CH463525A - Process for the production of new lysergic acid derivatives - Google Patents

Description

  

  
 



  Process for the production of new lysergic acid derivatives
The present invention relates to a process for the preparation of new heterocyclic compounds of general formula I (see formula sheet), in which Rt stands for hydrogen or the methyl group and R2 and R3 each mean an alkyl group with 1-4 carbon atoms substituted by a hydroxy group and xy for the grouping
EMI1.1
 stands and their salts.



   The compounds of general formula I and their salts can be obtained by combining a reactive functional acid derivative of an acid of general formula II, where xy and Rj have the above meaning, with compounds of general formula III, where R2 and R3 have the above meaning have reacted in a manner known per se and the compounds of the general formula I thus obtained, optionally subsequently converted into their salts in a manner known per se.



   Reactive functional acid derivatives of the acids of the general formula II are their azides, their acid chloride hydrochlorides and their mixed anhydrides with sulfuric acid.



   One embodiment of the process according to the invention is that the solution of the azide of an acid of the general formula II obtained in a manner known per se in an inert organic solvent with an excess of an amine of the general formula III (at least 2 mol), preferably at a temperature of 0-5 "is added and the reaction mixture is left to stand for a few hours at room temperature. Instead of an excess of amine, other acid-binding agents can also be used, for example the use of a suspension of potassium carbonate in a mixture of the amine with isopropanol and abs.ether proved advantageous.

   The reaction mixture is worked up and the compound of general formula I is isolated therefrom conveniently by methods known per se for amides of lysergic acid, for example chromatography, crystallization and / or purification using salts with organic or inorganic acids.



   A further embodiment of the process according to the invention consists in that a solution, prepared in a manner known per se (for example in acetonitrile or dimethylformamide) of a mixed anhydride of an acid of general formula II and sulfuric acid with 3-5 mol of an amine of general Formula III, conveniently diluted with the same solvent and left to stand for a few minutes at -30 to +20 to react. For work-up, the complex formed is destroyed at low temperature by adding water and the compound of general formula I is obtained from the reaction mixture obtained in a manner known per se, for B. isolated and purified by extraction, chromatography and / or crystallization.



   Furthermore, the new d-lysergic acid alkanolamides of the general formula I can also be prepared according to the invention by reacting acid chloride hydrochlorides of compounds of the general formula II with corresponding amines of the general formula III in an organic solvent.



  This process is advantageously carried out in such a way that the acid chloride hydrochloride in abs. Chloroform, methylene chloride, carbon disulfide, tetrahydrofuran or a mixture of these solvents with isopropanol or tert. Slurried butanol and mixed with an excess (at least 2 mol) of the amine component, optionally in an organic solvent. The reaction solution is then mixed with dilute soda solution and the amide is extracted with a water-immiscible solvent. After this solvent has been evaporated off, the desired amide either crystallizes out as a free base from the evaporation residue or is purified by chromatography and / or crystallization or can be isolated as a salt of an organic or inorganic acid.

   In this variant of the process too, the excess of an amine of the general formula III can be replaced by another acid-binding agent.



   The compounds of the general formula I obtained by the above processes, which are in amorphous or crystalline form after work-up, can then be converted into their acid addition salts in a manner known per se by reaction with organic or inorganic acids.



  Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, malic acid, acetic acid or tartaric acid.



   The compounds of general formula I and their salts with physiologically compatible organic or inorganic acids are distinguished by strong serotonin-antagonistic activity in vitro and in vivo as well as by a certain constricting effect on the smooth vascular muscles. They are suitable for the chronic interval treatment of vascular headaches such as migraines, Horton's syndrome and similar diseases. They can also be used successfully in the therapy of rheumatic affections, especially in inflammatory forms such as primary chronic rheumatoid arthritis, bursitis and tendinosis. They are also suitable for treating carcinoid syndrome.



   The compounds and their salts with therapeutically acceptable acids can be used as medicaments alone or in corresponding medicament forms for enteral or parenteral administration. In order to produce suitable dosage forms, these are processed with inorganic or organic, pharmacologically indifferent auxiliaries. The following additives are used for tablets and coated tablets, for example: lactose, starch, talc,
Stearic acid etc. for syrups: cane sugar, invert sugar, glucose solutions, etc. a. for injectables: water, alcohols,
Glycerol, vegetable oils and the like.



   Natural or hardened for suppositories: oils and waxes, etc. a. more
In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorants, flavorings, etc.



   In the following examples, which illustrate the implementation of the process but are not intended to reduce the scope of the invention in any way, all temperatures are given in degrees Celsius. The melting points are corrected.
EMI2.1




   Formula I Formula II Formula III
Example 1 d-Lysergic acid diethanolamide
A solution of 5 g of diethanolamine in 50 ml of absolute tetrahydrofuran is added to a suspension, cooled to 0 ", of 5 g of d-lysergic acid chloride hydrochloride in 350 ml of methylene chloride, stirring is continued for 30 minutes without cooling and then shaken between Dilute sodium carbonate solution and chloroform and evaporate the organic phase dried over potash. The dry residue is dissolved in chloroform + 10% methanol and the solution filtered through a short column of silica gel; after the filtrate has evaporated to dryness, a colorless foam remains cannot be brought to crystallization.



     [a] D20 = +160 (c = 0.5 in pyridine).



   Keller's color reaction: blue.



   Example 2
1-methyl-d-lysergic acid diethanolamide
To a suspension, cooled to 0, of 6 g of 1-methyl-d-lysergic acid chloride hydrochloride in 350 ml of abs. Methylene chloride is added with stirring to a solution of 10 g of diethanolamine in 100 ml of tetrahydrofuran, carried out for another 30 minutes without cooling, then shaken out between dilute soda solution and chloroform, and the organic phase, dried over Potasche, evaporated to dryness in vacuo. The dry residue is chromatographed on an aluminum oxide column, the compound mentioned in the title being washed into the filtrate with chloroform + 1-3% alcohol.



     [a] D20 = +290 (c = 0.5 in pyridine).



     Bimaleate: m.p. i42-1440 [a] 20 = +250 (c = 0.5 in water)
Keller's color reaction: blue.

 

Claims (1)

PATENT CLAIM Process for the preparation of new heterocyclic compounds of the general formula I in which Rt stands for hydrogen or the methyl group and R2 and R3 each mean an alkyl group with 14 carbon atoms substituted by a hydroxyl group and xy for the grouping EMI3.1 and their salts, characterized in that a reactive functional acid derivative of an acid of the general formula II, in which Rt and xy have the above meaning, with an amine of the general formula III, in which R2 and R3 have the above meaning, and the resulting compounds of general formula I are then optionally converted into their acid addition salts by reaction with organic or inorganic acids. SUBClaim Process according to patent claim, characterized in that the reactive functional acid used is an acid of the general formula II, its azides, acid chloride hydrochlorides or their mixed anhydrides with sulfuric acid.