WO2008140220A1 - Inhibiteurs du facteur xa comprenant des amidines cycliques en tant que sous-unité p4, leurs procédés de préparation, et compositions pharmaceutiques et dérivés de ceux-ci - Google Patents

Inhibiteurs du facteur xa comprenant des amidines cycliques en tant que sous-unité p4, leurs procédés de préparation, et compositions pharmaceutiques et dérivés de ceux-ci Download PDF

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WO2008140220A1
WO2008140220A1 PCT/KR2008/002619 KR2008002619W WO2008140220A1 WO 2008140220 A1 WO2008140220 A1 WO 2008140220A1 KR 2008002619 W KR2008002619 W KR 2008002619W WO 2008140220 A1 WO2008140220 A1 WO 2008140220A1
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compound
mmol
chemical formula
alkyl
preparation
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PCT/KR2008/002619
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Inventor
Young Lag Cho
Ho Young Song
Dae Yon Lee
Sung Yoon Baek
Sang Eun Chae
Sang Hui Jo
Yeon Ok Kim
Hyang Sook Lee
Ju Hyun Park
Tae Kyo Park
Sung Ho Woo
Yong Zu Kim
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Legochem Bioscience Ltd.
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Priority claimed from KR1020080042740A external-priority patent/KR101009594B1/ko
Application filed by Legochem Bioscience Ltd. filed Critical Legochem Bioscience Ltd.
Priority to US12/598,010 priority Critical patent/US8288423B2/en
Publication of WO2008140220A1 publication Critical patent/WO2008140220A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 present invention relates to novel oxazolidinone derivatives with cyclic amidines, represented by Chemical Formula (1), and prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof, and processes for preparing the same, and pharmaceutical compositions comprising the same .
  • A is selected from the following structures .
  • the antithrombotic and anticoagulant activities of the novel oxazolidinone derivatives with cyclic amidines, represented by Chemical Formula (1) according to the present invention result from inhibition against activated coagulation protease known as factor Xa, or inhibition of other activated serine proteases such as factor Xa, factor IXa or thrombin.
  • the blood coagulation factors are distributed in plasma, with various types of factors from 1 st coagulation factor to 13 th coagulation factor working sequentially to result in blood coagulation.
  • the mechanism wherein individual blood coagulation factors participate in blood coagulation is shown in Fig. 1.
  • blood coagulation is accomplished through very delicate and complex processes wherein reactions occur sequentially.
  • inactive precursors are activated by certain activated coagulation factors (indicated by "a" at the end of the designation of the coagulation factor) , and then the coagulation factors are activated.
  • Most of the activated coagulation factors are enzymes called serine protease. These bind to the surface of platelets to sequentially activate the blood coagulation factors to finally create fibrin clot to complete hemostasis.
  • Thrombin plays the most important role among them. Thrombin is activated from prothrombin (the precursor) via prothrombinase complex consisting of Va factor, Xa factor, Ca++ and phospholipids (PL) . When fibrinogen is converted into fibrin thereby, fibrins are crosslinked by the activated XIIIa factor to finally provide stabilized fibrin clot.
  • prothrombin the precursor
  • prothrombinase complex consisting of Va factor, Xa factor, Ca++ and phospholipids (PL) .
  • PL phospholipids
  • X factor In order to form prothrombinase complex, X factor should be activated to Xa factor; this occurs by means of factor Xase complex.
  • Factors produced via intrinsic pathway such as Villa factor, IXa factor, Ca++ and phospholipids (PL) , or factors produced via extrinsic pathway such as Vila factor, tissue factor (TF) and Ca++ serve as the factor Xase complex.
  • thrombin functions to activate V factor and VIII factor. If thrombin is excessively generated, problem of vaso-occlusion may occur. In order to control such a problem, thrombin would run a process for inhibiting blood coagulation. Thus, thrombin binds to thrombomodulin to activate protein C to generate protein Ca, which will bind to protein S to inactivate the activated Va and Villa factors.
  • Factor Xa is one of the proteases associated with complex processes of blood coagulation, catalyzing conversion of prothrombin into thrombin. Thrombin crosslinks with fibrinogen, and then decompose it into fibrin monomer which essentially contributes thrombus formation. Activation of thrombin may induce thromboembolism. However, inhibition of thrombin may inhibit formation of fibrin which is associated with thrombus formation. Thus, inhibition of factor Xa may prevent formation of thrombin, and the compounds of Chemical Formula (1) according to the present invention and salts thereof inhibit factor Xa, to participate in the processes of blood coagulation, thereby inhibiting thrombus formation.
  • protein inhibitors are antistasin (ATS) , tick anticoagulant peptide (TAP) , and the like.
  • ATS is a compound consisting of 119 amino acids, obtained from leeches, having Ki value for factor Xa of 0.05 nM
  • TAP tick anticoagulant peptide
  • ATS is a compound consisting of 119 amino acids, obtained from leeches, having Ki value for factor Xa of 0.05 nM
  • TAP is a compound consisting of 60 amino acids having Ki value for factor Xa of 0.5 nM.
  • Those protein inhibitors are not employed in clinical practices at present, while heparin, sulfated polysaccharides, or the like is rarely employed with limitation.
  • Factor Xa inhibitors employing indole derivatives are described in WO9933800.
  • Various types of factor Xa inhibitors have been reported, including nitrogen-containing heterocyclic compounds (WO2004058743) , imidazole derivatives (WO2004050636) , pyrazole derivatives (WO2004056815) , indole-2 -carboxamide derivatives (WO2003044014) , oxybenzamide derivatives (WO2002051831) , guanidine and amidine derivatives (WO2002046159) , amino- bicyclic pyrazinone and pyridinone derivatives (WO2004002405) .
  • those low molecular compounds have to overcome the problems to meet stability in plasma and liver, selectivity from other serine proteases (thrombin, trypsin, cathepsin G, or the like) , low toxicity and high bioavailability, as well as high pharmaceutical activity.
  • factor Xa inhibitors using Apixaban derivatives represented by Chemical Formula (C) with cyclic amidine group being incorporated or sulfonyl amidine derivatives represented by Chemical Formula (D) were disclosed in WO 2004/83174.
  • oxazolidinone derivatives with cyclic amidines have not been used in this regard.
  • amidoximes is ximelagatran. Such a tendency is equivalently observed in the studies on FXa inhibitors as well as on thrombin inhibitors. When such various trials face limitations, incorporation of neutral Pl group has been rather tried. However, being different from other drug substances, FXa and thrombin inhibitors are advantageous as the blood concentration increases, and the free drug concentration, without binding with protein in blood, is a very important field. In case of neutral Pl group inhibitor, the pharmacological effect rarely appears because the protein binding is relatively high.
  • the present inventors tried to incorporate a relatively polar group at the other site of the inhibitor, instead of limiting Pl group to neutral groups, in order to 1) improve water solubility and 2) lower the protein binding.
  • Lowered protein binding usually provides beneficial effects in PT assay. Practically, lowered protein binding can be indirectly checked by excellent PT value, in spite of relatively low binding affinity to FXa.
  • the inventors have proceeded with the studies for increasing pharmacological effect by reducing the protein binding.
  • the position for incorporation of polar group according to the invention is P4 site.
  • the theoretical background is described below.
  • the S4 site of FXa comprises the binding site of " c "-shape with three sides have been surrounded by Tyr99, Phel74 and Trp215. Since the binding site consists only of aromatic amino acid side chains, it is basically different from thrombin surrounded by Leu99, Ilel74 and Trp215. During the course of drug design, such differences are positively utilized.
  • the S4 pocket of FXa has high tendency of interaction with cationic residue, which is usually called " ⁇ -cation interaction" .
  • some inhibitors have been designed and synthesized as a positively charged group at P4 site.
  • the present invention intends to enhance the pharmacological effect by improving water solubility and lowering the protein binding, as described above, via incorporation of cyclic amidines at P4 site.
  • the reason for selecting cyclic amidine rather than non-substituted amidine is that amidine has three NH bonds (substantially four in biological PH) so that it negatively acts in terms of drug-likeness, while a cyclic amidine having 0 to 1 NH group is advantageous from the same aspect.
  • HBA hydrogen bond acceptor
  • the present inventors synthesized novel oxazolidinone derivatives with cyclic amidines having useful properties, which can be applied to preparations of pharmaceutical formulations.
  • the oxazolidinone derivatives with cyclic amidines exhibit factor Xa- inhibiting property, they can be used for treating or preventing thrombosis, myocardial infarction, arteriosclerosis, inflammation, cerebral apoplexy, angina pectoris, recurrent stricture after angioplasty, and thromboembolism such as intermittent claudication.
  • the oxazolidinone derivatives with cyclic amidines according to the present invention may function as an inhibitor against factor Villa, factor IXa and thrombin as coagulation factors in a blood coagulation cascade.
  • the object of the invention is to provide oxazolidinone derivatives with cyclic amidines exhibiting factor Xa-inhibiting property, and prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof .
  • Another object of the invention is to provide anticoagulant pharmaceutical composition containing oxazolidinone derivatives with cyclic amidines, and prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof, as an active ingredient.
  • Still another object of the invention is to provide pharmaceutical compositions comprising oxazolidinone derivatives with a cyclic amidines, prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof, as an active ingredient, for treating or preventing thrombosis, myocardial infarction, arteriosclerosis, inflammation, cerebral apoplexy, angina pectoris, recurrent stricture, intermittent claudication, phlebothrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia or thromboembolism.
  • Still another object of the invention is to provide pharmaceutical compositions comprising oxazolidinone derivatives with a cyclic amidines, prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof, in combination with a thrombolytic drug, for treating or preventing diseases in coronary, cerebral or peripheral arteries .
  • Still another object of the invention is to provide use of oxazolidinone derivatives with cyclic amidines, prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof, as an anticoagulant for preserving blood, plasma or blood products in vitro.
  • the present invention relates to novel oxazolidinone derivatives with cyclic araidines, represented by Chemical Formula (1), and prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof, and processes for preparing the same, and pharmaceutical compositions comprising the same .
  • A is selected from the following structures:
  • X represents hydrogen or halogen
  • Y represents halogen
  • R 1 and R 2 independently represent hydrogen, (C 1 -C 7 ) alkyl
  • (C 3 -Ci 2 ) cycloalkyl a 5- to 7-membered heterocycloalkyl containing one or more heteroatom (s) selected from N, O and S,
  • R 11 and R 12 independently represent hydrogen or (Ci- C 7 ) alkyl, or they may be linked via (C 2 -C 5 ) alkylene to form a ring;
  • R 13 and R 14 independently represent hydrogen, (Ci-C 7 ) alkyl or (Ci-C 7 ) alkoxy;
  • R 21 through R 23 independently represent hydrogen or (C x - C 7 ) alkyl, m represents an integer from 0 to 3 ; and n represents an integer from 1 to 3. ]
  • oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention include compounds represented by one of Chemical Formulas (2) and (3) : [Chemical Formula 2]
  • R 1 and R 2 independently represent hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, allyl, methylcarbonyl, methylsulfonyl, or a substituent selected from the following structures; and n is 1 or 2 :
  • R 41 represents hydrogen, (Ci-C 7 ) alkyl, halo (C 1 - C 7 )alkyl or halogen.
  • oxazolidinone derivatives with cyclic amidines according to the invention can be exemplified by the following compounds, but the invention is not restricted thereto.
  • the oxazolidinone derivatives with cyclic amidines, represented by Chemical Formula (1) according to the invention are classified into compounds of type (B) and type (C) depending on the structure of Ring (A) .
  • Type (B) compounds can be synthesized according to Reaction Scheme (1)
  • type (C) compounds can be synthesized according to Reaction Scheme (2) .
  • the preparation processes described below does not restrict the processes for preparing the oxazolidinone derivatives with cyclic amidines, represented by Chemical Formula (1) according to the invention, but modififcation of the processes are obvious to a person having ordinary skill in the art. Definitions of the substituents in the Reaction Schemes are identical to those in Chemical Formula (1) , if not specified otherwise.
  • Type (B) compounds among the compounds of Chemical Formula (1) can be synthesized according to Reaction Scheme (1) below: they were synthesized via Path (A) or Path (B) depending on the type of X in Chemical Formula (1) . Most of compounds of type (B) wherein X is hydrogen were synthesized via Path B, starting from Compound (VI) . The compounds wherein X is not hydrogen were synthesized via Path (A) or Path (B) , depending upon the starting materials commercially available.
  • Type (C) compounds of Chemical Formula (1) can be synthesized as shown in Reaction Scheme (2) below.
  • Compounds (C) can be synthesized via Path (C) or Path (D) , depending upon the type of X in Chemical Formula (1) .
  • Compound (XII) was protected by Boc, and reduced by using hydrogen gas under palladium catalyst. Then the product was reacted with 2-(((S)- oxiran-2-yl) methyl) isoindoline-1, 3-dione (III) to obtain Compound (XIV).
  • the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention can be employed in the field of medicines as a pharmaceutical active ingredient for treating and preventing thrombosis, myocardial infarction, arteriosclerosis, inflammation, cerebral apoplexy, angina pectoris, recurrent stricture after angioplasty, intermittent claudication, phlebothrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina based on thrombosis or thromboembolism such as attack.
  • the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention can be used for treating or preventing atherosclerotic diseases such as diseases in coronary, cerebral or peripheral arteries.
  • the oxazolidinone derivatives with cyclic amidines can be used in combination with other thrombolytic drugs (such as Alteplase, Tenecteplase) for treatment of myocardial infarction, and they can be also used for preventing thrombolysis, reocclusion after percutaneous transluminal coronary angioplasty (PTCA) or coronary bypass surgery.
  • thrombolytic drugs such as Alteplase, Tenecteplase
  • PTCA percutaneous transluminal coronary angioplasty
  • the oxazolidinone derivatives with cyclic amidines can be also used for preventing rethrombokinesis in precise operations, or as an anticoagulant in connection with artificial internal organs or in hemodialysis.
  • the compounds may be employed for washing catheters or medical assist devices used in a patient's body, or as an anticoagulant composition for preserving blood, plasma and other blood products in vitro.
  • the compounds according to the present invention can be used for treating diseases wherein coagulation of blood significantly contributes in the course of the diseases, such as cancers including metastatic cancers, or diseases wherein coagulation makes up secondary cause of lesions, such as inflammatory disorder (including arthritis) and diabetes .
  • the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention can be used as pharmaceutically acceptable salts thereof, including acid addition salts formed with pharmaceutically acceptable free acids .
  • the free acids include both inorganic and organic acids: inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid, and organic acids such as citric acid, acetic acid, lactic acid, maleic acid, umaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4- toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid.
  • inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid
  • organic acids such as citric acid, acetic acid, lactic acid, maleic acid, umaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succ
  • Example 1 and acetic anhydride (50 mg, 0.49 mmol) were sequentially added to pyridine (2 mL) , and the mixture was stirred at ambient temperature for 8 hours.
  • the reaction mixture was dissolved in dichloromethane (10 mL) , and the solution was washed with aqueous sodium bicarbonate solution (5 mL) and dried over sodium sulfate. Concentration under reduced pressure, and preparative chromatography gave the title compound (104) (35 mg, 0.08 mmol, 32%) as white solid.
  • Example 5 was treated with hydrochloric acid according to the same procedure as Example 15 to obtain white solid.
  • the solid was dissolved in acetic acid (4 mL) , and triethylorthopropionate (2 mL) was added thereto. After stirring the mixture under reflux for 5 hours, the solvent was thoroughly evaporated under reduced pressure.
  • the residue was diluted with saturated aqueous sodium hydrogen carbonate solution (20 mL) , and the solution was extracted with dichloromethane (25 mL x 2) .
  • the combined organic layer was dried over anhydrous sodium sulfate, and filtered.
  • Hydrochloric acid (0.2 mL, 4 N in 1,4-dioxane) was added thereto, and the mixture was concentrated under reduced pressure.
  • White solid produced during this stage was washed with diethyl ether and dried to obtain the title compound (116) (70 mg, 0.15 mmol, 70%).
  • the compound (210 mg, 0.37 mmol) thus obtained was dissolved in dichloromethane (5 mL) , and hydrochloric acid (5 mL, 4 M in 1,4-dioxane solution) was added thereto. After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated under reduced pressure and dried to obtain white solid (185 mg, 0.37 mmol, 99%).
  • the compound (210 mg, 0.45 mmol) thus obtained was dissolved in acetic acid (4 mL) and the solution was stirred under reflux for 16 hours.
  • IC 50 value concentration of the compound to inhibit 50% of the enzyme activity
  • the factor Xa inhibiting activity for an oxazolidinone derivative with a cyclic amidine group represented by Chemical Formula (1) according to the invention was determined by calculating the inhibition constant Ki according to Equation (1), as described in Chen and Prusoff, Biochem. Pharmacol. (1973) 22, 3099-3108:
  • Ki IC 50 / ⁇ l+( [S] /Km) ⁇
  • Km is Michaelis-Menten constant, exhibiting concentration of the substrate at the half of the maximum rate of the enzyme reaction, and IC 50 represents concentration of the inhibitor for 50% decrease in the rate of hydrolysis of the substrate.
  • the inhibition constant Ki represents the level of inhibition by the enzyme and the factor Xa inhibitor compound
  • lower dissociation constant implies stronger binding of the inhibitor to the enzyme, and thus higher inhibiting activity.
  • the inhibition constant can be obtained by spectrophotometry whereby the color development is determined as a function of time, after being reacted with a specific substrate which develops color upon hydrolysis caused by action of factor Xa.
  • Chromogenic substrate S-2765 (N-Z-D-Arg-Gly-Arg-pNA- 2HCl required for measurement of factor Xa activity was purchased from Chromogenics .
  • Factor Xa enzyme was purchased from Enzyme Research Laboratories, and a 96-well plate for microfactor was purchased from Costar.
  • the inhibition activity of the compounds of the present invention against factor Xa activity was determined according to the following description.
  • the substrate solution S-2765 was dissolved in third-distilled water in a concentration of 10 mM, and the solution was diluted with 100 mM Tris-HCl buffer (pH 7.8) containing 150 mM of NaCl and 0.1% PEG 8000, immediately before use, to give a concentration of 1.5 mM.
  • the substrate solution (20 ⁇ L) thus prepared was added to each well.
  • Kinetic analysis of the reaction was performed by a kinetic plate reader (Molucular Devices, Spectramax 190) at 37 ° C for 20 minutes. After adding S-2765 chromogenic substrate, the amount of p-nitroanilide generated from the reaction was monitored by means of change of absorbance at 405 nm for 5 minutes.
  • Relative rate of hydrolysis (compared to control group without inhibition) versus logarithm of the oxazolidinone derivative with a cyclic amidine group (Chemical Formula 1) was plotted to obtain the concentration of the inhibitor to decrease the rate of hydrolysis of the substrate by 50%.
  • GraFit version 5.0.12 program for statistical process purchased from Erithacus Software was employed.
  • Citrated plasma was purchased from Daejeon-Chungnam Blood Institute (located at Daej eon, Korea) .
  • a compound solution (5 ⁇ L) according to the invention (in a various concentration gradient, 5% DMSO solution) was added to the plasma (45 ⁇ m) , and the reaction was carried out at 37 ° C for 5 minutes.
  • Neoplastine (Diagnostica Stago) (100 ⁇ L) was then added thereto, and the duration for plasma coagulation was measured.
  • the duration for plasma coagulation is determined as the point when the absorbance at 340 nm reaches 0.1.
  • Antithrombotic effect of the compounds according to the present invention was evaluated by using arteriovenous shunt model in white rats.
  • the animals used were male Sprague Dawleys with the body weight of 200 - 250 g. For one day before the experiment, the animals were fasted. Five to six animals were used for each test group.
  • the compound of Example was orally administered 1 hour before opening of the shunt.
  • the rats were anesthetized by abdominal administration of Rompun (Bay Healthcare) and Chloral hydrate or urethane in an amount of 12 and 50 mg per kg of the body weight.
  • a polyethylene (PE) -60 tubing filled with physiological saline was inserted and secured.
  • Both ends of individual PE tubing were connected to a silicone tubing having a length of 5 cm in which a cottom thread have been incorporated diagonally, and the shunt was open to provide circulation for 15 minutes.
  • the shunt was then compressed by using jaws, and the cotton thread was carefully removed and the thrombus generated was weighed.
  • the % inhibition of thrombus formation was calculated by using the weight of thrombus obtained from white rats of the control group to which a solution of oral administration was administered .
  • the factor Xa inhibition constant, and PT, aPTT and % inhibition values determined according to the method described above are shown in Table 1.
  • Rivaroxaban (Chemical Formula A) was used as the control substance.
  • the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the present invention showed higher Ki value than that of Rivaroxaban (the control) , but frequently lower PT values.
  • factor Xa catalyzes conversion of prothrombin to thrombin, it is prothrombinase complex which practically plays a critical role in blood coagulation in vivo, so that the inhibition of the complex eventually results in the effect of inhibiting blood coagulation.
  • PT value rather than Ki value is directly associated with % inhibition of blood coagulation.
  • the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention might have better effect of inhibiting blood coagulation than the control substance, Rivaroxaban. Further, it is proved that the oxazolidinone derivatives according to the invention exhibit comparable level of pharmacological effect to that of Rivaoxaban (the control substance) from the experiments for determination of % inhibition of thrombus formation by using arteriovenous shunt model in white rats. Therefore, a compound having similar pharmacological activity to that of Rivaoxaban with controlling side effects, particularly increased bleeding, can make a better medicine than Rivaroxaban.
  • the compounds of the present invention can be converted into their salts by using an acid such as HCl, due to high basicity of cyclic amidines, thereby significantly increasing the aqueous solubility.
  • the filtrate (160 ⁇ L) was individually transferred to a uv-96 well plate (Costar) , and mixed with 40 ⁇ L of acetonitrile, and then agitated at ambient temperature for 10 minutes with a rate of 225 rpm.
  • a plate reader Molucular Devices, Spectramax 190
  • absorbances at the wavelengths of 280, 300, 320, 340, 360 and 800 nm were measured.
  • the aqueous solubility was calculated by subtracting absorbance at 800 nm from total sum of absorbances at 280, 300, 320, 340 and 360 nm of the sample and the reference solution.
  • the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention have at least 8 times of solubility as compared to that of Rivaroxaban, with at least 20% reduction of protein binding. These results suggest that the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention may exhibit better pharmacological activity when they are clinically used in an animal's body. Since the cyclic amidines are present in the form of salts with high solubility, the oxazolidinone derivatives with cyclic amidines represented by Chemical Formula (1) according to the invention have high favorableness to be employed as oral or injectable preparations .
  • novel oxazolidinone derivatives with cyclic amidine groups according to the present invention exhibit higher Ki values than that of Rivaroxaban, with lower PT and APTT values, thereby providing even higher clinical effect of inhibiting blood coagulation. Furthermore, having far higher aqueous solubility than Rivaroxaban, the compounds according to the invention can be favorably developed as oral or injectable preparations .

Abstract

La présente invention concerne de nouveaux dérivés d'oxazolidinone comprenant des amidines cycliques, et des promédicaments, hydrates, solvates, isomères et sels pharmaceutiquement acceptables de ces dérivés, ainsi que des procédés pour les préparer et des compositions pharmaceutiques qui les contiennent. Les dérivés d'oxazolidinone comprenant des amidines cycliques, et les promédicaments, hydrates, solvates, isomères et sels pharmaceutiquement acceptables de ces dérivés peuvent être employés avantageusement comme anti-coagulants pour traiter des thromboembolismes et des tumeurs par inhibition du facteur de coagulation Xa.
PCT/KR2008/002619 2007-05-09 2008-05-09 Inhibiteurs du facteur xa comprenant des amidines cycliques en tant que sous-unité p4, leurs procédés de préparation, et compositions pharmaceutiques et dérivés de ceux-ci WO2008140220A1 (fr)

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KR1020080042740A KR101009594B1 (ko) 2007-05-09 2008-05-08 Ｐ4 위치에 사이클릭 아미딘을 가지는 ＦＸａ 저해제, 이의유도체, 제조방법 및 이를 함유하는 의약 조성물

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Cited By (6)

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WO2010002115A3 (fr) * 2008-07-03 2010-03-11 Legochem Bioscience Ltd. Inhibiteurs de fxa avec l’amidoxime cyclique ou l’amidrazone cyclique en tant que sous-unité p4, procédés pour leur préparation et compositions pharmaceutiques et dérivés de ceux-ci
US20110201025A1 (en) * 2009-10-30 2011-08-18 Jenaffin Gmbh Polymer-coupled peptidases
CN104356124A (zh) * 2014-10-30 2015-02-18 广东东阳光药业有限公司 噁唑烷酮类化合物及其组合物和用途
CN104447729A (zh) * 2014-12-05 2015-03-25 广东东阳光药业有限公司 噁唑烷酮类化合物及其在药物中的应用
CN104478869A (zh) * 2014-12-05 2015-04-01 广东东阳光药业有限公司 噁唑烷酮类化合物及其在药物中的应用
EP3078378A1 (fr) 2015-04-08 2016-10-12 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie

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WO1999031092A1 (fr) * 1997-12-12 1999-06-24 Merck Patent Gmbh DERIVES DE BENZAMIDINE UTILISES COMME INHIBITEURS DU FACTEUR DE COAGULATION Xa
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WO2016162472A1 (fr) 2015-04-08 2016-10-13 Vaiomer Utilisation d'inhibiteurs du facteur xa pour réguler la glycémie

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