WO1986003206A1 - Esters d'hydrates de carbone d'acide acetylsalicylique, procede pour leur preparation et compositions pharmaceutiques - Google Patents

Esters d'hydrates de carbone d'acide acetylsalicylique, procede pour leur preparation et compositions pharmaceutiques Download PDF

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Publication number
WO1986003206A1
WO1986003206A1 PCT/AT1985/000050 AT8500050W WO8603206A1 WO 1986003206 A1 WO1986003206 A1 WO 1986003206A1 AT 8500050 W AT8500050 W AT 8500050W WO 8603206 A1 WO8603206 A1 WO 8603206A1
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WO
WIPO (PCT)
Prior art keywords
acetylsalicylic acid
acetylsalicyloyl
water
glucose
mono
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Application number
PCT/AT1985/000050
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German (de)
English (en)
Inventor
Gerhard Greber
Heinrich Gruber
Original Assignee
Evidenzbüro Österreichischer Zuckerfabriken Gesell
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Publication date
Application filed by Evidenzbüro Österreichischer Zuckerfabriken Gesell filed Critical Evidenzbüro Österreichischer Zuckerfabriken Gesell
Publication of WO1986003206A1 publication Critical patent/WO1986003206A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings

Definitions

  • Carbohydrate esters of acetylsalicylic acid process for their preparation and pharmaceutical compositions
  • the invention relates to new, analgesic and anti-rheumatic carbohydrate esters of acetylsalicylic acid, which are characterized by a broader therapeutic spectrum compared to acetylsalicylic acid and by good water solubility, a process for their preparation and pharmaceutical compositions containing the new esters.
  • Acetylsalicylic acid - best known under the trade name Aspirin - is a drug that has been known for over 100 years and has been successfully used to treat pain, fever, acute or chronic inflammation and as an aggregation inhibitor for platelets. Both the mechanism of action, the pharmacokinetics, the metabolism and the side effects of acetylsalicylic acid have meanwhile been examined very carefully, see for example A. Hawkins et al., Science 160 (1968) 780; H. Klotz u. G. Tarn, Proc. Nat. Acad. Sci. USA 70 (1973) 1313; C. Fereira et al., Nature 240 (1972) 340; D. Willis, Science 183 (1974) 325; E. hackenthal, Austrian. maschinerZeitung 36 (1982) 837.
  • acetylsalicylic acid Because of its poor solubility in water (approx. 1 g / 100 ml water at 37 ° C), acetylsalicylic acid has so far only been administered orally. For various therapeutic purposes, in particular when high doses are indicated, for example in the treatment of rheumatic diseases, it can therefore not be used or can only be used with insufficient action, since sufficient amounts of active ingredient cannot be obtained at the actual site of action. In addition, the oral application of the often required high doses also causes gastrointestinal symptoms, such as bleeding or other undesirable side effects, see L. Hussey et al, J. Am.Med.Ass. 228 (1974) 609.
  • No. 4,242,330 which relates to a very special, therapeutically useful derivative of acetylsalicylic acid, namely the compound 1-0- (2-acetoxy) benzoyl- ⁇ -D-2-deoxy / glucopyranose, is also used another carbohydrate ester derivative of acetylsalicylic acid, namely the compound 1-0- (2'-acetoxy) benzoyl- ⁇ -D-glucopyranose.
  • the latter compound tends to form the corresponding sugar derivative of salicylic acid instead of the therapeutically active acetylsalicylic acid during hydrolysis. If hydrolysis to acetylsalicylic acid takes place at all, this is extremely slow and to an extent insufficient for therapeutic use.
  • O-esters of monosaccharides are also known which, in addition to at least one ester substitution derived from a salicylic acid, have at least one further ether substitution.
  • Such at least doubly substituted monosaccharides are insoluble in water and are not suitable for releasing acetylsalicylic acid.
  • DE-PS 264654 describes a process for the preparation of compounds of the sugar types with the monooxybenzoic acids and their carboalkyloxy, acetyl and alkyl derivatives, the aim being as completely esterified sugar derivatives as possible.
  • dextrose is reacted with a very large excess of acetylsalicylic acid chloride, a highly substituted acetylsalicyloyl glucose is obtained which is almost insoluble in water.
  • the object of the present invention was to develop new, readily water-soluble, neutral and compatible acetylsalicylic acid derivatives with a comparable or improved spectrum of action to acetylsalicylic acid, which can be used not only orally but also according to known injection methods.
  • the invention relates to new, water-soluble carbohydrate derivatives with ester-like acetylsalicylic acid residues of the general formula (I)
  • Acetylsalicylic acid residue is not esterified with the 1-OH group.
  • the new acetylsalicylic acid derivatives of the general formula (I) are water-soluble carbohydrate esters of acetylsalicylic acid, namely pure monoesters with monosaccharides or at most diesters with disaccharides.
  • the acetylsalicylic acid esters of monosaccharides are thus pure monoesters, especially since diesters such as glucose - already have a significantly reduced solubility in water.
  • monoacetylsalicylic acid esters of monosaccharides are obtained according to the invention by esterification of monosaccharides, the hydroxyl groups of which are partially blocked by known protective groups, for example isopropylene groups, with acetylsalicylic acid or its derivatives, preferably acetylsalicylic acid halides or esters, and subsequent selective elimination of the protective groups.
  • protective groups for example isopropylidene group already mentioned, other protective groups for monosaccharides are known from carbohydrate chemistry. Groups suitable, for example ethylidene, cyclohexylidene, benzylidene, phenylboronic acid or trimethylsilyl groups.
  • Protected or unsung are used as starting materials for the esterification with acetylsalicylic acid or its derivatives protected monosaccharides, for example pentoses or hexoses such as xylose, arabinose, glucose, galactose, mannose, fructose or their glycosides with mono- or polyhydric alcohols.
  • Monosaccharides for example pentoses or hexoses such as xylose, arabinose, glucose, galactose, mannose, fructose or their glycosides with mono- or polyhydric alcohols.
  • Disaccharides such as sucrose, maltose, cellobiose, lactose are preferably esterified without protective groups.
  • the esterification can in principle be carried out in solvents which simultaneously act as acid scavengers (e.g. pyridine, triethylamine) or in other inert solvents (THF, dioxane, aliphatic or aromatic hydrocarbons, DMF, DMA) with the addition of an acid scavenger.
  • acid scavengers e.g. pyridine, triethylamine
  • THF dioxane
  • aliphatic or aromatic hydrocarbons e.g. aliphatic or aromatic hydrocarbons, DMF, DMA
  • the unprotected or protected by isopropylidene groups is presented in 10-20% solution * in pyridine, the acetylsalicylic acid halide, for example acetylsalicylic acid chloride, is added dropwise with stirring at 0-5 ° C. and then stirred for a further 15-20 hours at room temperature .
  • the excess solvent is distilled off and the residue is stirred with aqueous sodium bicarbonate solution. After the water has been distilled off, the residue is dissolved in an organic solvent, e.g. B.
  • the insoluble salts are filtered off and - in the case of the unprotected carbohydrates - the end product is obtained by distilling off the solvent and vacuum drying.
  • the intermediate can be isolated by distilling off the solvent and then split up, or the solution can be used directly for the selective removal of the protective groups.
  • the unprotected carbohydrate is preferably dissolved in water and the acetylsalicylic acid derivative is added dropwise with stirring, the pH being kept weakly alkaline at the same time by adding dilute alkali metal hydroxide solution.
  • the water is then distilled off in vacuo, the residue is taken up in an organic solvent, and the end product is obtained by filtering off the insoluble salts by distilling off the solvent and vacuum drying. If, instead of the carbohydrates, their protected derivatives are used in this reaction, the product obtained after working up must be subjected to acidic hydrolysis to remove the protective groups.
  • Halogenated hydrocarbons diethyl ether or petroleum ether, in which the carbohydrate esters of acetylsalicylic acid are soluble, are suitable for this purpose.
  • carboxylic acid esters for example methyl or ethyl acetylsalicylic acid
  • suitable organic solvents can be used as the reaction medium for the transesterification, which allow problem-free removal of the alcohol formed (for example methanol or ethanol) from the equilibrium by distillation, for example higher alcohols, dioxane, dimethylformamide, dimethylacetamide.
  • the free acetylsalicylic acid itself can also be used in the reaction with the carbohydrates.
  • a conventional condensing agent e.g. Dicyclohexylcarbodiimide, required.
  • the protective groups can be split off in all cases by known methods using dilute acids, acidic ion exchangers or weakly acidic catalysts.
  • the new carbohydrate esters of acetylsalicylic acid obtained according to the invention are solid substances which dissolve up to 40% in water or physiological aqueous saline solutions, resulting in stable solutions which can be applied by known injection methods and which show excellent antipyretic, antiphlogistic, antirheumatic and analgesic effects. This is due to the fact that sufficient amounts of active ingredient can be brought into the immediate vicinity of the pain zone without detour and without undesirable side effects.
  • the carbohydrate esters of acetylsalicylic acid according to the invention can also be administered orally both in substance and in solution.
  • sucrose 34.2 g (0.1 mol) of sucrose are dissolved in 600 ml of anhydrous pyridine and at 0 to 5 ° C., 6.6 g (0.033 mol) of acetylsalicylic acid chloride are added dropwise with stirring. The mixture is then warmed to room temperature and stirred for a further 20 hours. The solvent is distilled off on a rotary evaporator and the residue is stirred with saturated NaHCO 3 solution. The water is distilled off on a rotary evaporator and the residue is stirred with about 200 ml of isopropanol.
  • sucrose 34.2 g (0.1 mol) of sucrose are dissolved in 70 ml of water. Then 6.6 g (0.033 mol) of acetylsalicyl chloride are added dropwise at 0 to 5 ° C. while stirring, the pH being kept at 8 to 9 by the simultaneous addition of 20% sodium hydroxide solution. Then the water is distilled off on a rotary evaporator and the residue is stirred with about 200 ml of isopropanol. The insoluble matters are filtered off, the isopropanol is distilled off on a rotary evaporator and the residue is dried in vacuo at 60 ° C.
  • the solvent is distilled off on a rotary evaporator and the residue is taken up in chloroform.
  • the solution is washed with water, 1N H 2 SO 4 , 1N NaHCO 3 and water, dried with sodium sulfate and the chloroform is distilled off on a rotary evaporator.
  • the residue is dried in vacuo at 60 ° C.
  • the solution is washed with water, 1N H 2 SO 4 , 1N NaHCO 3 and water, dried with sodium sulfate and the chloroform is distilled off on a rotary evaporator. The residue is dried in vacuo at 60 ° C.
  • the solvent is distilled off on a rotary evaporator and the residue is taken up in chloroform.
  • the solution is washed with water, 1N H 2 SO 4 , 1N NaHCO 3 and water, dried with sodium sulfate and the chloroform is distilled off on a rotary evaporator.
  • the residue is dried in vacuo at 60 ° C.
  • the solution is washed with water, 1N H 2 SO 4 , 1N NaHCO 3 and water, dried with sodium sulfate and the chloroform is distilled off on a rotary evaporator. The residue is dried in vacuo at 60 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Des dérivés d'hydrates de carbone hydrosolubles avec des restes d'acide acétylsalicylique liés à la manière d'esters présentent un spectre d'activité analogue à celui de l'acide acétylsalicylique et peuvent être administrés aussi bien oralement qu'en particulier par injection.
PCT/AT1985/000050 1984-11-28 1985-11-27 Esters d'hydrates de carbone d'acide acetylsalicylique, procede pour leur preparation et compositions pharmaceutiques WO1986003206A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA3775/84 1984-11-28
AT0377584A AT382624B (de) 1984-11-28 1984-11-28 Verfahren zur herstellung von neuen kohlenhydrat-estern der acetylsalicylsaeure

Publications (1)

Publication Number Publication Date
WO1986003206A1 true WO1986003206A1 (fr) 1986-06-05

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT1985/000050 WO1986003206A1 (fr) 1984-11-28 1985-11-27 Esters d'hydrates de carbone d'acide acetylsalicylique, procede pour leur preparation et compositions pharmaceutiques

Country Status (3)

Country Link
EP (1) EP0202305A1 (fr)
AT (1) AT382624B (fr)
WO (1) WO1986003206A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017673A1 (fr) * 1996-10-21 1998-04-30 Cal International Limited Esters d'aspirinate d'isosorbide
US9012411B2 (en) 2009-12-31 2015-04-21 Organomed Corporation Formulations from derivatives of curcumin, paclitaxel, and aspirin

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9901858D0 (en) * 1999-01-29 1999-03-17 Secr Defence Optical filters

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE264654C (fr) *
FR1453M (fr) * 1961-10-09 1962-08-20 Pierre Louis Médicament analgéique, antithermique, antirhumatismal.
US3279990A (en) * 1963-01-31 1966-10-18 Jacobs Albert L Carbohydrate esters of salicylic acid, their production and administration
US4241055A (en) * 1979-05-30 1980-12-23 The University Of Kentucky Research Foundation Derivatives of aspirin
US4242330A (en) * 1979-05-30 1980-12-30 The University Of Kentucky Research Foundation Derivative of aspirin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE264654C (fr) *
FR1453M (fr) * 1961-10-09 1962-08-20 Pierre Louis Médicament analgéique, antithermique, antirhumatismal.
US3279990A (en) * 1963-01-31 1966-10-18 Jacobs Albert L Carbohydrate esters of salicylic acid, their production and administration
US4241055A (en) * 1979-05-30 1980-12-23 The University Of Kentucky Research Foundation Derivatives of aspirin
US4242330A (en) * 1979-05-30 1980-12-30 The University Of Kentucky Research Foundation Derivative of aspirin

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017673A1 (fr) * 1996-10-21 1998-04-30 Cal International Limited Esters d'aspirinate d'isosorbide
US9012411B2 (en) 2009-12-31 2015-04-21 Organomed Corporation Formulations from derivatives of curcumin, paclitaxel, and aspirin
US20150250844A1 (en) * 2009-12-31 2015-09-10 James N. Jacob Formulations from natural products, turmeric, paclitaxel, and aspirin

Also Published As

Publication number Publication date
ATA377584A (de) 1986-08-15
AT382624B (de) 1987-03-25
EP0202305A1 (fr) 1986-11-26

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