WO1997001338A1 - Inhibiteurs de la thrombine a base de pyridinone - Google Patents
Inhibiteurs de la thrombine a base de pyridinone Download PDFInfo
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- WO1997001338A1 WO1997001338A1 PCT/US1996/010778 US9610778W WO9701338A1 WO 1997001338 A1 WO1997001338 A1 WO 1997001338A1 US 9610778 W US9610778 W US 9610778W WO 9701338 A1 WO9701338 A1 WO 9701338A1
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- methyl
- pyridinone
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- amino
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- 0 Cc1c(CNC(CN2C3=O)=*C2=CC=C3NS(Cc(cc2)ccc2Cl)(=O)=O)ccc(N)n1 Chemical compound Cc1c(CNC(CN2C3=O)=*C2=CC=C3NS(Cc(cc2)ccc2Cl)(=O)=O)ccc(N)n1 0.000 description 3
- SFAAKBBANQLWSZ-UHFFFAOYSA-N CC(N(CC(NCC(CC1)CCC1N)=O)C1=O)=CC=C1NCCc1ccccc1 Chemical compound CC(N(CC(NCC(CC1)CCC1N)=O)C1=O)=CC=C1NCCc1ccccc1 SFAAKBBANQLWSZ-UHFFFAOYSA-N 0.000 description 1
- OENLWDVDUXTHLL-UHFFFAOYSA-N CC(N(CC(NCC(CC1)CCN1C(NO)=N)=O)C1=O)=CC=C1NS(Cc1ccccc1)(=O)=O Chemical compound CC(N(CC(NCC(CC1)CCN1C(NO)=N)=O)C1=O)=CC=C1NS(Cc1ccccc1)(=O)=O OENLWDVDUXTHLL-UHFFFAOYSA-N 0.000 description 1
- INDPQHZQXSBCCD-UHFFFAOYSA-N CC(N(CC(NCc(cc1)c(C)nc1N)=O)C1=O)=CC=C1NCCc1ccccc1 Chemical compound CC(N(CC(NCc(cc1)c(C)nc1N)=O)C1=O)=CC=C1NCCc1ccccc1 INDPQHZQXSBCCD-UHFFFAOYSA-N 0.000 description 1
- BIYJYMMRGQTLHD-UHFFFAOYSA-N CC(N(CC(NCc(cc1)c(C)nc1N)=O)C1=O)=CC=C1NS(Cc(cc1)ccc1Br)(=O)=O Chemical compound CC(N(CC(NCc(cc1)c(C)nc1N)=O)C1=O)=CC=C1NS(Cc(cc1)ccc1Br)(=O)=O BIYJYMMRGQTLHD-UHFFFAOYSA-N 0.000 description 1
- HGIFXVIBFRJKRZ-UHFFFAOYSA-N CC(N(CC(NCc(cc1)cnc1N)=O)C1=O)=CC=C1NC(Cc1ccccc1)=O Chemical compound CC(N(CC(NCc(cc1)cnc1N)=O)C1=O)=CC=C1NC(Cc1ccccc1)=O HGIFXVIBFRJKRZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- 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
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- 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
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 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.
- 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.
- Compounds of the invention are useful as thrombin inhibitors and have therapeutic value in for example, preventing coronary artery disease, and have the following structure:
- n 0-4, m is 1 or 2, and q is 0 or 1 , with the proviso that where n is 1 -4, q is 1 and m is 1 , and where n is 0, m is 1 or 2, and q is 0 or 1 , and where n is 0, m is 2 and q is 0, R 1 can be the same or different;
- R 2 O(CH 2 ) p , wherein p is 1-4; R 2 is
- phenyl unsubstituted or substituted with one or more of C 1 - 4 linear or branched alkyl, C 1 -4 linear or branched alkoxy, halogen, trifluoromethyl, hydroxy, COOH, or CONH 2 ,
- 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 three heteroatoms selected from the group consisting of N, O and S,
- A is chosen from one of the following Radicals:
- R 4 and R 5 are independently H, C 1 -4 linear or branched alkyl or alkoxy; C 3 -C 7 cycloalkyl; halogen; or trifluoromethyl;
- a useful class of compounds is the embodiment wherein W is R 1 or R 1 SO 2 .
- a further useful subclass of compounds is the embodiment wherein R 1 is R 2 (CH 2 ) n , (R 2 ) 2 CH(CH 2 ) n , phenyl, or (phenyl) 2 -CH.
- R 3 is C 1 -4 linear or branched alkyl and particularly wherein R 3 is methyl.
- R 4 is C 1 -4 linear or branched alkyl and R 5 is methyl or hydrogen and particularly wherein R 4 is methyl and R 5 is methyl or hydrogen and most particularly when R 4 is methyl and R 5 is hydrogen.
- W is R 1 SO 2 and A is Radical II (in which both configurations of the trans radical are contemplated within the scope of this invention).
- A is Radical II (in which both configurations of the trans radical are contemplated within the scope of this invention).
- Specific embodiments of this class include (note that the methyl group is conventionally indicated as a single bond attached to a ring):
- W is R 1 SO 2 and A is Radical III.
- Specific embodiments of this class include:
- W is R 1 SO 2 and A is Radical IV.
- Specific embodiments of this class include:
- 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.
- a racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
- 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 an 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, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
- C 3 -7cycloalkyl is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
- C 7- 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.
- heterocycle or "heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- 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 three 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.
- rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms are especially useful.
- 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,
- Morpholino is the same as morpholinyl.
- 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, camphorsulfonate, 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, tartrate, thiocyanate, tosylate, and undecanoate.
- 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.
- Thrombin inhibitors - therapeutic uses and methods of using
- 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
- 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 Hposome delivery systems, such as small unilamellar vesicles, large uni lamellar 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 0.1 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day and most preferably 1 -20 mg/kg/day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
- the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
- they can 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
- 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.
- thrombin inhibitors can also be co-administered with suitable anti-coagulation agents or thrombolytic agents such as
- 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. They may also be combined with heparin, aspirin, or warfarin.
- Methods A to E can be used to prepare the compounds of the present invention.
- Two methods for preparing compounds which contain radical IV as an end group are illustrated as Methods A and B and are exemplified by Examples I and XXV.
- methyl-2-hydroxy-6-methylpyridinone-3-carboxylate is alkylated with t-butylbromoacetate using a base such as cesium carbonate in DMF, or sodium hydride in THF.
- the t-butyl group is removed using a strong acid such as HCl gas and the amide of 4-aminomethyl-1-t-butoxycarbonylpiperidine is made using a standard coupling procedure.
- the methyl ester is hydrolyzed with lithium hydroxide and then a Curtius rearrangement (with acyl azide formation using DPPA and triethylamine as the base) gives the
- amidinopiperidine formation can be performed using an amidine transfer reagent such as aminoiminomethanesulfonic acid with triethylamine as a base in DMF.
- an amidine transfer reagent such as aminoiminomethanesulfonic acid with triethylamine as a base in DMF.
- One of the sulfonyl groups is then removed using aqueous lithium hydroxide.
- Amide couplings e.g., Step D in Method A, to form the compounds of this invention can be performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide.
- reagents such as dicyclohexylcarbodiimide, or 1-ethyl-3-(3-dimethyl-aminopropyl) 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 couplings 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.
- Methods A to E will allow different W, A and R 3 groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
- the starting pyridine in Step A can have as the 6-substituent, ethyl, isopropyl, cyclopropyl, and the like, to achieve the different operable values of R 3 .
- different W groups can be present by the use of an appropriate alkylating, carbonylating,
- Step H Use of, for example, an alkyl halide, alkoxycarbonyl halide, acyl halide, alkylsulfonyl halide, or alkyl isocyanate will yield the corresponding values of W where W is R 1 , R 1 OCO, R 1 CO, R 1 SO 2 , or
- Step A starting 6-methyl-2-hydroxy-pyridine carboxylic acid is reacted with diphenylphosphoryl azide (DPPA) and benzyl alcohol in Step A to afford the protected pyridinone.
- DPPA diphenylphosphoryl azide
- Step B benzyl alcohol
- This is alkylated with a glycine equivalent in Step B such as t-butylbromoacetate using a base such as cesium carbonate or sodium hydride.
- the t-butyl group is removed using a strong acid such as HCl gas in Step C and the amide of 4-aminomethyl-1-t-butoxycarbonylpiperidine is made using a standard coupling procedure in Step D.
- the CBZ group is removed in Step E via hydrogenation over a catalyst.
- the resulting amine is then reacted with the appropriate reagent, in this case benzylsulfonyl chloride, in Step F with pyridine as an acid scavenger and the BOC group is then removed in Step G using a strong acid such as HCl gas.
- Amidinopiperidine formation can be performed using an amidine transfer reagent such as aminoiminomethanesulfonic acid with triethylamine as a base in DMF.
- the product of step G can be reacted with cyanogen bromide to give the cyanamide in Step H which can be further reacted with hydroxylamine to give the hydroxyguanidine.
- Method B Modifications of Method B will allow different W, A and R 3 groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
- the starting pyridine in Step A can have as the 6-substituent, ethyl, isopropyl, cyclopropyl, and the like, to achieve the different operable values of R 3 .
- different W groups can be present by the use of an appropriate alkylating, carbonylating,
- Step F Use of, for example, an alkyl halide, alkoxycarbonyl halide, acyl halide,
- alkylsulfonyl halide, or alkyl isocyanate will yield the corresponding values of W where W is R 1 , R 1 OCO, R 1 CO, R 1 SO 2 , or
- hydroxide and the amide of trans -4-t-butoxycarbonylaminocyclohexylmethylamine is made using a standard coupling procedure.
- the nitro group is reduced by hydrogenation using a palladium catalyst under standard conditions.
- the amino group is alkylated by reduction with sodium triacetoxyborohydride of the imine formed from phenylacetaldehyde.
- the BOC group is removed using a strong acid such as HCl gas.
- Method C Modifications of Method C will allow different W, A and R3 groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
- the starting pyridine in Step A can have as the 6-substituent, ethyl, isopropyl, cyclopropyl, and the like, to achieve the different operable values of R3.
- different W groups can be present by the use of an appropriate alkylating, carbonylating,
- Step E Use of, for example, an alkyl aldehyde, alkyl halide, alkoxycarbonyl halide, acyl halide, alkylsulfonyl halide, or alkyl isocyanate will yield the following alkyl aldehyde, alkyl halide, alkoxycarbonyl halide, acyl halide, alkylsulfonyl halide, or alkyl isocyanate.
- Step A the CBZ group is removed from the product of Method B, Step B via hydrogenation over a catalyst.
- the resulting amine is then reacted with the appropriate reagent, in this case benzylsulfonyl chloride, in Step B with pyridine as an acid scavenger and the t-butyl ester is then removed under acidic conditions in Step C.
- the acid is then coupled in Step D with an amine, such as 2-t-butoxycarbonylamino-6-methyl-5-aminomethyl pyridine and the BOC group is removed in Step E with a strong acid.
- Method D Modifications of Method D will allow different W, A and R 3 groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
- the starting pyridinone in Step A can have as the 6-substituent, ethyl, isopropyl, cyclopropyl, and the like, to achieve the different operable values of R 3 .
- different W groups can be present by the use of an appropriate alkylating, carbonylating, sulfonylating, urealyting agent, and the like, in Step B.
- Use of, for example, an alkyl halide, alkoxycarbonyl halide, acyl halide, alkylsulfonyl halide, or alkyl isocyanate will yield the
- METHOD E For preparing compounds which contain a 6-trifluoromethylpyridinone, one can use the following illustrated Method E. As exemplified by Example XXIII, starting butyl-2-trifluoroacetylvinyl ether is condensed with nitroacetamide in the presence of a base such as sodium ethoxide in Step A. The resulting pyridinone is allylated using ⁇ -allyl palladium in Step B and the nitro- group is reduced in Step C. The amine is then reacted with the following illustrated Method E. As exemplified by Example XXIII, starting butyl-2-trifluoroacetylvinyl ether is condensed with nitroacetamide in the presence of a base such as sodium ethoxide in Step A. The resulting pyridinone is allylated using ⁇ -allyl palladium in Step B and the nitro- group is reduced in Step C. The amine is then reacted with the
- Step D with pyridine as an acid scavenger.
- olefin is oxidatively cleaved to give the aldehyde which is further oxidised to the acid in Step E.
- the acid is then coupled in Step F with an amine, such as 2-t-butoxycarbonylamino-6-methyl-5-aminomethyl pyridine and the BOC group is removed with a strong acid.
- Method E Modifications of Method E will allow different W and A groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
- different W groups can be present by the use of an appropriate alkylating, carbonylating, sulfonylating, urealyting agent, and the like, in Step E.
- alkylsulfonyl halide, or alkyl isocyanate will yield the corresponding values of W where W is R 1 , R 1 OCO, R 1 CO, R 1 SO 2 , or
- NMR field strength employed in the below given examples was either 300 or 400 MHz.
- Step D Methyl-6-methyl-1-(4-methylenecarboxamidomethyl-1- t-butoxycarbonylpiperidinyl)-2-pyridinone-3-carboxylate
- EDC hydrochloride (2.34 g, 12.18 mmol) was added to a stirred mixture of methyl-6-methyl-1-methylenecarboxy-2-pyridinone-3-carboxylate (2.0 g, 8.88 mmol), 4-aminomethyl-1-t-butoxycarbonyl-piperidine (3.0 g, 14.21 mmol), HOBT (1.65 g, 12.18 mmol) and diisopropylethylamine (3.6 ml, 10.30 mmol) in dry DMF (20 ml).
- Step E 6-Methyl-1-(4-methylenecarboxamidomethyl-1-t- butoxy-carbonylpiperidinyl)-2-pyridinone-3-carboxylic acid
- Lithium hydroxide (8.23 ml of 1 M aqueous solution) was added to a stirred solution of methyl-6-methyl-1-(4-methylenecarbox- amidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone-3-carboxy late (2.31 g, 5.48 mmol) in 1 : 1 methanol/THF (16 ml).
- Step F 3-Benzyloxycarbonylamino-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2- pyridinone
- DPPA (1.53 ml, 7.11 mmol) was added to a stirred solution of 6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone-3-carboxylic acid (1.93 g, 4.74 mmol) and triethylamine (0.99 ml, 7.11 mmol) in dry dioxane (10 ml) and the resulting solution was heated to reflux. After 48 h more triethylamine (0.99 ml, 7.11 mmol) and benzyl alcohol (0.74 ml, 7.11 mmol) were added and the solution was refluxed for a further 24 h.
- Step G 3-Amino-6-methyl-1-(4-methylenecarboxamidomethyl-1 - t-butoxycarbonylpiperidinyl)-2-pyridinone
- Step H 3-N,N-(Bis-benzylsulfonyl)amino-6-methyl-1-(4- methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone
- Benzylsulfonyl chloride (51 mg, 0.27 mmol) was added to a stirred solution of 3-amino-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone (68 mg, 0.18 mmol) and triethylamine (0.075 ml, 0.54 mmol) in dry methylene chloride (0.5 ml).
- Step I 3-Benzylsulfonylamino-6-methyl-1-(4-methylenecarboxamidomethyl-1-amidinopiperidinyl)-2-pyridinone HCl Gas was bubbled through a solution of 3-N,N-(Bis-benzylsulfonyl)amino-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone (30 mg, 0.044 mmol) in 1 : 1 methylene chloride/ethyl acetate (2 ml) for 5 min at 0°C. After a further 1 h the solution was degassed with argon and was evaporated in vacuo to a glass.
- Step C 3-Nitro-6-methyl-1-(methylenecarboxamido-trans-4-t- butoxycarbonylaminocyclohexylmethyl)--2-pyridinone
- EDC hydrochloride (249 mg, 1.30 mmol) was added to a stirred mixture of 3-nitro-6-methyl-1-methylenecarboxy-2-pyridinone (212 mg, 1.00 mmol), trans-4-t-butoxycarbonylaminocyclohexylmethylamine (228 mg, 1.00 mmol), HOBT (176 mg, 1.30 mmol) and
- Step D 3- Amino-6-methyl-1-(methylenecarboxamido-trans-4- t-butoxycarbonylaminocyclohexylmethyl)-2-pyridinone
- Step E 3-(2-Phenylethylamino)-6-methyl-1-(methylenecarboxamido-trans-4-t-butoxycarbonylaminocyclohexylmethyl)-2-pyridinone
- Step F 3-(2-Phenylethylamino)-6-methyl-1-(methylenecarboxamido-trans-4-aminocyclohexylmethyl)-2-pyridinone
- Step A 3-Benzylsulfonylamino-6-methyl-1 - (methylenecarboxamido-trans-4-t-butyloxycarbonylamino-cyclohexylmethyl)-2-pyridinone
- EDC hydrochloride 50 mg, 0.260 mmol was added to a stirred mixture of 3-benzylsulfonylamino-6-methyl-1-methylenecarboxy-2-pyridinone (73 mg, 0.217 mmol), trans-4-t-butoxycarbonylaminocyclohexylmethylamine (51 mg, 0.260 mmol), HOBT (35 mg, 0.260 mmol) and triethylamine (0.073 ml, 0.521 mmol) in dry DMF (3 ml).
- Step B 3-Benzylsulfonylamino-6-methyl-1 -(methylenecarboxamido-trans-4-aminocyclohexylmethyl)-2-pyridinone
- Step C 3-Amino-6-methyl-1-(t-butyl-methylenecarboxy)-2- pyridinone
- Step D 3-Benzylsulfonylamino-6-methyl-1 -(t-butyl-methylenecarboxy)-2-pyridinone
- the cloudy ethyl acetate layer was dried (Na 2 SO 4 ) and was evaporated in vacuo to give the desired product (1.42 g) as a pale pink solid. More product (0.97 g as a pale yellow solid) was recovered by washing the drying agent and filtration apparatus with methylene chloride.
- Step E 3-Benzylsulfonylamino-6-methyl-1 -methylenecarboxy-2- pyridinone
- HCl gas was bubbled through a stirred suspension of 3-benzylsulfonylamino-6-methyl-1-(t-butyl-methylenecarboxy)-2-pyridinone (1.42 g, 3.62 mmol) in ethyl acetate (15 ml) at 0°C until a solution had formed which was saturated with HCl. After 1 h at RT a thick suspension had formed. The mixture was degassed with argon and filtered to give the title compound (0.865 g, 71 %) as a solid:
- Step F 3-Benzylsulfonylamino-6-methyl-l -(2-amino-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
- EDC hydrochloride (34.2 mg, 0.178 mmol) was added to a stirred mixture of 3-benzylsulfonylamino-6-methyl-1-methylenecarboxy-2-pyridinone (50.0 mg, 0.149 mmol), 2-amino-4-methylaminopyridine (18.3 mg, 0.149 mmol), HOBT (24.1 mg, 0.178 mmol) and triethylamine (0.050 ml, 0.359 mmol) in dry DMF (1 ml). After 64 h the reaction was diluted with ethyl acetate and was washed with water, saturated sodium hydrogen carbonate solution, water and brine, dried (Na 2 SO 4 ) and evaporated in vacuo to a solid.
- DPPA (35.6 ml, 165 mmol) was added to a stirred solution of 2-hydroxy-6-methylpyridine-3-carboxylic acid (22.97 g, 165 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300 ml) and the resulting solution was heated to reflux. After 16 h more triethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 150 mmol) were added and the solution was refluxed for a further 24 h. The reaction was concentrated in vacuo to remove most of the volatiles.
- Step C 3-Amino-6-methyl-1-(t-butyl-methylenecarboxy)-2- pyridinone
- Step D 3-Benzylsulfonylamino-6-methyl-1 -(t-butyl-methylenecarboxy)-2-pyridinone
- Benzylsulfonyl chloride (3.146 g, 16.5 mmol) was added to a solution of 3-amino-6-methyl-1-(t-butyl-methylenecarboxy)-2-pyridinone (3.55 g, 14.9 mmol) in pyridine (30 ml) at 0° C and as the resulting solution was stirred a thick precipitate formed. After 1 h the reaction mixture was evaporated in vacuo to a thick paste. This was partitioned between methylene chloride and 10% potassium hydrogen sulfate solution.
- HCl gas was bubbled through a stirred suspension of 3-benzylsulfony lamino-6-methyl-1-(t-butyl-methylenecarboxy)-2-pyridinone (5.70 g, 14.52 mmol) in ethyl acetate (60 ml) at 0°C until a solution had formed which was saturated with HCl. After 1.5 h at RT a thick suspension had formed.
- Step F 3-Benzylsulfonylamino-6-methyl-1 -(2-amino-6-methyl- 5-methylenecarboxamidomethylpyridinyl)-2-pyridinone DCC (0.61 g, 2.98 mmol) was added to a stirred solution of 3-benzylsulfonylamino-6-methyl-1-methylenecarboxy-2-pyridinone ( 1.00 g, 2.98 mmol) and 2-t-butoxycarbonylamino-6-methyl-5-methylaminopyridine (0.71 g, 2.98 mmol) in methylene chloride (6 ml). After 3 h the reaction was filtered through celite and evaporated in vacuo to a pale yellow foam.
- Step C 3-Nitro-1-(2-t-butoxycarbonylamino-6-methyl- 5-methylenecarboxamidomethylpyridinyl)-2-pyridinone
- EDC hydrochloride (249 mg, 1.30 mmol) was added to a stirred mixture of 3-nitro-1-methylenecarboxy-2-pyridinone (198 mg, 1.00 mmol), 2-t-butoxycarbonylamino-5-methylamino-6-methylpyridine (237 mg, 1.00 mmol), HOBT (176 mg, 1.30 mmol) and triethylamine (0.32 ml, 2.30 mmol) in dry DMF (4 ml). After 16 h the solvent was evaporated in vacuo, and the residue was partitioned between methylene chloride and water. The organic layer was dried (Na 2 SO 4 ) and
- Step D 3- Amino-1-(2-t-butoxycarbonylamino-6-methyl- 5-methylenecarboxamidomethylpyridinyl)-2-pyridinone
- Step E 3-Benzylsulfonylamino-1-(2-t-butoxycarbonylamino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone
- Step F 3-Benzylsulfonylamino-1-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
- Step C 3-Benzylsulfonylamino-6-methyl-1 -(2-amino-3-methyl- 5-methylenecarboxamidomethylpyridinyl)-2-pyridinone
- EDC hydrochloride (69 mg, 0.36 mmol) was added to a stirred mixture of 3-benzylsulfonylamino-6-methyl-1-methylenecarboxy-2-pyridinone (101 mg, 0.30 mmol), 2-amino-5-methylamino-3-methylpyridine (63 mg, 0.30 mmol), HOBT (49 mg, 0.36 mmol) and triethylamine (0.22 ml) in dry DMF (1.2 ml). After 64 h the reaction was evaporated in vacuo then was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried (Na 2 SO 4 ) and evaporated in vacuo to a glass. The crude product was purified by preparative HPLC (C 18 ,
- HCl gas was bubbled through a stirred suspension of 3-benzloxycarbonylamino-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone (0.12 g) in ethyl acetate (5 ml) at 0° C until a solution had formed which was saturated with HCl.
- Step A 3-(3-Phenylpropionamido)-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2- pyridinone
- Hydrocinnamoyl chloride 56 mg, 0.329 mmol was added to a stirred solution of 3-amino-6-methyl-1-(4-methylene-carboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone (83 mg, 0.220 mmol) and triethylamine (92 ⁇ l, 0.660 mmol) in methylene chloride (1 ml).
- Step B 3-(3-Phenylpropionamido)-6-methyl-1-(4-methylenecarboxamidomethyl-1-amidinopiperidinyl)-2-pyridinone 3-(3-Phenylpropionamido)-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone
- Step A 3-(3,3-Diphenylpropionamido)-6-methyl-1-(4-methylenecarboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2- pyridinone
- EDC hydrochloride 75 mg, 0.393 mmol was added to a stirred mixture of 3-amino-6-methyl-1-(4-methylene-carboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone (99 mg, 0.262 mmol), 3,3-diphenylpropionic acid (71 mg, 0.314 mmol), HOBT (53 mg, 0.393 mmol) and diisopropylethylamine (0.14 ml, 0.786 mmol) in dry DMF (1 ml). After 64 h the reaction was diluted with ethyl acetate and was washed with water, dried (MgSO 4 ) and evaporated in vacuo.
- Step B 3-(3,3-Diphenylpropionamido)-6-methyl-1-(4-methylenecarboxamidomethyl-1-amidinopiperidinyl)-2-pyridinone 3-(3,3-Diphenylpropionamido)-6-methyl-1-(4-methylene ⁇ carboxamidomethyl-1-t-butoxycarbonylpiperidinyl)-2-pyridinone
- Step A 3-p-Toluenesulfonylamino-6-methyl-1-(4- methylenecarboxamidomethyl-1-t- butoxycarbonylpiperidinyl)-2-pyridinone
- Step A 3-p-Toluenesulfonylamino-6-methyl-1-(methylene- carboxamido-trans-4-t-butoxycarbonylaminocyclo- hexylmethyl)-2-pyridinone
- Step B 3-p-Toluenesulfonylamino-6-methyl-1-(methylenecarboxamido-trans-4-aminocyclohexylmethyl)-2-pyridinone
- Step A 3-Phenylacetamido-6-methyl-1-(2-t-butoxycarbonylamino- 5-methylenecarboxamidomethylpyridinyl)-2-pyridinone
- Phenylacetyl chloride (18 mg, 0.1 14 mmol) was added to a stirred solution of 3-amino-6-methyl-1-(2-t-butoxycarbonylamino-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone (40 mg, 0.103 mmol) in pyridine ( 1 ml). After 1 h the reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo.
- Step B Phenylacetamido-6-methyl-1-(2-amino-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
- the title compund was prepared from 1-napthylsulfonyl chloride (64 mg, 0.283 mmol) and 3-amino-6-methyl-1-(2-t-butoxycarbonylamino-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone (0.100 g, 0.258 mmol) using the procedure of EXAMPLE XIII, as a white solid, m.p.
- Step B 3-(4-Trifluoromethylbenzylsulfonyl)amino-6-methyl- 1-(2-t-butoxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
- the title compound was prepared from 3-amino-6-methyl-1-(2-t-butoxycarbonylamino-6-methyl-5-methylenecarboxamido-methylpyridinyl)-2-pyridinone (0.100 g, 0.249 mmol) and 4-trifluoromethylbenzylsulfonyl chloride (64 mg, 0.249 mmol) using the procedure of EXAMPLE XIII, as a white solid (60 mg), m.p.
- the title compound was prepared from 3-amino-6-methyl-1-(2-t-butoxycarbonylamino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone (0.100 g, 0.249 mmol) and 2-napthylsulfonyl chloride (56 mg, 0.249 mmol) using the procedure of EXAMPLE Xffl, as a white solid (72 mg), m.p. >200°C: 1 H NMR
- Step A The title compound was prepared from 4-fluoromethylbenzyl chloride (1.0 g) using the procedure of EXAMPLE XVI, Step A, as a heavy oil.
- Step B The title compound was prepared from 3-amino-6-methyl-1-(2-t-butoxycarbonylamino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone (0.100 g, 0.249 mmol) and 4-fluoromethylbenzylsulfonyl chloride (52 mg, 0.246 mmol) using the procedure of EXAMPLE XIII, as a white solid: 1 H NMR (CD 3 OD) ⁇ 2.33 (s, 3 H),
- the title compound was prepared from 3-amino-6-methyl-1- (2-t-butoxycarbonylamino-6-methyl-5-methylenecarboxamidomethyl pyridinyl)-2-pyridinone (0.060 g, 0.15 mmol) and phenylacetaldehyde (19.5 ⁇ l, 0.165 mmol) using the procedure of EXAMPLE III, as a pale yellow solid, m.p.
- Step A 3-(4-Chloro-benzylsulfonylamino)-6-methyl-1-(t-butyl- methylenecarboxy)-2-pyridinone
- Step B 3-(4-Chloro-benzylsulfonylamino)-6-methyl-1-(2-amino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone
- HCl gas was bubbled through a stirred suspension of 3-(4-chloro-benzylsulfonylamino)-6-methyl-1-(t-butyl-methylenecarboxy)-2-pyridinone (325 mg, 14.52 mmol) in ethyl acetate (10 ml) at 0°C until a solution had formed which was saturated with HCl. After 1.5 h a thick suspension had formed. The mixture was degassed with argon and filtered to give the title compound (202 mg) as a solid, m.p. >200°C: 1 H NMR (DMSO) see disappearance of the BOC group; HRMS (FAB) calc'd for C 22 H 25 N 5 O 4 SCI (M+1) + 490.1316, found 490.1300.
- the reaction was heated to reflux for 64 h, and more allyl acetate (13.5 ml, 125 mmol), triphenylphosphine (525 mg, 2.0 mmol), palladium acetate (122 mg, 0.5 mmol), and tetrahydrofuran (13 ml) were added. After a further 24 h and 48 h at reflux addditional allyl acetate (13.5 ml, 125 mmol), palladium acetate (122 mg, 0.5 mmol), and triphenylphosphine (525 mg, 2.0 mmol) were added and the reaction was heated to reflux for a further 24 h.
- reaction was cooled and evaported in vacuo to a gum which was purified by flash column chromatography on silica (15% ethyl acetate/hexane) to give the product contaminated with unreacted 3-nitro-6-trifluoromethyl-2-pyridinone.
- Step D 3-Benzylsulfonylamino-6-trifluoromethyl-1-allyl-2- pyridinone
- Step E 3-Benzylsulfonylamino-6-trifluoromethyl-2-pyridinone-1- methylenecarboxaldehyde
- Step F 3-Benzylsulfonylamino-6-trifluoromethyl-1 - methylenecarboxy-2-pyridinone
- Step A 3-Benzylsulfonylamino-6-methyl-1 -(4-methylenecarboxamidomethylpiperidinyl)-2-pyridinone
- Step C 3-Benzylsulfonylamino-6-methyl-1 -[4-methylenecarboxamidomethyl-1-(hydroxyamino)iminomethylpiperidinyl]-2- pyridinone
- Step A (+/-)-3-( ⁇ -Methylbenzylsulfonylamino)-6-methyl-1- (t-butyl-methylenecarboxy)-2-pyridinone
- Step B (+/-)-3-( ⁇ -Methylbenzylsulfonylamino)-6-methyl-1-(2- amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)- 2-pyridinone
- Step B 2-t-Butoxycarbonylamino-5-aminomethyl-6-ethylpyridine
- Step D 3-Benzylsulfonylamino-6-methyl-1-(2-amino-6-ethyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
- Step A 2-Cyclohexylethylamino-6-methyl-1-(2-t- butoxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl )-2-pyridinone
- Step B 2-Cyclohexylethylamino-6-methyl-1-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
- Step A ⁇ -N,N-Dimethylaminoethenylcyclopropyl ketone
- Step D 3-Amino-6-cyclopropyl-1-(t-butyl-methylenecarboxy)-2- pyridinone
- Step E 3-Benzylsulfonylamino-6-cyclopropyl-1-(t-butyl- methylenecarboxy)-2-pyridinone
- Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-(1H)-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and 1N NaOH at 0°C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 hr then at room temperature for an additional hour. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate.
- Step D 3-Amino-6-propyl-1-(t-butyl-methylenecarboxy)-2- pyridinone
- Step E 3-Benzylsulfonylamino-6-propyl-1-(t-butyl-methylenecarboxy)-2-pyridinone
- Step F 3-Benzylsulfonylamino-6-propyl-1-methylenecarboxy-2- pyridinone
- Step A 3-Benzyloxycarbonylmethylamino-6-methyl-1-(t-butyI- methylenecarboxy)-2-pyridinone
- Step B 3-Benzyloxycarbonylmethylamino-6-methyl-1-methylenecarboxy-2-pyridinone
- Step C 3-Benzyloxycarbonylmethylamino-6-methyl-1-(2-amino-6- methyl-5-methylenecarboxamidomethyl-pyridinyl)-2- pyridinone :
- Step A 3-(Ethyl L-phenylalanyl)-6-methyl-1-(t-butyl-methylenecarboxy)-2-pyridinone
- Step B 3-(Ethyl L-phenylalanyl)-6-methyl-1 -methylenecarboxy-2- pyridinone
- Step A 3-(4-Chlorobenzyl)sulfonylamino-6-cyclopropyl-1-(2-t- butoxycarbonylamino-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone
- Step A 3 -Cyclohexylethylsulfonylamino-6-methyl-1-(2-t-butoxycarbonylamino-5-methylenecarboxamidomethylpyridinyl)- 2-pyridinone
- Step A 3- Vinylsulfonylamino-6-methyl-1-(t-butyl- methylenecarboxy)-2-pyridinone
- Step B 3-[2-(4-Morpholmoemyl)sulfonylamino]-6-methyl-1-(t- butyl-methylene-carboxy) -2-pyridinone
- Trypsin assays also contained 1 mM CaCl 2 - In assays wherein rates of hydrolysis of a p-nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used was used to measure (at 405 nm) the time dependent appearance ofp- nitroaniline.
- p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm- 1 M -1 .
- 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 (V o ) or presence of inhibitor (V i ) were measured.
- V o /V i 1 + [I]/K i (1)
- 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.
- Compounds of Examples 1-4 inhibit human thrombin with Ki values less than 100 nM and inhibit human trypsin with Ki values greater than 500 nM.
- Treatment infusions were initiated 120 min before the placement of a 3 mm square piece of Whatman No. 1 filter paper saturated with 35% FeCl 3 onto the exposed carotid artery distal to the flow probe. Treatment infusions were continued for an additional 60 minutes after the application of FeCl 3 (total infusion duration 180 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 FeCl 3 to
- All of the active compound, cellulose, and a portion of the com starch are mixed and granulated to 10% com starch paste.
- the resulting granulation is sieved, dried and blended with the remainder of the com 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.
- 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
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96923399A EP0835109A4 (fr) | 1995-06-27 | 1996-06-24 | Inhibiteurs de la thrombine a base de pyridinone |
AU63917/96A AU703744B2 (en) | 1995-06-27 | 1996-06-24 | Pyridinone-thrombin inhibitors |
JP9504499A JPH11508558A (ja) | 1995-06-27 | 1996-06-24 | ピリジノン トロンビン阻害剤 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US56095P | 1995-06-27 | 1995-06-27 | |
US60/000,560 | 1995-06-27 | ||
US381895P | 1995-09-15 | 1995-09-15 | |
US60/003,818 | 1995-09-15 | ||
GBGB9603450.9A GB9603450D0 (en) | 1996-02-19 | 1996-02-19 | Pyridinone thrombin inhibitors |
GB9603450.9 | 1996-02-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997001338A1 true WO1997001338A1 (fr) | 1997-01-16 |
Family
ID=27268133
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/010778 WO1997001338A1 (fr) | 1995-06-27 | 1996-06-24 | Inhibiteurs de la thrombine a base de pyridinone |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0835109A4 (fr) |
JP (1) | JPH11508558A (fr) |
AU (1) | AU703744B2 (fr) |
CA (1) | CA2224437A1 (fr) |
WO (1) | WO1997001338A1 (fr) |
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US5932606A (en) * | 1997-03-24 | 1999-08-03 | Merck & Co., Inc. | Pyrazinone, pyridinone, piperidine and pyrrolidine thrombin inhibitors |
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WO1999064446A1 (fr) * | 1998-06-11 | 1999-12-16 | 3-Dimensional Pharmaceuticals, Inc. | Inhibiteurs de protease a base de pyrazinone |
US6011038A (en) * | 1997-09-05 | 2000-01-04 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
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WO2002042272A2 (fr) * | 2000-11-20 | 2002-05-30 | Pharmacia Corporation | Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation |
US6420397B1 (en) | 1999-07-09 | 2002-07-16 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl protease inhibitors and diagnostic imaging agents |
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US6476016B2 (en) | 2000-07-17 | 2002-11-05 | 3-Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
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US6635637B2 (en) | 2000-08-04 | 2003-10-21 | Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine protease inhibitors |
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US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
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US6777431B2 (en) * | 2001-07-13 | 2004-08-17 | Corvas International, Inc. | Non-convalent thrombin inhibitors |
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US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
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WO2009006217A1 (fr) * | 2007-06-29 | 2009-01-08 | Dow Agrosciences Llc | 4-chloro-4-alcoxy-1,1,1-trifluoro-2-butanones, leur préparation et leur utilisation pour la préparation de 4-alcoxy-1,1,1-trifluoro-3-buten-2-ones |
EP2253612A1 (fr) | 2005-04-14 | 2010-11-24 | Novartis AG | Composés organiques |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0509769A2 (fr) * | 1991-04-18 | 1992-10-21 | Zeneca Limited | Amides hétérocycliques ayant une activité inhibante de HLE |
US5405854A (en) * | 1992-03-06 | 1995-04-11 | Hoffmann-La Roche Inc. | Sulfonamidocarboxamides |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2155931C (fr) * | 1993-02-12 | 2002-11-19 | George Phillip Vlasuk | Inhibiteurs de la thrombose |
-
1996
- 1996-06-24 WO PCT/US1996/010778 patent/WO1997001338A1/fr not_active Application Discontinuation
- 1996-06-24 CA CA002224437A patent/CA2224437A1/fr not_active Abandoned
- 1996-06-24 EP EP96923399A patent/EP0835109A4/fr not_active Withdrawn
- 1996-06-24 AU AU63917/96A patent/AU703744B2/en not_active Ceased
- 1996-06-24 JP JP9504499A patent/JPH11508558A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0509769A2 (fr) * | 1991-04-18 | 1992-10-21 | Zeneca Limited | Amides hétérocycliques ayant une activité inhibante de HLE |
US5405854A (en) * | 1992-03-06 | 1995-04-11 | Hoffmann-La Roche Inc. | Sulfonamidocarboxamides |
Non-Patent Citations (2)
Title |
---|
J. MED. CHEM., 1994, Vol. 37, BERNSTEIN et al., "Nonpeptidic Inhibitors of Human Leukocyte Elastase. 3.1 Design, Synthesis, X-Ray Crystallographic Analysis, and Structure-Activity Relationships for a Series of Orally Active 3-Amino-6-Phenylpyridin-2-One Trifluoromethyl Ketones", pages 3313-3326. * |
See also references of EP0835109A4 * |
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US5869487A (en) * | 1996-10-24 | 1999-02-09 | Merck & Co., Inc. | Pyrido 3,4-B!pyrazines for use as thrombin inhibitors |
EP0934064A1 (fr) * | 1996-10-24 | 1999-08-11 | Merck & Co., Inc. | Inhibiteurs de thrombine |
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US5932606A (en) * | 1997-03-24 | 1999-08-03 | Merck & Co., Inc. | Pyrazinone, pyridinone, piperidine and pyrrolidine thrombin inhibitors |
EP0969840A4 (fr) * | 1997-03-24 | 2001-02-28 | Merck & Co Inc | Inhibiteurs de thrombine |
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US6369063B1 (en) | 1997-04-14 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
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US6011038A (en) * | 1997-09-05 | 2000-01-04 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
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US6087373A (en) * | 1997-09-23 | 2000-07-11 | Merck & Co., Inc. | Thrombin inhibitors |
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US6566379B1 (en) | 1997-11-26 | 2003-05-20 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
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US7402586B2 (en) | 1997-11-26 | 2008-07-22 | Ortho-Mcneil Pharmaceutical, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
US6350764B2 (en) | 1997-11-26 | 2002-02-26 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
US6706021B2 (en) | 1997-11-26 | 2004-03-16 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
US6245763B1 (en) | 1997-11-26 | 2001-06-12 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
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US7029654B2 (en) | 1997-11-26 | 2006-04-18 | Ortho-Mcneil Pharmaceuticals, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
US6037356A (en) * | 1997-11-26 | 2000-03-14 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
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EP1055683A1 (fr) * | 1998-02-17 | 2000-11-29 | Nippon Kayaku Kabushiki Kaisha | Nouveau derive d'acetamide et son utilisation |
EP1055683A4 (fr) * | 1998-02-17 | 2007-07-25 | Nippon Kayaku Kk | Nouveau derive d'acetamide et son utilisation |
US6147078A (en) * | 1998-05-19 | 2000-11-14 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
EP1082324A1 (fr) * | 1998-05-26 | 2001-03-14 | Merck & Co., Inc. | Composes d'imidazopyridine inhibiteurs de la thrombine |
US6093717A (en) * | 1998-05-26 | 2000-07-25 | Merck & Co., Inc. | Imidazopyridine thrombin inhibitors |
EP1082324A4 (fr) * | 1998-05-26 | 2002-01-02 | Merck & Co Inc | Composes d'imidazopyridine inhibiteurs de la thrombine |
US6204263B1 (en) | 1998-06-11 | 2001-03-20 | 3-Dimensional Pharmaceuticals, Inc. | Pyrazinone protease inhibitors |
US6514978B2 (en) | 1998-06-11 | 2003-02-04 | 3-Dimensional Pharmaceuticals, Inc. | Thromboresistant materials incorporating pyrazinone protease inhibitors |
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US6180627B1 (en) | 1998-08-14 | 2001-01-30 | Pfizer Inc. | Antithrombotic agents |
US6117888A (en) * | 1998-09-28 | 2000-09-12 | Merck & Co., Inc. | Thrombin inhibitors |
US6610692B1 (en) | 1998-10-30 | 2003-08-26 | Merck & Co., Inc. | Thrombin inhibitors |
US6376499B1 (en) | 1998-10-30 | 2002-04-23 | Merck & Co., Inc. | Thrombin inhibitors |
WO2000032574A1 (fr) * | 1998-11-27 | 2000-06-08 | Sanofi-Synthelabo | Nouveaux derives de 2-pyridone, leur preparation et leur application en therapeutique |
FR2786482A1 (fr) * | 1998-11-27 | 2000-06-02 | Synthelabo | Nouveaux derives de 2-pyridone, leur preparation et leur application en therapeutique |
US6962905B1 (en) | 1999-04-21 | 2005-11-08 | Astrazeneca Ab | Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug |
US6239132B1 (en) | 1999-04-23 | 2001-05-29 | Merck & Co., Inc. | Thrombin inhibitors |
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US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils 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 |
US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6870056B1 (en) | 1999-05-19 | 2005-03-22 | Pharmacia Corporation | Substitituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
EP1586565A1 (fr) * | 1999-05-19 | 2005-10-19 | Pharmacia Corporation | Pyrazinones d'hétéroaryle et d'aryle polycyclique substituées utiles à l'inhibition selective de la coagulation en cascade |
US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones 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 |
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US6458952B1 (en) | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils 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 |
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US6326492B1 (en) | 1999-05-27 | 2001-12-04 | 3-Dimensional Pharmaceuticals, Inc. | Heterocyclic protease inhibitors |
US6455532B1 (en) | 1999-06-04 | 2002-09-24 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
US6350745B1 (en) | 1999-06-04 | 2002-02-26 | Merck & Co., Inc. | Thrombin inhibitors |
JP2010150275A (ja) * | 1999-06-04 | 2010-07-08 | Merck Sharp & Dohme Corp | ピラジノントロンビン阻害剤 |
WO2000075134A1 (fr) * | 1999-06-04 | 2000-12-14 | Merck & Co., Inc. | Inhibiteurs de thrombine a base de pyrazinone |
US6420397B1 (en) | 1999-07-09 | 2002-07-16 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl protease inhibitors and diagnostic imaging agents |
US6962942B2 (en) | 1999-09-13 | 2005-11-08 | 3-Dimensional Pharmaceuticals, Inc. | Azacycloalkanone serine protease inhibitors |
WO2001019795A1 (fr) * | 1999-09-13 | 2001-03-22 | 3-Dimensional Pharmaceuticals, Inc. | Inhibiteurs de serine protease azacycloalcanone |
US6469029B1 (en) | 1999-09-13 | 2002-10-22 | 3-Dimensional Pharmaceuticals, Inc. | Azacycloalkanone serine protease inhibitors |
US6387911B1 (en) | 1999-11-23 | 2002-05-14 | Merck & Co., Inc. | Pyrazinone thrombin inhibitors |
US6852761B2 (en) | 2000-03-13 | 2005-02-08 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes 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 |
US6534510B2 (en) | 2000-03-23 | 2003-03-18 | Merck & Co., Inc. | Thrombin inhibitors |
WO2001077079A2 (fr) * | 2000-04-05 | 2001-10-18 | Pharmacia Corporation | Pyridones polycycliques 4-aryl et heteroaryl substituees utiles pour l'inhibition selective de la cascade de coagulation |
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 |
WO2001077079A3 (fr) * | 2000-04-05 | 2002-04-11 | Pharmacia Corp | Pyridones polycycliques 4-aryl et heteroaryl substituees utiles pour l'inhibition selective de la cascade de coagulation |
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 |
US6916847B2 (en) | 2000-04-05 | 2005-07-12 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
WO2001079262A1 (fr) * | 2000-04-14 | 2001-10-25 | Corvas International, Inc. | Inhibiteurs de la thrombine a base de derives de pyrazinone et pyridinone |
WO2001079195A2 (fr) * | 2000-04-14 | 2001-10-25 | Corvas International, Inc. | Nouveaux inhibiteurs de thrombine de type non covalent |
WO2001079261A1 (fr) * | 2000-04-14 | 2001-10-25 | Corvas International, Inc. | Derives de tetrahydro-azepinone servant d'inhibiteurs de la thrombine |
WO2001079195A3 (fr) * | 2000-04-14 | 2002-05-16 | Corvas Int Inc | Nouveaux inhibiteurs de thrombine de type non covalent |
US6506754B1 (en) | 2000-04-14 | 2003-01-14 | Corvas International, Inc. | Non-covalent thrombin inhibitors |
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 |
US6476016B2 (en) | 2000-07-17 | 2002-11-05 | 3-Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
US7030110B2 (en) | 2000-07-17 | 2006-04-18 | Ortho-Mcneil Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
US6635637B2 (en) | 2000-08-04 | 2003-10-21 | Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine protease inhibitors |
WO2002028825A3 (fr) * | 2000-10-06 | 2002-06-13 | Dimensional Pharm Inc | Phenylacetamides a substitution aminopyridinyle, aminoguanidinyle et alcoxyguanidinyle utilises comme inhibiteurs de proteases |
WO2002028825A2 (fr) * | 2000-10-06 | 2002-04-11 | 3-Dimensional Pharmaceuticals, Inc. | Phenylacetamides a substitution aminopyridinyle, aminoguanidinyle et alcoxyguanidinyle utilises comme inhibiteurs de proteases |
US6521663B2 (en) | 2000-10-06 | 2003-02-18 | 3-Dimensional Pharmaceuticals, Inc. | Aminoguanidinyl- and Alkoxyguanidinyl-substituted phenyl acetamides as protease inhibitors |
US6900231B2 (en) | 2000-10-06 | 2005-05-31 | 3-Dimensional Pharmaceuticals, Inc. | Aminopyridyl-substituted phenyl acetamides as protease inhibitors |
CN1315803C (zh) * | 2000-10-06 | 2007-05-16 | 三维药物公司 | 作为蛋白酶抑制剂的氨基吡啶基-,氨基胍基-和烷氧基胍基-取代苯基乙酰胺 |
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 |
US6828338B2 (en) | 2000-11-20 | 2004-12-07 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
WO2002042272A2 (fr) * | 2000-11-20 | 2002-05-30 | Pharmacia Corporation | Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation |
US6624180B2 (en) | 2000-11-20 | 2003-09-23 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines 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 |
WO2002042272A3 (fr) * | 2000-11-20 | 2003-07-24 | Pharmacia Corp | Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation |
US6777431B2 (en) * | 2001-07-13 | 2004-08-17 | Corvas International, Inc. | Non-convalent thrombin inhibitors |
US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds 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 |
WO2003048155A1 (fr) * | 2001-12-04 | 2003-06-12 | University Of Ljubljana | Inhibiteurs de thrombine |
US7524871B2 (en) | 2001-12-04 | 2009-04-28 | University Of Ljubljana, Faculty Of Pharmacy | Thrombin inhibitors |
WO2004091613A2 (fr) * | 2003-04-10 | 2004-10-28 | 3-Dimensional Pharmaceuticals, Inc. | Acetamides a substitution phenyle et leur utilisation en tant qu'inhibiteurs de protease |
US7550474B2 (en) | 2003-04-10 | 2009-06-23 | Johnson & Johnson Pharmaceuticals Research & Development, L.L.C. | Substituted phenyl acetamides and their use as protease inhibitors |
WO2004091613A3 (fr) * | 2003-04-10 | 2005-01-27 | Dimensional Pharm Inc | Acetamides a substitution phenyle et leur utilisation en tant qu'inhibiteurs de protease |
EP2253612A1 (fr) | 2005-04-14 | 2010-11-24 | Novartis AG | Composés organiques |
WO2006135323A1 (fr) * | 2005-06-17 | 2006-12-21 | Astrazeneca Ab | Derives de 2-oxo-1,2,5,6-tetrahydropyridine inhibiteurs de thrombines |
WO2009006217A1 (fr) * | 2007-06-29 | 2009-01-08 | Dow Agrosciences Llc | 4-chloro-4-alcoxy-1,1,1-trifluoro-2-butanones, leur préparation et leur utilisation pour la préparation de 4-alcoxy-1,1,1-trifluoro-3-buten-2-ones |
CN103382150A (zh) * | 2007-06-29 | 2013-11-06 | 陶氏益农公司 | 4-氯-4-烷氧基-1,1,1-三氟-2-丁酮的制备和用途 |
Also Published As
Publication number | Publication date |
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CA2224437A1 (fr) | 1997-01-16 |
JPH11508558A (ja) | 1999-07-27 |
EP0835109A4 (fr) | 1999-02-03 |
EP0835109A1 (fr) | 1998-04-15 |
AU6391796A (en) | 1997-01-30 |
AU703744B2 (en) | 1999-04-01 |
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