DE2013267A1 - Thiamine disulphide dinicotinate - Google Patents

Thiamine disulphide dinicotinate

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Publication number
DE2013267A1
DE2013267A1 DE19702013267 DE2013267A DE2013267A1 DE 2013267 A1 DE2013267 A1 DE 2013267A1 DE 19702013267 DE19702013267 DE 19702013267 DE 2013267 A DE2013267 A DE 2013267A DE 2013267 A1 DE2013267 A1 DE 2013267A1
Authority
DE
Germany
Prior art keywords
dinicotinate
thiamine
thiamine disulfide
vitamin
disulphide
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.)
Granted
Application number
DE19702013267
Other languages
German (de)
Other versions
DE2013267B2 (en
DE2013267C3 (en
Inventor
Josef Dr Voigt Hans Dr med 1000 Berlin Klosa
Original Assignee
Dr med Hans Voigt, Chemisch Phar mazeuüsche Fabrik, 1000 Berlin
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 Dr med Hans Voigt, Chemisch Phar mazeuüsche Fabrik, 1000 Berlin filed Critical Dr med Hans Voigt, Chemisch Phar mazeuüsche Fabrik, 1000 Berlin
Priority to DE19702013267 priority Critical patent/DE2013267C3/en
Publication of DE2013267A1 publication Critical patent/DE2013267A1/en
Publication of DE2013267B2 publication Critical patent/DE2013267B2/en
Application granted granted Critical
Publication of DE2013267C3 publication Critical patent/DE2013267C3/en
Expired legal-status Critical Current

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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

Thiamine disulphide dinicotinate (I): is prepd. by reacting molar quantities of thiamine disulphide and nicotinic acid in alcohols or water. It is used in avitaminosis, conventional vitamin B1-therapy, diseases of the liver and gall-bladder and for potentiating analgesics and sedatives. It gives high blood levels of vitamin B1 and is less toxic and bitter than the disulphide.

Description

Neues Vitamin B1-Salz, Verfahren zu dessen Herstellung und Verwendung Die Erfindung betrifft ein neues Vitamin B1-Salz, dessen Herstellung und Verwendung, nämlich das Dinikotinat des Thiamindisulfid der nachstehenden Konstitution: Es wurde gefunden, daß dieses Dinikotinat des Thiamindisulfid durch Umsetzung von Thiamindisulfid mit Nikotinsäure in molaren-Verhältnissen, gegebenenfalls in einem Lösungs- und Verdünnungsmittel, wie Alkoholen oder Wasser, bei gewöhnlicher oder erhöhter Temperatur erhalten wird. Dieses neue Thiamindisulfiddinikotinat bildet farblose Kristalle, die in Wasser leicht löslich sind und auch einen verminderten bitteren Geschmack gegenüber dem Ausgangsprodukt -ergeben. Es ist wesentlich ungiftiger als Thiamindisulfid, ergibt hohe Blutspiegelwerte an Vitamin B1, zeigt sich verstärkt bei Avitaminosen wirksam, potenziert die therapeutische Wirkung der Analgetika und von sedativ wirksamen Körpern, und ergibt eine ausgezeichnete Wirkung bei experimentell erzeugten Leberverfettungen.New vitamin B1 salt, process for its production and use The invention relates to a new vitamin B1 salt, its production and use, namely the dinicotinate of thiamine disulfide of the following constitution: It has been found that this dinicotinate of thiamine disulfide is obtained by reacting thiamine disulfide with nicotinic acid in molar proportions, optionally in a solvent and diluent, such as alcohols or water, at ordinary or elevated temperature. This new thiamine disulfide dinicotinate forms colorless crystals, which are easily soluble in water and also give a reduced bitter taste compared to the starting product. It is significantly less toxic than thiamine disulfide, produces high levels of vitamin B1 in the blood, is more effective in avitaminoses, potentiates the therapeutic effect of analgesics and sedative bodies, and has an excellent effect on experimentally produced fatty liver.

Es wurden zunächst die Toxizitätsdaten gegenüber den bekannten Vitamin B1-Derivaten gezeigt. Die Bestimmung der DL50 erfolgte nach Kärber an weißen Mäusen in mg/kg.First there were the toxicity data against the known vitamin B1 derivatives shown. The determination of the DL50 was carried out according to Kärber on white mice in mg / kg.

Substanz i.v. i.p. oral Vitamin B1-hydrochlorid 118 320 6000 Thiamindisulfid 140 480 7000 0,0'-Dibenzoylthiamindisulfid 190 800 7500 Thiamindisulfiddinikotinat 220 950 9000 Das neue erfindungsgemäße Dinikotinat des Thiamindisulfid ist also wesentlich weniger giftigals bekannte Vergleichssubstanzen.Substance i.v. i.p. oral vitamin B1 hydrochloride 118 320 6000 thiamine disulfide 140 480 7000 0,0'-dibenzoylthiamine disulfide 190 800 7500 thiamine disulfide dinicotinate 220 950 9000 The new dinicotinate of thiamine disulfide according to the invention is therefore much less toxic than known reference substances.

Die Gegenüberstellung der erhaltenen Blutspiegelwerte erfolgt in der nachstehenden Tabelle. Von jeder Substanz wurden 10 mg-Äquivalente Vitamin B1-hydrochlorid oral an Hauskaninchen pro 3 kg Durchschnittskörpergewicht verabreicht und die Blut-Thiaminspiegel ( %) festgehalten.The comparison of the blood level values obtained takes place in the table below. 10 mg equivalents of vitamin B1 hydrochloride were obtained from each substance administered orally to domestic rabbits per 3 kg of average body weight and blood thiamine levels (%) recorded.

Substanz nach Stunden 1 2 4 10 Vitamin B1-hydrochlorid 13,0 18,0 10,0 9,5 Thiamindisulfid 26,5 20,5 19,4 10,4 0,0'-Dibenzoylthiarnindisulfid 56,0 50,0 40,5 35,6 Thiamindisulfiddinikotinat 45,5 30,8 38,5 30,5 Die erhaltenen Blutspiegelwerte sind somit dem Vitamin B1-hydrochlorid weit überlegen, diese sind günstiger als gegenüber dem alleinigen Thiamindisulfid, und nur wenig schwächer als O,O'-Dibenzoylthiamindisulfid.Substance after hours 1 2 4 10 Vitamin B1 hydrochloride 13.0 18.0 10.0 9.5 thiamine disulfide 26.5 20.5 19.4 10.4 0.0'-dibenzoyl thiamine disulfide 56.0 50.0 40.5 35.6 Thiamine disulfide dinicotinate 45.5 30.8 38.5 30.5 The blood level values obtained are therefore far superior to vitamin B1 hydrochloride, they are cheaper than compared to the sole thiamine disulfide, and only slightly weaker than O, O'-dibenzoylthiamine disulfide.

Die antagonistische Wirkung gegenüber der durch Tetrachlorkohlenstoff hervorgerufenen Leberverfettung wurde an weiblichen Wistarratten auf die durch Tetrachlorkohlenstoff bedingte Verlängerung der Schlafdauer geprüft (Versuchsanordnung nach D. Lemke, Acta biol. med. germ. 3, 37 (1959). Die Behandlung wurde mit den geprüften Substanzen in Dosen von 100 mg 4 Tage lang peroral ausgeführt. Am zweiten Behandlungstag wurde Tetrachlorkohlenstoff gegeben. Die Ergebnisse sind in der nachfolgenden Tabelle angegeben.The antagonistic effect on that of carbon tetrachloride Fatty liver disease induced in female Wistar rats was compared to that caused by carbon tetrachloride conditional extension of sleep duration tested (test arrangement according to D. Lemke, Acta biol. med. germ. 3, 37 (1959). The treatment was with the tested substances carried out orally in doses of 100 mg for 4 days. The second day of treatment was Given carbon tetrachloride. The results are in the table below specified.

Kontrollen Tetrachlor- mit B1 Thiamin- Thiaminkohlenstoff 1 disulfid disulfid-Tiere dinikotina Schlafdauer in 28,5 ~ 1,8 64,5 ~ 3,5 65,4 ~ 3,2 64,8~3,5 38,3 ~ 3, Minuten Zahl der 15 15 16 16 16 Tiere Das Dinikotinat des'Thiamindisulfid hat also einen eindeutigen Einfluß auf die durch Tetrachlorkohlenstoff bedingte Leberverfettung. Controls carbon tetrachloride with B1 thiamine thiamine disulfide disulfide animals dinikotina sleep duration in 28.5 ~ 1.8 64.5 ~ 3.5 65.4 ~ 3.2 64.8 ~ 3.5 38.3 ~ 3, minutes Number of 15 15 16 16 16 animals The Dinicotinat des'Thiamindisulfid thus has a clear influence on the one caused by carbon tetrachloride Fatty liver.

Das neue Dinikotinat des Thiamindisulfids hat also neben einer guten Vitamin B1-Wirksamkeit eine beachtliche Leberschutzwirkung und wird in Dosen von 5, 25, 50 mg etc. in Form von Tabletten, Dragees, Pulvern oder anderen konventionellen Zubereitungsformen als Heilmittel gegen Avitaminose, zur Verstärkung von analgetisch und sedativ wirksamen Heilmitteln sowie bei Leber- und Gallenerkrankungen angewendet.The new dinicotinate of thiamine disulfide has a good one Vitamin B1 has a considerable liver protective effect and is available in doses of 5, 25, 50 mg etc. in the form of tablets, coated tablets, powders or other conventional ones Forms of preparation as a remedy for avitaminosis, to reinforce analgesic and sedative remedies as well as for liver and gallbladder diseases.

Es soll an einigen Beispielen eine vorteilhafte Herstellungsweise dieses neuen Salzes gezeigt werden, ohne daß für die Herstellung eine Begrenzung angezeigt wird.A few examples are intended to illustrate an advantageous production method this new salt can be shown without any limitation on its manufacture is shown.

Beispiel 1 28,6 g Thiamindisulfid werden in ca. 100 ml Methanol suspendiert.Example 1 28.6 g of thiamine disulfide are suspended in approx. 100 ml of methanol.

Dazu werden 12 g Nikotinsäure zugesetzt und alles 30 Minuten auf dem Wasserbade erwärmt. Es tritt Auflösung ein, und alsbald fällt das Nikotinat bereits während der Erwärmung aus. Man läßt erkalten, verdünnt zur Vervollständigung der Auskristallisation mit Äther, läßt 24 - 30 Stunden stehen und saugt die Kristalle ab und wäscht mit Äther nach. Ausbeute ca. 39 g.To this, 12 g of nicotinic acid are added and everything is left on for 30 minutes Heated water bath. Dissolution occurs, and the nicotinate immediately falls during heating off. Allow to cool, dilute to complete the Crystallize with ether, leave to stand for 24 - 30 hours and suck the crystals and washes with ether. Yield approx. 39 g.

Fp.: Sintert bei 1100 C, schmilzt bei 158 - 1600 C orangegefärbt.Fp .: sintered at 1100 C, melted orange at 158-1600 C.

Beispiel 2 26,6 g Thiamindisulfid und 12 g Nikotinsäure werden in ca.Example 2 26.6 g of thiamine disulfide and 12 g of nicotinic acid are used in approx.

60 ml warmem Wasser gelöst. Die Lösung wird alsdann im Vakuum eingedampft. Es werden 38 g farblose Kristalle erhalten, die durch Umkristallisation aus 80 %igem Methanol gereinigt werden können.Dissolve 60 ml of warm water. The solution is then evaporated in vacuo. There are 38 g of colorless crystals obtained by recrystallization from 80% Methanol can be purified.

Fp.: Sintert bei 1100 C, schmilzt bei 15B - 1600 C mit Orange-Farbe.Fp .: sintered at 1100 C, melts at 15B - 1600 C with an orange color.

Claims (3)

PatentansprücheClaims 1. Dinikotinat des Thiamindisulfid der Formel: 1. Dinicotinate of thiamine disulfide of the formula: 2. V rfahren zur Herstellung des Dinikotinates des Thiamindisulfid gemäß Anspruch 1,dadurch gekennzeichnet, daß a) Thiamindisulfid mit Nikotinsäure in molaren Verhältnissen umgesetzt wird, b) gemäß Anspruch 2 a), dadurch gekennzeichnet, daß die Umsetzung in einem Lösungs- und Verdünnungsmittel wie Alkoholen in -Wasser bei gewöhnlicher oder erhöhter Temperatur erfolgt.2. V process for the preparation of the dinicotinate of thiamine disulfide according to claim 1, characterized in that a) thiamine disulfide with nicotinic acid in molar proportions is implemented, b) according to claim 2 a), characterized in that the implementation in a solvent and diluent such as alcohols in water with ordinary or elevated temperature takes place. 3. Verwendung des Dinikotinates des Thiamindisulfid gemäß Anspruch 1 - 2 als Arzneimittel a-) bei Avitaminose b) bei Indikationen der konventionellen Vitamin B1-Therapie sowie zur Verstärkung von analgetischen und sedativ wirksamen Präparaten c) bei Leber- und Gallenerkrankungen d) äußerlich in Form von Salben, Lösungen oder den konventionellen äußerlichen Zubereitungen als Heil- und Pflegemittel der Häut uFd.Maare, f3. Use of the dinicotinate of thiamine disulfide according to claim 1 - 2 as medicinal products a-) for avitaminosis b) for conventional indications Vitamin B1 therapy as well as for strengthening analgesic and sedative effects Preparations c) for liver and gallbladder diseases d) externally in the form of ointments, Solutions or conventional external preparations as remedies and care products of the skin and hairs, f
DE19702013267 1970-03-20 1970-03-20 Vitamin B deep 1-disulfide-di-nicotinate Expired DE2013267C3 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19702013267 DE2013267C3 (en) 1970-03-20 1970-03-20 Vitamin B deep 1-disulfide-di-nicotinate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19702013267 DE2013267C3 (en) 1970-03-20 1970-03-20 Vitamin B deep 1-disulfide-di-nicotinate

Publications (3)

Publication Number Publication Date
DE2013267A1 true DE2013267A1 (en) 1971-10-07
DE2013267B2 DE2013267B2 (en) 1974-06-27
DE2013267C3 DE2013267C3 (en) 1975-02-20

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DE2013267B2 (en) 1974-06-27
DE2013267C3 (en) 1975-02-20

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Legal Events

Date Code Title Description
C3 Grant after two publication steps (3rd publication)
E77 Valid patent as to the heymanns-index 1977
8339 Ceased/non-payment of the annual fee