[go: up one dir, main page]

WO1998048798A1 - Agents antithrombotiques - Google Patents

Agents antithrombotiques Download PDF

Info

Publication number
WO1998048798A1
WO1998048798A1 PCT/US1998/008700 US9808700W WO9848798A1 WO 1998048798 A1 WO1998048798 A1 WO 1998048798A1 US 9808700 W US9808700 W US 9808700W WO 9848798 A1 WO9848798 A1 WO 9848798A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
methoxy
mmol
benzo
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/US1998/008700
Other languages
English (en)
Inventor
Nickolay Yuri Chirgadze
Richard Waltz Harper
Todd Jonathan Kohn
Ho-Shen Lin
Jefferson R. Mccowan
Alan David Palkowitz
Daniel Jon Sall
Gerald Floyd Smith
Kumiko Takeuchi
Michael Robert Wiley
Minsheng Zhang
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to EP98923316A priority Critical patent/EP0993300A4/fr
Priority to CA002287901A priority patent/CA2287901A1/fr
Priority to JP54737098A priority patent/JP2001523255A/ja
Priority to US09/423,166 priority patent/US6284756B1/en
Priority to AU75635/98A priority patent/AU7563598A/en
Publication of WO1998048798A1 publication Critical patent/WO1998048798A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D409/10—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 carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen 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

  • This invention relates to thrombin inhibitors which are useful anticoagulants in mammals.
  • it relates to heterocyclic derivatives having high anticoagulant activity, and antithrombotic activity.
  • this invention relates to new inhibitors of thrombin, pharmaceutical compositions containing the compounds as active ingredients, and the use of the compounds as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction and cerebral thrombosis, general hypereoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflammatory process.
  • the antithrombotic agents are useful as anticoagulants in in vi tro applications.
  • thrombosis The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin.
  • Anticoagulation currently is achieved by the administration of heparins and coumarins .
  • Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins.
  • Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin) . Because antithrombin III levels vary in plasma and because clot-bound thrombin seems resistant to this indirect mechanism, heparins can be an ineffective treatment.
  • R 3 is -X 3 - (CH2) s -NR s R t or -CH2-R k , in which X 3 is a direct bond, methylene or 0; s is 1 or 2; provided that when s is 1, then X 3 is a direct bond; and R s and R fc are independently hydrogen or (1-3C) alkyl or the group NR s Rt is pyrrolidino, piperidino, or morpholino; and R k is 2-oxopyrrolidin-l-yl or 3- (1-oxoethyl) imidazolidin-1-yl ; R5 is hydrogen; and R 6 is hydrogen, hydroxy or methoxy.
  • R 3 is -X 3 - (CH2) s -NR s R t is: E is CR e in which R e is methoxy and R 3 is pyrrolidinomethyl .
  • R ⁇ is methoxy.
  • a pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a prodrug of a thrombin inhibiting compound of formula I (or of a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions.
  • a compound of formula I in which R f is an ester or hydroxymethyl group may act directly as a thrombin inhibitor or indirectly as a result of its biotransformation to a corresponding compound of formula I in which R f is carboxy.
  • the thrombin inhibiting compounds of formula I are believed to be novel and, thus, to constitute an additional aspect of the invention.
  • a compound of formula I may exhibit polymorphism or may form a solvate with water or an organic solvent .
  • the present invention also encompasses any such polymorphic form, any solvate or any mixture thereof .
  • a particular value for a (1-3C) alkyl group is, for example, methyl, ethyl, propyl or isopropyl, and for a (1-4C) alkoxy group is, for example, methoxy, ethoxy, isopropoxy or t-butoxy.
  • Acids commonly employed to form pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbut
  • optically active isomers and diastereomers of the compounds of formula I are also considered part of this invention.
  • Such optically active isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by standard methods affords substantially optically pure isomers of the compounds of the present invention or their precursors. Further details regarding resolutions can be obtained in Jacques, et al . , Enantiomers, Racemates, and Resolutions, John Wiley & Sons, 1981.
  • compositions of the invention comprise an effective thrombin inhibiting amount of a compound of formula I in association with a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutically acceptable carrier e.g. physiological saline (0.9 percent), 5 percent dextrose, Ringer's solution and the like.
  • the compound of the present invention can be formulated in unit dosage formulations comprising a dose between about 0.1 mg and about 1000 mg.
  • the compound is in the form of a pharmaceutically acceptable salt such as for example the sulfate salt, acetate salt or a phosphate salt.
  • An example of a unit dosage formulation comprises 5 mg of a compound of the present invention as a pharmaceutically acceptable salt in a 10 mL sterile glass ampoule.
  • Another example of a unit dosage formulation comprises about 10 mg of a compound of the present invention as a pharmaceutically acceptable salt in 20 mL of isotonic saline contained in a sterile ampoule.
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • the assay is carried out by mixing 50 ⁇ L buffer (0.03M Tris, 0.15M NaCl , pH 7.4) with 25 ⁇ L of human thrombin solution (purified human thrombin, Enzyme Research Laboratories, South Bend, Indiana, at 8 NIH units/mL) and 25 ⁇ L of test compound in a solvent (50% aqueous methanol (v:v) ) . Then 150 ⁇ L of an aqueous solution of the chromogenic substate (at 0.25 mg/mL) are added and the rates of hydrolysis of the substrate are measured by monitoring the reactions at 405 nm for the release of p-nitroaniline . Standard curves are constructed by plotting free thrombin concentration against hydrolysis rate.
  • Human factors X, Xa, IXa, XIa, and XIla are purchased from Enzyme Research Laboratories, South Bend, Indiana; human urokinase from Leo Pharmaceuticals, Denmark; and recombinant activated Protein C (aPC) is prepared at Eli Lilly and Co. substantially according to U.S. Patent 4,981,952.
  • Chromogenic substrates N-Benzoyl-Ile-Glu-Gly- Arg-p-nitroanilide (for factor Xa) ; N-Cbz-D-Arg-Gly-Arg-p- nitroanilide (for factor IXa assay as the factor Xa substrate) ; Pyroglutamyl-Pro-Arg-p-nitroanilide (for Factor XIa and for aPC) ; H-D-Pro-Phe-Arg-p-nitroanilide (for factor XIla) ; and Pyroglutamyl-Gly-Arg-p-nitroanilide (for urokinase) ; are purchased from Kabi Vitrum, Swiss,
  • Glu, Gly, Pro, Arg, Phe, Val, Leu and Lys are used to indicate the corresponding amino acid group isoleucine, glutamic acid, glycine, proline, arginine, phenylalanine, valine, leucine and lysine, respectively.
  • Materials Dog plasma is obtained from conscious mixed-breed hounds (either sex Butler Farms, Clyde, New York, U.S.A.) by venipuncture into 3.8 percent citrate.
  • Fibrinogen is prepared from fresh dog plasma and human fibrinogen is prepared from in-date ACD human blood at the fraction 1-2 according to previous procedures and specifications. Smith, Biochem. J. , 185, 1-11 (1980); and Smith, et al . , Biochemistry, 11, 2958-2967, (1972) .
  • Human fibrinogen (98 percent pure/plasmin free) is from American Diagnostica, Greenwich, Connecticut. Radiolabeling of fibrinogen 1-2 preparations is performed as previously reported.
  • Urokinase is purchased from Leo Pharmaceuticals, Denmark, as 2200 Ploug units/vial. Streptokinase is purchased from Hoechst-Roussel Pharmaceuticals, Somerville, New Jersey.
  • the carotid arteries are isolated via a midline ventral cervical incision.
  • a thermocouple is placed under each artery and vessel temperature is recorded continuously on a strip chart recorder.
  • a cuff of tubing (0.058 ID x 0.077 OD x 4 mm, Baxter Med. Grade Silicone) , cut longitudinally, is placed around each carotid directly above the thermocouple.
  • FeCl 3 hexahydrate is dissolved in water and the concentration (20 percent) is expressed in terms of the actual weight of FeCl 3 only.
  • 2.85 ⁇ L is pipetted into the cuff to bathe the artery above the thermocouple probe.
  • Arterial occlusion is indicated by a rapid drop in temperature. The time to occlusion is reported in minutes and represents the elapsed time between application of FeCl 3 and the rapid drop in vessel temperature (see K.D. Kurz , Thromb . Res . ., 60:269, 1990) .
  • plasma thrombin time serves as a substitute for the assay of parent compound on the assumption that observed increments in TT resulted from thrombin inhibition by parent only.
  • the time course of the effect of the thrombin inhibitor upon TT is determined after i.v bolus administration to anesthetized rats and after oral treatment of fasted conscious rats. Due to limitations of blood volume and the number of points required to determine the time course from time of treatment to the time when the response returns to pretreatment values, two populations of rats are used. Each sample population represents alternating sequential time points. The average TT over the time course is used to calculate area under the curve (AUC) .
  • the index of bioavailability is calculated by the formula shown below and is expressed as percent relative activity.
  • the area under the curve (AUC) of the plasma TT time course is determined and adjusted for the dose. This index of bioavailability is termed "% Relative Activity" and is calculated as AUC po Dose iv
  • PrepLC indicates preparative liquid chromatography using "Prep Pak (TM) " silica cartridges; radial chromatography indicates preparative chromatography using a “Chromatotron (TM) " instrument .
  • Methyl 4-bromomethylbenzoate (5.43 g; 23.7 mmol) was dissolved in 50 mL of THF. Pyrrolidine (5.0 mL; 2.5 eq) was added, and the resultant mixture stirred at room temperature for 2 h. Water was added and extraction carried out with EtOAc (4 x 50 mL) . The combined organics were dried by passage through Na2S ⁇ 4. The title compound was isolated by flash chromatography on silica gel, eluting with EtOAc, as a colorless liquid (4.77 g; 92%).
  • Methyl 4- (1-pyrrolidinylmethyl) benzoate (2.0g; 9.12 mmol) was dissolved in 20 mL of a mixture of THF/MeOH/- H2O (3:1:1). LiOH (0.46 g; 1.2 eq) was added, and the resultant mixture stirred at room temperature for 3 days. The mixture was neutralized with cone HCl, and the solvent removed under reduced pressure. The crude 4- (1-pyrrolidinylmethyl) benzoic acid hydrochloride was dried in vacuo for 2 h, and used without purification.
  • Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and 10.81 g (60.7 mmol) of NBS were combined in 250 L of CCI4 and heated to reflux.
  • AIBN (0.75 g; 5.5 mmol) was added, and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure . The residue was triturated with hexanes and filtered to give the title compound as white needles (11.7 g; 82% yield) .
  • Example 1-E By following essentially the procedure of Example 1-E, the title compound was prepared from the above phenol (Part D) and methyl 4-chlorobutyrate in 85% yield. Purification was effected by flash chromatography on silica gel, eluting with a gradient of EtOAc (100-94%) /Et3N (0-5%) /MeOH (0-2%) .
  • Triethylsilane (12.5 mL; 78.3 mmol) was added, followed by dropwise addition of 8.6 mL (112.0 mmol) of TFA. Upon completion of addition of TFA, the bath was removed and stirring was continued for 2 h. Saturated aqueous sodium bicarbonate (50 mL) was added, and extraction was carried out with EtOAc. The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound (4.45 g; 90% yield) was isolated as a colorless oil by flash chromatography on silica gel, eluting with a gradient of EtOAc (100-95%) /Et3N(0-5%) .
  • Part B The above methyl ether (4.5 g; 10.1 mmol) (Part B) was dissolved in 45 mL of dichloroethane under an argon atmosphere and cooled in an ice-water bath. To this was added ethanethiol (6.0 mL; 81.1 mmol) and 5.41 g (40.6 mmol) of aluminum chloride, and the mixture was stirred in the cold bath for 1 h. Saturated NaHC03 was added, and stirring was continued while warming to room temperature for 1 h. The title compound (0.23 g; 74% yield) was isolated by filtration and washed with water.
  • Example 1-E By following essentially the procedure of Example 1-E the title compound was prepared from the above phenol (Part D) and methyl 4-chlorobutyrate in 83% yield. Purification was effected by flash chromatography on silica gel, eluting with a gradient of EtOAc (100-94%) /Et3N(0-5%) /MeOH (0-2%) .
  • the title compound was prepared in 77% yield by treating 2- [4-trityloxy-3- (1, 3-dioxolan-2-yl) phenyl] - benzo [b] thiophene-3 -carboxaldehyde (Part C) with 4- [2- ( 1-pyrrolidinyl) ethoxy] phenyl magnesium bromide in THF at 0 °C. The reaction was quenched at 0 °C with saturated aqueous NH4CI solution and extracted with EtOAc. The combined organic layers were dried (MgS ⁇ 4) , evaporated and purified by flash chromatography.
  • Triisopropylsilyl trifluoromethanesulfonate (24.4 mL, 90.7 mmol) was added to a stirred solution of 2-(4-bromo- phenoxy) ethanol (15.1 g, 69.8 mmol) and anhydrous triethylamine (19.4 mL, 140 mmol) in anhydrous CH2CI2 (30 mL) at 0 °C under nitrogen atmosphere. The resultant mixture was stirred for 1 h.
  • the Grignard solution was cooled to room temperature and diluted with anhydrous THF (10 mL) before it was added to a stirred solution of 6 -benzyloxy-2- (dimethylamino) benzo [Jb] thiophen-3- yl 3 -methoxy-4 -[ (4 -morpholinyl) methyl] phenyl ketone (2.50 g, 4.84 mmol) in anhydrous THF (10 mL) at 0 °C under argon atmosphere. The resultant mixture was stirred at 0 °C for 1.5 h, then quenched with saturated aqueous NH4CI (15 mL) .
  • Example 28 To the product (1 g, 1.94 mmol) of Example 28 dissolved in anhydrous THF (80 mL) was added LAH (0.47 g, 12.4 mmol) at 0-5° C under nitrogen. The reaction mixture was stirred for 2 hours and quenched with ice-cold NaOH (0.5 M) solution. The organic layer was extracted with ethyl acetate, combined, dried and concentrated in vacuo. To this residue (0.88 g, 1.8 mmol) dissolved in dichloromethane ( ⁇ 50 mL) was added triethylsilane (1.73 L, 10.8 mmol) and TFA (0.42 mL, 5.4 mmol) .
  • CS2CO3 (0.43 g; 1.31 mmol) were combined in 2 mL of DMF and heated in an oil bath maintained at 80° C for 3 h. After cooling to room temperature, water (30 mL) was added, and extraction was carried out with EtOAc (4 x 25 mL) . The combined organics were washed with brine and dried by passage through Na2S ⁇ 4. Purification was effected by flash chromatography on silica gel, eluting with
  • 3-Bromopropanol (1.3 mL; 1.44 mmol) was combined with 2,6-lutidine (4.2 mL; 36.0 mmol) in CH 2 C1 (25 mL) in a flame-dried, argon-filled flask. The mixture was cooled to 0 °C and triisopropylsilyl triflate (5 mL; 18.7 mmol) was added. After standing at room temperature for 1.5 h, water was added and extraction was carried out with EtOAc. The combined organics were dried by passage through a 2 S04. Concentration under reduced pressure left the 3-bromo-l- triisopropylsilyloxypropane, which was used without further purification.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés représentés par la formule (I) (et leurs sels pharmaceutiquement acceptables), tels que définis dans la description, des procédés et des intermédiaires pour leur préparation. La présente invention concerne également des formulations pharmaceutiques comprenant les nouveaux composés, et leur utilisation comme inhibiteurs de thrombine.
PCT/US1998/008700 1997-04-30 1998-04-30 Agents antithrombotiques Ceased WO1998048798A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP98923316A EP0993300A4 (fr) 1997-04-30 1998-04-30 Agents antithrombotiques
CA002287901A CA2287901A1 (fr) 1997-04-30 1998-04-30 Agents antithrombotiques
JP54737098A JP2001523255A (ja) 1997-04-30 1998-04-30 抗血栓剤
US09/423,166 US6284756B1 (en) 1998-04-30 1998-04-30 Antithrombotic agents
AU75635/98A AU7563598A (en) 1997-04-30 1998-04-30 Antithrombotic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4517397P 1997-04-30 1997-04-30
US60/045,173 1997-04-30

Publications (1)

Publication Number Publication Date
WO1998048798A1 true WO1998048798A1 (fr) 1998-11-05

Family

ID=21936403

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/008700 Ceased WO1998048798A1 (fr) 1997-04-30 1998-04-30 Agents antithrombotiques

Country Status (5)

Country Link
EP (1) EP0993300A4 (fr)
JP (1) JP2001523255A (fr)
AU (1) AU7563598A (fr)
CA (1) CA2287901A1 (fr)
WO (1) WO1998048798A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8653131B2 (en) 2008-08-22 2014-02-18 Baxter Healthcare S.A. Polymeric benzyl carbonate-derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4133814A (en) * 1975-10-28 1979-01-09 Eli Lilly And Company 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents
US5576343A (en) * 1991-10-31 1996-11-19 Daiichi Pharmaceutical Co., Ltd. Aromatic amidine derivatives and salts thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4133814A (en) * 1975-10-28 1979-01-09 Eli Lilly And Company 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents
US5576343A (en) * 1991-10-31 1996-11-19 Daiichi Pharmaceutical Co., Ltd. Aromatic amidine derivatives and salts thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SALL D. J., ET AL.: "DIBASIC BENZO(B)THIOPHENE DERIVATIVES AS A NOVEL CLASS OF ACTIVE SITE-DIRECTED THROMBIN INHIBITORS. 1. DETERMINATION OF THE SERINE PROTEASE SELECTIVITY, STRUCTURE-ACTIVITY RELATIONSHIPS, AND BINDING ORIENTATION.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 40., no. 22., 24 October 1997 (1997-10-24), US, pages 3489 - 3493., XP002910456, ISSN: 0022-2623, DOI: 10.1021/jm9704107 *
See also references of EP0993300A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8653131B2 (en) 2008-08-22 2014-02-18 Baxter Healthcare S.A. Polymeric benzyl carbonate-derivatives
US8962549B2 (en) 2008-08-22 2015-02-24 Baxter International Inc. Polymeric benzyl carbonate-derivatives

Also Published As

Publication number Publication date
CA2287901A1 (fr) 1998-11-05
AU7563598A (en) 1998-11-24
JP2001523255A (ja) 2001-11-20
EP0993300A1 (fr) 2000-04-19
EP0993300A4 (fr) 2002-07-31

Similar Documents

Publication Publication Date Title
EP0863755B1 (fr) Diamines antithrombotiques
EP1027051B1 (fr) Agents antithrombotiques
US6172100B1 (en) Antithrombotic agents
US6284756B1 (en) Antithrombotic agents
US6350774B1 (en) Antithrombotic agents
WO1998048798A1 (fr) Agents antithrombotiques
EP1244655B1 (fr) Agents antithrombotiques
US6359136B1 (en) Antithrombotic agents
EP0980366B1 (fr) Agents antithrombotiques
US6288105B1 (en) Antithrombotic agents
US6133262A (en) Antithrombotic agents

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998923316

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2287901

Country of ref document: CA

Ref country code: JP

Ref document number: 1998 547370

Kind code of ref document: A

Format of ref document f/p: F

Ref country code: CA

Ref document number: 2287901

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 09423166

Country of ref document: US

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1998923316

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998923316

Country of ref document: EP