WO2008069609A1 - Dérivés de pyrimidinone ou dérivés de pyridazinone pour une inhibition de l'activité du facteur viia - Google Patents

Dérivés de pyrimidinone ou dérivés de pyridazinone pour une inhibition de l'activité du facteur viia Download PDF

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WO2008069609A1
WO2008069609A1 PCT/KR2007/006341 KR2007006341W WO2008069609A1 WO 2008069609 A1 WO2008069609 A1 WO 2008069609A1 KR 2007006341 W KR2007006341 W KR 2007006341W WO 2008069609 A1 WO2008069609 A1 WO 2008069609A1
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oxo
methyl
dihydro
acetamide
isobutyl
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PCT/KR2007/006341
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English (en)
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Ho Young Song
Young Ock Lim
Sun Joo Oh
Hyang Sook Lee
Tae Kyo Park
Yong Zu Kim
Sung Ho Woo
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Legochem Bioscience Ltd.
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Publication of WO2008069609A1 publication Critical patent/WO2008069609A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pyrimidinone derivatives or pyridazinone derivatives having a novel structure and a method for preparing the same. And, the present invention relates to a composition for the prevention of blood clotting and the treatment of various thrombosis comprising the pyrimidinone derivatives or pyridazinone derivatives with a novel structure as an active ingredient.
  • FVIIa Factor Xa
  • FXa factor Xa
  • the generated thrombin activates platelets and converts fibrinogen into fibrin.
  • the fibrin forms an insoluble clot of blood by polymerization and cross-linking with factor XIII .
  • thrombin activates factors V and VIII which are involved in blood clotting to accelerate the process. Therefore, a thrombin inhibitor can suppress the platelet activation and the fibrin generation, resulting in the direct prevention of the thrombus generation. This is why scientists have been tried to develop a thrombin inhibitor first to prevent blood clotting and to treat various thrombosis. However, the developed thrombin inhibitors did not demonstrate satisfactory effect in clinical tests, that is the thrombin inhibitors did not inhibit the thrombin generation itself despite they reduced blood thrombin level, resulting in unsatisfactory anti-thrombus effect.
  • a thrombin inhibitor has to be administered excessively, which increases the risk of carrying side effects such as bleeding, etc.
  • factor Xa factor Xa
  • the TF. FVIIa complex is rising as an alternative for the treatment of thrombosis along with the FXa inhibitor (Curr. Med. Chem. , 2004, 11, 2535).
  • the TF. FVIIa complex always exists on the surface of vascular cell membrane, so that it limits the early stage of blood clotting.
  • a FVIIa inhibitor directly works for injured region of blood vessel and interrupts the very first step of blood clotting without affecting physiological hemostasis.
  • FVIIa level is very low in vivo, unlike thrombin or FXa, indicating that FVIIa inhibitor can be effective with a small amount and thereby reduces the risk of side effects such as bleeding.
  • It is another object of the present invention to provide a pharmaceutical composition for the prevention of blood clotting or the treatment of thrombosis comprising the pyrimidinone derivative or pyridazinone derivative with a novel structure and aprodrug, a hydrate, a solvate, a stereoisomer and a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present inventors have focused our study on the development of a novel compound having an excellent FVIIa inhibiting activity. And as a result, the inventors completed this invention by confirming that the compound represented by the following formula I was identified as a target compound to achieve the above objects.
  • the target of the present invention is the compound represented by formula I having an excellent FVIIa inhibiting 5 activity and a physiologically acceptable salt of the same.
  • Wh erein A is or
  • R 1 is Ce ⁇ Cio aryl substituted or non-substituted with one or
  • L5 R 2 is H, Ci ⁇ C 6 alkyl or cyclic compound selected from the group consisting of phenyl, pyridine, pyrrole, furan, thiophene, oxazole, isooxazole, imidazole, pyrazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, naphthalene, quinoline, isoquinoline, benzofuran, benzothiophene and indole, the cyclic compound can be substituted with one or more substituents selected from the group consisting of Ci-C 4 alkyl, halogen atom, -CN, -OH, -CF 3 , -OR, -CO 2 R and -NHR; each R of the substituent is, independently at each occurrence, C 1 -C4 alkyl;
  • Q x and Q 2 are independently H, or C-i ⁇ C 6 alkyl; m and n are independently an integer of 0 - 3;
  • each R 4 is, independently at each occurrence, C 1 -C1 0 alkyl;
  • R 3 is amidino, guanidino, amino methyl, amino, cyano (-CN) , cyano methyl, hydroxy, -OCH 2 CO 2 R 5 , hydroxyl methyl or chloro- substituted C 6 ⁇ Cio aryl, such that the aryl of R 3 can contain one or more hetero elements selected from the group consisting of N, S and 0 in its aromatic ring ; R 5 is H, methyl, ethyl or t-butyl.
  • the alkyl herein contains linear or side chained Ci ⁇ Ce noncyclic, saturated hydrocarbon residue, C 2 ⁇ Ce noncyclic, unsaturated hydrocarbon such as (C 2 ⁇ Cg) -alkenyl and (C2 ⁇ C ⁇ ) - alkynyl, and C 3 ⁇ Cs cyclic alkyl group, unless stated otherwise .
  • the alkyl group is either not substituted or substituted with one or more, for example one four identical or different substituents, no matter what substituent is attached to the alkyl group defined as formula I, unless stated otherwise.
  • the specific substituent attached on the substituted alkyl residue can be located as aimed unless this substitution does not induce unstable molecule.
  • the specific substituent herein can be exemplified by halogen atom, hydroxyl and carboxy group.
  • R 1 Is Ce ⁇ Cio aryl substituted or non-substituted with one or more substituents selected from the group consisting of nitro (-NO 2 ) , amino, hydroxy, carboxy (-CO 2 H) and C 2 -C 7 alkylcarboxy, such that the aryl of R 1 is selected from the group consisting of phenyl, thiophene, pyridine, pyrazole, oxazole and aminothiazole;
  • R 2 is selected from the group consisting of methyl, isopropyl, phenyl, pyridine, thiophene, oxazole, isooxazole, imidazole, pyrazole, thiazole and isothiazole;
  • Q 1 and Q 2 are independently H, or Ci ⁇ C4 alkyl; m and n are independently an integer of 0 - 2;
  • R 4 is, independently at each occurrence, Ci-Cio alkyl;
  • R 3 is amidino, amino methyl, amino, cyano (-CN) , cyano methyl, hydroxy, -OCH 2 CO 2 R 5 , hydroxyl methyl or chloro-substituted aryl, such that the aryl of R 3 is selected from the group consisting of phenyl, thiophene, pyridine and indole R 5 is H, methyl, ethyl or t-butyl.
  • R 1 is Ce ⁇ Cio aryl substituted or non-substituted with one or more substituents selected from the group consisting of nitro (-NO 2 ) , amino, hydroxy, carboxy (-CO 2 H) and C 2 -C 7 alkylcarboxy, such that the aryl of R 1 is selected from the group consisting of phenyl, thiophene, pyridine and aminothiazole;
  • R 2 is selected from the group consisting of methyl, isopropyl, phenyl, pyridine, thiophene, oxazole, pyrazole and thiazole;
  • Q 1 and Q 2 are independently H or methyl;
  • L is -CONH- ;
  • m and n are independently an integer of 0,1,2;
  • R 3 is amidino, amino methyl, amino, cyano (-CN) , cyano methyl, hydroxy, -OCH 2 CO 2 R 5 , hydroxy methyl or chloro-substituted aryl, such that the aryl or R 3 is selected from the group consisting of phenyl, thiophene and pyridine R 5 is H, methyl, ethyl or t- butyl.
  • the pharmaceutically acceptable salt thereof can be non-toxic acid added salt containing pharmaceutically acceptable anion, for example, the acid-added salts produced by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydrolodic acid; organocarboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid and maleic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, can be included.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydrolodic acid
  • organocarboxylic acids such as tartaric acid, for
  • pyridazinone compounds in which A is ** ⁇ The pyridazinone compound can be prepared by retrosynthesis as shown in reaction formula I, while the pyrimidinone compound can be prepared by retrosynthesis as shown in reaction formula 2. [Reaction Formula I] Retrosynthesis of pyridazinone compound
  • pyridazinone compound [2] issynthesized by amidation of organic carboxylic acid compound
  • Compound [3] is prepared by hydrolysis of compound [5] .
  • Compound [7] is prepared by alkylation of compound [8] with compound [9] having leaving group (LG).
  • Compound [8] is prepared by a series of process fromthe commercial compound LlO] .
  • pyrimidinone compound [11] is synthesized by amidation of organic carboxylic acid compound [12], the precursor compound, and amine [4].
  • Compound [12] is prepared by hydrolysis of compound [13] .
  • Compound [16] is prepared by a series of process with the commercial organic chlorideor compound [17] that can be prepared by converting the precursor organic acid into organic acid chloride.
  • the coupling reagent widely used for amidation can be exemplified by dicyclohexylcarbodiimide (DCC), 3-ethyl-3' - (dimethylamino) - propylcarbodiimide (EDC), bis- (2-oxo-3-oxazolidinyl) - phosphinic acid chloride (BOP-Cl) , diphenylphosphorylazide (DPPA), isobutylchloroformate, 0- (7-azabenzotriazole-l-yl) - N, N, N' ,N' -tetramethyluronium hexafluorophosphate (HATU), but not always limited thereto.
  • DCC dicyclohexylcarbodiimide
  • EDC 3-ethyl-3' - (dimethylamino) - propylcarbodiimide
  • BOP-Cl bis- (2-oxo-3-oxazolidinyl)
  • the conventional reagent for hydrolysis can be selected from the group consisting of hydroxides of alkali metal (lithium, sodium, potassium or cesium) , tetrabutylammonium hydroxide, hydrochloric acid and trifluoroacetic acid, but not always limited thereto.
  • the compound of formula I of the invention has a novel structure and thus has excellent pharmaceutical effect as a FVIIa inhibitor.
  • the present invention thus, provides a pharmaceutical composition for the prevention of blood clotting and the treatment of thrombosis comprising the compound of formula I and its derivatives (for example: prodrug) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of formula I can have isomer and enatiomer and in that case, every stereoisomer, optical isomer and racemic compound as well as a mixture containing an independent enatiomer thereof can be all included and its solvate and hydrate can also be included.
  • the activity of the compound of formula I of the invention was measured by the conventional method well known to those in the art and as a result it was confirmed to have up to 10 uM, preferably up to 1 uM of Ki against TF/FVIIa.
  • the compound of formula I of the invention can be co-treated with one or more components selected among thrombolytic agents and platelet activity inhibitors.
  • the thrombolytic agent is exemplified by t-PA, urokinase and streptokinase.
  • the platelet activity inhibitor is exemplified by aspirin, ticlopidin, clopidogrel and 7E3 monoclonal antibody.
  • the pharmaceutical composition containing the compound of the invention for the purpose of the prevention and treatment of thrombus is not limited to the above and any formulation that is useful for the prevention and treatment of thrombus can be included in this invention.
  • the pharmaceutical composition for theprevention of blood clotting and the treatment of thrombosis of the present invention can contain the effective dose of one or more components selected from the group consisting of the compound of formula I and its prodrug, its hydrate, its solvate, its isomer and its pharmaceutically acceptable salt, which can be mixed with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the invention can also include additives such as fillers, disintegrating agents, binders, lubricants, wetting agents, stabilizers, emulsifying agents, antiseptics, sweetening agents, coloring agents, aromatics, flavors, thickening agents, diluents, buffering substances, solubilizers, reagents for late releasing effect, salts for osmoconditioning, coating agents and antioxidants.
  • additives such as fillers, disintegrating agents, binders, lubricants, wetting agents, stabilizers, emulsifying agents, antiseptics, sweetening agents, coloring agents, aromatics, flavors, thickening agents, diluents, buffering substances, solubilizers, reagents for late releasing effect, salts for osmoconditioning, coating agents and antioxidants.
  • the effective dosage of the pharmaceutical composition for the prevention of blood clotting and the treatment of thrombosis of the present invention can be determined according to the type of compound, administration method, target subject and target disease but is determined based on the conventional medicinal standard.
  • the preferable dosage of the composition containing one or more components selected from the group consisting of the compound of formula I and its prodrug, its hydrate, its solvate, its isomer and its pharmaceutically acceptable salt is 0.01 mg/Kg 1 mg/Kg.
  • the administration frequency can be once or several times a day within the allowed one day dosage.
  • the effective dosage of the composition of the present invention can be determined according to weight, age, gender, health condition, diet, administration frequency, administration method, excretion and severity of a disease.
  • composition of the present invention can be administered orally (tablets, capsules, granules, powders, solutions and suppositories) or parenterally (for example, intravenous, subcutaneous, intraperitoneal and local injections or via visual pathway) .
  • parenterally for example, intravenous, subcutaneous, intraperitoneal and local injections or via visual pathway
  • the reaction solution was added into saturated ammonium chloride solution (500 mL) , followed by extraction with ethyl acetate (200 mL x 2) .
  • the organic layer was washed with water (100 mL x 2) and then dried over anhydride magnesium sulfate.
  • the reactant was passed through silica gel tube (10 cm(depth) x 12 cm(diameter) ) using dichloromethane/n-hexane (1:1, 1 L) and then concentrated again, followed by recrystallization with n-hexane (500 mL) to give the titledcompound as a white solid (49.8 g, 82%).
  • reaction solution was cooled down to room temperature and added into 1 N HCl solution to separate organic layer. Extraction with ethyl acetate (200 mL) was performed and the organic layer was washed with saturated saline and then dried over anhydride magnesium sulfate.
  • reaction solution was cooled down and water (300 mL) was added thereto, followed by extraction with ethyl acetate (150 mL x 2) .
  • organic layer was washed with saturated saline
  • Ethyl potassium malonate (21.4 g, 126 mmol) was suspended in acetonitrile (150 mL) , to which triethylamine (18.3 mL, 132 mmol) and anhydride magnesium chloride (14.2 g, 149 mmol) were added at 0 ° C followed by stirring for 150 minutes at room temperature in nitrogen atmosphere.
  • 3-nitrobenzoyl chloride (11.1 g, 59.8 mmol) was slowly added thereto, followed by stirring at room temperature for 16 hours.
  • the solvent was concentrated under reduced pressure, to which 1 N HCl solution (100 mL) was added, followed by extraction with ethyl acetate (100 mL x 2) .
  • reaction solvent was concentrated under reduced pressure, to which IN HCl solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3) .
  • the organic layer was dried over anhydride magnesium sulfate. After filtering, the reactant was concentrated under reduced pressure, followed by recrystallization in diethyl ether (100 mL) to give the titled compound as a white solid (2.85 g, 72%).
  • N,N-diisopropylethylamine (0.74 mL, 4.26 mmol)
  • 1- hydroxybenzotriazole hydrate 109 mg, 0.71 mmol
  • l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 408 mg, 2.13 mmol
  • the reaction solution was added to saturated ammonium chloride solution (30 mL) , followed by extraction with ethyl acetate (30 mL x 2) .
  • the organic layer was washed with saturated sodium bicarbonate solution (30 mL) and dried over anhydride magnesium sulfate.
  • ⁇ l-l-3> Preparation acetic acid salt of N-(4- carbamimidoylbenzyl] -2- [l-isobutyl-2-methyl-4- (3-aminophenyl) - 6-oxo-l, 6-dihydro-pyrimidine-5-yl] -acetamide
  • the compound obtained in example ⁇ l-l-2> (320 mg, 0.65 mmol) was dissolved in methanol (20 inL) , to which acetic acid (74 mL, 1.30 mmol) and palladium/charcoal (69 mg, 0.065 mmol) were added, followed by stirring at room temperature for 16 hours in the hydrogen balloon.
  • FVIIa/TF inhibitioncapacity of the compound of the invention was measured as follows. FXa, which was generated from FX used as a substrate for measuring the activity of FVIIa/TF, was tested for its activity to chromogenic substrate to investigate the FVIIa/TF inhibition capacity of the compound [JBC(2001), 276(31), 29195-29199]. FX (0.2 uM) dissolved in 60 mM Tris buffer (pH 7.4) containing 180 mM NaCl, 0.12% BSA (bovine serum albumin), and 6 mM CaCl 2 was loaded in a 96-well plate (50 uL/well) .
  • Tris buffer pH 7.4
  • BSA bovine serum albumin
  • the inhibitor compound of the invention was dissolved in dimethylsulfoxide (DMSO) at the concentration of 10 mM, which was diluted with third distilled water.
  • DMSO dimethylsulfoxide
  • 7.8-500 uM inhibition solution final 10% DMSO solution was prepared and added to the plate (10 uL/well) .
  • Neoplastin (0.1 mg/mL) dissolved in 50 mM Tris buffer (pH 7.4) containing 150 mM NaCl, 0.1% BSA and 5 mM CaCl 2 was added to the plate (20 uL/well) .Reaction was induced by adding FVIIa dissolved in the same buffer at the concentration of 5 nM (20 uL/well) . The reaction was continued at 37 ° C for 20 minutes. 250 mM Tris buffer (pH 7.8) containing 30 mM EDTA, 375 mM NaCl and 2.5% PEG8000 (polyethylene glycol, molecular weight: approximately 8000) was added to the plate (100 uL/well) at room temperature to stop the FVIIa activity. S-2765 dissolved in third distilled water at the concentration of 1.5 mM was added to the plate (50 uL/well) . The kinetic assay was performed at 37 ° C or 2 minutes with a kinetic plate reader
  • the FVIIa inhibition capacity of the compound of formula I can be determined by measuring IC 5O , which is the concentration of the compound that inhibits the FVIIa activity by 50% (associated with inhibition constant Ki) .
  • IC 5O concentration of the compound that inhibits the FVIIa activity by 50% (associated with inhibition constant Ki) .
  • Ki concentration of the compound that inhibits the FVIIa activity by 50% (associated with inhibition constant Ki) .
  • the log of the concentration of the compound of formula I / relative speed of hydrolysis (compared with the non-inhibited control) was floated, and then the concentration that can 50% reduce the hydrolysis speed was determined by linear regression.
  • the FVIIa inhibition capacity of the compound of formula I was investigated and as a result it was confirmed that the TF/FVIIa complex inhibition capacity of the compound was as excellent as Ki ⁇ 7 uM.
  • the pyrimidinone or pyridazinone compound of formula I of the present invention has excellent inhibition activity against FVIIa associated with blood clotting.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne le composé pyrimidinone ou le composé pyridazinone ayant une activité inhibitrice contre le facteur VIIa. Précisément, la présente invention concerne une composition pharmaceutique pour la prévention de la coagulation sanguine et le traitement de la thrombose contenant le composé pyrimidinone ou le composé pyridazinone ayant une activité inhibitrice contre le facteur VIIa et un promédicament, un hydrate, un solvate, un isomère et un sel pharmaceutiquement acceptable de ceux-ci comme principe actif.
PCT/KR2007/006341 2006-12-08 2007-12-07 Dérivés de pyrimidinone ou dérivés de pyridazinone pour une inhibition de l'activité du facteur viia WO2008069609A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011015641A1 (fr) * 2009-08-05 2011-02-10 Katholieke Universiteit Leuven Nouveaux inhibiteurs de réplication virale
US8785638B2 (en) 2009-05-15 2014-07-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
WO2015124671A1 (fr) * 2014-02-24 2015-08-27 Henkel Ag & Co. Kgaa Substances odoriférantes photolabiles
US9132129B2 (en) 2010-11-15 2015-09-15 Katholieke Universiteit Leuven Antiviral compounds

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WO1994009784A1 (fr) * 1992-11-02 1994-05-11 Nippon Soda Co., Ltd. Inhibiteur d'agregation plaquettaire
EP0658555A1 (fr) * 1993-12-16 1995-06-21 Nihon Nohyaku Co., Ltd. Dérivés de la pyridazinone, procédés de production et utilisation
WO2004002406A2 (fr) * 2002-06-26 2004-01-08 Bristol-Myers Squibb Company Pyrimidinones bicycliques inhibiteurs de la cascade de coagulation

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US6750342B1 (en) 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1994009784A1 (fr) * 1992-11-02 1994-05-11 Nippon Soda Co., Ltd. Inhibiteur d'agregation plaquettaire
EP0658555A1 (fr) * 1993-12-16 1995-06-21 Nihon Nohyaku Co., Ltd. Dérivés de la pyridazinone, procédés de production et utilisation
WO2004002406A2 (fr) * 2002-06-26 2004-01-08 Bristol-Myers Squibb Company Pyrimidinones bicycliques inhibiteurs de la cascade de coagulation

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8785638B2 (en) 2009-05-15 2014-07-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
US9499563B2 (en) 2009-05-15 2016-11-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
WO2011015641A1 (fr) * 2009-08-05 2011-02-10 Katholieke Universiteit Leuven Nouveaux inhibiteurs de réplication virale
JP2013501034A (ja) * 2009-08-05 2013-01-10 カトリック・ユニベルシティト・ルーヴァン 新規ウイルス複製阻害剤
AU2010280695B2 (en) * 2009-08-05 2014-09-11 Katholieke Universiteit Leuven Novel viral replication inhibitors
US8906906B2 (en) 2009-08-05 2014-12-09 Katholieke Universiteit Leuven Viral replication inhibitors
US20150051195A1 (en) * 2009-08-05 2015-02-19 Katholieke Universiteit Leuven Novel viral replication inhibitors
US9132129B2 (en) 2010-11-15 2015-09-15 Katholieke Universiteit Leuven Antiviral compounds
WO2015124671A1 (fr) * 2014-02-24 2015-08-27 Henkel Ag & Co. Kgaa Substances odoriférantes photolabiles
US9926258B2 (en) 2014-02-24 2018-03-27 Henkel Ag & Co. Kgaa Photolabile pro-fragrances
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