CH638488A5 - N- (2-AMINOCYCLOHEPTYL) -N-ACYLANILIDES OR THEIR 2-N-OXIDES AND MEDICINAL PRODUCTS CONTAINING THEM. - Google Patents

Description

The invention relates to new N- (2-aminocycloheptyl) acylanilides in which the amino radical is primary or secondary. The compounds according to the invention are analogs to the compounds known from DE-OS 2 749 213, but the amino radical of which is tertiary. It has been shown that the compounds according to the invention, in contrast to the compounds of, for example, the formula IV of US Pat.

The compounds according to the invention correspond to the general formula:

R

I.

C I

N

NHR

in which mean:

P = 0 or 1;

Q oxygen or sulfur;

R is a Q to C3 alkyl, C3 to C6 cycloalkyl, vinyl, ethoxy or methoxymethyl radical;

Rj is hydrogen or a Q to C3 alkyl radical, the N, N-dimethylaminoethyl, N, N-dimethylaminopropyl, benzyl, phenethyl or a C3 to C6 alkenyl radical and

Y and Z, which may be the same or different, are hydrogen, fluorine, chlorine or bromine or the trifluoromethyl, methyl, ethyl, azido, methoxy or ethoxy radical, with the proviso that (1) if one of the radicals Y and Z represents the trifluoromethyl or azido radical, the other radical represents hydrogen, (2) if one of the radicals Y and Z represents hydrogen and the other represents the methoxy or ethoxy radical, the methoxy or ethoxy radical is in the m position of the benzene ring and (3) if the radicals Y and Z both represent halogen atoms or methoxy and / or ethoxy radicals, there is no substituent in the o-position of the benzene ring.

The compounds according to the invention can also be present as pharmacologically acceptable salts.

It has been shown that the salts and compounds of the formula I can be used for pharmaceutical purposes. Accordingly, the invention also relates to a medicament which is characterized in that it contains at least one new compound of the formula I or a pharmaceutically acceptable salt thereof as the active ingredient component. The medicinal products can contain the usual extenders, in solid or liquid form.

The compounds according to the invention and their pharmacologically acceptable salts can be used in the same fields of application and in the same amounts as the compounds known from DE-OS 2 749 213.

In the compounds according to the invention, the substituents can be in 1- and 2-positions in a relative trans or cis configuration.

Preferred compounds according to the invention and their salts are those of the formula I in which R represents a Ct to C3 alkyl radical, for example the ethyl radical, or a C3 to C6 cycloalkyl radical, R denotes hydrogen or a C 1 -C 3 -alkyl radical and at least one of the radicals Y and

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Z represents m-fluorine, m-chlorine, m-bromine, p-fluorine, p-chlorine or p-bromine or the m-trifluoromethyl radical, Y corresponds to the m-methyl radical and Z represents p-fluorine, p-bromine or p-chlorine means or Y corresponds to the p-methyl radical and Z represents m-fluorine, m-chlorine or m-bromine. In particular, one of the radicals Y and Z should represent fluorine, chlorine or bromine or the m-methoxy or m-ethoxy radical.

As a rule, the radical R 1 should expediently be hydrogen or a C 1 -C 3 -alkyl radical, preferably hydrogen or the methyl radical.

Examples of preferred compounds are: 3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] propionanilide;

3,4-dichloro-N- (2-aminocycloheptyl) propionanilide; 3-trifluoromethyl-N- [2- (N-methylamino) cycloheptyl] propionanilide;

3,4-dichloro-N- [2- (N-ethyamino) cycloheptyl] propionanilide;

3-chloro-4-methyl-N- [2-aminocycloheptyl] propionanilide;

4-chloro-3-methyl-N- [2- (N-methylamino) cycloheptyl] propionanilide;

3-chloro-N- [2- (N-methylamino) cycloheptyl] propionanilide;

4-chloro-N- [2-aminocycloheptyl] propionanilide; 3-bromo-N- [2-aminocycloheptyl] propionanilide and 3-fluoro-N- [2- (N-methylamino) cycloheptyl] propionanilide, and their pharmacologically acceptable salts. These compounds are preferably in the trans configuration.

Another preferred group of compounds of the stated formula (in addition to medicaments containing these) include those in which R represents a vinyl, C3 to C6 cycloalkyl, ethoxy or methoxymethyl radical, R! Hydrogen or a C 1 -C 3 -alkyl radical, preferably the methyl radical, and at least one of the radicals Y and Z for a halogen atom having an atomic number of 9 to 35, preferably in the 3- or 4-position, the trifluoromethyl radical in the 3-position or the methyl radical in the 3- or 4-position in combination with one of the halogen atoms mentioned in the adjacent 3- or 4-position. Of course, this preferred class of compounds also includes the pharmacologically acceptable salts of these compounds.

Examples of such compounds are: 3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] cyclopropane-carboxanilide;

3-trifluoromethyl-N- [2- (N-methylamino) cycloheptyl] cyclo

hexane carboxanilide; 3,4-dichloro-N- [2- (N-ethylamino) cycloheptyl] acrylanilide;

3-chloro-4-methyl-N- [2-aminocycloheptyl] carbäthoxyanilid; 3,4-dichloro-N- (2-aminocycloheptyl) acrylanilide;

4-chloro-3-methyl-N- [2- (N-methylamino) cycloheptyl] meth-oxyacetanilide;

3-chloro-N- [2- (N-methylamino) cycloheptyl] cyclobutanecarboxanilide;

4-chloro-N- [2-aminocycloheptyl] cycloheptane carboxanilide; 3-bromo-N- [2-aminocycloheptyl] acrylanilide and 3-fluoro-N- [2- (N-methylamino) cycloheptyl] carbäthoxy-

anilide,

especially in trans configuration, and their pharmacologically acceptable salts.

The compounds according to the invention have been used in standard laboratory animal experiments, e.g. the standard Yohim toxicity potentiation and the oxotremorine hypothermic antagonism test, strong antidepressant properties. Thus, the 2 primary or secondary aminocycloheptylanilides according to the invention can be used in appropriate pharmaceutical applications in appropriate doses, such as the N- [2- (N, N-disubstituted amino) cycloheptyl] anilides known from DE-OS 2 749 213.

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The trans compounds according to the invention which are indicated can be obtained using the following reaction formula, in which R! for a hydrogen atom or scheme:

Alkyl radical and p, Q, R, Y and Z have the indicated loading

0 * H; .1J -

purple

XI

y /

NU I

XIII

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The method is preferably carried out as follows:

The reaction of the cycloheptane oxide of the formula lilac with an aniline under known conditions leads to the formation of the N- (2-hydroxycycloheptyl) aniline of the formula IX which, on reaction with chlorosulfonic acid in a non-polar organic solvent, e.g. Methylene chloride, at a temperature of 20c to 30 ° C and then heating together with the respective Q to C3 monoalkylamine (aqueous) or ammonium hydroxide (aqueous) to a temperature of 100 ° to 150 ° C for 40 to 55 h at elevated pressure (2.03 to 10.13 bar), for example for 48 h in an autoclave at a temperature of 125 ° C., which gives the diamine of the formula X. When reacting the diamine of the formula X with 2,2,2-trichloroethylchloroformate or an equivalent N-blocking compound at a temperature of 20 ° to 30 ° C. in the presence of an acid scavenger, for. B. of triethylamine, a 2- (N-blocked amino) compound of the formula XI is obtained. A 12- to 30-hour acylation of the N-blocked compound of the formula XI with a suitable acid anhydride of the formula (RC0) 20 at a temperature of 90 ° to 120 ° C gives the N-blocked anilide of the formula XII. The protective group on the 2-amino function of the 2-N-blocked anilide of formula XII is then removed by reaction with an N-deblocking agent, e.g. Metal dust in an acid, such as zinc in acetic acid, in a polar organic solvent, e.g. Methanol, at a temperature of 20 ° to 100 ° C for 2 to 6 h. The work-up, isolation and cleaning are carried out in the usual known manner.

The cis compounds can be prepared by oxidation of the 2-hydroxycycloheptylanilide of the formula:

R

C = 0

with a known oxidizing agent, e.g. Jones reagent to form the ketone of formula:

R

C = 0

respectively.

The ketone obtained is then usually treated with ammonium azelate or with the Rj-NH, - (primary) amine in the presence of a reducing agent, e.g. B. of sodium cyano

borohydride, reacted, wherein an aminoanilide isomer mixture of the formula:

R

C = 0

Nil receives. In the chromatographic separation of the two isomers, the cis-aminoanilide (XIII-cis) can be separated off with Ri in the meaning given.

The compounds of formula XIII can be converted into compounds of formula I with Q equal to a sulfur atom by reaction with a suitable sulfur-containing compound by a method known for replacing the oxygen atom of the carbonyl radical bonded to the group R. Analogous processes can also be carried out if the radical R is not intended to represent an alkyl radical.

The following examples are intended to illustrate the invention in more detail.

example 1

trans-3,4-dichloro-N- (2- (N-methylamino) cycloheptyl] propionanilide and its p-toluenesulfonate salt

A) trans-N- (2-hydroxycycloheptyl) -3,4-dichloroaniline and its hydrochloride

A solution of 1.23 moles of 3,4-dichloroanilide, cyclophthaloxide and 2 ml of concentrated hydrochloric acid is heated to reflux temperature for 7 days, after which the unreacted epoxide evaporates at a temperature of 60 ° C. and the evaporation residue with excess ethereal hydrochloric acid is treated. Here you get a syrup. This is washed with 100 ml of ether, then brought to crystallization and recrystallized from a 1: 5.5 volume mixture of methanol and ether. This gives trans-3,4-dichloro-N- (2-hydroxycycloheptyl) aniline, hydrochloride.

B) trans-3,4-dichloro-N- (2-sulfonyloxycycloheptyl) aniline

A stirred solution / suspension of 1.0 mol of the amino alcohol salt obtained according to Part A trans-3,4-di-chloro-N- (2-hydroxycycloheptyl) aniline hydrochloride in 21 methylene chloride is mixed with 1.1 mols of chlorosulfonic acid in 500 within 4 h ml of methylene chloride are added. When about half of the acid solution is added, the amino alcohol has completely dissolved. After the mixture was stirred overnight, the precipitate formed was filtered off, washed with methylene chloride and ethyl ether and then dried in an oven at a temperature of 45 ° C., giving trans-3,4-dichloro-N- (2-sulfonyloxycycloheptyl) aniline is obtained.

C) trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline and its dihydrochloride

0.7 mol of the 3,4-dichloro-N- (2-sulfonyloxy-cycloheptyl) aniline obtained are reacted with 40% monomethylamine in water at a temperature of 125 ° C. for 48 hours, trans-3,4-dichloro-N - [2- (N-methylamino) cycloheptyl] aniline is formed in solution.

The reaction product mixture (about 1500 ml) is nuo with a 1: 1 volume mixture of water and ethyl ether

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washed, whereupon the organic layer is separated from the aqueous layer and the aqueous layer is extracted with 500 ml of ethyl ether. The combined ether layers are washed with 500 ml of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a brown oily residue. The brown oily residue obtained is chromatographed on 1500 g of silica gel. Elution is carried out with 101 ethyl acetate and 101 methanol, with 2000 ml fractions being collected. Fractions 6 to 10 contain the diamine product trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline. The preliminary run (fractions I to 5) consists of a mixture. This forerun is chromatographed again on 500 g of silica gel, eluting with 3000 ml of ethyl acetate and 2000 ml of methanol. 500 ml of eluate fractions are collected. Fractions 2 to 4 of this second chromatography form the preliminary run, fractions 5 to 10 contain more amine product. After evaporation of the solvent, the diamine fractions provide the diamine in the form of an orange oil. The oily diamine product obtained is converted into its hydrochloride with excess ethereal hydrochloric acid solution. The desired diamine hydrochloride is obtained by recrystallization from 1000 ml of methanol and about 1200 ml of ethyl ether.

A second reaction, starting from the amino alcohol, but without the pure presentation of the 2-sulfonyloxy compound obtained as an intermediate, is carried out as follows:

A stirred solution of the amino alcohol salt trans-3,4-dichloro-N- (2-hydroxycycloheptyl) aniline hydrochloride in 200 ml of chloroform is mixed with chlorosulfonic acid in 50 ml of chloroform within 15 minutes. The mixture is transferred to a warm water bath to accelerate the escape of the by-product hydrogen chloride. The reaction mixture, which is in the form of a solution, is then concentrated, whereupon the evaporation residue is dissolved in 100 ml of 40% monomethylamine in water. The mixture obtained is then heated to a temperature of 125 ° C. overnight in a bomb-shaped reactor. After the reaction mixture has cooled, it is extracted with 500 ml of ethyl ether. The ether extract obtained is washed with 200 ml of saturated sodium chloride solution, then dried over magnesium sulfate and finally evaporated to a yellow oil. The oil obtained as the evaporation residue is chromatographed on 300 g of silica gel, eluting with 31 ethyl acetate to remove the amino alcohol starting material. The oil in the chromatography column is then eluted with 3 l of methanol, 6.5 g of oily crude product being obtained after evaporation of the solvent. The resulting oily diamine product trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline is converted into its hydrochloride with excess ethereal hydrochloric acid solution. This is finally recrystallized in about 300 ml of ethyl ether with 40 ml of methanol, the desired diamine hydrochloride being obtained.

D) trans-3,4-dichloro- (N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cycloheptyllaniline hydrochloride

A mixture of 0.03 mol of triethylamine and 0.03 mol of the diamine released from its hydrochloride with sodium hydroxide trans-3,4-dichloro-N- [2-N-methylamino) -cycloheptyllaniline in 250 ml of ethyl ether is mixed with 0.03 mol 2,2,2-trichloroethyl chloroformate in 50 ml of ethyl ether was added, and the mixture was stirred at room temperature for 2 hours. After adding 100 ml of saturated sodium bicarbonate solution, the organic layer is separated off, dried over magnesium sulfate and concentrated to a yellow oil. This oil is made by treating it with excess

ethereal hydrochloric acid converted into its hydrochloride. The hydrochloride formed is finally recrystallized from a mixture of 120 ml of methanol and 400 ml of ethyl ether, giving trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cycloheptyl] aniline hydrochloride .

E) trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cycloheptyl] propionanilide

A mixture of 0.02 mol of the diamine prepared according to Part D and converted into the free base and 10 ml of propionic anhydride is heated on a steam bath overnight, after which 50 ml of water are heated again for 1 hour. The mixture is then diluted with 300 ml of ethyl ether. After the organic layer has been separated off, it is washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an orange oil. This gives 9.8 g of crude propionanilide in 100% yield.

In a test which ran over two stages without isolating the 2-N-blocked diamine (part D), 0.05 mol of 2,2,2-trichloroethylchloroformate in 50 ml of ethyl ether was converted into a mixture of 0. 05 mol of triethylamine and 16.6 g (0.05 mol) of the diamine trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline, which was liberated from its hydrochloride, in 400 ml of ethyl ether added.

After stirring for 2 hours at room temperature, 200 ml of a saturated aqueous sodium bicarbonate solution are added. After separating the organic layer, it is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a yellow oil. 30 ml of propionic anhydride are then added to the oil, and the solution obtained is heated on a steam bath overnight. After adding 150 ml of water, the mixture is heated with stirring for 1 hour, then made basic with 15% sodium hydroxide solution and finally extracted with ethyl ether. The ethyl ether extract obtained is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an orange oil, namely trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cycloheptyl] propionanilide.

F) trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] propionanilide and its p-toluenesulfonate salt

0.02 mol of the N-blocked propionanilide obtained according to Part E and 0.2 mol of zinc dust in 100 ml of 5% acetic acid in methanol are stirred for 3 hours at room temperature, then heated to reflux temperature for 1 hour and finally cooled to room temperature. The mixture is then filtered through a filter aid and washed with methanol. After evaporation of the solvent, the evaporation residue obtained is treated with 100 ml of 5N ammonium hydroxide solution and 250 ml of ethyl ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a yellow oil, namely trans-3,4-di-chloro-N- [2- (N-methylamino) cycloheptyl] propionanilide. The propionanilide obtained is converted into the p-toluenesulfonate by treating the oil with 3.4 g of p-toluenesulfonic acid in 20 ml of methanol and about 450 ml of ethyl ether.

Example 2

trans-3,4-dichloro-N- (2-aminocycloheptyl) propionanilide and its β-naphthylsulfonate salt

A) trans-3,4-dichloro-N- (2-aminocycloheptyl) aniline and its hydrochloride

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A mixture of 0.05 mole of 3,4-dichloro-N- (2-sulfonyl-oxycycloheptyl) aniline from Example 1, Part B and 50 ml of 17N ammonium hydroxide solution (0.85 mole) is placed in a sealed bottle for 48 hours heated to a temperature of 125 ° C. After the mixture has cooled to room temperature, the contents of the bottle are dissolved in a mixture of ethyl ether and water. The separated ethereal layer is washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a brown oil. The oil obtained is chromatographed on 300 g of silica gel, eluting with 2000 ml of ethyl acetate and 3000 ml of methanol. A thin layer chromatographic analysis of the last 2000 ml of methanol eluent shows that it contains the trans-3,4-dichloro-N- (2-amino-cycloheptyl) aniline. After evaporation of most of the methanol from the diamine, the evaporation residue is treated with excess ethereal hydrochloric acid solution to form the diamine hydrochloride. The salt formed is recrystallized from a mixture of about 5 ml of methanol and about 20 ml of ethyl ether to give the desired diamine hydrochloride.

B) trans-3,4-dichloro-N- [2- (N-trichloroethoxycarbonylamino) cycloheptyl] aniline and its hydrochloride

A mixture of 0.03 mol of the diamine from Part A, which had been released from the hydrochloride, and 0.03 mol of triethylamine in 250 ml of ethyl ether, after cooling in ice with 0.03 mol of 2,2,2-trichloroethylchloroformate in 25 ml of ethyl ether are added, whereupon the mixture obtained is stirred over the weekend at room temperature. After adding 200 ml of saturated sodium bicarbonate solution, the organic layer is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a yellow oily residue, namely the desired aniline. Its hydrochloride is obtained by treating the yellow oily residue with excess ethereal hydrochloric acid. The salt formed is recrystallized from a mixture of about 300 ml of methanol and 700 ml of ethyl ether, giving a first batch of the desired aniline salt. The filtrate is concentrated, whereupon the evaporation residue is recrystallized again from a mixture of 100 ml of methanol and about 500 ml of ethyl ether. This gives another batch of the desired aniline salt.

C) trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cycloheptyl] propionanilide

A mixture of 0.1 mol of trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cyclopentyl] aniline and 10 ml of propionic anhydride is heated on a steam bath overnight and after adding 50 ml of water heated again for 1 h. The mixture is then diluted with 300 ml of ethyl ether. After separating the organic layer from the aqueous layer, the former is washed with 50 ml of 15% sodium hydroxide solution and with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a yellow oil. This is saturated with ethyl ether and petroleum ether to give the desired N-blocked propionanilide.

D) trans-3,4-dichloro-N- (2-aminocycloheptyl) propionanilide and its β-naphthylsulfonate salt

A mixture of 0.01 mol of trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cycloheptyl] propionanilide from part C and 13.1 g (0.20 mol) of zinc dust in 100 ml of 5% acetic acid in methanol is stirred at room temperature overnight, whereupon the mixture is filtered through a filter aid and washed with methanol. The filtrate is evaporated to dryness, whereupon the evaporation residue is heated with 75 ml of 5N ammonium hydroxide solution and 250 ml of ethyl ether. After the Ab638 488

separate the ether layer, this is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a yellow oil. The latter is converted into its β-naphthylsulfonic acid salt with 3.62 g (0.016 mol) of [3-naphthylsulfonic acid in 20 ml of methanol and about 200 ml of ethyl ether.

Example 3

trans-3,4-dichloro-N- [2- (N-allylamino) cycloheptyl] propionanilide

A) trans-3,4-dichloro-N- [2- (N-allylamino) cycloheptyl] aniline

A mixture of 0.20 mol of 3,4-dichloro-N- (2-sulfo-cycloheptyl) aniline and 250 ml of a 50% aqueous allylamine solution is heated in an autoclave to a temperature of 125 ° C. for 48 hours, whereupon the The reaction mixture is washed out with 1500 ml of methanol. The methanolic solution obtained is evaporated until an oil appears as a separate layer. The oily layer is extracted with 500 ml of methylene chloride, then separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an orange oil. The oil obtained is then chromatographed on 600 ml of silica gel, eluting with 21 chloroform and 41 ethyl acetate. The ethyl acetate fraction is separated and evaporated to an oil. The oil is trans-3,4-dichloro-N- [2- (N-allylamino) cycloheptyl] aniline. The oily amine is converted into its hydrochloride with excess ethereal hydrochloric acid. The latter is recrystallized from a mixture of 450 ml of methanol and about 2000 ml of ethyl ether, giving trans-3,4-dichloro-N- [2- (N-allyl-amino) cycloheptyl] aniline hydrochloride.

B) trans-3,4-dichloro-N- [2- (N-allyl-N-trichloroethoxycarbonylamino) cycloheptyl] aniline and its hydrochloride

A mixture of 0.05 mol of the trans-3,4-dichloro-N- [2- (N-allylamino) cycloheptyl] aniline prepared according to Part A, which had been released from its hydrochloride, and 5.5 g (0 , 05 mol) of triethylamine in 400 ml of ethyl ether is added dropwise within 30 min while cooling the reaction vessel (in ice) with 10.6 g (0.05 mol) of 2,2,2-trichloroethylchloroformate in 50 ml of ethyl ether whereupon the mixture is stirred at room temperature overnight. The next day, 250 ml of saturated sodium bicarbonate solution are added, whereupon the organic layer is separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate and finally evaporated to an oil. This oil is crude trans-3,4-dichloro-N- [2- (N-allyl-N-trichloroethoxycarbonylamino) cycloheptyl] aniline. 1.0 g of the oily amine are converted into its hydrochloride with excess ethereal hydrochloric acid. This is recrystallized from a mixture of 15 ml of methanol and 80 ml of ethyl ether, the trans-3,4-dichloro-N- [2- (N-allyl-N-trichloroethoxycarbonylamino) cycloheptyl] aniline hydrochloride being obtained.

C) trans-3,4-dichloro-N- [2- (N-allyl-N-trichloroethoxycar bonylamino) cycloheptyl] propionanilide

A mixture of 0.05 mol of trans-3,4-dichloro-N- [2- (N-allyl-N-trichloroethoxycarbonylamino) cycloheptyl] aniline and 50 ml of propionic anhydride is heated on a steam bath overnight, then 250 ml of water are added and finally warmed for another 30 minutes. After cooling, the mixture is made basic with 15% sodium hydroxide solution and then extracted with ethyl ether. The separated organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a brown oil, the desired propionanilide. The crude product obtained is used in the next stage without purification.

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D) trans-3,4-dichloro-N- [2- (N-allylamino) cycloheptyl] propionanilide

A mixture of the resulting trans-3,4-dichloro-N- [2- (N-allyl-N-trichloroethoxycarbonylamino) cycloheptyl] propionanilide (about 0.05 mol) and 32.7 g (0.50 mol) Zinc dust in 250 ml of 5 volume percent acetic acid in methanol is stirred overnight at room temperature, then filtered through a filter aid and finally evaporated to an oil. The resulting oily residue is treated with 100 ml of a 15% sodium hydroxide solution and 300 ml of methylene chloride and then filtered to remove the excess zinc and zinc hydroxide. After separating the organic layer, it is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a yellow oil. The trans-3,4-dichloro-N- [2- (N-allylamino) cycloheptyl] propionanilide is finally converted into its oxalic acid salt and identified as this by analysis.

Example 4

trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] cyclopropanecarboxanilide and its p-toluenesulfonate salt (Method A)

A) trans-N- (2-hydroxycycloheptyl) -3,4-dichloroaniline and its hydrochloride salt

A solution of 200 g (1.23 moles) of 3,4-dichloroaniline, 400 ml of cycloheptenoxide and 2 ml of concentrated hydrochloric acid is heated to reflux temperature for 7 days, after which the unreacted epoxide is evaporated off at a temperature of 60 ° C. and the evaporation residue with excess ethereal hydrochloric acid is treated. This gives a syrup that is washed with 1000 ml of ether. The syrupy residue is then crystallized and recrystallized from a 1: 5.5 volume mixture of methanol and ether, giving trans-3,4-dichloro-N- (2-hydroxycycloheptyl) aniline, hydrochloride.

B) trans-3,4-dichloro-N- (2-sulfonyloxycycloheptyl) aniline

A stirred solution / suspension of 1.0 mole of the amino alcohol salt prepared according to Part A, trans-3,4-dichloro-N- (2-hydroxycycloheptyl) aniline hydrochloride in 21 methylene chloride, is mixed with 129 g (1.1 moles) of chlorosulfonic acid within 4 h added in 500 ml of methylene chloride. After adding about half of the acid solution, the amino alcohol has completely dissolved. The mixture is stirred overnight. The precipitate formed is then filtered off, washed with methylene chloride and ethyl ether and dried in an oven at a temperature of 45.degree. This gives trans-3,4-dichloro-N- (2-sulfonyloxycycloheptyl) aniline.

C) trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline and its hydrochloride salt

0.7 mol of 3,4-dichloro-N- (2-sulfonyloxycycloheptyl) aniline is converted into trans-3,4-dichloro-N- by reaction for 48 hours with 700 ml of 40% monomethylamine in water at a temperature of 125 ° C. [2- (N-methylamino) cycloheptyl] aniline converted into solution.

The reaction product mixture (about 1500 ml) is washed with a 1: 1 volume mixture of water and ethyl ether, whereupon the organic layer is separated from the aqueous layer. The aqueous layer is extracted with 500 ml of ethyl ether. The combined ether extracts are now washed with 500 ml of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a brown oil. The brown oil obtained is chromatographed on 1500 g of silica gel, eluting with 101 ethyl acetate and 10 ml of methanol and collecting 2000 ml fractions. Fractions 6 to 10 contain the diamine product trans-3,4-dichloro-N- [2- (N-methyl-

amino) cycloheptyl] aniline. The preliminary run (fractions 1 to 5) consists of a mixture. The forerun is again chromatographed on 500 g of silica gel, eluting with 3000 ml of ethyl acetate and 2000 ml of methanol. The eluate is collected in 500 ml fractions. Fractions 2 to 4 from the second chromatography form a preliminary run, fractions 5 to 10 contain more amine product. After the solvent has evaporated, the diamine fractions provide an oil. This oily diamine product is converted into its hydrochloride with excess ethereal hydrochloric acid solution.

The trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyljanilin formed is recrystallized from 1000 ml of methanol and about 1200 ml of ethyl ether.

A second reaction, starting from the amino alcohol and without purifying the 2-sulfonyl compound formed as an intermediate, is carried out as follows.

A stirred solution of 28.2 g of the amino alcohol salt trans-3,4-dichloro-N- (2-hydroxycycloheptyl) aniline hydrochloride in 200 ml of chloroform is mixed with 12.9 g of chlorosulfonic acid in 50 ml of chloroform within 15 minutes, whereupon the mixture is placed in a warm water bath to accelerate the escape of the hydrogen chloride formed as a by-product. The reaction mixture is then concentrated, whereupon the evaporation residue formed is dissolved in 100 ml of 40% monomethylamine in water. The mixture obtained in this way is heated to a temperature of 125 ° C. overnight in a bomb-shaped reactor and then cooled and finally extracted with 500 ml of ethyl ether. The ether extract obtained is washed with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to a yellow oil. The oily residue obtained is chromatographed on 300 g of silica gel, eluting with 31 ethyl acetate to remove the amino alcohol starting material. The oil in the chromatography column is then eluted with 3 ml of methanol, 6.5 g of oily crude product being obtained after evaporation of the solvent in 25% yield. This oily diamine product trans-3,4-dichloro-N- [2- (N-methylamino) cyclo-heptyl] aniline is converted into its hydrochloride with excess ethereal hydrochloric acid solution. The latter is recrystallized from 40 ml of methanol in about 300 ml of ethyl ether.

D) trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cycloheptyl] aniline hydrochloride

A mixture of 3.03 g (0.03 mol) of triethylamine and 0.03 mol of the free diamine trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline, which was prepared with sodium hydroxide from its hydrochloride had been released, in 250 ml of ethyl ether, 6.36 g (0.03 mol) of 2,2,2-trichloroethyl chloroformate in 50 ml of ethyl ether were added, and the mixture was stirred at room temperature for 2 hours. After adding 100 ml of saturated sodium bicarbonate solution, the organic layer is separated off, dried over magnesium sulfate and concentrated to a yellow oil. The oily residue obtained in this way is converted into its hydrochloride by treatment with excess ethereal hydrochloric acid. The hydrochloride obtained is recrystallized from a mixture of 120 ml of methanol and 400 ml of ethyl ether.

E) trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cycloheptyl] cyclopropane carboxanilide

A mixture of the 2-N-blocked diamine prepared according to Part D, which had been converted into its free base, and an equimolar amount of cyclopropane-carboxylic anhydride is heated on a steam bath overnight. After adding water, the mixture is again

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5

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15

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35

40

45

SO

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60

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Heated for 1 hour. The mixture is then diluted with ethyl ether, the organic layer separated, washed with 15% sodium hydroxide solution and then saturated sodium chloride solution, dried over magnesium sulfate and finally concentrated to an oil, the desired cyclopropane carboxanilide.

In a further two-stage experiment without isolating the 2-N-blocked diamine (part D), 10.6 g (0.05 mol) of 2,2,2-trichloroethylchloroformate in 50 ml of ethyl ether are mixed with cooling within 30 minutes Ice in a mixture of 5.06 g (0.05 mol) of triethylamine and 0.05 mol of the diamine trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] aniline, which is derived from its hydrochloride had been released, entered in 400 ml of ethyl ether. After stirring for 2 hours at room temperature, 200 ml of saturated sodium cicarbonate solution are added, whereupon the organic layer is separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate and finally concentrated to a yellow oil. The oil is then mixed with cyclopropanecarboxylic anhydride. The solution thus obtained is heated on a steam bath overnight. After adding water, the mixture is stirred under heat for an additional hour. The mixture is then made basic with 15% sodium hydroxide solution and extracted with ethyl ether. The ethyl ether extract obtained is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. The oil is the desired cyclopropane carboxanilide.

F) trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] cyclopropanecarboxanilide and its p-toluenesulfonate salt

The N-blocked cyclopropanecarboxanilide from Part E and a large excess of zinc dust in 5% acetic acid in methanol are stirred at room temperature for 3 hours, then heated to reflux temperature for 1 hour and finally cooled to room temperature. After filtering the mixture through a filter aid, the filter residue is washed with methanol. The solvent is evaporated from the filtrate, whereupon the evaporation residue is treated with 5N ammonium hydroxide and ethyl ether. The ethyl ether extract obtained is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil. The oil is the desired cyclopropane carboxanilide. This is converted into its p-toluenesulfonate salt by treating the oil with p-toluenesulfonic acid in a solvent mixture of methanol and ethyl ether.

Example 5

trans-3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] cyclopropanecarboxanilide and its p-toluenesulfonate salt (Method B)

A mixture of 3,4-dichloro-N- [2- (N-methylamino) -cycloheptyljcyclopropanecarboxanilide, which had been released from its oxalate salt with sodium hydroxide, and an excess of mercury (II) acetate in 5% acetic acid in water becomes about Heated on a steam bath for 3 days. The precipitate is filtered off and washed with 10% hydrochloric acid. A small amount of precipitate is filtered off, after which the filtrate is made basic with concentrated ammonium hydroxide and then extracted with ethyl ether. The ether extract obtained is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil.

9 638 488

The oil obtained is converted into its p-toluenesulfonate salt with p-toluenesulfonic acid in methanol and ethyl ether. After recrystallization, the desired cyclopropanecarboxanilide salt is obtained.

5

Example 6

trans-3,4-dichloro-N- (2-aminocycloheptyl) acrylanilide and its β-naphthylsulfonate salt

A) trans-3,4-dichloro-N- (2-aminocycloheptyl) aniIin and

10 its hydrochloride

A mixture of 16.3 g (0.05 mol) of 3,4-dichloro-N- (2-sulphonyloxycycloheptyl) aniline and 50 ml of 17n-ammonium hydroxide (0.85 mol) is placed in a sealed bottle for 48 hours heated to a temperature of 125 ° C and then cooled to 15 room temperature. The contents of the bottle are dissolved in a mixture of ethyl ether and water. After separation, the ethereal layer is washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a brown oil. The oil obtained is chromatographed on 300 g of silica gel, eluting with 2000 ml of ethyl acetate and 3000 ml of methanol. A thin layer chromatographic analysis of the last 2000 ml of methanol eluent shows that it contains the desired diamine product. After the major part of the methanol is evaporated from the amine, the residue is treated with excess ethereal hydrochloric acid to obtain the desired diamine hydrochloride salt.

B) trans-3,4-dichloro-N- [2- (N-trichloroethoxycarbonyl-30 amino) cycloheptyl] aniline and its hydrochloride

A mixture of 0.03 mol of the diamine from Part A, which had been released from its hydrochloride, and 3.03 g (0.03 mol) of triethylamine in 250 ml of ethyl ether is cooled with ice in 6.36 g (0, 03 mol) of 2,2,2-trichloroethyl-35 chloroformate in 25 ml of ethyl ether, whereupon the mixture obtained is stirred at room temperature over the weekend. After adding 200 ml of saturated sodium bicarbonate solution, the organic layer is separated off, washed with saturated sodium chloride solution, dried over 40 magnesium sulfate and concentrated to a yellow oily residue, the desired aniline. Its hydrochloride salt is obtained by treating the yellow oily residue with excess ethereal hydrochloric acid. The salt is recrystallized from a mixture of about 300 ml of methanol 45 and 700 ml of ethyl ether to give a first batch of the desired aniline salt. The filtrate is then evaporated, whereupon the evaporation residue is recrystallized again from a mixture of 100 ml of methanol and about 500 ml of ethyl ether. Here you get another batch of aniline salt.

C) trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cycloheptyl] acrylanilide

A mixture of trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cycloheptyl] aniline and an equimolar amount of acrylic acid anhydride is heated on a steam bath overnight, whereupon water is added and the mixture is heated again for 1 h. After dilution with ethyl ether, the organic layer which forms is separated from the aqueous layer, washed with 15% sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness, giving the desired N-blocked acrylic anilide compound.

65 D) trans-3,4-dichloro-N- (2-aminocycloheptyl) acrylanilide and its β-naphthylsulfonate salt

A mixture of the trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonyl-

638488

amino) cyclopentyl] acrylanilide and a large molar excess of zinc dust in 5% acetic acid in methanol is stirred at room temperature overnight, after which the mixture is filtered through a filter aid. After washing the filter residue with methanol, the combined filtrate is evaporated. The evaporation residue formed in this process is mixed with 5n ammonium hydroxide and

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Ethyl ether warmed. After the aqueous layer has been separated off, the ethereal layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil. This is converted into its ß-naphthylsulfonic acid salt using an equi-5 molar amount of ß-naphthylsulfonic acid in methanol / ethyl ether.

Claims (2)

638488 2nd PATENT CLAIMS 1. N- (2-aminocycloheptyl) -N-acylanilides or their 2-N-oxides of the formula R I. in which mean: P = O or 1; Q oxygen or sulfur; R is a Cr to C3 alkyl, a C3 to C6 cycloalkyl, the vinyl, ethoxy or methoxymethyl radical; R, hydrogen, a C, - to C3-alkyl radical, the N, N-dimethylaminoethyl, N, N-dimethylaminopropyl, benzyl or phenethyl radical or a C3 to C6 alkenyl radical and Y and Z, which may be the same or different, are hydrogen, fluorine, chlorine or bromine or the trifluoromethyl, methyl, ethyl, azido, methoxy or ethoxy radical, with the proviso that if (1) one of the substituents Y or Z is the trifluoromethyl or azido radical, the other is hydrogen, if (2) one of the substituents Y or Z is hydrogen and the other is methoxy or ethoxy, the methoxy or ethoxy group is in the m-position Benzene ring is, and if (3) both substituents Y and Z are halogen atoms, methoxy and / or ethoxy groups, there is no substituent in the o-position on the benzene ring, or their pharmacologically acceptable salts. 2. Pharmaceutical composition, characterized in that it contains at least one new compound of the formula as active ingredient R I. (0), wherein P 0 or 1 Q oxygen or sulfur R is a C, - to C3-alkyl, a C3 to C6-cycloalkyl, the vinyl, ethoxy or methoxymethyl radical R! Hydrogen, a Q to C3 alkyl, the N, N-dimethylaminoethyl, N, N-dimethylaminopropyl, benzyl or phenethyl or a C3 to C6 alkenyl and Y and Z, which may be the same or different, hydrogen, fluorine, chlorine or bromine or the trifluoromethyl, methyl, ethyl, azido, methoxy or ethoxy radical means with the proviso that if (1) one of the substituents Y or Z is the trifluoromethyl or azido radical, the other (I) is hydrogen if (2) one of the substituents 10 Y or Z is hydrogen and the other is the methoxy or ethoxy radical, the methoxy radical or ethoxy group in the m-position on the benzene ring, and if (3) both substituents Y and Z represent halogen atoms, methoxy and / or ethoxy groups, there is no substituent in the o-position on the benzene ring, or a pharmacologically acceptable salt Contains compound of formula I. 3. Composition according to claim 2, characterized in that in the compound of formula IR a 20 C3- to C6-cycloalkyl radical and Rx are hydrogen or a Cj-to C3-alkyl radical and that at least Y or Z denotes an m or p-fluorine, m or p-chlorine, m or p-bromine atom or the m-trifluoromethyl radical, or that Y is the m-methyl radical and Z is a p-fluorine, p-chlorine or p-25 bromine atom, or that Y is a p-methyl radical and Z is an m-fluorine, m Represents chlorine or m-bromine. 4. Composition according to claim 3, characterized in that in the compound of formula I at least one of the substituents Y or Z fluorine, chlorine or 30 represents bromine or the m-methoxy or m-ethoxy group. 5. Composition according to claim 2, characterized in that it is 3,4-dichloro-N- (2-aminocycloheptyl) propionanilide or a pharmacological Contains 35 gisch acceptable salt of the same. 6. Composition according to claim 2, characterized in that it contains 3,4-dichloro-N- [2- (N-methylamino) cycloheptyl] propionanilide or a pharmacologically acceptable salt thereof as the active component. 40 7. Composition according to claim 2, characterized in that in the compound of formula IR is a Ct to C3 alkyl radical and Rj is hydrogen or a Q to C3 alkyl radical and at least one of the substituents 45 th Y or Z represents chlorine or bromine in the m- or p-position of the phenyl ring. 8. The composition according to claim 7, characterized in that it contains 3,4-dichloro-N- [2- (allylamino) cycIoheptyl] propionanilide or a phar- Contains 50 macologically active salt of the same. 9. The composition according to claim 2, characterized in that in the compound of formula IR the vinyl radical and Rj is hydrogen or a Cj- to C3-alkyl 55 are radical and at least one of the substituents Y or Z represents chlorine or bromine in the m- or p-position of the phenyl ring. 10. The composition according to claim 9, characterized in that it is 3,4-dichloro-N- as the active component Contains [2-aminocycloheptyl] acrylanilide or a pharmacologically acceptable salt thereof. (I>