EP1232172A1 - Nouveaux composes a base de ribose - Google Patents

Nouveaux composes a base de ribose

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Publication number
EP1232172A1
EP1232172A1 EP00980179A EP00980179A EP1232172A1 EP 1232172 A1 EP1232172 A1 EP 1232172A1 EP 00980179 A EP00980179 A EP 00980179A EP 00980179 A EP00980179 A EP 00980179A EP 1232172 A1 EP1232172 A1 EP 1232172A1
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EP
European Patent Office
Prior art keywords
compound
formula
compound according
pyrimidin
triazolo
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.)
Withdrawn
Application number
EP00980179A
Other languages
German (de)
English (en)
Inventor
David AstraZeneca R & D Charnwood HARDERN
Anthony AstraZeneca R & D Charnwood INGALL
Paul AstraZeneca R & D Charnwood WILLIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1232172A1 publication Critical patent/EP1232172A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/12—Triazine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

  • the present invention provides novel ribose analogues, their use as medicaments, compositions containing them and processes for their preparation.
  • Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and platelet-mediated occlusion or re-occlusion also compromises angioplasty.
  • the final common event is a cross-linking of platelets by binding of fibrinogen to a membrane-binding site, glycoprotein Ilb/ ⁇ ia (GPEb fla).
  • GPEb fla glycoprotein Ilb/ ⁇ ia
  • the high anti-platelet efficacy of antibodies or antagonists for GPnb/Tfla is explained by their interference with this final common event. However, this efficacy may also explain the bleeding problems that have been observed with this class of agent.
  • Thrombin can produce platelet aggregation largely independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms.
  • Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again may produce excessive bleeding because they function as both anti-platelet and anti-coagulant agents (The T I 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) Ha Investigators (1994) Circulation 90, pp. 1631- 1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp. 1638-1642). It has been found that ADP acts as a key mediator of thrombosis. ADP-induced platelet aggregation is mediated by the P 7 - receptor subtype located on the platelet membrane.
  • the P 2 r receptor (also known as P2Y AD P or P2T A c) is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor.
  • the pharmacological characteristics of this receptor have been described, for example, in the references by Humphries et al., Br. J. Pharmacology, (1994), 113, 1057-1063, and Fagura et al., Br. J. Pharmacology (1998) 124, 157-164. Recently it has been shown that antagonists at this receptor offer significant improvements over other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213). There is a need to find P 2r (P2Y AD p or P2T AC ) antagonists as anti- thrombotic agents.
  • R 6 is H or alkyl C ⁇ . 6 ; or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
  • the compound of formula (I) has the following stereochemistry:
  • R 1 , R 2 and R 3 are as defined above
  • R 3 is R 5 , where R 5 is defined above, the stereochemistry is preferably
  • R 1 is CH 2 OH, (CH 2 ) 2 OH, COOH or CONHEt.
  • R 2 is alkyl C 3 optionally substituted by three halogen atoms.
  • Particularly preferred compounds of the invention include: (l ⁇ -tr ⁇ 5)-N-(2-Phenylcyclopropyl)-5-(propylthio)-3-( ⁇ -D-ribofurarosyl)-3H : [ 1 ,2,3]- triazolo[4,5-J]pyrimidin-7-amine;
  • R 2 is defined above and P is a protecting group, preferably benzoyl, with R 3 NH , where R 3 is defined above, and a base, preferably triethylamine or NN-di- isopropylethylamine, in the presence of dipolar aprotic solvent, preferably N,N- dimethylformamide or an alcohol, preferably n-butanol, at a temperature between about 100 and about 150°C, and optionally thereafter removing any protecting groups.
  • dipolar aprotic solvent preferably N,N- dimethylformamide or an alcohol, preferably n-butanol
  • Protecting groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in 'Protective Groups in Organic Chemistry', edited by J W F McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
  • R 5 is phenyl substituted by one or more groups selected from Cj. 6 alkyl, halogen and OR 6 it may be prepared as described in International Patent Application WO 9905143.
  • a compound of formula (II) can be prepared by reacting a compound of formula (HI):
  • R 2 is defined above, with l-0-acetyl-2,3,4-tri-0-benzoyl- ⁇ -D-ribofuranose and an acid, preferably p-toluenesulphonic acid, at a temperature between about 100 and about 150°C.
  • a compound of formula (HI) can be prepared by reducing a compound of formula (IV):
  • R 2 is defined above, with a metal, preferably iron powder, in the presence of an acid, preferably acetic acid, followed by diazotization using a C ⁇ -6 alkyl nitrite, preferably iso- amyl nitrite, in the presence of an inert dipolar aprotic solvent, preferably acetonitrile, at a temperature between about 20 and about 100°C.
  • a metal preferably iron powder
  • an acid preferably acetic acid
  • diazotization using a C ⁇ -6 alkyl nitrite preferably iso- amyl nitrite
  • an inert dipolar aprotic solvent preferably acetonitrile
  • a compound of formula (IV) can be prepared by reacting a compound of formula (V):
  • R" is defined above, with aqueous ammonia in the presence of an inert ethereal solvent, preferably 1,4-dioxane, at a temperature between about 0 and about 50°C.
  • an inert ethereal solvent preferably 1,4-dioxane
  • the compound of formula (V) may be prepared as described in International Patent Application WO 9828300.
  • R"" and R are as defined above, i) with sodium hydrosulphide (NaSH) in the presence of a dipolar aprotic solvent, preferably N,N-dimethylformamide, at a temperature between about 0 and about 50°C and treating the product of this reaction with an alkyl halide (R 2 X), preferably l-bromo-3,3,3- trifluoropropane, in the presence of a dipolar aprotic solvent, preferably N,N- dimethylformamide, at a temperature between about 0 and about 50°C, or ii) with a sodium alkylthiolate (R S ⁇ a) in the presence of a dipolar aprotic solvent, preferably N,N-dimethylformamide, at a temperature between about 0 and about 50°C, where R 2 is different from the R" being interconverted.
  • NaSH sodium hydrosulphide
  • a dipolar aprotic solvent preferably N,N-dimethylformamide
  • a compound of formula (VI) may be made by the oxidation of a compound of formula (VII):
  • R" and R are as defined above, with a peracid, preferably m-chloroperoxybenzoic acid, in the presence of a chlorocarbon solvent, preferably dichloromethane, at a temperature between about 0 and about 50°C.
  • a peracid preferably m-chloroperoxybenzoic acid
  • a chlorocarbon solvent preferably dichloromethane
  • step a The preparation of the compound of formula (VII) was described above in step a.
  • P and P are protecting groups, preferably CMe 2 , and R 2 and R 3 are as defined above, with a metal hydride, preferably di-isobutylaluminiumhydride, in the presence of an inert solvent, preferably toluene, at a temperature between about 0 and about 50°C and optionally thereafter removing any protecting groups.
  • a metal hydride preferably di-isobutylaluminiumhydride
  • an inert solvent preferably toluene
  • the protecting groups are removed by reaction with trifluoroacetic acid, using water or aqueous acetonitrile as solvents, at a temperature between about 0 and about 100°C.
  • a compound of formula (VHI) can be made by reacting a compound of formula (IX):
  • a compound of formula (IX) can be made by reacting a compound of formula (X):
  • P, P , R 2 and R 3 are as defined above, with an alkylchloroformate, preferably iso- butylchloroformate, in the presence of a base, preferably N-methylmorpholine, followed by reaction with diazomethane in the presence of an ethereal solvent, preferably a mixture of tetrahydrofuran and diethylether, at a temperature between about -10 and about 20°C
  • a compound of formula (X) can be made by oxidising a compound of formula (XI):
  • a compound of formula (XI) can be made by reacting a compound of formula (VII) with a ketal or acetal, preferably 2,2-dimethoxypropane in acetone, and an acid, preferably p- toluenesulphonic acid, at a temperature between about 0 and about 100°C.
  • a compound of formula (VII) with a ketal or acetal, preferably 2,2-dimethoxypropane in acetone, and an acid, preferably p- toluenesulphonic acid, at a temperature between about 0 and about 100°C.
  • the preparation of the compound of formula (VII) was described above.
  • activating the carboxylic group of a compound of formula (X) with a suitable activating reagent preferably benzotriazolyl-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate, and reaction with R 6 ⁇ H 2 , where R 6 is defined above, in the presence of a base, preferably N,N-di- isopropylethylamine in inert ethereal solvent, preferably tetrahydrofuran, at a temperature between about 0 and about 50°C and optionally thereafter removing any protecting groups.
  • the protecting groups are removed using trifluoroacetic acid in water or aqueous acetonitrile at a temperature between about 0 and about 100°C.
  • Salts of the compounds of formula (I) may be formed by reacting the free base, or a salt or a derivative thereof, with one or more equivalents of the appropriate acid (for example a hydrohalic (especially HC1), sulphuric, oxalic or phosphoric acid).
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. water, ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying.
  • the reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
  • the non-toxic physiologically acceptable salts are preferred, although other salts may be useful, e.g. in isolating or purifying the product.
  • the compounds of the invention act as P 7 - (P2Y AD p or P2T A c) receptor antagonists. Accordingly, the compounds are useful in therapy, including combination therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, coronary revascularisation procedures including angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps,
  • platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process. Further indications include treatment of CNS disorders and prevention of the growth and spread of tumours.
  • a compound according to the invention as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of the above disorders.
  • the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and stable and unstable angina, especially unstable angina.
  • the invention also provides a method of treatment or prevention of the above disorders which comprises administering a therapeutically effective amount of a compound according to the invention to a person suffering from or susceptible to such a disorder.
  • the compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally.
  • the compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier.
  • a pharmaceutically acceptable diluent, adjuvant or carrier particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
  • Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol.
  • Suitable carriers include sugars and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler e.g. that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active compound with or without a carrier substance is delivered to the patient.
  • the pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration.
  • the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • the tablet may be coated with a suitable polymer dissolved either in a readily volatile organic solvent or an aqueous solvent.
  • the compound may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • NMR spectra were measured on a Varian Unity Inova 300 or 400 spectrometer and the MS spectra were measured as follows: El spectra were obtained on a VG 70-250S or Finnigan Mat Incos-XL spectrometer, FAB spectra were obtained on a VG70-250SEQ spectrometer, ESI and APCI spectra were obtained on Finnigan Mat SSQ7000 or a Micromass Platform spectrometer. Preparative HPLC separations were generally performed using a Novapak ® , Bondapak ® or Hypersil ® column packed with BDSC-18 reverse phase silica.
  • Iron powder (5g) was added in portions over 2 hours to a solution of the product from step a) (5g) in acetic acid (200ml) at 25 °C and the suspension stirred for a further 2 hours.
  • the reaction mixture was neutralised with sodium bicarbonate solution and extracted with dichloromethane.
  • the organic extract was dried (MgSO ) and concentrated in vacuo.
  • the resultant oil was dissolved in acetonitrile (25ml), isoamyl nitrite (7.5ml) added and the solution stirred at 65 °C for 1 hours.
  • the reaction mixture was concentrated in vacuo and the residue purified by chromatography (Si0 , dichloromethane followed by ethyl acetate as eluants) to give the sub-title compound (5g).
  • the sub-title compound was prepared by the method of example 1, step d) using (IR- tr /w)-2-(4-chlorophenyl)cyclopropylamine (prepared as described in International Patent Application WO 9905143).
  • the title compound was prepared by the method of example 1 , step e) using the product from step a).
  • the sub-title compound was prepared by the method of example 1 step d) using (IR-trans)- 2-(3,4-difluorophenyl)cyclopropylamine [ ⁇ -(i?*J?*)]-2,3-dihydroxybutanedioate (1 : 1) (prepared as described in International Patent Application WO 9905143).
  • the title compound was prepared by the method of example 1 , step e) using the product from step a).
  • the sub-title compound was prepared by the method of example 1, step d) using (IR- tra/25)-2-(4-fluorophenyl)cyclopropylamine (prepared as described in International Patent Application WO 9905143). MS (APCI) 789 (M+H + , 100%).
  • the title compound was prepared by the method of example 1 , step e) using the product from step a).
  • step a) To the product from step a) (0.5g) in dimethylformamide (5ml) solution was added sodium hydrosulphide (0.2g) over 15 minutes. l-Bromo-3,3,3-trifluoropropane (1ml) was added and the mixture stirred for 4 hours at 25 °C. Water was added and the product extracted into ethyl acetate. The organic phase was concentrated in vacuo and the residue purified by chromatography (SiO 2 , ethyl acetate ⁇ sohexane 1 :4 as eluant) to afford the title compound (O.lg).
  • step b) 0.4 lg in anhydrous tetrahydrofuran (10ml) was added benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.39g) followed by N,N-diisopropylethylamine (0.1 lg) and the resultant solution was stirred at room temperature for 40 minutes. The reaction mixture was then treated with a 70% solution of aqueous ethylamine (0.5ml) and stirring continued for a further 1 hour at room temperature.
  • Human venous blood (100 ml) was divided equally between 3 tubes, each containing 3.2% trisodium citrate (4 ml) as anti-coagulant.
  • the tubes were centrifuged for 15 minutes at 240G to obtain a platelet-rich plasma (PRP) to which 300 ng/ml prostacyclin was added to stabilize the platelets during the washing procedure.
  • PRP platelet-rich plasma
  • Red cell free PRP was obtained by centrifugation for 10 minutes at 125G followed by further centrifugation for 15 minutes at 640G.
  • CFT Calcium Free Tyrode solution (10 ml) (CFT), composition: NaCl 137mM, NaHCO 3 11.9mM, NaH 2 PO 4 0.4mM, KC1 2.7 mM, MgCl 2 1.1 mM, dextrose 5.6 mM, gassed with 95% O 2 /5% CO 2 and maintained at 37°C.
  • CFT Calcium Free Tyrode solution
  • the pooled suspension was centrifuged once more for 15 minutes at 640G.
  • Pi-agonist activity of compounds were added to give final concentrations of 0.2 mg/ml (60 ⁇ l of 10 mg/ml solution of clottable protein in saline) and 300 nM (10 ⁇ l of 15 mM solution in 6% glucose), respectively. Platelets or buffer as appropriate were added in a volume of 150 ⁇ l to the individual wells of a 96 well plate. All measurements were made in triplicate in platelets from each donor. The agonist/antagonist potency was assessed as follows
  • the absorbance of each well in the plate was read at 660 nm to establish a baseline figure.
  • Saline or the appropriate solution of test compound was added to each well in a volume of 10 ⁇ l to give a final concentration of 0, 0.01 , 0.1 , 1 , 10 or 100 mM.
  • the plate was then shaken for 5 min on an orbital shaker on setting 10 and the absorbance read at 660 nm. Aggregation at this point was indicative of agonist activity of the test compound.
  • Saline or ADP (30 mM; 10 ⁇ l of 450 mM) was then added to each well and the plate shaken for a further 5 min before reading the absorbance again at 660 nm.
  • Antagonist potency was estimated as a % inhibition of the control ADP response to obtain an IC 50 .
  • Compounds exemplified have pIC 5 o values of more than 5.0.

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  • Animal Behavior & Ethology (AREA)
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  • Saccharide Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés à base de ribose de la formule (I) et leur utilisation en tant que médicaments. Elle concerne des compositions contenant ces composés et des méthodes de préparation desdits composés.
EP00980179A 1999-11-15 2000-11-14 Nouveaux composes a base de ribose Withdrawn EP1232172A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9904128A SE9904128D0 (sv) 1999-11-15 1999-11-15 Novel compounds
SE9904128 1999-11-15
PCT/SE2000/002230 WO2001036438A1 (fr) 1999-11-15 2000-11-14 Nouveaux composes a base de ribose

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EP1232172A1 true EP1232172A1 (fr) 2002-08-21

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EP (1) EP1232172A1 (fr)
JP (1) JP2003514827A (fr)
AU (1) AU1747501A (fr)
SE (1) SE9904128D0 (fr)
WO (1) WO2001036438A1 (fr)

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US7335648B2 (en) 2003-10-21 2008-02-26 Inspire Pharmaceuticals, Inc. Non-nucleotide composition and method for inhibiting platelet aggregation
JP2007509180A (ja) 2003-10-21 2007-04-12 インスパイアー ファーマシューティカルズ，インコーポレイティド 疼痛を治療するための、非ヌクレオチド組成物および方法
US7749981B2 (en) 2003-10-21 2010-07-06 Inspire Pharmaceuticals, Inc. Drug-eluting stents coated with non-nucleotide P2Y12 receptor antagonist compound
US7504497B2 (en) 2003-10-21 2009-03-17 Inspire Pharmaceuticals, Inc. Orally bioavailable compounds and methods for inhibiting platelet aggregation
US7368438B2 (en) 2003-10-21 2008-05-06 Inspire Pharmaceuticals, Inc. Non-nucleotide compositions and method for inhibiting platelet aggregation
JP2005287503A (ja) * 2004-04-01 2005-10-20 Aventis Pharma Deutschland Gmbh ＴＡＦＩ−Ｉｌｅ３４７多型を決定することによって血栓形成性障害に関する危険性を同定する方法
US7932376B2 (en) 2005-05-05 2011-04-26 Inspire Pharmaceuticals, Inc. Pyrimidine-based non-nucleotide composition and method for inhibiting platelet aggregation
WO2007020935A1 (fr) * 2005-08-17 2007-02-22 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour soulager la douleur, comprenant un récepteur p2y12 et/ou un bloqueur de récepteur p2y14
WO2014206187A1 (fr) 2013-06-24 2014-12-31 苏州明锐医药科技有限公司 Procédé de préparation du ticagrelor et de ses intermédiaires

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WO1998028300A1 (fr) * 1996-12-20 1998-07-02 Astra Pharmaceuticals Ltd. Derives de triazolo(4,5-d)pyrimidinyle et leur utilisation comme medicaments
SE9702772D0 (sv) * 1997-07-22 1997-07-22 Astra Pharma Prod Novel compounds
AR017014A1 (es) * 1997-07-22 2001-08-22 Astrazeneca Ab Compuestos de triazolo [4,5-d]pirimidina, composiciones farmaceuticas, uso de los mismos para preparar medicamentos y procesos para la preparacionde dichos compuestos

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WO2001036438A1 (fr) 2001-05-25
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AU1747501A (en) 2001-05-30

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