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WO2004062661A1 - Derives d'acide 2[-5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl] carboxylique comme inhibiteurs du facteur viia - Google Patents

Derives d'acide 2[-5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl] carboxylique comme inhibiteurs du facteur viia Download PDF

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Publication number
WO2004062661A1
WO2004062661A1 PCT/US2003/041636 US0341636W WO2004062661A1 WO 2004062661 A1 WO2004062661 A1 WO 2004062661A1 US 0341636 W US0341636 W US 0341636W WO 2004062661 A1 WO2004062661 A1 WO 2004062661A1
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WO
WIPO (PCT)
Prior art keywords
carbamimidoyl
biphenyl
benzoimidazol
dihydroxy
acid
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Ceased
Application number
PCT/US2003/041636
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English (en)
Inventor
Aleksandr Kolesnikov
Steven M. Torkelson
Tomas Vojkovsky
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Axys Pharmaceuticals Inc
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Axys Pharmaceuticals Inc
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Priority to AU2003300106A priority Critical patent/AU2003300106A1/en
Publication of WO2004062661A1 publication Critical patent/WO2004062661A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2

Definitions

  • the present invention relates to novel inhibitors of Factors Vila, IXa, Xa, Xla, in particular Factor Vila, pharmaceutical compositions comprising these inhibitors, and methods for using these inhibitors for treating or preventing thromboembolic disorders. Processes for preparing these inhibitors are also disclosed.
  • Thrombosis results from a complex sequence of biochemical events, known as the coagulation cascade.
  • a triggering event in coagulation is the binding of the serine protease Factor Vila (FVIIa) found in the circulation, to tissue factor (TF), a receptor which is found on the surface of blood vessels after damage or inflammation.
  • FVIIa serine protease Factor Vila
  • TF tissue factor
  • Factor Vila catalyzes the formation of the serine protease Factor Xa, which subsequently forms the final protease in the cascade, thrombin.
  • thrombosis ranges from acute myocardial infarction (AMI or heart attack) and unstable angina (UA) which occur in the key blood vessels of the heart (coronary vasculature) to deep vein thrombosis (DVT) which is the formation of blood clots in lower extremities which often follows orthopedic surgery on the hip and knee, as well as general abdominal surgery and paralysis.
  • AMI acute myocardial infarction
  • U unstable angina
  • DVT deep vein thrombosis
  • Formation of DVT is a risk factor for the development of pulmonary embolism (PE) in which part of a blood clot formed in the lower extremities, breaks off and travels to the lung where it blocks the flow of blood.
  • PE pulmonary embolism
  • Thrombosis can also be generalized systemically, with microclot formation occurring throughout the vascular system.
  • This condition known as disseminated intravascular coagulation (DIG)
  • DIG disseminated intravascular coagulation
  • Ebola certain viral diseases
  • sepsis certain cancers
  • Severe DIG can lead to a dramatic reduction in the coagulation factors due to the excessive activation of the clotting response which may result in multiple organ failure, hemorrhage and death.
  • the formation or embolization of blood clots in the blood vessels of the brain is the key event resulting in ischemic stroke.
  • Triggering factors that lead to stroke are atrial fibrillation or abnormal rhythm of the atria of the heart and atherosclerosis followed by thrombosis in the main artery leading from the heart to the brain (carotid artery). Over 600,000 individuals suffer strokes each year in the U.S. Two-thirds of these stroke victims suffer some disability, and one-third suffer permanent and severe disability. Accordingly, there is a need for antithrombotic agents for the treatment of a variety of thrombotic conditions. The present invention fulfills this and related needs.
  • this invention is directed to a compound selected from the group consisting of:
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound selected from the group consisting of:
  • this invention is directed to a method of treating a disease in an animal mediated by Factors Vila, IXa, Xa and/or Xla, preferably Vila, which method comprises administering to said animal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound selected from the group consisting of 2-[5-(5-carbamimidoyl-lH-benzoimidazol-2-yl)-5'- ureidomethyl-6,2'-dihydroxy-biphen-3-yl]-2-methylpropionic acid; 2-[5-(5-carbamimidoyl- lH-benzoimidazol-2-yl)-3 '-aminosulfonyl-6-hydroxy-biphen-3-yl]- 2-methylpropionic acid; 2-[5-(5-carbamimidoyl-lH-benzoimidazol-2-yl)-5'-fluoro-6,2'
  • the disorder is a thromboembolic disorder or cancer, more preferably a thromboembolic disorder.
  • the disorder is deep vein thrombosis.
  • this invention is directed to a method of treating a thromboembolic disorder in an animal which method comprises administering to said animal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound selected from the group consisting of 2-[5-(5-carbamimidoyl-lH- benzoimidazol-2-yl)-5'-ureidomethyl-6,2 , -dihydroxy-biphen-3-yl]-2-methylpropionic acid; 2- [5-(5-carbamimidoyl-lH-benzoimidazol-2-yl)-3'-aminosulfonyl-6-hydroxy-biphen-3-yl]-2- methylpropionic acid; 2-[5-(5-carbamimidoyl-lH-benzoimidazol-2-y
  • this invention is directed to a method for inhibiting the coagulation of a biological sample (e.g., stored blood products and samples) comprising the administration of a compound selected from the group consisting of 2-[5-(5-carbamimidoyl-lH- benzoimidazol-2-yl)-5'-ureidomethyl-6,2'-dihydroxy-biphen-3 -yl]-2-methylpropionic acid; 2- [5 -(5-carbamimidoyl- lH-benzoimidazol-2-yl)-3 ' -aminosulfonyl-6-hydroxy-biphen-3 -yl]-2- me thylpropionic acid; 2-[5-(5-carbamimidoyl- lH-benzoimidazol-2-yl)-5'-fluoro-6,2'- dihydroxy-biphen-3-yl]-2-methylpropionic acid; 5-(5-carbamimidoyl-lH-benz
  • this invention directed to the use of a compound selected from the group consisting of 2-[5-(5-carbamimidoyl-lH-benzoimidazol-2-yl)-5'-ureidomethyl-6,2'- dihydroxy-biphen-3-yl] -2-methylpropionic acid; 2-[5-(5-carbamimidoyl-lH-benzoimidazol- 2-yl)-3 '-aminosulfonyl-6-hydroxy-biphen-3-yl] -2-methylpropionic acid; 2-[5-(5- carbamimidoyl-lH-benzoimidazol-2-yl)-5'-fluoro-6,2'-dihydroxy-biphen-3-yl]-2- methylpropionic acid; 5-(5-carbamimidoyl-lH-benzoimidazol-2-yl)-5'-fluoro-6,2'-dihydroxy- biphen-3
  • the present invention also includes the prodrugs of above compounds.
  • the term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the above compounds, when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
  • Prodrugs of of above compounds include compounds wherein a hydroxy, amidino, ureido, or carboxylic group in the above compound is modified.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or acid functional groups in above compounds.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • Prodrugs of compounds of this invention are also within the scope of this invention.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulf
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier/excipient as used in the specification and claims includes both one and more than one such excipient.
  • a “therapeutically effective amount” means the amount of above compounds that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the compounds of the present invention may have asymmetric centers.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, enantiomeric, diastereomeric, racemic forms and all geometric isomeric forms of a structure representing a compound of the invention are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • the compounds of this invention inhibit Factors Vila, IXa, Xa, and Xla, in particular Factor Vila, and are therefore useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals.
  • venous thrombosis e.g. DVT
  • pulmonary embolism e.g. in myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis
  • systemic embolism usually from the atrium during atrial fibrillation or from the left ventricle after transmural myocardial infarction, or caused by congestive heart failure
  • prophylaxis of reocclusion i.e., thrombosis
  • thrombosis after thrombolysis, percutaneous trans-luminal angioplasty (PTA) and coronary bypass operations
  • PTA percutaneous trans-luminal angioplasty
  • coronary bypass operations the prevention of rethrombosis after microsurgery and vascular surgery in general.
  • Further indications include the therapeutic and/or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any other medical device; and anticoagulant treatment when blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in haemodialysis; the therapeutic and/or prophylactic treatment of idiopathic and adult respiratory distress syndrome, pulmonary fibrosis following treatment with radiation or chemotherapy, sepsis, septic shock, septicemia, inflammatory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary arterial disease and the formation of atherosclerotic plaques, cerebral arterial disease, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral arterial disease, ischaemia, angina (including unstable
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of a compound of this invention may range from approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.
  • compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of in general, a compound of the present invention in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of of the present invention.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for i ⁇ jectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the amount of the compound in a formulation can vary within the Ml range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of the present invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of this invention described below. [0129] The compounds of this invention can be administered alone or in combination with other compounds of the present invention or in combination with one or more other active ingredient(s).
  • a compound of this invention can be administered in combination with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, and a factor Xa inhibitor.
  • a thrombin inhibitor is Inogatran®, Melagatran® or prodrugs thereof which are disclosed in PCT Application Publication Nos. WO 94/29336 and WO 97/23499, the disclosures of which are incorporated herein by reference in their entirety.
  • Factor Xa inhibitors that may be used in the combination products according to the invention include those described in Current Opinion in Therapeutic Patents, 1993, 1173-1179 and in international patent applications WO 00/20416, WO 00/12479, WO 00/09480, WO 00/08005, WO 99/64392, WO 99/62904, WO 99/57096, WO 99/52895, WO 99/50263, WO 99/50257, WO 99/50255, WO 99/50254, WO 99/48870, WO 99/47503, WO 99/42462, WO 99/42439, WO 99/40075, WO 99/37304, WO 99/36428, WO 99/33805, WO 99/33800, WO 99/32477, WO 99/32454, WO 99/31092, WID 99/26941, WO 99/26933, WO 99/26932, WO 99/26919, WO 99/26918, WO 99/25720,
  • Factor Xa inhibitors also include those disclosed in international patent applications WO 96/10022, WO 97/28129, WO 97/29104, WO 98/21188, WO 99/06371, WO 99/57099, WO 99/57112, WO 00/47573, WO 00/78749, WO 99/09027 and WO 99/57113, the specific and generic disclosures in all of which documents are hereby incorporated by reference, as well as 4- ⁇ 4-[4-(5-chloroindol-2-ylsulfonyl) piperazine-l-carbonyl]phenyl ⁇ -pyridine-l -oxide and pharmaceutically acceptable derivatives thereof.
  • Preferred Factor Xa inhibitors include antistatin, tick anticoagulant protein and those known as SQ-311 and SQ-315 (see international patent application WO 98/57951); SN-292 (see international patent application WO 98/28282); SN-429 and SN 116 (see international patent application WO 98/28269); RPR-208707 (see international patent application WO 98/25611 at Example 48); XU-817 (see international patent application WO 98/01428); SF-324 and SF-303 (see international patent application WO 97/23212); YM 60828 (see international patent application WO 96/16940 at Example 75); FACTOREX (see US patent No.
  • anticoagulant agents that can be used in the combination therapy are those disclosed in U.S. Patent Applications Publication Nos. 20020065303, 20020061842, 20020058677, 20020058657, 20020055522, 20020055469, 20020052368, 20020040144, 20020035109, 20020032223, 20020028820, 20020025963, 20020019395, 20020019394,20020016326, 20020013314, 20020002183, 20010046974, 20010044537, 20010044536, 20010025108, 20010023292, 20010023291, 20010021775, 20010020020033, 20010018423, 20010018414, and 20010000179, which are incorporated herein by reference in their entirety.
  • Suitable formulations for use in administering melagatran and derivatives (including prodrugs) thereof are described in the literature, for example as described in inter alia international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO 97/39770, WO 97/45138, WO 98/16252, WO 99/27912, WO 99/27913, WO 00/12043 and WO 00/13671, the disclosures in which documents are hereby incorporated by reference.
  • suitable formulations for use in administering Factor Xa inhibitors and derivatives (including prodrugs) thereof are described in the literature, for example as described in the prior art documents relating to Factor Xa inhibitors that are mentioned hereinbefore, the disclosures in which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations, and in particular combined preparations including both melagatran/derivative and Factor Xa inhibitor/derivative may be achieved non-inventively by the skilled person using routine techniques.
  • melagatran, Factor Xa inhibitor, or derivative of either, in the respective formulation(s) will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • Suitable doses of melagatran, Factor Xa inhibitors and derivatives of either, in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients may be determined routinely by the medical practitioner or other skilled person, and include the respective doses discussed in the prior art documents relating to melagatran (or derivatives (including prodrugs) thereof), and to Factor Xa inhibitors, that are mentioned hereinbefore, the disclosures in which documents are hereby incorporated by reference.
  • tert-Butylamine (3.14 g, 3.0 mmol, 1.1 eq.) and triethylamine (5.94 g, 58.6 mmol, 1.5 eq.) were dissolved in dichloromethane (20 mL) and the solution was stirred at room temperature while 3-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) was added slowly. The mixture was stirred for 1 hour and then concentrated by evaporation under reduced pressure. The residue is taken up in 5% citric acid and ethyl acetate. The organic layer was washed repeatedly with brine and water and dried over anhydrous magnesium sulfate. Evaporation of the filtrate gave N-tert-butyl-3-bromobenzenesulfonamide as a white powder (10.94 g).
  • Tetrakis palladium (1.11 g, 0.98 mmol, 0.25 eq.) was added and the mixture was refluxed for 3 to 4 hours.
  • the reaction mixture was poured onto ethyl acetate and the mixture was washed several times with 5% citric acid solution, dried and concentration by evaporation.
  • the reaction mixture was filtered of solids and poured into IM hydrochloric acid (600 mL). The mixture was extracted with ethylacetate (x3) and the combined organic phases were backwashed with water and then brine, dried (MgSO 4 ) and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and hexanes were added to the solution until precipitation began to occur. The preciptitate was collected and washed with hexanes. Drying gave methyl 6-ber-zyloxy-5'-tert-butylsulfamoyl-5-formyl-2'-methoxy-biphenyl- 3-carboxylate (492 mg, 17%) as grey/brown powder.
  • EXAMPLE 1 In Vitro Factor Vila Inhibitor Assay [0275] Mixtures of human Factor Vila (typically supplied at 7 nM) and test compound (present at varying concentrations) in assay medium (comprising: ⁇ aCl, 150 mM (pH 7.4); CaCl 2 , 5 mM ; Tween-20, 0.05% ; Dade Innovin tissue factor [Dade Behring, Newark, DE, USA]; EDTA, 1.5 mM; and dimethylsulfoxide, 10 %) were incubated for 30 minutes at room temperature.
  • assay medium comprising: ⁇ aCl, 150 mM (pH 7.4); CaCl 2 , 5 mM ; Tween-20, 0.05% ; Dade Innovin tissue factor [Dade Behring, Newark, DE, USA]; EDTA, 1.5 mM; and dimethylsulfoxide, 10 %) were incubated for 30 minutes at room temperature.
  • EXAMPLE 2 In Vitro Factor Xa Inhibitor Assay [0278] Mixtures of human Factor Xa (typically supplied at 3 nM) (from Haematologic Technologies, Essex Junction, VT, USA) and test compound (varying concentrations) in assay medium (comprising: Tris, 50 mM (pH 7.4); NaCl, 150 mM; CaCl 2 , 5 mM; Tween-20, 0.05%; EDTA, ImM; and dimethylsulfoxide, 10%) were incubated for 30 minutes at room temperature.
  • assay medium comprising: Tris, 50 mM (pH 7.4); NaCl, 150 mM; CaCl 2 , 5 mM; Tween-20, 0.05%; EDTA, ImM; and dimethylsulfoxide, 10%
  • EXAMPLE 3 Pharmacokinetic Assay [0281] Rats with pre-implanted jugular vein catheters, which were filled with heparin/saline/PVP lock prior to shipment, were bought from Charles River. Three rats were selected for each study, weighed, and injected with test compound by tail vein injection. Any residual test compound was retained and stored at -70 °C for later analysis. [0282] Blood samples (0.25 mL each) were collected from the indwelling catheters at specified times over 120 hours. The catheters were flushed with physiological saline immediately after each collection and filled with heparinized saline after each 8, 24 and 48 hour collection. In the event that a catheter failed, blood samples were collected via the retro- orbital sinus under isoflurane anesthesia at the appropriate time.
  • Plasma samples were placed in 0.5 mL Microtainer® tubes (lithium heparin), shaken gently and stored on wet ice. The samples were centrifuged for 10 minutes at 2400 rpm in a refrigerated centrifuged. Plasma samples (0.1 mL) from each tube were transferred to 0.5 mL Unison polypropylene vials (Sun - 500210) and stored below -70 °C for later analysis by LC/MS-MS.
  • Coagulation assays were carried out based on the procedure described in Hougie, C. Hematology (Williams, W. J., Beutler, B., Erslev, A. J., and Lichtman, M. A., Eds.), pp. 1766-1770 (1990), McGraw-Hill, New York.
  • the assays were performed using normal human citrated plasma and were performed at 37 °C on a coagulometer (Electra 800) in accordance with the manufacturer's instructions (Medical Laboratory Automation- Pleasantville, New York). The instrument was calibrated with plasma immediately prior to collecting clotting times for samples with inhibitors. The aPTT and PT doubling concentrations were calculated by fitting inhibitor dose response curves to a modified version of the Hill equation.
  • Tablet Formulation [0288] The following ingredients are mixed intimately and pressed into single scored tablets.
  • Ingredient tablet mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5
  • Suspension Formulation [0290] The following ingredients are mixed to form a suspension for oral administration.
  • Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
  • Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilled water q.s. to 100 mL
  • Injectable Formulation [0291] The following ingredients are mixed to form an injectable formulation.
  • Ingredient Amount compound of this invention 1.2 g sodium acetate buffer solution, 0.4 M 2.0 mL HCl (1 N) or NaOH (1 N) q.s. to suitable pH water (distilled, sterile) q.s.to 20 mL
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol ® H-15 (triglycerides of saturated vegetable fatty acid; Riches- Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg

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Abstract

L'invention concerne de nouveaux inhibiteurs des facteurs VIIa, IXa, Xa, XIa, en particulier du facteur VIIa, des compositions pharmaceutiques contenant ces inhibiteurs et des procédés d'utilisation de ceux-ci pour traiter ou prévenir des troubles thrombo-emboliques. L'invention concerne aussi des procédés de préparation de ces inhibiteurs.
PCT/US2003/041636 2003-01-08 2003-12-23 Derives d'acide 2[-5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl] carboxylique comme inhibiteurs du facteur viia Ceased WO2004062661A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003300106A AU2003300106A1 (en) 2003-01-08 2003-12-23 2-'5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl!- carboxylic acid derivatives as factor viia inhibitors

Applications Claiming Priority (2)

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US43908303P 2003-01-08 2003-01-08
US60/439,083 2003-01-08

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WO2004062661A1 true WO2004062661A1 (fr) 2004-07-29

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US8778625B2 (en) 2002-12-03 2014-07-15 Pharmacyclics, Inc. 2-(2-hydroxybiphenyl-3-yl)-1H-Benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors
US9162986B2 (en) 2002-12-03 2015-10-20 Pharmacyclics Llc 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors
US8299110B2 (en) 2002-12-03 2012-10-30 Pharmacyclics, Inc. 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors
US7129264B2 (en) 2003-04-16 2006-10-31 Bristol-Myers Squibb Company Biarylmethyl indolines and indoles as antithromboembolic agents
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
US8729117B2 (en) 2004-06-02 2014-05-20 Pharmacyclics, Inc. Factor VIIa inhibitor
WO2005121102A3 (fr) * 2004-06-02 2006-01-26 Axys Pharm Inc Inhibiteur du facteur viia
US8415328B2 (en) 2004-06-02 2013-04-09 Pharmacyclics, Inc Factor VIIa inhibitor
US9181280B2 (en) 2004-06-02 2015-11-10 Pharmacyclics Llc Factor VIIa inhibitor
US8552046B2 (en) 2007-10-16 2013-10-08 Pharmacyclics, Inc. Manufacture, compositions and uses of coagulation factor VIIa modulator
EA019258B1 (ru) * 2007-10-16 2014-02-28 Фармасайкликс, Инк. КОМПОЗИЦИИ, СОДЕРЖАЩИЕ МОДУЛЯТОРЫ ФАКТОРА КОАГУЛЯЦИИ VIIa, И ИХ ПРИМЕНЕНИЕ
US8748468B2 (en) 2007-10-16 2014-06-10 Pharmacyclics, Inc. Manufacture, compositions and uses of coagulation factor VIIa modulator
WO2009052323A3 (fr) * 2007-10-16 2009-09-11 Pharmacyclics, Inc. Fabrication, compositions et utilisations d'un modulateur du facteur de coagulation viia
WO2020015717A1 (fr) * 2018-07-19 2020-01-23 Betta Pharmaceuticals Co., Ltd Immunomodulateurs, compositions et procédés associés
CN112424194A (zh) * 2018-07-19 2021-02-26 贝达药业股份有限公司 免疫调节剂及其组合物和制备方法
CN112424194B (zh) * 2018-07-19 2024-02-06 贝达药业股份有限公司 免疫调节剂及其组合物和制备方法
CN111793077A (zh) * 2019-04-01 2020-10-20 东莞市东阳光新药研发有限公司 Pd-1/pd-l1小分子抑制剂及其在药物中的应用
CN111793077B (zh) * 2019-04-01 2023-08-04 东莞市东阳光新药研发有限公司 Pd-1/pd-l1小分子抑制剂及其在药物中的应用

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