SK41292A3 - Acethylsalicyloylcarnitine and method of its preparation - Google Patents
Acethylsalicyloylcarnitine and method of its preparation Download PDFInfo
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- SK41292A3 SK41292A3 SK41292A SK41292A SK41292A3 SK 41292 A3 SK41292 A3 SK 41292A3 SK 41292 A SK41292 A SK 41292A SK 41292 A SK41292 A SK 41292A SK 41292 A3 SK41292 A3 SK 41292A3
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- acetoxybenzoyloxy
- butyric acid
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Abstract
Description
Oblast technikyTechnical field
Predložený vynález se týká betalnu kyseliny 3-C2-acetoxybenzoy 1 oxy )-4-( tr imethy 1 araon i o)náse 1 né, acety lsalicyloyl -L-karnitlnu vzorce IThe present invention relates to betalic acid of 3-C2-acetoxybenzoyloxy) -4- (trimethyl araonic acid) acetylsalicyloyl-L-carnitine of the formula I
CI) v racemlcké a opticky aktívni formé, jeho farmaceutický prijaté Iných solí a zp&sobu jeho výroby. Betaln kyseliny 3-(2-acetoxybenzoy loxy)-4-(trlmethylamonio)máselné je jako ester kyseliny acety lsal icy lové s karnltlnem (acety lsal icy loy lkarnitin) derivát kyseliny salicylové s velmi slibnými terapeutickými vlastnostni.CI) in a racemic and optically active form, its pharmaceutically acceptable other salts, and a process for its manufacture. Beta-3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid is a salicylic acid derivative with very promising therapeutic properties as an acetylsalicylic acid ester with carnitine.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
Kyselina sallcylová ve forraé svého acetylderivátu se používá jako analgetikum v širokém rozsahu. Pflvodné byl tento acetylderivát (znáraý neži j iným jako Aspirín®) vyvinut ke snížení rušivých vediejších účlnkfi jlž dríve známé kyseliny salicylové. Pfesto má tento derivát nékteré vlastnosti, které omezují jeho použití. K témto nepŕíznivým vlastnostem patrí pŕedevším jeho malá rozpustnost ve vodé, zvlášté v kyselém prostredí, tedy napríklad v žaludeční štávé. Malá rozpustnost mfiže p?i orálním podaní vodních roztokfl vést k vysrážení účinné látky v žalúdku. Tento efekt je nežádoucí ne jen u lldí s citlivou nebo poškozenou sliznici žaludku, pretože mflže u téchto osob zpflsoblt vážné vedlejší účinky. Zcela obecné však malá rozpustnost zpomaluje resorpcl a tím také zahájení analgetlckého účinku. Navíc lze kyse-.Salcylic acid in the form of its acetylderivative is widely used as an analgesic. Initially, this acetylderivative (known as others as Aspirin®) was developed to reduce disturbing by-effects of the previously known salicylic acid. However, this derivative has some properties that limit its use. These unfavorable properties include, in particular, its low solubility in water, especially in an acidic environment, e.g. gastric juice. Low solubility may lead to precipitation of the active ingredient in the stomach when administered orally with aqueous solutions. This effect is undesirable not only in people with sensitive or damaged gastric mucosa, as it can cause serious side effects in these persons. Generally, however, the low solubility slows the resorption and thus also the initiation of the analgesic effect. In addition, acid can be used.
linu acetylsalicylovou aplikovať prakticky len orálni. ne však parenterálni. tedy napríklad intravenózni nebo intraperitoneálne nebo místni. Právi z dflvodu rychlého zahájení pflsobení a/nebo šetrného pflsobení na gastrointestinální trakt by často byla parenterální aplikace potrebná.of acetylsalicylic compound applied practically only orally. but not parenteral. i.e., intravenous or intraperitoneal or local. Precisely because of the rapid initiation of adjustment and / or gentle adaptation to the gastrointestinal tract, parenteral administration would often be necessary.
Podstata vynálezuSUMMARY OF THE INVENTION
Úkolem predloženého vynálezu Je tedy dát k disposici derivát kyseliny salicylové. který je dobre rozpustný ve vodé i v kyselé oblasti, lehce se resorbuje. vykazuje co možná nejmenší toxicitu a mfiže se aplikovať jak orálni, tak také parenterálni nebo místni. Ve všech formách aplikace by tento derivát mil rýchle analgetlcky účinkovať.It is therefore an object of the present invention to provide a salicylic acid derivative. which is well soluble in both the water and acidic regions, is easily absorbed. exhibits as low toxicity as possible and can be administered both orally, parenterally or topically. In all forms of administration, this derivative would have a rapid analgesic effect.
Tento úkol je ŕešen podie vynálezu podie patentového nároku 1 zamii?eného na betaln kyseliny 3-(2-acetoxybenzoyloxy)-4-(trimethylamonio)máselné. Sloučenina má asymetrický atóm uhlíku a mflže se proto vyskytovať ve dvou zrcadlových opticky aktivních formách a jako racemická smis. Výhodný je pritom enantlomer s (R)-konfigurací. který se odvozuje od prírodního L-karnitinu. Pŕíznivé fyzikálni-chemické vlastnosti. jako jsou vysoká rozpustnost ve vodé a vhodná hodnota pH roztoku, se rovniž dosáhnou s (S)-enantiomerem a s racemátem. L-karnitin je pŕece známy jako pŕenašeč acylových skupín pri látkové pŕemini tukfl. Je aktívni prijímán ve vétšiné orgánfl téla pomoci vysokoafinních transportních systémfi. Je také prijímán v bunečných organelách (mitochondriich atd.) pomoci antiport-transportéru. Dá se pfedpokládat. že také acetylsalicyloyl-L-karnitin se dostává do bunik a organel pomoci tichto transportních systémfi a tím je zahájení účinku ješti urychleno. Acyl-L-karnitiny jsou dále lehce štépené bunéčnými enzymy. takže je možné počítať s rychlým uvolniním zbytku salicylátu.This object is achieved according to the invention according to claim 1 directed to betalic 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid. The compound has an asymmetric carbon atom and may therefore occur in two mirror optically active forms and as a racemic mixture. An enantometer with the (R) -configuration is preferred. which is derived from natural L-carnitine. Favorable physico-chemical properties. such as high aqueous solubility and a suitable pH of the solution are also achieved with the (S) -enantiomer and the racemate. However, L-carnitine is known as a carrier of acyl groups for the fatty substance metabolism. It is actively received in most organs by high-efficiency transport systems. It is also taken up in cellular organelles (mitochondria, etc.) by an antiport transporter. We can assume. It is also believed that acetylsalicyloyl-L-carnitine also enters the cells and organelles via these transport systems, and thus the onset of action is accelerated. Furthermore, the acyl-L-carnitines are slightly cleaved by cellular enzymes. so that rapid release of the salicylate residue can be envisaged.
Pokusy na krysách už ukázaly extrémni malou akútni toxicitu acetylsalicyloy1-L-karnitinu. Dávky až 1000 mg/kg tilesné váhy orálni podané jsou bez potíží snášeny a pri intravenózním a lntraperitoneálním podávání terapeutických dávek nejsou pozorovány žádné škodlivé vedlejší účinky.Experiments in rats have already shown extremely low acute toxicity of acetylsalicyloy1-L-carnitine. Doses of up to 1000 mg / kg orally administered orally are tolerated without difficulty and no harmful side effects are observed with intravenous and intraperitoneal administration of therapeutic doses.
Do rozsahu vynálezu samozrejmé rovniž spadá tvorba solí acetylsalicyloylkarnltlnu s farmaceutický pMjatelnýrai kyselinami a použití sloučenin v této formä.Of course, the invention also includes the formation of salts of acetylsalicyloylcarboxylic acid with pharmaceutically acceptable acids and the use of the compounds in this form.
Podie vynálezu se acetylsalicyloylkarnitin vyrábí acetylací salicyloylkarnitinu. Jako acetylační činidlo se zvlášté hodí acetylchlorld nebo anhydrid kyseliny octové v prítomnosti katalytického množství kyseliny sírové. Účelné se acetylace provádí v teplôtnim rozmezí od 40 °C a 100 °C v prítomnosti kyseliny octové jako rozpouštédla.According to the invention, acetylsalicyloylcarnitine is produced by acetylation of salicyloylcarnitine. Particularly suitable as the acetylating agent are acetyl chloride or acetic anhydride in the presence of a catalytic amount of sulfuric acid. Suitably, the acetylation is carried out in a temperature range between 40 ° C and 100 ° C in the presence of acetic acid as the solvent.
Podie zkušeností lze získat acetylsalicyloylkarnltin v dobrém výtéžku a ve vysoké člstoté po približné 5 hodinách reakční doby a po obvyklém zpracování. Do rozsahu vynálezu rovnéž spadá zpflsob výroby, kdy se dále pŕidáním farmaceutický prijatelné kyseliny pŕevede betaln na odpovídající sfll.Experience has shown that acetylsalicyloylcarnitine can be obtained in good yield and high density after about 5 hours reaction time and after usual working up. It is also within the scope of the invention to provide a process wherein the addition of a pharmaceutically acceptable acid is further converted to betalane by the addition of a pharmaceutically acceptable acid.
Následující príklad ilustruje provedení zpflsobu výroby podie vynálezu.The following example illustrates an embodiment of a method of manufacture according to the invention.
Príklad provedení vynálezu .DETAILED DESCRIPTION OF THE INVENTION.
Príklad 1Example 1
Acetylsalicyloyl-L-karnitin.HC1Acetylsalicyloyl-L-karnitin.HC1
0.95 g salicyloyl-L-karnitinu.HC1 CCotlp20- -31,2° Cc-l, HzO) t.t.:185-187 °C) se smíchá s 2.35 g acetylchloridu a 5.0 ml kyseliny octové a po dobu 5 hodín se zahŕívá na 60 °C. Pak se reakční smés vákuové odparuje a odparek se suspenduje s 10.0 ml estéru kyseliny octové. Kryštalický produkt se promyje 5.0 ml esteru kyseliny octové a suší ve vákuu pri 40 °C. Získá se 0,95 g bílého kryštalického acetylsalicyloyl-L-karnitinu.HC1 o t.t. 154-158 °C.0.95 g of salicyloyl-L-carnitine.HCl (pH 20 - -31.2 ° C -1.1 H 2 O) (185-187 ° C) is mixed with 2.35 g of acetyl chloride and 5.0 ml of acetic acid and heated for 5 hours on 60 ° C. The reaction mixture was then evaporated in vacuo and the residue suspended with 10.0 ml of acetic acid ester. The crystalline product is washed with 5.0 ml of acetic acid ester and dried under vacuum at 40 ° C. 0.95 g of white crystalline acetylsalicyloyl-L-carnitine.HCl, m.p. 154-158 ° C, is obtained.
1H-NMR CDMSO-de. 300 MHz) 6-12.9 Cbr.s. 1H). 1 H-NMR CDMSO-d 6. 300 MHz) 6-12.9 Cbr.s. 1H).
2.33 (s. 3H).2.33 (s, 3H).
[«b2°- -41.7° (c-1. H20).[ 'B 2 ° - -41.7 ° (c = 1. H 2 0).
Test žaludeční snášenlivosti na krysách (Ulcer index)Test of gastric tolerance in rats (Ulcer index)
Hydrochorid betainu kyseliny (R)-(-)-3-(2-acetoxybenzoy1oxy )-4-(trimethylamon i o)roáse1né (acety1sa1icy1oy1-L-karn i t i n.HC1 ASC) se testuje na krysích samečcích ve srovnání s kyselinou acetylsallcylovou (ASA). Pri tomto testu se postupuje podie metódy Okabe a spol., Japan. J. Pharmacol. 1974. 24. 363 a další. pri které se Indukuj í zmény žaludeční sliznice. Testované látky se podávaj £ testovaným krysám p.o. v 1 % suspenzi karboxymethy1celulózy (1 % CMC). Zmény žaludeční sliznice se méfí pomoci Ulcer Indexu podie Chaumontet a spol., Arzneimittelforschung 1978. 28. 2047-2178.(R) - (-) - 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) oxoic acid (acetylsylicyl-L-carnitine n.HC1 ASC) is tested in male rats as compared to acetylsallicylic acid (ASA) ). This assay is performed according to the method of Okabe et al., Japan. J. Pharmacol. 1974. 24. 363 et seq. in which gastric mucosal changes are induced. Test substances are administered to test rats p.o. in 1% carboxymethylcellulose suspension (1% CMC). Changes in the gastric mucosa are measured by the Ulcer Index of Chaumontet et al., Arzneimittelforschung 1978. 28. 2047-2178.
V tabulce 1 jsou uvedený výsledky.Table 1 shows the results.
Tabulka 1Table 1
Látka Ulcer index (U.I.) Počet krýsUlcer index (U.I.) Number of rats
CMC » karboxymethylcelulozaCMC »carboxymethylcellulose
ASA kyselina acety 1 sal icy lováASA acetyl 1 salicylic acid
ASC - acetylsalicyloyl-L-karnitin.HC1 srovn. « srovnáníASC - acetylsalicyloyl-L-carnitine.HC1 cf. «Comparison
Prflmyslová využltelnostIndustrial usability
Betaln kyseliny 3-(2-acetoxybenzoyloxy)-4-(trimethylamonio) máselné a jeho soli jsou použitelné jako terapeuticky účinné látky.Betaine of 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid and its salts are useful as therapeutically active substances.
Claims (12)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CS92412A CZ284755B6 (en) | 1992-02-12 | 1992-02-12 | Betaine of 3-)2-acetoxybenzoyloxy(-4-)trimethylammonio)butyric acid and process for preparing thereof |
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Publication Number | Publication Date |
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SK41292A3 true SK41292A3 (en) | 1995-02-08 |
SK280148B6 SK280148B6 (en) | 1999-09-10 |
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SK412-92A SK280148B6 (en) | 1992-02-12 | 1992-02-12 | Acetylsalicyloyl-l-carnitine and method for its preparation |
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CZ (1) | CZ284755B6 (en) |
SK (1) | SK280148B6 (en) |
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1992
- 1992-02-12 CZ CS92412A patent/CZ284755B6/en not_active IP Right Cessation
- 1992-02-12 SK SK412-92A patent/SK280148B6/en not_active IP Right Cessation
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CZ284755B6 (en) | 1999-02-17 |
CZ41292A3 (en) | 1994-02-16 |
SK280148B6 (en) | 1999-09-10 |
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Effective date: 20100212 |