DE1223849B - Process for the preparation of lactic acid 7- (N-beta-dimethylaminoaethoxy) -flavone - Google Patents

Process for the preparation of lactic acid 7- (N-beta-dimethylaminoaethoxy) -flavone

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Publication number
DE1223849B
DE1223849B DEV19477A DEV0019477A DE1223849B DE 1223849 B DE1223849 B DE 1223849B DE V19477 A DEV19477 A DE V19477A DE V0019477 A DEV0019477 A DE V0019477A DE 1223849 B DE1223849 B DE 1223849B
Authority
DE
Germany
Prior art keywords
flavone
lactic acid
dimethylaminoethoxy
preparation
dimethylaminoaethoxy
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
DEV19477A
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German (de)
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.)
HANS VOIGT CHEM PHARM FABRIK D
Original Assignee
HANS VOIGT CHEM PHARM FABRIK D
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 HANS VOIGT CHEM PHARM FABRIK D filed Critical HANS VOIGT CHEM PHARM FABRIK D
Priority to DEV19477A priority Critical patent/DE1223849B/en
Publication of DE1223849B publication Critical patent/DE1223849B/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Description

Verfahren zur Herstellung von milchsaurem 7-(N-ß-Dimethylaminoäthoxy)-flavon Die Erfindung betrifft ein Verfahren zur Herstellung von milchsaurem 7-(N-ß-Dimethylaminoäthoxy)-flavon.Process for the preparation of lactic acid 7- (N-ß-dimethylaminoethoxy) -flavone The invention relates to a process for the preparation of lactic acid 7- (N-ß-dimethylaminoethoxy) flavone.

Es wurde gefunden, daß diese Verbindung eine stärkere coronardurchblutende Wirkung besitzt als das bekannte 7-(N-ß-Dimethylaminoäthoxy)-flavonhydrochlorid und dabei fast doppelt sowenig toxisch ist wie das Hydrochlorid. Außerdem ist das milchsaure Salz leichter in Wasser löslich als das mineralsaure Salz und ist selbst in großer Konzentration gut verträglich. It has been found that this compound has a stronger coronary blood flow Has an effect as the well-known 7- (N-ß-dimethylaminoethoxy) flavone hydrochloride and is almost twice as toxic as the hydrochloride. Besides, this is Lactic acid salt is more soluble in water than the mineral acid salt and is itself well tolerated in large concentrations.

Während z. B. 5- bis 10010ige wäßrige Lösungen des mineralsauren Salzes gewisse Reizerscheinungen, wie Brennen im Auge, hervorrufen, ist dies bei dem milchsauren Salz nicht der Fall.While z. B. 5- to 10010 aqueous solutions of the mineral acid salt produce certain symptoms of irritation, such as a burning sensation in the eye, this is the case with the lactic acid Salt not the case.

Die Coronarwirkung wurde gegenüber Theophyllin (als Theophyllinum Natrium aceticum) als Vergleichssubstanz am isolierten Meerschweinchenherzen (Gewicht der Meerschweinchen 400 bis 500 g) geprüft. Die für die Versuche verwendete Nährlösung entsprach der nach Fr. Uhlmann und Fr. Nobile im Archiv für experimentelle Pathologie und Pharmakologie, 192, S. 189 bis 198 (1939), beschriebenen Zusammensetzung. Die Bestimmung der Coronardurchblutung erfolgt nach der Methode von L an g e nd r ff (sogenanntes Langendorffherz), wobei die Vermehrung des coronaren Durchströmungsvolumens in Prozent der Ausgangsmenge bestimmt wurde, und zwar bei Verabreichung von verschieden hohen Dosen. The coronary effect was compared to theophylline (as Theophyllinum Sodium aceticum) as a comparison substance on the isolated guinea pig heart (weight of guinea pigs 400 to 500 g) tested. The nutrient solution used for the experiments corresponded to that of Ms. Uhlmann and Ms. Nobile in the archive for experimental pathology and Pharmakologie, 192, pp. 189 to 198 (1939). the The coronary blood flow is determined according to the method of L an g e nd r ff (so-called Langendorff heart), whereby the increase in the coronary flow volume was determined as a percentage of the initial amount, with administration of different high doses.

Hierbei wurden die in der nachstehenden Tabelle zusammengestellten Ergebnisse erhalten: Steigerung des coronaren DL50 Durchströmungsvolumens in in Prozent der Ausgangs- Substanz mg/kg menge bei Verabreichung Maus s.c. von 250# 300# 400# Theophyllin . . . . . . . 300 15 (6) 18 (7) 20 (6) 7-(N-ß-Dimethyl- aminoäthoxy)- flavon-hydrochlorid 400 60 70 75 Milchsaures 7-(N-B-Dimethyl- aminoäthoxy)- flavon .. ........ 950 92 95 110 Die in Klammern angegebene Zahl bedeutet die Anzahl der Versuche.The results compiled in the table below were obtained: Increase in coronary DL50 flow volume as a percentage of the initial Substance mg / kg amount when administered mouse sc of 250 # 300 # 400 # Theophylline. . . . . . . 300 15 (6) 18 (7) 20 (6) 7- (N-ß-dimethyl- aminoethoxy) - flavone hydrochloride 400 60 70 75 Lactic acid 7- (NB-dimethyl- aminoethoxy) - flavone .. ........ 950 92 95 110 The number in brackets means the number of attempts.

Aus den gefundenen Werten geht hervor, daß auch bei unterschiedlichen Versuchsdosen das milchsaure 7-(N-ß-Dimethylaminoäthoxy)-flavon gegenüber den bekannten Substanzen eine mehrfache Überlegenheit besitzt. The values found show that even with different Test doses the lactic acid 7- (N-ß-dimethylaminoethoxy) -flavone compared to the known Substances possesses a multiple superiority.

Ferner wurde die periphere Gefäßwirkung am isolierten Kaninchenohr (mit l-noradrenalinhaltiger Tyrode durchströmt) bestimmt. Für die Gefäßerweiterung wurden bei einer Dosis von 10-6 bis 10-4 die folgenden Ergebnisse erhalten, wobei die Wirksamkeit der geprüften Verbindungen, bezogen auf Theophyllin = 1, angegeben wurde: Gefäß- Wirk- Substanz erweiterung sam- O/o keit Theophyllin .................. 17 bis 20 1 7-(N-ß-Dimethylaminoäthoxy)- flavon-hydrochlorid . . 50 bis 55 3 Milchsaures 7-(N-ß-Dimethyl- aminoäthoxy)-flavon .... 80 bis 85 5 Außerdem wurde die musculotrop-spasmolytische Wirkung nach M a g n u s am isolierten Meerschweinchendarm bestimmt. Die mit einer Bariumchloridlösung in einer Konzentration von 10-4 hervorgerufenen Spasmen wurden aufgehoben durch Papaverin in Konzentrationen von 1: 60000 bis 1: 100000 (= 1), durch 7-(N-ß-Dimethylaminoäthoxy)-flavonhydrochlorid in Konzentrationen von 1: 25000 bis 1: 40000 (= 0,5) und durch milchsaures 7-(N-ß-Dimethylaminoäthoxy)-flavon in Konzentrationen von 1: 80000 bis 1: 110000 (= 1). Das Verfahrensprodukt ist hierbei zwar nur halb so stark wirksam wie das entsprechende Hydrochlorid, jedoch ist es infolge seiner weitaus geringeren Toxizität gegenüber den geprüften bekannten Verbindungen überlegen.The peripheral vascular effect was also determined on the isolated rabbit ear (perfused with L-noradrenaline-containing Tyrode). For vasodilation, the following results were obtained at a dose of 10-6 to 10-4, the effectiveness of the compounds tested being given based on theophylline = 1: Vascular active Substance expansion sam- O / o speed Theophylline .................. 17 to 20 1 7- (N-ß-dimethylaminoethoxy) - flavone hydrochloride. . 50 to 55 3 Lactic acid 7- (N-ß-dimethyl- aminoethoxy) flavone .... 80 to 85 5 In addition, the musculotropic-spasmolytic effect was determined on the isolated guinea pig intestine after m agnus. The spasms caused with a barium chloride solution in a concentration of 10-4 were relieved by papaverine in concentrations of 1: 60,000 to 1: 100,000 (= 1), by 7- (N-ß-dimethylaminoethoxy) -flavone hydrochloride in concentrations of 1: 25,000 up to 1: 40,000 (= 0.5) and lactic acid 7- (N-ß-dimethylaminoethoxy) flavone in concentrations of 1: 80,000 to 1: 110,000 (= 1). The process product is only half as effective as the corresponding hydrochloride, but due to its far lower toxicity it is superior to the known compounds tested.

Das milchsaure 7 - (N -ß- Dimethylaminoäthoxy)-flavon soll vor allem in der Herztherapie angewandt werden, wo also jegliche Zuführung von Chlorionen (wie es bei den chlorwasserstoffsauren Salzen der Fall ist) zu unterbleiben hat, so daß es demnach erhebliche Vorteile gegenüber den entsprechenden bekannten mineralsauren Salzen besitzt. The lactic acid 7 - (N -ß- dimethylaminoethoxy) -flavone is said to be above all can be used in heart therapy, where there is any supply of chlorine ions (as is the case with the hydrochloric acid salts), so that it therefore has considerable advantages over the corresponding known mineral acids Owns salts.

Das erfindungsgemäße Verfahren zur Herstellung vonrnilchsaurem7-(N-ß-Dimethylaminoäthoxy)-flavon ist dadurch gekennzeichnet, daß man 7-(N-fl-Dimethylaminoäthoxy)-flavon in an sich bekannter Weise mit der äquimolaren Menge oder einem Überschuß an Milchsäure umsetzt. The process according to the invention for the preparation of lactic acid 7- (N-ß-dimethylaminoethoxy) flavone is characterized in that one 7- (N-fl-dimethylaminoethoxy) flavone in itself in a known manner with the equimolar amount or an excess of lactic acid.

Beispiel 1 30 g (0,1 Mol) 7-(N-fl-Dimethylaminoäthoxy)-fiavon werden mit 9 g (0,1 Mol) Milchsäure in 40ccm ALkohol 15 bis 20 Minuten zum Sieden erhitzt. Dann wird die Lösung eingedampft, der Rückstand mit Aceton verrieben und kristallisieren gelassen. Nach mehreren Stunden Stehen in der Kälte scheiden sich schöne farblose Kristalle von milchsaurem 7-(N-fl-Dimethylaminoäthoxy)-Ravon ab, die abfiltriert werden. Example 1 30 g (0.1 mol) of 7- (N-fl-dimethylaminoethoxy) -fiavon become heated to the boil for 15 to 20 minutes with 9 g (0.1 mol) of lactic acid in 40ccm alcohol. The solution is then evaporated, the residue is triturated with acetone and crystallized calmly. After standing in the cold for several hours, beautiful, colorless ones separate Crystals of lactic acid 7- (N-fl-dimethylaminoethoxy) -Ravon, which are filtered off will.

Die Verbindung schmilzt bei 115 bis 117"C und ist spielend leicht löslich in Wasser, gut löslich in Alkoholen, unlöslich in Äther. Die Ausbeute beträgt 7501o der Theorie.The connection melts at 115 to 117 "C and is very easy soluble in water, readily soluble in alcohols, insoluble in ether. The yield is 7501o of theory.

Beispiel 2 30 g (0,1 Mol) 7-(N-fl-Dimethylaminoäthoxy)-flavon werden mit 31 bis 32 g (etwa 0,3 Mol) wäßriger, 80 bis 90%iger Milchsäure des Handels in 100 ccm Xylol 30 Minuten zum Sieden erhitzt. Dann wird das Xylol im Vakuum - abdestilliert und der Rückstand mit Aceton verrieben, wobei dieser leicht kristallisiert. Example 2 30 g (0.1 mol) of 7- (N-fl-dimethylaminoethoxy) flavone become with 31 to 32 g (about 0.3 mol) of aqueous 80 to 90% lactic acid commercially available in 100 cc xylene heated to the boil for 30 minutes. Then the xylene is distilled off in vacuo and the residue was triturated with acetone, which easily crystallized.

Man erhält das milchsaure 7-(N-ß-Dimethylaminoäthoxy)-flavon vom F. 115 bis 117"C in einer Ausbeute von 80 0/, der Theorie..The lactic acid 7- (N-ß-dimethylaminoethoxy) -flavone from F. 115 to 117 "C in a yield of 80 0 /, the theory ..

Claims (1)

Patentanspruch: Verfahrei zur Herstellung von milchsaurem 7-(N-ß-Dimethylaminoäthoxy)-flavon, d a d u r c h gekennzeichnet, daß man 7-(N-ß-Dimethylaminoäthoxy)-flavon in an sich bekannter Weise mit der äquimolekularen Menge oder einem Überschuß an Milchsäure umsetzt. Claim: Process for the production of lactic acid 7- (N-ß-dimethylaminoethoxy) -flavone, d a d u r c h that one has 7- (N-ß-dimethylaminoethoxy) flavone in itself known manner with the equimolecular amount or an excess of lactic acid implements. In Betracht gezogene Druckschriften: Deutsche Auslegeschrift Nr. 1 054 091. Documents considered: German Auslegeschrift No. 1 054 091.
DEV19477A 1960-10-11 1960-10-11 Process for the preparation of lactic acid 7- (N-beta-dimethylaminoaethoxy) -flavone Pending DE1223849B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DEV19477A DE1223849B (en) 1960-10-11 1960-10-11 Process for the preparation of lactic acid 7- (N-beta-dimethylaminoaethoxy) -flavone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEV19477A DE1223849B (en) 1960-10-11 1960-10-11 Process for the preparation of lactic acid 7- (N-beta-dimethylaminoaethoxy) -flavone

Publications (1)

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DE1223849B true DE1223849B (en) 1966-09-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018597A1 (en) * 1990-06-04 1991-12-12 Erickson Ronald H Sigma binding site agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1054091B (en) * 1958-05-30 1959-04-02 Chemiewerk Homburg Ag Process for the preparation of N-substituted 2-phenyl-7-aminoalkoxy-chromones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1054091B (en) * 1958-05-30 1959-04-02 Chemiewerk Homburg Ag Process for the preparation of N-substituted 2-phenyl-7-aminoalkoxy-chromones

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018597A1 (en) * 1990-06-04 1991-12-12 Erickson Ronald H Sigma binding site agents
US5278174A (en) * 1990-06-04 1994-01-11 Scios Nova, Inc. Sigma binding site agents
US5359098A (en) * 1990-06-04 1994-10-25 Guilford Pharmaceuticals Inc. Intermediates for making sigma binding site agents

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