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WO2003006462A1 - Procedes pour produire des inhibiteurs de thrombine et des n-pyridin-4-yl-oxazolidin-2-ones servant de produits intermediaires pour cette production - Google Patents

Procedes pour produire des inhibiteurs de thrombine et des n-pyridin-4-yl-oxazolidin-2-ones servant de produits intermediaires pour cette production Download PDF

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Publication number
WO2003006462A1
WO2003006462A1 PCT/GB2002/003185 GB0203185W WO03006462A1 WO 2003006462 A1 WO2003006462 A1 WO 2003006462A1 GB 0203185 W GB0203185 W GB 0203185W WO 03006462 A1 WO03006462 A1 WO 03006462A1
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formula
compound
halogen
alkyl
represents hydrogen
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English (en)
Inventor
David Colclough
Iain Douglas Macgilp
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel intermediate which can be used in an improved process for the preparation of certain benzamide derivatives known to be useful as thrombin inhibitors.
  • Thrombin is a serine proteinase present in plasma and is formed by conversion from its prothrombin precursor by the action of Factor Xa. Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein, fibrinogen, into insoluble fibrin. Thrombin inhibitors have been described as being useful in the treatment of acute vascular diseases such as coronary thrombosis, stroke, pulmonary embolism, deep vein thrombosis, restenosis, atrial fibrillation, myocardial infarction, and unstable angina.
  • acute vascular diseases such as coronary thrombosis, stroke, pulmonary embolism, deep vein thrombosis, restenosis, atrial fibrillation, myocardial infarction, and unstable angina.
  • thrombin inhibitors have been described as anti-coagulant agents both in- vivo and ex-vivo, and in oedema and inflammation, whereby a low dose of thrombin inhibitor can reduce platelet and endothelial cell thrombin mediated inflammatory responses without concomitant anticoagulant effects.
  • thrombin has been reported to contribute to lung fibroblast proliferation, thus, thrombin inhibitors could be useful for the treatment of some pulmonary fibrotic diseases.
  • Thrombin inhibitors have also been reported in the treatment of tumour metastasis.
  • Thrombin inhibitors and processes for their preparation have been previously described in WO97/22589 (Glaxo Group Limited) and WO00/20394 (Glaxo Group Limited). Summary of the Invention
  • the present inventors have found a novel intermediate, an oxazolidinone, that can be used in an improved process for preparing benzamide derivatives.
  • the improved process is more direct, provides increased yield and avoids the use of potential alkylating intermediates compared to the previous processes such as those described in WO97/22589 & WO00/20394.
  • R 7 represents hydrogen or C ⁇ -6 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 and R 2 independently represent a group /X 'R* or R 1 and R 2 together form a C 3 - 7 heterocycloalkyl or heterocycloalkenyl group which may be optionally substituted by C ⁇ -6 alkyl, halogen, carboxylic acid or a acid ester group;
  • R 3 represents hydrogen, C 1-3 alkyl, halogen, or C 1-2 alkoxy
  • R 4 , R 5 and R 6 independently represent hydrogen, or halogen
  • R 7 represents hydrogen or C ⁇ -6 alkyl
  • R 8 represents hydrogen, Cs-ecycloalkyl, C 3-7 cycloalkenyl, C 3-7 heterocycloalkyl, C 3 - 7 heterocycloalkenyl, aryl, or heteroaryl, which groups are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C-i- ⁇ alkyl, C 1-6 alkoxy, C 1-6 acyloxy, NR 9 R 10 , NHCOR 11 , NHSO 2 R 12 , COR 13 , CO 2 R 14 , CONR 15 R 16 , and SO 2 NHR 17 ;
  • X represents a bond, a C ⁇ -6 alkyl chain, or a C 3-6 alkenyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 acyloxy, NR 9 R 10 , NHCOR 11 , NHSO 2 R 12 , COR 13 , CO 2 R 14 , CONR 15 R 16 , and SO 2 NHR 17 ;
  • R 9 -R 17 represent hydrogen, C 1-6 alkyl, or R 9 and R 10 or R 15 and R 16 form a C 3-7 heterocycloalkyl ring, or R 12 additionally may represent trifluoromethyl.
  • the invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 and R 2 independently represent a group
  • R 1 and R 2 together form a C 3-7 heterocycloalkyl or heterocycloalkenyl group which may be optionally substituted by C ⁇ -6 alkyl, halogen, carboxylic acid or a acid ester group;
  • R 3 represents hydrogen, C ⁇ -3 alkyl, halogen, or C ⁇ alkoxy
  • R 5 4 , R° and R independently represent hydrogen, or halogen;
  • R 7 represents hydrogen or C h alky!;
  • R 8 represents hydrogen, C 3-8 cycloalkyl, C 3-7 cycloalkenyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, aryl, or heteroaryl, which groups are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C ⁇ _ 6 alkyl, C ⁇ -6 alkoxy, C 1-6 acyloxy, NR 9 R 10 , NHCOR 11 , NHSO 2 R 12 , COR 13 , CO 2 R 14 , CONR 15 R 16 , and SO 2 NHR 17 ;
  • X represents a bond, a C ⁇ -6 alkyl chain, or a C 3-6 alkenyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C 1-6 alkyl, d -6 alkoxy, C 1-6 acyloxy, NR 9 R 10 , NHCOR 11 , NHS0 2 R 12 , COR 13 , CO 2 R 14 , CONR 15 R 16 , and SO 2 NHR 17 ;
  • R 9 -R 17 represent hydrogen, C ⁇ -6 alkyl, or R 9 and R 10 or R 15 and R 16 form a C 3-7 heterocycloalkyl ring, or R 12 additionally may represent trifluoromethyl.
  • alkyl and alkoxy mean both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl (- CH 3 ), ethyl (-C 2 H 5 ), propyl (-C 3 H 7 ) and butyl (-C Hg).
  • alkoxy groups include methoxy (-OCH 3 ) and ethoxy (-OC 2 H 5 ).
  • halogen means fluorine, chlorine, bromine and iodine.
  • cycloalkyl group means an aliphatic ring.
  • examples of cycloalkyl groups include cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkenyl means an aliphatic ring containing at least one double bond incorporated in the ring.
  • heterocycloalkyl means an aliphatic ring containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, for example, pyrrolidine, morpholine or a tetrahydropyran-4-yl group.
  • heterocycloalkenyl means an aliphatic ring containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, together with at least one double bond incorporated in the ring.
  • aryl means optionally substituted monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl.
  • heteroaryl includes 5 or 6 membered aromatic heterocyclic rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, and fused bicyclic ring systems containing one or more nitrogen, sulfur, and oxygen atoms.
  • heteroatoms selected from nitrogen, sulphur and oxygen atoms
  • fused bicyclic ring systems containing one or more nitrogen, sulfur, and oxygen atoms examples include oxadiazole, thiazole, thiadiazole, triazole, tetrazole, benzimidazole, pyridine, furan and thiophene.
  • X is suitably a bond or C ⁇ -6 alkyl group, e.g. methyl, isopropyl or isobutyl
  • R 8 suitably represents hydrogen, C 3-8 cycloalkyl, aryl, or heteroaryl.
  • R 8 is preferably phenyl optionally substituted by one or more halogen groups, or C 3-8 cycloalkyl, e.g. cyclobutyl, cyclopentyl or cyclohexyl.
  • R 8 is preferably hydrogen, cycloalkyl, e.g. cyclohexyl, or heteroaryl, e.g. thienyl or furyl. More preferably, R 1 represents propyl, isopropyl, butyl, cyclopentyl or cyclohexyl. Most preferably R 1 represents isopropyl.
  • R 2 represents a group X is suitably C 3-6 alkenyl, e.g. allyl, or C ⁇ -6 alkyl, e.g. methyl, ethyl, propyl or pentyl, which optionally contains an oxygen group within the chain and is optionally substituted by a group selected from hydroxy, C 1-6 alkoxy, NHSO 2 R 12 , CO 2 R 14 , CONR 15 R 16 , or SO 2 NHR 17 , and R 8 is suitably hydrogen, C 3-7 heterocycloalkyl, e.g. pyrrolidine or morpholine, aryl, e.g.
  • R 2 represents methyl, ethyl, propyl or isopropyl. Most preferably R 2 represents ethyl.
  • R 3 is preferably C ⁇ -3 alkyl, e.g. methyl, or halogen, e.g. chlorine or bromine. More preferably, R 3 represents methyl or chlorine. Most preferably, R 3 represents methyl.
  • R 4 , R 5 and R 6 are preferably hydrogen, or halogen, e.g. fluorine. More preferably R 4 , R 5 and R 6 represent hydrogen.
  • R 7 is preferably hydrogen, methyl or ethyl. More preferably R 7 is methyl.
  • Particularly preferred compounds, or compounds of the processes of the invention include those in which each variable is selected from the preferred groups for each variable. Even more preferable compounds, or compounds of the processes of the invention, include those in which each variable is selected from the more preferred or most preferred groups for each variable.
  • R 1 represents C h alky! or C 3-
  • R 2 represents C 1-4 alkyl or C 3- alkenyl
  • R 3 represents hydrogen, C-i- 3 alkyl or halogen;
  • R 4 represents hydrogen;
  • R 5 represents hydrogen;
  • R 6 represents hydrogen;
  • R 7 represents hydrogen or
  • the compound of formula (I) is N-Ethyl-N-isopropyl-3-methyl-5-[2S- (pyridin-4-ylamino)-propoxy]-benzamide or a pharmaceutically acceptable salt or solvate thereof.
  • pharmaceutically acceptable means a compound which is suitable for pharmaceutical use.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p_-sulphonic, di- ⁇ -toluoyl tartrate, sulfanilic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • Preferred pharmaceutically acceptable salts of the compounds of formula (I) include the toluene- ⁇ -sulphonic acid salt.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • reaction of a compound of formula (II) with a compound of formula (III) is carried out in the presence of an organic solvent, preferably a dipolar organic solvent, e.g. N,N-dimethylformamide (DMF), N-methyl pyrrolidone (NMP), preferably NMP, and a suitable base, e.g. Cs 2 CO 3 or K CO 3 , preferably Cs 2 CO 3 .
  • an organic solvent preferably a dipolar organic solvent, e.g. N,N-dimethylformamide (DMF), N-methyl pyrrolidone (NMP), preferably NMP
  • a suitable base e.g. Cs 2 CO 3 or K CO 3 , preferably Cs 2 CO 3
  • the reaction is suitably carried out at elevated temperature, preferably at about 110-120°C.
  • the compound of formula (I) may be converted into a pharmaceutically acceptable salt.
  • a tosylate salt of a compound of formula (I) may be prepared by treatment with p-toluene sulphonic acid monohydrate (pTSA.H 2 O).
  • pTSA.H 2 O p-toluene sulphonic acid monohydrate
  • the conversion is carried out at room temperature or elevated temperature, preferably elevated temperature, more preferably at about 55-70°C in a suitable solvent, eg ethyl acetate/IMS, isopropyl acetate/isopropylalcohol or methylisobutylketone (MIBK), preferably MIBK.
  • a compound of formula (II) may be prepared by cyclisation of a compound of formula (IV):
  • the reaction is carried out in the presence of a dipolar aprotic solvent, e.g. DMF, DMSO or N-methyl pyrrolidone (NMP), preferably NMP; carbonyl equivalents, e.g. diethyl carbonate ((EtO) 2 CO), phosgene, ethyl chloroform, preferably diethyl carbonate; and a base, e.g. Cs 2 CO 3 or K 2 CO 3 , preferably Cs 2 CO 3 .
  • the reaction is carried out at elevated temperature.
  • the reaction is carried out in the presence of NMP, diethyl carbonate and Cs 2 CO 3 at a temperature of about 90-125°C.
  • the present invention provides a process for preparing a compound of formula (I) comprising the step of preparing a compound of formula (II) wherein the compound of formula (II) is prepared by cyclisation of a compound of formula (IV).
  • the conversion of a compound of formula (IV) to a compound of formula (II) and subsequent reaction of a compound of formula (II) with a compound of formula (III) to form a compound of formula (I) may be carried out separately or in situ.
  • the reaction is preferably carried out in situ.
  • a compound of formula (IV) may be prepared according to processes described in the art, e.g. WO97/22589, WO 00/20394.
  • a compound of formula (IV) may be prepared by reacting a compound of formula (V) with a compound of formula (VI):
  • R 18 represents hydrogen, or a suitable oxygen protecting group, preferably R 18 represents hydrogen.
  • R 19 represents hydrogen, or a suitable amino protecting group, preferably R 19 represents hydrogen
  • R 20 represents halogen, preferably R 20 represents chlorine.
  • the compound of formula (VI) is an acid salt, e.g. acetate, HCI or HBr, preferably, an HCI salt.
  • the reaction is suitably carried out at a temperature greater than or equal to about 110°C, preferably, at about 120-140°C.
  • the reaction is carried out in the presence of a solvent selected from 2-methoxyethanol, 2-ethoxyethanol, propan-1-ol or ethyleneglycol, preferably 2- ethoxyethanol or propan-1-ol.
  • the reaction may be quenched using an aqueous solution of an inorganic base, e.g. LiOH, NaOH, preferably, NaOH.
  • the compound of formula (IV) is (S)-2-(Pyridin-4-ylamino)-propan-1- ol.
  • a further aspect of the present invention is a process for preparing a compound of formula (I) comprising the step of preparing a compound of formula (IV) by reacting a compound of formula (V) with a compound of formula (VI).
  • suitable oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert- butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
  • suitable amino protecting groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.
  • An arylalkyl group such as benzyl may be cleaved by hydrogenolysis in the presence of a catalyst, e.g., palladium on charcoal; an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation.
  • a catalyst e.g., palladium on charcoal
  • an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation.
  • N-Ethyl-N-isopropyl-3-methyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide (1.0 eq., 1.0 wt) was dissolved in ethyl acetate/IMS (15 vol., 60:1 ratio), the resultant solution was then warmed to approx. 70°C.
  • p-toluene sulphonic acid monohydrate (1.1 eq.) was added and stirred at approx. 70°C, the resultant solution was then cooled to approx. 30-40°C.
  • Diethyl carbonate (0.96 vol., 0.93 wt., 1.2 mol. eq) is added to a pre-formed suspension of (S)-2-(Pyridin-4-ylamino)-propan-1-ol (1wt.,1 mol.eq.) (Intermediate 1 prepared as described above or as described in WO97/22589 and WO00/20394), caesium carbonate (3.2 wt., 1.5 mol. eq.) and N-ethyl-3- hydroxy-N-isopropyl-5-methylbenzamide (1.6 wt., 1.1 mol. eq.) in NMP (5.0 vol.) at approx.110°C.
  • the resultant suspension is then heated to approx. 130°C and maintained for at least 18 hours.
  • the contents are cooled and diluted with water (8.0 vol.) and MIBK (3.0 vol.).
  • the layers are separated and the aqueous layer backwashed with MIBK (2.0 vol.).
  • the organic layers are combined and washed with 2M NaOH (5.0 vol.) then water (2 x 5.0vol.).
  • the layers are separated and the product containing organic layer retained.
  • N-ethyl-N-isopropyl-3-methyl-5-[2S-(pyridin-4-ylamino)-propoxy]-benzamide (1.0 wt, 1.0 mol. eq.) in MIBK (3-3.5vol.) is heated to approx. 50°C.
  • p-Toluene sulfonic acid monohydrate (1.0 mol. eq., 0.54 wt.) pre dissolved in MIBK (7 vol.) is then charged and the contents maintained at 50-55°C.
  • the resultant solution is then concentrated by vacuum distillation, 5.0 vol. of MIBK are removed and cooled to approx.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau produit intermédiaire de formule (II), utilisé dans un processus amélioré pour préparer des dérivés de benzamide de formule (I), inhibiteurs de thrombine. Dans la formule (I), R1 et R2 représentent indépendamment un groupe (VII) ou R1 et R2 forment conjointement un groupe hétérocycloalkyle C¿3-7? ou hétérocycloalcényle qui peut éventuellement être substitué par alkyle C1-6, alkoxy C1-4, halogène, de l'acide carboxylique ou un groupe ester d'acide carboxylique C1-4, R?3¿ représente hydrogène, alkyle C¿1-3?, halogène ou alkoxy C1-2, R?4, R5 et R6¿ représentent indépendamment hydrogène ou halogène, R7 représente hydrogène ou alkyle C¿1-6, R?8 représente hydrogène, cycloalkyle C¿3-8?, cycloalcényle C3-7, hétérocycloalkyle C3-7, hétérocycloalcényle C3-7, aryle ou hétéroaryle, ces groupes étant éventuellement substitués par un ou plusieurs groupes choisis parmi halogène, hydroxy, CN, alkyle C1-6, alkoxy C1-6, acyloxy C1-6, NR?9R10, NHCOR11¿, NHSO¿2?R?12, COR13, CO¿2R?14, CONR15Rl6¿ et SO¿2NHR?17, X représente une liaison, une chaîne alkyle C¿1-6? ou une chaîne alcényle C3-6, un ou deux atomes d'azote, d'oxygène ou de soufre pouvant éventuellement être contenus dans chaque chaîne et les chaînes étant éventuellement substituées par un ou plusieurs groupes choisis parmi halogène, hydroxy, CN, alkyle C1-6, alkoxy C1-6, acyloxy C1-6, NR?9R10, NHCOR11¿, NHSO¿2?R?12, COR13, CO¿2R?14, CONR15Rl6¿ et SO¿2?NHR?17 et R9-R17¿ représentent hydrogène, alkyle C¿1-6? ou R?9 et R10 ou R15 et R16¿ forment un noyau hétérocycloalkyle C¿3-7? ou R?12¿ peut éventuellement représenter trifluorométhyle.
PCT/GB2002/003185 2001-07-13 2002-07-10 Procedes pour produire des inhibiteurs de thrombine et des n-pyridin-4-yl-oxazolidin-2-ones servant de produits intermediaires pour cette production Ceased WO2003006462A1 (fr)

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GB0117144A GB0117144D0 (en) 2001-07-13 2001-07-13 Process
GB0117144.6 2001-07-13

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WO2003006462A1 true WO2003006462A1 (fr) 2003-01-23

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AR (1) AR034867A1 (fr)
GB (1) GB0117144D0 (fr)
WO (1) WO2003006462A1 (fr)

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EP2281901A2 (fr) 2005-08-02 2011-02-09 Eisai R&D Management Co., Ltd. Composition pharmaceutique anti-tumeur avec des inhibiteurs d'angiogénèse
US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
EP2364699A1 (fr) 2004-09-13 2011-09-14 Eisai R&D Management Co., Ltd. Utilisation conjointe d'un composé à base de sulfonamide avec un inhibiteur de l'angiogénèse
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
US8772269B2 (en) 2004-09-13 2014-07-08 Eisai R&D Management Co., Ltd. Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
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US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US12220398B2 (en) 2015-08-20 2025-02-11 Eisai R&D Management Co., Ltd. Tumor therapeutic agent
US12226409B2 (en) 2017-05-16 2025-02-18 Eisai R&D Management Co., Ltd. Treatment of hepatocellular carcinoma
US12303505B2 (en) 2017-02-08 2025-05-20 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition

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