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WO1998017673A1 - Esters d'aspirinate d'isosorbide - Google Patents

Esters d'aspirinate d'isosorbide Download PDF

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Publication number
WO1998017673A1
WO1998017673A1 PCT/IE1997/000069 IE9700069W WO9817673A1 WO 1998017673 A1 WO1998017673 A1 WO 1998017673A1 IE 9700069 W IE9700069 W IE 9700069W WO 9817673 A1 WO9817673 A1 WO 9817673A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
compound
isosorbide
oil
aspirinate
Prior art date
Application number
PCT/IE1997/000069
Other languages
English (en)
Inventor
William Byrne
John Francis Gilmer
Andrew Rynne
Original Assignee
Cal International Limited
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 Cal International Limited filed Critical Cal International Limited
Priority to AU48817/97A priority Critical patent/AU4881797A/en
Publication of WO1998017673A1 publication Critical patent/WO1998017673A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • the invention relates to aspirinate compounds.
  • Aspirin which has been available for about 100 years, possesses analgesic, anti- inflammatory and antipyretic properties. This compound has also been shown to be effective in cardiovascular disease and this action dependent upon its effects on platelet function. Aspirin can improve the mortality figures associated with acute myocardial infarction and reduces the risk of this in patients with unstable angina by between 30 and 50%. It is used to prevent re-occurrence in those patients after recovery from myocardial infarction. It is also likely to be of benefit to individuals suffering from stable angina since it reduces the risk of myocardial infarction in apparently healthy, middle-aged men. Aspirin is used to reduce the likelihood of stroke in patients with transient cerebral ischaemic attacks. It also lowers the risk of thromboembolism in patients with atrial fibrillation and following valve replacement.
  • Aspirin reduces platelet aggregation by irreversibly inhibiting fatty acid cyclo- oxygenase, a precursor in the biosynthesis of prostaglandins and thromboxanes. This occurs by acetylation of a serine residue and thus prevents access of arachidonic acid to the active site by steric hindrance.
  • Thromboxane A2 is the main cyclo-oxygenase product of activated platelets and is proaggregatory and a vasoconstrictor. Therefore, aspirin exerts its antithrombotic action by preventing thromboxane A2 biosynthesis.
  • other non-steroidal anti-inflammatory drugs also possess this effect they are much less effective because, unlike aspirin, they reversibly inhibit the enzyme.
  • Aspirin is also relatively unstable, especially in formulations with other therapeutically active substances.
  • an isosorbide aspirinate compound According to the invention there is provided an isosorbide aspirinate compound.
  • the invention provides the compounds Isosorbide -2-aspirinate, Isosorbide-5-aspirinate and, especially Isosorbide -2, 5-diaspirinate.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention which may be adapted for oral administration as a capsule or tablet or for percutaneous administration, for example in the form of a transdermal patch.
  • the composition may also be in the form of a suppository.
  • the invention also provides the use of the compound to achieve anti-platelet activity and/or other aspirin type activities such as anti-pyretic and/or anti- inflammatory activity.
  • the composition includes another pharmaceutical entity, especially a therapeutic oil, typically a fish oil such as cod liver oil, or a vegetable oil such as evening primrose oil.
  • a therapeutic oil typically a fish oil such as cod liver oil, or a vegetable oil such as evening primrose oil.
  • the composition maybe in the form of a capsule having a retaining shell containing a filling including the active ingredients.
  • the filling may include a suspending agent such as one selected from one or more of colloidal silicon dioxide, hydrogenated vegetable oils (optionally in combination with beeswax), high melting point partial glycerides, and/or lecithins.
  • the filling may also include an antioxidant such as one selected from one or more of D-alpha tocopherol, D-alpha tocopherol acetate, mixed tocopherols and ascorbic acid.
  • the shell may be a gelatin shell.
  • the invention also provides a process for preparing a compound of the invention.
  • the title compound was prepared in satisfactory yield without the use of chromatography by stirring a mixture of isosorbide, triethylamine and acetylsalicyloyl chloride in toluene for a period of 24-36 hours.
  • the reaction mixture was then washed with 2M HCl, to remove some of the side products and the excess base.
  • the removal of any unreacted aspirin was achieved by washing with a saturated sodium bicarbonate solution. This afforded a material whose major component was the title diaspirinate ester by Thin Layer Chromatography. This ester was crystallised by dissolving it in ethanol. Much of the colour was removed following the first crystallisation.
  • a second crystallisation yielded a higher purity material.
  • a third or fourth recrystallisation was required to achieve a purity of greater than 99.8%.
  • a sample procedure is given below. The reaction was performed under anhydrous conditions so that only a small excess of the acid chloride was required.
  • Acetylsalicyloyl chloride* (6.3 g, 30 mmol, 2.2 eq.) was suspended in toluene (50 cm 3 ) and triethylamine (5 cm 3 ) was added. The mixture was cooled to 0°C and light excluded. Maintaining the temperature, isosorbide (2.0 g, 13.7 mmol) was added to the stirring solution. When the addition was complete the resulting mixture was allowed to reach room temperature with vigorous stirring. The reaction was monitored by TLCf (following a mini-work up). After 36 hours the reaction was pale orange.
  • Dichloromethane (recorded on an optical activity LTD AAIO Automatic Polarimeter, using a 2dm sample tube).
  • the stability of the solid compound (isosorbide - 2, 5 - diaspirinate) under accelerated conditions of 40°C over a 12 week period was studied.
  • O approximately 1.5 g of the solid compound (100% pure by HPLC) was distributed between six sealed sample bottles.
  • a heated sample ( « 0.020 g) was weighed into a 10 ml volumetric flask, acetonitrile (4 ml) added, and the volume was brought up to 10 ml with Milli - Q (trade mark) purified water. 1 ml of this solution was transferred to a clean dry class A volumetric flask and 4 ml of acetonitrile were added. The volume was made up to 10 ml with aqueous mobile phase.
  • Each sample was filtered, using a disposable syringe with an Acrodisc (trade mark) filter connected, into a sampling vial for analysis using HPLC. Samples were tested every 2 weeks and the concentrations in mg/ml of the compound and any breakdown components at 40°C were determined. No breakdown components were detected and the concentration of the compound was maintained as follows.
  • the stability of the compound (isosorbide - 2, 5 - diaspirinate) (ISDasp) in cod liver oil (CLO - BP) in the presence of water and/ or glycerol was also determined.
  • the stability of the compound compared to that of aspirin under the same conditions was also determined.
  • Samples A - E were mixtures of the ISDasp in CLO-BP with variable water/ glycerol concentrations (0.208 mmol of aspirinate).
  • Samples F-J were mixtures of aspirin in CLO-BP with similar concentrations of water/glycerol to that for the ISDasp samples (0.208 mmol aspirin). Each set was prepared six times for studying in weeks 0, 1, 2, 4, 8 and 12.
  • a 120 ml sample of the remaining aqueous layer was added to a class A 10 ml volumetric flask and 5 ml acetonitrile, 2 ml aqueous mobile phase added and the volume made up to 10 ml with milli-Q water.
  • a sample of this slightly cloudy mixture was filtered using a disposable syringe and Gelman FP Vericel membrane filter to give a clear solution.
  • Isosorbide diaspirinate Isosorbide diaspirinate; ISDasp samples were analysed using a similar chromatographic procedure to that used in the solid stability study; acetonitrile: buffer 40:60, PDA detection with chromatogram extraction at 230 nm.
  • Aspirin Aspirin samples were analysed using a mobile phase of acetonitrile: buffer 15.85, PDA detection with chromatogram extraction at 230 nm.
  • Amount % salicylic acid is calculated with respect to the weight of aspirin.
  • Amount % salicylate calculated with respect to Diaspirinate a.n. _ > % area by area normalisation of chromatograms of samples following extraction and dilution.
  • the compounds of the invention have potential therapeutic use by virtue of the inclusion of an aspirin moiety as an anti-platelet agent and/ or to achieve other aspirin type activities such as anti-pyretic and/ or anti-inflammatory activity.
  • Isosorbide diaspirinate administered at 2 mg/kg in single oral doses to adult beagle dogs have shown that the compound has aspirin - like activity as measured by inhibition of arachidonic acid - induced platelet aggregation (inhibition of cyclooxygenase activity), and inhibition of ex vivo production of thromboxane B 2 .
  • the compounds of the invention may be formulated in any suitable pharmaceutical compositions using conventional excipients/ vehicles.
  • the composition may be presented in a form for oral administration
  • a suppository formulation may in some cases be preferred as a route of administration because it avoid absorption in the gut.
  • One typical suppository formulation is as follows. Micronised isosorbide-diaspirinate (6g) was added to 5g of a suppository base such as Novata E (trade mark of Henkle) which was previously gently melted over a steam bath at 80 to 90°C. The mixture was allowed to cool slightly and then poured with vigorous stirring into 10 x 1 g suppository moulds.
  • the compounds of the invention may be administered at a suitable dose to achieve the desired therapeutic benefit.
  • an oral dose to achieve anti-platelet activity an amount of the compound equivalent to 50 to 150, preferably 100, mg of aspirin per day may be administered.
  • a higher dose would typically be administered.
  • the dosage would also typically be higher.
  • the compounds may be formulated with cod liver oil to achieve a combined therapeutic effect.
  • the compounds may also be combined with another fish oil or a therapeutic oil in general such as a vegetable oil, for example evening primrose oil.
  • the formulation may be in the form of a gelatine capsule with a filling including the active ingredients.
  • the filling may include an antioxidant and/ or a suspending agent.
  • the suspending agent may be selected from one or more of colloidal silicon dioxide, hydrogenated vegetable oils (optionally in combination with beeswax), high melting point partial glycerides, and/or lecithins.
  • the antioxidant may be selected from one or more of D-alpha tocopherol acetate, mixed tocopherols and ascorbic acid.
  • the compound may be combmed with other therapeutic agents to achieve a combined therapeutic effect.
  • the invention also provides the following compounds which may be formulated and used as described above in relation to the compound of example 1.
  • Isosorbide-5-aspirinate (IS-5-A)
  • Isosorbide-2-as ⁇ irinate (IS-2-A) Example 2:
  • Isosorbide-2-mononitrate 4 (1.38g, 7.2mmol) was dissolved in anhydrous dichloromethane (50ml) and triethylamine (2.19g, 21.6mmol) was added. The mixture was cooled to 0°C for the introduction of acetylsalicyloyl chloride (1.43g,
  • Isosorbide-5-aspirinate-2-mononitrate 5 (O.l ⁇ g, 0.45mmol) was dissolved in a mixture of ethyl acetate and anhydrous methanol (20ml, 1:1), and a catalytic amount of palladium on charcoal was added. The mixture was stirred under an atmosphere of hydrogen for 4h. TLC indicated the formation of two products: the desired isosorbide-5-aspirinate 6, and its salicylate. The reaction mixture was filtered and concentrated under vacuum. Flash column chromatography, using dichloromethane /ethyl acetate/pet. ether (1:1:1) as the eluant, was carried out on the crude product, yielding the aspirinate 6 as a colourless oil (0.1 lg, 79%).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Cette invention se rapporte à des composés 2-aspirinate d'isosorbide, 5-aspirinate d'isosorbide et, en particulier, 2,5-diaspirinate d'isosorbide, qui constituent des composés stables pouvant être administrés pour produire une activité antiplaquettaire et/ou d'autres activités du type aspirine. Ces composés peuvent être utilisés avec d'autres agents thérapeutiques pour produire un effet thérapeutique combiné. Ces composés peuvent notamment être formulés en une capsule avec une huile thérapeutique, en particulier de l'huile de foie de morue.
PCT/IE1997/000069 1996-10-21 1997-10-21 Esters d'aspirinate d'isosorbide WO1998017673A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48817/97A AU4881797A (en) 1996-10-21 1997-10-21 Isosorbide aspirinate esters

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IE960740 1996-10-21
IE960740 1996-10-21

Publications (1)

Publication Number Publication Date
WO1998017673A1 true WO1998017673A1 (fr) 1998-04-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IE1997/000069 WO1998017673A1 (fr) 1996-10-21 1997-10-21 Esters d'aspirinate d'isosorbide

Country Status (3)

Country Link
AU (1) AU4881797A (fr)
WO (1) WO1998017673A1 (fr)
ZA (1) ZA979404B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098427A3 (fr) * 2001-06-05 2003-02-20 Control Delivery Systems Composes analgesiques a liberation continue
WO2009080795A1 (fr) * 2007-12-21 2009-07-02 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin Promédicaments efficaces de l'aspirine
US20150291615A1 (en) * 2011-01-21 2015-10-15 Solvotrin Therapeutics Ltd. Compounds with super-aspirin effects
USRE50049E1 (en) 2015-03-27 2024-07-23 Sytheon Ltd. Compositions and methods for treating psoriasis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2031161A1 (de) * 1969-07-03 1971-01-07 Ciba Geigy Ag O Ester von Athergruppierungen aufweisenden Monosacchanden
WO1986003206A1 (fr) * 1984-11-28 1986-06-05 Evidenzbüro Österreichischer Zuckerfabriken Gesell Esters d'hydrates de carbone d'acide acetylsalicylique, procede pour leur preparation et compositions pharmaceutiques
WO1994003421A2 (fr) * 1992-07-30 1994-02-17 Cal International Limited Esters et combinaisons d'un nitrate organique et d'un salicylate
WO1997004757A1 (fr) * 1995-07-27 1997-02-13 Cal International Limited Formulation transdermique a base de nitrate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2031161A1 (de) * 1969-07-03 1971-01-07 Ciba Geigy Ag O Ester von Athergruppierungen aufweisenden Monosacchanden
WO1986003206A1 (fr) * 1984-11-28 1986-06-05 Evidenzbüro Österreichischer Zuckerfabriken Gesell Esters d'hydrates de carbone d'acide acetylsalicylique, procede pour leur preparation et compositions pharmaceutiques
WO1994003421A2 (fr) * 1992-07-30 1994-02-17 Cal International Limited Esters et combinaisons d'un nitrate organique et d'un salicylate
WO1997004757A1 (fr) * 1995-07-27 1997-02-13 Cal International Limited Formulation transdermique a base de nitrate

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098427A3 (fr) * 2001-06-05 2003-02-20 Control Delivery Systems Composes analgesiques a liberation continue
AU2002305816B2 (en) * 2001-06-05 2008-04-10 Psivida Us Inc. Sustained-release analgesic compounds
WO2009080795A1 (fr) * 2007-12-21 2009-07-02 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin Promédicaments efficaces de l'aspirine
JP2011517657A (ja) * 2007-12-21 2011-06-16 ザ プロボースト，フェローズ アンド スカラーズ オブ ザ カレッジ オブ ザ ホーリー アンド アンディバイディッド トリニティ オブ クイーン エリザベス ニア ダブリン 効率的アスピリンプロドラッグ
US8486974B2 (en) 2007-12-21 2013-07-16 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Efficient aspirin prodrugs
CN101925604B (zh) * 2007-12-21 2014-11-26 都柏林伊丽莎白女王圣三一学院教务长董事及学者 有效的阿司匹林前药
US20150291615A1 (en) * 2011-01-21 2015-10-15 Solvotrin Therapeutics Ltd. Compounds with super-aspirin effects
US9670223B2 (en) * 2011-01-21 2017-06-06 Solvotrin Therapeutics Ltd. Compounds with super-aspirin effects
USRE50049E1 (en) 2015-03-27 2024-07-23 Sytheon Ltd. Compositions and methods for treating psoriasis

Also Published As

Publication number Publication date
AU4881797A (en) 1998-05-15
ZA979404B (en) 1998-06-01

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