DE2157289A1 - Nicotine acid derivatives - Google Patents
Nicotine acid derivativesInfo
- Publication number
- DE2157289A1 DE2157289A1 DE19712157289 DE2157289A DE2157289A1 DE 2157289 A1 DE2157289 A1 DE 2157289A1 DE 19712157289 DE19712157289 DE 19712157289 DE 2157289 A DE2157289 A DE 2157289A DE 2157289 A1 DE2157289 A1 DE 2157289A1
- Authority
- DE
- Germany
- Prior art keywords
- nicotinic acid
- chloro
- hydroxy
- pharmaceutically acceptable
- acid
- 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
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
&& 1Z.HÖV. 19711Z.HÖV. 1971
RAN 4039/25 KRAN 4039/25 K
F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel/SchweizF. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland
NicotinsäurederivateNicotinic acid derivatives
Die vorliegende Erfindung betrifft Nicotinsäurederivate, und zwar die 2-Chlor-6-hydroxy-nicotinsäure und deren Salze mit Basen, sowie ein Verfahren zur Herstellung dieser Verbindungen.The present invention relates to nicotinic acid derivatives, namely the 2-chloro-6-hydroxy-nicotinic acid and its salts with Bases, as well as a process for the preparation of these compounds.
Die 2-Chlor-6-hydroxy-nicotinsäure kann sowohl als solche al's auch in Form von Salzen mit Basen vorliegen. Derartige LS.-i.lze können durch Umsetzung der freien Säure mit einer Base erhalten werden. Beispiele derartiger Basen sind Alkalimetall- und Erdalkalimetallhydroxyde und Carbonate, wie beispielsweise Natriumhydroxyd, Kaliumhydroxyd, CaIciumhydroxyd, Calciumcarbonat, sowie Ammoniak, primäre, sekundäre und tertiäre Amine, wie Mono-, Di- und Trialkylamine, beispielsweise Methylamin, Dimethylamin und Trimethylamin, und stickstoffhaltige heterozyklische Amine, beispielsweise Piperidin und dergleichen.The 2-chloro-6-hydroxy-nicotinic acid can be present either as such or in the form of salts with bases. Such LS.-i.lze can be obtained by reacting the free acid with a base. Examples of such bases are alkali metal and alkaline earth metal hydroxides and carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium carbonate, and ammonia, primary, secondary and tertiary amines, such as mono-, di- and trialkylamines, for example methylamine, dimethylamine and trimethylamine, and nitrogen-containing heterocyclic amines such as piperidine and the like.
Das erfindungsgemässe Verfahren zur Herstellung von 2-Chlor-6-hydroxy-nicotinsäure und deren Salzen mit Basen ist dadurch gekennzeichnet, dass man 2,6-Dichlor-nicotinsäure oder ein Salz davon mit einer Base hydrolysiert, dass man, wenn die freieThe process according to the invention for the preparation of 2-chloro-6-hydroxy-nicotinic acid and their salts with bases is characterized in that one has 2,6-dichloro-nicotinic acid or a Salt of it hydrolyzed with a base that one if the free
209823/1163
As/19,10.71209823/1163
As / 19,10.71
Säure hergestellt werden soll, das Hydrolyseprodukt ansäuert und; dass man gewünsentenfalls die freie Säure in ein Salz überführt.Acid is to be produced, the hydrolysis product acidifies and; that if desired, the free acid is converted into a salt.
Zur Hydrolyse wird hierbei zweckmässig ein Alkalimetallhydroxyd, beispielsweise Natriumhydroxyd, Kaliumhydroxyd oder dergleichen verwendet, und zwar wird die Hydrolyse vorzugsweise bei der Rückflusstemperatur des Reaktionsgemisches durchgeführt. Das Ansäuern des Hydrolyseproduktes kann beispielsweise mit einer Halogenwasserstoffsäure, wie Chlorwasserstoffsäure, durchgeführt werden.An alkali metal hydroxide is expediently used for the hydrolysis, for example sodium hydroxide, potassium hydroxide or the like is used, and the hydrolysis is preferably used in carried out the reflux temperature of the reaction mixture. The acidification of the hydrolysis product can, for example, with a Hydrohalic acid such as hydrochloric acid will.
Die erfindungsgemässen Verbindungen senken den Fettspiegel von warmblütigen Tieren und des Menschen und sind daher zur Gewichtsverminderung verwendbar.The compounds according to the invention lower the fat level of warm-blooded animals and humans and can therefore be used for weight reduction.
Für diesen Verwendungszweck wird die erfindungsgemässe 2-Chlor-6-hydroxy-nicotinsäure, beziehungsweise ein pharmazeutisch verträgliches Salz derselben in eine für die ärztliche Verabreichung geeignete Dosierungsform für die orale oder parenterale Verabreichung gebracht. Solche Dosierungsformen sind beispielsweise Tabletten, Suspensionen, Lösungen, Kapseln und dergleichen. Als Trägermaterialien können hierbei anorganische oder organische ™ Trägermaterialien, beispielsweise Wasser, Gelatine, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche OeIe, Polyalkylenglykole und dergleichen verwendet werden. Ferner können derartige pharmazeutische Gebrauchsformen Konservierungsmittel, Stabilisierungsmittel, Netzmittel, Emulgiermittel, Salze zur Veränderung des osmotischen Druckes, Puffer oder dergleichen enthalten.The 2-chloro-6-hydroxy-nicotinic acid according to the invention, or a pharmaceutical one, is used for this purpose acceptable salt thereof in a dosage form suitable for medical administration for oral or parenteral use Administration brought. Such dosage forms are, for example, tablets, suspensions, solutions, capsules and the like. The carrier materials used here can be inorganic or organic ™ Carrier materials, for example water, gelatine, milk sugar, Starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like can be used. Furthermore, such pharmaceutical forms of use can contain preservatives, stabilizers, Wetting agents, emulsifying agents, salts for changing the osmotic pressure, buffers or the like.
Die Menge der in solchen Arzneimittelformen enthaltenen Wirksubstanz beträgt im Falle von Kapseln und Tabletten vorzugsweise etwa 100 bis etwa 1000 mg, beispielsweise 150 mg, 250 rag oder 500 mg Wirkstoff.The amount of the active substance contained in such pharmaceutical forms is preferably in the case of capsules and tablets about 100 to about 1000 mg, for example 150 mg, 250 rag or 500 mg of active ingredient.
209823/1163209823/1163
Die Häufigkeit der Verabreichung solcher medizinischer Gebrauchsformen hängt von den· jeweiligen Umständen ab. Unter normalen Bedingungen können jedoch bis zu 500 mg 2-Chlor-6-hydroxy-nicotinsäure pro Tag in verschiedenen Dosen verabreicht werden.The frequency of administration of such medical forms of use depends on the particular circumstances. However, under normal conditions, up to 500 mg of 2-chloro-6-hydroxy-nicotinic acid per day can be administered in various doses.
Ein Gemisch von 6 g 2,6-Dichlor-nicotinsäure und 78 ml 2N Natronlauge wird zwei Stunden am Rückfluss erhitzt, abgekühlt und mit 17 ml einer ION Salzsäure angesäuert. Das Gemisch wird Minuten in einem Eisbad gekühlt und der ausgeschiedene Peststoff wird abfiltriert und mit Wasser gewaschen. Dieser Feststoff wird in 25 ml warmem Aethanol aufgeschlämmt, filtriert und mit warmem Aethanol gewaschen. Die in Aethanol unlösliche feste Substanz (!Schmelzpunkt 296-298 , unter Zersetzung) wird aus 1500 ml eines Λethanol-Wassergemisches (1:2 Volumsteiie) umkristallisiert, wobei man 2—Chlor—6—hydroxy-nicotinsäure mit einem ochrnc3 zpunkt von 3OO-j5O2° (Zersetzung) erhält.A mixture of 6 g of 2,6-dichloro-nicotinic acid and 78 ml of 2N sodium hydroxide solution is refluxed for two hours, cooled and acidified with 17 ml of an ION hydrochloric acid. The mixture is chilled in an ice bath for minutes and the precipitated pesticide is filtered off and washed with water. This solid is slurried in 25 ml of warm ethanol, filtered and washed with warm ethanol. The solid substance which is insoluble in ethanol (! Melting point 296-298, with decomposition) is recrystallized from 1500 ml of an ethanol-water mixture (1: 2 by volume), whereby 2-chloro-6-hydroxy-nicotinic acid with an ochrnc3 z point of 300- j5O2 ° (decomposition).
2-Chlor-6-hydroxy-nicotinsäure 100 mg2-chloro-6-hydroxy-nicotinic acid 100 mg
Milchzucker 20k" mgMilk sugar 20k "mg
Maisstärke 80 mgCorn starch 80 mg
Vorhydrolysierte Maisstärke 20 mgPrehydrolyzed corn starch 20 mg
Calciumstearat 8 mgCalcium stearate 8 mg
Gesamtgewicht 410 mgTotal weight 410 mg
Die obigen Tabletten werden hergestellt, indem man die 2-Chlor-6-hydroxy-nicotinsäure, den Milchzucker, die Mai .sntärke und die vorhydrolysierte Maisstärke miteinander vermischt, das Gemisch mit Wasser granuliert, trocknet, das Calciumstearat zusetzt, vermischt und zu Tabletten verpresst.The above tablets are made by adding 2-chloro-6-hydroxy-nicotinic acid, lactose, to starch and the prehydrolyzed corn starch mixed together, the mixture granulated with water, dried, the calcium stearate added, mixed and pressed into tablets.
209823/1163209823/1163
2-Chlor-6-hydroxy-nicotinsäure 250 mg2-chloro-6-hydroxy-nicotinic acid 250 mg
Milchzucker 200 mgMilk sugar 200 mg
Maisstärke 100 mgCorn starch 100 mg
Vorgelatinierte Maisstärke 25 mgPre-gelatinized corn starch 25 mg
Calciumstearat 10 mgCalcium stearate 10 mg
Gesamtgewicht 585 mgTotal weight 585 mg
Diese Tabletten werden hergestellt, indem man die 2-Chlor- -6-hydroxy-nicotinsäure, den Milchzucker, die Maisstärke und die vorgelatinierte Maisstärke miteinander vermischt, das Gemisch zerkleinert und granuliert, trocknet, das Calciumstearat zusetzt, vermischt und zu Tabletten verpresst.These tablets are made by adding the 2-chloro -6-hydroxy-nicotinic acid, the lactose, the corn starch and the pregelatinized corn starch mixed together, the mixture crushed and granulated, dries, the calcium stearate adds, mixed and pressed into tablets.
Beispiel 4 Kaps elzusammens et zung Example 4 Capsule Composition
Gesamtgewicht 350 mgTotal weight 350 mg
Die obigen Kapseln erhält man, indem man 2-Chlor-6-hydroxynicotinsäure mit dem Milchzucker und der Maisstärke vermischt, das Gemisch zerkleinert, den Talk zusetzt und das erhaltene Gemisch in Hartgelatinkapseln einfüllt.The above capsules are obtained by adding 2-chloro-6-hydroxynicotinic acid mixed with the milk sugar and corn starch, crushed the mixture, added the talc and the mixture obtained filled in hard gelatin capsules.
209823/1163209823/1163
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9229570A | 1970-11-23 | 1970-11-23 | |
| US9229470A | 1970-11-23 | 1970-11-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2157289A1 true DE2157289A1 (en) | 1972-05-31 |
Family
ID=26785491
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19712157289 Pending DE2157289A1 (en) | 1970-11-23 | 1971-11-18 | Nicotine acid derivatives |
Country Status (9)
| Country | Link |
|---|---|
| AT (1) | AT319241B (en) |
| CH (1) | CH557817A (en) |
| DE (1) | DE2157289A1 (en) |
| ES (1) | ES397242A1 (en) |
| FR (1) | FR2115359B1 (en) |
| GB (1) | GB1312196A (en) |
| IL (1) | IL38006A (en) |
| NL (1) | NL7115453A (en) |
| SE (1) | SE371195B (en) |
-
1971
- 1971-10-25 IL IL38006A patent/IL38006A/en unknown
- 1971-10-27 CH CH1564071A patent/CH557817A/en not_active IP Right Cessation
- 1971-11-10 NL NL7115453A patent/NL7115453A/xx unknown
- 1971-11-18 DE DE19712157289 patent/DE2157289A1/en active Pending
- 1971-11-22 AT AT1006171A patent/AT319241B/en not_active IP Right Cessation
- 1971-11-22 SE SE7114910A patent/SE371195B/xx unknown
- 1971-11-22 ES ES397242A patent/ES397242A1/en not_active Expired
- 1971-11-23 FR FR7141923A patent/FR2115359B1/fr not_active Expired
- 1971-11-23 GB GB5436571A patent/GB1312196A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IL38006A (en) | 1974-07-31 |
| CH557817A (en) | 1975-01-15 |
| AT319241B (en) | 1974-12-10 |
| IL38006A0 (en) | 1971-12-29 |
| NL7115453A (en) | 1972-05-25 |
| ES397242A1 (en) | 1975-03-01 |
| GB1312196A (en) | 1973-04-04 |
| SE371195B (en) | 1974-11-11 |
| FR2115359A1 (en) | 1972-07-07 |
| FR2115359B1 (en) | 1974-10-18 |
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