Classifications

• • 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
• • 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.
• These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
• the compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
• the invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reoccl ⁇ sion 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:
• R 1 (Rl)m(CH2)nNHqCO, where n is 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 0(CH2)p, wherein p is 1-4;
• R 2 is hydrogen, phenyl, unsubstituted or substituted with one or more of Cl- 4 linear or branched alkyl, Ci .4 linear or branched alkoxy, halogen, trifluoromethyl, hydroxy, COOH, or CONH2, naphthyl, biphenyl, 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,
• R4 and R5 are independently H, Cl-4 linear or branched alkyl or alkoxy; C3-C7 cycloalkyl; halogen; or trifluoromethyl;
• Y is hydrogen, hydroxy, or CN
• R6 is hydrogen, or
• a useful class of compounds is the embodiment wherein W is Rl or RlS ⁇ 2-
• a further useful subclass of compounds is the embodiment wherein R 1 is R 2 (CH2)n, (R 2 )2CH(CH2)n, phenyl, or (phenyl)2-CH.
• R3 is Cl-4 linear or branched alkyl and particularly wherein R3 is methyl.
• R ⁇ is Cl-4 linear or branched alkyl and R 5 is methyl or hydrogen and particularly wherein R4 is methyl and R 5 is methyl or hydrogen and most particularly when R4 is methyl and R 5 is hydrogen.
• W is RlS ⁇ 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 lS02 and A is Radical UI.
• A is Radical UI. Specific embodiments of this class include:
• W is R 1 S02 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.
• 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.
• 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.
• 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
• 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, nico
• Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
• the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl
• diamyl sulfates long chain halides
• 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 extraco ⁇ oreal 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 Co ⁇ oration.
• 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, polyglycohc acid, copolymers of polylactic and polyglycohc 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 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 inco ⁇ orated into the mixture.
• suitable binders, lubricants, distintegrating agents and coloring agents can also be inco ⁇ orated 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.
• the thrombin inhibitors can also be co-administered with suitable anti -coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
• suitable anti -coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
• 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 and B 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 isocyanate which is trapped with benzyl alcohol in the presence of triethylamine giving the Cbz protected aminopyridinone.
• the Cbz group is removed by hydrogenolysis using Pearlman's catalyst under standard conditions.
• Bis-benzylsulfonylation can be accomplished using benzylsulfonyl chloride and triethylamine in methylene chloride.
• the BOC group is removed using a strong acid such as HCl gas and 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 l-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
• different W groups can be present by the use of an appropriate alkylating, carbonylating, sulfonylating, urealating agent, and the like, in 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 Rl, R*OCO, R ⁇ CO, R*S02, or (Rl)m(CH2)nNCO.
• the different Radicals A can be present by the appropriate choice of the radical precursor in Step D. Obvious variations and modifications of the Methods to produce similar and obvious variants thereof, will be apparent to one skilled in the art.
• step l(i) HCl, EtOAc Method A.
• 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-l-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 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, sulfonylating, urealating agent, and the like, in Step F.
• 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, sulfonylating, urealyting agent, and the like, in Step E.
• 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.
• stepC HCl, EtOAc
• Method D 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 pyridinone 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, sulfonylating, urealyting agent, and the like, in Step B.
• Step E The 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.
• an amine such as 2-t-butoxycarbonylamino- 6-methyl -5 -aminomethyl pyridine
• step F i. RuCI 3 , Nal0 4 ii. Cr0 3 , H 2 S0 4 Method E (cont'd
• 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.
• 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 Rl , RlOCO, RlCO, R ⁇ S02, or (Rl)m(CH2)nNCO.
• NMR field strength employed in the below given examples was either 300 or 400 MHz.
• Step B Methyl-6-methyl-l(t-butyl-methylenecarboxy)-2- pyridinone-3-carboxylate t-Butylbromoacetate (13.8 ml, 93.46 mmol) was added to a stirred suspension of methyl-2-hydroxy-6-methylpyridine-3-carboxylate (15.62 g, 93.44 mol) and cesium carbonate (30.44 g, 93.43 mmol) in dry DMF (180 ml). After 64 h, the reaction was evaporated in vacuo to a thick paste which was partitioned between ethyl acetate and brine, adding enough water to dissolve all the salts.
• Step C Methyl-6-methyl-l -methylenecarboxy-2-pyridinone-3- carboxylate
• Step D Methyl -6-methyl-l -(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-l-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-l-(4-methylenecarbox- amidomethyl-l-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-methylene- carboxamidomethyl- 1 -t-butoxycarbonylpiperidinyl)-2- pyridinone
• DPPA (1.53 ml, 7.11 mmol) was added to a stirred solution of 6-methy 1- 1 -(4-methylenecarboxamidomethyl- 1 -t-butoxycarbonyl- piperidinyl)-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-methy lenecarboxamidomethyl- 1 - t-butoxycarbonylpiperidinyl)-2-pyridinone
• Step H 3-N,N-(Bis-benzylsulfonyl)amino-6-methyl-l -(4- methylenecarboxamidomethyl- 1 -t-butoxycarbonyl- piperidinylV2-pyridinone
• Benzylsulfonyl chloride 51 mg, 0.27 mmol was added to a stirred solution of 3-amino-6-methyl-l-(4-methylenecarboxamidomethyl- l-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-methylenecarbox- amidomethyl- 1 -amidinopiperidinyD-2-pyridinone HCl Gas was bubbled through a solution of 3-N,N-(Bis- benzylsulfony l)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.
• Step A 3-Nitro-6-methyl- 1 (ethyl-methylenecarboxyV 2-pyridinone Ethylbromoacetate (0.61 ml, 5.5 mmol) was added to a stirred suspension of 3-nitro-2-hydroxy-6-methylpyridine (0.77 g, 5.0 mmol) and cesium carbonate (1.63 g, 5.0 mmol) in dry DMF (10 ml). After 16 h, the reaction was acidified with 1 M HCl and was extracted into ethyl acetate, washed with sodium hydrogen carbonate solution and brine, dried (Na2S ⁇ 4) and evaporated in vacuo to a gum.
• Step B 3-Nitro-6-methyl- 1 -methylenecarboxy-2-pyridinone
• Lithium hydroxide (86 mg, 2.05 mmol) was added to a stirred solution of 3-Nitro-6-methyl- 1 (ethyl-methylenecarboxy)-2- pyridinone (0.45 g, 1.86 mmol) in 1 :1 : 1 methanol/THF/water (6 ml). After 64 h the reaction was diluted with sodium hydrogen carbonate solution and was washed with methylene chloride (3 times). The aqueous layer was acidified with concentrated HCl to pH 1 and was concentrated in vacuo to the point when sodium chloride started to crystallize from the solution.
• Step C 3-Nitro-6-methyl- 1 -(memylenecarboxamido-trans-4-t- butoxycarbonylaminocvclohexylmethvD-2-pyridinone
• EDC hydrochloride (249 mg, 1.30 mmol) was added to a stirred mixture of 3-nitro-6-methyl-l-methylenecarboxy-2-pyridinone (212 mg, 1.00 mmol), trans-4-t-butoxycarbonylaminocyclohexylmethyl- amine (228 mg, 1.00 mmol), HOBT (176 mg, 1.30 mmol) and triethylamine (0.18 ml, 1.30 mmol) in dry DMF (4 ml).
• Step D 3- Amino-6-methyl- 1 -(methylenecarboxamido-trans-4- t-butoxycarbonylaminocyclohexylmethyl)-2-pyridinone
• Step E 3-(2-Phenylethylamino)-6-methyl-l -(methylene- carboxamido-trans-4-t-butoxycarbonylaminocyclo- hex ylmeth yl V 2-p yridinone
• Step F 3-(2-Phenylethylamino)-6-methyl- 1 -(methylenecarbox- amido-trans-4-aminocvclohexylmethyl)-2-pyridinone 3-(2-Phenylethylamino)-6-methyl- 1 -(methylenecarbox- amido-trans-4-t-butoxycarbonylaminocyclohexylmethyl)-2-pyridinone (52.7 mg, 0.106 mmol) was dissolved in ethyl acetate saturated with HCl gas (5 ml). After 30 min the solution was evaporated in vacuo to a yellow solid.
• Step B 3-Benzylsulfonylamino-6-methyl- 1 -(methylenecarbox- amido-trans-4-aminocyclohexylmethyl)-2-pyridinone HCl Gas was bubbled through a solution of 3-benzyl- sulfonylamino-6-methyl- 1 -(methylenecarboxamido-trans-4-t- butoxycarbonylaminocyclohexylmethyl)-2-pyridinone (118.6 mg, 0.217 mmol) in ethyl acetate (20 ml) for 5 min at 0°C. After 0.5 hour the solution was degassed with argon and evaporated in vacuo .
• Step B 3-Benzyloxycarbonylamino-6-methyl- 1 -(t-butyl- methylenecarboxyV2-pyridinone t-Butylbromoacetate (12.1 ml, 81.98 mmol) was added to a stirred suspension of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (21.15 g, 81.98 mmol) and cesium carbonate (26.71 g, 81.98 mmol) in dry DMF (170 ml). After 36 h, the reaction was evaporated in vacuo to a thick paste which was partitioned between ethyl acetate and water.
• Step C 3-Amino-6-methyl- 1 -(t-buty l-methylenecarboxy)-2- pyridinone
• Step D 3-Benzy lsulfonylamino-6-methyl- 1 -(t-butyl-methylene- carboxy V2-pyridinone
• Step E 3-Benzylsulfonylamino-6-methyl-l -methylenecarboxy-2- pyridinone
• HCl gas was bubbled through a stirred suspension of 3- benzylsulfony lamino-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.
• 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-l-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).
• 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 B 3-Benzyloxycarbonylamino-6-methyl- 1 -(t-butyl- methylenecarboxy)-2-pyridinone t-Butylbromoacetate (12.98 ml, 87.89 mmol) was added to a stirred suspension of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (22.70 g, 87.89 mmol) and cesium carbonate (28.64 g, 87.89 mmol) in dry DMF (175 ml). After 16 h, the reaction was evaporated in vacuo to a thick paste which was partitioned between ethyl acetate and water.
• Step C 3- Amino-6-methyl- 1 -(t-buty l-methylenecarboxy)-2- pyridinone
• Step D 3-Benzylsulfonylamino-6-methyl-l -(t-butyl-methylene- carboxy)-2-pyridinone
• Benzylsulfonyl chloride (3.146 g, 16.5 mmol) was added to a solution of 3-amino-6-methy 1-1 -(t-buty l-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-methy lenecarboxy )-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-Benzy lsulfonylamino-6-methyl- 1 -(2-amino-6-methyl-
• HCl gas was blown onto the stirred mixture at 0°C causing the bulk of the material to dissolve. Undissolved material was broken up with a spatula and after bubbling HCl through the mixture for 15 min dissolution was complete. Over one hour some precipitate formed.
• the mixture was degassed with nitrogen and was evaporated in vacuo to a solid. Water (100 ml) was added and the undissolved material was removed by filtering through a frit. The solution was washed with methylene chloride (2 times, adding sufficient brine to dissipate the emulsion) and ethyl acetate, then was basified with sodium hydrogen carbonate.
• Step C 2-t-Butoxycarbonylamino-5-methylamino-6-methylpyridine
• 2-t-butoxycarbonylamino-5-cyano-6- methylpyridine 14.68 g, 62.9 mmol
• 10% Pd/C 1.5 g
• glacial acetic acid 150 ml
• Step A 3-Nitro- 1 -(t-buty lmethylenecarboxyV 2-pyridinone t-Butylbromoacetate (1.48 ml, 10 mmol) was added to a stirred suspension of 2-hydroxy-3-nitropyridine (1.40 g, 10 mmol) and cesium carbonate (3.26 g, 10 mmol) in dry DMF (20 ml). After 16 h, the solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate.
• Step C 3-Nitro- 1 -(2-t-butoxycarbonylamino-6-methyl-
• Step D 3- Amino- 1 -(2-t-butoxycarbonylamino-6-methyl-
• Step E 3-Benzy lsulfonylamino- 1 -(2-t-butoxycarbonylamino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone 3- Amino- 1 -(2-t-butoxycarbonylamino-6-methyl-
• Step F 3-Benzylsulfonylamino- 1 -(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone 3-Benzy lsulfonylamino- 1 -(2-t-butoxycarbonylamino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone (122 mg) was was deprotected using the procedure of Step B, to give the title compound (93 mg): ⁇ H NMR (DMSO) see disappearance of the BOC 564egroup; Anal. (C21H23N5O4.I.O HCl. 0.6 H2O. 0.4 EtOAc).
• Step B 2-amino-5-methylamino-3-methylpyridine
• a mixture of 2-amino-5-cyano-3-methylpyridine (1.40 g) and 10% Pd/C (0.18 g) in 1 :1 ethanol/lM HCl (64 ml) was shaken on a Parr apparatus at 57 psi for 16 h.
• the reaction was filtered through celite and was evaporated in vacuo, azeotroping with ethanol.
• Step C 3-Benzylsulfonylamino-6-methyl-l -(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-l-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).
• HCl gas was bubbled through a stirred suspension of 3- benzloxycarbonylamino-6-methy 1- 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-methylene- carboxamidomethyl- 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-methylene- carboxamidomethyl- 1 -amidinopiperidinyl V 2-pyridinone 3-(3-Phenylpropionamido)-6-methyl- 1 -(4-methylene- carboxamidomethyl- 1 -t-butoxycarbonylpiperidinyl)-2-pyridinone
• Step A 3-(3,3-Diphenylpropionamido)-6-methyl- 1 -(4-methylene- carboxamidomethyl- 1 -t-butoxycarbonylpiperidinyl)-2- pyridinone
• EDC hydrochloride 75 mg, 0.393 mmol
• 3-amino-6-methyl-l-(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
• diisopropylethylamine (0.14 ml, 0.786 mmol) in dry DMF (1 ml).
• Step B 3-(3,3-Diphenylpropionamido)-6-methyl- 1 -(4-methylene- carboxamidomethyl- 1 -amidinopiperidinylV 2-pyridinone 3-(3,3-Diphenylpropionamido)-6-methyl- 1 -(4-methylene- carboxamidomethyl- 1 -t-butoxycarbonylpiperidinyl)-2-pyridinone
• Step A 3-p-Toluenesulfonylamino-6-methy 1- 1 -(4- methy lenecarboxamidomethyl- 1 -t- butoxycarbonylpiperidinyl)-2-pyridinone
• Step A 3-/?-Toluenesulfonylamino-6-methy 1- 1 -(methylene- carboxamido-trans-4-t-butoxycarbony laminocyclo- hexylmethylV2-pyridinone
• Step B 3- -Toluenesulfonylamino-6-methy 1- 1 -(methylenecarbox- amido-trans-4-aminocvclohexylmethyl)-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-l-(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.
• Step B Phenylacetamido-6-methy 1- 1 -(2-amino-5- methylenecarboxamidomethylpyridinyl -2-pyridinone
• the title compound was prepared from phenylacetamido-6- methyl- 1 -(2-t-butoxycarbonylamino-5-methy lenecarboxamido- methylpyridinyl)-2-pyridinone (0.028 g) using the procedure of EXAMPLE XII, Step B as a white solid (4.2 mg).
• the title compund was prepared from 1-napthylsulfonyl chloride (64 mg, 0.283 mmol) and 3-amino-6-methyl-l-(2-t- butoxycarbonylamino-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone (0.100 g, 0.258 mmol) using the procedure of EXAMPLE Xi ⁇ , as a white solid, m.p.
• Step B 3-(4-Trifluoromethylbenzylsulfonyl)amino-6-methyl- l-(2-t-butoxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl -2-pyridinone
• the title compound was prepared from 3-amino-6-methyl-l- (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 Xffl, as a white solid (60 mg), m.p.
• 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-l ⁇ (2-t-butoxycarbonylamino-6-methyl-5-methylenecarboxamidomethyl- pyridinyl)-2-pyridinone (0.100 g, 0.249 mmol) and 4-fluoromethyl- benzylsulfonyl chloride (52 mg, 0.246 mmol) using the procedure of EXAMPLE Xffl, as a white solid: *H NMR (CD3OD) ⁇ 2.33 (s, 3 H),
• 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-l-(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: *H NMR (DMSO) see disappearance of the BOC group; HRMS (FAB) calc'd for C22H25N5O4SCI (M+l)+ 490.1316, found 490.1300.
• Step B 3-Nitro-6-trifluoromethyl- 1 -allyl-2-pyridinone
• THF tetrahydrofuran
• 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 C 3-Amino-6-trifluoromethyl- 1 -allyl-2-pyridinone
• Step D 3-Benzylsulfonylamino-6-trifluoromethyl- 1 -allyl-2- pyridinone
• Benzylsulfonyl chloride (103 mg, 0.542 mmol) was added to a stirred solution of 3-amino-6-trifluoromethy 1-1 -allyl -2-pyridinone (106.5 mg, 0.488 mmol) in pyridine (1 ml) at 0° C.
• Step E 3-Benzylsulfonylamino-6-trifluoromethyl-2-pyridinone- 1 ⁇ methylenecarboxaldehyde
• Step F 3-Benzylsulfonylamino-6-trifluoromethyl- 1 - methylenecarboxy-2-pyridinone Jones Reagent (2.7 ) was added dropwise to a stirred solution of 3-benzylsulfonylamino-6-trifluoromethyl-2-pyridinone-l- methylenecarboxaldehyde (89 mg) in acetone (5 ml) at 0°C until the color remained orange.
• Step G 3-Benzylsulfonylamino-6-trifluoromethyl-l-(2-amino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone
• Step A 3-Benzylsulfonylamino-6-methyl- 1 -(4-methylene- carboxamidomethylpiperidinyl)-2-pyridinone
• Step C 3-Benzylsulfonylamino-6-methyl-l -[4-methylenecarbox- amidomethyl-l-(hydroxyamino)iminomethylpiperidinyl]-2- pyridinone
• Step A (+/-)-3-( ⁇ -Methylbenzylsulfonylamino)-6-methyl- 1 -
• Step B (+/-)-3-( ⁇ -Methylbenzylsulfonylamino)-6-methyl- 1 -(2- amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-
• Step A 2-t-Butoxycarbonylamino-5-cyano-6-ethylpyridine
• 2-t-butoxycarbonylamino-5-cyano-6- methylpyridine (0.50g, 2.145 mmol) in dry THF (15 ml) at -78°C was added n-BuLi (1.75 ml, 2.5 M in hexanes) dropwise.
• n-BuLi (1.75 ml, 2.5 M in hexanes
• Step B 2-t-Butoxycarbonylamino-5-aminomethyl-6-ethylpyridine
• Step C 3-Benzylsulfonylamino-6-methyl-l -(2-t- butoxycarbonylamino-6-ethyl-5- methylenecarboxamidomethylpyridinylV2-pyridinone DCC (50 mg, 0.242 mmol) was added to a stirred solution of 3-benzylsulfonylamino-6-methyl- 1 -methylenecarboxy-2-pyridinone (79 mg, 0.235 mmol) and 2-t-butoxycarbonylamino-6-ethyl-5- methylaminopyridine (60 mg, 0.239 mmol) in methylene chloride (2 ml).
• Step D 3-Benzylsulfonylamino-6-methyl- 1 -(2-amino-6-ethyl-5- methylenecarboxamidomethylpyridinylV2-pyridinone
• Step A 2-Cyclohexylethylamino-6-methyl- 1 -(2-t- butoxycarbony lamino-6-methy 1-5 - methylenecarboxamidomethylpyridinylV2-pyridinone
• cyclohexylacetaldehyde 25.9 mg, 0.206 mmol
• 2-amino-6-methyl-l-(2-t-butoxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone 75 mg, 0.187 mmol
• aluminum foil 37.8 mg, 1.40 mmol
• mercury(II) chloride 5.1 mg, .0187 mmol
• Step B 2-Cyclohexylethylamino-6-methyl-l-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinylV2-pyridinone
• Step A ⁇ -N.N-Dimethylaminoethenylcvclopropyl ketone
• Step B 6-Cvclopropyl-3-nitro-2-(lH ' )-pyridinone
• Step C 3-Nitro-6-cyclopropyl-l-(t-butyl-methylenecarboxy)-2- pyridinone
• Step D 3-Amino-6-cyclopropyl- 1 -(t-butyl-methylenecarboxy)-2- pyridinone
• Step E 3-Benzylsulfonylamino-6-cyclopropyl- 1 -(t-butyl - methylenecarboxy)-2-pyridinone
• Step F 3-Benzylsulfonylamino-6-cyclopropyl-l-methylenecarboxy-
• Step C 3 Benzy loxy carbonylamino-6-propyl- 1 -(t-butyl- methylenecarboxy -2-pyridinone
• Step D 3- Amino-6-propyl- 1 -(t-butyl-methylenecarboxy)-2- pyridinone
• Step E 3-Benzylsulfonylamino-6-propyl- 1 -(t-butyl-methylene- carboxyV2-pyridinone
• Step F 3-Benzylsulfonylamino-6-propyl- 1 -methylenecarboxy-2- pyridinone
• Step A 3-Benzyloxycarbonylmethylamino-6-methyl- 1 -(t-buty I - methylenecarboxy)-2-pyridinone
• Step B 3-Benzyloxycarbonylmethylamino-6-methyl- 1 -methylene- carboxy-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-l-(t-butyl-methylene- carboxy)-2-pyridinone
• Step B 3-(Ethyl L-phenylalanyl)-6-methyl-l -methylenecarboxy-2- pyridinone
• Step C 3-(Ethyl L-phenylalanyl)-6-methyl-l-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyD-2-pyridinone
• Step A 3-(4-Chlorobenzyl)sulfonylamino-6-cyclopropyl- 1 -(2-t- butoxycarbonylamino-5-methylenecarboxamidomethyl- pyridinyl)-2-pyridinone
• Step A 3 -Cy clohexy lethy lsulf ony ⁇ amino-6-methy 1- 1 -(2-t-butoxy- carbonylamino-5-methylenecarboxamidomethylpyridinyl)-
• Step A 3- Vinylsulfonylamino-6-methyl- 1 -(t-butyl - methylenecarboxyV2-pyridinone
• Step B 3-[2-(4-Mo ⁇ holmoemyl)sulfonylammo]-6-methyl-l -(t- butyl-methylene-carboxyV2-pyridinone
• Morpholine (106 ⁇ l, 1.2 mmol) was added to a stirred solution of 3-vinylsulfonylamino-6-methyl-l-(t-butyl- methylenecarboxy)-2-pyridinone (200 mg, 0.61 mmol) in methylene chloride (50 ml). After 64 h the reaction mixture was washed with 10% sodium carbonate, dried (magnesium sulfate) and evaporated in vacuo. iH NMR (CDC13) ⁇ 2.36 (s, 3 H), 2.52 (s, 3H), 3.62 (s, 4 H), 3.88 (s,
• p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm-lM-!. In certain studies with potent inhibitors (Ki ⁇ 10 nM) where the degree of inhibition of thrombin was high, a more sensitive activity assay was employed.
• the rate of thrombin catalyzed hydrolysis of the fluorogenic substrate Z-GPR-afc was determined from the increase in fluorescence at 500 nm (excitation at 400 nm) associated with production of 7-amino-4-trifluoromethyl coumarin.
• Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7-amino-4-trifluoromethyl coumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin.
• Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (Vo) or presence of inhibitor (Vi) were measured.
• the activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
• 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.
• Rats (8-10/group) were randomized to continuous intravenous infusions of saline or test compound administered via the tail vein at a rate of 0.028 ml/min. Treatment infusions were initiated 120 min before the placement of a 3 mm square piece of Whatman No. 1 filter paper saturated with 35% FeCl3 onto the exposed carotid artery distal to the flow probe. Treatment infusions were continued for an additional 60 minutes after the application of FeCl3 (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 FeCl3 to thrombotic occlusion of the vessel.
• Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of the following active compounds are prepared as illustrated below:
• 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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• 1996
  • 1996-06-24 JP JP9504499A patent/JPH11508558A/ja active Pending
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  • 1996-06-24 WO PCT/US1996/010778 patent/WO1997001338A1/en not_active Ceased
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