DE947424C

DE947424C - Process for the production of solutions of substituted xanthines

Info

Publication number: DE947424C
Application number: DEB14712A
Authority: DE
Inventors: Dr Helmut Weissenburger
Original assignee: Byk Gulden Lomberg Chemische Fabrik GmbH
Current assignee: Takeda GmbH
Priority date: 1951-04-24
Filing date: 1951-04-24
Publication date: 1956-08-16

Description

Verfahren zur Herstellung von Lösungen substituierter Xanthine Zusatz zum Patent 944518 In dem deutschen Patent 944 5I8 wird ein Verfahren beschrieben, mit Hilfe von Salzen und Derivaten der Pyridincarbonsäuren in I, 3-Stellung substituierte Xanthine in Lösung zu bringen.Process for the preparation of solutions of substituted xanthines additive for patent 944518 In the German patent 944 5I8 a method is described, substituted in the I, 3-position with the help of salts and derivatives of pyridinecarboxylic acids Bringing xanthines into solution.

Es wurde nun gefunden, daß an Stelle von Salzen der Pyridincarbonsäuren bzw. Derivaten dieser Säuren auch pyridinsulfonsaure Salze und auch Derivate von Pyridinsulfonsäuren, wie Ester, Amide, substituierte Amide usw. verwendet werden können. Es können sowohl die Salze und Derivate von Monosulfonsäuren wie auch von Disulfonsäuren Verwendung finden. It has now been found that instead of salts of pyridinecarboxylic acids or derivatives of these acids also pyridinsulphonic acid salts and also derivatives of Pyridine sulfonic acids such as esters, amides, substituted amides, etc. can be used can. Both the salts and derivatives of monosulfonic acids as well as of Disulfonic acids find use.

Darüber hinaus wurde gefunden, daß diese Pyridinsulfonsäuren im Pyridinkern durch Alkyl-, Aryl-, Alkoxy-, Oxy-, Carboxyl-, veresterte Carboxyl-, Carbonamid-, Aminogruppen oder auch durch Halogenatome substituiert sein können. Vielfach ist die lösungsvermittelnde Eigenschaft dieser Verbindungen gegenüber substituierten Xanthinen noch besser, als bei Verwendung von pyridincarbonsauren Salzen bzw.It has also been found that these pyridinesulfonic acids are in the pyridine nucleus by alkyl, aryl, alkoxy, oxy, carboxyl, esterified carboxyl, carbonamide, Amino groups or can be substituted by halogen atoms. Is multiple the solubilizing property of these compounds compared to substituted ones Xanthines even better than when using pyridinecarboxylic acid salts or

Derivaten derselben. So sind beispielsweise die Salze und Derivate folgender Pyridinsulfonsäuren geeignet: Pyridin-3-sulfonsäure, Pyridin-2-sulfonsäure, Pyridin-4-sulfonsäure, Pyridin-3, 5-disulfonsäure, a-Picolin-3-sulfonsäure, a-Picolin-5-sulfonsäure, cr-Picolin-3, 5-di- sulfonsäure, 3-Brompyridin-5-sulfonsäure, 5-Sulfoa-picolinsäure, 3-Pyndinsulfonsäure-5-carbonamid.Derivatives thereof. So are the salts and derivatives, for example the following pyridine sulfonic acids are suitable: pyridine-3-sulfonic acid, pyridine-2-sulfonic acid, Pyridine-4-sulfonic acid, pyridine-3, 5-disulfonic acid, a-picolin-3-sulfonic acid, a-picolin-5-sulfonic acid, cr-picoline-3,5-di- sulfonic acid, 3-bromopyridine-5-sulfonic acid, 5-sulfo-picolinic acid, 3-Pyndinsulfonic acid-5-carboxamide.

Als Salz im Sinne dieser Erfindung können die Salze mit anorganischen Basen wie auch mit organischen Basen verwendet werden. Die organischen Basen können aliphatische Konstitution haben, aber auch aromatischer oder heterocyclischer Natur sein. Insbesondere können auch die Salze von Alkaloiden oder diesen therapeutisch ähnlichen Basen Anwendung finden. As a salt in the context of this invention, the salts with inorganic Bases can be used as well as with organic bases. The organic bases can aliphatic constitution, but also aromatic or heterocyclic in nature be. In particular, the salts of alkaloids or these can also be used therapeutically similar bases are used.

Als besonders geeignet im Sinne des Verfahrens, d. h. von besonders löslichkeitserhöhender Wirkung auf substituierte Xanthine, erwiesen sich die Sulfonamide des Pyndins, die am Amidstickstoff unsubstituiert oder auch mono- oder disubstituiert sein können, beispielsweise durch Alkyl-, Aralkyl- oder auch heterocyclische Reste. As particularly suitable in terms of the method, d. H. of special The sulfonamides proved to have a solubility-increasing effect on substituted xanthines des Pyndin, which is unsubstituted or mono- or disubstituted on the amide nitrogen can be, for example by alkyl, aralkyl or heterocyclic radicals.

Claims

It is known that theobromine, which differs from theophylline only by the position of a methyl group differs, generally even more difficult in solution is to be brought as theophylline. So it turns out that. Salts of pyridinecarboxylic acids or their pyridinecarboxamides, which are claimed in the main patent, the solubility of theobromine by about a power of ten, but this is enough Effect for practical utilization in general is not sufficient. In contrast, was found that pyridinesulfonic acids and especially Pyndinsulfonsäureamide the solubility can increase in some cases quite considerably.

Caffeine and theophylline, in particular, are substituted xanthines in question, however, most have pyridinesulfonic acid compounds, in particular those with a sulfonamide residue, also a solubility-increasing one compared to theobromine Effect, which is why theophylline is expressly included.

However, synthetic products can also be used that instead of the methyl groups of the natural xanthines, other substituents, for example Ethyl or oxyethyl groups.

With the help of the aforementioned salts and derivatives of pyridinesulfonic acids it is possible to use neutral or weakly acidic solutions of substituted xanthines to produce, just as it is in the main patent of the corresponding compounds of Pyridinecarboxylic acids was shown. As a result of the neutral reaction can also alkali-sensitive compounds are combined with the purine derivative solutions, without the fear of decomposition.

According to the invention, the solutions are preferably at elevated temperature manufactured. When using salts it is also possible to use either theophylline first to be combined with the sulfonic acid and then to neutralize with alkali or to first dissolve the purine derivative in the base used and then add sulfonic acid.

It should be particularly emphasized that several solubilizers can be used at the same time can be used e.g. B.

Salts of various pyridinesulphonic acids or salts of pyridinesulphonic acids and nicotinic acid amides and the like.

The solutions obtained according to the invention can also be used to dryness be steamed. A powder is obtained from it, which is processed into tablets or can also be brought back into solution quickly and easily at any time.

Example I 5 g of theophylline and 7.5 g of pyndine-β-sulfonic acid sodium are heated with about 80 ccm of water until they dissolve. After cooling down, it will open 100 ccm filled, the solution filtered, filled into ampoules and sterilized. The solution is durable.

Example 2 Instead of sodium pyridiaß-sulfonic acid in the example I used 2-chloropyridine-5-sulphonic acid sodium.

Example 3 Instead of sodium pyridine, 3-sulfonic acid in the example 1 pyridon (2) sulfonic acid (5) sodium is used.

Example 4 Instead of sodium pyridine-β-sulfonic acid in the example 1 a mixture of a-picoline-3- and -5-sulphonic acid sodium is used.

Example 5 10 g of theophylline and is gpyridine-3, 5-disulfonic acid ethylenediamine are heated with 70 ccm of water until they dissolve, 5 g of papaverine and until they are reached a pn value of 6.4 a 250/0 solution of pyndin-3, 5-disulfonic acid is added, of which about 7.2 g are required. The solution is made up to 100 cc, in ampoules bottled and sterilized.

Example 6 5 g of theophylline and 5 g of pyridine-ß-sulfonamide are in Dissolve 90 ccm of water with warming and make up the solution to 100 ccm.

Example 7 5 g of theophylline and 4 g of pyndine-3, 5-disulfonamide become Dissolved in 3 cc of water with warming and the solution made up to 100 cc. PATENT CLAIMS : I. Process for the preparation of solutions of substituted xanthines according to the patent 944 5I8, characterized in that as a solubilizer instead of salts, Amides or esters of pyndincarboxylic acids, the salts of mono- or polyvalent pyridinesulfonic acids, which optionally have further substituents with inorganic or organic Bases and / or their 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 a solubilizer Salts of pyridine-3-sulfonic acid with inorganic, aliphatic or cyclic amines be used.

3. The method according to claim I and 2, characterized in that as Solubilizers are the salts of pyridinesulfonic acids with pharmacologically important ones organic bases, in particular also alkaloids or pharmacologically similarly effective, synthetic, basic substances, used alone or in a mixture with other salts will.

4. The method according to claim I, characterized in that optionally pyridine-3-sulfonamide mono- or disubstituted on the amide nitrogen is used and the resulting solution may have a neutral or weakly acidic pn value is set.

5. The method according to claim I, characterized in that the diamides and / or the salts of monoamides of pyridinedisulfonic acids, in particular of pyridine-3, 5-disulfonic acid, can be used.

6. The method according to claim I to 5, characterized in that in addition to the salts or derivatives of pyndinsulfonic acids further solubilizers, preferably neutral reaction, such as salts of salicylic acid and / or nicotinic acid and / or nicotinic acid amide can be used.