NO133068B - - Google Patents

Description

Process for the production of new phosphorus-containing indole derivatives.

It has been shown that it is possible to

arrive at new phosphorus-containing indole derivatives with the general formula I

where R, and R, mean the same or different

alkyl groups with 1-4 carbon atoms or together with the nitrogen atom a piperidine ring, in that a 4-hydroxy-indole derivative

with the general formula II

where R, and Ro have the same meaning as

above, in the form of its salt with an inorganic base in an inert solvent

is transferred to the phosphoric acid ester by treatment with reactive derivatives of

phosphoric acid.

The new phosphorus-containing indole derivatives are distinguished by interesting therapeutically useful pharmacodynamic properties. They cause in particular a stimulation of the central sympathetic nervous system, which manifests itself in mydriasis, rise in blood pressure, rise in temperature and rise in blood sugar. Further

promotes the spinal reflexes. Simultaneous

the substances are to a small extent sedating and work-inhibiting. Because of their centrally vegetative and their inhibitory and sedative properties, they can be used for

treatment of a wide variety of mental illnesses, primarily obsessive-compulsive disorders as well as depression, moodiness and

anxiety states of a neurotic and psychotic nature. The phosphorus-containing indole derivatives of formula I have very little toxicity. The

is absorbed practically quantitatively by the body and is therefore preferably used orally, but can just as easily be taken

under the skin, in the muscles or in the veins. They must be used in therapy.

The new compounds are very slightly soluble in almost all organic solvents, but relatively easily in water. With Keller's reagent (glacial vinegar containing ferric chloride and concentrated sulfuric acid) they give a positive color reaction.

The indole derivatives of formula II which are used as starting material in the process according to the invention can be prepared in the following way: 4-benzyloxy-indole is dissolved in ether and the solution is mixed at low temperature first with oxalyl chloride and then with a lower dialkylamine or piperidine. The thus obtained substituted [4-benzyloxy-indolyl-(3)]-glycolic acid dimethyl-amide is reduced with lithium aluminum hydride in abs. dioxane, whereby a 4-benzyloxy-tryptamine is obtained which is substituted on the nitrogen atom of the side chain. To split off the benzyl group, the tryptamine derivative is shaken in methanol solution with a palladium catalyst in a hydrogen atmosphere. After completion of hydrogen uptake, the compound is purified, e.g. by sublimation in vacuum or by crystallization.

The method can, for example, be carried out in the following way: For example, a 4-hydroxy-indole derivative of formula II in the form of the alkali salt is reacted with 1 mol of dibenzylphosphoryl chloride and 1 inert solvent, e.g. toluene, dimethoxyethane, tert. amyl alcohol etc., after which the solution is shaken or allowed to stand for a few hours at room temperature, possibly under a nitrogen atmosphere. Evaporation to a dry state is then carried out, absorption in a suitable organic solvent, e.g. alcohol or alcohol/chloroform mixture, filtering off undissolved matter and then it is usually possible to bring the dibenzyl phosphoric acid ester of the 4-hydroxy-indole derivative to crystallization directly. Where this is not successful, it is recommended to filter through a column of aluminum oxide.

Of the dibenzyl phosphoric acid ester of the 4-hydroxy-indole derivative obtained in this way, the benzyl groups are cleaved off by shaking in methanolic solution with a palladium catalyst and hydrogen, after which the phosphoric acid ester that is formed, after separation of the catalyst, is brought to crystallize from a suitable solvent, preferably methanol.

Some examples will now be given of how the method according to the invention can be carried out. All temperatures are indicated in °C. The melting points are not corrected.

Example 1.

4-hydroxy-dimethyltryptamine phosphoric acid ester.

408 mg of 4-hydroxydimethyltryptamine (2 millimoles) was transferred to the sodium salt with the calculated amount of sodium methylate in methanol. The evaporation residue was dissolved in 15 cms of 1,2-dimethoxyethane and shaken under a nitrogen atmosphere for one hour with 2 millimoles of dibenzyl phosphoryl chloride. Then

evaporation was again carried out to a dry state, the remainder was taken up in abs. chloroform, then filtration was carried out from undissolved matter and the chloroform solution chromatographed on a column of aluminum oxide. The dibenzyl phosphoric acid ester of 4-hydroxy-dimethyltryptamine was washed with chloroform + 5-10 per cent alcohol to the filtrate. It formed a white foam and later could not be crystallized.

350 mg of 4-hydroxy-dimethyltryptamine-dibenzyl-phosphoric acid ester was hydrated in 8 ems methanol in the presence of a palladium catalyst. After the hydrogen absorption had stopped, filtration was carried out from the catalyst and the filtrate carefully evaporated. The 4-hydroxy-dimethyl-tryptamine-phosphoric acid ester crystallized under evaporation in small, colorless prisms. Temp. 210—212° (sp). Keller color reaction: blue.

Example 2.

4- hydroxydiethyltryptamine phosphoric acid ester.

1.19 g of 4-hydroxy-diethyltryptamine was transferred to the sodium salt with the calculated amount of methanolic caustic soda under nitrogen and dried in high vacuum at 60°. Dissolution was then carried out in 20 cm 3 of dimethoxyethane, mixing with a solution of 1.53 g of dibenzyl phosphoryl chloride in carbon tetrachloride and shaking for 18 hours at room temperature. Clear filtration was then carried out, the filtrate was evaporated to dryness and the residue chromatographed on 60 g of aluminum oxide. 4-Hydroxy-diethyltryptamine-dibenzyl-phosphoric acid ester was washed with chloroform + 10-20% alcohol to filtrate. It could not be crystallized from any solvent. 1.4 g of 4-hydroxy-diethyltryptamine-dibenzyl-phosphoric acid ester was hydrated in 50 ems methanol in the presence of a palladium catalyst. After the hydrogen absorption had stopped, filtration was carried out, the catalyst was washed with hot methanol and the combined methanol solutions were evaporated. 4-Hydroxy-diethyltryptamine phosphoric acid ester crystallized below in syrupy prisms. 257°. Keller color reaction: blue-violet.

Example 3.

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

indole phosphoric acid ester.

1.35 g of 4-hydroxy-3-(2'-piperidino-ethyl)-indole was dissolved in 30 cm» of methanol,

mixed with 5.64 ems 0.96-n. NaOH and

evaporated under nitrogen to dryness.

The residue was taken up in 30 ems of dimethoxyethane, a solution of dibenzyl phosphoryl chloride in 20 cm" of carbon tetrachloride, which was

prepared from 1.45 g of dibenzyl phosphite, was added and the mixture shaken for 20 hours. The

secreted sodium chloride was then filtered from, the filtrate

evaporated and the residue chromatographed on

the 30-fold amount of aluminum oxide.

The 4-hydroxy-3-(2'-piperidino-ethyl)-indole-dibenzyl phosphoric acid ester was washed with

chloroform to titrate. Amorphous foam like

could not be crystallized from any solvent.

A solution of 2 g of 4-hydroxy-3-(2'-piperidino-ethyl)-indole-dibenzyl-phosphoric acid ester in 20 cm 3 of methanol was shaken with 1 g of palladium catalyst and hydrogen until the hydrogen absorption stopped. Filtration was then carried out, the residue was boiled with water and the combined filtrates were evaporated to a small volume. There-under, the 4-hydroxy-3-(2'-piperidino-ethyl)-indole phosphoric acid ester crystallized out in

form of colorless prisms with m.p. 260—

262°. Keller color reaction: violet. Used to

Urk color reaction: brown-orange.

Claims (1)

new, therapeutically effective, phosphorus-containing process for the production of indole derivatives with the general formula where R, and R2 mean the same or different alkyl groups with 1-4 carbon atoms or, together with the nitrogen atom, a piperidine ring, characterized in that a 4-hydroxy-indole derivative with the general formula where R, and R2 have the same meaning as above, in the form of its salt with an organic base in an inert solvent is transferred to the phosphoric acid ester by treatment with reactive phosphoric acid derivatives.