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WO1997032863A1 - Derives de thiazolidine-2,4-dione - Google Patents

Derives de thiazolidine-2,4-dione Download PDF

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Publication number
WO1997032863A1
WO1997032863A1 PCT/JP1997/000639 JP9700639W WO9732863A1 WO 1997032863 A1 WO1997032863 A1 WO 1997032863A1 JP 9700639 W JP9700639 W JP 9700639W WO 9732863 A1 WO9732863 A1 WO 9732863A1
Authority
WO
WIPO (PCT)
Prior art keywords
thiazolidine
dione
ethyl acetate
benzyl
dissolved
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1997/000639
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English (en)
Japanese (ja)
Inventor
Seizo Taira
Atsushi Sugimoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Torii Pharmaceutical Co Ltd
Original Assignee
Torii Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Torii Pharmaceutical Co Ltd filed Critical Torii Pharmaceutical Co Ltd
Priority to AU22313/97A priority Critical patent/AU2231397A/en
Publication of WO1997032863A1 publication Critical patent/WO1997032863A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or 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
    • C07D277/34—Oxygen atoms

Definitions

  • the present invention relates to a novel thiazolidine-2,4-dione derivative and a therapeutic agent for diabetes containing the same. Further, the present invention relates to an intermediate for producing the derivative.
  • Insulin desensitizers that have been used to date have not yet been satisfied with weak or side effects, and there is a need for the development of drugs that are stronger and have no side effects.
  • R is a cycloalkyl group, an unsubstituted or substituted phenyl group, a naphthyl group, or at least one of nitrogen, oxygen, and sulfur atoms.
  • Represents a monocyclic or bicyclic heterocyclic ring containing at least one, and one or both of R 2 and R 3 are hydrogen, a lower alkyl group, a cycloalkyl group, an alkoxy group, a halogen atom, a hydroxy group, an amino group ( Which may be protected by a protecting group), a phenyl group, or — (CH 2 ) n-(n 2 to 6), and A represents an amide bond.
  • a thiazolidine-2,4-dione derivative represented by However, they have found that they have excellent blood sugar lowering action and lipid lowering action, and completed the present invention.
  • the cycloalkyl group represented by R includes cyclopentane, cyclohexane, cycloheptane and the like.
  • Examples of the unsubstituted or phenyl group having one or more substituents represented by are phenyl, 2-, 3-, or 4-chlorophenyl, 2-, 3-, or 4-fluorophenyl, 2-, 3- , Or 4-bromophenyl, 2-, 3-, or 4-nitrophenyl, 2-, 3-, or 4-tritolyl, 2-, 3-, or 4-methoxyphenyl, 2-, 3-, or 4- Ethoxyphenyl, 2-, 3-, or 4-benzyloxyphenyl, 2-, 3-, or 4-hydroxyphenyl, 2-, 3-, or 4-biphenyl, 2-, 3- or 4-dimethylaminophenyl, 4- (p-toluenesulfonylamide) phenyl, 2,4-dinitrophenyl, 3,4-dimethoxyphenyl, 4-
  • Examples of the unsubstituted or naphthyl group having one or more substituents represented by R and are 1-naphthyl, 2-naphthyl, 4-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 1-naphthyl , 2,3,4-tetrahydro-2-naphthyl group and the like.
  • An unsubstituted or a monocyclic or bicyclic heterocyclic ring containing at least one of nitrogen, oxygen, and sulfur atoms having at least one substituent represented by R and Examples include 2-pyridyl, 3-pyridyl, 2-phenyl, 3-phenyl, 3-inyl, 2-methyl-3-indolyl, 5-hydroxy-1-3-indolyl, 5-methoxy-2-methyl-3. Examples include indolyl, 1,2,3,4-tetrahydro-13-isoquinolyl and quinolyl groups.
  • the lower alkyl group of R 2 and R 3 represents a straight-chain or branched-chain methyl, ethyl, propyl, butyl, pentyl, hexyl group and the like.
  • the cyclic alkyl group of R 2 and R 3 represents a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl group or the like.
  • the alkoxy group for R 2 and R 3 represents methoxy, ethoxyquin, or a methoxy group.
  • the halogen atom of R 2 and R 3 represents an atom such as fluorine, chlorine, and bromine.
  • Preferred R is cyclohexyl, phenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 2,4-dinitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl.
  • R 2 and R 3 are hydrogen, fluorine, bromine, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, hydroxy, methoxy, or-(CH 2 ) 2 -,-( CH 2 ).
  • the present invention provides a novel thiazolidine-1,2, dione derivative having an excellent blood glucose lowering action and lipid lowering action. Further, the present invention provides an intermediate useful for producing the compound.
  • the thiazolidine-1,2,4-dione derivative represented by the formula (I) is compounded with a compound represented by the formula ( ⁇ ) and a compound represented by the formula (III) as shown in Scheme 1. It is obtained by condensing the compound (X ⁇ Y).
  • the compound (I la, X 2 NH 2 ) can be synthesized by a known method (Chem. Pharm. Bui 1., 30, 3580, (1982)).
  • the ester derivative (V) can be obtained by reacting with an acrylate in the presence of a copper catalyst.
  • HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) as condensing agents Used.
  • the reaction temperature is between 0 and 100 ° C, but it is usually carried out at room temperature.
  • the reaction time is between 0.5 and 24 hours.
  • the compound represented by the formula (I) is purified by ordinary purification means, for example, recrystallization, thin-layer chromatography such as silica gel, column chromatography, high-performance liquid chromatography and the like. You.
  • the compound (I) of the present invention forms a salt since it has an acidic nitrogen on the thiazolidine ring.
  • the salt is formed into a salt by a known method, for example, a neutralization method or an ion exchange resin method.
  • Salts include alkali metal salts such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and pharmaceutically acceptable amines. Examples of such amines include organic compounds such as methylamine, ethylamine, dimethylamine, getylamine, triethylamine, isopropylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, and arginine. Bases.
  • the compound of the present invention has one or more asymmetric carbon atoms and thus has optical isomers.
  • the present invention also includes those optical isomers and racemates.
  • NMR nuclear magnetic resonance spectrum
  • MS mass spectrometry spectrum
  • Example 1 Synthesis of 5- (4-carboxybenzyl) thiazolidine-l, 4-dione (II-lb) 16.5 g of aminoethyl benzoate are added to a mixture of acetone and water (165 ml, 55 ml), and then 106 ml of concentrated hydrochloric acid are added. To this mixture, 25 ml of an aqueous solution of 9.34 g of sodium nitrite was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. Then, 80 ml of ethyl acrylate is added to the mixture, 1.6 g of cuprous oxide is gradually added at about 40 ° C with stirring, and the mixture is further stirred for 2 hours.
  • the obtained compound (VII) 4.0 was dissolved in a mixture of 30 ml of 4N hydrochloric acid and 350 ml of ethanol, and the mixture was heated under reflux for 8 hours. Then, ethanol was distilled off under reduced pressure, 20 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 8 hours. After cooling, the precipitate was collected and washed with water to give 3.5 g of the desired compound.
  • 5- (4-aminobenzyl) thiazolidine mono 2,4-dione 1.5g, cyclohexyl S1 acid 960nig, HOBT 1.03g, WSC. It was dissolved in 20 ml and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, an aqueous solution of saturated sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 1.7 g of 5- (4- (2-cyclohexylacetamide) benzyl) -1,000azolidine-1,2,4-dione.
  • 5- (4-aminobenzyl) thiazolidine 1,2,4-dione 1.5 g, 2-pyridyl acetic acid hydrochloride 1.17 g, triethylamine 0.91 ⁇ 21, HOBT 1.03 g, WSC.HCl 1.3 g are dissolved in DMF 15 ml, and it is left overnight at room temperature. Stirred. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane, whereby powder is deposited. The powder was collected by filtration and dried to obtain 1.26 g of 5- (4- (2- (2-pyridyl) acetoamide) benzyl) thiazolidine-1,2 dione.
  • Table 1 shows the chemical structural formulas of the compounds of Examples 2 to 51. (Continued from Table 1)
  • KK Six KK-Ay mice confirmed to be positive for urinary sugar by Listaix (Bayer Sankyo), were orally administered 100 mg / kg of pioglitazone as a compound of the present invention and a control. Blood is collected from the tail vein immediately before administration and 24 hours after administration, and the amount of glucose in the serum obtained by centrifugation (Oorpm, lOmin) is measured by glucose B test (available from Wako Pure Chemical Industries, Ltd.). I asked. The results are shown in Table 2. The compound numbers correspond to the numbers in Examples, respectively.
  • the compound of the present invention is orally administered to KK-Ay mice whose urinary sugar was confirmed to be positive by Listaix (Bayer Sankyo), and serum triglyceride was measured by triglyceride G test kit (Wako Pure Chemical) As a result, the compound of the present invention showed an excellent serum triglyceride lowering effect.
  • compositions for oral or parenteral administration such as tablets, capsules, granules, and powders , Pills, suspensions, injections, suppositories and the like.
  • it is manufactured by an ordinary method using a usual pharmaceutical carrier.
  • the liquid may be in the form of an aqueous or oily suspension, emulsion, syrup, elixir or the like, or a lyophilized product which can be re-dissolved in water or another suitable solvent before use. Is raised.
  • These liquid preparations may contain conventional additives such as suspending agents, wetting agents, flavors, diluents or emulsifiers.
  • the dosage is 0.05 mg to 400 mg Z days, preferably 0.05 mg to 16 O mgZ days.
  • the dose when administered to a human for the purpose of treatment is appropriately adjusted depending on the severity of the disease, age, weight and the like.
  • the compound represented by the formula (I) of the present invention exhibits excellent blood glucose lowering action and lipid lowering action. According to the present invention, a novel compound having excellent properties as a therapeutic agent for diabetes can be provided.
  • the compound represented by the formula (lib) is important as an intermediate in producing the compound represented by the formula (lb), and via this compound, the compound of the present invention represented by (lb) The compound could be easily prepared.

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

Abstract

Nouveaux dérivés de thiazolidine-2,4-dione représentés par la formule générale (I), sels de ces dérivés et médicaments contre le diabète contenant ces dérivés ou sels. Dans ladite formule, R1 est cycloalkyle, substitué ou non, naphtyle ou un groupe hétérogène à un ou deux cycles comprenant un ou plusieurs atomes choisis parmi azote, oxygène et soufre; R2 et R3 sont indépendamment l'un de l'autre hydrogène, alkyle inférieur, cycloalkyle, alkoxy, halogéno, hydroxy (facultativement protégé), amino, phényl ou -(CH2)n- (considérant que n est un entier de 2 à 6); et A est une liaison amide.
PCT/JP1997/000639 1996-03-08 1997-03-03 Derives de thiazolidine-2,4-dione Ceased WO1997032863A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22313/97A AU2231397A (en) 1996-03-08 1997-03-03 Thiazolidine-2,4-dione derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/51532 1996-03-08
JP5153296 1996-03-08

Publications (1)

Publication Number Publication Date
WO1997032863A1 true WO1997032863A1 (fr) 1997-09-12

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PCT/JP1997/000639 Ceased WO1997032863A1 (fr) 1996-03-08 1997-03-03 Derives de thiazolidine-2,4-dione

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AU (1) AU2231397A (fr)
WO (1) WO1997032863A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001007423A1 (fr) * 1999-07-26 2001-02-01 Shionogi & Co., Ltd. Compositions medicamenteuses possedant une activite agoniste de la thrombopoietine
WO2001014350A1 (fr) * 1999-08-23 2001-03-01 Kyorin Pharmaceutical Co., Ltd. Derives de benzylthiazolidine-2,4-dione substitues
WO2001014351A1 (fr) * 1999-08-23 2001-03-01 Kyorin Pharmaceutical Co., Ltd. Derives de benzylthiazolidine-2,4-dione substitues
WO2001014349A1 (fr) * 1999-08-23 2001-03-01 Kyorin Pharmaceutical Co., Ltd. Derives de benzylthiazolidine-2,4-dione substitues
WO2001081328A3 (fr) * 2000-04-24 2002-02-21 Aryx Therapeutics Compositions et methodes destinees au traitement du diabete, de l'hyperlipidemie, de l'hypercholesterolemie et de l'atherosclerose
WO2002046161A1 (fr) * 2000-12-05 2002-06-13 Kyorin Pharmaceutical Co., Ltd. Derives de l'acide carboxylique substitues
WO2002059099A1 (fr) * 2001-01-26 2002-08-01 Shionogi & Co., Ltd. Composes cycliques presentant un agonisme envers le recepteur de thrombopoietine
WO2002059100A1 (fr) * 2001-01-26 2002-08-01 Shionogi & Co., Ltd. Composes halogene ayant un agonisme envers le recepteur de thrombopoietine
EP1103552A4 (fr) * 1998-08-07 2003-01-15 Takeda Chemical Industries Ltd Derives de benzothiepine, leur procede de preparation et leurs utilisations
WO2003024943A3 (fr) * 2000-04-24 2003-05-22 Aryx Therapeutics Matieres et procedes pour le traitement de diabetes, de l'hyperlipidemie, de l'hypercholesterolemie, et de l'atherosclerose
US6680387B2 (en) 2000-04-24 2004-01-20 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6780431B1 (en) 1999-08-23 2004-08-24 Kyorin Pharmaceutical Co., Ltd. Substituted benzylthiazolidine-2,4-dione derivatives
US6958355B2 (en) 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
JP2005535710A (ja) * 2002-08-09 2005-11-24 トランス　テック　ファーマ，インコーポレイテッド アリールおよびヘテロアリール化合物ならびに凝固を調節する方法
US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
US7691902B2 (en) 2005-12-28 2010-04-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01299289A (ja) * 1988-03-08 1989-12-04 Pfizer Inc 血糖降下剤としてのチアゾリジンジオン誘導体
JPH08143556A (ja) * 1994-11-15 1996-06-04 Terumo Corp ジオキソチアゾリジン誘導体及びそれを含有する医薬組成物
JPH08157462A (ja) * 1994-12-08 1996-06-18 Terumo Corp ジオキソチアゾリジン誘導体及びそれを含有する医薬組成物
WO1996038428A1 (fr) * 1995-06-02 1996-12-05 Kyorin Pharmaceutical Co., Ltd. Derives de n-benzyldioxothiazolidylbenzamide et leur procede de production
JPH08333355A (ja) * 1995-06-02 1996-12-17 Kyorin Pharmaceut Co Ltd Ｎ−置換ジオキソチアゾリジルベンズアミド誘導体及びその製造法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01299289A (ja) * 1988-03-08 1989-12-04 Pfizer Inc 血糖降下剤としてのチアゾリジンジオン誘導体
JPH08143556A (ja) * 1994-11-15 1996-06-04 Terumo Corp ジオキソチアゾリジン誘導体及びそれを含有する医薬組成物
JPH08157462A (ja) * 1994-12-08 1996-06-18 Terumo Corp ジオキソチアゾリジン誘導体及びそれを含有する医薬組成物
WO1996038428A1 (fr) * 1995-06-02 1996-12-05 Kyorin Pharmaceutical Co., Ltd. Derives de n-benzyldioxothiazolidylbenzamide et leur procede de production
JPH08333355A (ja) * 1995-06-02 1996-12-17 Kyorin Pharmaceut Co Ltd Ｎ−置換ジオキソチアゾリジルベンズアミド誘導体及びその製造法

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* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., Vol. 35, No. 10, (1992), HULIN, BERNARD et al., "Novel Thiazolidine-2,4-Diones as Potent Euglycemic Agents", p. 1853-1864. *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6531604B2 (en) * 1998-07-08 2003-03-11 Takeda Chemical Industries, Ltd. Benzothiepine derivatives, their production and use
EP1103552A4 (fr) * 1998-08-07 2003-01-15 Takeda Chemical Industries Ltd Derives de benzothiepine, leur procede de preparation et leurs utilisations
WO2001007423A1 (fr) * 1999-07-26 2001-02-01 Shionogi & Co., Ltd. Compositions medicamenteuses possedant une activite agoniste de la thrombopoietine
WO2001014349A1 (fr) * 1999-08-23 2001-03-01 Kyorin Pharmaceutical Co., Ltd. Derives de benzylthiazolidine-2,4-dione substitues
AU778720B2 (en) * 1999-08-23 2004-12-16 Kyorin Pharmaceutical Co. Ltd. Substituted benzylthiazolidine-2,4-dione derivatives
AU778723B2 (en) * 1999-08-23 2004-12-16 Kyorin Pharmaceutical Co. Ltd. Substituted benzylthiazolidine-2,4-dione derivatives
AU778721B2 (en) * 1999-08-23 2004-12-16 Kyorin Pharmaceutical Co. Ltd. Substituted benzylthiazolidine-2,4-dione derivatives
US6780431B1 (en) 1999-08-23 2004-08-24 Kyorin Pharmaceutical Co., Ltd. Substituted benzylthiazolidine-2,4-dione derivatives
US6730687B1 (en) 1999-08-23 2004-05-04 Kyorin Pharmaceutical Co., Ltd. Substituted benzylthiazolidine-2, 4-dione derivatives
WO2001014351A1 (fr) * 1999-08-23 2001-03-01 Kyorin Pharmaceutical Co., Ltd. Derives de benzylthiazolidine-2,4-dione substitues
US6545026B1 (en) 1999-08-23 2003-04-08 Kyorin Pharmaceutical Co., Ltd. Substituted benzylthiazolidine-2,4-dione derivatives
US6734199B1 (en) 1999-08-23 2004-05-11 Kyorin Pharmaceutical Co., Ltd. Substituted benzylthiazolidine-2, 4-dione derivatives
WO2001014350A1 (fr) * 1999-08-23 2001-03-01 Kyorin Pharmaceutical Co., Ltd. Derives de benzylthiazolidine-2,4-dione substitues
US6680387B2 (en) 2000-04-24 2004-01-20 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2001081328A3 (fr) * 2000-04-24 2002-02-21 Aryx Therapeutics Compositions et methodes destinees au traitement du diabete, de l'hyperlipidemie, de l'hypercholesterolemie et de l'atherosclerose
US7022722B2 (en) 2000-04-24 2006-04-04 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6958355B2 (en) 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2003024943A3 (fr) * 2000-04-24 2003-05-22 Aryx Therapeutics Matieres et procedes pour le traitement de diabetes, de l'hyperlipidemie, de l'hypercholesterolemie, et de l'atherosclerose
WO2002046161A1 (fr) * 2000-12-05 2002-06-13 Kyorin Pharmaceutical Co., Ltd. Derives de l'acide carboxylique substitues
US7176204B2 (en) 2000-12-05 2007-02-13 Kyorin Pahrmaceutical Co., Ltd. Substituted carboxylic acid derivatives
EP1361220A4 (fr) * 2001-01-26 2005-09-07 Shionogi & Co Composes cycliques presentant un agonisme envers le recepteur de thrombopoietine
WO2002059099A1 (fr) * 2001-01-26 2002-08-01 Shionogi & Co., Ltd. Composes cycliques presentant un agonisme envers le recepteur de thrombopoietine
WO2002059100A1 (fr) * 2001-01-26 2002-08-01 Shionogi & Co., Ltd. Composes halogene ayant un agonisme envers le recepteur de thrombopoietine
US7169931B2 (en) 2001-01-26 2007-01-30 Shionogi & Co., Ltd. Cyclic compounds exhibiting thrombopoietin receptor agonism
JP2005535710A (ja) * 2002-08-09 2005-11-24 トランス　テック　ファーマ，インコーポレイテッド アリールおよびヘテロアリール化合物ならびに凝固を調節する方法
US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
US7691902B2 (en) 2005-12-28 2010-04-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters

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