DE1695218A1 - Therapeutically effective nicotinic acid esters of xylitol, adonitol and arabitol - Google Patents

Therapeutically effective nicotinic acid esters of xylitol, adonitol and arabitol

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Publication number
DE1695218A1
DE1695218A1 DE19671695218 DE1695218A DE1695218A1 DE 1695218 A1 DE1695218 A1 DE 1695218A1 DE 19671695218 DE19671695218 DE 19671695218 DE 1695218 A DE1695218 A DE 1695218A DE 1695218 A1 DE1695218 A1 DE 1695218A1
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DE
Germany
Prior art keywords
nicotinic acid
xylitol
acid esters
arabitol
acid ester
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
DE19671695218
Other languages
German (de)
Inventor
Klaus Herbrand
Willy Dr Herbrand
Hermann Dr Kasparek
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HERBRAND KG DR
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HERBRAND KG DR
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 HERBRAND KG DR filed Critical HERBRAND KG DR
Publication of DE1695218A1 publication Critical patent/DE1695218A1/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

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

Description

Therapeutisch wirksame Nikotinsäure-ester von Xylit Adonit und Arabit.Therapeutically effective nicotinic acid esters of xylitol Adonit and Arabitol.

B E S C H R E I B U N G Die Erfindung betrifft die bisher unbekannten Nikotinsäureester von Xylit, Adonit und Arabit der allgemeinen Formel: R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in der R1, R2, R3, R4 und R5 Wasserstoff und/oder Nikotinoyl-Reste bedeuten. The invention relates to the previously unknown Nicotinic acid esters of xylitol, adonitol and arabitol of the general formula: R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in which R1, R2, R3, R4 and R5 are hydrogen and / or Mean nicotinoyl residues.

Die neuen Nikotinsäure-ester zeichnen sich durch eine starke gefäßerweiternde Wirkung aus, bei gleichzeitiger guter Verträglichkeit. Bei den Mono- und Di-nikotinsäure-estern ergeben sich durch den Gehalt an hydrophilen und hydrophoben Gruppen besonders günstige Resorptionsverhältnisse; daduroh wird ein rascher Wirkungseintritt erreicht. Der Penta-nikotinsäure-ester besitzt einen Langzeiteffekt, sodaß die Zahl der Applikationen niedrig gehalten werden kann. Die Verbindungen haben sich besonders bei der Behandlung peripherer Durchblutungsstörungen bewährt.The new nicotinic acid esters are characterized by a strong vasodilator Effect from, while at the same time being well tolerated. With the mono- and di-nicotinic acid esters result from the content of hydrophilic and hydrophobic groups particularly favorable Absorption ratios; daduroh a quick onset of action is achieved. Of the Penta-nicotinic acid ester has a long-term effect, so that the number of applications can be kept low. The compounds have proven particularly useful in treatment peripheral circulatory disorders.

Die Darstellung der Nikotinsäure-ester von Xylit, Adonit und Arabit erfolgt durch Umsetzung der Pentite mit Nikotinsäurechlorid, dessen Menge im äquivalenten Verhältnis der Zahl der Hydroxylgruppen, die verestert werden sollen, angepaßt ist. Das Nikotinsäurechlorid kann sowohl als freie Slave als auch als Hydrochlorid verwendet werden. Am zweokmä#igsten führt man die Reaktion in geeigneten Lösungsmitteln, vorzugsweise in Pyridin aus, bei Temperaturen zwischen 30 und 50° C.The representation of the nicotinic acid esters of xylitol, adonitol and arabitol takes place by reacting the pentite with nicotinic acid chloride, the amount of which is equivalent The ratio of the number of hydroxyl groups to be esterified is adjusted. The nicotinic acid chloride can be used both as a free slave and as a hydrochloride will. The simplest way is to carry out the reaction in suitable solvents, preferably in pyridine, at temperatures between 30 and 50 ° C.

Die Nikotinsäure-ester können als Hydrochloride isoliert werden. Zur Darstellung der freien Basen hat sich besonders die Behandlung der isolierten Xydrochloride oder der Reaktionsgemische mit stark basischen Ionenaustauschern bewährt.The nicotinic acid esters can be isolated as hydrochlorides. To the The treatment of the isolated Xydrochloride has become particularly important for the preparation of the free bases or the reaction mixtures with strongly basic ion exchangers.

Therapeutisch wirksame Nikotinsäure-ester von Xylit, Adonit und Arabit.Therapeutically effective nicotinic acid esters of xylitol, adonitol and arabitol.

BEISPIELE 1.) Darstellung von Xylit-di-nikotinsäure-ester-(1,5) In einem 500 ml Kolben, versehen mit Rührer, Tropftrichter, Thermometer und Kalziumoxyd-Röhrchen werden 15,2 g Xylit in 150 ml trockenem Pyridin gelöst. Unter kräftigem Rühren tropft man eine frisch bereitete Lösung von 29,6 g Nikotinsäurechlorid in 100 ml trockenem Pyridin zu. Die Zugabegeschwindigkeit wird so eingestellt, 0 daß die Reaktionstemperatur 30 C nicht überschreitet. EXAMPLES 1.) Preparation of xylitol di-nicotinic acid ester- (1.5) In a 500 ml flask equipped with a stirrer, dropping funnel, thermometer and calcium oxide tube 15.2 g of xylitol are dissolved in 150 ml of dry pyridine. Drips while stirring vigorously a freshly prepared solution of 29.6 g of nicotinic acid chloride in 100 ml of dry Pyridine too. The rate of addition is adjusted so that the reaction temperature Does not exceed 30 C.

Nach beendigter Zugabe läßt man das Reaktionsgemisch 24 Stunden stehen. Das Lösungsmittel wird im Vakuum abdestilliert und der sirupöse Rückstand durch wiederholtes Behandeln mit Aceton zur Kristallisation gebracht, Durch Umkristallisation aus einem Methanol-Aceton-Gemisch erhält man das Di-hydrochlorid in Form kleiner farbloser Kristalle. When the addition is complete, the reaction mixture is left to stand for 24 hours. The solvent is distilled off in vacuo and the syrupy residue through repeated treatment with acetone brought about crystallization, by recrystallization the dihydrochloride is obtained in the form of a small amount from a methanol-acetone mixture colorless crystals.

Zur Darstellung der freien Base wird das Reaktionsgemisch nach Entfernung des Pyridins in wässrigem Methanol gelöst und die Lösung durch eine mit aktivem Amberlite IRA 400 ausgestattetenSäule ( 5cm, Länge 80 cm) geschickt. Den Austauscher wäscht man mit wässrigem Methanol nach, vereinigt die Lösungen und engt im Vakuum ein. Aus dem gonzentrat wird der Ester durch Zusatz von Aceton-Äther gefällt. Durch Umkristallisation aus Essigester erhält man farblose Kristalle. After removal, the reaction mixture is used to prepare the free base of the pyridine dissolved in aqueous methanol and the solution by an active Amberlite IRA 400 equipped column (5cm, length 80 cm). The exchanger it is washed with aqueous methanol, the solutions are combined and concentrated in vacuo a. The ester is precipitated from the concentrate by adding acetone-ether. By Recrystallization from ethyl acetate gives colorless crystals.

2.) Darstellung von lylit-penta-nikotinsäure-ester.2.) Representation of lylitol-penta-nicotinic acid ester.

36 g Nikotinsäurechlorid-hydrochlorid und 150 ml trockenes Pyridin werden in einem Dreihalskolben mit Rührer, Thermometer und Kalziumoxyd-Röhrchen unter kräftigem Rühren mit einer Lösung von 6 g Xylit in 50 ml Pyridin versetzt. Nach beendigter Zugabe wird das Gemisch noch 3 Stunden gerührt und anschließend über Nacht stehen gelassen. Dann destilliert man im Vakuum das Pyridin ab und behandelt den Rückstand wiederholt zunächst mit wässriger Natriumhydrogencarbonat-Lösung und dann mit kaltem Wasser. Der gummiartige Rückstand wird durch Erwärmen in absolutem Alkohol aufgenommen. Beim Abkühlen scheiden sich kleine Kristalle ab. 36 g nicotinic acid chloride hydrochloride and 150 ml dry pyridine are in a three-necked flask with a stirrer, thermometer and calcium oxide tubes A solution of 6 g of xylitol in 50 ml of pyridine is added while stirring vigorously. When the addition is complete, the mixture is stirred for a further 3 hours and then left overnight. The pyridine is then distilled off in vacuo and treated the residue is repeated first with aqueous sodium hydrogen carbonate solution and then with cold water. The gummy residue becomes by heating in absolute Alcohol ingested. Small crystals separate out on cooling.

3.) Darstellung von Xylit-di-nikotinsure-ester-(1) 17 g 1-Chlor-1-desoxy-iylit und 16 g pulverisiertes Natriumnikotinat werden in 200 ml trockenem Pyridin 3 Stunden unter Rühren auf 600 C erhitzt. Das Lösungsmittel wird abdestilliert, der Rückstand in heißem, absolutem Äthanol aufgenommen und filtriert. Beim Abkühlen scheidet sich das Produkt in feinkristalliner Form ab.3.) Preparation of xylitol di-nicotinic acid ester (1) 17 g of 1-chloro-1-deoxy-iylitol and 16 g of powdered sodium nicotinate are placed in 200 ml of dry pyridine for 3 hours heated to 600 ° C. with stirring. The solvent is distilled off, the residue taken up in hot, absolute ethanol and filtered. Separates as it cools the product in fine crystalline form.

Claims (1)

Therapeutisch wirksame Nikotinsäure-ester von Xylit, Adonit und Arbeit.Therapeutically effective nicotinic acid esters of xylitol, adonit and work. P A T E N T A N S P R Ü C H E 1.) Nikotinsäure-ester von Xylit der allgemeinen Formel: R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in der R1, R2, R3, R4, und R5 Wasserstoff und/oder Nikotionyl-Reste bendeuten. P A T E N T A N S P R Ü C H E 1.) Nicotinic acid ester of xylitol general formula: R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in the R1, R2, R3, R4 and R5 denote hydrogen and / or nicotionyl radicals. 2.) Nikotionsäure-ester von Adonit der allgemeinen Formel R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in der R1, R2, R3, R4, R5 Wasserstoff und/oder Nikotionyl-Reste bedeuten.2.) Nicotionic acid esters of Adonit of the general formula R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in which R1, R2, R3, R4, R5 are hydrogen and / or Mean nicotionyl residues. 3.) Nikotinsäure-ester von Arabit der allgemeinen formel: R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in der R1, R2, R3, R4, R5 Wasserstoff und/oder Nikotinoyl-Reste bedeuten.3.) Nicotinic acid ester of arabitol of the general formula: R1O-CH2 - CH-OR2 - CH-OR3 - CH-OR4 - CH2-OR5 in which R1, R2, R3, R4, R5 are hydrogen and / or Mean nicotinoyl residues. 4.) Xylit-mono-nikotinsäure-ester(1) 5.) Xylit-di-nikotinsäure-ester(1,5) 6.) Xylit-penta-nikotinsäure-ester 7.) Verfahren zur Herstellung von Nikotinsäure-estern des Xylits, Adonits und Arabitst gemäß den Ansprüchen 1-6, dadurch gekennzeichnet, daß man die Pentite in geeigneten Lösungsmitteln, vorzugsweise in Pyridin mit Nikotinsaurechlorid, dessen Menge im äquivalenten Verhältnis der Zahl der Hdroxylgruppen,--die verestert werden sollen, angepa#t ist, bei Temperaturen, die meist zwischen 30 und 50° C liegen, behandelt.4.) Xylitol mono-nicotinic acid ester (1) 5.) Xylitol di-nicotinic acid ester (1.5) 6.) Xylitol penta-nicotinic acid ester 7.) Process for the production of nicotinic acid esters of xylitol, adonite and arabitol according to claims 1-6, characterized in that that the pentite in suitable solvents, preferably in pyridine with nicotinic acid chloride, whose Amount in the equivalent ratio of the number of hydroxyl groups - which are esterified should, is adapted, at temperatures, which are usually between 30 and 50 ° C, treated. 8.) Verfahren zur Herstellung von kono-nikotinsäure-estern von Xylit, Adonit und Arabit, dadurch gekennzeichnet, daß man die Mono-halogen-monodesoxy-pentite mit Natriumnikotinat in geeigneten Lösungsmitteln bei höheren Temperaturen behandelt.8.) Process for the production of kono-nicotinic acid esters of xylitol, Adonite and arabitol, characterized in that the mono-halogen-monodeoxy-pentite treated with sodium nicotinate in suitable solvents at higher temperatures. 9.) Verfahren zur Herstellung von Di-nikotinsäure-estern von Xylit, Adonit und jrabit, dadurch gekennzeichnet, daß man die Di-halogen-di-desoxypentite mit Natriumnikotinat in geeigneten Lösungsmitteln bei höheren Temperaturen behandelt.9.) Process for the production of di-nicotinic acid esters of xylitol, Adonit and jrabit, characterized in that the di-halogen-di-deoxypentite treated with sodium nicotinate in suitable solvents at higher temperatures.
DE19671695218 1967-12-28 1967-12-28 Therapeutically effective nicotinic acid esters of xylitol, adonitol and arabitol Pending DE1695218A1 (en)

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DEH0064898 1967-12-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1243351B (en) * 1963-10-03 1967-06-29 Haslocher Ausziehtisch Und Moe Table with pull-out base
FR2457684A1 (en) * 1979-06-01 1980-12-26 Ferrokemia Ipari COMPOSITIONS FOR USE AS COSMETICS AND PROCESS FOR THE PREPARATION OF THEIR ACTIVE INGREDIENTS

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1243351B (en) * 1963-10-03 1967-06-29 Haslocher Ausziehtisch Und Moe Table with pull-out base
FR2457684A1 (en) * 1979-06-01 1980-12-26 Ferrokemia Ipari COMPOSITIONS FOR USE AS COSMETICS AND PROCESS FOR THE PREPARATION OF THEIR ACTIVE INGREDIENTS

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