WO2002022584A1 - Inhibiteur de la thrombine - Google Patents

Inhibiteur de la thrombine Download PDF

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Publication number
WO2002022584A1
WO2002022584A1 PCT/US2001/028791 US0128791W WO0222584A1 WO 2002022584 A1 WO2002022584 A1 WO 2002022584A1 US 0128791 W US0128791 W US 0128791W WO 0222584 A1 WO0222584 A1 WO 0222584A1
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Prior art keywords
mmol
ring
alkyl
pharmaceutically acceptable
compound
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PCT/US2001/028791
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English (en)
Inventor
Richard C. Isaacs
Peter D. Williams
Terry A. Lyle
Donnette D. Staas
Kelly L. Savage
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Merck & Co., Inc.
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Priority to AU2001294557A priority Critical patent/AU2001294557A1/en
Publication of WO2002022584A1 publication Critical patent/WO2002022584A1/fr

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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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

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.
  • 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 ische ic 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 ofthe invention.
  • Compounds of the invention are useful for inhibiting thrombin and treating blood coagulation and cardiovascular disorders.
  • the invention includes compounds having the structure
  • u, v and w same or different, are CH or N;
  • X is O, S, S(O), S(0)2, NH, C alkenyl, C(O), C(0)NH, -C(O)O-,CR10R11, -OfeNH-, CH2O-, or
  • Y is (CH 2 )0-l(CR 4 R5)(CH 2 )o-i;
  • Z is O, S, S(0), S(0) 2 , C(O), NR*2, CR12R13, 0 r CF or a bond;
  • Rl is hydrogen, or C 1-4 alkyl, (CH2) ⁇ -lCN, C(0)Rl4, (CH2) ⁇ -lC ⁇ 2Rl 4 , CF3, OR 14 , halogen, SR 4 , S(0)Rl 4 S(0) 2 R 14 , NRl 4 R 5;
  • a 5-membered heterocyclic unsaturated ring having 1 heteroatom selected from the group consisting of N, O, and S, 2 N atoms, 2 S atoms, or 2 heteroatoms comprising 1 N and 1 S atom, wherein the ring is unsubstituted or monosubstituted with C1.4 alkyl;
  • phenyl, unsaturated ring system unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with C1-8 alkyl, -(CH2)o-4C3_7 cycloalkyl, or CO2R 20 , 2) a 6-membered heterocyclic saturated ring system wherein 1 or 2 ring atoms are independently selected from the group of heteroatoms consisting of N, O and S, wherein the ring is unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with C s alkyl,
  • a 5- or 6-membered heterocyclic unsaturated ring having i) 1 heteroatom selected from N, S and O, ii) 2 heteroatoms selected from 1 N atom and 1 S atom, 1 N atom and 1 O atom, 1 S atom and 1 O atom, 2 N atoms, and 2 S atoms, iii) 3 heteroatoms selected from 3 N atoms and 2 N atoms and 1 S atom, or iv) 4 N atoms, wherein the ring is unsubstituted, monosubstituted, or disubstituted, same or different, with Ci-8 alkyl, C3-7 cycloalkyl, -(CH2) ⁇ -4C3-7 cycloalkyl, NH2, or (CH2) ⁇ - 4Xl(CH 2 )0-3CH3, wherein ⁇ is a bond, S, S(0), S(0)2, O, or NH,
  • R , 9 i.s hydrogen or C ⁇ -8 alkyl
  • R 21 is H, C 6 alkyl, or C 3 . 7 cycloalkyl, or
  • R 4 and R5 are independently hydrogen or C ⁇ .4 alkyl; R6 and R8 are independently
  • R 7 is halogen;
  • RlO, RU, Rl2, Rl3, R14, R15, R16, R17, R18, R19 an R20 are independently hydrogen or C1.4 alkyl, or a pharmaceutically acceptable salt thereof.
  • Rl is hydrogen, CH3, CN or Cl; R is hydrogen or CH3, R5 is hydrogen or CH3; X is -0-, -C(0)NH-, -C(0)0-, -CH2NH- or -CH2O-; Y is - CH2CH2-, -CH 2 CH(CH3)-, or -CH2"; and Z is -NH-, -0-, or a bond.
  • R 2 is selected from the group consisting of 1) a 5-membered unsaturated heterocyclic ring containing 2 N ring atoms, substituted with Cl-4 alkyb 2) a 6-membered unsaturated heterocyclic ring containing 1 or 2 N ring atoms unsubstituted or substituted with one or two substituents independently selected from R6, and 3) phenyl, unsubstituted or substituted with one or two substituents independently selected from ⁇ .
  • R is selected from the group consisting of
  • R3 is selected from the group consisting of
  • Inhibitory activity as measured by the in vitro assay described in the specification, where indicated, is represented by "*”, indicating Ki greater than or equal to 20 nM, or "**", indicating Ki less than 20 nM.
  • a subset of examples of the invention includes
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • the compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.
  • the compounds of the present invention also include tautomeric forms, with all tautomeric forms being included in the present invention.
  • alkyl includes 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); “substituted” alkyl groups refer to groups having one or more defined substituents.
  • alkenyl includes both branched- and straight-chain unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms (e.g. ethenyl, propenyl, 1- butenyl, 2-butenyl); "substituted” alkenyl groups refer to groups having one or more defined substituents.
  • alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge;
  • Halo as used herein, means fluoro, chloro, bromo and iodo;
  • 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
  • aryl represents a stable 6- to 10- membered mono- or bicyclic ring system such as phenyl, or naphthyl.
  • the aryl ring can be unsubstituted or substituted with one or more of C ⁇ _4 lower alkyl; hydroxy; alkoxy; halogen; amino.
  • heterocycle represents a stable 5- to 7-membered monocyclic- or stable 8- to 11-membered fused bicyclic or stable 11- to 15-membered tricyclic ring system, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • Bicyclic unsaturated ring systems include bicyclic ring systems which may be partially unsaturated or fully unsaturated.
  • Partially unsaturated bicyclic ring systems include, for example, cyclopentenopyridinyl, benzodioxan, methylenedioxyphenyl groups.
  • Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, mo ⁇ holinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimi
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfa ic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, 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-phenylpro ⁇ ionate, picrate, pivalate, propionate, succinate, sulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be 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
  • Anticoagulant therapy is indicated for the freatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
  • patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.
  • Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g. obstruction or occlusion of a vein by a detached thrombus; obstruction or occlusion of a lung artery by a detached thrombus), cardiogenic thromboembolism (e.g. obstruction or occlusion of the heart by a detached thrombus), arterial thrombosis (e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery), atherosclerosis (e.g. arteriosclerosis characterized by irregularly distributed lipid deposits) in mammals, and for lowering the propensity of devices that come into contact with blood to clot blood.
  • venous thromboembolism e.g. obstruction or occlusion of a vein by a detached thrombus
  • cardiogenic thromboembolism e.g. obstruction or occlusion of the heart by a detached thrombus
  • Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds ofthe invention are useful for maintaining patency of indwelling catheters.
  • cardiogenic thromboembolism examples include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.
  • arterial thrombosis examples include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterial thrombosis, compounds of the invention are useful for maintaining patency in arteriovenous cannulas.
  • Atherosclerosis examples include arteriosclerosis.
  • Examples of devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems
  • the thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non- toxic amount of the compound desired can be employed as an anti-aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
  • the thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Co ⁇ oration.
  • the thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the thrombin inhibitors when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis).
  • an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day.
  • a suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg.
  • the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
  • a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
  • the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day.
  • Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day.
  • a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g. 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml, and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg.
  • an 80 kg patient receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day.
  • Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers.
  • buffers Consideration should be given to the solubility of the drug in choosing an The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
  • the compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
  • thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, 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.
  • the invention also includes a method for treating an inflammatory disease in a patient which comprises treating the patient with a composition comprising a compound of the present invention.
  • diseases include but are not limited to nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, and sacoidosis.
  • the invention is also a method for treating an inflammatory disease in a patient that comprises treating the patient with a combination comprising a compound of the invention and an NSAID, e.g., a COX-2 inhibitor.
  • NSAID e.g., a COX-2 inhibitor.
  • diseases include but are not limited to nephritis, systemic lupus, erythematosus, rheumatoid arthritis, glomerulonephritis, vasculitis and sacoidosis.
  • the present invention is a method for relieving pain, fever and inflammation of a variety of conditions including nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, sacoidosis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures in a patient by administering to the patient a therapeutically effective amount of a compound of the invention.
  • Thrombin inhibitors may also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer Disease.
  • Fibrin serves as a matrix onto which inflammatory cells can migrate and adhere, (see Sherman et al., 1977 J. Exp. Med. 145:76-85; Altieri et al., 1986 J. Clin. Invest. 78:968- 976; Wright et al., 1983 Proc. Natl. Acad. Sci, 85:7734-7738; Altieri et al., 1993 J. Biol. Chem. 268;1847-1853).
  • Fibrin also enhances expression of the inflammatory cytokine IL-lbeta and decreases expression of IL-1 receptor antagonist by human peripheral blood mononuclear cells (see Perez 1995 J. Immunol. 154: 1879-1887).
  • the anticoagulants warfarin and heparin attenuate delayed-type hypersensitivity reactions and experimental nephritis in animals, (see Jasain et al., Immunopathogenesis of Rheumatoid Arthritis Eds. G.S. Panayi et al., Surrey, UK, Reedbooks, Ltd. and Halpern et al., 1965 Nature 205:257-259).
  • compositions for treating inflammatory diseases as defined above comprising a non-toxic therapeutically effective amount of a compound of the invention as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextrametho ⁇ han;
  • the invention encompasses a method of treating inflammatory diseases comprising administration to a patient in need of such treatment a non-toxic therapeutically effect amount of a compound of the invention, optionally co-administered with one or more of such ingredients as listed immediately above.
  • the instant invention also involves a novel combination therapy comprising the administration of a therapeutically effective amount of an NSAID such as a COX-2 inhibitor in combination with a therapeutically effective amount of a compound of the invention to a mammal, and more particularly, to a human.
  • the combination therapy is used to treat inflammatory diseases.
  • the instant pharmaceutical combinations comprising a compound of the invention in combination with an NSAID such as a COX-2 inhibitor include administration of a single pharmaceutical dosage formulation which contains both a compound of the invention and the NSAID, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
  • the compund of the invention and the NSAID can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially.
  • the "instant pharmaceutical combination” is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial pharmaceutical effect of the compound of the invention and the NSAID are realized by the patient at substantially the same time.
  • Such beneficial effect is preferably achieved when the target blood level concentrations of each active drug are maintained at substantially the same time. It is preferred that the compound of the invention and the NSAID be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the compound of the invention once per day and the NSAID once, twice or more times per day, or the NSAID once per day and the compound of the invention once, twice or more times per day, is also encompassed herein.
  • a single oral dosage formulation comprised of both the compound of the invention and the NSAID is preferred.
  • a single dosage formulation will provide convenience for the patient.
  • the instant invention also provides pharmaceutical compositions comprised of a therapeutically effective amount of an NSAID, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • One embodiment ofthe instant compositions is a single composition adapted for oral administration comprised of a therapeutically effective amount of a COX-2 inhibitor in combination with a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the combination can also be administered in separate dosage forms, each having one of the active agents. If administered in separate dosage forms, the separate dosage forms are administered such that the beneficial effect of each active agent is realized by the patient at substantially the same time.
  • Common NSAIDs include salicylates such as aspirin, sodium salicylate, choline salicylate, salicylsalicylic acid, diflunisal, and salsalate; indoleacetic acids such as indomethacin and sulindac; pyrazoles such as phenylbutazone, oxyphenbutazone; pyrrolealkanoic acids such as tolmetin; phenylacetic acids such as ibuprofen, feroprofen, flurbiprofen, and ketoprofen; fenamates such as mefanamic acid, and meclofenamate; oxicams such as piroxicam; and naphthaleneacetic acids such as naproxen.
  • salicylates such as aspirin, sodium salicylate, choline salicylate, salicylsalicylic acid, diflunisal, and salsalate
  • indoleacetic acids such as indomethacin and sulindac
  • Cyclo-oxygenase inhibitors such as COX-1 and COX-2 inhibitors are also NSAIDs.
  • the compounds employing the human whole blood COX-1 assay and the human whole blood COX-2 assay described in C. Brideau et al, Inflamm. Res. 45: 68-74 (1996), herein inco ⁇ orated by reference, preferably, the compounds have a cyclooxygenase-2 IC50 of less than about 2 ⁇ M in the human whole blood COX-2 assay, yet have a cyclooxygenase-1 IC50 of greater than about 5 ⁇ M in the human whole blood COX-1 assay.
  • the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and more preferably of at least 40.
  • the resulting selectivity may indicate an ability to reduce the incidence of common NS AID-induced side effects.
  • the inhibitor of cyclooxygenase-2 may be administered at a dosage level up to conventional dosage levels for NSAIDs. Suitable dosage levels will depend upon the antiinflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50 mg/kg per day, preferably 0.005 to 30mg/kg per day, and especially 0.05 to lOmg/kg per day.
  • the compound may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and especially once per day.
  • NSAID is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition ofthe 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 or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the interactive effects achieved by combining them together must also be taken into account. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the pu ⁇ ose of determining the therapeutically effective or prophylactically effective dosage amounts needed to prevent, counter, or arrest the progress of the condition. Administration of the drug combination to the patient includes both self- administration and administration to the patient by another person.
  • Additional active agents may be used in combination with the compound of the invention in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration.
  • additional active agents include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; vitamin B ⁇ (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin B 12 (also known as cyanocobalamin); ⁇ -adrenergic receptor blockers;
  • the thrombin inhibitors can also be co-administered with suitable anti-platelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin and simvastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis.
  • fibrinogen receptor antagonists e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis
  • anticoagulants such as aspirin
  • thrombolytic agents such as plasminogen activators or streptokinas
  • thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
  • Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.
  • Typical doses of thrombin inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
  • the protecting group "PG" can be, for example, benzyl, trialkylsilyl, or acetyl or other suitable protecting group useful for protecting the relevant portion of the molecule from the indicated reaction step.
  • the most convergent route to this class of compounds is a metal mediated coupling reaction between two suitably functionalized and where necessary, protected components.
  • the key step is the palladium mediated Suzuki coupling reaction of an aryl borate ester or boronic acid with an aryl or heteroaryl halide or triflate.
  • the roles of the two coupling fragments have been reversed. While the Suzuki reaction was used exclusively, it should be understood that any metal mediated coupling reaction which effects a similar single bond construction from appropriately functionalized components (e.g., Stille, Negishi, Buchwald reactions) could be employed where possible based upon availability of the required components.
  • the ether linkage is installed late in the sequence via either a Mitsunobu reaction or a simple alkylation. It is understood that where appropriate, this step may be performed prior to the organometallic coupling step.
  • the second aryl or heteroaryl ring of the biaryl moiety may be elaorated from suitably attached functional groups residing on one of the fragments.
  • R' is Ci-8 alkyl, -(CH2) ⁇ -4C3-7 cycloalkyl, or COOR20, an( j S serving as part of a protecting group, is, for example, Cj.4 alkyl or benzyl.
  • R' is Ci-8 alkyl, -(CH2) ⁇ -4C3-7 cycloalkyl, or COOR20, and R, serving as part of a protecting group, is, for example, Ci .4 alkyl or benzyl.
  • R' is C ⁇ _8 alkyl, -(CH2) ⁇ -4C3-7 cycloalkyl, or COOR20, and R, serving as part of a protecting group, is, for example, C ⁇ _4 alkyl or benzyl.
  • Y is O or NH
  • Y' is OH or NH2-
  • R' is Ci_8 alkyl, -(CH2) ⁇ -4C3-7 cycloalkyl, or COOR20, and the ring containing W,
  • X, Y and Z corresponds with the 5-membered ring defined in the general formula for R ⁇ .
  • R serving as part of a protecting group, is, for example, C1..4 alkyl or benzyl.
  • Q is hydrogen or C ⁇ .4 alkyl.
  • Trifluoromethanesulfonic anhydride (2.6 mL, 15.5 mmol) was added slowly to a solution of 3-benzyloxy-5-methylphenol (2.6 g, 12 mmol) and 2,6-di-tert-butyl-4-methylp ⁇ ridine (3.2 g, 15.6 mmol) in dichloromethane (100 mL) at -30°C.
  • the reaction mixture was allowed to warm gradually to room temperature. It was diluted with a threefold excess of pentane. The precipitated solids were removed via filtration and the filtrate concentrated almost to dryness. Ether was added and the mixture filtered once more. The filtrate was concentrated once more and then dissolved in 19:1 hexane / ether.
  • Step D l-(3'-Benzyloxy-5'-methylbiphenyl-2-ylV2-methylpropan-l-ol
  • Step E 2'-Isobutyl-5-methylbiphenyl-3-ol
  • Step F (5-Methyl-3-trityl-3_ft-imidazol-4-yl)acetonitrile and (5-methyl-l-trityl-l-tf-imidazol-
  • Step I 2-(5-Methyl-3-trityl-3/_t-imidazol-4-yl ethyl methanesulfonate and 2-(5-methyl-l- trityl- l /-imidazol-4-yl ' )ethyl methanesulfonate
  • Step J 5-r2-(2'-Isobutyl-5-methyl-biphenyl-3-yloxy)-ethvn-4-methyl-lfl r -imidazole
  • Step A 2-(2-Isopropylphenyl)-4,4.5,5-tetramethyl- ⁇ ,3,21dioxaborolane
  • Step D -r2-(2'-Isopropyl-5-methylbiphenyl-3-yloxyVl-methyl-ethvn- ⁇ yridin-4-yl-amine
  • Diethyl azodicarboxylate (0.21 mL, 1.3 mmol) was added in a dropwise manner to a mixture of 2'-isopropyl-5-methylbiphenyl-3-ol (270 mg, 1.2 mmol), _S-2-(pyridin-4-ylamino)propan-l- ol (WO 00/20394)(200 mg, 1.3 mmol) and triphenylphosphine (345 mg, 1.3 mmol) in toluene (5 mL). The urea biproduct was removed via filtration.
  • Step A 2-(2-Nitrophenyl ethyl acetate
  • Acetic anhydride (4 mL, 42 mmol) was added at 0°C to a solution of 2- nitrophenethanol (5 mL, 36 mmol) and pyridine (3.5 mL, 43 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm gradually to room temperature overnight. The reaction mixture was diluted with ether and washed with 1M HCl. Drying over sodium sulfate and concentration gave a peach colored oil.
  • Step B 2-(2-Aminophenyl ' )ethyl acetate
  • the sample of 2-(2-nitrophenyl)ethyl acetate from the previous step was hydrogenated at 50 psi in EtOAc (250 mL) in the presence of 10% Pd/C to give a pink oil.
  • Step C 2-(2-Tetrazol-l-ylphenvDethyl acetate
  • Step D 2-(2-Tetrazol- l-ylphenvDethanol
  • the title compound was prepared essentially according to the Mitsunobu protocol for Example II, Step D using 2'-isopropyl-5-methylbi ⁇ henyl-3-ol and a mixture of 2-(5-methyl-3-trityl-3H- imidazol-4-yl)ethanol and 2-(5-methyl-l-trityl-lr7-imidazol-4-yl)ethanolas the coupling partners.
  • the trityl group was then removed essentially according to the procedure for Example I, Step J.
  • the product was purified by HPLC and isolated as the TFA salt.
  • Benzyl bromide (24 mL, 200 mmol) was added to a well stirred mixture of orcinol (25 g, 200 mmol), cesium carbonate (66 g, 200 mmol), and tetrabutylammonium iodide (4 g, 10 mmol) in DMF (400 mL). After stirring for 4 h, the reaction mixture was poured onto ice. 6 M HCl (100 mL) was added and the resulting mixture extracted with several portions of ether. The combined organic extracts were washed three times with ice cold water and dried over sodium sulfate.
  • Trifluoromethanesulfonic anhydride (2.6 mL, 15.5 mmol) was added slowly to a solution of 3-benzyloxy-5-methylphenol (2.6 g, 12 mmol) and 2,6-di-tert-butyl-4-methylpyridine (3.2 g, 15.6 mmol) in dichloromethane (100 mL) at -30°C.
  • the reaction mixture was allowed to warm gradually to room temperature. It was diluted with a threefold excess of pentane. The precipitated solids were removed via filtration and the filtrate concentrated almost to dryness. Ether was added and the mixture filtered once more. The filtrate was concentrated once more and then dissolved in 19: 1 hexane / ether.
  • Step D 1 -(3 '-Benzyloxy-5'-methylbiphenyl-2-ylV2-methylpro ⁇ an- 1 -ol
  • Step F (5-Methyl-3-trityl-3ff-imidazol-4-yl acetonitrile and (5-methyl- l-trityl-lfl'-imidazol-
  • Step I 2-(5-Methyl-3-trityl-3H-imidazol-4-v ⁇ ethyl methanesulfonate and 2-(5-methyl-l- trityl-l/_t-imidazol-4-yl ' )ethyl methanesulfonate
  • methylene chloride 10 mL
  • triethylamine 0.16 mL, 1.15 mmol
  • mesyl anhydride 160 mg, 0.92 mmol
  • Step J 5-r2-(2'-Isobutyl-5-methyl-biphenyl-3-yloxy)-ethyll-4-methyl-l J r -imidazole .
  • Step A 2-(2-Isopropylphenyl)-4.4.5.5-tetramethyl-ri,3.21dioxaborolane
  • Step B 3-Benzyloxy-2'-isopropyI-5-methylbiphenyl
  • 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-[ 1 ,3,2]-dioxaborolane (0.43 g, 1.75 mmol)
  • 3-benzyloxy-5-methyl ⁇ henyl trifluoromethane-sulfonate 0.6 g, 1.75 mmol
  • 2M aqueous sodium carbonate 4.4 mL
  • diphenylphosphinoferrocene)palladium dichloride 80 m g, 0.1 mmol)in DMF (9 mL) was heated at 80°C overnight.
  • Diethyl azodicarboxylate (0.21 mL, 1.3 mmol) was added in a dropwise manner to a mixture of 2'-isopropyl-5-methylbiphenyl-3-ol (270 mg, 1.2 mmol), 2-(pyridin-4-ylamino)propan-l-ol (200 mg, 1.3 mmol) and triphenylphosphine (345 mg, 1.3 mmol) in toluene (5 mL). The urea biproduct was removed via filtration. Concentration gave a residue which was purified by flash chromatography eluting with 19:1 - 9:1 chloroform / 10% NH 4 OH in MeOH. The product was further purified by
  • Step A 2-(2-Nitrophenyl ' )ethyl acetate
  • Acetic anhydride (4 mL, 42 mmol) was added at 0°C to a solution of 2- nitrophenethanol (5 mL, 36 mmol) and pyridine (3.5 mL, 43 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm gradually to room temperature overnight. The reaction mixture was diluted with ether and washed with 1M HCl. Drying over sodium sulfate and concentration gave a peach colored oil.
  • Step B 2-(2-Amino ⁇ henyl')ethyl acetate
  • the sample of 2-(2-nitrophenyl)ethyl acetate from the previous step was hydrogenated at 50 psi in EtOAc (250 mL) in the presence of 10% Pd/C to give a pink oil.
  • Step C 2-(2-Tetrazol- 1 -ylphenvDethyl acetate
  • Step D 2-(2-Tetrazol- 1 -ylphenyllethanol
  • Step E l- ⁇ 2-r2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxyVethyn-phenyl -ltf-tetrazole
  • the title compound was prepared essentially according to the Mitsunobu protocol for
  • Example VI Step D using 2-(2-tetrazol-l-ylphenyl)ethanol and 2 , -Isopro ⁇ yl-5-methylbiphenyl-3-ol as the coupling partners.
  • the title compound was prepared essentially according to the Mitsunobu protocol for Example VI, Step D using 2'-isopropyl-5-methylbiphenyl-3-ol and a mixture of 2-(5-methyl-3-trityl-3H-imidazol-4- yl)ethanol and 2-(5-methyl-l-trityl-li_t-imidazol-4-yl)ethanol as the coupling partners.
  • the trityl group was then removed essentially according to the procedure for Example V, Step J.
  • the product was purified by HPLC and isolated as the TFA salt.
  • Step B 5-Chloro-2-[T.2.41triazol-l-yl-benzoic acid
  • a suspension of 5-chloro-2-[l,2,4]triazol-l-yl-benzonitrile (8.4 g) in concentrated hydrochloric acid (50 mL) was brought to 100°C and the resulting yellow solution stirred there for 96 h. After cooling to room temperature, the solution was poured onto crushed ice. The resulting white suspension was made alkaline by addition of a 50% aqueous sodium hydroxide solution. The resulting solution was extracted twice with dichloromethane and once with ethyl acetate. The aqueous phase was cooled in ice and acidified with concentrated hydrochloric acid. The resulting white precipitate was filtered off, washed well with water and dried.
  • Step C 5-Chloro-2-n,2.41triazol-l-yl-benzyl alcohol
  • Step H l-f4-Chloro-2-r2-(2'-isopropyl-5-methylbiphenyl-3-yloxy)-ethvn-phenyll-l_g- ll,2,4ltriazole
  • Step A Acetic acid 2-(2-bromo-phenyl " )-ethyl ester
  • Acetic anhydride (1.7 mL, 18 mmol) was added to a mixture of 2-(2-bromo-phenyl)- ethanol (3 g, 15 mmol) and triethylamine (2.9 mL, 15 mmol) in methylene chloride (10 mL) at 0°C.
  • the reaction mixture was allowed to warm to room temperature whereupon it was diluted with ethyl acetate and extracted with saturated sodium bicarbonate. Drying over sodium sulfate and then concentration yielded a pale yellow oil (3.75 g).
  • Step D 2-F2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxyVethyl -benzylamine
  • the Mitsunobu product (38 mg) from the previous step was hydrogenated at 45 psi in ethanol containing cone.
  • HCl (3 eq.) in the presence of 10% Pd/C to give the HCl salt of the title compound as a white solid.
  • Step A 2-(2-Isopropyl-phenylV4.4,5,5-tetramethyl-11.3,21dioxaborolane
  • Trifluoromethanesulfonic anhydride (4.5 mL, 27 mmol) was added slowly to a solution of 3-hydroxy-5-methyl-benzoic acid methyl ester (Turner & Gearien, JOC 1959 p. 1952)(3.3 g, 20 mmol) and 2,6-di-tert-butyl-4-methylpyridine (5.5 g, 27 mmol) in dichloromethane (100 mL) at - 15°C.
  • the reaction mixture was allowed to warm gradually to room temperature and was then diluted with pentane.
  • the resulting white solid was filtered off and the filtrate concentrated to one quarter of the initial volume. It was diluted with ether and filtered once again through the original residue.
  • Step C 2'-Isopropyl-5-methyl-biphenyl-3-carboxylic acid methyl ester A mixture of 3-methyl-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1 g,
  • Step D 2'-Isopropyl-5-methyl-biphenyl-3-carboxylic acid
  • Step E 2'-Isopropyl-5-methyl-biphenyl-3-carbonyl chloride
  • Oxalyl chloride (0.06 mL, 0.63 mmol) was added to a solution of 2'-isopropyl-5- methyl-biphenyl-3-carboxylic acid (140 mg, 0.55 mmol) in dichloromethane (5 mL) containing a few drops of at 0°C. the cold bath was removed and the reaction mixture allowed to warm gradually to room temperature and then stir there overnight. All volatile components were then removed and the residual acid chloride used directly.
  • Step F Isopropyl-5-methyl-biphenyl-3-carboxylic acid 5-chloro-2-ri.2,41triazol-l-yl- benzylamide
  • Step A (2'-Isopropyl-5-methyl-biphenyl-3-yl")-methanol
  • Lithium aluminum hydride (2.85 mL, 1 M in THF) was added to a solution ofthe 2'- isopropyl-5-methyl-biphenyl-3-carboxylic acid methyl ester (765 mg, 2.85 mmol) in dichloromethane (10 mL) at 0°C.
  • the reaction mixture was stirred for 0.45 h then excess reductant was destroyed via slow addition of ethyl acetate (2 mL). Following Fieser work up and drying over sodium sulfate, the product was isolated as an oil and used without further purification.
  • Step C (5-Chloro-2-ri,2.41triazol-l-yl-benzyl)-(2'-isopropyl-5-methyl-biphenyl-3-ylmethyl')- amine
  • 5-Chloro-2-ri,2.41triazol-l-yl-benzyl (2'-isopropyl-5-methyl-biphenyl-3-ylmethyl')- amine
  • 2'-iso ⁇ ropyl-5-methyl-biphenyl-3-carbaldehyde 290 mg, 1.22 mmol
  • Step A 3-Methyl-5-( ,4,5.5-tetramethyl-ri,3,21dioxaborolan-2-vf)-benzoic acid methyl ester
  • a mixture of 3-methyl-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1.4 g, 4.7 mmol), pinacol diboron (1.4 g, 5.6 mmol), potassium acetate (1.4 g, 14 mmol) and PdCl 2 (dp ⁇ f) (103 mg) in DMF (20 mL) was heated at 90°C for 1.5 h. The reaction mixture was then cooled and the DMF removed under reduced pressure. The residue was chromatographed directly (19:1 hexane / ethyl acetate) to give the borate as a white crystalline solid.
  • Step B 3-(4-Isopropyl-pyridin-3-yl)-5-methyl-benzoic acid methyl ester
  • Step C 3-(4-Isopro ⁇ yl-pyridin-3-yl -5-methyl-benzoic acid
  • Step D 3-(4-Isopro ⁇ yl-pyridin-3-yl)-5-methyl-benzoic acid 5-chloro-2-ri,2.41triazol-l-yl- benzyl ester
  • DBU dibenzyl ether
  • 5-chloro-2-[l,2,4]triazol-l-yl-benzyl bromide 120 mg
  • Methyltrioxorhenium (a smidgen) was added to a solution of 3-(4-isopropyl-pyridin-3-yl)-5-methyl- benzoic acid 5-chloro-2-[l,2,4]triazol-l-yl-benzyl ester (67 mg, 0.15 mmol) in dichloromethane (2 mL) containing 30% aqueous hydrogen peroxide (0.05 mL). The reaction mixture was stirred for 2 h then excess oxidant destroyed by very careful addition of manganese dioxide (a spatula tip). The reaction mixture was then washed with brine, dried (sodium sulfate) and concentrated to give the title compound as a white solid.
  • Step D l-13-(Benzyloxy ⁇ phenyl1-4-methylpentan-l-one
  • isobutylmagnesium bromide prepared from magnesium turnings (790 mg), l-bromo-3-methylbutane (3.6 mL )and catalytic I 2 in 25 mL anhydrous ether
  • the mixture was stirred at 0 °C for 90 min and was then poured into a mixture of 5% HCl and ice.
  • Step H l-(4-chloro-2- ⁇ 2-r3-(5-isobutyl-l,3-oxazol-4-yl)phenoxylethyllphenyl -lfl r -l,2,4- triazole
  • 3-(5-isobutyl-l,3-oxazol-4-yl)phenol 108 mg, 0.50 mmol
  • 2-(l#-l,2,4-triazol-l-yi)phenyl]ethanol (112 mg, 0.50 mmol), diisopropyl azodicarboxylate (140 ⁇ L, 0.70 mmol) and triphenylphosphine (184 mg, 0.70 mmol) in CH 2 C1 2 was stirred at room temperature for 3 days.
  • the crude product was purified by reverse phase preparative HPLC and the resulting TFA salt was neutralized with aqueous K 2 C0 3 .
  • the product was extracted into CH 2 C1 2 and the organic extract was dried over Na 2 S0 4 , filtered and concentrated to an oil.
  • Step B l-(-4-chloro-2-(2-r3-(l-isobutyl-lH-imidazolvnphenoxylethyllphenyl ' )- -1.2.4- triazole
  • Step A 3-Hvdroxy-5-methylbenzoic acid To a solution of methyl 3-hydroxy-5-methylbenzoate (5.0 g, 30 mmol) in EtOH (32 mL) was added sodium hydroxide (1.2 g, 30 mmol). The reaction was heated to 60 °C for 18 h. The mixture was concentrated to dryness and was then suspended in saturated HCl MeOH with stirring for 15 min.
  • Step D 5-r3-(Benzyloxy -5-methylphenyll-l-isobutyl-lH-tetraazole
  • the title compound was prepared from 5-[3-(benzyloxy)-5-methylphenyl]-l-isobutyl- lH-te raazole essentially according to the procedure described in Example III, Step G.
  • the product was isolated by flash column chromatography (2:1 - 1:1 hexanes/EtOAc to EtOAc) as a clear oil.
  • Step F S-G-l ⁇ -rS-Chloro ⁇ -dg-l ⁇ -triazol-l-yllphenyllethoxyl-S-methylphenvn-l- isobutyl- lH-tetraazole
  • the title compound was prepared essentially according to the procedure described in
  • Step C 5-r3-(Benzyloxy phenyll-l-isobutyl-lH-tetraazole
  • Step D 3-(T-Isobutyl-lff-tetraazol-5-yl)phenol
  • Step E 5-(3- ⁇ 2-r5-chloro-2-( -1.2.4-triazol-l-yl ' )phenyllethoxy)phenyl ' )-l-isobutyl-l /- tetraazole
  • the title compound was prepared essentially according to the Mitsunobu protocol described in
  • Example XVII, Step H with 3-(l-isobutyl-lH-tetraazol-5-yl)phenol (300 mg, 1.4 mmol) and 2-[5- chloro-2-(lH-l,2,4-triazol-l-yl)phenyl]ethanol (308 mg, 1.4 mmol) as the coupling partners.
  • the crude product was purified by reverse phase HPLC. The sticky solid was partitioned between EtOAc and saturated K 2 C0 3 solution, and the organic layer was dried over MgS0 4 and concentrated to dryness. The residue was suspended in 4.0M HCl/Et 2 0 and the solvent was removed in vacuo. Drying under high vacuum afforded the coupled product as a tan crystalline powder.
  • Step A Methyl 3-(benzyloxy -5-chlorobenzoate To a solution of methyl 3-chloro-5-hydroxybenzoate (Takahashi, K.; Shimizu, S.;
  • Step D 5-r3-(Benzyloxy -5-chlorophenyll-l-isobutyl-l//-tetraazole
  • Step E 3-Chloro-5-( 1-isobutyl- lH-tetraazol-5-yl " )phenol
  • Step F 5-(3-chloro-5- ⁇ 2-r5-chloro-2-(lH-l,2.4-triazol-l-yl)phenyllethoxy)phenylVl- isobutyl- lH-tetraazole
  • the title compound was prepared essentially according to the procedure of Example XVII, Step H, with 3-chloro-5-(l-isobutyl-l#-tetraazol-5-yl)phenol (75 mg, 0.30 mmol) and 2-[5-chloro-2- (1H-1, 2 ,4-triazol-l-yl)phenyl] ethanol (65 mg, 0.30 mmol) as the coupling partners.
  • the crude product was purified by reverse phase HPLC.
  • Step A 2-(2-Bromo-5-chlorophenyl " )ethanol To a solution of 2-bromo-5-chlorophenylacetic acid (3.00 g, 12 mmol) in anhydrous THF (70 mL) at 0 °C under inert atmosphere was added borane/dimethyl sulfide complex (6.84 mL, 72 mmol) over 5 min. The reaction was allowed to warm to 25 °C while stirring for 18 h. MeOH (15 mL) was added slowly to the reaction solution and the solvents were then removed in vacuo. MeOH (15 mL) was added to the remaining viscous material and was again removed in vacuo. Flash column chromatography (1:1 EtOAc/hexanes) provided the alcohol as a clear oil.
  • Step B l-Bromo-4-chloro-2-[2-(methoxymethoxy)ethyllbenzene
  • Step D (4-Chloro-2-r2-(methoxymethoxy)ethyllphenyl ⁇ methanol To a solution of 4-chloro-2-[2-(methoxymethoxy)ethyl]benzaldehyde (500 mg, 2.2 mmol) in
  • Step E l-(Azidomethyl)-4-chloro-2-r2-(methoxymethoxy)ethyllbenzene
  • Step F 1 - ⁇ 4-Chloro-2- r2-( ' methoxymethoxy ' )ethyllphenyl ⁇ methanamine
  • Step G 2-f2-(AminomethylV5-chlorophenvnethanol To a solution of l- ⁇ 4-chloro-2-[2-(methoxymethoxy)ethyl]phenyl ⁇ methanamine (153 mg, 0.67 mmol) in THF (2 mL) was added 6 N HCl (1 mL). The reaction was stirred for 5 h and was then concentrated to yield the deprotected product as a clear oil.
  • Step H tert- utyl 4-chloro-2-f2-hvdroxyethyl)benzylcarbamate
  • Step I fe ⁇ Butyl 4-chloro-2- ⁇ 2-r3- ⁇ -isobutyl-lff-tetraazol-5- vDphenoxylethyl Ibenzylcarbamat
  • the title compound was prepared essentially according to the procedure described in
  • Step J l-(4-Chloro-2- ⁇ 2-r3-(l-isobutyl- -tetraazol-5-vDphenoxyl- ethyl IphenvDmethanamine ferf-Butyl 4-chloro-2- ⁇ 2-[3-(l-isobutyl-l -tetraazol-5-yl)phenoxy]ethyl ⁇ benzylcarbamate
  • Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
  • Mannitol, microcrystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.
  • p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm " IM "1 .
  • Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7-amino-4- trifluoromethyl coumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin.
  • Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 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 0 ) or presence of inhibitor (V ) were measured. Assuming competitive inhibition, and that unity is negligible compared K m /[S],
  • the activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
  • the inhibitory activity of compounds of the invention against human thrombin, represented by Ki is less than 24 nM. These are selective compounds, as evidenced by their inhibitory activity against human trypsin (represented by Ki), which is at least 1000 nM.
  • compositions A-I Active I is 5-[2-(2'-Isobutyl-5- methyl-biphenyl-3-yloxy)-ethyl]-4-methyl-lH-imidazole; Active II is _S-[2-(2 -Isopropyl-5- methylbiphenyl-3-yloxy)-l-methyl-ethyl]-pyridin-4-yl-amine; Active III is l- ⁇ 2-[2-(2 -Isopropyl-5- methyl-biphenyl-3-yloxy)-ethyl]-phenyl ⁇ -H_f-tetrazole.
  • compositions containing from 25-100 mg of active compound (mg amounts)
  • Active II - - - 25 50 100 - Active III - - . . . 25 50 100 Microcrystalline
  • All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • Active IV, mannitol and microcrystalline cellulose were sieved through mesh screens of specified size (generally 250 to 750 ⁇ m) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water- soluble polymers and pigment.
  • Tablet preparation via dry granulation Alternatively, a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size. The granules are then mixed with magnesium stearate and tabletted as stated above.
  • compositions A-C are as follows:
  • buffer acids such as L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be substituted for glucuronic acid.

Abstract

L'invention concerne des composés pouvant inhiber la thrombine et traiter la coagulation sanguine et les troubles cardiovasculaires. Ces composés présentent la structure suivante dans laquelle R1 est hydrogène ou alkyle C¿1-4?, (CH2)0-1CN, C(O)R?14, (CH¿2)0-1CO2R14, CF3, OR14, halogène, SR?14, S(O)R14¿, S(O)¿2?R?14, NR14R15¿.
PCT/US2001/028791 2000-09-11 2001-09-11 Inhibiteur de la thrombine WO2002022584A1 (fr)

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WO2005115984A2 (fr) * 2004-05-31 2005-12-08 Tanabe Seiyaku Co., Ltd. Composés bicycliques
JP2006510737A (ja) * 2002-12-13 2006-03-30 サイトピア・リサーチ・ピーティーワイ・リミテッド ニコチンアミド系キナーゼ阻害薬
US7208507B2 (en) * 2003-04-04 2007-04-24 Cell Therapeutics, Inc. Pyridines and uses thereof
WO2007098352A2 (fr) * 2006-02-16 2007-08-30 Boehringer Ingelheim International Gmbh Pyridineamides substitués pouvant être employés en tant qu'inhibiteurs d'époxyde hydrolase soluble
JP2010513361A (ja) * 2006-12-22 2010-04-30 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ ヘテロシクリル基によって置換されたエチルアミノフェニル誘導体、その調製方法、および医薬としての使用方法
US7923451B2 (en) 2007-02-14 2011-04-12 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
JP2011514894A (ja) * 2008-02-29 2011-05-12 レノビス， インコーポレイテッド アミド化合物、組成物およびそれらの使用
US8247401B2 (en) * 2007-10-31 2012-08-21 Merck Sharp & Dohme Corp. P2X3 receptor antagonists for treatment of pain
WO2013135672A1 (fr) 2012-03-13 2013-09-19 Basf Se Composés de pyrimidine fongicides
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
US9040558B2 (en) 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9133122B2 (en) 2008-09-18 2015-09-15 Evotec Ag Amide compounds, compositions and uses thereof
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
WO2022030976A1 (fr) * 2020-08-04 2022-02-10 연세대학교 산학협력단 Composition pour prévenir ou traiter la fibrose hépatique, contenant un dérivé de triazole comme principe actif
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

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US6034103A (en) * 1995-03-10 2000-03-07 Berlex Laboratories, Inc. Benzamidine derivatives and their use as anti-coagulants

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006510737A (ja) * 2002-12-13 2006-03-30 サイトピア・リサーチ・ピーティーワイ・リミテッド ニコチンアミド系キナーゼ阻害薬
JP4896518B2 (ja) * 2002-12-13 2012-03-14 ワイエム・バイオサイエンシズ・オーストラリア・ピーティーワイ・リミテッド ニコチンアミド系キナーゼ阻害薬
US7208507B2 (en) * 2003-04-04 2007-04-24 Cell Therapeutics, Inc. Pyridines and uses thereof
WO2005115984A3 (fr) * 2004-05-31 2006-03-02 Tanabe Seiyaku Co Composés bicycliques
WO2005115984A2 (fr) * 2004-05-31 2005-12-08 Tanabe Seiyaku Co., Ltd. Composés bicycliques
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9040558B2 (en) 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
WO2007098352A2 (fr) * 2006-02-16 2007-08-30 Boehringer Ingelheim International Gmbh Pyridineamides substitués pouvant être employés en tant qu'inhibiteurs d'époxyde hydrolase soluble
WO2007098352A3 (fr) * 2006-02-16 2007-10-25 Boehringer Ingelheim Int Pyridineamides substitués pouvant être employés en tant qu'inhibiteurs d'époxyde hydrolase soluble
JP2010513361A (ja) * 2006-12-22 2010-04-30 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ ヘテロシクリル基によって置換されたエチルアミノフェニル誘導体、その調製方法、および医薬としての使用方法
US7923451B2 (en) 2007-02-14 2011-04-12 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US8716475B2 (en) 2007-02-14 2014-05-06 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US8686142B2 (en) 2007-02-14 2014-04-01 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US8415366B2 (en) 2007-02-14 2013-04-09 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US8247401B2 (en) * 2007-10-31 2012-08-21 Merck Sharp & Dohme Corp. P2X3 receptor antagonists for treatment of pain
AU2008319308B2 (en) * 2007-10-31 2013-01-31 Merck Sharp & Dohme Corp. P2X3, receptor antagonists for treatment of pain
JP2014065737A (ja) * 2008-02-29 2014-04-17 Evotec Ag アミド化合物、組成物およびそれらの使用
US8946439B2 (en) 2008-02-29 2015-02-03 Evotec Ag Amide compounds, compositions and uses thereof
JP2011514894A (ja) * 2008-02-29 2011-05-12 レノビス， インコーポレイテッド アミド化合物、組成物およびそれらの使用
US9133122B2 (en) 2008-09-18 2015-09-15 Evotec Ag Amide compounds, compositions and uses thereof
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
WO2013135672A1 (fr) 2012-03-13 2013-09-19 Basf Se Composés de pyrimidine fongicides
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10689383B2 (en) 2014-08-04 2020-06-23 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11254681B2 (en) 2014-08-04 2022-02-22 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors
WO2022030976A1 (fr) * 2020-08-04 2022-02-10 연세대학교 산학협력단 Composition pour prévenir ou traiter la fibrose hépatique, contenant un dérivé de triazole comme principe actif

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