionanilide.  

This compound can be treated with an etheric Solution of hydrochloric acid in the corresponding hydrochloride being transformed.

Example 18 Preparation of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dibromoacrylanilide and the corresponding hydrochloride, and of N - [(2-dimethylamino-2-methyl) ethyl] -3 ', 4'-dibromoacrylanide and the hydrochloride of this compound

According to the manufacturing process described in Example 3b) was obtained by the method according to Example 17a) Mixture of compounds with the acrylic acid chloride and treated with triethylamine. Then you went to the Reaction mixture water and made the mixture using of sodium hydroxide basic and finally extracted with ether. The separated ether extracts were with Washed water and then using 10 percent Hydrochloric acid extracted. The hydrochloric acid Extracts were then made with ether washed, the ether layers obtained thereby discarded and then the aqueous solution was purified using Sodium hydroxide made basic and extracted with ether. The ether layers obtained were first washed and then evaporated to dryness. The residue obtained was chromatographed on silica gel using ethyl acetate was used as eluent. It was N - [(2-Dimethylamino-1-methyl) ethyl] -3 ′, 4′-dibromoacrylanilide eluted.

The compound so obtained became ethereal Treated hydrochloric acid, and you got it  Hydrochloride of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dibromoacrylanilides.

The silica gel column remaining after the first elution was then continued using ethyl acetate + Extracted methanol as eluent. You got the N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′- dibromoacrylic anilide. This connection can be implemented by using an ethereal solution of hydrochloric acid in the corresponding Hydrochloride can be converted.

Example 19 Preparation of N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′- dibromocyclopropanecarboxanilide and the corresponding hydrochloride, and also of N - [(2-dimethylamino-2-methyl) ethyl] - 3 ′, 4′-dibromocyclopropanecarboxanilide and the hydrochloride this connection

According to the working procedure described in example 3b) was obtained by the method according to Example 17a) Mixture of compounds with cyclopropanecarboxylic acid chloride and treated with triethylamine. Then it became water added, and the mixture using sodium hydroxide made basic and then extracted with ether. The so obtained ether extracts were washed with water and then extracted with 10 percent hydrochloric acid. The received Hydrochloric acid extracts were washed with ether and discarded the layers of ether. Then the aqueous layer was made using sodium hydroxide made basic and extracted again with ether. The ethereal solutions were washed first and then evaporated to dryness and the residue on silica gel,  using ethyl acetate as eluent, chromatographed. The N - [(2-dimethylamino- 1-methyl) ethyl] -3 ′, 4′-dibromocyclopropanecarboxanilide.

The anilide thus obtained was then treated with an ethereal Hydrochloric acid treated, being a product the hydrochloride of N - [(2-dimethylamino-1-methyl) ethyl] -3,4- dibromocyclopropanecarboxanilides.

The silica gel column left after the first elution was then using a mixture of ethyl acetate + Methanol extracted as eluent, and thereby the N - [(2-dimethylamino-2-methyl) - was obtained ethyl] -3 ′, 4′-dibromocyclopropanecarboxanilide. This product was made using an ethereal solution of hydrochloric acid converted into the corresponding hydrochloride.

Example 20 Preparation of N- [5- (dimethylamino) pentyl] -3 ′, 4′-dichloropropionanilide and the corresponding hydrochloride

A solution of 57.6 g (1.28 mol) of dimethylamine in 500 ml of ether is cooled in an ice bath. About this solution 50.0 g (0.32 Mol) of 5-chloro-valeric acid chloride (5-chloro-valeryl chloride) in 50 ml ether and slowly add 100 ml after this time Water at. Then the organic layer is separated, with 100 ml of an aqueous saturated sodium bicarbonate solution washed and over anhydrous magnesium sulfate dried. The mixture was then evaporated to give  41.5 g of 5-chloro-valeryl-N, N-dimethylamide in the form of a yellow oil. This corresponds to a yield of 79% of theory.

The oil thus obtained is mixed with a suspension of 40.5 g (0.25 mol) of 3,4-dichloroaniline and 1.0 g of potassium iodide combined in 250 ml of dimethylformamide and the mixture is heated For 16 hours under reflux conditions. Then the Pour the mixture into 1500 ml of water and then set 100 ml of a 20 percent aqueous sodium hydroxide solution to, causing the pH of the total amount of 1600 ml to be around 8 comes to rest.

A precipitate is formed, which is filtered off and washed with water. Then crystallize twice from ether and thus receives 16.7 g of the 5- (3 ′, 4′-dichloroanilino) - N, N-dimethylvaleramide, which has a melting point of Had 114 ° C. The yield achieved corresponds to 23% of theory.

The following values were found in the elementary analysis:
calculated for C₁₃H₁₈N₂Cl₂O:
C 53.99; H 6.27; N 9.69; Cl 24.52;
found:
C 53.65; H 6.28; N 9.45; Cl 24.41.

To a solution of 14.5 g (0.05 mol) of the 5- (3 ′, 4′-dichloroanilino) -N, N-dimethylvaleramide in 200 ml tetrahydrofuran, which was cooled to -5 ° C, 200 ml was added Borane solution in tetrahydrofuran. The 200 ml of the borane solution contained 0.20 moles of borane. The mixture is then left overnight leave at room temperature and then boil for 2½ hours  long on a boiling water bath under reflux conditions received a milky suspension. It was added to this suspension slowly 100 ml of a 6 normal aqueous hydrochloric acid to. After about 30 minutes the gas evolution (nitrogen gas) stopped on. Then the mixture is distilled to give the tetrahydrofuran to remove and the remaining aqueous solution is washed with 200 ml ether. Then you do using 100 ml of a 40 percent aqueous sodium hydroxide solution the aqueous phase is basic and extracted then using 300 ml ether. The so won Ether extracts are made with saturated aqueous sodium chloride solution washed and then over anhydrous magnesium sulfate dried and finally evaporated to dryness, whereby 12.9 g of the N- (3 ′, 4′-dichlorophenyl) -N ′, N′-dimethyl-1,5- pentanediamine in the form of a yellow oil. The achieved Yield corresponds to 94% of theory.

Then 1 g of the oil thus obtained was added to the corresponding one Dihydrochloride is converted by mixing it with hydrochloric acid treated in ether. This gave 0.8 g on the dihydrochloride of N- (3 ′, 4′-dichlorophenyl) -N ′, N′-dimethyl- 1,5-pentanediamines, which has a decomposition melting point of 183 ° C. The yield corresponded to 63% of theory.

Elemental analysis of this dihydrochloride gave the following values:
calculated for C₁₃H₂₀N₂Cl₂ 2HCL:
C 44.84; H 6.37; N 8.05; Cl 40.74;
found:
C 44.96; H 6.27; N 8.04; Cl 41.22.

11.9 g (0.043 mol) of the oily N- (3,4-dichlorophenyl) - N ', N'-dimethyl-1,5-pentanediamines and 80 ml of propionic anhydride  were heated on the boiling water bath overnight. 250 ml of water were then added to the mixture thus obtained and heated for another 30 minutes. Then was the mixture using 150 ml of a 40 percent made aqueous sodium hydroxide solution and extracted with 200 ml ether. The ether extracts obtained in this way were treated with 100 ml of a saturated aqueous sodium chloride solution washed and then over anhydrous magnesium sulfate dried and finally evaporated to dryness, whereby the N- [5- (dimethylamino) pentyl] -3 ′, 4′-dichloropropionanilide in the form of a yellow oil.

The oxalate of the N- [5- (Dimethylamino) pentyl] -3 ′, 4′-dichloropropionanilide, by using oxalic acid in a mixture of 50 ml of methanol and 50 ml of ether treated. The oxalate thus obtained had a melting point from 166-167 ° C.

Elemental analysis of this oxalate gave the following values:
calculated for C₁₆H₂₄Cl₂N₂O · C₂H₂O₄:
C 51.31; H 6.22; N 6.65; Cl 16.83;
found:
C 51.74; H 6.24; N 6.64; Cl 17.14.

According to the working procedure described in example 4 this oxalate salt was converted into the corresponding hydrochloride salt converted.

Example 21 Preparation of N- [5- (dimethylamino) butyl] -3 ′, 4′-dichloropropionanilide and the corresponding hydrochloride.

The starting product was the N, N-dimethyl-4-chlorobutyramide used, the production of J. Falbe et al., in Chem. Ber. 97 2544 (1964). there has been a Solution of 30 g (0.2 mol) of the N, N-dimethyl-4-chlorobutyramide and 32.4 g (0.2 mol) of the 3,4-dichloroaniline and one Gram of potassium iodide in 250 ml of dimethylformamide and this mixture was heated under reflux conditions for 17 hours. The reaction mixture thus obtained was then used of 100 ml of a 20 percent aqueous sodium hydroxide solution made basic in 1500 ml of water. Precipitation falls from which is filtered off and then with 500 ml Ether is washed. This precipitate is then in 500 ml Dissolved methanol. If you get the solution concentrated to 200 ml 13.5 of a solid which is the 4- (3 ′, 4′-dichloroanilino) - Is N, N-dimethylbutyramide. This has one Melting point of 154-155 ° C.

The elementary analysis gave the following results:
calculated for C₁₂H₁₆Cl₂N₂O:
C 52.37; H 5.86; N 10.18; Cl 25.77;
found:
C 52.73; H 5.99; N 10.04; Cl 25.40.

According to the working procedure described in example 20 the 4- (3 ′, 4′-dichloroanilino) thus obtained is then N, N-dimethylbutyramide reduced with borane in tetrahydrofuran, where the product is N- (3 ', 4'-dichlorophenyl) -N'N'-dimethylbutane 1,4-diamine in the form of an oil.

The hydrochloride of this oil is made by to treat it with hydrogen chloride gas in ether. Man receives a dihydrochloride whose molecular weight is 334.14 is and which has a melting point of 200-201 ° C.  

The elementary analysis gave the following results:
calculated for C₁₂H₁₈N₂Cl₂ 2 HC:
C 43.13; H 6.03; N 8.39; Cl 42.45;
found:
C 43.62; H 6.15; N 8.91; Cl 42.07.

9.0 g of the N- (3 ′, 4′-dichlorophenyl) thus obtained - N'N'-dimethylbutane-1,4-diamines were mixed with 60 ml of propionic acid anhydride heated, the product being the N- [4- (Dimethylamino) butyl-3 ′, 4′-dichloropropionanilide in the form of an oil receives.

The oil obtained in this way is then mixed with hydrochloric acid treated in ether, giving 7.3 g of the hydrochloride des N- [4- (dimethylamino) butyl] -3 ′, 4′-propionanilide obtained, which has a melting point of 162-163 ° C. The yield corresponds to 63% of theory.

Elemental analysis of this hydrochloride gave the following values:
calculated for C₁₅H₂₂N₂Cl₂O HCl:
C 50.73; H 6.55: N 7.92: Cl 30.07;
found:
C 51.02; H 6.58; N 8.11; Cl 30.54.

According to those described in the previous examples Working methods can still make further connections which correspond to formula III.

Examples of compounds made in this way are as follows:
N - [(2-dimethylamino) ethyl] -3 ′, 4′-dibromoacrylanilide;
N - [(2-dimethylamino) ethyl] -3 ′, 4′-dibromocyclopropanecarboxanilide;
N - [(3-dimethylamino) propyl] -3 ′, 4′-dibromoacrylanilide;
N - [(3-dimethylamino) propyl] -3 ′, 4′-dichlorocyclopropanecarboxanilide;
N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′-dichloropropionanilide;
N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′-dichloroacrylanilide;
N - [(3-Dimethylamino-2-methyl) propyl] -3 ′, 4′-dichlorocyclopropanecarboxa-nilide.

If you consider these amino compounds mentioned above or those obtained by the methods described in the examples Amino compounds with stoichiometrically calculated amounts treated by pharmaceutically acceptable acids, then obtained the corresponding acid addition salts from the free amines with the pharmaceutically acceptable acids. Examples for such salts are the salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, the Sulfuric acid and phosphoric acid. Other salts are the Acetates, lactates, salts with malic acid (malates), the salts with maleic acid (Maleate), the salts of succinic acid (Succinate), the salts of tartaric acid (tartrate), the salts with citric acid (citrate) and the benzenesulfonates, the methanesulfonates and the sulfamates.  

Example 22

1002 pieces of hard gelatin capsules for oral administration were prepared, each 2.5 mg of the hydrochloride des N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloropropionanilides contained. These capsules contain those in the following Ingredients given in the table in the following concentrations:

When making the capsules, the corresponding ones were Amounts of the starting materials thoroughly together mixed and then encapsulated in the usual way. To People to fix depression were 1-2 capsules all Orally administered for 4 hours.

Capsules can also be produced in the same way be the 5 mg or 10 mg or 15 mg or 20 mg or 25 mg or contain 30 mg of the active ingredients, whereby also the same working procedures are used for this purpose can.

Example 23

There were 1000 tablets for oral administration made, each tablet 25 mg of the hydrochloride  des N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloropropionanilides contained. Each of the tablets contained the following Components listed in the table Concentrations:

The components listed were in the corresponding Proportions thoroughly mixed together, resulting in a mass. This mass was then broken up by pressing it through a No. 16 sieve. The the grains obtained were then pressed into tablets, each tablet containing 25 mg of the hydrochloride of N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloropropionanilides contained.

The tablets so made are useful around Treat depression in adult people, taking one Tablet is administered orally 1 to 3 times a day.

Example 24 Preparation of a syrup for oral administration

1000 ml of an aqueous suspension for oral administration, in which a dose unit of 5 ml each 10 mg on the hydrochloride of N- [2- (dimethylamino) ethyl] -3 ′, 4′-dichloropropionanilides was made by  the components listed in the following table in the specified proportions mixed.

In making this syrup, citric acid, benzoic acid, sucrose, tragacanth and the lemon oil is suspended in a sufficient amount of water, to get 850 ml of solution. Then you stirred that Hydrochloride of N- [2- (dimethylamino) ethyl] -3 ′, 4′-dichloropropionanilides into the syrup until a uniform distribution occurred. Then a sufficient amount of water added to achieve a total volume of 1000 ml.

The syrup so produced is useful for depression to treat in adult people, taking a dosage administered by a full teaspoon 4 times a day becomes.

Example 25 Preparation of a solution for parenteral administration

A sterile aqueous solution was made  which is suitable for intramuscular administration. These The solution contained 25 mg of the hydrochloride in 1 ml des N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloropropionanilides. The solution mentioned was carried out using the in ingredients specified in the sequence in the proportions mentioned produced:

The ingredients are dissolved in the water and sterilize the solution by filtration. The sterile solution is filled into vials and the vials are sealed.

Example 26 Suppositories for rectal administration

1000 suppositories are produced, whereby each of these suppositories weighs 2.0 g and 5 mg of the N - [(2-dimethylamino- 1-methyl) ethyl] -3 ', 4'-dichloropropionanilide contains. The Suppositories are made from the following ingredients:

In the preparation of this composition the N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′-dichloropropionanilide Hydrochloride added to the propylene glycol and the Mixture is ground until the powder is finely divided and uniform are dispersed. The polyethylene glycol 4000 is melted and the propylene dispersion becomes slow with stirring added. The suspension comes in non-refrigerated forms 40 ° C filled. Then the mixture is allowed to cool and solidify and remove them from the mold. Every so won Suppository is then wrapped in foil.

The suppositories described above are suitable for Prevent Depression by Rectally Supposing 1 Suppository introduces every 4 hours.

Example 27

Formulations were made by following the procedures described in Examples 22-26. However, the active components used there have now been replaced by an equimolar amount of the active compounds mentioned below:
N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′-dichloropropionanilide;
N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′-dichloropropionanilide;
N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′-dibromocyclopropanecarboxane ilide;
N - [(3-dimethylamino-2-methyl) propyl] -3 ′, 4′-dibromoacrylanilide;
N - [(3-dimethylamino-1-methyl) propyl] -3 ′, 4′-dibromoacrylanilide;
N- [3-dimethylamino-1-methyl) propyl] -3 ′, 4′-dibromocyclopropanecarboxanide;
N- [2- (dimethylamino) ethyl] -3 ′, 4′-dibromopropionanilide:
N- [3-dimethylamino) propyl] -3 ′, 4′-dibromopropionanilide;
N - [(2- (dimethylamino-1-methyl) ethyl] -3 ′, 4′dichloroacrylanilide;
N - [(2-methylamino-2-methyl) ethyl] -3 ′, 4′-dichloroacrylanilide.

The above compounds can be in the form of free base or in the form of the hydrochloride, hydrobromide, sulfate, Tartrates, lactates, citrates, methanesulfonates, maleates, Malates or sulfamates of the free Bases are used.

Claims (7)

1. Aminoamides of the general formula III:

• where: A represents a remainder of the formulas X a chlorine or a bromine atom and pure ethyl, cyclopropyl or vinyl radicals of which pharmacologically acceptable acid addition salts.

2. N- [2- (dimethylamino) ethyl] -3 ′, 4′-dichloropropionanilide and its hydrochloride 3. N- [3- (dimethylamino) propyl] -3 ′, 4′-dichloropropionanilide and its hydrochloride 4. N - [(2-dimethylamino-2-methyl) ethyl] -3 ′, 4′-dichloropropion anilide and its hydrochloride.   5. N - [(2-dimethylamino-1-methyl) ethyl] -3 ′, 4′-dichloropropionanilide and its hydrochloride 6. A process for the preparation of aminomamides according to claim 1, characterized in that an aniline of the general formula I wherein X has the meaning given in claim 1, either a) with a halogen-containing amino compound of the general formula: where A for a remainder of the formulas: and X 'represents a chlorine, bromine or iodine atom, to a diamine of the general formula II implements
or b) with a compound of the general formula wherein n = 3 or 4 and X 'represents a chlorine, bromine or iodine atom to a compound of formula V. wherein X and n have the meaning given, and reacted with a metal hydride to give a diamine of the general formula VI wherein A is a - (CH₂) ₄- or - (CH₂) ₅ radical and X has the meaning given, reduced
and the diamines obtained of the general formulas II or VI are acylated in the presence of a base with propionic anhydride or the chloride or bromide of propionic, acrylic and / or cyclopropanecarboxylic acid. 7. Medicament with antidepressant effect, containing an effective amount of at least one aminoamide or a pharmacologically acceptable acid addition salt the same according to claims 1 to 5.