WO1999027930A1 - Thrombin inhibitors - Google Patents
Thrombin inhibitors Download PDFInfo
- Publication number
- WO1999027930A1 WO1999027930A1 PCT/US1998/025362 US9825362W WO9927930A1 WO 1999027930 A1 WO1999027930 A1 WO 1999027930A1 US 9825362 W US9825362 W US 9825362W WO 9927930 A1 WO9927930 A1 WO 9927930A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mammal
- blood
- pharmaceutically acceptable
- compound
- 6alkyl
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
Definitions
- Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
- European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
- Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or ⁇ -keto carboxyl derivatives.
- Thrombin inhibitors described in prior publications contain sidechains of arginine and lysine. These structures show low selectivity for thrombin over other trypsin-like enzymes. Some of them show toxicity of hypotension and liver toxicity.
- European Publication 601 459 describes sulfonamido heterocyclic thrombin inhibitors, such as N-[4-[(aminoimino- methyl)amino]butyl]-l-[N-(2-naphthalenylsulfonyl)-L-phenylalanyl]-L- prolinamide.
- WO 94/29336 describes compounds which are useful as thrombin inhibitors.
- Compounds of the invention are bicyclic pyridone thrombin inhibitors. Dornow et al., Chem. Ber., Vol. 99, pp. 244-253 (1966) describes a procedure for making bicyclic pyridone s. SUMMARY OF THE INVENTION
- the invention relates to compounds of the formula:
- Rl is selected from the group consisting of hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
- R and R5 are independently selected from the group consisting of
- R8 and R9 are independently hydrogen or Ci-4alkyl, -OCH2CO2H,
- RlO and RU are independently hydrogen, C ⁇ _4alkyl, C3-7 cycloalkyl, or -CH2CF3,
- R6 is hydrogen
- R ⁇ is -CH3.
- l is selected from the group consisting of Ci-6 alkyl, C3-8cycloalkyl Cl-6alkyl, aryl C ⁇ _6alkyl and heteroaryl Cl-6alkyl.
- Exemplary compounds of the invention include
- the pharmaceutically-acceptable salts of the compounds of the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
- acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos
- Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
- the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
- lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
- long chain halides such as decyl, lauryl, myristyl and stearyl
- the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
- the compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.
- the invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
- These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
- the compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
- the invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
- These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
- the invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
- the invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation, preventing thrombus formation, inhibiting thrombin, inhibiting formation of fibrin, and inhibiting formation of blood platelet aggregates, in a mammal.
- Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
- patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
- p-nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm-lM-1.
- Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7-amino-4-trifluoromethyl coumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin.
- Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.5 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (Vo) or presence of inhibitor (Vi) were measured.
- the activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "Halo” or “halogen” as used herein, means fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, single negatively- charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
- C3-7cycloalkyl is intended to include cyclopropyl, cyclobutyl,
- C7-12 bicyclic alkyl is intended to include bicyclo[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl, 1,1,3-trimethyl- bicyclo[2.2.1]heptyl (bornyl), and the like.
- aryl as used herein except where noted, represents a stable 6- to 10-membered mono- or bicyclic ring system such as phenyl, or naphthyl.
- the aryl ring can be unsubstituted or substituted with one or more of C 1-4 lower alkyl; hydroxy; alkoxy; halogen; amino.
- heteroaryl refers to a 5- to 7- membered unsaturated ring containing 1 or 2 heteroatoms selected from O, N, or S.
- heterocycle or "heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 9- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- Bicyclic unsaturated ring systems include bicyclic ring systems which may be partially unsaturated or fully unsaturated.
- Partially unsaturated bicyclic ring systems include, for example, cyclopentenopyridinyl, benzodioxan, methylenedioxyphenyl groups.
- Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimid
- Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
- patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
- Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
- the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.
- Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g.
- obstruction or occlusion of a vein by a detached thrombus obstruction or occlusion of a lung artery by a detached thrombus
- cardiogenic thromboembolism e.g. obstruction or occlusion of the heart by a detached thrombus
- arterial thrombosis e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery
- atherosclerosis e.g. arteriosclerosis characterized by irregularly distributed lipid deposits
- Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds of the invention are useful for maintaining patency of indwelling catheters.
- cardiogenic thromboembolism examples include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.
- arterial thrombosis examples include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterial thrombosis, compounds of the invention are useful for maintaining patency in arteriovenous cannulas.
- Atherosclerosis examples include arteriosclerosis.
- devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems
- the thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions.
- they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
- An effective but non- toxic amount of the compound desired can be employed as an anti-aggregation agent.
- the compounds may be administered intraocularly or topically as well as orally or parenterally.
- the thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
- the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
- Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.
- the thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- the thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl- methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
- the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
- biodegradable polymers useful in achieving controlled release of a drug
- a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
- the dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
- An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
- Oral dosages of the thrombin inhibitors when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1- 0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis).
- an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day.
- a suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg.
- the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
- a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
- the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day.
- Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day.
- a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g.
- 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg.
- an 80 kg patient receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day.
- Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers.
- the solubility of the drug in choosing an
- the choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
- the compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
- thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
- carrier suitable pharmaceutical diluents, excipients or carriers
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
- suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
- Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
- Mannitol, micro crystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.
- the thrombin inhibitors can also be co-administered with suitable anti-platelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis.
- fibrinogen receptor antagonists e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis
- anticoagulants such as aspirin
- thrombolytic agents such as plasminogen activators or streptokinase
- thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
- Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.
- Typical doses of thrombin inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional antiplatelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
- 4-hydroxy-6-methyl-3-nitropyridone is chlorinated with, for example, phosphorous oxychloride, acetonitrile and benzyltriethylammonium chloride, to form
- I is then alkylated with for example, sodium hydride, dimethyl formamide and tert-butyl bromoacetate, to form
- R ⁇ NH2 is then added to II using, for example, ethyl alcohol under heated conditions, to form
- 3-1 was prepared in an analogous 6-step sequence outlined in Example 1 starting from intermediate 1-2 and aminomethylcyclopropane. The final compound was chromatographed with CHCI3/CH3OH/NH4OH as the eluent to afford the free base 3-1 as a white solid.
- An intravenous dosage form of the above-indicated active compound is prepared as follows:
- the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000522916A JP2001524522A (en) | 1997-12-01 | 1998-11-25 | Thrombin inhibitor |
EP98959636A EP1039907A4 (en) | 1997-12-01 | 1998-11-25 | Thrombin inhibitors |
AU15395/99A AU741766B2 (en) | 1997-12-01 | 1998-11-25 | Thrombin inhibitors |
CA002309347A CA2309347A1 (en) | 1997-12-01 | 1998-11-25 | Thrombin inhibitors |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6709697P | 1997-12-01 | 1997-12-01 | |
US60/067,096 | 1997-12-01 | ||
GBGB9809784.3A GB9809784D0 (en) | 1998-05-07 | 1998-05-07 | Thrombin Inhibitors |
GB9809784.3 | 1998-05-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999027930A1 true WO1999027930A1 (en) | 1999-06-10 |
Family
ID=26313616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/025362 WO1999027930A1 (en) | 1997-12-01 | 1998-11-25 | Thrombin inhibitors |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1039907A4 (en) |
JP (1) | JP2001524522A (en) |
AU (1) | AU741766B2 (en) |
CA (1) | CA2309347A1 (en) |
WO (1) | WO1999027930A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000040583A2 (en) * | 1999-01-08 | 2000-07-13 | Merck Patent Gmbh | Imidazo[4,5-c]-pyridine-4-on-derivatives |
EP1124822A1 (en) * | 1998-10-30 | 2001-08-22 | Merck & Co., Inc. | Thrombin inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
Citations (1)
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US5658930A (en) * | 1994-12-13 | 1997-08-19 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2224437A1 (en) * | 1995-06-27 | 1997-01-16 | Merck & Co., Inc. | Pyridinone-thrombin inhibitors |
WO1997030708A1 (en) * | 1996-02-22 | 1997-08-28 | Merck & Co., Inc. | Pyridinone thrombin inhibitors |
-
1998
- 1998-11-25 AU AU15395/99A patent/AU741766B2/en not_active Ceased
- 1998-11-25 WO PCT/US1998/025362 patent/WO1999027930A1/en not_active Application Discontinuation
- 1998-11-25 EP EP98959636A patent/EP1039907A4/en not_active Withdrawn
- 1998-11-25 CA CA002309347A patent/CA2309347A1/en not_active Abandoned
- 1998-11-25 JP JP2000522916A patent/JP2001524522A/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5658930A (en) * | 1994-12-13 | 1997-08-19 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
Non-Patent Citations (3)
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BANTICK J R, ET AL.: "NEW NON-PEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS 2: STRUCTURE - ACTIVITY RELATIONSHIPS OF A SERIES OF ANNELATED 2(1H)-PYRIDINONES", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 04, no. 01, 1 January 1994 (1994-01-01), AMSTERDAM, NL, pages 127 - 132, XP002916792, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(01)81134-3 * |
BROWN F J, ET AL.: "DESIGN OF ORALLY ACTIVE, NON-PEPTIDE INHIBITORS OF HUMAN LEUKOCYTE ELASTASE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 37, 1 January 1994 (1994-01-01), US, pages 1259 - 1261, XP002916793, ISSN: 0022-2623, DOI: 10.1021/jm00035a004 * |
See also references of EP1039907A4 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1124822A1 (en) * | 1998-10-30 | 2001-08-22 | Merck & Co., Inc. | Thrombin inhibitors |
EP1124822A4 (en) * | 1998-10-30 | 2002-04-03 | Merck & Co Inc | Thrombin inhibitors |
WO2000040583A2 (en) * | 1999-01-08 | 2000-07-13 | Merck Patent Gmbh | Imidazo[4,5-c]-pyridine-4-on-derivatives |
WO2000040583A3 (en) * | 1999-01-08 | 2000-09-21 | Merck Patent Gmbh | Imidazo[4,5-c]-pyridine-4-on-derivatives |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
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CA2309347A1 (en) | 1999-06-10 |
AU1539599A (en) | 1999-06-16 |
EP1039907A1 (en) | 2000-10-04 |
AU741766B2 (en) | 2001-12-06 |
JP2001524522A (en) | 2001-12-04 |
EP1039907A4 (en) | 2001-09-19 |
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