DE944518C - Process for the preparation of solutions of xanthines substituted in the 1,3-position - Google Patents

Description

Process for the preparation of solutions of 1,3-substituted Xanthines Xanthines substituted in the I, 3-position, in particular I, 3-dimethyl compounds, such as theophylline and caffeine, are generally poor but inadequate at the same time soluble in water. In order to bring them into solution, quite a number of them are required alkaline substances of organic origin are suggested. The effect of this Bases on the xanthines, especially theoph.ylline, is based on salt formation. Neutral salts, for example, were also used to make the xanthines soluble of salicylic acid, benzoic acid, resorcylic acid, and metaoxybenzoic acid are suggested. However, the use of phenol derivatives, especially salicylic acid, is from from a medical point of view undesirable,. as they give rise to side effects can go. According to more recent findings, theophylline for the dissolution ring from Theo the sodium salts of amino acids, especially glycine, can also be used.

It is also known to use liquid, water-soluble, amide nitrogen, ff alkylated pyridinecarhonic acid amides as solubilizers for caffeine, theophylline and to use other medicines.

It has now been found that the derivatives of pyridine carboxylic acids for solubilizing xanthines substituted in the 1,3-position, e.g. B. theophylline and. Caffeine are usable. For these purposes, the ammonium-alkali and also Alkaline earth salts of a-picolinic acid, nicotinic acid, the Isonicotinic acid, but also of polybasic pyridinecarboxylic acids, such as. B. pyridine-2, 6-dicarboxylic acid. The salts with are just as useful as the alkali salts organic bases. It can be both the salts with aliphatic amines, for example Ethylenediamine, oxyethylamine, diethanolamine, triethanolamine, butylamine, etc., such as also find use with aromatic and complex bases, for example with ephedrine, adrenaline, papaverine, quinidine, etc .; just like the salts of pyridinecarboxylic acids the amides as well as the esters or, if they are dicarboxylic acids, also have an effect the salts of the monoesters, the monoamides as well as the diesters and the diamides.

This effect could by no means be foreseen, as neither an analogy to the aromatic carboxylic acids, for example salicylic acid, also exists to the amino acids, for example glycine, especially with the salts of amino acids there is another factor, namely that these salts have an alkaline reaction, while the salts of pyridinecarboxylic acids due to the low basicity of the ring nitrogen react roughly neutrally.

It should be noted that the free acids of the pyridinecarboxylic acids are the xanthines not able to solve, but their compounds or salts.

With the help of these compounds and salts it is possible, practical Prepare neutral solutions suitable for injections. The pharinacological and practical interest in the solutions produced in this way is very great, as stich among the compounds in question a number of such compounds are found already have found medical application for themselves and through their properties the Substantially complement and potentiate the pharmacological effect of the xanthine bodies capital.

The special value of the solutions prepared according to the procedure is based on theophylline preparations normally injected intravenously rapid injection will result in a very sudden drop in blood pressure which can be too serious Incidents cause kaam, while the proposed solutions are essential are better tolerated and generally unproblematic even with rapid injection be tolerated.

The solubility-increasing effect of the pyridine derivatives, which for example allow theophylline to produce ten and more highly concentrated solutions, probably based on secondary valence bonds.

Since it is possible to produce neutral solutions, this can also be done Solutions or such substances are added, which against, an acidic, alkaline pH or both are sensitive, especially grape sugar and glucosides such as. B.

Strophantin, Digitoxin, etc. There are also the organic bases and theirs Salts can be used, which sometimes have important therapeutic properties themselves have it is. In this way possible to also use clear, durable solutions manufacture these substances, so that one depending on the desired therapeutic Effect has very large possibilities for variation.

Example I 2 parts by weight of theophylline, 4 parts by weight of nicotinic acid Sodium and 50 parts by volume of water are heated in a small flask until they dissolve.

After cooling, it is made up to a volume of with distilled water IOO parts by volume set.

The resulting solution is colorless and completely stable also against heating. Its p-value is 6.9. It can be filled into ampoules and the ampoules can be sterilized.

Example 2 According to Example I, a solution is prepared, but the same amount instead of 4 parts by weight of sodium nicotinate Contains sodium a-picolinic acid. The characteristics of this solution are the same.

Example 3 2 parts by weight theophylline, 3 parts by weight nicotinic acid and 1.075 parts by weight of a 7o, 50% ethylenediamine are with the addition of Heated 50 parts by weight of water until dissolved. The resulting solution is through Adding small amounts of nicotinic acid adjusted to a p-Weft of 6.8, and on tooVolume parts filled up. This solution is also colorless, durable and sterilizable.

Example 4 2 parts by weight of theophylline, with the addition of 3.5 Parts by weight of nicotinic acid amide dissolved in 50 parts by weight of water with heating The solution is brought to a pH of 6.8 by adding sodium hydroxide solution set, for which about 6.75 parts by volume are required. The resulting solution will filled up to 100 parts by volume.

Claims (5)

PATENT CLAIMS: I. Process for making durable solutions the substituted in the I, 3-position xanthines, characterized in that under Adjustment to an approximately neutral p-value as solubilizer the salts mono- or polyvalent pyridinecarboxylic acids, which optionally have further substituents have, with inorganic or organic bases andl or their unsubstituted Amides and / or their esters can be used. 2. The method according to claim I, characterized in that as substituted Xanthine theophylline and / or caffeine and, as solubilizers, salts of nicotinic acid be used with inorganic, aliphatic or acyclic amines. 3. The method according to claim and 2, characterized in that as Solubilizers are the salts of pyridinecarboxylic acids with pharmacologically important ones organic bases, especially special also alkaloids or pharmacological similarly effective synthetic basic substances, alone or in a mixture with others Salts, can be used. 4. The method according to claim, characterized in that the ester Nicotinic acid, especially those of low molecular weight, alone or in Mixture with salts or amides. of pyridinecarboxylic acids can be used. 5. The method according to claim I to 4, characterized in that the if necessary, solutions adjusted to a neutral pH value at the same time or subsequently other pharmacologically active substances, preferably grape sugar, Glucosides or calcium salts can be added. Attached publications: German patent specifications No. I64424, 167 140, I68 293, I70 302, I72 932, I99 108, 2I4 376, 2I7 620, 223 695, 224 98I, 264 389, 285 579, 287801, 290600, 340 744, 374 097, 406 211, 469 788, 583 054, 629 662, 633 786, 638 030, 642260, 667 2II, 686413, 690 488, 691339, 709176, 742602, 748005; Journal for Circulatory Research, Volume 33, Issue 20, 1941, p. 775; Year 33, Booklet I3; Münchner Med. Wochenschrift, 1940, p. II42; U.S. Patent No. I 867 332.