WO2003053439A1 - Utilisation de derives de benzofuroxan comme agents anti-plaquettes - Google Patents

Utilisation de derives de benzofuroxan comme agents anti-plaquettes Download PDF

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Publication number
WO2003053439A1
WO2003053439A1 PCT/IB2002/005353 IB0205353W WO03053439A1 WO 2003053439 A1 WO2003053439 A1 WO 2003053439A1 IB 0205353 W IB0205353 W IB 0205353W WO 03053439 A1 WO03053439 A1 WO 03053439A1
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WO
WIPO (PCT)
Prior art keywords
benzofuroxan
carbonyl
lower alkyl
hydrogen
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2002/005353
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English (en)
Inventor
Alangudi Sankaranarayanan
Original Assignee
Alangudi Sankaranarayanan
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 Alangudi Sankaranarayanan filed Critical Alangudi Sankaranarayanan
Priority to AU2002366756A priority Critical patent/AU2002366756A1/en
Publication of WO2003053439A1 publication Critical patent/WO2003053439A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to the use of benzofuroxan compounds of general formula (I) as defined herein, their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, as antiplatelet agents.
  • the compounds are found to be potent inhibitors of platelet aggregation in the treatment of cardiovascular diseases.
  • Antiplatelet agents' are those compounds, which either prevent adhesion, activation or aggregation of platelets.
  • Antiplatelet drug therapy can be used in treatment or prevention of myocardial infarction, unstable angina, venous thromboembolism, coronary artery bypass graft (CABG), percutaneous transluminal angioplasty (PTCA), cerebrovascular disease like stroke, atrial fibrillation, prosthetic heart valve, valvular heart disease, acute peripheral occlusive disease, primary and secondary prevention of arterial thromboembolism, clot prevention in extra corporeal devices as the aetiology in all the above disease state is platelet activation and subsequent thrombus formation.
  • CABG coronary artery bypass graft
  • PTCA percutaneous transluminal angioplasty
  • cerebrovascular disease like stroke atrial fibrillation
  • prosthetic heart valve valvular heart disease
  • acute peripheral occlusive disease primary and secondary prevention of arterial thromboembolism
  • Pharmacologic therapy with antiplatelet agents such as aspirin provide clinical benefit in acute ischemic syndromes.
  • Prostaglandin Ei has been reported as a powerful endothelium derived inhibitor of platelet aggregation.
  • PGEi Prostaglandin Ei
  • PDE PGEi phosphodiesterase III inhibitors
  • inotropic agents, amrinone and milrinone increase cAMP by inhibition of PDE III and inhibit platelet aggregation in vitro.
  • the other anti-platelet aggregatory drug developed included cyclo-oxygenase and thromboxane synthase inhibitors, prostaglandin derivatives, thromboxane A 2 receptor antagonists, and GPIIb/IIIa antagonists, which apart from PDE inhibitors have been widely used in clinical situation (Schafer, 1996, Anti platelet therapy, Am. J. Med, 101, 199-209).
  • the benzofuroxan compounds of the instant invention which can exhibit dual activity viz. antianginal as well as antiplatelet activity make them most suitable for cardiovascular applications. .
  • the invention provides a group of benzofuroxan compounds, their derivatives, analogues, tautomers, stereoisomers, polymorphs, their pharmaceutically acceptable salts or solvates as antiplatelet agents.
  • the invention also provides a method of treatment or prevention of disease conditions caused by formation of platelets in human and non-human mammals by administration of said benzofuroxan compounds, their derivatives, analogues, tautomers, stereoisomers, polymorphs, their pharmaceutically acceptable salts or solvates.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the said benzofuroxan compounds, their derivatives, analogues, tautomers, stereoisomers, polymorphs, their pharmaceutically acceptable salts or solvates in admixture with a pharmaceutically acceptable diluent, carrier or excepient effective as an antiplatelet agent.
  • the invention provides for use of said benzofuroxan compounds, their derivatives, analogues, tautomers, stereoisomers, polymorphs, their pharmaceutically acceptable salts or solvates in the manufacture of a medicament useful as an antiplatelet agent.
  • the present invention relates to the new use of benzofuroxan compounds of formula (I),
  • R is -C(O)-R ⁇ , halogen, acetoxy, -X-R 2 or -C(O) NR 3 R 4 , or C(O)Cl R ⁇ is -O- (CH 2 )
  • n 1 to 6
  • X is oxygen, sulfur, -C (O)-, or -C (O) O-
  • R 2 is hydrogen, straight chain or branched lower alkyl (C ⁇ -C 8 ), aromatic, heteroaromatic, and substituted or unsubstituted saturated heterocyclic ring with one or two heteroatoms such as nitrogen or oxygen wherein substitution on nitrogen is with hydrogen or lower alkyl;
  • R 3 and are independently hydrogen, straight chain or branched lower alkyl (Ci-
  • R 3 and R 4 are linked together with or without a heteroatom selected from the group consisting of oxygen and nitrogen wherein substitution on nitrogen is with hydrogen or lower alkyl;
  • Y is -NHC (O)- or oxygen
  • R 5 is lower alkyl (C ⁇ -C 8 ), aromatic, heteroaromatic, and substituted or unsubstituted saturated heterocyclic ring with one or two heteroatoms such as nitrogen or oxygen wherein substitution on nitrogen is with hydrogen or lower alkyl;
  • R 6 is hydrogen, nitro, lower alkyl or -C (O)-R ;
  • R 7 is hydrogen, lower alkyl or aryl
  • R 8 is hydrogen ; or "Ri" is selected from the group consisting of
  • the substituent R 8 in the said compounds of formula is a halogen selected from the group F, CI, Br and I.
  • the compounds of the present invention can be prepared according to the methods disclosed in US6,248,895 (Sankaranarayanan, 2001) and US 6,232,331 (Sankaranarayanan, 2001).
  • PRP platelet rich plasma
  • PPP platelet poor plasma
  • PRP The anticoagulated blood sample was centrifuged at 250g for 10 minutes and the supernatant (PRP) removed carefully into a plastic tube, and retained at 18 - 26°C for the duration of the test.
  • Preparation of PPP The sediment (cells) from the above contrifugation is again re-centrifuged at 1500g for 10 minutes and the supernatant (PPP) is collected and kept at 18 -26°C for the duration of the test.
  • the compounds 31 and 10 were tested for their antiplatelet activity using E 840 aggregometer.
  • the inhibition of platelet aggregation by the test compounds was studied according to the modified method of Nishikawa M, et al.1981 using three different platelet aggregation reagents viz. (a) Adenosine -5' - diphosphate (ADP) : 10 ⁇ M, (b) Collagen: 0.2 mg/ml and (c) Epinephrine: 10 ⁇ M. (All agonists are obtained from Sigma-Aldrich - 'platelet aggregation reagents'). Assay Procedure:
  • test drug solution final cone, of 46 ⁇ M or 57 ⁇ M OR saline (for control) was added to the PRP cuvettes and incubated for 1 min. 5.
  • the aggregant was brought to room temperature (18 - 26°C) and swirled to mix.
  • the aggregation response was measured for 5 min or till the max response is reached. 8.
  • the extent of aggregation was expressed by the maximum change of light transmission expressed as a percentage, taking the difference between light transmission for PRP and PPP as 100.
  • test compound 31 showed good inhibitory activity of 92%, 88% and 84% respectively at concentration (46 ⁇ M) with the three aggregants ADP, epinephrine and collagen.
  • the test compound 10 showed about 25% inhibition with epinephrine as aggregant, while at higher concentration it showed marked increase in inhibitory activity.
  • Platelet aggregation induced by an aggregating agent has also measured using a whole blood aggregometer which monitors the change in the electrical-impedance. It is the first simple method by which aggregation of human platelets can be measured in their natural environment (Zwierzina and Kunz, 1985).
  • the tests were performed using venous blood sample of normal healthy male volunteers, (non smokers, non alcoholics) who were not on any medication known to affect platelet aggregation for at least 2 weeks prior to the study.
  • the anticoagulant used was 3.8% tri sodium citrate, in the ratio of 9:1.
  • the samples were kept at room temperature until tested and the experiments were completed within 2-3 hrs of blood- collection (Zwierzina and Kunz, 1985; Mutsuhito kikura et al., 2000).
  • the test compounds and the reference compound Nicorandil were tested for their antiplatelet activity using chronolog whole blood aggregometer.
  • the inhibition of platelet aggregation by the test compounds was studied using the aggregate collagen (chrono-log corp, chrono-par 385 collagen reagent).
  • benzofuroxan compounds useful for the invention may be prepared by the process as disclosed in US 6,248,895 and US 6,232,331.
  • This compound can be prepared by the same method as described in Example 3 infra for Step 2 of Compound No. 37 using 5(6)-azidocarbonyl benzofuroxan (0.50 gm, 0.0024 mole) and N-(2-hydroxyethyl-2-pyrrolidinone)(0.32 gm, 0.0024 mole). Yield: 0.60 gm. m. p.. : 164-165°C
  • Step 1 Preparation of 5(6)-azidocarbonyl benzofuroxan
  • Step 2 Preparation of 5(6)- ⁇ 2-(3-pyridylcarbonylamino)-ethyl ⁇ oxy carbonyl amino benzofuroxan
  • a solution of azido comp. (0.41 g, 0.002 mole, as prepared in step 1) in toluene (20 ml) was refluxed for 2 hrs.
  • Added N-(2-hydroxyethyl)-nicotinamide (0.33 gm, 0.002 mole) to the above solution and refluxed for another 2 hr., cooled to the room temp, precipitated product filtered and dried.
  • Step 2 Preparation of 4-azido-3-bromo-5-nitro benzoic acid.
  • Step 4 Preparation of 5(6)-[4-bromo]-isopropyloxycarbonyl benzofijroxan
  • Compound of Formula (I) is dissolved in propylene glycol and warmed to about 40 °C to obtain a clear solution.
  • the volume of the above solution is made up with 0.9% sodium chloride solution.
  • a tablet can be prepared with the compounds of the invention and following ingredients together in the proportions by weight specified below:
  • Compound of Formula (I) is mixed with Starch and Microcrystalline Cellulose and granulated with Starch mucilage (prepared by gelatinizing starch in water). The wet mass is dried at 50°C and the dried granules are sized through ASTM #20 sieve. The sized granules are blended with Sodium Starch Glycolate and Magnesium Stearate and the blend was compressed into tablets using 7 mm punches to contain 25 mg of
  • Compound of Formula (I) Other tablets may be compressed to contain 50, 75,100,
  • the pharmaceutical composition can be in the range of 0.5 % to 90 % by weight of the total composition.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de composés de benzofuroxan, de dérivés, d'analogues, de formes tautomères, de stéréoisomères, de polymorphes, d'hydrates, de sels, de solvates et de compositions acceptables sur le plan pharmaceutique de ceux-ci comme agents anti-plaquettes destinés à la prévention ou au traitement d'états pathologiques engendrés par une agrégation des plaquettes chez un mammifère humain ou non humain, ainsi qu'un procédé et une composition associés.
PCT/IB2002/005353 2001-12-20 2002-12-13 Utilisation de derives de benzofuroxan comme agents anti-plaquettes WO2003053439A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002366756A AU2002366756A1 (en) 2001-12-20 2002-12-13 Use of benzofuroxan derivatives as antiplatelet agents

Applications Claiming Priority (2)

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US34128301P 2001-12-20 2001-12-20
US60/341,283 2001-12-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2515413C2 (ru) * 2012-07-05 2014-05-10 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Производные 1,2,5-оксадиазолов, обладающие анти-вич активностью, фармацевтическая композиция, способ ингибирования интегразы вич-1
CN114920722A (zh) * 2021-06-02 2022-08-19 何黎琴 一种7-羟基-3-乙酰基香豆素肟类化合物、其制备方法及医药用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431944A2 (fr) * 1989-12-08 1991-06-12 Merck & Co. Inc. Dérivés de benzofurazane possédant des propriétés antiarythmiques
EP0574726A1 (fr) * 1992-06-10 1993-12-22 Hoechst Aktiengesellschaft Oxadiazole-1,2,5 oxydes-2 annelés et leur application comme agents pharmacologiques
US5424326A (en) * 1992-06-20 1995-06-13 Cassella Aktiengesellschaft Phenyl-1,2,5-oxadiazolecarboxamide-2-oxides, their preparation and their use
WO1998035950A1 (fr) * 1997-02-13 1998-08-20 Cortex Pharmaceuticals, Inc. Composes a base de benzofurazan renforçant l'activite du recepteur de l'ampa
US6232331B1 (en) * 1998-05-22 2001-05-15 Torrent Pharmaceutical Ltd. Benzofuroxan derivatives, their therapeutic uses and pharmaceutical compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431944A2 (fr) * 1989-12-08 1991-06-12 Merck & Co. Inc. Dérivés de benzofurazane possédant des propriétés antiarythmiques
EP0574726A1 (fr) * 1992-06-10 1993-12-22 Hoechst Aktiengesellschaft Oxadiazole-1,2,5 oxydes-2 annelés et leur application comme agents pharmacologiques
US5424326A (en) * 1992-06-20 1995-06-13 Cassella Aktiengesellschaft Phenyl-1,2,5-oxadiazolecarboxamide-2-oxides, their preparation and their use
WO1998035950A1 (fr) * 1997-02-13 1998-08-20 Cortex Pharmaceuticals, Inc. Composes a base de benzofurazan renforçant l'activite du recepteur de l'ampa
US6232331B1 (en) * 1998-05-22 2001-05-15 Torrent Pharmaceutical Ltd. Benzofuroxan derivatives, their therapeutic uses and pharmaceutical compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GHOSH P B ET AL: "Potential antileukemic and immunosuppressive drugs. Preparation and in vitro pharmacological activity of some benzo-2,1,3-oxadiazoles (benzofurazans) and their N-oxides (benzofuroxans)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 11, no. 2, 1968, pages 305 - 11, XP002113125 *
GHOSH, P. B. ET AL: "Potential antileukemic and immunosuppressive drugs. 3. Effects of homocyclic ring substitution on the in vitro drug activity of 4-nitrobenzo-2,1,3-oxadiazoles (4-nitrobenzofurazans) and their N-oxides (4-nitrobenzofuroxans)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 15, no. 3, 1972, pages 255 - 260, XP002232282 *
ZHANG W ET AL: "Synthesis and hypoxia-selective cytotoxicity of benzofuraxans and quinoline di-N-oxides", CHEMICAL ABSTRACTS + INDEXES, AMERICAN CHEMICAL SOCIETY. COLUMBUS, US, vol. 1, no. 125, 1 July 1996 (1996-07-01), pages 1182, XP002113146, ISSN: 0009-2258 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2515413C2 (ru) * 2012-07-05 2014-05-10 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Производные 1,2,5-оксадиазолов, обладающие анти-вич активностью, фармацевтическая композиция, способ ингибирования интегразы вич-1
CN114920722A (zh) * 2021-06-02 2022-08-19 何黎琴 一种7-羟基-3-乙酰基香豆素肟类化合物、其制备方法及医药用途
CN114920722B (zh) * 2021-06-02 2024-03-08 何黎琴 一种7-羟基-3-乙酰基香豆素肟类化合物、其制备方法及医药用途

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