CH463524A - 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 the general formula I, in which R represents hydrogen or the methyl group and xy represents the grouping
EMI1.1
 stand and their acid addition salts.



   According to the invention, compounds of general formula I and their acid addition salts are obtained by reacting a sufficiently reactive functional acid derivative of an acid of general formula II, in which R has the above meaning, with 3-hydroxymethylpyridine in a manner known per se and the compounds thus obtained of the general formula I are then optionally converted into their acid addition salts in a manner known per se.



   As the reactive functional acid derivative of an acid of the general formula II, its acid chloride hydrochloride or its acid azide can preferably be used.



   One embodiment of the process according to the invention is that an acid chloride hydrochloride of an acid of the general formula II and 3 hydroxymethylpyridine are allowed to react with one another in an organic solvent which is inert under the reaction conditions and in the equivalent of an acid-binding agent, advantageously at a temperature between 0 and 100 .



   For example, methylene chloride, dioxane or dimethylformamide can be used as organic solvent, and an excess of 3-hydroxymethylpyridine or tertiary organic bases such as pyridine and trimethylamine as acid-binding agents.



   After the reaction has taken place, the reaction mixture is left to stand for a further 1/2 to 1 hour at room temperature and then shaken as quickly as possible and with ice cooling between an aqueous weakly alkaline solution and an organic solvent which is immiscible with water. An aqueous sodium bicarbonate solution, for example, can be used as the aqueous alkaline solvent, and methylene chloride, chloroform or ethyl acetate as the organic solvent.



   The organic phase is separated off, dried, e.g. B. over magnesium sulfate and evaporated to dryness in vacuo. The compound of general formula I is isolated and purified from the remaining residue by methods known per se, for example by chromatography on a column of aluminum oxide or silica gel, and then optionally converted into one of its acid addition salts by reaction with organic or inorganic acids.



   The process according to the invention can also be carried out in such a way that a solution of the acid azide of a compound of the general formula II in an organic solvent which is inert under the reaction conditions and is not miscible with water, such as. B. benzene or diethyl ether, freed from traces of water contained therein by thorough drying and then treated with 3-hydroxymethylpyridine, advantageously in excess to bind the hydrazoic acid formed during the reaction. The hydrazoic acid formed during the reaction can optionally also be obtained by adding organic bases, such as. B. pyridine or quinoline, are bound.



   But you can also proceed in such a way that the solution of the azide in benzene or diethyl ether is evaporated to dryness at a temperature of not more than 50 and the residue is reacted with a solution of 3-hydroxymethylpyridine in an inert solvent. The reaction is advantageously carried out at a temperature between 00 and room temperature; the reaction time depends on the temperature used and is between a few minutes and about 1 hour. At least 1 mole of 3-hydroxypyridine should be used per mole of azide, but advantageously a small excess of the alcohol.



  The compounds of the general formula I obtained in this way are then isolated and purified from the reaction mixture as described above and, if appropriate, subsequently converted into their acid addition salts.



   The compounds of general formula I prepared according to the invention are basic substances which crystallize at room temperature, are easily saponified by alkalis and give characteristic colorations with Keller's or VanUrk's color reagent.



  With organic or inorganic acids they form stable, mostly crystallized salts. Such salts are, for example, the hydrochlorides, hydrobromides, sulfates, phosphates, fumarates, maleinates, malates, acetates or tartrates.



   The compounds prepared according to the invention are distinguished by pharmacologically valuable properties, above all by a strong antihistamine action with relatively weak serotonin antagonism. Their oliguric effect suggests cardiovascular effects. The compounds thus show the effects typical of the lysergic acid derivatives with clear sympathomimetic activity and relatively low toxicity.



   The new compounds 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. As auxiliaries are used z.

   B. for tablets and dragees: lactose, starch, talc,
Stearic acid etc. for syrups: cane sugar, invert sugar, glucose solutions, etc. a. for injection preparations: water, alcohols, olcerin, vegetable oils and the like. for suppositories:: natural or hardened ¯ - ^ = i 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 restrict the invention in any way, all temperatures are given in degrees Celsius and have been corrected.
EMI2.1




   example 1
O- (d-Lysergyl) -3-hydroxymethyl-pyridine
A suspension of 4 g of d-lysergic acid chloride hydrochloride in 150 ml of methylene chloride is treated at 20 with a solution of 2.7 g of 3-hydroxymethylpyridine in 50 ml of methylene chloride, the temperature rising to 100. The mixture is stirred for a further 30 minutes at room temperature, then shaken between methylene chloride and ice-cold sodium bicarbonate solution, the organic phase is dried over magnesium sulfate, evaporated to dryness and the dry residue is chromatographed on 100 g of silica gel. The by-products are washed with chloroform 4-120 / o alcohol and the compound mentioned in the title is washed into the filtrate with chloroform + 5 O / o alcohol.

   It crystallizes from chloroform / ether in prisms of m.p. 167-1690 [a] r20 = +410 (c = 0.5 in pyridine).



   Keller's color reaction: blue van Urk's color reaction: blue.



   Example 2 O- (9, 10-dihydro-d-lysergyl) -3-hydroxymethyl-pyridine
A suspension of 3.6 g of O-dihydro-d-lysergic acid chloride hydrochloride in 150 ml of methylene chloride is treated at 1 "with a solution of 3.1 g of 3-hydroxymethyl-pyridine in 50 ml of methylene chloride, the temperature being increased to 6" increases. The mixture is stirred for a further 45 minutes at room temperature and then worked up as described in Example 1.



   When the crude product is chromatographed on 70 g of aluminum oxide, the compound mentioned in the title with abs. Washed chloroform into the filtrate. It crystallizes from chloroform / ether in prisms of melting point 189-191. [a] D20 = ¯ 1060 (c = 0.5 in pyridine).



   Keller's color reaction: blue van Urk's color reaction: blue.

 

Claims (1)

PATENT CLAIM Process for the preparation of new heterocyclic compounds of the general formula I, in which R is hydrogen or the methyl group and xy is the grouping EMI3.1 and their acid addition salt, characterized in that a sufficiently reactive functional acid derivative of an acid of the general formula II, in which R has the above meaning, is reacted with 3-hydroxymethylpyridine and the compounds of the general formula I thus obtained, if appropriate, subsequently converted into their acid addition salts by reaction with inorganic or organic acids. SUBClaim Process according to patent claim, characterized in that the reactive functional acid derivative used is an acid of the general formula I, its acid chloride hydrochloride or its acid azide.