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DE1135474B - Process for the preparation of double salts of theophylline with quaternary ammonium salts - Google Patents

Process for the preparation of double salts of theophylline with quaternary ammonium salts

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Publication number
DE1135474B
DE1135474B DEK42017A DEK0042017A DE1135474B DE 1135474 B DE1135474 B DE 1135474B DE K42017 A DEK42017 A DE K42017A DE K0042017 A DEK0042017 A DE K0042017A DE 1135474 B DE1135474 B DE 1135474B
Authority
DE
Germany
Prior art keywords
theophylline
salts
preparation
quaternary ammonium
double
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
DEK42017A
Other languages
German (de)
Inventor
Dr Rer Nat Josef Klo Dipl-Chem
Dr Med Habil Hans Seel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BARBARA SEEL GEB MEHLING
JOSEF KLOSA DIPL CHEM DR RER N
Original Assignee
BARBARA SEEL GEB MEHLING
JOSEF KLOSA DIPL CHEM DR RER N
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BARBARA SEEL GEB MEHLING, JOSEF KLOSA DIPL CHEM DR RER N filed Critical BARBARA SEEL GEB MEHLING
Priority to DEK42017A priority Critical patent/DE1135474B/en
Publication of DE1135474B publication Critical patent/DE1135474B/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Verfahren zur Herstellung von Doppelsalzen des Theophyllins mit quaternären Ammoniumsalzen In der deutschen Patentschrift 1067821 ist ein Verfahren zur Herstellung von Jodcholin-7anthinaten beschrieben. In diesen Verbindungen ist die freie Jodcholinbase mit Xanthinen, wie Theophyllin, salzartig verbunden. Diese Verbindungen haben sich pharmakodynamisch vorzüglich wirksam bei arteriosklerotischen Erkrankungen erwiesen. Process for the preparation of double salts of theophylline with quaternary Ammonium salts In the German patent specification 1067821 is a process for the preparation of iodocholine-7anthinaten described. In these compounds is the iodocholine free base combined with xanthines, such as theophylline, in a salt-like manner. These connections have become Pharmacodynamically proven to be extremely effective in arteriosclerotic diseases.

Es wurde nun gefunden, daß man Doppelsalze des Theophyllins mit quaternären Ammoniumsalzen erhält, wenn man Jodalkyl-trialkylammoniumjodide der allgemeinen Formel in welcher n die Zahl 2 oder 3 und R Alkylreste mit 1 bis 3 Kohlenstoffatomen bedeutet, mit Theophyllin im äquimolaren Verhältnis entweder in Gegenwart eines Lösungs- oder Verdünnungsmittels, wie Wasser oder Alkoholen, oder durch Verreiben oder Vermahlen der Reaktionspartner umsetzt. It has now been found that double salts of theophylline with quaternary ammonium salts are obtained when iodoalkyl-trialkylammonium iodides of the general formula in which n is the number 2 or 3 and R is alkyl radicals having 1 to 3 carbon atoms, is reacted with theophylline in an equimolar ratio either in the presence of a solvent or diluent, such as water or alcohols, or by triturating or grinding the reactants.

Hierbei haben n und R die obengenannte Bedeutung. Here, n and R have the meaning given above.

Diese Doppelsalze lassen sich wieder in die Komponenten zerlegen, wenn sie mit verdünntem Ammoniak oder anderen milden Alkalien behandelt werden; hierbei wird Theophyllin aus dem Komplex herausgelöst, während die quaternäre Verbindung durch geeignete Fällungsreagenzien nachgewiesen werden kann. These double salts can be broken down again into the components, when treated with dilute ammonia or other mild alkalis; here theophylline is released from the complex, while the quaternary compound can be detected by suitable precipitation reagents.

Die neuen Verfahrensprodukte zeigen sich bereits in Dosen von 1 bis 2 mg/kg gegen die bei Kaninchen durch Verabreichung von in Sonnenblumenöl unter Zusatz von Methyltiouracil gelöstem Cholesterin hervorgerufene Cholesterinämie wirksam, während die bekannten Jodcholin-7-xanthinate erst bei 4 mg/kg wirksam sind. Auch beim Blutdrucksenkungsversuch erweisen sich die Verfahrensprodukte 1 bis 2 mal wirksamer. The new process products can already be seen in doses from 1 to 2 mg / kg against that in rabbits by administration of in sunflower oil Addition of methyltiouracil to dissolved cholesterol effective in causing cholesterolemia, while the well-known iodocholine-7-xanthinate are only effective at 4 mg / kg. Even When attempting to lower the blood pressure, the products of the process prove to be 1 to 2 times more effective.

Die Toxizität der neuen Verfahrensprodukte ist geringer als diejenige des unter dem Handelsnamen Euphyllin bekannten Theophyllin-Athylendiaminprä- parats oder des Jodcholi.n-7-theophyllinats. Die Bestimmung der akuten D L,, erfolgte nach G. Kärber [»Naunyn-Schmiedebergs Archiv der experimentellen Pharmakologie und Pathologie«, Bd. 162 (1931) S. 480] mit je 30 männlichen Mäusen, deren Durchschnittsgewicht 28 g betrug. Die nachstehende Tabelle gibt die Ergebnisse an: DL50 subcutan Substanz in mg/kg Theophyllin-Äthylendiamin . . 185 Jodcholin theophyllinat . .. 162 Jodcholinjodid-theophyllin . . 220 Die neuen Verfahrensprodukte besitzen keinerlei diuretische Wirkung, dagegen aber eine gute blutdrucksenkende Wirkung, welche bekannten Verbindungen ähnlicher Körperklassen überlegen ist. Die blutdrucksenkende Wirkung wurde nach der Methodik von Trendelenburg an der Normal- und Spinalkatze geprüft (blutige Messungen aus der Arteria femoralis, Narkose mit 75 mg/kg des bekannten Natriumsalzes der B-Bromallyl-sek. -butylbarbitursäure, intramuskulär.The toxicity of the new process products is lower than that of the theophylline-ethylenediamine preparation known under the trade name Euphyllin or the iodocholine-7-theophyllinate. The acute DL was determined according to G. Kärber [Naunyn-Schmiedebergs Archiv der experimental Pharmakologie und Pathologie], vol. 162 (1931) p. 480] with 30 male mice each, the average weight of which was 28 g. The table below gives the results: DL50 subcutaneously substance in mg / kg Theophylline ethylenediamine. . 185 Iodocholine theophyllinate. .. 162 Iodocholine iodide theophylline. . 220 The new products of the process do not have any diuretic effect, but have a good antihypertensive effect, which is superior to known compounds of similar body classes. The antihypertensive effect was tested on normal and spinal cats using the Trendelenburg method (bloody measurements from the femoral artery, anesthesia with 75 mg / kg of the well-known sodium salt of B-bromoallyl-secondary butylbarbituric acid, intramuscularly.

Für jeden Versuch wurden 10 ausgewachsene Katzen beiderlei Geschlechts verwendet. Die durchschnittlichen Blutdruckänderungen werden in folgenden Tabellen angegeben: Versuche an Normalkatze Dosis Substanz in mg/kg Druckabfall intravenös Theophyllin-Athylen- diamin . . - 0,6 -8mmHg (# 3,5 mm Hg) Jodcholin-(7)-theo- phyllinat . . 0,6 -48 mm Hg 4,4 mm Hg) Jodcholinjodid-theo- phyllin . 0,2 -42mmHg (# 3,8 mm Hg) Versuche an Spinalkatze Dosis Substanz in mg/kg Druckabfall intravenös Theophyllin-Athylen- diamin . . 1,0 - 8 mm Hg (+1,5mmHg) Jodcholin-(7)-theo- phyllinat . . 0,6 -14mmHg (+2,OmmHg) Jodcholinjodid-theo- phyllin. .. 0,4 -16mmHg (# 1,8 mm Hg) Die neuen Doppelsalze sollen daher als Heilmittel Verwendung finden.Ten adult cats of both sexes were used for each experiment. The average changes in blood pressure are given in the following tables: Tests on normal cats dose Substance in mg / kg pressure drop intravenous Theophylline ethylene diamine. . - 0.6-8mmHg (# 3.5 mm Hg) Iodocholine- (7) -theo- phyllinate. . 0.6-48 mm Hg 4.4 mm Hg) Iodocholine iodide-theo- phyllin. 0.2 -42mmHg (# 3.8 mm Hg) Attempts on spinal cats dose Substance in mg / kg pressure drop intravenous Theophylline ethylene diamine. . 1.0 - 8 mm Hg (+ 1.5mmHg) Iodocholine- (7) -theo- phyllinate. . 0.6-14mmHg (+ 2, OmmHg) Iodocholine iodide-theo- phyllin. .. 0.4-16mmHg (# 1.8 mm Hg) The new double salts should therefore be used as a remedy.

Beispiel 1 34 g (ß-Jodäthyl-trimethyl)-ammoniumjodid werden mit 18 g Theophyllin in 60 bis 80ml Wasser 20 Minuten zum Sieden erhitzt. Es löst sich alles auf. Example 1 34 g of (ß-iodoethyl-trimethyl) ammonium iodide with 18 g theophylline in 60 to 80ml water heated to boiling for 20 minutes. It dissolves all on.

Nun wird heiß filtriert und in der Kälte einige Stunden stehengelassen. Aus dem Filtrat kristallisieren farblose Kristalle aus. F. 224 bis 2260 C unter Violettfärbung und Zersetzung. Ausbeute etwa 95e/o.Now it is filtered hot and in the cold for a few hours ditched. Colorless crystals crystallize out of the filtrate. F. 224 to 2260 C below Violet color and decomposition. Yield about 95e / o.

Beispiel 2 34 g (ß-Jodäthyl-trimethyl)-ammoniumjodid werden mit 18 g wasserfreiem Theophyllin in einer Reibschale innig miteinander verrieben und einige Zeit stehengelassen. Das Produkt hat einen Schmelzpunkt von 224 bis 2260 C, der auch nach Umkristallisieren in Wasser beibehalten wird. Example 2 34 g of (ß-iodoethyl trimethyl) ammonium iodide are 18 g anhydrous theophylline thoroughly rubbed together in a mortar and some Time left standing. The product has a melting point of 224 to 2260 C, the is retained even after recrystallization in water.

Beispiel 3 48 g (γ-Jodpropyl-trimethyl)-ammoniumjodid werden mit 18 g Theophyllin in 60 ml Wasser oder 200 ml Äthanol 15 bis 25 Minuten zum Sieden erhitzt. Hierauf wird heiß filtriert. Aus dem Filtrat scheiden sich beim Stehen in der Kälte farblose Kristalle des Doppelsalzes aus. F. 207 bis 2090 C. Ausbeute 8O0/o. Example 3 48 g of (γ-iodopropyl trimethyl) ammonium iodide become boil with 18 g theophylline in 60 ml water or 200 ml ethanol for 15 to 25 minutes heated. It is then filtered hot. Separate from the filtrate on standing colorless crystals of the double salt in the cold. F. 207-2090 C. Yield 8O0 / o.

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung von Doppelsalzen des Theophyllins mit quaternären Ammoniumsalzen, dadurch gekennzeichnet, daß man Jodalkyl-trialkyl-ammoniumjodide der allgemeinen Formel in welcher n die Zahl 2 oder 3 und R Alkylreste mit 1 bis 3 Kohlenstoffatomen bedeuten, mit Theophyllin im äquimolaren Verhältnis entweder in Gegenwart eines Lösungs- oder Verdünnungsmittels oder durch Verreiben oder Vermahlen der Reaktionspartner umsetzt.PATENT CLAIM: Process for the preparation of double salts of theophylline with quaternary ammonium salts, characterized in that iodoalkyl-trialkyl-ammonium iodides of the general formula are used in which n is the number 2 or 3 and R is alkyl radicals having 1 to 3 carbon atoms, is reacted with theophylline in an equimolar ratio either in the presence of a solvent or diluent or by triturating or grinding the reactants. In Betracht gezogene Druckschriften: Deutsche Patentschrift Nr. 1 067821. Documents considered: German Patent No. 1 067821.
DEK42017A 1960-10-31 1960-10-31 Process for the preparation of double salts of theophylline with quaternary ammonium salts Pending DE1135474B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1067821B (en) 1956-02-21 1959-10-29 Dr Med Habil Hans Seel Process for the production of iodocholine- (7) -xanthine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1067821B (en) 1956-02-21 1959-10-29 Dr Med Habil Hans Seel Process for the production of iodocholine- (7) -xanthine

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