Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

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analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.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.
• 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 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 the use of a compound of the invention in the manufacture of a medicament 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.
• 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.
• X is O or H2
• Rl .and R ⁇ are independently selected from the group consisting of hydrogen, Ci-6 alkyl-, C2-6 alkenyl,
• C2-6 alkynyl C3-8 cycloalkyl- C3-8cycloalkyl Ci-6alkyl-, di(C3-8cyclo ⁇ Qkyl) Cl- ⁇ alkyl-, aryl, aryl Ci-6 alkyl-, di(aryl) Cl-6 alkyl-,
• aryl is an unsaturated 6-carbon ring, either unsubstituted or substituted with -OH, -NH2, Ci- ⁇ alkyl, C3-8cycloalkyl, or halogen;
• R ⁇ and R ⁇ are independently selected from the group consisting of
• R 8 and R 9 are independently hydrogen or Ci-4alkyl
• RlO and R 11 are independently hydrogen, C ⁇ _4alkyl, C3.7 cycloalkyl, or -CH2CF3,
• R > and Rl2, same or different, are hydrogen, Ci-6 alkyl-, C2-6 alkenyl-, C2-6 alkynyl, C3-8 cycloalkyl-, aryl, aryl Cl-6alkyl-
• aryl is an unsaturated 6-carbon ring either unsubstituted or substituted with -OH, -NH2, Ci-6alkyl, C3-8 cycloalkyl, or halogen.
• Rl and R ⁇ are independently selected from the group consisting of: hydrogen, Ci-6alkyl,
• aryl is unsubstituted, monosubstituted or disubstituted with halogen
• R ⁇ and R ⁇ are independently selected from the group consisting of
• R > and R ⁇ are hydrogen or -CH3, and pharmaceutically acceptable salts thereof.
• R1 is hydrogen
• R 2 is hydrogen, CH3, Ci-6 alkyl, and arylCi- ⁇ alkyl
• Rl is hydrogen
• Exemplifications also include the pharmaceutically acceptable salts of the above-identified compounds.
• 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.
• alkyl is intended to include both branched- and straight- chain saturated aliphatic hydrocarbon groups having, unless otherwise noted, 1-8 carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl).
• Alkenyl is intended to include both branched- and straight- chain unsaturated aliphatic hydrocarbon groups having, unless otherwise noted, 1-8 carbon atoms, e.g. ethenyl, propenyl, etc.
• Cycloalkyl includes cyclic saturated aliphatic hydrocarbon groups having 3-8 carbon atoms (e.g.
• C3- ⁇ cycloalkyl is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like).
• C7-I2 bicyclic alkyl is intended to include bicyclo[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl, l,l,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 Cl- 4 lower alkyl; hydroxy; alkoxy; halogen; amino.
• Alkoxy represents an alkyl group having 1-8 carbon atoms attached through an oxygen bridge.
• Halo as used herein, means fluoro, chloro, bromo and iodo.
• Counterrion is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluroacetate, perchlorate, nitrate, benzoate, maleate, tartrate, hemitartrate, benzene sulfonate, and the like.
• Formula I in the form of water- or oil-soluble or dispersible products
• 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, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nic
• 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 steary
• 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.
• 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 prothesis, 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.
• 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.
• compounds of the invention may be used to coat a stent in order to inhibit local coagulation which frequently occurs with stent implantation.
• 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. Likewise, 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. For treating ocular build up of fibrin, 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 specified 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. Consideration should be given to 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, disintegrating agents and coloring agents can also be incorporated into the mixture.
• suitable binders, lubricants, disintegrating 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, microcrystalline 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, heparin or warfarin, 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.
• fibrinogen receptor antagonists e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis
• anticoagulants such as aspirin, heparin or warfarin
• thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies
• lipid lowering agents including antihyperchol
• HMG CoA reductase inhibitors such as lovastatin or simvastatin, HMG CoA synthase inhibitors, etc.
• HMG CoA reductase inhibitors such as lovastatin or simvastatin, HMG CoA synthase inhibitors, etc.
• atherosclerosis For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors.
• 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.
• the following examples are illustrative of the invention as contemplated by the inventors and should not be construed as being limits on the scope or spirit of the instant invention.
• Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3- dimethylaminopropyl) carbodiimide.
• reagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3- dimethylaminopropyl) carbodiimide.
• Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester.
• solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
• Step B Ethyl 2-methoxy-6-methyl-3-nitropyridine 4-carboxylate
• the solution was dried (MgSO4), concentrated and chromatographed
• p-nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm-lM-1.
• 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.
• V f Vi 1 + [I]/Ki (1)
• 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.
• Thrombosis Research, No. 60, page 269(1990) by Kurtz et al were used to determine in vivo activity of the thrombin inhibitors of the invention.
• Male Sprague-Dawley rats (body weights 200-350 grams) were anesthetized with dial-urethane solution (0.1 ml/100 gm body weight i.p.), and a lateral tail vein was cannulated with a 23 gauge needle connected to a 12 inch length of PE50 tubing. The tubing was attached to a 3-way valve by a tubing adapter. Saline (control) or test compound, as appropriate, was administered via the tail vein catheter.
• a tracheostomy was performed with a 0.75 inch length of PE205 tubing.
• the right carotid artery is exposed and a 1.3 mm diameter Doppler flow probe was placed on the vessel.
• Body temperature was maintained at 37°C using a heat lamp.
• Rats were randomized to continuous intravenous infusions of saline or test compound administered via the tail vein.
• Test compound was administered at a rate of 10 ⁇ g/kg/min.
• Treatment infusions were initiated 60 min before the placement of a 3 mm square piece of Whatman No. 1 filter paper saturated with 35% FeCl3 onto the exposed carotid artery distal to the flow probe. Treatment infusions were continued for an additional 90 minutes after the application of FeCl3
• total infusion duration 150 minutes if thrombotic occlusions did not occur, or were terminated 30 minutes after thrombotic occlusion of the vessel.
• Time to occlusion was defined as the time from application of FeCl3 to thrombotic occlusion of the vessel.
• 3 ml blood samples were drawn by cardiac puncture into 0.3 ml of 3.8% sodium citrate.
• All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
• the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
• the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
• compositions of compound 1-7 tablets are shown below:
• Active IV, mannitol and microcrystalline cellulose were sieved through mesh screens of specified size (generally 250 to 750 ⁇ m) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water-soluble polymers and pigment.
• Tablet preparation via dry granulation Alternatively, a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size. The granules are then mixed with magnesium stearate and tabletted as stated above.
• Intravenous formulations of compound 1-7 were prepared according to general intravenous formulation procedures.
• compositions A-C are as follows:
• buffer acids such as 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 substituted for glucuronic acid.

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