DE2751905A1 - AMINOAMIDES, METHOD OF MANUFACTURING AND USING THE SAME - Google Patents

Description

Henkel, Kern, Feiler Cr Hänzel THE UPJOHN COMPANY

Möhlstrasse 37 Kalamazoo, Michigan, D-8000 Munich 80

V - St. A. TeIj 089 / 982085-87

Telex: 0529802 hnkld Telegranrune: ellipsoid

Nov 21, \ m

Aminoamides, method for
Manufacture and use

the same

809823/0628

The present invention relates to new organic compounds and in particular to dimethylaminoalkyl-3 », 4 * -dihalogenanilida of the formula III, their pharmacologically acceptable acid addition salts and the use of these compounds of the formula III and their salts, and also synthetic processes for the preparation of the compounds of the formula III and of the corresponding salts.

The compounds of formula III and method too their manufacture can be explained using the following manufacturing processes:

Manufacturing process I

NAX ¹

Acylating agents

Il

y y

- 2

ι 8098237062 «

Horstolltingsverfabren II NH ₂

CH ₃

CH

₃ v ^ «

> NC (CHa) _n X

Il ^ CH:

HN -

η = 3 or

Reducing agent

HN-Ai-I

CH ₃ CH ₃

Acylating agents

CH ₃
CH ₃

VII

809823/0628

In the production processes given above, A ₀ denotes a grouping of the formulas

- (CH ₂ J ₂ -; - (CH ₂ ) S-; -CH ₂ -CH-; and -CH-CH ₂ -; -CH ₂ -CH-CH ₂ -;

• t I

CH ₃ CH ₃ CH ₃

and A _{Q is} a grouping of the formulas

or -

Furthermore, in the above formula scheme for the preparation process I and II, X represents a bromine atom or Represents chlorine atom; X 'is a chlorine atom, bromine atom or iodine atom, and R denotes an ethyl radical, a cyclopropyl radical or a vinyl residue.

Particularly preferred compounds made in this synthesis have the following formula IIIA

UiA

on in which

A is a group of the formulas - (CH ₂ J ₂ -; - (CH ₂ J ₃ - _; - (CH ₂ ) -

^xaaA - (CHj -; - tH _a -tH-; -CH-CH ₂ - or - CH ₂ -CH-CH ₂ -;

¹ I.

j; _a

¹ II

^CH 3 CH ₃ CH ₃

is and X is a bromine atom or a chlorine atom

Especially preferred compounds according to the invention have the following formula IIIB

COC ₂ H ₅

/ Ib

Ii IB

in which

Α »is an ethylene group of the formula -CH ₂ -CH ₂ - or a trimethylene group of the formula -CH ₂ -CH ₂ -CH ₂ -.

Compounds which have a structure similar to that of the invention are described in the US patent No. 3,016,281. However, the compounds mentioned in this patent act as analgesics, i.e. as pain relievers Means, while the compounds according to the invention, in contrast, have antidepressant activity.

In U.S. Patent No. 3,573,320, compounds having antidepressant effects described, but not claimed, having the following formula

have, in these compounds

B is a sulfur atom or an oxygen atom, R _{9 is} a grouping of the formula

-N <

«5

stands in which

η is 2 or 3,

R ^ denotes a hydrogen atom or an alkyl group,

809823/0628

2751905 or the grouping of the formula -N '

for a morpholino group, a piperidino group, a pyrrolidino group or a piperazino group stands, and

R, an alkyl radical, an aryl radical or a similar radical is.

In the USA patent no. 3, 2.'5k _t 276 and the French patent no. 2,073,286 (see also Chem. Abstracts 77fO31O3) similarly structured compounds are also described and claimed, but the compounds mentioned there are used for other purposes .

In none of the above-described references, however, is anything about the new according to the invention Substances with antidepressant effectiveness said.

If the compounds according to the invention Manufacturing process I, then it is expedient to proceed as follows:

1 hol equivalent of a 3 »4-dihaloaniline of the formula I. is with about 1 hol equivalent to 1 hol equivalent of a dimethylaminoalky! halide heated to obtain the compounds of formula II. If you have an excess of the compound of the formula I uses, then this is the base which is used to trap the hydrogen halide which is formed during the reaction. Subsequent the compound of formula II thus obtained is then aeylated, for example by adding an acid halide, for example an acid chloride or bromide of propionic acid, acrylic acid or cyclopropanecarboxylic acid is used, namely

809823/0628

ig

preferably in the presence of a base. Mim can do acylation but also with a corresponding acid anhydride, for example Propicnsäureanhydrid, carry out, and in this case too, the corresponding compounds are then obtained of formula IV

If one carries out the production process II according to the invention, then one proceeds with advantage as follows: 1 molar equivalent of 3, A-dibaloganiline is heated with about 1 molar equivalent of Ν, ίΙ-Dinethylamino-halogenbutterGäurearaid or N, N-dimethyl'-halo-valeric acid amide, where one in the implementation of the compounds of formula V receives. These compounds of the formula V are then reduced, for example using a metal hydride des, whereby the compounds of the formula VI are obtained. These compounds of the formula VI are then acylated with formation of the compounds of the formula VII.

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

A further subject matter of the present invention are pharmaceutically acceptable acid addition salts of the compounds of the formula III including the salts of the preferred compounds of the formulas IHA and IHB. Examples of such salts are: hydrochlorides, hydrobromido, sulfates, halates (salts of malic acid), maleates (salts of maleic acid), tartrates, lactates, citrates, cyclohexanesulfamates, methanesulfonates and älinliciie salts. These salts can be prepared by reacting the compounds of the formula III with a stoichiometrically calculated amount of the corresponding acid, for example in aqueous

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Solution or ethereal solution, and finally the solvent evaporates

The present invention also relates to the use of the compounds of the formula III and their salts in pharmaceutical formulations for the treatment of depression of an endogenous character and exogenous character.

The compounds of the formula III were tested for their antidepressant effectiveness according to standard test procedures tested, which are described in more detail in the rim · <

_• The main effectiveness of an antidepressant agent is to restore the depressed creature to normal function. Jfan should distinguish very precisely between substances with an antidepressant effect and psychological stimulants, such as amphetamines, which lead to over-stimulation in a normal living being.

Many different methods have been used before and are still being used to provide an antidepressant Determine activity. In general, these methods consist in determining the counteraction, i.e. the antagonism, against an agent with a depressive effect, such as the Example reserpine or tetrabenazine, or in a synergistic increase in the toxicity of certain compounds, ' such as yohimbine or 3,4-dihydroxyphenylalanine, and also in a comparison of the effectiveness of the hays Compounds with other already known compounds with antidepressant activity. It is not possible with one single test alone to determine whether a new compound is an anti-doping agent or not, but through different tests one finally obtains an action profile,

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ZO

from which one can see whether the agents in question have antidepressant activity. A number of such Tests is now described below:

A) Hypothermic tests with oxotremorine, namely 1-14- (1-pyrrolidinyl) -2-butynyl-2-pyrrolidinone.

Like apomorphine and tetrabenazine, oxotremorine leads to a hypothermic reaction, i.e. to a body temperature below normal at Hausen. This effect can be achieved through anti-cholinergic effects Means, i.e. anticholinergics, i.e. drugs weakened by their effect choline-fed organs of success react to nerve impulses, as well as being blocked by means with antidepressant activity, such as ia with the help of atropine or imipramine.

Oxotremorine produces a very strong hypothermia which peaks 60 minutes after administration.

The working methodology is the following:

The compounds to be tested are injected intraperitoneally into 4 male mice from the Carworth Farm (CF-) group, and these mice are kept in plastic cages for 30 minutes / ere then in a refrigerator maintained at a temperature of 19 ⁰ C was added. A group of 4 mice of the above species were given saline by injection instead of the compound to be tested, and then 30 minutes later they were injected with the oxotremorine hydrochloride and refrigerated in the same way. 30 minutes after administration of the Oxotreuiorine, the body temperature of the mice is rectally with

CU

Using a thermistor probe determined · A rise of 2.2 ⁰ C (4 ° F) in the body temperature of the treated mice, namely that to which both the oxotremorine was administered compound to be tested as well, compared to the mice for comparison purposes that is, to which only the oxotremorine was administered, indicates that the tested compound has antidepressant activity.

B) Enhancement of the toxicity caused by yohimbine.

The LD50 ^{of YoilimD} in-Hydrochlorides in mice is 45 mg per kg body weight when administered intraperitoneally. If yohimbine hydrochloride is given in an amount of 20 mg per kg of body weight, then it is not lethal. If you first give an agent with antidepressant effectiveness and then yohimbine hydrochloride, the lethality is increased.

An 4 male mice (CF-Mäu3e) which had g a body weight of 18 to 22, was induced by injecting a Iienge of 20 mg per kg body weight of yohimbine hydrochloride in saline administered by injection, in a 3O ⁰ C chamber having . The number of deaths was determined after 2 hours. With this applied concentration of yohimbine hydrochloride, either no mouse at all or at most one mouse will have died.

If a compound with an antidepressant effect is injected 30 minutes before the administration of the yohimbine hydrochloride, the lethality of the yohimbine is increased. If three of the 4 mice die at a certain concentration of the compound to be tested, the test results obtained in this way are thinly evaluated as a positive indicator TMv

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275 190 $ '

considered the antidepressant effectiveness of the tested compound.

C) Apomorphine gnawing method.

To one group of h male mice, viz
CF-j mice weighing 18 to 22 g
the compound to be tested is administered intraperitoneally 1 hour before the subcutaneous injection of apoinorphine hydrochloride in an amount of 10 mg per kg. The mice are then placed individually in plastic boxes, while stereotypical gnawing is observed. If 3 or 4 of the mice show this behavior, then it is determined that the compound in question is active at the dosage used.

Those described in the examples below
Compounds were tested, and en showed that they
Have efficacies equal to or better than that
of previously commercially available substances with antidepressant activity, such as imipramin hydrochloride.

The pharmaceutical Verabreichungoformen the compounds of formula III and salts thereof which are the subject dor invention are pharmaceutical formulations comprising the orelen to oinor, parentsralen or rectal administration are suitable, such as tablets, Pulververpackungexi, lozenges, dragees, capsules, solutions, suspensions, , sterile injectable forms, suppositories, tube administrable compounds, or wax-incorporated formulations. Selenium mentioned as examples of suitable thinning agents or carrier materials: carbohydrates, lactose, sucrose, mannitol, proteins, lipoids, calcium phosphate, paint starch, stenic acid, methyl cellulose and the like. D.Leco materials

· ■) η 2 * / η κ 2 η

can either be used as carrier materials or for coating can be used. Water or oil, such as coconut oil, You can use sesame oil, safflower oil, cottonseed oil, and peanut oil for the production of solutions or suspensions for the active ingredient are used. Artificial sweeteners, colourants, and flavoring agents can be used also be added.

The compounds of the formula III and the preferred compounds according to the invention can be used as antidepressant agents of the formulas IIIA and HIB, as well as their pharmacological acceptable acid addition salts can be used in dosages ranging from 0.01 to 2 mg per kg of body weight depending on the specific vorwondeten Compound, weight, age and other condition of the individual or patient to be treated. Preferably dosages will be in the range of 0.05 to 1 mg per kg of body weight applied when using oral or injectable preparations such as those above have been described. With such dosages, the depressive states of the patients can then be remedied.

In the treatment of depression in humans, dosage units can be administered that range from 1.0 to Contain 30 mg of the active compound, and these Dcsierungseinheit can be given one to four times a day, depending on the body weight, age and condition of the patient, and depending on the particular compound of Foiinel III, to be applied. These dosage units can be administered orally or by injection, specifically subcutaneously or intravenous or intramuscular, and rectal administration is also possible.

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The for the preparation of the compounds according to the invention of the formula III required 3,4-dihaloanilines, in which the halogen atoms are Chloratoiae or Broin atoms known connections. In the same way they are with them chlorinated or brominated dimethy laininoalkane to be converted described in the literature.

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

In a preferred embodiment of the invention Process are the 3 »^ + - Dihalogenaniline in one Ratio of 1 to 2 molar equivalents per molar equivalent of the halodialkylaminoalkanes 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 a further basic compound is necessary to free the To release base. If the halogen-substituted aniline of the formula I is used in excess, then it serves as an additional one Base. However, inorganic eases, vie for example sodium bicarbonate or potassium bicarbonate or Carbonute has been used as an additionally attached base. Pauls carried out the reaction in the presence of solvents: v / ii'd, then q are typical preferred solvents those which reflux at a temperature of more than 85 ° C, such as for example toluene, xylene, trimethylbcnzolo, Ethylbenzene and dioxane. DioL'e solvents can

- 13 V.

2%

serve either as a solvent or as a suspending agent. The reaction is preferably carried out at a temperature which is between 100 ° C. and the boiling point of the solvent or suspending agent which may be present. The reaction time is generally 1 to 5 days under the conditions mentioned. As soon as the reaction has ended, the product of the formula II, which is an N, K-dimethyl · N ^f - (3 »^ - dihalogenophenyl) alkanediarain, is obtained in the customary manner, for example by extracting the diamine of the formula II in the form of free base with an organic, water-insoluble solvent, such as ether, benzene or toluene. Furthermore, the compound of the formula II can also be obtained in the form of the salt, for example as the hydrochloride, which is then present in an acidified aqueous phase. The compound of the formula II can be purified by customary working methods, for example by additional extractions, by chromatography or by recrystallization. This compound can also be obtained as a salt, for example in the form of the Hydrochloride ^.

The compounds of the formula II can be used in UbIichar Wise acylated, for example by reacting 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. Propionic anhydride may be mentioned as a specific example. If you have a Acyl halide used, then should expediently Base, such as, for example, triethylamine, methyldiethylarain, N-methylpiperidine or a similar one can be added. The reaction is generally carried out with the acid halide and one Base or with the acid anhydride and generally a solvent, such as methylene chloride, chloroform,

809821/0628

Tetrahydrofuran, Dtoxan or similar carried out. The reaction time is in the range of 1 to 8 hours at room temperature. If mon propionic anhydride is used, mail needs 2 to Zk hours at a temperature that is in Berti! oh is from 75 to 10O ⁰ C, and to this end a water bath or steam is generally used. As soon as the reaction is complete, the compound of the formula III is isolated in the form of the free base or its acid addition salt by adding acid to the mixture and extracting it with water. The product obtained can then be further purified by recrystallization and further extraction processes or chromatography processes can be used. The compounds of the formula III or their acid addition salts can also be isolated in the crystalline state in the form of solvates, for example with a certain amount of solvent, such as, for example, water, ethanol and similar solvents. This solvent is physically bound and can accordingly be removed without any significant change in the chemical structure taking place in and of itself.

The invention will now be explained in more detail with reference to the following examples, in which products according to the invention and Process for their production, as well as their application are described in more detail.

) \ JL A. £ ... H Jr, ff- \ 1

Horste Llung von HN-t Hriothyl-N'- p. ^ - dLchLorpheny L) - üth ylom iinmin and dos corresponding to en OUiYdr ochloridos.

A solution of 71.7 g (Q, hh mol) of the 3, A-dichloroniline and 2'5 _ψ ι \ g (0.22 Hol) i-chloro <2-dLmnthyianinoath: ii

- if)

verden on a boiling water bath for 72 hours. · heated. The 1-chloro-2-dimethylaminoethsn used in the starting product is obtained from its acid addition salt with the 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 it is distilled under reduced pressure (boiling point 128 to 135 ^° C. at 0.1 mm Hg) whereby 50.6 g of a mixture of 3, A-dichloroaniline and the desired product, namely N, N-dimethyl-N »- (3,4-dichlorophenyl) ethylenediawin, are obtained 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. With a further elution with 3000 ml of chloroform containing 20 % methanol is obtained 4.4 g of the N, N-Diinethyl-N '- (3 »4-dichlorophenylEthylenediamine in the form of an oil. The hydrochloride of N, N-Dimethy1-N ^f - (3» 4-dichlorophenyl) Ethylenediamines is produced by ma n the oil is reacted with an excess of an ethereal hydrochloric acid solution and this hydrochloride is then recrystallized from a mixture of methanol and ether, 4.2 (6.2 % of theory) of the dihydrochloride of N, N-dimethy IHN ¹ ^ - (3,4-dichlorophenyl) äthy lendiaiaines is obtained, which has a melting point of 151 to 153 ° C. The elemental analysis provided the following values:

calculated for C ₁₀ H ₁ ^ Cl ₂ N ₂ · 2 HCl · ^ CH ₃ OH:

C 39.25; H. 5.63; Cl. 44.03; H. 8.70 found: C. 39.58; H. 5.51; Cl. 44.03; N. 9, C6.

16 -

809823/0628

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

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

example

Production of N-Γ2- (Dimethylamine) äthvl 1-3.4'-dichloropropionanilide and its maleate (the salt with maleic acid).

2.60 g (0.028 Hol) of propionyl chloride are added over a period of 30 minutes to a solution of 2.84 g (0.026 mol) of triethylamine and 3.26 g (0.024 mol) of N, N-dimethyl-N ^t - (3,4-dichlorophenyl) ethylenediamine given in 100 al of methylene chloride. After 4 hours, 100 ml of saturated aqueous sodium bicarbonate are added. The organic layer is then washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give a yellow oil. The acid addition salt bit of maleic acid is then prepared by reacting with 1.62 g (0.014 mol) of maleic acid in a mixture of methanol and ether and then recrystallizing from a mixture of ethanol and water.

The elemental analysis provided the following results:

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door calculated C ₁₅ H ₁₈ Cl ₂ N ₂ OC ^ H ^ O ^:

C. 50.39; H. 5.47; Cl. 17.50; N. 6.91 found: C. 50.15; H. 5.46; Cl. 17.56; H. 6.82.

If the salt of maleic acid is treated with aqueous sodium hydroxide and the mixture is extracted with ether and evaporated, then the ether layer gives the corresponding free base, namely the N - [(2-dimethylamino) ethyl] -3 *, 4'-dichloropropionanilide.

When this free base is mixed with hydrochloric acid Treated in ether, the hydrochloride of N - [(2-dimethylamino) äthylJ-3 *, 4 * -dichloropropionanilide is obtained.

Example 3

Manufacture of NN-Dimethvl-N ^t - (3.4-dichlorophenyl) trimethvlene-1 «3-diamine and the dihydrochloride of this diamine.

A mixture of 60.8 g (0.38 mol) 3,4-dichloroaniline and 39.5 g (0.25 mol) i-chloro-3-dimethylaminopropane hydrochloride and 53.0 g (0.50 mol) sodium carbonate in 250 ml Toluene is refluxed for 72 hours. Then Vasser is added and the organic layer that forms is washed with water and extracted with 10 percent hydrochloric acid. Then the separated acidic phase washed with ether, made basic with the addition of 40 percent sodium hydroxide solution and extracted with ether. the The ether layer obtained is washed with saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and finally evaporated. A crude oil is obtained, which on 100 g of silica gel in a sintering

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3ο

Glass funnel is chromatographed, and it is eluted three times with 250 ml of chloroform and then with 700 ml of methanol. After the methanol has evaporated, 5.1 g of the N, N-dimethyl-N * - (3,4-dichlorophenyl) trimethylene-1,3-diamine are obtained in the form of a brown oil. The hydrochloride is prepared by treating with an excess of ethereal hydrochloric acid and recrystallizing the product from methanol + ether, 5.1 g of the dihydrochloride of N, N-dimethyl-N ¹ - (3 »4-dichlorophenyl) trimethylene -1,3-diamine is obtained having a melting point of 182-183 ⁰ C.

The elemental analysis gave the following values: calculated for C ₁₁ H ₁₈ Cl ₂ N ₂ - 2HCl:

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.

example

Preparation of N- [3- (Dimethylamlno) propvl1-3 ^l propionanilides and the corresponding hydrochloride.

A solution of 3.70 g (0.015 mol) of the N, N-dimethyl-N · - prepared by the method according to Example 3 (3,4-dichlorophenyl) trimethylene-1,3-diamines and 20 ml of propionic anhydride is heated on the boiling water bath overnight. Then 100 ml of water are added and more is heated For 30 minutes. The mixture is then cooled using 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

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evaporated to dryness, vobel aan receives a yellow oil. The hydrochloride is prepared from this by treating it with an excess of ethereal hydrochloric acid and then recrystallizing the product from a mixture of methanol and ether. This gives 3.3 g of the hydrochloride of H - [(3 ^ lJWthylaeino) propyl] -3 ^l , ^ '- di-

The elemental analysis provided the following results: calculated for

C 49.50; H · 6.23J Cl. 31 # 311 H. 8.25 found: C, 49.59 * H. 6.31) Cl. 31.61; H. 8.52.

If old an aqueous NatriuahydroxydlOsung treated aan the resulting hydrochloride, then extracted with ether and the ethereal layer is evaporated to dryness, then we obtain the free base, namely, the H - [(3-Dieethylamino) ^{propylj-3-liter,} 4 * Hlichlorproplo & anilide ·

example 5

Production of * - (3 «4 — dichlorophenYl) -1I« M «1 — triaethvl— ttthylendiaain.

A mixture of 16.2 g of 3,4-dichloroaniline as well 39.6 g t>, 25 mol) of the hydrochloride of 2-chloro-i-diaethylaminopropanes and 26.5 g (0.25 mol) of hatriu carbonate, and 21.1 g (0.25 mol) of sodium carbonate in 200 ml of toluene is used Heated for 72 hours on a boiling water bath. 250 ml of water are then added to the reaction mixture and the mixture is separated

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the organic phase. This is then evaporated in vacuo, 17 g of olner mixture of the N ¹ , (3 »4-dichlorophenyl) -N, N, 1-trimethylethylenediamine and the Ν · - (Ο1ο1ι1θΓρ1ιβην1) -Ν, Ν, 2-trimethyläthylendlamln , this mixture also containing a certain amount of unreacted starting material.

Example 6

Preparation of N - [(2-Dlmethylamlno-i-methyl) ethvlΊ-3 «.4'-dichloropropionic oxide and the corresponding hydrochloride.

The obtained by the method according to Example 5 Mixture and 50 ml of propionic anhydride are 16 hours heated for a long time on the boiling water bath. 400 ml of water are then added to the reaction mixture and heated for another hour. The mixture is then made basic using a 40 percent aqueous sodium hydroxide solution and extracted with 500 ml of ether. Of the The essential extract is then washed with 200 ml of water and then shaken out again by adding 200 ml an aqueous 10 percent hydrochloric acid solution is used. This second extract obtained in this way, i.e. the aqueous one Phase, is washed with 250 ml of ether and then the aqueous layer is made basic using a 40 percent aqueous sodium hydroxide solution and extracted with ether. The ether extracts obtained are with 100 ml of saturated sodium chloride solution. The ethereal layers are then dried over anhydrous magnesium sulphate and evaporated to dryness an oily material remains, which is chromatographed using 500 g of silica gel, all eluting media being ethyl acetate. You get 200

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Fractions of 20 ml each and contain the fractions 91 to 180 only a single component. These fractions 91 to 180 together give 6.5 g of a yellow oil after evaporation. This oil is the free base, namely N - [(2-dimethylamino-1-methyl) äthylj-3 ·, 4 · -dichloroanilide.

The oil is treated with an excess of ethereal hydrochloric acid and the salt which precipitates out is recrystallized twice from a mixture of methanol and ether in a volume ratio of 1:10. This gives 5.6 g, corresponding to 16% of theory, of the hydrochloride of N- [(2-dimethylamino-1-methyl) äthylJ-3 », ^ - dichlorpropionanilides, having a melting point of 196 - 197 having ⁰ C ·

The elemental analysis gave the following values: Calculated for C ₁₄ H ₁₀ N ₂ Cl ₂ OtHCl-H ₂ O:

C. 47.10} H. 5.87; N. 7.84 found: C. 47.45; H. 5.99; N. 7.91.

Example 7

Production of N - [(2-Dimethvlamino-2-methvl) äthyl1-3'.4 «- dichloropropionanilld.

Next, in the procedure described in Example 6, the elution of the free base from the chromatography column is complete, then further using a Mixture of ethyl acetate and methanol in a ratio of 9: 1 eluted. Fractions of 500 ml each are collected. the Fractions 5 up to and including 8 are combined with one another and evaporated to give 2.2 g of a yellow oil

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OD 9 U 1 3AO528

receives which the Nt ^ -
dichloropropionanilide is. This product obtained in this way is then treated with 1 g of oxalic acid in 20 ml of methanol and 200 ml of ether. It is then crystallized from a mixture of methanol + ether to and receives this 2,3 g (6% of theory) of the oxalate of N - [(2-dimethylamino-2-methyl) ethyl] -3 ^l, 4 "-dichlorpropionanilides , which has a melting point of 183 ^° C.

The elemental analysis gave the following values: calculated for CJ ^ Hp ₀ N ₂ CL ·, 0 · CpHp0. :

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 treated with aqueous sodium hydroxide solution and the aqueous mixture is extracted with ether, the ether layer is separated off and treated with gaseous hydrogen chloride, the hydrochloride salt of N - [(2-dimethylamino-2-methyl) äthylJ-3 ', 4 ^f -dichloropropionanilides receives.

Example 8

Preparation of N - [(3-Dimethylamino-2-methvl) propyl] -3 * ^ '- dichloropropionanilide.

A) Preparation of the N '- (3,4-dichlorophenyl) -N, N, 2-trimethylpropane-1,3-diamines.

43 g (0.75 mol) of the hydrochloride de3 1-chloro-2-methy1-3- (dimethylamine) propanes were with 25 ml of a 40 percent aqueous sodium hydroxide solution in 250 ml of ether

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heated. 16 g (0 ₉ 10 Hol) of 3 dichloroaniline were added to this mixture. The ether was then removed by distillation and the mixture was heated on a boiling water bath for 72 hours aqueous sodium hydroxide solution was added and it was treated for 1 hour on the boiling water bath and then extracted using 250 ml of ether. The ether extracts were dried over anhydrous magnesium sulfate and then evaporated to give an oil. The black oil obtained in this way is filtered with suction through 200 g of Slllzlumdioxid, eluting with methylene chloride until no more material could be washed out. -N, N, 2-tri-methylpropane-1,3-diamine obtained in the form of an orange colored oil.

B) Production of K - [(3 - ^> imethylamino-2-methyl) propylJ-3 * »4 · -dichlorproplonanilide ·

The orange colored oil, which was obtained according to process step A) described above, was treated with 25 ml of propionic anhydride and heated on the boiling Vaeserbath for 20 hours. Then it was added

water i

100 ml of the reaction mixture to · The mixture was then made basic using a 40 percent aqueous solution of sodium hydroxide, extracted with 250 μl of ether, the extracts washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to dryness -2-ethyl) propyl] -3 ^l , 4 ^t -dichloropropionanilide · The free base obtained in this way is converted into the corresponding hydrochloride salt by adding an excess

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essential hydrogen chloride is used. The compound was then recrystallized from a mixture of methanol + ether in a volume ratio of 1:12, and 2.8 g of the hydrochloride of N - [(3-dimethylamino-2-methyl) propylJ-3 ^t , 4'- _{dichlorpropionanilides>} which possessed a melting point of 209 -210 ^0C. The yield corresponded to θ % of theory

The elemental analysis gave the following values: Calculated for C ₁₅ H ₂₂ N ₂ Cl ₂ O-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 9

Production of Nr (2-Dimethvlamino) äthvl1-3 ^t propi onanilid.

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

In the catfish described in Example 2, _{propionyl chloride was added to a solution of N t} N-dimethy 1-· - (3,4-dibromophenylethylenediamine and triethylamine, the N- [2- (dimethy1- aminoethyl] ^ ¹ , V-dibromopropionanilide.

Example 10

Production of N-I 3- (Dimethylamine) propyl 1-3 * .4 * -dibrom « proplon anilide.

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According to the procedure described in Example 1, a mixture of 3,4-dibromaniline and 1-chloro-3-dimethylaminopropane was ^{heated to 90 to 100 °} C. for 72 hours, the N, N-dimethyl-N ^t - ( 3, A-dit »romphenyl) trimethylene-1,3-diamine.

Propionyl chloride is added according to the procedure described in Example 2 to a solution of N, N-dimethyl-N ^f - (3 _f A-dibronphenyl) trimethylene-1,3-diamine and triethylamine, and the product is then N- [3 - (Dimethylamine) · propylJ-3 ¹ , 4 * -dibromopropionanilide.

Example 11

Manufacture of N-r3- (Dimethvlamino) propvll-3 ^t .4 ^t -dibromcvclopropancarboxanilld.

The 3 »4-dibromaniline and the Hydrochloric! of i-chloro-3-dimethylaminopropanes and sodium bicarbonate in Heated toluene, the product N, N-dimethyl- (3,4-dibromophenyl) trimethylenediamine being obtained.

The diamine thus prepared was then reacted with the chloride of cyclopropanecarboxylic acid in the presence of triethylamine, in a manner similar to that described in Example 2. In this case, the product obtained is the corresponding N- [3- (Dimethylamlno) ^{propylJ-3-liter,} V-dibromcyclopropancarboxanilid.

When this anilide is treated with hydrochloric acid in ether, one then obtains the hydrochloric! des N- [3- (dimethylaminopropyl)] -3 ^f ^ • -dibromocyclopropanecarboxanilides

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Example 12

Production of N- [2- (Dlmethylaiaino) äthvl] - 3 ^t .4 ^f -dichloroacrylanilide.

Following the procedure described in Example 1 were 3 »4-dichloroaniline, the hydrochloride of 1-chloro-2-dimethylaminoethane as well as sodium / bicarbonate heated, and one received the NjN-dimethyl-N'-O ^ -dichloropheny1) ethylenediamine as the product.

The diamond obtained in this way was then reacted with the acid chloride of acrylic acid in the presence of triethylamine in a manner similar to that described in Example 2. The product obtained is the corresponding N- [2- (Dimethy1-amino) äthy1J-3 ^f , 4 · -dlchloroacrylanilide ·

Treatment of this anilide with hydrochloric acid in ether gives the hydrochloride of N- [2- (dimethylamine-diethyl j-3 ', 4 -dichloracry! anilides

Example 13

Preparation of N - [(3-Dlmethylamino-2-methyl) propyl I-3 *, ^ '- dibromopropionanllide.

Using the procedure described in Example 8A, 3,4-dibromaniline and the hydrochloride were combined des i-chloro ^ -methyl ^ -dimethylaminopropanes and sodium hydroxide heated, the product being N '- (3,4-dibromophenyl) -N, N, 2-trimethylpropylene-1,3-diamine received.

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If this diamine was treated with propionyl chloride in the presence of triethylamine in a similar manner, As described in Example 2, the product obtained is the corresponding H - [(3-I> ynethylanino-2-methyl) propylJ-3 *, 4 * -dibromopropionanilide.

This anilide thus obtained was then with Treated hydrochloric acid in ether, the product obtained being the corresponding hydrochloride of N- [3- (dimethylamino-2-methyl) propylJ-3 *, 4 * -dlbromopropionanllldes.

Example 14

Preparation of N-r (3-Dinethylamino-2-methvl) propvll-31.41 -dlbromcvclopropanecarboxanilide.

According to the procedure described in Example 5, the 3 »4-Dibromanllln, the hydrochloride of 3-chloro-2-ethyl-1-dimethylaminopropanes and sodium carbonate were heated together in toluene, the product N * - (3» 4-dibromophenyl ) -N _f N _t 2-trimethylpropane-1,3-dlamine was obtained.

Then this diamine became similar with the cyclopropanecarboxylic acid chloride in the presence of triethylamine Veise implemented as described in Example 2 1st. Man received the N - [(3-4> iiMiäVlaiiiino-2-methyl) propyl] -3 *, 4 * -dlbromocyclopropanecarboxanilide as product

The anilide prepared in this way was then treated with hydrochloric acid in ether, the product obtained being the corresponding hydrochloride of N - [(3-Dlmethylamino-2-methyl) propylJ-3 *, 4 ^> -dibromocyclopropanecarboxanilides.

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Example 15

Preparation of N - [(3-Dlmethvlamino-2-methyl) propvl3-3 ¹ , ^ - dibromoacrylanilide.

According to the procedure described in Example 5, the 3,4-dibromaniline, the hydrochloride of 1-chloro-2-methyl. 3-dlmethylaminopropanes and sodium carbonate and sodium bicarbonate were heated in toluene, the product obtained being N- (3 »4-Dlbromophenyl) -N, N, 2-trimethylpropane-1,3-diamine.

If one transposed this thus prepared diamine with the acrylic acid chloride in the presence of triethylamine in a similar Veise, as described in Example 2, then the product obtained is the N - [(3-dimethylamine-2-methyl) propylJ-3 ^l »4 ^l dibromoacrylanilide.

The anilide thus produced was then treated with hydrochloric acid in ether, the product being the Hydrochloride of N - [(3-dimethylamino-2-methyl) propylJ-3 ·, 4 · - dibromacry! anilides received.

Example 16

Production of N-f2- (Dimethvlamlno) äthvl I-3 ¹ .V-dlchlorcyclopropanecarboxanilide.

Following the manufacturing process described in Example 5, the 3,4-dichloroaniline, the hydrochloride of the 1-chloro-2-dimethylaminoethanes and sodium carbonate in toluene heated, and the product obtained was the corresponding N, N-dimethyl-N * - (3,4-dichlorophenyl) ethylenedlamine «

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This diamine thus obtained was then used the cyclopropanecarboxylic acid chloride reacted in the presence of triethyl amine in a manner similar to that described in Example 2. The product obtained was N - [(2-diaiethylamino) äthylJ-3 », 4» -dichlorocyclopropanecarboxanilide

The anilide thus obtained was then treated with hydrochloric acid in ether, the corresponding Hydrochloride of N - [(2-dimethylamino) äthylJ-3 », propancarboxanilides won.

Example 17

Production of N-Γ5- (Dimethylamine) propvlI-3 * .fr'-dichloroacrvlanilid.

According to the procedure described in Example 3, the 3,4-dichloroaniline, the hydrochloride of 1-chloro-3-dimethylaininopropanes and sodium carbonate were in toluene heated together, the product obtained being N, N-dimethyl-N · (3 f4-dichlorophenyl) propylene-1,3-diamine.

This diamine thus prepared was then heated with the acrylic acid chloride in the presence of triethylamine in a manner similar to that described in Example 2, the corresponding N - [(3 ^{-dimethylamino) propyl] -3 f} tV-dichloroacrylanilide being obtained as the product became.

The anilide thus obtained was then treated with hydrochloric acid in ether and thus converted into the corresponding one Hydrochloride of N - [(3-dimethylamino) propylJ-3 ', ^' - dichloroacry! Anilides transferred.

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Example 18

Preparation of a mixture of N '- ^. A-dibromophenvD-NNI-trimethylethylenediamine and N ^> ~ (304- »dit> romphenyl) ~ NN2 -tri-» methylethylenediamine.

Following the procedure described in Example 5, a mixture of 3,4-dibromaniline and the 2 ~ chloro-1-dimethylaminopropanes hydrochloride and sodium carbonate and sodium bicarbonate in toluene heated on a boiling water bath for 72 hours. Then there was water added to the mixture, and the organic phase separated and then evaporated to dryness, leaving as product a mixture of N- (3,4-dibromophenyl) -N, N, 1-trimethylethylenediamine and N- (3,4-dibromophenyl) -N, N, 2-trimethylethylenediamine received.

Example 19

Production of N-Γ (2-Dimethvlam.lno-1 -methyl) ether 1-3 *. 4'-dichloroacrylanilide and the corresponding hydrochloride and No. (2-dimethylamino-2-methyl) ethyl | -3 ^f .V-dlchloroacrylanilide and the corresponding hydrochloride.

Following a procedure similar to that described in Example 6, the mixture was made of compounds obtained by the process according to Example 5 was treated with the acrylic acid chloride in the presence of triethylamine. Then water was added to the mixture Made basic with sodium hydroxide and extracted the aqueous phase with ether. The severed essential Extracts were washed with water and with 10 percent

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Hydrochloric acid extracted. The hydrochloric acid extracts obtained in this way were then washed old ether, the ether discarded and the aqueous solution purified in this way Solution made basic using sodium hydroxide. Subsequently, the basic solution was extracted again with ether, the ether layer was washed and then for Evaporated dry. The product obtained in this way was chromatographed on silica gel, ethyl acetate being used as the eluting agent. The product obtained was the N - [(2-di-

The product thus obtained was then treated with ethereal hydrochloric acid, whereby the hydrochloride of N- [(2-dimethylamino-1-ynethyl) ethyl] -3,4-dichloroacrylanillides was obtained.

The chromatography column was then extracted further after the fractionation carried out to obtain the N - [(2-dimethylamino-1-ethyl) ethylJ-3,4-dichloroacrylanilides, using a mixture of ethyl acetate + methanol. The N - [(2-Dimethylamlno-2-methyl) ethyl] -3 ^l , ^ • -dichloroacrylanilide was obtained in the extract. This product was then converted to the corresponding hydrochloride using an ethereal solution of hydrochloric acid.

Example 20

Production of Nr (2-Dimethvlamino-1iaethvl) äthvll-3'.4 ^t dichlorcvclopropancarboxanilid. of the Hvdrochlorldes of this connection as well as of Nr (2-Dlmethvlamlno-2 "« ethvl) ethvl] -3 ^> .4 ^< -dichlorcvcvclopropancarboxanilld and the corresponding Hydrochlorldes.

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809823/0628 /

Following the procedure described in Example 6, the mixture of compounds prepared according to the in Example 5 described method was obtained old treated with the acid chloride of cyclopropanecarboxylic acid and triethylamine. Then water was added, the mixture was 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 the ether layers obtained and then using the aqueous solution obtained Made sodium hydroxide 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 Elutlonsmlttel Ethyl acetate was used. Nan eluted from the column the N - [(2-dimethylamino-1-methyl) ethyl] -3 », 4 · - dichlorocyclopropanecarboxanilide

The compound so obtained was then treated with ethereal hydrochloric acid, whereby the Hydrochloric! des N - [(2-dimethylamino-1-methyl) ethyl] -3S4 «-dichlorocyclopropanecarboxanilides could win.

The silica gel column remaining after the extraction described above is then further extracted using a mixture of ethyl acetate and methanol as the eluent. The N - [(2-dimethylamino-2-methyl) ethyl3-3.4 · -dlchlorocyclopropanecarboxanilide is obtained. This product can be converted to the corresponding hydrochloride by treating it with an ethereal solution of hydrochloric acid.

809823/0628

Example 21

Production of N-rte-Dlmethvlamino-i-methvltethvll ^ * .4'-dlbromproplonanllid and the Hvdrochlorldes of this compound and also of N - [(2-Dimethvlamino-2-methYl) ethyl] -3 ^> .4 ^t -dlbrompropionanllid and des corresponding hydrochlorides

Following the procedure described in Example 6, the mixture of compounds obtained by following the procedure described in Example 18 was treated with the anhydride of propionic acid. Then they sat then water to _9, the mixture made basic using sodium hydroxide and extracted with ether. The separated ethereal extracts were washed with water and then extracted with 10 percent hydrochloric acid. The hydrochloric acid extracts obtained in this way were then washed with ether, the ether layers discarded and the aqueous solution was then made basic using sodium hydroxide and extracted again with ether. After washing, the ethereal solution is evaporated off and the residue is chromatographed on silica gel using ethyl acetate as the eluent. The N - [(2-dimethylamino-1-methyl) äthylJ-3 ^t , ^ • -dibromopropionanilide is obtained from the eluates.

Then the compound thus obtained was treated with ethereal hydrochloric acid, whereby the hydrochloride of N - [(2-dimethylamino-1-methyl) -äthylj-3'f 4 * -dibromopropionanilides obtained as a product ·

The silica gel column remaining after the first extraction is then extracted further with a mixture of ethyl acetate and methanol, N-L (2-dimethylamino-2-methyl) ethyl-3 *, 4 * -dibromopropionanilide being obtained.

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This compound can be converted into the corresponding hydrochloride by treatment with an ethereal solution of hydrochloric acid being transformed.

Example 22

Production of N - [(2-dimethylamino-1- »methyl) ethyl] -3 '.4'-dlbromacrylanilld and the corresponding hydrochloride, as well as from Ν-Γ (2-Dimethvlamino ~ 2-methyl) äthvl I-3 * «A'-dibromoacrylanilide and the hydrochloride of this compound.

According to the production process described in Example 6, the mixture of compounds obtained by the process according to Example 18 was treated with acrylic acid chloride and triethylamine. Then water was added to the reaction mixture and the mixture was made basic using sodium hydroxide and finally extracted with ether. The separated ether extracts were washed with water and then extracted using 10 percent hydrochloric acid. The hydrochloric acid extracts obtained in this way were then washed with ether, the ether layers thus obtained were discarded and finally the aqueous solution was made basic using sodium hydroxide and extracted with ether. The ether layers thus obtained were first washed and then evaporated to dryness. The residue obtained was chromatographed on silica gel using ethyl acetate as the eluent. [(2-dimethylamino-1-methyl) äthylJ-3, ^l eluted 4'-dibromacrylanilid - Here, the N is.

The compound thus obtained was treated with ethereal hydrochloric acid to obtain the

- 35 -809823/0628

N-dibromoacrylanilide hydrochloride.

The remaining after the first elation silica gel column was then further extracted using ethyl acetate + methanol as Elutionspittel ·, there was obtained N - [(2-dimethylaminopropyl * ino-2-eetbyl) athylJ-3 ^t, 4 x - dibromacrylanilid. This compound can be converted into the corresponding hydrochloride by adding an ethereal solution of hydrochloric acid.

Example 23

Production of H - [(2-Diaethyif "p1i O-1 ne ^<tttyl) äthvl] -3 ^{t t} .4 dibromcvclopropancarboxanilid and the related Hvdrochlorides. and also of Hr (2-Dimethvlamino-2-methyl) äthyl] -3 ^> * 4 ^t -dibromcvclopropanecarboxanilide and the hydrochloride this connection.

Following the working procedure described in Example 6, the mixture of compounds obtained by the procedure described in Example 18 was treated with cyclopropanecarboxylic acid chloride and triethylamine. Then there was water added, and the mixture made basic using sodium hydroxide and then extracted with ether obtained ether extracts were washed with water and then extracted with 10 percent hydrochloric acid. The hydrochloric acid extracts obtained were washed with ether and the resulting ether layers were discarded. The aqueous layer was then made basic using sodium hydroxide and extracted again with ether. The essential solutions were first washed and then evaporated to dryness and the residue on silica gel,

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using ethyl acetate as the eluent, chromatographed. The N - [(2-dimethylamino-1-methyl) ethyl] -3 ^f , A * -dibromocyclopropanecarboxanilide was obtained from the eluates.

The anilide thus obtained was then treated with an ethereal hydrochloric acid to obtain the product the hydrochloride of N - [(2-dimethylamino-1-methyl) ethyl] -3,4-dibromocyclopropanecarboxanilides received

The silica gel column remaining after the first elution was then extracted further using a mixture of ethyl acetate + methanol as the eluting medium, and the N - [(2-dimethylamino-2-methyl) -ethylj-3 ¹ fA'-dibromocyclopropanecarboxanilide was obtained. This product was converted to the corresponding hydrochloride using an ethereal solution of hydrochloric acid.

Example 24

Production of N- (3 *, ^ - dichlorophenyl) -N- [5- (dimethylamine) pentyl] propionamide 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. To this solution 50.0 g (0.32 mol) of S-chloro-valeric acid chloride (S-chloro-valeryl chloride) are added dropwise over 30 minutes in 50 ml of ether and after this time slowly add 100 ml of water. The organic layer is then separated off, washed with 100 ml of an aqueous saturated sodium bicarbonate solution and over anhydrous magnesium sulfate dried. It was then evaporated and obtained

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/ 809823/0628

41.5 g of S-chlorvaleryl-N ^ -dimethylamide in the form of a yellow oil. This corresponds to a yield of 79 % of theory.

The oil thus obtained is with a suspension of 40.5 g (0.25 mole) 3,4-dichloroanal and 1.0 g of potassium iodide combined in 250 ml of dimethylformamide, and the mixture is heated under reflux for 16 hours The mixture is poured into 1500 ml of water and then 100 ml of a 20 percent aqueous sodium hydroxide solution is used to, whereby the pH of the total amount of 1600 ml comes to be around 8.

A precipitate forms, which is filtered off and washed with water. It is then crystallized twice from ether, thus obtaining 16.7 g of the so 5- (3 ^f, 4'-DiChIOranilino) -N, N-dimethylvaleramide, which had a melting point of 114 ⁰ C. The yield achieved corresponds to 23 % of theory.

The following values were found in the elemental analysis:

calculated for C ₁ ^ H ₁₈ N ₂ Cl ₂ O:

C 53.99; H. 6.27; N. 9.69; Cl. 24.52 found: C. 53 _f 65; H. 6.28; N. 9.45; Cl. 24.41.

To a solution of 14.5 g (0.05 mol) of 5- (3 ¹ , 4 ^f -dichloroanilino) -N, N-dimethylvaleramide in 200 ml of tetrahydrofuran, which was cooled to -5 ° C., was added 200 ml a borane solution in tetrahydrofuran. The 200 ml of the borane solution contained 0.20 moles of borane. The mixture is then left at room temperature overnight and then boiled for 2 hours

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809823/0628

on a boiling water bath under reflux for a long time to give a milky suspension. To this suspension was slowly added 100 ml of 6 normal aqueous hydrochloric acid. After about 30 minutes the evolution of gas (nitrogen gas) ceased. Then the mixture is distilled in order to remove the tetrahydrofuran and the remaining aqueous solution is washed with 200 ml of ether. The aqueous phase is then made basic using 100 ml of a 40 percent aqueous sodium hydroxide solution and then extracted using 300 ml of ether. The ether extracts obtained in this way are washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate and finally evaporated to dryness, giving 12.9 g of the N- (3 ^f ^ • -dichlorophenylJ-N ¹ , N ¹ -dimethy1-1 5-pentanediamine is obtained in the form of a yellow oil The yield obtained corresponds to 94 % of theory.

Then 1 g of the oil thus obtained was converted into the corresponding dihydrochloride by treating it with hydrochloric acid in ether. This gave 0.8 g of the dihydrochloride of N- (3 * ^ »- dichlorophenyl-N ¹ , ^ - dimethyl-1, 5-pentanediamines, which had a decomposition melting point of 183 ^° C. The yield corresponded to 63 % of theory .

The elemental analysis of this dihydrochloride gave the following values:

calculated for C ₁₃ H ₂₀ N ₂ Cl ^ HGl

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 ¹ , N ¹ -dimethyl-i, 5-pentandinraines and 80 ml of propionic an-

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hydride were heated on a boiling water bath overnight. 250 ml of water were then added to the mixture obtained in this way and the mixture was heated for a further 30 minutes. The mixture was then made basic using 150 ml of a 40 percent aqueous sodium hydroxide solution and extracted with 200 ml of ether. The ether extracts obtained in this way were washed with 100 ml of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate and finally evaporated to dryness, the N- (3 ^f , ^{/ | l} -dichlorophenyl) -N- (5-dimethylaminopentyl) propionamide received in the form of a yellow oil.

It presented the oxalate of N- (3 ^t, 4 ^{<-Dichlorphenyl)} -N- (5-dimethylaminopentyl) propionamides prepared by mixing treated with oxalic acid in a mixture of 50 ml of methanol and 50 ml ether. The oxalate obtained in this way had a melting point of 166 - 167 ° C

The elemental analysis of this oxalate gave the following values:

calculated for C ^ I ^^ ClgNgO · C ₂ H ₂ O ^

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.

Following the procedure described in Example 7, this oxalate salt was converted to the corresponding hydrochloride salt.

Example 25

Production of N- (3 * .4 ^t -Dichlorphcnvl) -N- (4-dimethylaminobutylpropionamide and the corresponding hydrochloride.

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809823/0628

The starting product used was N, N-dimethyl-4-chlorobutyramide, the preparation of which was described by J. Falbe et al., In Chem. Ber. 97 2544 (1964). 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 was obtained and this mixture was refluxed for 17 hours. The reaction mixture thus obtained was then made basic using 100 ml of a 20 percent aqueous sodium hydroxide solution in 1500 ml of water. A precipitate separates out, which is filtered off and then washed with 500 ml of ether. This precipitate is then dissolved in 500 ml of methanol. If the solution is concentrated to 200 ml, 13.5 ^{% of a solid is obtained which is 4- (3 f} , 4'-DiChIOranilino) -N, N-dimethylbutyramide. This has a melting point of 154-155 ⁰ C.

The elemental analysis provided the following results:

calculated for C ₁₂ H ₁₆ Cl ₂ N ₂ O:

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.

Following the procedure described in Example 24, the thus obtained

Ν, Ν-dimethylbutyramide is reduced with borane in tetrahydrofuran, the product N- (3 ^f , 4 "-dichlorophenyl) -N" N ^l -diiiiethyl butane-1,4-diamine being obtained in the form of an oil.

The hydrochloride of this oil is prepared by treating it with hydrogen chloride gas in ether. This gives a dihydrochloride, whose molecular weight is 334.14, and a melting point of 200 - 201 having ⁰ C.

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809823/0628

The elemental analysis provided the following results:

calcd for C ₁₂ H ₁₈ N ₂ Cl _{2 2HCl}

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 ^I , 4 ^I -dichlorophenyl) -N'N'-dimethylbutane-1,4-diamines obtained in this way were heated with 60 ml of propionic anhydride, the N- (3 ^l _f 4 ^l -Dichlorophenyl) -N- (4-dimethylaminobutyl) propionamide is obtained in the form of an oil.

The oil thus obtained is then treated with hydrochloric acid in ether, 7.3 g of the hydrochloride of N- (3 ·, 4 »-dichlorophenyl) -N- (4-dimethylamino) butyl-propionamide, which has a melting point of 162 - 163 ⁰ C. The yield corresponds to 63 % of theory.

The elemental analysis of this Hydrochlorld provided the following values:

calcd for C ₁ CH ₂₂ N ₂ Cl ₂ O 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.

Further compounds can be prepared using the procedures described in the preceding examples which correspond to formula III.

Typical examples of connections made in this way are the following:

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809823/0628

N - [(2-dimethylamino) ethylJ-3 ¹ , V-dibromoacrylanilide;

N - [(2-dimethylamino) ethyl] -3 * »4 * -dibromocyclopropanecarboxanilide;

N - [(3-dimethylamino) propylJ-3 ^f , 4 »-dibromoacrylanllide;

N - [(3-dimethylamino) propyl] -3 *, 4'-dichlorocyclopropanecarboxanilide;

N - [(3-dimethylamino-2-methyl) propylJ-3 ^f , 4 · -dichloropropionanilide;

N- [(3-dimethylamino-2-methyl) propyl J-15 *, 4 »-dichloroacrylanilide;

N - [(3-dimothylamino-2-methyl) propylJ-3 ^f , 4 · -dichlorocyclopropanecarboxanilide;

and similarly structured connections.

If these above-mentioned amino compounds or the amino compounds obtained by the processes described in the examples are treated with stoichiometrically calculated amounts of pharmaceutically acceptable acids, the corresponding acid addition salts with the pharmaceutically acceptable acids are obtained from the free amines. Examples of such salts are the salts with hydrochloric acid, hydrobromic acid, hydroiodic acid , sulfuric acid and phosphoric acid. Further salts are the acetates, the lactates, the salts with malic acid (malates), the salts with the maleic acid (maleates), the salts of succinic acid (succinates), the salts of tartaric acid (tartrates), the salts with the citric acid (citrates) ) as well as the benzenesulfonates, the methanesulfonates, the sulfamates and similar salts.

809823/0628

Example 26

1002 pieces of hard gelatin capsules for oral administration were produced, each of which contains 2.5 eg of the hydro- chlorldes des N- [3- (Dljeethylajrijao) piOpylJ-3 ^l , 4 ^l -dlchlorproplonanilides. These capsules contain the ingredients listed in the following table in the following concentrations:

Beatand part N- [3- (Dlmethylamlno) propylJ-3 ·,

propionanillide hydrochloride. 2.5

Lactose 130 corn starch 25

Talc 20

Magnesium stearate 2.0

In the manufacture of the capsules, the appropriate quantities of the starting materials were thoroughly mixed together and then encapsulated in the usual manner in order to obtain an People to correct depression were taking 1-2 capsules every Orally administered for 4 hours

Capsules containing 5 mg or 10 mg or 15 mg or 20 mg or 25 mg can also be produced in the same way or 30 mg of the active ingredients, using the same procedures for this purpose can.

Example 27

1000 tablets were prepared for oral administration, with each tablet 25 mg of the hydro-

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chloride of N- [3- (Dimethylamino) propylJ-3 ', ^' - dichloropropionanilides. Each of the tablets contained the ingredients listed in the following table in those specified Concentrations:

Component . Amount in g

N- [3- (Dimethylamine JpropylJ-3 ^f , 4 * -dichloropropionanilide hydrochloride 25

Lactose 125

Cornstarch 65 Magnesium stearate 2.5 Light liquid petrolatum 3

The listed ingredients have been thoroughly mixed with one another in the appropriate proportions, whereby a hatred resulted. This mass was then broken up by forcing it through a No. 16 sieve The resulting grains were then compressed into tablets, each tablet containing 25 mg of the hydrochloride of W- [3- (dimethylamino) propyl] -3 *, 4'-dlchlorpropionanilides.

The tablets so produced are useful in treating depression in adult people, one being Tablet administered orally 1 to 3 times a day.

Example 28 Manufacture of a syrup for oral administration.

1000 ml of an aqueous suspension for oral administration, in which a dose unit of 5 ml each contained 10 mg of dcra hydrochloride dos N- [2- (dimethylamino) ethyl] -3 ^l »^ ^t -di · - chlorpropionanilides, was prepared by nan

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809823/0628

5? "275190b

the components listed in the following table specified proportions mixed

Component quantity

N- [2- (Dimethylamino) äthylJ-3 ·, 4 »-dichloropropionanilide hydrochloride 2g

Citric acid 2 g Benzoic acid 1 g Sucrose 700 g

Tragacanth 5 g

Lemon oil 2 ml Deionized water, up to 1000 ml

In making this syrup, citric acid, benzoic acid, sucrose, tragacanth and lemon oil were suspended in a sufficient amount of water to obtain 850 ml of solution. The hydrochloride of N- [2- (dimethylamino) äthyl] was then stirred -3 ^l , 4 "-dichloropropionanllides into the syrup until a uniform distribution occurred. A sufficient amount of water was then added to achieve a total volume of 1000 ml.

The syrup so prepared is useful for treating depression in adult humans, with a dosage of one full teaspoon given 4 times a day will.

Example 29 Preparation of a solution for parenteral administration « A sterile aqueous solution was prepared

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809823/0628

which is suitable for intramuscular administration. This solution contained in 1 ml an amount of 25% of the hydrochloride of N- [3- (dimethylamino) propylJ-3 ^f , ^ - dichloropropionanilides. The solution mentioned was prepared using the ingredients listed below in the proportions mentioned:

Component quantity

N- [3- (Dimethylamino) propy1J-3 ^f , 4 »-dichloropropionanilide hydrochloride 25 g

Lidocaine hydrochloride 4 g

Methyl paraben 2.5 g

Propyl paraben 0.17 g

Water for injections, up to 1000 ml

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

Example 30 Suppositories for rectal administration.

1000 suppositories are made, each of these suppositories weighing 2.0 g and 5 mg of the N- [£ 2-dimethylamino ~ 1-methyl) äthylJ-3 ' Contains ^ -dichloropropionanilide. The suppositories are made from the following ingredients:

Component quantity

N - [(2-Dimethylamino-1-methyl) ethyl] -3 », 4'-dichloropropionanilide 5 g

Propylene glycol 162.5 g

Polyethylene glycol 4000, up to 2000 g

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809823/0628

In the preparation of this composition, the N- [(2-dimethylamino-1-ethyl) ethyl] -3 "^" -dichloropropionylide hydrochloride is added to the propylene glycol and the Mixture is milled until the powders are finely divided and uniformly dispersed · The polyethylene glycol 4000 is melted and the propylene dispersion is slowly stirred added. The suspension is poured into non-cooled molds at 40 ° C. Then the mixture is allowed to cool and solidify and remove them from the mold. Each suppository obtained in this way is then wrapped in foil.

The suppositories described above are suitable to prevent depression by taking 1 suppository rectally introduces every 4 hours.

Example 31

Formulations were prepared using the procedures described in Examples 26-30. However, now those were used there active components replaced by an equimolar amount of the active compounds listed below:

N - [(3-Di * ethyl-amino-2-methyl) propylJ-3 ^f , 4 * -dichloropropionanilide;

N - [(2-Dimethyla "ino-2- * ethyl) äthylJ-3", 4 ⁽ -dichloropropionanilidf

Ν- [(3-dimeth7lamino-2-methyl) propylJ-3 ^t , 4 "-dibromocyclopropanecarboxanilide;

N- [(3-Dinethylamino-2-methyl) propylJ-3 ·, 4 "-dlbroaacrylanilide; -

N - [(3-Dinethyliimino-1-eethyl) ^{propylJ-3-liter,} 4 ^f -dibromacrylanilid;

ι 809823/0628

N - [(3-dimethylamino-1-methyl) propylJ-3 ^f , 4'-dibrcmcyclopropanecarboxanilide;

N- [2- (dimethylamino) ethyl] -3 *, 4 * -dibromopropionanilide]

N- [3- (dimethylamino) propylJ-3 ', 4 ¹ -dibromopropionanilide; ^:

N- [£ -dimethylamino-1-methyl) ethylJ-3 *, 4 · -dichloroacrylanilide;

Nt (2-methylamino-2-methyl) ethylI-3 ¹ , 4 »-dichloroacrylanilide.

The above compounds can be in the form of the free base or in the form of the hydrochlorides, hydrobromides, sulfates, Tartrates, lactates, citrates, methanesulfonates, maleates, Malates, sulfamates or similar acid addition salts of the free ones Bases are used.

809823/0628

Claims (1)

Henkel, Kern, Feiler £ r Hänzel Pa tontan walte Möhlstrasse 37 The Upjohn Company D-8000 Munich 80 KalamazOO, Mich., V.St.A. Tel: 089/982085 87 Telex: 0529802 hnkld telegrams: ellipsoid TUC 3326 1.lAmlnoamlde claims of the formula: IN THE CH ₃ ^ _ ^ p N-A- CH ₃ ^ where mean: A is a radical of the formulas - (CH ₉ ), -, - (CH ₉ ), -, - (CH ₉ ) /.-, - (CH ₂ ) ₅ -t -CH-CH ₂ -, -CH ₂ "^ "or -CH ₂ -CH-CH ₂ -; CH ^ CH ^ QH ^ X is a chlorine or bromine atom and R is an ethyl, cyclopropyl or vinyl radical and their pharmacologically acceptable acid addition salts. 809823/0628 ORIGINAL INSPECTED 2. Amino amides of the formula: ΜΙΑ where mean: A is a residue of the formulas: - (CH ₉ J ₉ -, - (CH ₉ ), -, -I 12 1 2 ^ * * ° "^ - (CH ₂ ) ₅ -, -CH-CH ₂ -, -CH ₂ -CH-, or -CH ₂ -CH-CH ₂ - and 3 3 3 X is a chlorine or bromine atom, and their pharmacologically acceptable acid addition salts. 3. Aminoamides of the formula: 0 Il CC ₂ H ₅ Cl ^ - ^ k. it CH ₃ ' wherein A ^{1 is} an ethylene or trimethylene radical, and their pharmacologically acceptable acid addition salts. 4. Aminoamld according to claim 3, characterized in that it corresponds to the formula given, where A * for a 809823/0628 -JH- Ethylene radical, namely N- (2- (dimethylamino) ethyl] -3 « ₁ 4« -dichloropropionanllide. 5. N- [2- (dimethylamino) ethyl] -3.4 "-dichloropropionanilide hydrochloride. 6. Aminoamide according to claim 3 »characterized in that it corresponds to the formula given, in which A ^{1 is} a trimethylene radical, namely N- [3- (dimethylamino) propyl] -3 *, 4« -dichloropropionanilide. 7. N- [3- (Dimethylamino) propyl] -3 ·, 4 · -dichloropropionanilide hydrochloride. 8. Aminoamide according to claim 2, characterized in that it corresponds to the formula given, in which A stands for a 1 2 radical of the formula -CH-CH ₉ - and X represents a chlorine atom- represents, namely N - [(2-dimethylamino-1-methyl) ethyl] -3 ', 4 "-dichloropropionanilide. 9. N - [(2-dimethylamino-1-methyl) ethyl] -3 ^f ₁ 4 * -dichlorpropionanilid hydrochloride. 10. Aminoamide according to claim 2, characterized in that it corresponds to the formula given, in which A stands for a 1 2 radical of the formula -CH ₂ -CH- and X represents a chlorine atom- represents, namely NC (2-dimethylamino-2-methyl) äthyl35 ^l, 4 x - dichloropropionanilide. 11. N - [(2-Dimethylamino-2-methyl) ethyl] -3.4 · -dichloropropionanilide hydrochloride. 809873/0629 12. Aminoamide according to claim 2, characterized in that it corresponds to the formula given in which A is a radical of the formula -CH ₂ -CH-CH ₂ - and X is a chlorine atom CH ₃ represents, namely N - [(3-dimethylamino-2-methyl) propyl] -3 ·, 4 · -dichloropropionanilide. 13. N - [(3-Dimethylamino-2-methyl) propyl] -3 ', 4'-dichloropropionanilide hydrochloride. 14. Aminoamide according to claim 2, characterized in that it corresponds to the formula given, wherein A is for one Tetramethylene radical and X represents a chlorine atom, namely N- (3 ', 4'-dichlorophenyl) -N- (4-dimethylaminobutyl) propionamide. 15. N- (3 ', 4'-dichlorophenyl) -N- (4-dimethylaminobutyl) propionamide hydrochloride. 16. Aminoamide according to claim 2, characterized in that A is a pentamethylene radical and X is a chlorine atom namely N- (3 ', 4'-dichlorophenyl) -N- (5-dimethylaminopentyl) propionamide. 17. N- (3 ', 4'-dichlorophenyl) -N- (5-dimethylaminopentyl) propionamide hydrochloride. 18. Process for the preparation of aminoamides of the formula: I V 809823/0620 where mean: 1 2 A _{n is} a residue of the formulas: - (CIU) ₉ -, - (CH ₉ ) * -, -CH ₉ -CH-, 1 2 ³ -CH-CH ₂ or -CH ₂ -CH-CH ₂ -; X is a chlorine or bromine atom and R an ethyte> Cyclopropyl or vinyl residue » characterized in that an aniline of the formula: NH ₂ wherein X has the meaning given, with a halogen-containing amino compound of the formula: CHa CH; wherein Aq has the meaning given and X ^{1 is} a chlorine, bromine or iodine atom, and the diamine is reacted in the presence of a base with an acylating agent consisting of propionic anhydride or the chloride or bromide of propionic, acrylic and / or Cyclopropanecarboxylic acid, can react to form an amino amide of the formula IV. 809823/0628 19. The method according to claim 18, characterized in that one ala used with the acyling agent base triethylamine used. 20. Process for the preparation of aminoamides of the formula: CHa CH :, where mean: a remainder of the formulas: - (CIL ,) ₂ -, - (CII ₂ ), -, 1
^- * wXX * 1 2
-CH-CH ₂ or -OT ₂ -CH-CH ₂ -; CH ₃ CH ₃ 2
2. - t
CH X is a chlorine or bromine atom and R is an ethyl, cyclopropyl or vinyl radical, characterized in that a compound of the formula: N-Ao-NH
I. wherein Aq and X have the meaning given, in the presence of a base with an acylating agent consisting of Acylated propionic anhydride or the chloride or bromide of propionic, acrylic and / or cyclopropanecarboxylic acid. 21. Process for the preparation of aminoamides of the formula: CHa where mean: A ₀ ^{1 is} - (CH ₂ ) ^ or X is a bromine or chlorine atom and R is an ethyl, cyclopropyl or vinyl reet, characterized in that an aniline of the formula: wherein X has the meaning given, with a compound of the formula: 0 CH ₃ . ν > MC- (CH ₂ Jn - X ¹ CH ₃ ^ 809823/0628 where η «3 or 4 and X ^{1 is} a chlorine, bromine or iodine atom, to a compound of the formula: CH ₃ . ff, H NC- (CH ₂ J _n N _v wherein X and η have the meaning given, converts the compound of the formula V with a metal hydride to form a compound of the formula: CH * in which Aq ¹ and X have the meaning given, reduced and the compound of the formula VI in the presence of a base with an acylating agent consisting of propionic anhydride or the chloride or bromide of propionic, acrylic and / or cyclopropanecarbonic acid to give a compound of the formula VII acylated. 22. Medicinal product, characterized in that it consists of at least one aminoside of the formula: 809823/0628 CM: i Il CHm where mean: A is a residue of the formulas - (CH ₉ ) ₉ -, - (CH ₉ ), -, - (CH ₉ ) /.-, 12 12 ^{ZZ Z3} . * * »- (CH ₂ ) c-, -CH-CH ₂ -, -CH ₂ -CH- or -CH ₂ -CH-CH ₂ -; CH, CH, CH, X is a chlorine or bromine atom and R is an ethyl, cyclopropyl or vinyl radical, or a pharmacologically acceptable acid addition salt thereof or contains at least one such amine amld or its pharmacologically acceptable acid addition salt and optionally a pharmaceutical carrier. 23 * Medicament according to claim 22, characterized in that that the active ingredient is made up of an amlnoamld of the formula: CC _S H ₅ 809823/0628 wherein A ^{1 is} an ethylene or trimethylene radical, or a pharmacologically acceptable acid addition salt thereof. 24. Medicament according to claim 23 »characterized in that that it is in the form of a unit dose or a unit dose. 25. Medicament according to claim 23 »characterized in that the active ingredient consists of N- [2-0imethylamino) ethyl] -3 ^l , 4'-dichloropropionanllide or a pharmacologically acceptable acid addition salt thereof. 26. Medicament according to claim 23, characterized in that that the active ingredient consists of N- [3- (Dimethylamine) propyl] -3 ', V-dichloropropionanilide or a pharmacologically acceptable acid addition salt thereof. 27.Use of aminoamides of the formula: Il C-R CH _{: 1} where mean: A is a residue of the formulas - (CH ₉ )., -, - (CH ₉ ), -, - (CH ₀ ) /.-, 12 1 2 ^z * ^^ ² ^ - (CH ₂ ) ₅ -, -CH-CH ₂ -, -CH ₂ -CH- or -CH ₂ -CH-CH ₂ -; Cn, CtI, Cn, 809823/0628 X is a chlorine or broaatoa and R «Inen ethyl, cyclopropyl or vinyl radical, or their pharmaceutically acceptable acid addition salts, possibly gurmwan old a pharaaxeutic carrier, (in an effective manner) in the treatment of depressive disorders in mammals and humans. 28.Use of a forael eel noamide: CC ₂ M ₅ Jl CHi ^^ I P ^{= S} \ ^ N-A'-H- C. CHa ^ where A 'is an ethylene or trimethylene radical, or an a pharaakologically acceptable slurry addition salt a deaaelben gea & B Anapruoh 27. 809823/0628