DE957036C - Process for the production of new diammonium compounds that influence muscle tone - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED JANUARY 31, 1957

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 12q GROUP 3201 INTERNAT. CLASS C07c; d -

Dr. Emil Girod, Riehen, Basel (Switzerland)

has been named as the inventor

J. R. Geigy A, -G., Basel (Switzerland)

Process for the production of new ones that affect muscle tone

Diammonium compounds

Patented in the territory of the Federal Republic of Germany on April 21, 1953 Patent application known since July 26th, 1956 Grant of patent announced on January 10, 1957 The priority of the application in Switzerland of April 21, 1952 has been claimed

The invention relates to methods of making compounds that affect muscle tone and in particular have a muscle-relaxing effect.

From the German patent 841 917 are Ver '' - ■ '. idings known to have a muscle-relaxing effect,

R ',

which correspond to the general formula (I) below, but where R 'is an alkyl radical with 1 to 4 Means carbon atoms.

It has now been found that the new diammonium compounds of the general formula

-0— (CH ₂ ) "—0 - (CH ₂ ) _m -

where N (low molecular weight dialkylamino groups, piperidino, methylpiperidino, pyrrolidino, methyl

.R '

ΘΘ

2 An

(I)

pyrrolidino, morpholino or methylmorpholino groups, R 'benzyl radicals, which in the benzene nucleus also by low molecular weight alkyl groups, as well

Alkoxy groups, a methylenedioxy group and / or halogen atoms can be substituted, m integers from 2 to 4, η an integer from 8 to 20 and An a monovalent anion, in particular of hydrohalic acids, or a normal equivalent of a polyvalent anion, a similar one Have an effect. However, they differ from the above-mentioned known compounds in that they have the advantage of an approximately two to four times shorter duration of action, which iür certain areas of application, e.g. B. in the electroshock treatment, the straightening of joints and "intubation, if no or only little muscle relaxation is necessary for the subsequent operation, is of essential importance.

Such compounds are made by reacting di-tertiary bis-aminoalkoxy-alkanes of the general formula

: N- (CH ₂ ) _m -O- (CH ₂ ) n -O- (CH ₂ ) _m -N;

(Π)

with 2 moles of benzyl halides of the general formula

R '- Shark, (III)

where N ^, R ', m and η have the meaning given above

tung and Hai means a halogen atom.

^R \ If in the end product the group ρ N— goes through

a low molecular weight dialkylamino group (R = low molecular weight alkyl radical) should be embodied, can one also has a di-tertiary bis-aminoalkoxy-alkane of the general formula

R ',

: N- (CH _{2) ro-O- (CH2) K-O-} (CH _{2) m} -N;

(IV)

with a reactive alkyl compound of the general formulas

R - Hai, R - O - SO ₂ - O - R or aryl - SO ₂ OR (V, VI, VII) handle.

Finally, you can also use 2 moles of tertiary amines of the general formula

(VIII)

R-N

a bis-haloalkoxyalkane of the general formula

Hal- (CH ₂ ) _m -O- (CH ₂ ) "- O- (CH ₂ ) _m -Hal

(IX) let it take effect.

The ditertiary bis-aminoalkoxyalkanes required as starting materials for the first-mentioned process the general formula (II) can - if not already known - z. B: by converting α, α> -Α1-kandiols the general formula

HO - (CH ₂ ) _B -OH

advantageously in the form of their metal compounds (alcoholates) with 2 moles of tertiary aminoalkyl halides the general formula

- (CH ₂ ) _m - Shark

or by reaction of α, ω-dihaloalkanes general formula

Hal- (CH ₂ ) ,, - Shark

with 2 moles of tertiary amino alcohols of the general formula

N- (CH ₂ ^ -OH

can also be obtained with advantage in the form of their metal compounds. The second method is preferable if the corresponding tertiary aminoalkyl halides required in the first process would be very volatile, e.g. B. for the production of di-tertiary bis ((5-aminobutoxy) alkanes. But you can also use the bis-haloalkoxyalkanes general formula (IX) instead of tertiary amines with secondary amines of the general formula

; n -H

R '

convert to the ditertiary bis-aminoalkoxyalkanes of the general formula (II) to arrive.

Examples of ditertiary bis-aminoalkoxy-alkanes are:

i, 8-bis (/ S-dimethylamino-ethoxy) -octane, b.p. 0.05 142 to 144 ⁰ ;

i, 8-bis (/ S-diethylamino-ethoxy) -octane, b.p. 0.08 I56bisi58 °;

1,8-bis (γ-diethylamino-propoxy) -octane, b.p. 0.05 i63 to 65 °;

i, 9-Bis - (^ - dimethylamino-ethoxy) -nonane, b.p. 0.06 I48bisi5o °;

i, 9-bis (/ 3-diethylamino-ethoxy) -nonane, b.p. 0.06 154 to 159 °;

i, io-bis (/ 5-dimethylamino-ethoxy) -decane, b.p. 0.04 I34bisi37 °; iao

i, io-bis (j5-diethylamino-ethoxy) -decane, bp 0.035 153 to 157 ⁰ ;

i, io-bis (j5-pyrrolidino-ethoxy) -decane, dihydrobromide m.p. 154 ⁰ ;

i, io-bis- (j8-piperidino-ethoxy) -decane, bp 0.04 ias I59bisi68 °;

ι, io-bis (/ J-morpholino-ethoxy) -decane, boiling point 0.15 211-2i5 °;

i- (β -dimethylamino-ethoxy) -το- (γ -diethylaminopropoxy) -decane, bp 0.07 153 to 158 °;
τ- (β- diethylamino-ethoxy) -το- (γ -dimethylaminopropoxy) -decane, bp 0.03 144 to 149 °;

i, io-bis (y-dimethylamino-propoxy) -decane, boiling point o, O2 140 to 144 ⁰ ;

i, io-bis (γ-diethylamino-propoxy) -decane, b.p. 0.03 ίο 164 to 169 °;

1, io-bis (y-dibutylamino-propoxy) -decane, b.p. 0.09 230 to 231 °;

i, ii-bis (ß-dimethylamino-ethoxy) -undecane;

i, i2-bis (y-diethylamino-propoxy) -dodecane;
i, i4-bis (^ - diethylamino-ethoxy) -tetradecane;

i, i5-bis (-dimethylamino-butoxyj-pentadecane;

i, i6-bis (/ S-dimethylamino-ethoxy) -hexadecane;

i, i6-bis (γ-dimethylamino-propoxy) -hexadecane;

1, 18-bis (^ - diethylamino-ethoxy) -octadecane;
i, 20-bis- (j8-dimethylamino-ethoxy) -eicosane.

As benzyl halides of the general formula

R'— Hal (HI)

for reaction with the ditertiary bis-aminoalkoxyalkanes for example:

Benzyl chloride, bromide and iodide, 2-methyl, 3-methyl and 4-methyl benzyl chloride and benzyl bromide, 3,5-dimethyl-benzyl chloride and -benzyl bromide, 4-isopropyl-benzyl chloride and -benzyl bromide, 2-methoxy, 3-methoxy, 4-methoxy-benzyl chloride and -benzyl bromide, 3,4-dimethoxy-benzyl bromide, 3, 4-methylenedioxy-benzyl bromide, 2-, 3- and 4-chlorobenzyl chloride and benzyl bromide, 2-, 3- and 4-bromobenzyl chloride and benzyl bromide.

Is used in the specified process for the preparation of di-tertiary bis-aminoalkoxy-alkanes as starting materials, compounds which have a benzyl-alkylamino group in place of the dialkylamino group included by z. B. tertiary aminoalkyl halides of the general formula

R '.

R '

) N- (CH ₂ ) _ro -Hal

with metal compounds of α, ω-alkanediols or tertiary amino alcohols of the general formula

R ',

: N- (CH ₂ ) _m -OH

with a, co-dihaloalkanes, also N-alkyl-benzylamines of the general formula

R '

Ν —Η

with bis-haloalkoxyalkanes of the general formula (IX) converts, then one arrives in an analogous manner to the starting materials for the second-mentioned manufacturing process for the diammonium compounds, e.g. E.g.zumi, io-bis - (/? - (benzyl-methyl-aminb -) - ethoxy) -dekan or 1, io-bis (y- (benzyl-methyl-amino) -propoxy) -decane.

In addition, for the preparation of such starting materials, for example, diprimary bis-aminoalkoxy-alkanes, such as the reaction of α, co-alkanediols with 2 moles of acrylonitrile and subsequent hydrogenation easily accessible bis-aminopropoxy-alkanes, with 2 moles of optionally "by low molecular weight alkyl or alkoxy groups, a methylene-dioxy group and / or halogen atoms substituted benzaldehyde under reducing and hydrogenating conditions' and the resulting bis (benzylamino-alkoxy) alkanes either first converted into bis (benzyl-alkylaminoalkoxy) alkanes of the general formula (IV) or the desired ones in one operation without isolation of the said ditertiary intermediates Prepare diammonium compounds of the general formula (I). From this manufacturing opportunity for the ditertiary starting materials and also from the easy accessibility of the N-alkylbenzylamines from optionally substituted benzaldehyde and monoalkylamines results in the second-mentioned production process for the diammonium compounds is particularly suitable if the one for the former general manufacturing processes required substituted benzyl halides to be less readily available or are less easy to handle than the corresponding substituted ones due to instability Benzaldehydes.

As reactive alkyl compounds, which according to the second production process with bis (benzylalkylaminoalkoxy) alkanes can be implemented, for example, methyl bromide, methyl iodide, Ethyl chloride, ethyl bromide, ethyl iodide, propyl bromide, propyl iodide, butyl bromide, butyl iodide, isobutyl bromide, Hexyl bromide, allyl bromide and allyl iodide as well as dimethyl sulfate and diethyl sulfate.

To the bis-haloalkoxy-alkanes of the general formula (IX) as starting materials for the third process for the preparation of the new diammonium compounds, such as i, 2-bis (o-bromobutoxy) butane, you can, for. B. by reacting bis-oxyalkoxy-alkanes with phosphorus halides, bis-oxyalkoxyalkanes are z. Example, by reacting α, co-dihaloalkanes with excess a, ω-alkanediols obtainable by means of sodium. The tertiary substituted benzylamines required as the second reaction component in this process are z. B. easily accessible by reacting benzyl halides with corresponding secondary amines.

Since the pharmacological activity of the salts according to the invention depends primarily on the cation, the type of anion is of lesser importance in the context of this invention. For therapeutic Use, salts of those inorganic or organic acids should be used, which are not have strong intrinsic toxicity and thereby cause pharmacological side effects. Furthermore the choice of the anion depends on various aspects, such as the price of the acid or the quaternary

nating agent, ease of implementation, crystallizability (possibility of cleaning) and water solubility of the products, the most suitable solution from case to case through a few preliminary experiments is easy to find.

Compounds in which An ⁰ differs from Hai®, (—Ο —SO ₂ —OR) Q or (Aryl — SO ₂ —O) ^Θ are expediently produced by subsequently exchanging these anions for others.

The diquartary salts are almost colorless, crystallizing compounds or, more rarely, viscous yellow oils. Organic solvents or suitable mixtures are particularly suitable for crystallization such, e.g. B. of generally good dissolving agents, such as alcohols, with poorly dissolving agents, such as acetone or ethyl acetate, or very little solvent, such as ether or benzene. These salts are generally good in water and soluble with a practically neutral reaction.

ao The following examples are intended to illustrate the production explain the new connections in more detail. Parts therein mean parts by weight, preferably in grams. Parts by weight are related to parts by volume like

g to ecm.

example 1

I ₁ io-bis - [/ J- (dimethyl-benzyl-ammonium) -ethoxy] -

Decane dichloride 3.16 parts of 1, io-bis (j8-dimethylamino-ethoxy) decane, 3 parts of pure benzyl chloride and 20 parts by volume of butanone are refluxed for about 14 hours. The quaternary salt deposited as a viscous oil is by adding a little abs. Dissolved methanol and heating. The product crystallizes out on standing in the cold. It is filtered off with suction, washed with acetone and dried in vacuo at 50 to 60 °. F. 145 to 146 ⁰ .

Example 2

i, io-bis [y- (dimethylbenzylammonium) propoxy] decane dichloride

3.44 parts of i, io-bis (y-dimethylamino-propoxy) -de-

Kan and 3 parts of pure benzyl chloride are heated in a bath at 90 to 100 ° for about 14 hours with exclusion of moisture. The product is crystallized by cooling and by trituration with dry acetone, suction filtered, washed with a little acetone, then with absolute ether and dried in a high vacuum at 50 to 60 °. The hygroscopic product melts at around 155 ^° .

Example 3

i, io-bis - [) S- (dimethyl-4'-methylbenzyl-ammonium) ethoxy] -dekan-dibromide

3.16 parts 1, io-bis (/? - dimethylamino-ethoxy) -dekan, 20 parts by volume of dry acetone and 4 parts of 4-methylbenzyl bromide are taken for about 14 hours Refluxed. The "product is solid; it becomes Sucked off after cooling, washed with acetone and, if desired, recrystallized from isopropanol + butanone. It melts at around 110 °.

Example .4

ι, io-bis - [^ - (dimethyl-4'-methoxybenzyl-ammonium) -

ethoxy] decane dichloride

The procedure is as in Example 3, using 3.5 parts of 4-methoxy-benzyl chloride instead of 4-methyl-benzyl bromide. The initially oily salt precipitates out on standing, it can be recrystallized from hot butanone with the addition of isopropanol to dissolve and then melts at 133 ^° .

Example 5

11.6 parts of 1, io-bis (/? - bromoethoxy) decane and 25 parts of N-methyl-3,4-dimethoxy-benzylamine are mixed and heated in a boiling water bath for 6 hours. After cooling, is dissolved in dilute hydrochloric acid + water, the solution removed by extraction with ether and collected by filtration to coal of impurities, is in the cold 3o ° / ₀ sodium hydroxide solution to strongly alkaline reaction and decreases the precipitated bases in ether. After drying the ether solution with potassium carbonate, the ether is distilled off, and N-methyl-3, 4-dimethoxybenzylamine followed by distillation under high vacuum (less than 10- ³ mm) at about 100 ° removed completely. The residue is stirred warm with animal charcoal and filtered off with suction. The 1, io-bis - [/? - (methyl-3 ', 4'-dimethoxybenzylamino) ethoxy] decane is obtained as a viscous light yellow oil.

5.9 parts of this product are dissolved in 50 parts by volume of acetone, 3 parts by volume of methyl] odide are added while cooling and the mixture is reboiled for about 10 hours. The quaternary salt separates out as a viscous oil. It is obtained as a light yellow viscous mass by dissolving in hot water, filtering with animal charcoal and evaporating in vacuo. The perchlorate melts at 92 to 93 ⁰ . iöo

In an analogous way, for example, can also be produced:

i, 8-bis- [j3- (benzyl-dimethyl-ammonium) -ethoxy] -octane dichloride, F. 135 °,

i, io-bis - [/ 3- (3 ', s'-dimethylhenzyl-dimethyl-ammonium) -ethoxy] -dekan-dibromid, F. 129 to 130 °,

i, io-bis- [j8- (benzylpyrrolidinium) ethoxy] decanedibromide, F. - (hygroscopic crystals),

i, 10-bis- [ß- (benzyl-piperidinium) -ethoxy] - decandibromide, melting point 110 to 112 °,

i, io-bis- [J3 (benzyl-4-methylpiperidinium) -ethoxy] -dekan dibromide, F. 150-151 ^0,

i, 10-bis-Q3- (benzyl-morpholinium) -ethoxy] -dekandibromid, F. 134 to 137 ⁰ ,

i, io-bis- [y- (4'-chlorobenzyl-dibutyl-ammonium) -propoxy] -dekan-dibromid, F. 122 to 123 °,

i, i2-Bis - [/ J- (benzyl-dimethyl-ammonium) -ethoxy] -dodecane dichloride, F. 152 ⁰ ,

i, i4-bis-fj8- (3 ', 4'-dichlorobenzyl-diethylammonium) ethoxy] -tetradecane dibromide, F. 144 to 145 ⁰ .

Claims (1)

Claim: Process for the production of new diammonium compounds that influence muscle tone the general formula ^R '\ R --Ν - -0- (CEy _n -N ^ - © θ • 2 An® where N ^ low molecular weight dialkylamino- groups, piperidino, methylpiperidino, pyrrolidino, methylpyrrolidino, morpholino or methylmorphdino groups, R 'benzyl radicals, which in the benzene nucleus can also be "substituted by low molecular weight alkyl groups, the same alkoxy groups, a methylenedioxy group and / or halogen atoms, with integers of 2 to 4, η is an integer from 8 to 20 and An © is monovalent anions, in particular of hydrohalic acids, or normal equivalents of polyvalent anions, characterized in that corresponding di-tertiary bis-aminoalkoxyalkanes of the general formula IN- (CEy _1n -O- (CEy _n -O- (CH ₈ ), -n; .R where NC ^ , m and η has the above meanings, with 2 moles of benzyl halides of the general formula _R , _ _Ha l, wherein R 'has the above meanings and Hai ) N- (CH ₂ ) ^ - O- (CH ₂ ^ -O- (CH ₂ LN means a halogen atom, converts it in a manner known per se and then optionally replaces Hai® with other anions or a ditertiary bis-aminoalkoxy-alkane) general formula in which R, R ', m and η have the above meanings, in a known manner with a reactive alkyl compound of the general formulas R — Hai, R — 0— SO ₂ -OR or Aryl— SO ₂ OR, where R denotes a low molecular weight alkyl radical, reacts and, if appropriate, subsequently the anion is replaced by another anion or to 2 moles of tertiary amines of the general formula ^R '\
RN a bis-haloalkoxy alkane of the general formula HaI- (CBy _1n -O- (CEy _n -O- (CEy _1n -HaI, where N {, R ', Hai, m and η have the above meaning can act in a manner known per se, and if necessary then Hai® replaced by another anion. Considered publications: German patent application G473iIVb / i2q
(Patent 841,917). © 609 576/534 7.56 (609 777 1.57)