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WO2005051934A1 - Composes antithrombotiques a fonction double - Google Patents

Composes antithrombotiques a fonction double Download PDF

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Publication number
WO2005051934A1
WO2005051934A1 PCT/SI2004/000040 SI2004000040W WO2005051934A1 WO 2005051934 A1 WO2005051934 A1 WO 2005051934A1 SI 2004000040 W SI2004000040 W SI 2004000040W WO 2005051934 A1 WO2005051934 A1 WO 2005051934A1
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Prior art keywords
group
amino
benzyl
coor
oxo
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Inventor
Danijel Kikelj
Petra Stefanic Anderluh
Janez Mravljak
Marija Sollner Dolenc
Marko Anderluh
Mojca Stegnar
Andrej Prezelj
Slavko Pecar
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Lek Pharmaceuticals dd
Univerza Ljubljana v Fakulteta za Farmazijo
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Lek Pharmaceuticals dd
Univerza Ljubljana v Fakulteta za Farmazijo
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • 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
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical industry and relates to new heterocyclic mimetics of tripeptides Arg-Gly-Asp and D-Phe-Pro-Arg that inhibit binding of fibrinogen to platelet fibrinogen receptor and simultaneously inhibit serine proteases of the blood coagulation cascade.
  • Compounds of the present invention possess antithrombotic activity due to their inhibition of platelet aggregation and inhibition of blood coagulation.
  • the invention also relates to the methods for their preparation, to pharmaceutical compositions containing them and to their therapeutic use.
  • Cardiovascular diseases represent the most frequent reason for hosp/tal/zation and mortality in the western world.
  • Current therapy of cardiovascular complications applies anticoagulant drugs including unfractioned and fractioned heparins and antagonists of vitamin , and antiaggregatory drugs such as acetyisaiicyiic acid, ti opidine, clopidogrel and dipiridamol.
  • Heparins exert indirect inhibition of coagulation factors by potentiating inhibitory action of endogenous antithrombin III. They have to be administered several times per day due to their narrow therapeutic window and low plasma half-life. Additionally, they express a weak correlation of dose to anticoagulant effect; therefore laboratory monitoring of coagulation parameters during treatment is indispensible.
  • Indirect anticoagulants express high variations in dose- response relationship, therefore treatment must be accompanied with monitoring of coagulation parameters. In addition, they possess various side effects and interact with other therapeutic agents.
  • Acetyisaiicyiic acid is the most frequently used antiaggregatory compound. It acts by irreversible acetylation of serine hydroxy group in the enzyme cyclooxygenase and in this way blocks the transformation of arachidonic acid and TXA 2 formation.
  • acetyisaiicyiic acid can not inhibit the activation of platelets through other signal pathways and can not assure the complete inhibition of platelet activation.
  • New approaches in the development of novel antithrombotic agents focus on various new targets (i) involved in inhibition of formation of thrombin as the main prothrombotic factor in the coagulation cascade, (ii) involved in effective inhibition of the platelet activation and platelet aggregation.
  • inhibitors of coagulation cascade serine proteases and antagonists of the fibrinogen receptor receive the greatest research attention. Due to the presented disadvantages of antithrombotic drugs currently used in therapy there is a great need for novel antithrombotic agents, which should be effective, safe and administered orally.
  • the possible solution to this problem represent antithrombotic compounds with dual function that inhibit the binding of fibrinogen to the fibrinogen receptor and simultaneously inhibit coagulation cascade serine proteases.
  • Fibrinogen receptor (integrin ⁇ n b ⁇ 3 ) is a transmembrane heterodimeric glycoprotein from the family of integrin receptors, which is found predominantly on the surface of platelets. It is composed of non-covalently attached ⁇ and ⁇ subunits, where the ⁇ /-terminal domains of both subunits form the extracellular part of the receptor with the ligand-binding site, whereas the shorter intracellular C-terminal domains, which represent the place for interaction of cellular signal proteins with a membrane, enable signalization processes through the membrane.
  • fibrinogen receptor In normal physiological conditions fibrinogen receptor is in the resting state. Under the influence of various agonists, which are released form endothelial cells and platelets during tissue injury the fibrinogen receptor is activated. The activation results in the conformational change of the receptor and consequently its higher binding affinity for fibrinogen. Fibrinogen binds to its receptor at the surface of platelets and thus connects adjacent platelets leading to thrombus formation.
  • thrombin Parallel to platelet aggregation runs the process of blood coagulation through the action of coagulation cascade serine proteases.
  • Coagulation factors are responsible for cascade-like activation of other factors in the coagulation cascade what in turn leads to factor Xa and thrombin formation, respectively.
  • Thrombin cleaves fibrinogen to form fibrin and thus enables the cross-linking of fibrin monomers and the formation of mechanically stable blood clot.
  • Thrombin additionally activates FXIII, which additionally stabilizes fibrin polymer and activates prothrombin, FV, FVIII and FXI, thus creating a positive feed-back process responsible for the amplification mechanism, which is needed for quick respose and effectiveness of the coagulation process.
  • Thrombin also activates protein C as as inhibitory mechanism of hemostasis. Thrombin influences activation of platelets for further adhesion and aggregation. Thrombin has a series of cellular effects in the process of tissue reparation. Due to its central role in the hemostatic process, thrombin is an attractive target for design of new agents for cardiovascular therapy. In the development of new antithrombotic agents, other serine proteases of the coagulation cascade, especially factor Xa, are of great interest as well.
  • Factor Xa expresses its proteolytic activity in the starting part of the amplification mechanism of the coagulation cascade, therefore in the coagulation process the plasma level of factor Xa is lower compared to the level of thrombin and thus lower plasma level of inhibitor is needed for successful inhibition.
  • fibrinogen receptor antagonists and thrombin inhibitors are the key peptide sequences of their natural substrates: RGD (Arg-Gly-Asp) sequence for the fibrinogen receptor antagonists and D-Phe-Pro-Arg sequence for thrombin inhibitors.
  • RGD Arg-Gly-Asp
  • D-Phe-Pro-Arg sequence for thrombin inhibitors.
  • Peptide nature of both lead compounds is the reason for low bioavailability, metabolic instability and low selectivity of the peptide ligands prepared on this basis for modulation of the hemostasis processes.
  • Development of fibrinogen receptor antagonists has therefore turned form simple linear and cyclic peptides to peptidomimetic compounds.
  • new fibrinogen receptor antagonists with non-peptide heterocyclic (benzofurane, thiazole, izoxazole, indole, benzodiazepine, benzimidazole, benzopirane etc.) scaffolds bearing the crucial pharmacophoric groups were developed.
  • Benzamidine or various cyclic amines are used most frequently as an arginine mimetic and as an aspartate mimetic different more or less complex fragments bearing the carboxylate group are applied. In this way a great number of highly efficient and highly selective fibrinogen receptor antagonists were developed among which many are active after peroral administration.
  • Tirofiban is a representative low-molecular weight non-peptide fibrinogen receptor antagonist used in therapy of acute coronary syndrome.
  • Thrombin inhibitors were designed on the basis of the peptide sequence D-Phe-Pro-Arg and the known structure of the thrombin active site (Bode W., Mayr I., Baumann U., Huber R., Stone S. R., Hofsteenge J. EMBO J. 1989, 8, 3467-3475). It is well known that basic P1 inhibitor residues bind to the S1 pocket; smaller lipophilic residues bind to S2 pocket and larger lipophilic residues bind to S3 pocket of the thrombin active site.
  • the covalent inhibitors which form a covalent bond in the active site with Ser 195.
  • thrombin inhibitors Due to their low selectivity towards other serine proteases and slow binding kinetics they were not suitable for therapeutic use. Further trends in the development of thrombin inhibitors led to reversible low-molecular weight thrombin inhibitors.
  • peptide analogues were designed, which were followed by various peptidomimetic analogues. Non-peptide compounds possess higher metabolic stability towards peptidases, higher lipophilicity and consequently higher bioavailability (Rewinkel, J. B. M.; Adang, A. E. P. Curr. Pharm.Des. 1995, 5, 1043-1075; Tucker, T.; Isaacs, C. A. JAI Press Inc. 1999, 2, 53-87; Sanderson, P. E. J.; Med. Res. Rev.
  • An object of the invention is, therefore, to provide novel compounds suitable for the use in therapy or in manufacturing novel medicaments.
  • A is O, S, NH or CH 2 ;
  • R1 is selected from H, branched or unbranched C1-C4 alkyl, benzyl group or group
  • R is H, branched or unbranched C1-C4 alkyl or benzyl
  • R2 is H, COOR, CONHR or substituent K, which is selected from the moieties
  • X is CONH, NHCO, CH 2 NH, NHCH 2 , OCH 2 or CH 2 O;
  • Y is CO or CH 2 .
  • R52 is a group or a group COOR ,
  • R62 is R, COOR or a group NHz wherein R in R1 are as defined above;
  • R3 is H, branched or unbranched C1-C4 alkyl, benzyl, OH, COR or substituent L, which is selected from the moieties
  • Z is CO, CH 2 , a group CH 2 CONH bound at N atom of the bicycle by the CH 2 CO fragment or a group CH 2 CONHCH 2 bound at N atom of the bicycle by the CH 2 CO fragment;
  • W is (CH 2 ) n , (CH 2 ) n CO or CO(CH 2 ) n group, where n is 1 , 2, 3 or 4
  • R53 is a group or a group -COOR , -R1
  • R63 is R, COOR or a group NH;! wherein R in R1 are as defined above;
  • R4 is a moiety bound at position 6 or 7 of the bicycle and is selected from H, a group Q-CH(R7)-COOR, Q-CH(R7)CH 2 COOR, Q-CH(R7)-CONH-(R9) or substituent M, which can be selected from
  • Q is a group CON(R8), N(R8)CO, CH 2 N(R8), N(R8)CH 2;
  • Y is CO or CH 2;
  • R7 is H, branched or unbranched C1-C4 alkyl, benzyl, C4-C6 cycloalkyl, phenyl or benzyl;
  • R8 is H or a group -[CH 2 ] n COOR, where n is 0, 1 , 2, 3 or 4, and the substituent R has the above defined meaning;
  • R9 is a group CH(R10)COOR or a group CH 2 CH(NHSO 2 C 6 H 4 -4-R)COOR , where R has the above defined meaning and wherein
  • R10 means a group R, a group CH 2 COOR or a group CH 2 CH 2 COOR with R as defined above;
  • R54 is a group , a group or a group -COOR
  • R64 is R, COOR or a group wherein R in R1 are as defined above;
  • R52 is a group , then R4 is H, and the groups R53 and R63 are COOR, whereby R63 can not be COOH;
  • R54 and R64 are COOR, whereby R64 can not be COOH and R3 can not be the group L;
  • R53 is a group , then R4 is H, the groups R52 and R62 are COOR, whereby R62 can not be COOH;
  • R54 and R64 are COOR, whereby R64 can not be COOH, and R2 can not be the group K;
  • R54 is a group then R52 and R62 are COOR, whereby R62 can not be COOH, and R3 can not be the group L;
  • R53 and R63 are COOR, whereby R63 can not be COOH, and R2 cannot be the group K.
  • the compounds of the invention possess one or more chiral centres, where the absolute configuration is R or S.
  • the compounds can also appear in the form of racemates, racemic mixtures, pure enantiomers, pure diastereomers or mixtures of diastereomers.
  • the invention also includes pharmaceutically acceptable salts of compounds of formula
  • the pharmaceutically acceptable salts of the cmpounds of formula (I) include the conventional non-toxic salts or the quaternarymonium salts which are formed, e.g. from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, hydrobromide, hydrochloride, hydroiodide, lactate, maleate, methanesulfonate,acitinate, nitrate, oxalate, pamoate, 3- phenylpropionate, picrate, pivalate, propionate, pectinate, succinate, sulfate, tartrate, thio
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, N-methyl-D-glucamine and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, dialkylsulfates, and diamylsulfates, long chain halides, aralkyl halides and others. The selection of the inorganic or organic acids or bases should not be restricted by these examples.
  • the invention also relates to processes for the preparation of compounds of general formula (I).
  • the starting heterocyclic compounds for the synthesis of compounds of the present invention may be prepared according to the known synthetic procedures.
  • Ethyl 4-[(2,2-dichloroacetyl)amino]-3-hydroxybenzoate (39) may be prepared from ethyl 4-amino-3-hydroxybenzoate (38) by acylation with dichloroacetyl chloride (March, J. Advanced organic chemistry. Reactions, mechanisms and structure. John Wiley & Sons, Inc., New York, 4th Ed, 1992, 417-419) and subsequent cyclization in alkaline medium. (Honkanen, E.; Virtanen, A. I. Acta Chem. Scand. 1960, 14, 504-507).
  • Ethyl 2-hydroxy-4-methyl-3-oxo-3,4-dihydro-2W-1 ,4-benzoxazine-7- carboxylate (41) may be prepared by alkylation of ethyl 2-hydroxy-3-oxo-3,4-dihydro-2H- 1 ,4-benzoxazine-7-carboxylate (40) with dimethyl sulfate in the presence of potassium carbonate in acetone (Bourlot, A.-S.; Sanchez, I.; Dureng, G.; Nicolast, G.; Massingham, R.; Monteil, A.; Winslow, E.; Pujol, M. D.; Merour, J.-Y. J. Med. Chem.
  • Ethyl esters may be prepared according to the method of classical acid-catalyzed esterification in absolute ethanol in the presence of concentrated H 2 SO 4 (March, J. Advanced Organic Chemistry. Reactions, mechanisms and structure. John Wiley & Sons, Inc., New York, 4th Ed, 1992, 393-396).
  • the ether 42 may be prepared from alcohol 40 and 4-(bromomethyl)bezonitrile in the presence of potassium fluoride in DMF.
  • the reduction of nitro groups to the amino groups for the preparation of compounds 4 and 38 may be performed, as generally known in the art, by catalytic hydrogenation with palladium on activated charcoal as a catalyst.
  • Reduction of the nitro group in the synthesis of 3-oxo-3,4-dihydro-2 -/-1 ,4-benzoxazine-7-carbaldehyde (27) may be performed with stannous (II) chloride in ethanol.
  • the hydrolysis of esters may be performed by alkaline hydrolysis, as generally known in the art.
  • 2-Benzyl 3-methoxy-3-oxopropanoic acid (7) may be prepared by alkylation of benzyl methyl malonate (5) according to a modified literature procedure (Chorew, M.; Goodman, M. Int J. Peptide Proteine Res. 1983, 21, 258-268.) followed by catalytic hydrogenation of 2-benzyl benzyl methyl malonate (6).
  • compositions of the formula (I) may be prepared by treatment of compounds of formula I with the suitable acids or bases according to procedures, which are generally known in the art.
  • the invention further provides the use of compounds of the formula (I) for manufacturing of medicaments which inhibit coagulation factors thrombin and factor Xa, fibrin formation and blood clots formation.
  • the subject of the invention are also pharmaceutical compositions comprising compounds of the formula (l) and use thereof in therapy as antithrombotic agents.
  • Compounds of the invention may be applied in the form of injections or products for oral use, whereby these can be prepared in forms with controlled or sustained release of the active agent. Besides the active compound these products may contain standard pharmaceutical excipients. The dose, type and the frequency of administration depend on the specific compound and its pharmacokinetic properties and the condition of the patient.
  • the compounds of the present invention are antagonists of fibrinogen receptor and inhibitors of thrombin and factor Xa. They inhibit platelet aggregation by inhibition of fibrinogen binding to platelets and inhibit the formation of mechanically stable blood clot by inhibition of thrombin and factor Xa in the secondary hemostasys process. They may be used for prevention and treatment of arterial and venous thrombosis, ischemic stroke, peripheral arterial disease, acute coronary syndrome, pulmonary embolism and for prevention of systemic embolism in cardiac patients, ischemic complications in patients with surgery, e.g. prevention of occlusion in arterial recanalization, for prevention of blood coagulation in extracorporal circulation and hemodialysis.
  • Enzyme amidolytic method for determination of inhibitory activity of serine proteases is based on the spectrophotometric determination of absorbance of the product, which is formed after amide bond cleavage in the presence of the enzyme.
  • a serine protease cleaves the chromogenic substrate giving the yellow coloured p-nitroaniline as a product.
  • the concentration of the released p-nitroaniline correlates with the enzyme activity and is proportional to the absorbance measured at 405 nm.
  • Inhibitor which binds to the active site of the enzyme, inhibits the enzymatic cleavage of the substrate resulting in the decrease of the amidolytic activity of the enzyme.
  • IC 50 and Ki which represent the quantitative measure of inhibitor potency, are determined by spectrophotometric measurement of enzyme kinetics without and with the addition of the inhibitor. (Cheng, Y. O; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108). Determination of inhibitory activity against all serine proteases is based on the same principle. The procedures differ in the type and the procedure for preparation of the corresponding serine protease and their chromogenic substrates. Because of the high degree of the structural similarity in the coagulation factors thrombin and factor Xa compared to trypsin, the measurement of inhibitory potency of the tested inhibitors on trypsin inhibition is performed in order to determine their selectivity.
  • Thrombin preparation The content of the reagent flask is diluted with distilled water to obtain the solution with activity 20 NIH unit/mL. The solution is divided in portions of 0.5 mL and stored at -70°C. Immediately before use, the stock solution with the activity 2 NIH unit/mL is prepared with HBSA buffer. The final thrombin activity in the microtiter plate is 0.5 NIH units/mL
  • Factor Xa preparation The content of the reagent flask is diluted with distilled water to obtain the solution with activity 10 nkat/mL. The solution is divided in portions of 0.5 mL and stored at -20°C. Immediately before use, the stock solution with the activity 2 nkat/mL is prepared with HBSA buffer. The final factor Xa activity in the microtiter plate is 0.5 nkat/mL.
  • Trypsin preparation The content of the reagent flask is diluted with distilled water to obtain the solution with activity 300 E/mL. The solution is divided in portions of 0.2 mL and stored at -70°C. Immediately before use, the stock solution with the activity 4 mE/mL is prepared with HBSA buffer. The final typsin activity in the microtiter plate is 1 mE/mL.
  • Preparation of thrombin chromogenic substrate 1 mM solution of the substrate is prepared, divided into portions of 0.5 L and stored at -20°C. Immediately before use, substrate solutions with concentrations 80 and 160 ⁇ M are prepared. The final substrate concentrations in the microtiter plate are 20 and 40 ⁇ M.
  • Preparation of factor Xa chromogenic substrate 2 mM solution of substrate is prepared, divided into portions of 0.3 mL and stored at -20°C. Immediately before use, substrate solutions with concentrations 400 and 800 ⁇ M are prepared. The final substrate concentrations in the microtiter plate are 100 and 200 ⁇ M.
  • Preparation of trypsin chromogenic substrate 2 mM solution of substrate is prepared, divided into portions of 0.3 mL and stored at -20°C. Immediately before use, substrate solutions with concentrations 200 and 400 ⁇ M are prepared. The final substrate concentrations in the microtiter plate are 50 and 100 ⁇ M.
  • HBSA buffer 10 mM Hepes buffer, 150 mM NaCl and 0,1% (w/v) bovine serum albumin are diluted in bidistilled water and pH adjusted with 0.1 M NaOH solution.
  • Inhibitors are dissolved in DMSO to give a 10 mM stock solution.
  • the solutions with concentrations from 10 to 100 ⁇ M are prepared with distilled water.
  • the concentration of DMSO in microtiter plate should not exceed 3%.
  • Measurements measurements are carried out with two inhibitor concentrations and two concentrations of the substrate. The rate of reaction without the inhibitor and with inhibitor is measured. 50 ⁇ M HBSA buffer, 50 ⁇ M solution of different inhibitor concentrations and 50 ⁇ M serine protease solution is pipetted into the microtiter plate. The plate is incubated for 15 minutes at 25°C and subsequently 50 ⁇ M chromogenic substrate is added. The microtiter plate is put into the spectrophotometer (Tecan, Sunrise) and the increase of absorbance at wavelength 405 nm and at 25°C is measured every 10 seconds.
  • spectrophotometer Tecan, Sunrise
  • Inhibitory constant Ki is determined from the change of absorbance form the initial, linear part of the curve according to the method of Cheng and Prusoff.
  • the inhibition constant Ki is calculated by the equation:
  • Measurements are carried out with two combinations of the inhibitors and two concentrations of the substrate. For every combination of concentrations Ki is calculated, and as a final result given as their average value. The result can also be given as the IC 50 value which represents the concentration of the inhibitor that decreases the activity of the enzyme to 50% of the initial value.
  • the method is based on the measurement of chemiluminiscence produced in the enzyme- catalysed reaction.
  • the test is performed on microtiter plates with bound fibrinogen receptor.
  • the solutions of natural agonist (biotinylated fibrinogen) and the tested antagonist are added so that the competitive process of binding to the receptor may occur.
  • antibodies with conjugated horseradish peroxidase against biotin, which bind to biotinylated fibrinogen is added, followed by addition of specific substrate for peroxidase.
  • the substrate is chemically transformed with concomitant light emmition and its intensity is measured by luminometer.
  • the intensity of the emitted light is proportional to quantity of bound agonist (biotinylated fibrinogen) and the ratio of binding of antagonist against agonist is proportional to binding affinities of fibrinogen and antagonist.
  • ENZYME IMMUNOASSAY The integrin solution is poured off the plate and free binding sites blocked with 1 % BSA solution in Tris buffer (200 ⁇ L/well) for 1 hour at room temperature. The plates are washed with Tris buffer containing 0.01% Tween 20. The solutions of antagonists with concentrations 200 ⁇ M, 60 ⁇ M, 20 ⁇ M, 6 ⁇ M, 2 ⁇ M, 0.6 ⁇ M, 0.2 ⁇ M, 0.06 ⁇ M and 0.02 ⁇ M are prepared by diluting the starting 10 mM solutions in DMF with Tris buffer.
  • the plates are washed three times with Tris buffer containing 0.01% Tween 20. Subsequently chemiluminiscence reagent (50 ⁇ L) is added and in 15 minutes the emmited light is measured (using Tecan Genios and Magellan (Version 3.0) software). The measurement is perfomed three times.
  • IC 50 is an inhibitor concentration, which results in 50% inhibition of fibrinogen binding to the receptor.
  • the reaction mixture was stirred for 30 min at -10 °C, then the temperature of the reaction mixture was allowed to raise to room temperature.
  • the reaction mixture was washed with 10 % citric acid (2 x 20 mL), dried with Na 2 SO 4 and the solvent evaporated under reduced pressure.
  • the reaction mixture was cooled and the solvent was evaporated under reduced pressure.
  • Triethylamine (0.20 mL, 0.56 mmol) and a solution of ethyl chloroformate (0.152 g, 1.403 mmol) in dry dichloromethane (5 mL) were added.
  • the reaction mixture was stirred for 30 min at -10 °C , then the temperature of the reaction mixture was allowed to raise to room temperature.
  • the reaction mixture was washed with 10 % citric acid (2 x 20 mL), dried with Na 2 SO 4 and the solvent evaporated under reduced pressure.
  • the intermediate was cyclized in refuxing toluene until the completed reaction was detected by TLC.
  • the reaction mixture was cooled and the solvent was evaporated under reduced pressure.
  • the obtained iminoether was dissolved in absolute EtOH (40 mL), ammonium acetate (0.57 g, 7.42 mmol) was added and the reaction mixture stirred for 4 days. The solvent was then evaporated to 1/3 of the starting volume and the residual solution stored at 4° C.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I) suivante : (I) et des sels de ceux-ci répondant aux normes pharmaceutiques, dans lesquels les substituants présentent dans les descriptions une signification spécifiée. Ces composés sont utilisés comme agents antithrombotiques possédant une activité inhibitrice sur l'agrégation plaquettaire et une activité inhibitrice de thrombine et de facteur Xa simultanée.
PCT/SI2004/000040 2003-11-28 2004-11-26 Composes antithrombotiques a fonction double Ceased WO2005051934A1 (fr)

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SIP-200300287 2003-11-28
SI200300287A SI21658A (sl) 2003-11-28 2003-11-28 Antitrombotične učinkovine z dualnim mehanizmom delovanja na osnovi 3,4-dihidro-2H-1,4-benzoksazinskega skeleta

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102920709A (zh) * 2012-11-15 2013-02-13 山东大学齐鲁医院 2,3-二氢-3-羟甲基-6-甲基-[1,4]-苯并噁嗪在制备抗乳腺癌药物中的应用
US9101634B2 (en) 2010-05-20 2015-08-11 Shandong University Application of 2, 3-dihydro-3-hydroxymethyl-6-amino-[1,4]-benzoxazine in preparation of drugs inducing embryonic stem cells to differentiate to vascular endothelial cells
WO2019151270A1 (fr) 2018-01-31 2019-08-08 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée

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WO1999000371A1 (fr) * 1997-06-26 1999-01-07 Boehringer Ingelheim Pharma Kg Derives phenylalkyles a effet inhibiteur de thrombine
WO1999050257A1 (fr) * 1998-03-31 1999-10-07 Warner-Lambert Company Benzoxazinones/benzothiazinones utilisees comme inhibiteurs de serines-proteases
WO2001012600A1 (fr) * 1999-08-12 2001-02-22 Cor Therapeutics, Inc. INHIBITEURS DU FACTEUR Xa
WO2001057003A1 (fr) * 2000-02-01 2001-08-09 Cor Therapeutics, Inc. 3,4-DIHYDRO-2H-BENZO[1,4]OXAZINES UTILISEES COMME INHIBITEURS DU FACTEUR Xa

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999000371A1 (fr) * 1997-06-26 1999-01-07 Boehringer Ingelheim Pharma Kg Derives phenylalkyles a effet inhibiteur de thrombine
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US9101634B2 (en) 2010-05-20 2015-08-11 Shandong University Application of 2, 3-dihydro-3-hydroxymethyl-6-amino-[1,4]-benzoxazine in preparation of drugs inducing embryonic stem cells to differentiate to vascular endothelial cells
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WO2019151270A1 (fr) 2018-01-31 2019-08-08 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée
KR20200115491A (ko) 2018-01-31 2020-10-07 도레이 카부시키가이샤 환상 아민 유도체 및 그 의약 용도

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