DE1110159B - Process for the preparation of analeptically active N-substituted amino orcamphan derivatives or of their acid addition salts and quaternary ammonium compounds - Google Patents

Description

GERMAN

PATENT OFFICE

kl. 12 o 25

INTERNATIONAL KL.

C07c; d

M 42332 IVb / 12 ο

REGISTRATION DAY:

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL. ·

August 1st, 1959

JULY 6, 1961

From the Belgian patents 557 666 and 557 667 alkyl-substituted 6-aminobicyclo- [2,2,1] -heptanes and -heptenes have become known, which have ganglion-blocking effects. One The N-substituted compounds described in German Patent 1,039,061 have a similar effect Derivatives of 3-aminoisocamphane which have two methyl groups in the 2-position and on the nitrogen atom are substituted by lower alkyl radicals. Furthermore, in the German patent specification 1 001 257, the production of 1,4-endomethylenecyclohexylamines that increase blood pressure described. In addition, Experientia, Vol. 14, 1958, p. 222, on the antihypertensive and ganglia-blocking effects of methylene-substituted 3-aminonorcamphans have been reported.

The present invention relates to the preparation of new analeptically active N-substituted amino orcamphan derivatives as well as the conversion of these compounds into their acid addition salts or quaternary Ammonium compounds.

It has been found that the compounds of the general formula II

R ₃

(CH ₂ );

Z) X

n
R ₂

procedure

to produce more analeptically effective
N-substituted amino orcamphan derivatives

or of their acid addition salts
and quaternary ammonium compounds

Applicant:

E. Merck Aktiengesellschaft,
Darmstadt, Frankfurter Str. 250

Dipl.-Chem. Dr. Jan Thesing,

Nieder-Ramstadt-Trautheim via Darmstadt,

Dipl.-Chem. Dr. Georg Seitz, Dr. med. Rudolf Hotovy and Dr. med. Siegmund Sommer, Darmstadt,

have been named as inventors

where R ₁ = aryl, aralkyl, cycloalkyl or a heterocyclic radical and these radicals can be functionally or monosubstituted or polysubstituted by a hydrocarbon radical, R ₂ = H, alkyl or aryl, R ₃ and R ₄ = H, alkyl, cycloalkyl or Aralkyl and these radicals can be the same, different or components of a ring which may contain further heteroatoms, but both radicals R ₃ and R _{4 cannot be} H or methyl at the same time, and .v = 1 or 2, as well as their acid addition salts and quaternary Ammonium compounds have strong analeptic effects without increasing blood pressure or affecting the heart. The new compounds are extremely well tolerated and show no side effects. Compared to the most similar compound known from the literature, 2-phenyl-3-dimethylaminobicyclo- [2.2, l] -heptane, the compounds prepared according to the invention show a significant increase in activity. So is z. B. the 2-phenyl

3-methyläthylaminobicyclo- [2.2, l] -heptane twice that 2-phenyl-3-äthylaminobicyclo- [2.2, l] -heptane and 2-phenyl-3-diethylaminobicyclo- [2.2, l] -heptane three times more effective than the known compound.

It has also been found that the new compounds can be made by making a compound of the general formula I.

(CH ₂ ) ,!

NH ₂
R ₂

wherein R ₁ , R ₂ and χ have the meaning given above, monosubstituted or polysubstituted in a manner known per se and optionally converting the compounds of general formula II thus obtained into their acid addition salts or quaternary ammonium compounds.

109 620 / 44S

The process according to the invention proceeds according to the following reaction scheme:

.Ν:

(CH ₂ ),

III

R ₁ to R ₄ and x have the meaning given, R ₅ = alkyl or aralkyl, X = physiologically harmless anion.

The invention therefore relates to a process for the preparation of N-substituted compounds with analeptic activity Aminonorcamphanderivate, which consists in that one compound of the general formula I. (see. Reaction scheme) according to known substitution methods in a corresponding, am Nitrogen atom mono- or disubstituted compound of the general formula II is converted and that one optionally the amine of the general formula II prepared in this way by treatment with a Converts acid into an acid addition salt of the general formula III or according to known methods Quaternization methods in a quaternary ammonium compound of the general formula IV converted.

The compounds of the general formula II can be substituted by any of the customary methods of hydrogen atoms linked to a nitrogen atom from the corresponding primary amines are prepared in a manner known per se.

So you can, for example, the compounds of general formula I with alkyl or aralkyl halides converted in the usual way into the compounds mono- or disubstituted on the nitrogen. One can they also condense with aldehydes to form Schiff bases and either hydrogenate them or treat with an alkylating agent and then hydrolyze. Likewise one arrives at the new compounds of general formula II, if you have an amine of general formula I with an aldehyde in the presence of formic acid. Also the implementation of an amine of the general Formula I with alcohol in the presence of Raney nickel and its acylation and subsequent Reduction, for example with lithium aluminum hydride, can be carried out with good success will.

The acid addition salts are obtained by treating a compound of the general formula II with an acid of the general formula III. For this implementation, those acids come into question that Deliver physiologically harmless salts. For example, you can make the following salts: Chloride, orthophosphate, nitrate, sulfate, maleate, fumarate, citrate, tartrate, oxalate, methane sulfate, Sodium disulfonate, hemisuccinate, propionate, butyrate and acetate.

The quaternary compounds of the general formula IV can be prepared by Implementation of a compound of the general formula II with all compounds suitable for quaternization, z. B. alkyl or aralkyl halides or dialkyl sulfate.

The primary amines used as starting material can be used in a manner known per se, for. B. following the procedures in J. Am. Chem. Soc, Vol. 61, 1939, p. 521; Vol. 73, 1951, p. 5068, and J. Org. Chem., Vol. 8, 1943, p. 373, by diene addition of ω-nitrostyrene or ring-substituted and / or / S-methylated Nitrostyrene derivatives of cyclopentadiene or cyclohexadiene and subsequent hydrogenation, which in can be done in one operation or in stages. In the same way you can go to Use dicyclopentadiene in place of cyclopentadiene.

Some of the compounds obtainable according to the invention are compiled in the table below:

No. R ₁ R ₂ R ₃ R ₅ CH ₃ R ₅ χ M.p. hydrochloride (a)
Bp base (b) 1 C ₆ ed H H C ₂ H ₅ H 1 a = 198 ° C 2 C ₆ H ₅ H H C ₂ H ₅ H 1 a = 192 ° C 3 H C ₂ ed C ₂ H ₅ H 1 a = 222 ° C 4th QH ₅ H CH ₃ ι C ₃ H ₇ H 1 a = 200 ° C 5 C ₆ H ₅ H H l C ₃ H ₇ H 1 a = 206 ° C 6th C ₆ H ₅ H CH ₃ Cyclohexyl H 1 b = 138 ° C (2 mm Hg) 7th QH ₅ H H Cyclohexyl H 1 b = 145 ° C (0.05 mm Hg) 8th QH ₅ H CH ₃ n -C ₃ H ₇ H 1 b = 165 ° C (0.1 mm Hg) 9 C ₆ H ₅ H H η - C ₄ H ₉ H 1 a = 184 ° C 10 QH ₅ H H η - C ₃ H ₇ H 1 a = 185 ° C 11 C ₆ ed H C ₂ H ₅ CH ₃ H 1 a = 175 ° C 12th C ₆ ed H H C ₆ H ₅ CH ₂ H 2 a = 272 ° C 13th C ₆ ed H H C ₆ H ₅ - C ₂ H ₄ H 1 a = 184 ° C 14th QHg H C ₂ H ₅ C ₆ H ₅ - C ₂ H ₄ H 1 b = 61 ° C 15th C ₆ ed H H (C ₆ Hg) ₂ - C ₃ H ₅ H 1 a = 254 ° C 16 QHg H H R ₃ + R ₄ H 1 a = 274 ° C Pyrrolidino 17th QHg H Piperidino H 1 a = 216 ° C 18th QHg H Morpholino H 1 a = 222 ° C 19th C ₆ ed H H 1 a = 258 ° C

The new compounds can be used as analeptics in human medicine. Since they The new compounds can neither increase blood pressure nor affect heart activity In contrast to the previously known analeptics, also administered to hypertensive patients.

example 1
2-phenyl-3-methylaminobicyclo- [2,2,1] -heptane

37.46 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane are heated with 22 g of benzaldehyde for 10 minutes on the steam bath. The Schiff base formed is freed from the water formed in the reaction by evacuation, mixed with 20 g of dimethyl sulfate and the mixture is heated to 80 to 85 ° C. for 4 hours. After cooling, it is dissolved in water and acidified with a little hydrochloric acid and washes off the benzaldehyde produced with ether. The acidic solution is made alkaline with sodium hydroxide solution and the deposited base is taken up in ether. The evaporation residue of the ether gives 28 g of base with bp ₂₅ = 158 to 162 ° C. during distillation.

The hydrochloride prepared in ethyl acetate with ethereal hydrochloric acid melts after Recrystallize from benzene-petroleum ether at 198 ° C.

Example 2
2-phenyl-3-ethylaminobicyclo- [2,2,1] -heptane

a) 28.05 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane are mixed with 6.9 g of acetaldehyde with cooling. The mixture is refluxed for a further 20 minutes on the steam bath and freed Reaction product in vacuo at 60 ° C from the water. The crude base is dissolved in 300 ecm of methanol and Hydrogenated with 2 g of pre-reduced platinum oxide. After taking up the calculated amount of hydrogen, distilled the solvent is removed in vacuo, the residue is taken up in dilute hydrochloric acid and shaken neutral by-products with ether. The aqueous solution is made alkaline with sodium hydroxide solution and

etherified. 13.2 g of base with bp _{0) 1} = 128 to 131 ° C. are obtained from the ethereal solution.
The hydrochloride melts after recrystallization from acetone at 192 ° C.

b) 25 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane are combined with 15 g of Raney nickel and 75 ecm absolute Alcohol refluxed for 15 hours. The filtrate from the catalyst is neutralized with dilute Hydrochloric acid and concentrate it to dryness in a vacuum.

The hydrochloride remaining as residue is purified by recrystallization from acetone or dioxane-petroleum ether. Yield 21.5 g mp. 191 ⁰ C.

The compound does not give a depression of the melting point with the substance prepared according to a).

Example 3
2-phenyl-3-diethylaminobicyclo- [2,2,1] -heptane

3.8 g of the 2-phenyl-3-äthylaminobicyclo- [2.2, prepared according to Example 2, 1] -heptane hydrochloride with 20 ecm pyridine and 3.8 g acetic anhydride Stored for 12 hours at room temperature. The solution that became clear while standing becomes distilled to dryness in vacuo. The residue is rubbed with water, the insoluble in Ether and washes the ether with dilute acid, bicarbonate solution and water. The as off

Crystallized acetyl compound obtained from vapor residue of the ether (2.6 g) is processed further as a crude product. They are dissolved in 20 ecm of absolute ether and a small excess of lithium alanate is added to them in 25 ecm absolute ether. The mixture is then stirred at room temperature for 2 hours and refluxed for a few more minutes. Carefully add 5 g of tartaric acid in 50 ecm of water mixed solution is strongly alkalized with sodium hydroxide solution. From the separated ether one obtains the one we are looking for Base as evaporation residue. After dissolving in ethyl acetate and adding ethereal hydrochloric acid 2.6 g of hydrochloride are obtained, which melts at 222 ° C. after recrystallization from acetone.

7 8

Example 4 Example 9

2-phenyl-3-cyclohexylaminobicyclo- [2,2,1] -heptane 2-phenyl-3-morpholinobicyclo- [2,2,1] -heptane

18.7 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane are made from 9.35 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane

that with 10 g of cyclohexanone at 100 ° C. for 20 hours and 7.9 g of β / S'-dichlorodiethyl ether are obtained analogously

warmed up. The mixture is cooled and the crude Example 7 2-phenyl-3-morpholinobicyclo- [2,2,1] -

Schiff's base in 180 ecm of methanol and hydrogenated with heptane hydrochloride with a melting point of 258 ° C.
after adding 2 g of pre-reduced platinum oxide

3 atü. After 30 minutes, the hydrogen uptake is Example 10

completed. The catalyst is filtered off and io.

from the concentrated filtrate after the distillation 2-phen _y l-3-benz _y lammobicyclo- [2.2, l] -heptane

18.2 g of base from ₀ bp, ₀₅ = 145 ° C. 74.8 g of 2-phenyl-3-aminobicyclo [2,2, l] heptane 26.6 g of benzyl chloride are 8 hours at ^155. C.

Example 5 heated. The reaction mixture obtained is rubbed

. ,. . . "", 15 with absolute ether on, filtered, washes the filtrate

2-phenyl-3-cyclohexylmethylaminobicyclo- [2,2, l] - _zwe i _ma l with water and neutralized with sodium

heptane sulfate dried ethereal solution with hydrochloric acid gas.

10.75 g of the 2-phenyl prepared according to Example 4 The amorphous hydrochloride which precipitates is crystalline 3-cyclohexylaminobicyclo- [2.2, l] -heptane are lysed when rubbed with acetone. After around 5.5 g of formic acid and 3.82 ecm of 33% by volume crystallize from isopropyl alcohol — ether, the formaldehyde solution is heated to 100 ° C for 4 hours. the melting point 184 ° C.
After cooling, the mixture is made alkaline with dilute sodium hydroxide solution and extracted with ether. Example 11

From the ether one receives 9.6 g of base with bp ₀ , i - _{n ,,, rxT} fO,, ..., _{1X xr} ..,., "

= 165 "C 25 2-phenyl-3- [N - (/ S-phenylethyl) -N-ethyl] -

~. , aminobicyclo- [2,2,1! -heptane

Example 6 ^{JLJ v}

, ..., "". ,,, 21.5 g of 2-phenyl-3-ethylaminobicyclo- [2.2, l] -heptane

2-Phenyl-3-äthylpropylaminobicyclo- [2.2, l] -heptane _{and 9 <25 g} ^ phenylethyl bromide are 20 hours

43.07 g of the 2-phenyl obtained according to Example 2 are heated to 160.degree. You rub the cooled down

3-äthylaminobicyclo- [2.2, l] -heptans are combined with 12.3 g of reaction product with absolute ether, sucks off,

n-Propyl bromide for 12 hours in a sealed tube, the filtrate washes with water and dries with it

120 ^: C heated. After cooling, the sodium sulfate is diluted. When evaporating the filtered ethereal

the mixture with absolute ether separates the solution, the base crystallizes out and melts again

divorced 2-phenyl-3-äthylpropylaminobicyclo- [2.2, recrystallization from methanol at 6I ⁰ C.
1] -heptane hydrobromide and shakes the ether 35

Solution of the reaction product with a little acetic acid - Example 12

anhydride and so much soda that the mixture is alkaline "_,, _", ...,, ·, -, _r *> -. π ι

remain. From the ethereal solution, the sought-after base becomes ^ phenyl ^ -phenylethylaminobicyclo- ^ Jl-heptane

obtained as evaporation residue with bp j = 138 ° C. Analogously to Example 11, reaction is obtained

The hydrochloride melts at 175 ° C. 40 of 2-phenyl-3-äthylaminobicyclo- [2.2, l] -heptane with

jS-phenylethyl chloride 2-phenyl-3- / S-phenylethyl-

Example 7 aminobicyclo- [2,2,1] -heptane hydrochloride. Melting point 254 ⁼ C after recrystallization from water.
2-phenyl-3-pyrrolidinobicyclo [2,2,1] heptane

9.35 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane are 45 Example 13

the one with 11.8 g of tetramethylene bromide and 50 g of 10% iger ^ -Phenvl-S-iv-diDhenvloroDvn-

Sodium hydroxide solution for 10 hours with stirring under reflux -SLt 2 ηί? Γ2

cooked cooler. The oily base becomes after the abaminobicyclo- [2.2, l] -heptane

cool and extract from the ethereal solution with 6.25 g /?, / 3-diphenylacrolein with 5.62 g

extracted from dilute hydrochloric acid. The from the acid 50 2-phenyl-3-aminobicyclo- [2.2, l] -heptane in 100 ecm

the base, which separates out during alkalization, is refluxed for 10 minutes with methanol. the

etherified and from the solution of the Schiff's base obtained with sodium sulfate dried in this way is after

neten ether obtained by evaporation. Addition of 2 g of platinum oxide hydrogenated at 6 atm and 50 ° C,

The residue is taken up in acetone, neutral, with the calculated hydrogen uptake in a few Sizes it with essential hydrochloric acid and gets done after 55 minutes. From the addition of the catalyst of ether 12.3g of crude 2-phenyl-3-pyrrolidino-filtered solution is obtained on concentration to bicyclo- [2.2, l! -heptane hydrochloride from the melting point. Dry the base, which is converted into the 207 ° C. When recrystallizing from acetone or hydrochloride is converted. Yield 10.5 g of Dioxane, the melting point rises to 216 ° C. Mp. 274 ° C.

⁶⁰ Example 14

^{Example 8} 2-Phenyl-3- (l '- * - methylnaphthyl) -

2-phenyl-3-piperidinobicyclo- [2.2.1] -heptane aminobicyclo- [2.2.1] -heptane

Analogously to Example 7, 19.4 g of 2-phenyl-3-aminobicyclo- [2.2, l] -heptane are obtained by reaction

of 9.35 g of 2-phenyl-3-aminobicyclo- [2.2.1] -heptane with 65 den with 9.3 g of -chloromethylnaphthalene in 130 ecm

12.65 g of pentamethylene bromide 2-phenyl-3-piperidino-toluene boiled under reflux for 20 hours. the

bicyclo- [2,2,1! -heptane hydrochloride, which after the cooled toluene solution is washed with water,

Recrystallize from acetone at 222 ° C melts. dried and the toluene was distilled off. The back

• 5

stand you solve in ^; Isopro> yl alcohol oil and neutralizes it with essential hydrochloric acid. 12 g of hydrochloride crystallizes out; which melt after recrystallization from isopropyl alcohol ether at 177 ° C.

Example 15

2-phenyl-3-N- (l '- «- methylnaphthyl) -N-methylaminobicyclo- [2,2,1] -heptane

6.0 g of 2-phenyl-3- (l '- «- methylnaphthyty-aminobicyclo- ίο [2.2, l] -heptane hydrochloride are mixed with 1.84 g of formaldehyde solution (30%), 1.13 g of sodium formate, 1.53 g Formic acid and 3 ecm of absolute alcohol heated to 90 to 100 ° C for 15 hours. One distills the Alcohol is removed, the residue is taken up in a little water and the solution is made alkaline with sodium hydroxide solution. The precipitating base is extracted with ether, the ether solution is dried with sodium sulfate, filtered and the Ether distilled off. The residue is dissolved in ethyl acetate and neutralized with ethereal Hydrochloric acid, 4.3 g of hydrochloride being obtained, the melting point of which after recrystallization 243 ° C.

Example 16
2-p-cumyl-3-ethylaminobicyclo- [2,2,1] -heptane

5.1 g of p-cumyl-3-aminobicyclo- [2,2,1] -heptane become boiled with 1 g of Raney nickel in 20 ecm of absolute alcohol for 48 hours under reflux and stirring. The solution is filtered off from the catalyst, it is washed with alcohol and the alcohol is evaporated off the filtrate. The residue is dissolved in 100 ecm of ether and exhausted with dilute acetic acid shaken out. The base set free by alkalizing the acetic acid extracts is taken in ether up, dries the ethereal solution with sodium sulfate and acidifies it with ethereal hydrochloric acid. To If you stand for a long time, the precipitated crystals are suctioned off, washed with ether and dried. 4.8 g of hydrochloride are obtained, which after recrystallization from alcohol-ether at 206 to 207 ° C melts.

Example 17
2- (p-Cumyl) -3-benzylaminobicyclo- [2,2,1] -heptane

45

2.6 g of 2 - (p - cumyl) - 3 - aminobicyclo - heptane with 0.81 g of benzyl chloride 8 hours to 155 ⁰ C heated - [2,2, I]. The cooled reaction mixture is taken up in ether and washed several times with water. The ether solution is the reaction product extracted by repeated shaking with 10 ⁰ / cent acetic acid. The acetic acid extracts are made alkaline with caustic soda and etherified. The hydrochloride is obtained from the ethereal solution, dried with sodium sulphate and slightly concentrated, when neutralized with ethereal hydrochloric acid. It can be recrystallized from absolute alcohol with the addition of ether and melts at 211 ^° C. The yield is 1.0 g.

Example 18

2-p-Ethoxyphenyl-3-butylaminobicyclo- [2.2.1] -heptane

7 g 2-p-ethoxyphenyl-3-aminobicyclo [2,2, l] -heptane are with 2.2 g of n-butyraldehyde and heated 20 minutes 100 ⁰ C. The formed Schiff base is dissolved in 100 ecm of methanol and shaken under hydrogen after adding 1 g of platinum oxide. When the hydrogen uptake is complete, the catalyst is filtered off, the filtrate evaporated in vacuo ^'1 dryness, the residue taken up in water, alkalized with sodium hydroxide and extracted with ether. The ether solution is dried with sodium sulphate, filtered and the ether is distilled off. The residue left is 5 g of base, which are dissolved in alcohol and converted into the hydrochloride by neutralizing with ethereal hydrochloric acid. It first crystallized, a small amount of unreacted 2- (p-ethoxyphenyl) - 3 - aminobicyclo - [2,2, I] - heptane hydrochloride of melting point 208 ⁰ C, which is filtered off. Upon concentration of the filtrate and re-addition of absolute ether to obtain 3.0 g of 2- (p-Äthoxyphenyty-S-P-butylaminobicyclo ^ lJ-heptane hydrochloride which melts after recrystallization from alcohol ether at 175 ⁰ C.

Example 19

2- (o-Fluorophenyl) -3-pyrrolidinobicyclo- [2.2.1] -heptane

a) 6.05 g of 2- (o-fluorophenyl) -3-aminobicyclo- [2.2, l] -heptane hydrochloride are refluxed with 5.9 g of tetramethylene bromide and 34 g of 10% sodium hydroxide solution for 15 hours while stirring. A little more alkali is then added to the reaction mixture and it is etherified. The evaporation residue of the ether solution dried with sodium sulphate is dissolved in acetone and neutralized with ethereal hydrochloric acid. 6 g of hydrochloride are obtained, which melts ^{at 206 ° C. after recrystallization from acetone-ether.}

b) An ethereal solution of 2.1 g of 2- (o-fluorophenyl) -3-pyrrolidinobicyclo- [2.2, l] -heptane is added with 1.9 g of methyl iodide, 2.5 g of iodine methylate crystallize out on standing; after recrystallization from alcohol - ether the melting point is 131 ° C.

Example 20

2- (m-xylyl) -3-cyclohexylaminobicyclo- [2,2,1] -heptane

8.5 g of 2 - (m - xylyl) - 3 - aminobicyclo - [2.2.1] - heptane are heated to 100 ° C. with 3.9 g of cyclohexanone for a few hours. The Schiff base formed is dissolved in 100 ecm of methanol and, after 1 g of platinum oxide has been added, it is shaken under hydrogen until the uptake of hydrogen has ceased. The catalyst is filtered off, the filtrate is concentrated, the remaining oily base (4.8 g) is dissolved in ethyl acetate and neutralized with ethereal hydrochloric acid. The hydrochloride which separates out melts after recrystallization from ethyl acetate at 229 ^° C.

Claims (1)

PATENT CLAIM: Process for the preparation of analeptically active N-substituted amino orcamphan derivatives of general formula where R ₁ = aryl, aralkyl, cycloalkyl or a heterocyclic radical and these radicals can be functionally or monosubstituted or polysubstituted by a hydrocarbon radical, 109 620/448 R ₂ - H ₅ denote alkyl or aryl, R ₃ and R ₄ = H, alkyl, cycloalkyl or aralkyl, where R ₃ and R _{4 can be the} same, different or components of a ring which optionally contains further heteroatoms, but not both at the same time R ₃ and R ₄ radicals can denote H or methyl, and each denotes 1 or 2, or their acid addition salts and quaternary ammonium compounds, characterized in that a primary amine of the general formula -NH ₂ (CH ₂ ), wherein R ₁ , R ₂ and χ have the meaning given above, alkylated by methods known per se, such as by reaction with alkyl or aralkyl halides or by reaction with an aldehyde in the presence of hydrogen or formic acid or an alkylating agent with subsequent hydrolysis of the Alkylation product or by reaction with an alcohol in the presence of Raney nickel or by reaction with an acylating agent and subsequent reduction, such as with lithium alanate, and that the obtained secondary or tertiary amines, if desired, in the usual manner with physiologically acceptable acids in acid addition salts or after known quaternization processes, e.g. B. with alkyl or aralkyl halides or dialkyl sulfates, converted into quaternary ammonium compounds.