WO1999059591A1 - Pyrazinone thrombin inhibitors - Google Patents
Pyrazinone thrombin inhibitors Download PDFInfo
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- WO1999059591A1 WO1999059591A1 PCT/US1999/010730 US9910730W WO9959591A1 WO 1999059591 A1 WO1999059591 A1 WO 1999059591A1 US 9910730 W US9910730 W US 9910730W WO 9959591 A1 WO9959591 A1 WO 9959591A1
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- alkyl
- cycloalkyl
- substituted
- unsubstituted
- hydrogen
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- ZPZRZJQSVJSJSV-DEHPOCNJSA-N Cc1c(CNC(CC(CCC2=O)/C(/CSc3ccccc3)=C\CC/C=C2/NCCP)=O)ccc(N)n1 Chemical compound Cc1c(CNC(CC(CCC2=O)/C(/CSc3ccccc3)=C\CC/C=C2/NCCP)=O)ccc(N)n1 ZPZRZJQSVJSJSV-DEHPOCNJSA-N 0.000 description 1
- 0 Cc1c(CNC(CN(C(SC)=CC*=C2NCC*)C2=O)=O)ccc(N)n1 Chemical compound Cc1c(CNC(CN(C(SC)=CC*=C2NCC*)C2=O)=O)ccc(N)n1 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
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- 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
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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 a-keto carboxyl derivatives.
- the invention includes compounds 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 compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
- the compounds can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
- the invention also includes a compound 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 compounds 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.
- Compounds of the invention useful as thrombin inhibitors and having therapeutic value in for example, preventing coronary artery disease, have the following structure:
- A is chosen from one of the following radicals:
- ⁇ l and Y ⁇ are independently hydrogen, Cl-4 alkyl, Cl-4 alkoxy, C3-7 cycloalkyl, halogen, or trifluoromethyl ;
- R 9 is H or Cl-4 alkyl
- lO and RU are independently i) hydrogen, ii) C3-7 cycloalkyl, iii) aryl, iv) heteroaryl, v) heterocycloalkyl, vi) -(CH2)1-2NCH2CH3, vii) Cl-4 alkyl unsubstituted or substituted with one or more of: hydroxy, COOH, amino, aryl, heteroaryl, or heterocycloalkyl, or RlO and RU are joined to form a four to seven membered cycloalkyl ring unsubstituted or substituted with hydroxy, amino or aryl,
- Z is 0, S or CH2;
- R ⁇ is hydrogen, halogen, Cl-4 alkyl, Cl-4 alkoxy, CF3,
- W is hydrogen
- R2 a) R2, b) R 2 (CH2)mC(R 12 )2, where m is 0-3, and each R 12 can be the same or different, c) (R2)(OR 2 )CH(CH2) P , where p is 1-4,
- R2 can also form a ring with CH represented by C3-7 cycloalkyl, C7-12 bicylic alkyl, Cl ⁇ -16 tricylic alkyl, or a 5- to 7- membered mono- or bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S, h) R 2 0(CH2)p, wherein p is 1-4, j) (R 2 CH2)(R 2 CH2)CH, or k) R 2 (COOR 1 3)(CH2)r, where r is 1-4;
- R2 IS a) phenyl, unsubstituted or substituted with one or more of Cl-4 alkyl, Cl-4 alkoxy, halogen, hydroxy, COOH, CONH2 . CH2OH, CO2R', where R' is Cl-4 alkyl, or SO2NH2, b) naphthyl, c) biphenyl, d) a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring contains from one to four heteroatoms selected from the group consisting of N, 0 and S, and wherein the heterocyclic or non- heterocyclic ring is unsubstituted or substituted with halogen or hydroxy, e) Cl-7 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, C3-7 cycloalkyl,
- R3 is selected from the group consisting of a) Y 15 wherein
- Y is 0 or S(0) n , where n is 0, 1, or 2, and Rl5 is H, Cl-4 alkyl or C3-7 cycloalkyl, or
- Y is O or S(0)n, where n is 0, 1, or 2, and Rl6 is H, Cl-4 alkyl, C3-7 cycloalkyl or aryl;
- Rl3 i s selected from the group consisting of hydrogen, Cl-4 alkyl, C3-7 cycloalkyl, or trifluoromethyl;
- X is hydrogen, or halogen
- Rl2 is a) hydrogen, b) phenyl, unsubstituted or substituted with one or more of Cl-4 alkyl, Cl-4 alkoxy, halogen, hydroxy, COOH, CONH2, c) naphthyl, d) biphenyl, e) a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to four heteroatoms selected from the group consisting of N, O and S, f) Cl-4 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, heteroaryl, or heterocycloalkyl, g) CF 3 h) C3-7 cycloalkyl, i) C7-12 bicyclic alkyl, or j) C10-I6 tricyclic alkyl.
- Cl-7 alkyl unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl,
- X is hydrogen
- One of the compounds of the invention which is an oxidative metabolite of the compound
- Inhibitory activity of compounds of the invention is represented by "*”, indicating Ki greater than or equal to 20 nM, or "**", indicating Ki less than 20 nM. Values are as determined according to the in vitro assay described later in the specification.
- 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 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”, 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, trifluoro acetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
- C3-7cycloalkyl is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
- 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.
- the aryl ring can be unsubstituted or substituted with one or more of Cl-4 lower alkyl; hydroxy; alkoxy; halogen; amino.
- Examples of "aryl” groups include phenyl and naphthyl.
- 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, 0 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, thiophenyl, oxazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl,
- the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, 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, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate,
- 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 quatemized 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
- diamyl sulfates long chain halides
- the assays were carried out at 25°C in 0.05 M TRIS buffer pH 7.4, 0.15 M NaCl, 0.1% PEG. Trypsin assays also contained 1 mM CaCl2.
- a Thermomax 96-well plate reader was used to measure (at 405 nm) the time dependent appearance of p- nitroaniline.
- p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm ⁇ lM ⁇ l.
- Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 K m 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. Assuming competitive inhibition, and that unity is negligible compared K m /[S], [I]/e, and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (Ki) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of Vo/ i on [I] shown in equation 1.
- V 0 /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.
- the compounds of the invention are selective compounds, as evidenced by their inhibitory activity against human trypsin (represented by Ki), which is at least 1000 nM.
- 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 which may be treated or prevented with compounds of the invention 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.
- 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
- cardiogenic thromboembolism associated with heart disease examples include unstable angina
- Atherosclerosis includes arteriosclerosis.
- Examples of 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. 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 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:
- 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.
- HMG CoA reductase inhibitors such as lovastatin, 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 anti- platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
- Step A Starting l-ethoxycarbonylmethyl-3-hydroxy-6- methylpyrazinone is reacted with a dehydrating chloride source such as phosphorous oxychloride in toluene to give the 3-chloropyrazinone in Step A.
- a dehydrating chloride source such as phosphorous oxychloride in toluene
- Step B This is brominated under radical conditions in Step B using N- bromosuccinamide and an initiator such as benzoyl peroxide to give the bromomethyl derivative.
- Step C the bromine is displaced with the appropriate nucleophile such as thiophenol in the presence of a base such as triethylamine.
- the 3-chloro group is then displaced with the appropriate amine, in this case phenethylamine, to give the 3- aminopyrazinone in Step D.
- Step A Starting 2,6-dichloropyrazine is reacted with ammonia to give the aminopyrazine in Step A.
- the second chlorine is displaced with the appropriate nucleophile, in this case thiomethoxide in Step B to give the thioether.
- Step C the pyrazine is brominated using an electrophilic source of bromine such as NBS.
- the amino group as then hydrolysed via the diazonium salt to give the hydroxypyrazine in Step D.
- Alkylation with an acetate equivalent such as t -butyl bromoacetate in Step E gives the N-alkylated pyrazinone.
- Phosphorous oxychloride (2.8 mL, 30 mmol) was added to a stirred mixture of l-ethoxycarbonylmethyl-3-hydroxy-6- methylpyrazinone (5.3 g, 25 mmol) in dry toluene (50 mL) under argon. The resulting mixture was heated to 60 °C.
- Step B 6-Bromomethyl-3-chloro-l-ethoxycarbonylmethyl- pyrazinone
- N-Bromosuccinimide (2.61 g, 14.7 mmol) was added to a stirred solution of 3-chloro- l-ethoxycarbonylmethyl-6- methylpyrazinone (3.38 g, 14.7 mmol) in dry benzene (50 mL).
- Benzoyl peroxide (70%, 30 mg, 0.087 mmol) was added and the solution was heated to 75 °C. After 16 h the mixture was partitioned between methylene chloride and 5% sodium metabisulfite. The organic layer was dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (30% EtOAc/hexanes) to give the title compound as a crystalline solid:
- Step D l-Ethoxycarbonylmethyl-3-(2-phenethylamino)-6- phenylthiomethylpyrazinone
- Step E l-Hydroxycarbonylmethyl-3-(2-phenethyla ⁇ _ino)-6- phenylthiomethylpyrazinone
- Step F 3-(2-Phenethylamino)-6-phenylthiomethyl-l-(2-amino-6- methyl-5-methylcarboxamidomethylpyridinyl)-pyrazinone
- EDC.HC1 (2.3 g, 12.0 mmol) was added to a stirred solution of l-hydroxycarbonylmethyl-3-(2-phenethylamino)-6- phenylthiomethylpyrazinone (3.2 g, 8.0 mmol), 2-amino-5- aminomethyl-6-methylpyridine dihydrochloride (1.7 g, 8.0 mmol), HOBT.H 2 0 (2.3 g, 12.0 mmol) and NMM (7.7 mL, 70 mmol) in DMF (75 mL) at 0 °C. After 16 h the mixture was poured into water.
- Step G 3-(2-Phenethylamino)-6-phenylsulfinylmethyl-l-(2-amino- 6-methyl-5-methylcarboxamidomethylpyridinyl)- pyrazinone
- Step H 6-Hydroxymethyl-3-(2-phenethylamino)-l-(2-amino-6- methyl-5-methylcarboxamidomethylpyridinyl)-pyrazinone dihydrochloride
- Step E 3-Bromo-l- -butoxycarbonylmethyl-6-methylthio- pyrazinone
- Step F 6-Methylthio-3-(2-phenethylamino)-l-_ butoxycarbonyl- methylpyrazinone
- Step G 6-Methylthio-3-(2-phenethylamino)-l-hydroxycarbonyl- methyl-pyrazinone
- Step H 3-(2-Phenethylamino)-6-methylthio-l-(2-amino-6-methyl- 5-methylcarboxamidomethylpyridinyl)-pyrazinone dihydrochloride
- the title compound was prepared as the free base from 1- hydroxycarbonylmethyl-3-(2-phenethylamino)-6- methylthiopyrazinone and 2-amino-5-aminomethyl-6- methylpyridine dihydrochloride using the procedure of
- Step I 3-(2-Phenethylamino)-6-methylsulfinyl-l-(2-amino-6- methyl-5-methylcarboxamidomethylpyridinyl)-pyrazinone bis-trifluoroacetic acid salt
- Exact location of the hydroxylation was determined by the application of NMR on a sample isolated by preparative HPLC, to be on the methyl group of the pyrazinone ring (i.e., 3-(2-Phenethyleneamino)-6-hydroxymethyl-l-(2-methyl-6-amino-3- methylenecarboxamidomethyl)pyrazin-2-one) as evident by the appearance of a new methylene singlet at 4.35 ppm, which showed a long-range coupling with the singlet at 6.76 ppm due to the proton at 5- position of the pyrazinone ring.
- the urine was fractionated by HPLC.
- compositions A-I are 6-Hydroxvmethyl-3-(2-phenethylamino)-l- (2-amino-6-methyl-5-methylcarboxamido-methylpyridinyl)-pyrazinone; Active II is 6-Methoxymethyl-3-(2-phenethylamino)-l-(2-amino-6-methyl- 5-methylcarboxamidomethyl-pyridinyl)-pyrazinone dihydrochloride; Active III 6-Methylthiomethyl-3-(2-phenethylamino)-l-(2-amino-6- methyl-5-methylcarboxamido-methylpyridinyl)-pyrazinone bis- trifluoroacetic acid salt; and Active IV is 6-Methylsulfinyl-3-(2- phenethylamino)-l-(2-amino-6-methyl-5- methylcarboxamidomethylpyridinyl)-pyrazinone bis-trifluoroacetic
- 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 6-Methylsulfinyl-3-(2- phenethylamino)-l-(2-amino-6-methyl-5-methylcarboxamido- methylpyridinyl)-pyrazinone bis-trifluoroacetic acid_salt 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 aqueous formulations of 6-Methylsulfinyl-3-(2- phenethylamino)-l-(2-amino-6-methyl-5-methylcarboxamido- methylpyridinyD-pyrazinone bis-trifluoroacetic acid_salt were prepared according to general intravenous formulation procedures.
- Exemplary aqueous compositions A-C are as follows:
- Component A (mg/ml) B(mg/ml) C(mg/ml)
- 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.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP19990923087 EP1079835A4 (en) | 1998-05-19 | 1999-05-14 | Pyrazinone thrombin inhibitors |
AU39936/99A AU753479B2 (en) | 1998-05-19 | 1999-05-14 | Pyrazinone thrombin inhibitors |
CA002329914A CA2329914A1 (en) | 1998-05-19 | 1999-05-14 | Pyrazinone thrombin inhibitors |
JP2000549256A JP2002515434A (en) | 1998-05-19 | 1999-05-14 | Pyrazinone thrombin inhibitors |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8598098P | 1998-05-19 | 1998-05-19 | |
US60/085,980 | 1998-05-19 | ||
GBGB9813580.9A GB9813580D0 (en) | 1998-06-24 | 1998-06-24 | Pyrazinone thrombin inhibitors |
GB9813580.9 | 1998-06-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999059591A1 true WO1999059591A1 (en) | 1999-11-25 |
Family
ID=26313923
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/010730 WO1999059591A1 (en) | 1998-05-19 | 1999-05-14 | Pyrazinone thrombin inhibitors |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1079835A4 (en) |
JP (1) | JP2002515434A (en) |
AU (1) | AU753479B2 (en) |
CA (1) | CA2329914A1 (en) |
WO (1) | WO1999059591A1 (en) |
Cited By (24)
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WO2000069834A1 (en) * | 1999-05-19 | 2000-11-23 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
WO2000075134A1 (en) * | 1999-06-04 | 2000-12-14 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
WO2001087854A1 (en) * | 2000-05-18 | 2001-11-22 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
WO2002006248A2 (en) * | 2000-07-17 | 2002-01-24 | 3-Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
US6387911B1 (en) | 1999-11-23 | 2002-05-14 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
US6458952B1 (en) | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
WO2003028729A2 (en) * | 2001-10-03 | 2003-04-10 | Pharmacia Corporation | Prodrugs of substituted polycyclic compounds useful for selective inhibition of the coagulation cascade |
US6624180B2 (en) | 2000-11-20 | 2003-09-23 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6660885B2 (en) | 2000-03-13 | 2003-12-09 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
US6693121B2 (en) | 2000-04-05 | 2004-02-17 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US6875791B2 (en) | 2000-04-05 | 2005-04-05 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6908919B2 (en) * | 1999-05-19 | 2005-06-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
EP1586565A1 (en) * | 1999-05-19 | 2005-10-19 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US6969715B2 (en) | 2001-10-03 | 2005-11-29 | Pharmacia Corporation | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
US10335407B2 (en) | 2005-08-03 | 2019-07-02 | Sprout Pharmaceuticals, Inc. | Use of flibanserin in the treatment of obesity |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5455348A (en) * | 1991-08-19 | 1995-10-03 | Karl Thomae | 2-pyrrolidinones, pharmaceutical compositions containing these compounds and processes for preparing them |
US5866573A (en) * | 1997-04-21 | 1999-02-02 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3140790B2 (en) * | 1996-04-23 | 2001-03-05 | メルク エンド カンパニー インコーポレーテッド | Pyrazinone thrombin inhibitors |
-
1999
- 1999-05-14 EP EP19990923087 patent/EP1079835A4/en not_active Withdrawn
- 1999-05-14 JP JP2000549256A patent/JP2002515434A/en not_active Withdrawn
- 1999-05-14 WO PCT/US1999/010730 patent/WO1999059591A1/en not_active Application Discontinuation
- 1999-05-14 AU AU39936/99A patent/AU753479B2/en not_active Ceased
- 1999-05-14 CA CA002329914A patent/CA2329914A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5455348A (en) * | 1991-08-19 | 1995-10-03 | Karl Thomae | 2-pyrrolidinones, pharmaceutical compositions containing these compounds and processes for preparing them |
US5866573A (en) * | 1997-04-21 | 1999-02-02 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
Non-Patent Citations (1)
Title |
---|
See also references of EP1079835A4 * |
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Also Published As
Publication number | Publication date |
---|---|
AU3993699A (en) | 1999-12-06 |
EP1079835A1 (en) | 2001-03-07 |
AU753479B2 (en) | 2002-10-17 |
EP1079835A4 (en) | 2002-10-29 |
JP2002515434A (en) | 2002-05-28 |
CA2329914A1 (en) | 1999-11-25 |
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