DE1156077B - Process for the production of 4-hydroxytryptamine derivatives and their salts - Google Patents

Description

GERMAN

PATENT OFFICE

S 64817 IVd / 12p

DAY OF NOTIFICATION: SEPTEMBER 8, 1959

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: OCTOBER 24, 1963

The inventive method for the preparation of 4-hydroxytryptamine derivatives of the general formula

OH
j, R ₁

/ \ CH ₂ - CH ₂ - NC '(I)

R ₂

in which R ₁ and R _{2 are} alkyl groups with 1 to 4 carbon atoms or R ₁ and R ₂ together with the nitrogen atom are a piperidine ring, and the salts thereof are characterized in that 4-benzyloxyindole with dihalides of oxalic acid and then with secondary amines of the general formula

R ₁

HN:

(Π)

Method of manufacture

of 4-hydroxytryptamine derivatives

and their salts

Applicant:
Sandoz AG, Basel (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:

Switzerland from September 12, 1958 to January 16

and February 27, 1959 (No. 63 874, No. 68 425 and No. 70 154)

Dr. Albert Hofmann and Dr. Franz Troxler,

Bottmingen (Switzerland),
have been named as inventors

converts the [4-benzyloxy-indolyl- (3)] -glyoxylic acid amides obtained reduced with lithium aluminum hydride and the 4-benzyloxytryptamine derivatives in one Solvent treated with catalytically excited hydrogen and optionally the bases obtained Reacts with inorganic or organic acids.

The 4-hydroxytryptamine derivatives obtained according to the process of the general formula (I) are solid, crystallized compounds at room temperature and form stable, water-soluble salts with inorganic and organic acids. With the Keller reagent [Glacial acetic acid and concentrated sulfuric acid containing iron (III) chloride] give it a positive Color reaction.

It was already known (see, for example, Journal of the American Chemical Society, Vol. 76 [1954], Pp. 6208 to 6210), tryptamine derivatives such as 5-hydroxytryptamine (serotonin) and its dimethyl derivative (Bufotenin), via the corresponding indolyl- (3) -glyoxylic acid chlorides and amides.

The subject of the earlier patent 1068 259 is a process for the preparation of 3 - (/? - aminoethyl) indoles by reducing indolyl (3) glyoxylic acid amides with lithium aluminum hydride. Opposite to However, the subject of this patent is a multi-stage process under the invention Protection provided, the second stage of which leads to Benzyloxytryptaminen, which is in the documents of the patent 1 068 259 are not mentioned.

Serotonin and Bufotenin as well as other previously known indolylalkylamines are characterized by a contracting «effect on the smooth muscles as well as by vasoconstrictor and blood pressure increasing Properties.

4-Hydroxyindolylalkylamines of the general given Formula (I), however, were previously unknown, and it was surprising that the new compounds develop particularly pronounced effects on the central nervous system. So they do in particular a stimulation of the central sympathetic nervous system, which results in mydriasis, increase in blood pressure, Increases in temperature and blood sugar as well as in an inhibition of intestinal activity expresses itself. Further promote spinal reflexes. At the same time, the substances have a mildly calming and drive-inhibiting effect. As a result of their central vegetative and their impulsive and sedative properties they can be used to treat a wide variety of mental illnesses, especially obsessive-compulsive disorder as well as from depression, moods and anxiety states of neurotic and psychotic Genesis, can be used.

For drug treatment of these and similar therapeutic indications are already

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Compounds of other structures, such as aralkyl hydrazines and carboxylic acid hydrazides, have been described which have a stimulatory, antidepressant effect due to their monoamine oxidase-inhibiting properties. On the other hand, the antidepressant N- (γ - dimethylaminopropyl) - iminodibenzyl hydrochloride in no way affects the monoamine oxidase, on the other hand it intensifies the physiological effects of adrenaline and noradrenaline. The following comparison shows the essential difference in pharmacodynamic properties between the known compound and 4-hydroxydimethyltryptamine.

link Promoting spinal
Reflexes (cat) Reserpine antagonism Adrenaline potentiation
on the circulatory system (cat) Temperature increase
on the awake rabbit N- (y-dimethyl-
aminopropyl) -
iminodibenzyl
hydrochloride
4-hydroxy
dimethyltrypt
amine is missing
at
10 μΗ / kg
intravenous weakly pronounced
and only after more
one-time appointment
verifiable
at
100 mg / kg
subcutaneous at
1 mg / kg
intravenous
practically absent
or very
weak is missing
at
10 µg / kg
intravenous

The stimulating effect on spinal reflexes is based on the method of H. Weidmann and A. Cerletti (HeIv. Physiol. Acta, Vol. 18 [1960], pp. 174 to 182). Reserpine antagonism is at of the mouse measured by the extent of the inhibitory effect which the compound has on the promoter Effect of reserpine on 1,5-pentamethylenetetrazole induced stretching spasms unfold (see archive for experimental pathology and pharmacology, Vol. 233 [1958], pp. 559 to 566).

It is thus evident that similar mental disorders are caused by compounds of different structure and Effectiveness can be treated.

When comparing the compounds mentioned for acute toxicity and average therapeutic The daily dose is 4-hydroxydimethyltryptamine, the N- (y-dimethylaminopropyl) -iminodibenzyl hydrochloride clearly superior and has a far greater therapeutic breadth.

The products of the process also represent valuable intermediate products for the manufacture of drugs represent.

The method is preferably carried out as follows: z. B. a solution of 4-Benzyloxyindole in ether at low temperature initially with oxalyl chloride and then with excess, anhydrous dimethylamine and filtered after the end Implementation of the reaction product at room temperature, whereupon the by-product Dimethylamine hydrochloride is removed with water. The obtained [4-benzyloxy-indolyl- (3)] -glyoxylic acid dimethylamide is reduced with lithium aluminum hydride in anhydrous dioxane, and after the usual work-up the base is released set. The 4-benzyloxydimethyltryptamine formed is used in methanol solution to split off the benzyl group shaken with palladium in a hydrogen atmosphere. After the uptake of hydrogen has ended can the connection z. B. purified by sublimation in a high vacuum or by crystallization will.

In the following examples the melting points are uncorrected.

example 1
4-hydroxydimethyltryptamine

It is added to 12 g of 4-benzyloxyindole in 300 ecm of ether with stirring at a temperature of 0 to 3 ° C Add 9.6 g of oxalyl chloride dropwise. 30 minutes after the end of the dropwise addition, while cooling with ice, and Stir slowly in 20 g of anhydrous dimethylamine, stir for a few more minutes at room temperature

as and filtered off. The precipitate is washed well with water and the water-insoluble part is dried in vacuo. [4-BenzyIoxy-indolyl- (3)] -glyoxylic acid dimethylamide is obtained as a yellowish crystal powder which is recrystallized from a mixture of benzene-methanol with the gradual addition of petroleum ether. Mp. 148 to 150 of ⁰ C. Yield 78%.

A solution of 4 g of [4-benzyloxy-indolyl- (3)] -glyoxylic acid dimethylamide in 80 ecm of absolute dioxane is added dropwise to a solution of 5 g of lithium aluminum hydride in 100 ecm of absolute dioxane, and the mixture is heated under reflux for 24 hours Stir. It is then decomposed with methanol and saturated sodium sulfate solution, filtered and the filtrate is partitioned by shaking between an aqueous tartaric acid solution and ether. After the usual liberation and isolation of the bases from the tartaric solution, a solidifying oil is obtained, which is purified through a column of aluminum oxide to separate off by-products in benzene solution. One gets the 4-Benzyloxydimethyltryptamin as a colorless oil which crystallized from ether-petroleum ether in prisms, mp. 119 to 121 ⁰ C. Yield 87%> based on [4-benzyloxy-indolyl- (3)] -glyoxylic acid dimethylamide.

A solution of 4 g of 4-benzyloxy-dimethyltryptamine in 100 ecm of methanol is shaken with 2 g of palladium on an aluminum oxide carrier and hydrogen. When the hydrogen uptake has ended, it is filtered and the filtrate is evaporated to dryness. The residue is sublimed in a high vacuum at 130 ^° C. and colorless 4-hydroxydimethyltryptamine which ^{melts at 173 to 176 °} C. is obtained. Keller's color reaction: blue. Yield 83%> based on the 4-benzyloxydimethyltryptamine.

4-hydroxydimethyltryptamine oxalate

204 mg of 4-hydroxydimethyltryptamine are dissolved in 1.5 ecm of methanol, a solution of 80 mg of oxalic acid in 1.5 ecm of acetone is added and slowly diluted with ether, the neutral oxalate of 4-hydroxydimethyltryptamine in spherical aggregates of small prisms of mp. 239 to 240 ⁰ C crystallized out. Yield 210 mg.

Example 2
4-Hydroxydiethyltryptamine

_ A solution of 5 g of 4-benzyloxyindole in 120 ecm Ether becomes at -5 to -7 ° C while stirring with 4 ecm Oxalyl chloride added. The mixture is left to stand at -5 ° C. for 1 hour and then added dropwise at this temperature a solution of 20 ecm anhydrous diethylamine in 20 ecm ether with stirring. After 2 hours is filtered, the precipitate is washed with water and the water-insoluble [4-benzyloxy-indolyl- (3)] -glyoxylic acid diethylamide recrystallized from alcohol. M.p. 131 to 132 ° C. Yield 75%.

6.3 g of lithium aluminum hydride are dissolved in 150 ecm of anhydrous dioxane, a solution of 4.9 g of [4-benzyloxyindolyl- (3)] -glyoxylic acid diethylamide in dioxane is added dropwise at the boiling point with stirring and the mixture is refluxed for 24 hours. It is then decomposed with methanol and saturated sodium sulfate solution, filtered and the filtrate is distributed by shaking between ether and 0.5N tartaric acid solution. After the usual liberation and isolation of the bases from the tartaric acid solution, the crude 4-benzyloxydiethyltryptamine is first filtered through a column of aluminum oxide in benzene solution and then recrystallized from benzene. . Mp 100-101 ⁰ C. Yield 81%, based on the [4-benzyloxy-indolyl (3)] - glyoxylsäurediäthylamid.

A solution of 2.8 g of 4-benzyloxydiethyltryptamine in 50 ecm of methanol is shaken with 2 g of PaÜadium on an aluminum oxide carrier and hydrogen. After the hydrogen uptake has ended, the mixture is filtered, the filtrate is evaporated to dryness, the 4-hydroxydiethyltryptamine is distilled in a high vacuum and the distillate is recrystallized from ether. Mp. 99 to 101 of ⁰ C. Yield 77% based on 4-Benzyloxydiäthyltryptamin.

Example 3
4-hydroxy-3- (2'-piperidino-ethyl) indole

In a solution of 10 g of 4-benzyloxyindole in 200 ecm of absolute ether, 8 ecm of oxalyl chloride in 70 ecm of ether is added dropwise at 0 ° C., stirring is continued for 30 minutes at room temperature and then 40 ecm of piperidine and 50 ecm of ether are added with cooling. After standing for 2 hours at room temperature, the precipitate is filtered off and distributed by shaking it between water and chloroform. The chloroform solution on evaporation pure [4-benzyloxy-indolyl (3)] - glyoxylsäurepiperidid of melting point 191 to 193 ⁰ C (from ethanol or ethyl acetate).. Yield 64%.

7.1 g of [4-benzyloxy-indolyl- (3)] -glyoxylic acid piperidide are stirred in 250 ecm boiling anhydrous dioxane with 8.7 g of lithium aluminum hydride, decomposed with methanol and saturated sodium sulfate solution, filtered and the filtrate is distributed by shaking between ether and tartaric acid solution . The 4-benzyloxy-3- (2'-piperidino-ethyl) -indole released and isolated in the usual way is recrystallized from ethyl acetate. Mp 126 to 128 ⁰ C. Yield 73%> based on the [4-benzyloxy-indolyl (3)] -. Glyoxylsäurepiperidid.

3.6 g of 4-benzyloxy-3- (2'-piperidino-ethyl) -indole are shaken in 100 ecm of methanol with 3.4 g of palladium catalyst on an aluminum oxide support and hydrogen until the uptake of hydrogen has stopped. The catalyst is filtered off, the filtrate is evaporated to dryness and the 4-hydroxy-3- (2'-piperidino-ethyl) -indole is recrystallized from ethyl acetate. Solid plates of mp. 182-183 ⁰ C. Yield 85%> based on 4-benzyloxy-3- (2'-piperidino-ethyl) -indole. Keller's color reaction: green.

Claims (1)

Claim: Process for the preparation of 4-hydroxytryptamine derivatives of the general formula OH N / A -CH ₂ -CH ₂ -N: in which R ₁ and R _{2 are} alkyl groups with 1 to 4 carbon atoms or R ₁ and R ₂ together with the nitrogen atom are a piperidine ring, and salts thereof, characterized in that 4-benzyloxyindole with dihalides of oxalic acid and then with secondary amines of the general formula .R ₁ HN: converts the [4-benzyloxy-indolyl- (3)] -glyoxylic acid amides obtained reduced with lithium aluminum hydride and the 4-benzyloxytryptamine derivatives in Treated a solvent with catalytically excited hydrogen and optionally the the bases obtained are reacted with inorganic or organic acids. Considered publications:
Journal of the American Chemical Society, 76: 6208-6210 (1954). A priority document was displayed when the registration was announced. © 309 729/297 10.63