DE1921525A1 - Vasodilatory sorbitol esters of nicotinic - acid - Google Patents

Vasodilatory sorbitol esters of nicotinic - acid

Info

Publication number
DE1921525A1
DE1921525A1 DE19691921525 DE1921525A DE1921525A1 DE 1921525 A1 DE1921525 A1 DE 1921525A1 DE 19691921525 DE19691921525 DE 19691921525 DE 1921525 A DE1921525 A DE 1921525A DE 1921525 A1 DE1921525 A1 DE 1921525A1
Authority
DE
Germany
Prior art keywords
nicotinic acid
sorbitol
ester
nicotinic
acid esters
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
DE19691921525
Other languages
German (de)
Inventor
Klaus Herbrand
Kasparek Dr Hermann
Herbrand Dr Willy
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.)
HERBRAND KG DR
Original Assignee
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
Priority to DE19691921525 priority Critical patent/DE1921525A1/en
Publication of DE1921525A1 publication Critical patent/DE1921525A1/en
Pending legal-status Critical Current

Links

Classifications

    • 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

Abstract

New cpds. have the formula R1O-CH2-CHOR2-CHOR3-CHOR4-CHOR5-CH2-OR6 (in which R1R2,R3,R4,R5 and R6 denote H or nicotinyl groups). They are produced by transesterifying lower nicotinic acid esters of sorbitol in a solution at an elevated temperature, optionally in the presence of K2CO3.

Description

Therapeutisch wirksame Nikotinsäure-ester von Sorbit.Therapeutically effective nicotinic acid ester of sorbitol.

BESCHREIBUNG In der Patentanmeldung Nr. P 16 95 218.4 werden neue Nikotinsäure-ester von Xylit, Adonit und Arabit beschrieben, die sich durch starke gefäßerweiternde Wirkung bei sehr guter Verträgliohkeit auszeichnen. DESCRIPTION In the patent application no. P 16 95 218.4 new Nicotinic acid esters of xylitol, adonit and arabitol are described, which are characterized by strong show vasodilating effect with very good tolerability.

Es wurde nun gefunden, daß man durch Veresterung von Sorbit mit Nikotinsäure ebenfalls therapeutisch interessante Nikotinsäure-ester erhält. Diese Verbindungen haben die allgemeine Formel: R1O-CH2-CHOR2-CHOR3-CHOR4-CHOR5-CH2-CR6 in der R1 R2, R3, R4, R5, und R6 Wasserstoff und/oder Nikotinoyl-Reste bedeuten.It has now been found that esterifying sorbitol with nicotinic acid also contains therapeutically interesting nicotinic acid esters. These connections have the general formula: R1O-CH2-CHOR2-CHOR3-CHOR4-CHOR5-CH2-CR6 in the R1 R2, R3, R4, R5 and R6 are hydrogen and / or nicotinoyl radicals.

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. Besonders der Hexa-nikotinsäure-ester des Sorbits zeichnet sich durch eins ausgeprägte Langzeitwirkung aus, sodaß die Zahl der Applikationen niedrig gehalten werden kann. Gleichzeitig ist es möglioh, durch Wahl geeigneter Dosierungen über einen längeren Zeitraum, Blutspiegelverte im optimalen Bereich einzustellen und überhöhte Initialkonzentrationen zu vermeiden.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. Particularly the hexa-nicotinic acid ester of sorbitol is characterized by a pronounced long-term effect off so that the number of applications can be kept low. Simultaneously is it possible, by choosing suitable dosages over a longer period of time, Set blood level vertices in the optimal range and excessive initial concentrations to avoid.

Die Darstellung der Nikotinsäure-ester erfolgt durch Umsetzung von Sorbit mit Nikotinsäurechlorid, dessen Menge im äquivalenten Verhältnis der Zahl der Hydroxylgruppen, die verestert werden sollen, angepaßt ist. Das Nikotinsäurechlorid kann sowohl als freie Bass, als auch als Hydrochlorid verwendet werden. Am zweckmäßigsten führt man die Reaktion in geeigneten Lösungsmitteln, z.B. in Pyridin oder Dimethylformamid aus, bei Temperaturen zwischen 30 und 500 C.The nicotinic acid ester is represented by converting Sorbitol with nicotinic acid chloride, the amount of which in the equivalent relationship the number of hydroxyl groups to be esterified is matched. The nicotinic acid chloride can be used both as a free bass and as a hydrochloride. Most convenient the reaction is carried out in suitable solvents, e.g. in pyridine or dimethylformamide off, at temperatures between 30 and 500 C.

Man kann jedoch auch die erfindungsgemäßen Produkte durch Umeaterung gewinnen. Zweckmäßigerweise verwendet man hierzu als Ausgangsmaterial den Xethi- oder ethylester der Nikotinsaure und setzt diese mit Sorbit in geeigneten Lösungsmitteln bei höheren Temperaturen um. Man führt die Reaktion bei mäßig erniedrigtem Druck aus, um den frei werdenden niederen Alkohol dem Reaktionsgemisch laufend zu entziehen. Zur Erleichterung der Umesterung kann dem Reaktionsgemisch wasserfreies Ealiucarbonat zugesetzt werden.However, the products according to the invention can also be obtained by re-heating to win. It is expedient to use the Xethi- or ethyl ester of nicotinic acid and sets this with sorbitol in suitable solvents at higher temperatures around. The reaction is carried out under moderately reduced pressure in order to continuously remove the lower alcohol released from the reaction mixture. To facilitate the transesterification, anhydrous aluminum carbonate can be added to the reaction mixture can be added.

Die gebildeten Nikotinsäure-ester werden durch Umkristallisation gereinigt. Sie können als freie Basen oder auch in Form ihrer Salze, z.B. als Hydrochloride verwendet werden.The nicotinic acid esters formed are purified by recrystallization. They can be used as free bases or in the form of their salts, e.g. as hydrochlorides be used.

Therapeutisch wirksame Nikotinsäure-ester von Sorbit.Therapeutically effective nicotinic acid ester of sorbitol.

B E I S P I E L E 1.) Darstellung von Sorbit-hexa-nikotinsäure-ester 110,6 g Nikotinsäurechlorid-hydrochlorid und 400 ml trockenes Pyridin werden in einem Dreihalskolben, veraehen mit Rührer, Uhermometer und Rückflußkühler, unter kräftigem Rühren mit einer Lösung von 18,2 g Sorbit in 250 ml Pyridin versetzt. Nach beendigter Zugabe wird das Gemisch 5 Stunden auf 500 C erwärmt und anschließend über Nacht stehen gelassen. Das Pyridin destilliert man im Vakuum ab und behandelt den Rückstand wiederholt mit wässriger Natriumhydrogenoarbonat-Lö sung und dann mit kaltem Wasser. Die gummiartige Masse wird in heißem, absolutem Alkohol gelöst. Beim Abkühlen scheiden stich farblose, kleine Kristalle ab. B E I S P I E L E 1.) Representation of sorbitol hexa-nicotinic acid ester 110.6 g of nicotinic acid chloride hydrochloride and 400 ml of dry pyridine are in a three-necked flask equipped with a stirrer, thermometer and reflux condenser vigorous stirring with a solution of 18.2 g of sorbitol in 250 ml of pyridine. When the addition is complete, the mixture is heated to 500 ° C. for 5 hours and then left to stand overnight. The pyridine is distilled off in vacuo and treated the residue repeatedly with aqueous sodium bicarbonate solution and then with cold water. The gummy mass is dissolved in hot, absolute alcohol. When it cools down, colorless, small crystals separate.

2.) Darstellung von Sorbit-di-nikotinsäure-esterZ .6) In einem 500 ml Dreihalskolben, versehen mit Rührer, Tropftrichter, Thermometer und Kalziumoxyd-Röhrchen werden 18,2 g Sorbit in 250 ml trockenem Pyridin gelöst. Unter kräftigem Rühren tropft man eine frisch bereitete Lösung von 29,7 g Nikotinsäurechlorid in 100 ml trookenem Pyridin zu. Die Zugabegeschwindigkeit wird so eingestellt, daß die Reaktionstemperatur 30°C nicht überschreitet. Nach beandigter Zugabe rührt man noch 6 Stunden und läßt dann dae Reaktionsgemisch 48 Stunden stehen. Das Pyridin wird im Vakuum abdestilliert und der Rückstand durch wiederhites Behandeln mit absoluten Äther zur Kristallisation gebracht. Durch Umkristallisation aus einem Methanol-Aceton-Gemisch erhält man das Di-hydrochlo rid in Form farbloser Kristalle.2.) Representation of sorbitol di-nicotinic acid ester Z. 6) In a 500 ml three-necked flask equipped with a stirrer, dropping funnel, thermometer and calcium oxide tube 18.2 g of sorbitol are dissolved in 250 ml of dry pyridine. While stirring vigorously a freshly prepared solution of 29.7 g of nicotinic acid chloride in 100 ml is added dropwise trookenem pyridine too. The rate of addition is adjusted so that the reaction temperature Does not exceed 30 ° C. After the addition is complete, the mixture is stirred for a further 6 hours and left then the reaction mixture stand for 48 hours. The pyridine is distilled off in vacuo and the residue by repeated treatment with absolute ether to crystallize brought. This is obtained by recrystallization from a methanol-acetone mixture Di-hydrochloride in the form of colorless crystals.

Claims (1)

Therapeutisch wirksame Nikotinsäure-ester von Sorbit.Therapeutically effective nicotinic acid ester of sorbitol. PATENTANSPRÜCHE 1.) Nikotinsäure-ester von Sorbit der allgemeinen Formel: R1O - CH2 - CHOR2 - CHOR3 - CHOR4 - CHOR5 - CH2 - OR6 in der R1, R2, R3, R4, R5 und R6 Wasserstoff und/oder Nikotinoyl-Reste bedeuten. PATENT CLAIMS 1.) Nicotinic acid ester of sorbitol of general Formula: R1O - CH2 - CHOR2 - CHOR3 - CHOR4 - CHOR5 - CH2 - OR6 in R1, R2, R3, R4, R5 and R6 are hydrogen and / or nicotinoyl radicals. 2.) Sorbit-mono-nikotinsäure-ester-(1) 3.) Sorbit-di-nikotinsäure-ester-(1,6) 4.) Sorbit-hexa-nikotinsäure-ester 5.) Verfahren zur Herstellung von Nikotinsäure-estern des Sorbits, gemäß den Ansprüchen 1-4, dadurch gekennzeichnet, daß man Sorbit in geeigneten Lösungsmitteln, vorzugsweise in Pyridin oder Dimethylformamid mit Nikotinsäure-chlorid, dessen Menge im äquivalenten Verhältnis der Zahl der Hydroxylgruppen, die verestert werden sollen, angepaßt ist, bei Temperaturen, die zweckmäßig zwischen 30 und 50 C liegen, behandelt.2.) Sorbitol-mono-nicotinic acid-ester- (1) 3.) Sorbitol-di-nicotinic acid-ester- (1,6) 4.) Sorbitol hexa-nicotinic acid ester 5.) Process for the production of nicotinic acid esters of sorbitol, according to claims 1-4, characterized in that sorbitol is in suitable solvents, preferably in pyridine or dimethylformamide with nicotinic acid chloride, its amount in an equivalent ratio to the number of hydroxyl groups that are esterified are to be adjusted, at temperatures which are expediently between 30 and 50 C lying, treated. 6.) Verfahren zur Herstellung von Nikotinsäure-estern des Sorbits gemäß den Ansprüchen 1-5, dadurch gekennzeichnet, daß man niedere Nikotinsäure-ester mit Sorbit bei höheren Temperaturen in geeigneten Lösungsmitteln und gegebenenfalls in Gegenwart von Kaliumcarbonat umestert.6.) Process for the production of nicotinic acid esters of sorbitol according to claims 1-5, characterized in that lower nicotinic acid esters with sorbitol at higher temperatures in suitable solvents and optionally transesterified in the presence of potassium carbonate.
DE19691921525 1967-12-28 1969-04-26 Vasodilatory sorbitol esters of nicotinic - acid Pending DE1921525A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19691921525 DE1921525A1 (en) 1967-12-28 1969-04-26 Vasodilatory sorbitol esters of nicotinic - acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEH0064898 1967-12-28
DE19691921525 DE1921525A1 (en) 1967-12-28 1969-04-26 Vasodilatory sorbitol esters of nicotinic - acid

Publications (1)

Publication Number Publication Date
DE1921525A1 true DE1921525A1 (en) 1970-11-05

Family

ID=5732592

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19691921525 Pending DE1921525A1 (en) 1967-12-28 1969-04-26 Vasodilatory sorbitol esters of nicotinic - acid

Country Status (1)

Country Link
DE (1) DE1921525A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0019260A1 (en) * 1979-05-18 1980-11-26 Laboratorio Guidotti & C. S.p.A. A process for the preparation of D-glucitol hexanicotinate

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0019260A1 (en) * 1979-05-18 1980-11-26 Laboratorio Guidotti & C. S.p.A. A process for the preparation of D-glucitol hexanicotinate

Similar Documents

Publication Publication Date Title
CH644263A5 (en) PREPARATIONS USED FOR COSMETIC PURPOSES AND METHOD FOR PRODUCING THE ACTIVE SUBSTANCES OF THESE PREPARATIONS.
DE1921525A1 (en) Vasodilatory sorbitol esters of nicotinic - acid
DE2320945A1 (en) NEW ESTERS OF ACETYL SALICYLIC ACID
DE1695218A1 (en) Therapeutically effective nicotinic acid esters of xylitol, adonitol and arabitol
DE800413C (en) Process for the production of neutral solutions of polyalkylxanthines
DE2122070A1 (en) 1 Veratryl 4 methyl 5 ethyl 7,8 dimethoxy 2,3 diazabicyclo square brackets to 5,4,0 square brackets to undeca pentaen (1,3,6,8,10) and its use
DE1793462B2 (en) N-aryl-anthranilic acid esters of monosubstituted gem-diols, process for their preparation and pharmaceutical preparations containing these compounds
AT212980B (en) Process for the preparation of deserpidic acid
AT299938B (en) Process for the preparation of the new sodium salt of (1-nicotinoyl-2-methyl-5-methoxy-3-indolyl) -acetic acid, optionally mixed with the free acid
DE716579C (en) Process for the production of ester amides of almond acid
AT146504B (en) Process for the preparation of amides of pyrazine monocarboxylic acid.
AT239252B (en) Process for the partial or complete carbamylation of dihydric alcohols or of their partially O-substituted derivatives
DE657055C (en) Process for the representation of higher molecular compounds
AT216151B (en) Process for the preparation of deserpidic acid esters
AT203005B (en) Process for the preparation of new esters of piperidyl- (2) -phenylcarbinol and their salts
DE1620556C (en) 1 Cyclohexylbarbituric acid derivatives
DE3707719A1 (en) METHOD FOR PRODUCING (R) -4-AMINO-3-HYDROXYBUTANIC ACID (GABOB)
AT216524B (en) Process for the preparation of new theophylline derivatives
DE1518988A1 (en) Process for the production of di- and triesters of ascorbic acid
AT217048B (en) Process for the preparation of new theophylline derivatives substituted in the 7-position
DE2320119C3 (en) N, N-Difluoro-alkyl carbamates and processes for making difluoroamine therefrom
DE2024805C3 (en) Process for the preparation of 2-amino-3-chloropyrazine
DE882247C (en) Process for the preparation of basic esters
AT229856B (en) Process for the production of new sulfur-containing esters
DE2128808C3 (en) Quaternary compounds of BIs- (2-ttiienyl) - (N-metriyl-5-memoxy-3plperMylidene) methane