WO2016093285A1 - ジヒドロインドリジノン誘導体 - Google Patents
ジヒドロインドリジノン誘導体 Download PDFInfo
- Publication number
- WO2016093285A1 WO2016093285A1 PCT/JP2015/084573 JP2015084573W WO2016093285A1 WO 2016093285 A1 WO2016093285 A1 WO 2016093285A1 JP 2015084573 W JP2015084573 W JP 2015084573W WO 2016093285 A1 WO2016093285 A1 WO 2016093285A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- fluoro
- salt
- disease
- prodrug
- Prior art date
Links
- AIMDYPMHNJACAF-UHFFFAOYSA-N Cc1nc(F)c(-c(cc2)ccc2N)[nH]1 Chemical compound Cc1nc(F)c(-c(cc2)ccc2N)[nH]1 AIMDYPMHNJACAF-UHFFFAOYSA-N 0.000 description 1
- JLSBKUUDUWIJAA-UHFFFAOYSA-N Cc1nc(F)c(-c2ccc(N)nc2F)[nH]1 Chemical compound Cc1nc(F)c(-c2ccc(N)nc2F)[nH]1 JLSBKUUDUWIJAA-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to general formula (I) (Wherein all symbols have the same meanings as described below), salts thereof, solvates thereof, N-oxides thereof or prodrugs thereof (hereinafter sometimes abbreviated as compounds of the present invention). .)
- thromboembolic disease thromboembolic disease
- a thromboembolic disease occurs when a thrombus is formed at a site of vascular injury, or when the thrombus is released and carried into the bloodstream and carried into another blood vessel to occlude the blood vessel.
- thromboembolic diseases include venous thromboembolism, which is a generic term for deep vein thrombosis and pulmonary embolism, stroke, angina pectoris, myocardial infarction, and various other arterial and venous thrombosis.
- Tissue factor expressed in the blood vessel wall due to blood vessel damage or the like becomes a starting point of the blood coagulation cascade and forms a complex with blood coagulation factor VII present in a minute amount in the blood.
- the complex activates blood coagulation factor IX and blood coagulation factor X, and activated blood coagulation factor X converts prothrombin to thrombin.
- Thrombin converts fibrinogen to fibrin, eventually forming insoluble fibrin (starting phase). Thrombin produced in this process is thought to promote the formation of thrombus in the initial stage and is considered important for hemostasis.
- it activates blood coagulation factor XI and activates blood coagulation factor XI (hereinafter referred to as FXIa). It has been reported that explosive thrombin production is caused through (the amplification phase), and as a result, thrombus increases (see Non-Patent Documents 1-3).
- Anticoagulant drugs are generally used for the treatment and / or prevention of thromboembolic diseases, but existing anticoagulant drugs have excellent antithrombotic activity, but have serious side effects such as bleeding complications. May cause a problem or may not cause bleeding complications, the dose may be limited, and sufficient antithrombotic activity may not be exhibited. Under such circumstances, there is a need for a therapeutic and / or prophylactic agent for thrombosis and thromboembolism having a new mechanism of action that inhibits the growth or increase of pathological thrombus and does not affect the formation of hemostatic thrombus. Has been. In recent years, FXIa has attracted attention as one of its targets.
- Blood coagulation factor XI is one of the serine proteases in plasma involved in the regulation of blood coagulation and becomes FXIa by activated blood coagulation factor XII, thrombin, or itself.
- FXIa is one of the components of the blood coagulation pathway called the intrinsic system or contact system in the classical blood coagulation cascade, and by selectively cleaving the peptide bond between Arg-Ala and Arg-Val, Activates coagulation factor IX.
- the safety of FXIa is supported by observations characterized by mild to moderate bleeding mainly after surgery or trauma in human blood coagulation factor XI deficiency called hemophilia C.
- FXIa is a very attractive target without the side effect of bleeding in developing an antithrombotic therapeutic agent and / or preventive agent, and the FXIa inhibitor has no undesirable side effects such as bleeding, It is expected to be a very powerful and safe antithrombotic treatment or prevention agent.
- Patent Document 1 a general formula (A) (Wherein A A represents a 5- to 12-membered heterocyclic ring; L 1A represents —CH ⁇ CH— or the like; R 11A represents benzyl or the like; M A represents imidazolyl or the like).
- a A represents a 5- to 12-membered heterocyclic ring; L 1A represents —CH ⁇ CH— or the like; R 11A represents benzyl or the like; M A represents imidazolyl or the like.
- An object of the present invention is a potent FXIa inhibitor, which is excellent in oral absorption and blood kinetics, exhibits strong anticoagulant activity for a long time after oral administration, and between anticoagulant activity and CYP inhibitory activity.
- the goal is to develop compounds with discrepancies.
- a pharmaceutical composition comprising the compound according to any one of [1] to [5], a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof as an active ingredient, [7] An FXIa inhibitor comprising as an active ingredient the compound according to any one of [1] to [5], a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof, [8] Prevention of thromboembolic diseases containing the compound, salt, solvate, N-oxide or prodrug thereof according to any one of [1] to [5] as an active ingredient And / or therapeutic agent, [9] The thromboembolic disease is arterial cardiovascular thromboembolic
- the compound of the present invention is a potent FXIa inhibitor, it is an effective prophylactic and / or therapeutic agent for thromboembolic diseases.
- FIG. 2 shows the plasma compound concentration transition of the compound described in Example 2 (10) when administered orally (1 mg / kg) to rats and the relationship with APTT ⁇ 2 in an in vitro assay.
- the vertical axis represents the plasma compound concentration
- the horizontal axis represents the time after oral administration.
- 2 shows the relationship between plasma compound concentration transition of the compound described in Example 4 (10) and APTT ⁇ 2 in in vitro assay when orally administered to rats (1 mg / kg).
- the vertical axis represents the plasma compound concentration
- the horizontal axis represents the time after oral administration.
- the relationship between the compound concentration in plasma of the compound described in Comparative Example 2 (3) and the APTT ⁇ 2 in the in vitro assay when orally administered to rats (1 mg / kg) is shown.
- the vertical axis represents the plasma compound concentration
- the horizontal axis represents the time after oral administration.
- alkyl groups include straight chain and branched chain.
- isomers R, S form, ⁇ , ⁇ configuration, enantiomers, diastereomers
- optically active substances having optical activity D, L, d, 1 form
- chromatographic separation due to the presence of asymmetric carbon etc.
- Polar forms high polar forms, low polar forms
- equilibrium compounds eg, tautomers formed in amide bonds, etc.
- rotamers mixtures of these in any proportion, and racemic mixtures are all included in the present invention. .
- optical isomers in the present invention may include not only 100% pure but also other optical isomers of less than 50%.
- the compound of the present invention is converted into a corresponding salt by a known method.
- the salt is preferably a pharmaceutically acceptable salt, and more preferably a water-soluble salt.
- Suitable salts include acid addition salts (eg, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate, lactate, tartrate.
- alkali Salts of metals potassium, sodium, etc.
- alkaline earth metals calcium, magnesium, etc.
- the compound of the present invention and its salt can be converted into a solvate.
- the solvate is preferably low toxic and water soluble.
- Suitable solvates include, for example, solvates with water and alcohol solvents (for example, ethanol).
- the N-oxide form of the compound of the present invention represents an oxidized nitrogen atom of the compound of the present invention. Further, the N-oxide form of the compound of the present invention may further be the above alkali (earth) metal salt, ammonium salt, organic amine salt, or acid adduct salt.
- the prodrug of the compound of the present invention refers to a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like in a living body.
- the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranyl , Pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compounds, and the like, and these compounds can be produced by known methods.
- the prodrug of the compound of the present invention may be either a hydrate or a non-hydrate. Further, the prodrug of the compound of the present invention is a compound that changes to the compound of the present invention under physiological conditions as described in Yodogawa Shoten, 1990, “Pharmaceutical Development”, Volume 7, “Molecular Design”, pages 163 to 198. There may be.
- each atom constituting the compound of the present invention has its isotope (for example, 2 H, 3 H, 13 C, 14 C, 15 N, 16 N, 17 O, 18 O, 35 S, 36 Cl, 77 Br). , 125 I, etc.).
- the compound of the present invention can form a pharmaceutically acceptable cocrystal or cocrystal salt.
- co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
- the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
- the compound of the present invention can be obtained by a known method, for example, the method described below, the method described in Examples, or Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999). It can manufacture by improving the described method etc. suitably and using it in combination.
- the toxicity of the compound of the present invention is sufficiently low and can be used safely as a pharmaceutical product.
- the compound of the present invention has potent FXIa inhibitory activity. Accordingly, the compounds of the present invention are thromboembolic diseases such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and Useful for the prevention and / or treatment of thromboembolic disorders in the heart chamber or peripheral circulation.
- thromboembolic diseases such as arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and Useful for the prevention and / or treatment of thromboembolic disorders in the heart chamber or peripheral circulation.
- arterial cardiovascular thromboembolic disorders include coronary artery disease, ischemic cardiomyopathy, acute coronary syndrome, coronary artery thrombosis, unstable angina and non-Q-wave myocardial infarction ischemic complications, medically Angina, such as ST-elevated and / or non-ST-elevated acute myocardial infarction with stable or percutaneous coronary intervention, stable (working) angina, variant angina, unstable narrowness Heart disease, myocardial infarction (such as initial or recurrent myocardial infarction), acute myocardial infarction, vascular re-occlusion and stenosis after coronary artery bypass surgery, percutaneous transluminal angioplasty, cardiac / transcoronary stent placement Examples include reocclusion and stenosis or sudden ischemic death after thrombolytic therapy for coronary arteries.
- Angina such as ST-elevated and / or non-ST-elevated acute myocardial infarction with stable
- venous cardiovascular thromboembolic diseases include major general surgery, abdominal surgery, hip replacement, knee replacement, hip fracture surgery, multiple fractures, multiple trauma, trauma, spinal cord injury, burns, Or deep vein thrombosis (DVT) and / or pulmonary embolism (PE) when entering a critical care room, DVT and / or PE in patients with acute internal illness with significantly restricted physical activity, DVT in patients undergoing cancer chemotherapy and And / or PE, DVT in stroke patients and / or PE, symptomatic or asymptomatic DVT with or without PE, and the like.
- DVT and / or PE in patients with acute internal illness with significantly restricted physical activity
- DVT in patients undergoing cancer chemotherapy and And / or PE DVT in stroke patients and / or PE, symptomatic or asymptomatic DVT with or without PE, and the like.
- Arterial cerebrovascular thromboembolic disorders include, for example, stroke, ischemic stroke, acute cerebral infarction, stroke in patients with non-valvular atrial fibrillation or valvular atrial fibrillation, cerebral artery thrombosis, cerebral infarction, Examples include transient cerebral ischemic attack (TIA), lacunar infarction, atherothrombotic cerebral infarction, cerebral artery embolism, cerebral thrombosis, cerebrovascular disorder, asymptomatic cerebral infarction or cerebrovascular dementia.
- TIA transient cerebral ischemic attack
- lacunar infarction lacunar infarction
- atherothrombotic cerebral infarction atherothrombotic cerebral infarction
- cerebral artery embolism cerebral thrombosis
- cerebrovascular disorder asymptomatic cerebral infarction or cerebrovascular dementia.
- venous cerebrovascular thromboembolic disorders include intracranial venous thrombosis, cerebral embolism, cerebral thrombosis, cerebral venous sinus thrombosis, intracranial sinus thrombosis or cavernous sinus thrombosis.
- Thromboembolic diseases in the heart chamber or peripheral circulation include venous thrombosis, systemic venous thromboembolism, recurrent venous thromboembolism, thrombophlebitis, non-valvular and valvular atrial fibrillation, cardiogenic Embolism, disseminated intravascular coagulation syndrome (DIC), sepsis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease, antiphospholipid antibody syndrome, liver embolism, central hepatic vein occlusion Disease (VOD), renal embolism, renal vein thrombosis, renal artery occlusion, intractable nephrosis due to membranous nephropathy or focal glomerulosclerosis, splenic vein thrombosis, superior mesenteric artery occlusion, portal vein thrombus , Retinal vein occlusion, atherosclerosis, atherothrombosis, peripheral
- thromboembolic disease As the thromboembolic disease, coronary artery disease, unstable angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction (such as initial myocardial infarction or recurrent myocardial infarction), ischemic sudden death, transient cerebral ischemia Seizure, stroke, peripheral arterial disease, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, venous thromboembolism, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery Thrombosis, cerebral embolism, kidney embolism, portal vein thrombosis, pulmonary embolism, pulmonary infarction, hepatic embolism, central hepatic vein occlusion (VOD) / sinusoidal obstruction syndrome (SOS), thrombotic microangiopathy (TMA), disseminated intravascular coagulation syndrome (DIC),
- Atrial fibrillation, atherosclerosis or sepsis includes thromboembolic diseases caused by atrial fibrillation, atherosclerosis or sepsis.
- the thromboembolic disease is venous thromboembolism (VTE), ischemic stroke, thromboembolic disease caused by a treatment in which blood is exposed to an artificial surface that promotes thrombus formation, acute coronary syndrome, coronary artery disease Or a peripheral artery disease etc. are mentioned.
- VTE venous thromboembolism
- ischemic stroke thromboembolic disease caused by a treatment in which blood is exposed to an artificial surface that promotes thrombus formation
- acute coronary syndrome coronary artery disease Or a peripheral artery disease etc.
- Venous thromboembolism includes deep vein thrombosis (DVT), pulmonary embolism (PE) or pulmonary embolism with deep vein thrombosis.
- VTE deep vein thrombosis
- PE pulmonary embolism
- pulmonary embolism with deep vein thrombosis For prevention and / or treatment of VTE, patients with lower extremity orthopedic surgery (total knee replacement, total hip replacement, hip fracture, etc.) undergoing VTE onset and acute with markedly limited physical activity This includes suppression of the onset of DVT and / or PE in patients with internal medical diseases, suppression of the onset of VTE during and / or after surgery for patients undergoing abdominal surgery, and suppression of the onset of DVT and / or PE in patients undergoing cancer chemotherapy.
- Prevention and / or treatment of ischemic stroke includes suppression of the development of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, recurrent stroke in patients with embolic stroke (ESUS) who cannot identify the source of embolism, and Suppression of systemic embolism, Suppression of ischemic stroke and systemic embolism in patients with atrial fibrillation complicated with acute coronary syndrome (ACS), patients with atrial fibrillation with chronic kidney disease (CKD) or end stage renal failure Inhibition of ischemic stroke and systemic embolism in Japan, and suppression of recurrence after ischemic stroke (excluding cardiogenic cerebral embolism).
- ACS acute coronary syndrome
- CKD chronic kidney disease
- end stage renal failure Inhibition of ischemic stroke and systemic embolism in Japan, and suppression of recurrence after ischemic stroke (excluding cardiogenic cerebral embolism).
- thromboembolic disease caused by treatment where blood is exposed to the surface of an artificial object that promotes thrombus formation
- prevention and / or treatment of thromboembolic disease in patients undergoing artificial valve replacement Prevention and / or treatment of thromboembolic diseases in patients with implantable, total replacement, percutaneous or extracorporeal heart assist devices, and prevention and / or treatment of thromboembolic diseases in patients with coronary stents Is included.
- ACS acute coronary syndrome
- coronary artery disease peripheral arterial disease
- ACS acute coronary syndrome
- peripheral arterial disease includes suppression of cardiovascular events in patients with acute coronary syndrome (ACS), suppression of cardiovascular events in patients with coronary artery disease or peripheral arterial disease, Inhibition of cardiovascular events in diabetic patients (more preferably type 2 diabetic patients) at high cardiovascular risk.
- the compound of the present invention since the compound of the present invention has a plasma kallikrein inhibitory action, it is useful for the prevention and / or treatment of diseases involving plasma kallikrein.
- Diseases involving plasma kallikrein include, for example, retinopathy, diabetic retinopathy, hypertensive retinopathy, proliferative and nonproliferative retinopathy, age-related macular degeneration (AMD), prevention and / or treatment of hematoma Disorders associated with increased vascular permeability, edema-related diseases, hereditary angioedema (HAE), diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), retina Edema, collagen-related edema, brain edema, lymphedema, angioedema, traumatic brain injury, hemorrhagic stroke, intracerebral hemorrhage, cerebral aneurysm, arteriovenous malformation, spinal cord injury, ischemia reperfusion injury, ischemia, cerebral imagination Blood, pain, disorders with inflammatory components, encephalitis, multiple sclerosis, pruritus,
- Diseases involving plasma kallikrein are preferably edema-related diseases, hereditary angioedema, macular edema, brain edema, retinopathy, edema formation related to ischemia-reperfusion injury, during surgery such as cardiopulmonary bypass or coronary artery bypass grafting Blood loss can be mentioned.
- the compound of the present invention is used as a single agent, (1) complementation and / or enhancement of its prevention, treatment and / or symptom improvement effect, (2) To improve its kinetics / absorption, reduce dosage, and / or (3) to reduce its side effects, combined with other active ingredients, such as the drugs listed below, and used as a concomitant drug May be.
- the combination drug used in combination with the compound of the present invention includes, for example, an anticoagulant, an antiplatelet agent, a thrombolytic agent, a fibrinolytic agent, Examples include serine protease inhibitors, elastase inhibitors, steroids or combinations thereof.
- Anticoagulants include thrombin inhibitors, antithrombin III activators, heparin cofactor II activators, other FXIa inhibitors, plasma and / or tissue kallikrein inhibitors, plasminogen activation inhibitor (PAI-1) inhibition Agent, thrombin activated fibrinolysis inhibitor (TAFI) inhibitor, factor VIIa inhibitor, factor VIIIa inhibitor, factor IXa inhibitor, factor Xa inhibitor, factor XIIa inhibitor, or combinations thereof Is mentioned.
- PAI-1 plasminogen activation inhibitor
- TAFI thrombin activated fibrinolysis inhibitor
- GPII / IIIa blockers As antiplatelet agents, GPII / IIIa blockers, protease activated receptor (PAR-1) antagonists, PAR-4 antagonists, phosphodiesterase III inhibitors, other phosphodiesterase inhibitors, P2X1 antagonists, P2Y1 receptor antagonists, P2Y12 antagonists, Thromboxane receptor antagonist, thromboxane A2 synthase inhibitor, cyclooxygenase-1 inhibitor, phospholipase D1 inhibitor, phospholipase D2 inhibitor, phospholipase D inhibitor, glycoprotein VI (GPVI) antagonist, glycoprotein Ib (GPIB) An antagonist, a GAS6 antagonist, aspirin, or a combination thereof.
- PAR-1 protease activated receptor
- PAR-4 antagonists As antiplatelet agents, GPII / IIIa blockers, protease activated receptor (PAR-1) antagonists, PAR-4 antagonists, phosphodiesterase III inhibitors, other phosphodiesterase inhibitor
- the anti-platelet agent is preferable as a concomitant drug.
- antiplatelet agent preferably, clopidogrel, prasugrel, ticagrelol, cangrelor, erinogrel, cilostazol, sarpogrelate, iloprost, beraprost, limaprost and / or aspirin, or a combination thereof can be mentioned.
- a concomitant drug preferably warfarin, unfractionated heparin, low molecular weight heparin, enoxaparin, dalteparin, bemiparin, tinzaparin, semeloparin sodium (AVE-5026), danaparoid, synthetic pentasaccharide, fondaparinux, hirudin, disulfatohirudin , Repirudine, bivalirudin, decyldine, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, prasugrel, progretol , Limaprost, tirofiban, eptifibatide, absiki Mab, melagatran, ximelagatran, dabiga
- the combination drug in the present invention includes, for example, potassium channel opener, potassium channel blocker, calcium channel blocker, sodium hydrogen exchanger transporter inhibitor, antiarrhythmic agent, antiatherosclerotic agent, anticoagulant Agent, antiplatelet agent, antithrombotic agent, thrombolytic agent, fibrinogen antagonist, diuretic antihypertensive agent, ATPase inhibitor, electrolyte corticoid receptor antagonist, phosphodiesterase inhibitor, antidiabetic agent, protease inhibitor, elastase inhibitor, anti Inflammatory, antioxidant, angiogenesis modulator, osteoporosis treatment, hormone replacement therapy, hormone receptor modulator, oral contraceptive, antiobesity, antidepressant, anxiolytic, antipsychotic, antiproliferative, antitumor Agent, anti-ulcer and gastroesophageal reflux disease agent, growth hormone agent and / or growth hormone Prophylactic substances, thyroid mimetics, anti-infectives, antivirals, antibacterials, antifungal agents,
- the combination drug in the present invention includes, for example, an antiarrhythmic agent, an antihypertensive agent, an anticoagulant, an antiplatelet agent, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, and a potassium channel blocker.
- an antiarrhythmic agent for example, an antiarrhythmic agent, an antihypertensive agent, an anticoagulant, an antiplatelet agent, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, and a potassium channel blocker.
- examples include drugs, cholesterol / lipid lowering agents, serine protease inhibitors, elastase inhibitors, anti-inflammatory agents, or combinations thereof.
- antiarrhythmic agents examples include IKur inhibitors, elastase inhibitors, serine protease inhibitors, steroids and the like.
- antihypertensive agents include ACE inhibitors, AT-1 receptor antagonists, ⁇ -adrenergic receptor antagonists, ETA receptor antagonists, dual ETA / AT-1 receptor antagonists, vasopeptidase inhibitors, and the like.
- the concomitant drug in the present invention is an antiplatelet agent or a combination thereof.
- the combination of the compound of the present invention and these other drugs may be administered in the form of a combination preparation in which both components are combined in one preparation, or separate preparations are administered by the same administration route or different administration routes. You may take When different preparations are administered, it is not always necessary to administer them simultaneously, and a time difference may be provided in the administration as necessary. Moreover, when providing a time difference in administration, there is no restriction
- the dose of these other drugs used in combination with the compound of the present invention can be appropriately increased or decreased based on the clinically used dose of the drug or similar drug.
- the compounding ratio of the compound of the present invention and other drugs can be appropriately adjusted in consideration of the age and weight of the administration subject, administration method, administration time, target disease, symptom and the like. In general, 0.01 to 100 parts by weight of another drug may be combined with 1 part by weight of the compound of the present invention.
- a plurality of other drugs may be used.
- the other drug may be a drug having the same mechanism. Such drugs include not only those found so far, but also those found in the future.
- the compound of the present invention is usually administered systemically or locally in an oral or parenteral form.
- oral preparations include liquids for internal use (for example, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for internal use (for example, tablets (sublingual tablets, buccal cavity) Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and troches.
- parenteral agents examples include liquids (eg, injections (intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions, etc.), eye drops (eg, aqueous Eye drops (aqueous eye drops, aqueous suspension eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, etc.))), external preparations (for example, , Ointments (eye ointment etc.)), ear drops and the like.
- These preparations may be release control agents such as immediate-release preparations and sustained-release preparations. These preparations can be produced by a known method, for example, a method described in the Japanese Pharmacopoeia.
- Oral liquids for oral use are produced, for example, by dissolving, suspending or emulsifying active ingredients in diluents (eg, purified water, ethanol or a mixture thereof) generally used.
- this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
- the solid preparation for internal use as an oral preparation includes, for example, an active ingredient as an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (for example, hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). Magnesium oxide, etc.), disintegrating agents (eg, calcium calcium glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. According to the formulation. Moreover, you may coat
- an active ingredient as an excipient for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.
- a binder for example, hydroxy
- External preparations as parenteral preparations are produced by known methods or commonly used formulations.
- an ointment is produced by kneading or melting an active ingredient in a base.
- the ointment base is selected from known or commonly used ones.
- higher fatty acids or higher fatty acid esters for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.
- waxes E.g., beeswax, whale wax, ceresin, etc.
- surfactants e.g., polyoxyethylene alkyl ether phosphates, etc.
- higher alcohols e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.
- silicone oils e.g., Dimethylpolysiloxane, etc.
- hydrocarbons eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.
- glycols eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene
- glycols e
- the parenteral injection includes solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent at the time of use.
- An injection is used, for example, by dissolving, suspending or emulsifying an active ingredient in a solvent.
- the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
- this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like.
- a sterile solid preparation for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.
- the compound of the present invention or the concomitant drug of the present compound and another drug for the above purpose is usually administered systemically or locally in an oral or parenteral form.
- the dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 ng to 1000 mg per adult per dose. Or it may be administered parenterally once to several times a day in the range of 0.1 ng to 10 mg per adult or continuously intravenously in the range of 1 hour to 24 hours per day.
- an amount smaller than the above dosage may be sufficient, or administration may be necessary beyond the range.
- the solvent in the parenthesis shown in the chromatographic separation site and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
- the parentheses shown in the NMR part indicate the solvent used for the measurement.
- the compound name used in this specification is generally a computer program for naming according to IUPAC rules, Advanced Chemistry Development ACD / Name (registered trademark), or named according to IUPAC nomenclature. Is.
- t R denotes the retention time.
- Example 1 2-methyl-2-propanyl (6-fluoro-5-iodo-2-pyridinyl) carbamate 6-fluoro-5-iodopyridin-2-amine (17 g) in acetonitrile (150 mL) Di-tert-butyl dicarbonate (17.14 g) and 4-dimethylaminopyridine (0.87 g) were added and the mixture was stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (7.8 g) was further added, and the mixture was further stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture to remove insoluble matters.
- Compound (34.4 g) prepared in Example 1 (2) was added to tetrahydrofuran (150 mL). And water (50 mL), and N-bromosuccinimide (21.7 g) was added under ice cooling. The mixture was stirred under ice-cooling for 30 minutes, diluted with ethyl acetate, and washed twice with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried and concentrated.
- Example 1 (4): 2-methyl-2-propanyl [5- (2- ⁇ (3S) -7- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -5-oxo- 1,2,3,5-tetrahydro-3-indolidinyl ⁇ -1H-imidazol-5-yl) -6-fluoro-2-pyridinyl] carbamate (3S) -7- [5-chloro-2- (1H-1 , 2,3,4-tetrazol-1-yl) phenyl] -5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid (described in Example 9 of Patent Document 6) (27.58 g ) And an N-methylpyrrolidone solution (200 mL) of the compound (25.68 g) prepared in Example 1 (3), N, N-diisopropylethylamine (26.7 mL) was added under ice cooling.
- reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous ammonium chloride (500 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water (500 mL) and saturated brine (500 mL), dried and concentrated. The residue was dissolved in toluene (500 mL) and glacial acetic acid (50 mL), ammonium acetate (59.4 g) was added, and the mixture was stirred at 100 ° C. for 3 hours.
- Example 1 2-methyl-2-propanyl [5- (2- ⁇ (3S) -7- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -5-oxo- 1,2,3,5-Tetrahydro-3-indolidinyl ⁇ -4-fluoro-1H-imidazol-5-yl) -6-fluoro-2-pyridinyl] carbamate
- Compound prepared in Example 1 (4) (350 mg) was dissolved in tetrahydrofuran (1.2 mL) and acetonitrile (3.6 mL), pyridine (0.14 mL) was added, and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2 was added at ⁇ 18 ° C.
- Example 2 6-Fluoro-5-iodo-2-pyridinamine N-iodosuccinimide (56.5 g) was cooled to ice with 6-fluoro-2-pyridinamine (25.6 g) in N, N-dimethylformamide ( 200 mL) solution was dividedly added (three times). After stirring at room temperature for 3 hours, city water (0.5 L) was added to the reaction solution. Extract three times with ethyl acetate / hexane (1/1, 300 mL), and the organic layer was saturated aqueous sulfite (0.5 L), saturated aqueous sodium carbonate (0.5 L, twice), city water (0.5 L), and saturated saline. (0.5 L), dried and concentrated.
- Example 2 (2) Bis (2-methyl-2-propanyl) (6-fluoro-5-iodo-2-pyridinyl) imide dicarbonate Compound (36.7 g) prepared in Example 2 (1) and 4 A solution of di-tert-butyl dicarbonate (74.0 g) in acetonitrile (100 mL) was added to a solution of dimethylaminopyridine (0.9 g) in acetonitrile (300 mL), and the mixture was stirred at room temperature for 3 hours.
- Example 2 2-methyl-2-propanyl [6-fluoro-5- (N-hydroxycarbamimidoyl) -2-pyridinyl] carbamate
- Compound (1.56 g) prepared in Example 2 (3) N, N-diisopropylethylamine (2.84 mL) was added to a solution of hydroxylamine hydrochloride (0.91 g) in ethanol (40 mL), and the mixture was stirred at 40 ° C. overnight. The reaction solution was concentrated, and the resulting residue was dissolved in ethyl acetate (50 mL). After adding city water (50 mL) and washing, the organic layer was dried and concentrated to give the crude title compound (1.93 g) having the following physical properties.
- Example 2 2-Methyl-2-propanyl (5- carbamimidoyl -6-fluoro-2-pyridinyl) carbamate Acetate Acetic acid (10 mL) of the compound prepared in Example 2 (4) (1.93 g) ) Acetic anhydride (0.75 mL) was added to the solution and stirred at room temperature for 1 hour. Palladium (II) hydroxide (20%, 250 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (2.99 g) having the following physical property values. LC / MS t R 0.59 min; MS (ES +) m / z 255 (M + H) ( condition a).
- Example 2 2-methyl-2-propanyl [5- (5- ⁇ 7- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -5-oxo-1,2, 3,5-Tetrahydro-3-indolidinyl ⁇ -1H-imidazol-2-yl) -6-fluoro-2-pyridinyl] carbamate
- Potassium carbonate (0.70 g) was added to a solution of the compound prepared in (1.0 g) in acetonitrile (50 mL), and the mixture was stirred at 80 ° C. for 17 hours.
- reaction solution was diluted with ethyl acetate (100 mL), washed with city water (100 mL) and saturated brine (200 mL), dried and concentrated.
- Example 2 (9): 2-methyl-2-propanyl [5- (5- ⁇ (3S) -7- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -5-oxo- 1,2,3,5-tetrahydro-3-indolidinyl ⁇ -4-fluoro-1H-imidazol-2-yl) -6-fluoro-2-pyridinyl] carbamate and 2-methyl-2-propanyl [5- (5 - ⁇ (3R) -7- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -5-oxo-1,2,3,5-tetrahydro-3-indolidinyl ⁇ -4-fluoro- 1H-imidazol-2-yl) -6-fluoro-2-pyridinyl] carbamate
- Concentrated hydrochloric acid (2 mL) was added to a suspension of the S form compound (436 mg) of Example 2 (9) in ethyl acetate (6 mL), and the mixture was stirred at room temperature for 20 minutes.
- the reaction solution was concentrated under reduced pressure, and the resulting residue was redissolved with tetrahydrofuran (10 mL).
- Example 2 (11): (3S) -3- [2- (6-Amino-2-fluoro-3-pyridinyl) -4-fluoro-1H-imidazol-5-yl] -7- [5-chloro- 2- (1H-tetrazol-1-yl) phenyl] -2,3-dihydro-5 (1H) -indolidinone dihydrochloride Trifluoroacetic acid (1 mL) was added to a solution of the S-form compound (43 mg) of Example 2 (9) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 70 minutes.
- moving bed B (0.1% trifluoroacetic acid / acetonitrile
- Preparative purification was performed.
- the obtained product was redissolved in ethyl acetate, an excess amount of 4M hydrochloric acid / ethyl acetate solution was added, and the mixture was concentrated and dried to obtain the title compound (28 mg) having the following physical property values.
- the title compound having the following physical data was obtained by conducting the same operations as in Example 2 (10) using the R compound of Example 2 (9).
- Example 2 (13) (3S) -3- [2- (6-Amino-2-fluoro-3-pyridinyl) -4-fluoro-1H-imidazol-5-yl] -7- [5-chloro-2 -(1H-tetrazol-1-yl) phenyl] -2,3-dihydro-5 (1H) -indolidinone dihydrate
- the compound of Example 2 (10) (100 mg) was dissolved in acetonitrile (1.0 mL) and water (0.018 mL) by heating at 75 ° C., and then stirred at 40 ° C. for 2 hours and then stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (76 mg).
- Example 3 (1): (6S) -6- (chloroacetyl) -2- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -7,8-dihydropyrrolo [1,2- a] pyrimidin-4 (6H) -one (6S) -2- [5-chloro-2- (1H-1,2,3,4-tetrazol-1-yl) phenyl] -4-oxo-4H, 6H , 7H, 8H-pyrrolo [1,2-a] pyrimidine-6-carboxylic acid (described in Example 336 of Patent Document 6) is used to carry out the same operations as in Example 2 (7), The title compound having the following physical property values was obtained. LC / MS t R 0.75 min; MS (ES +) m / z 391 (M + H) ( condition a).
- Example 3 (2) 2-Methyl-2-propanyl [5- (5- ⁇ 2- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] -4-oxo-4,6 7,8-Tetrahydropyrrolo [1,2-a] pyrimidin-6-yl ⁇ -1H-imidazol-2-yl) -6-fluoro-2-pyridinyl] carbamate
- Compound prepared with Example 2 (6) Using the compound of Example 3 (1), the title compound having the following physical data was obtained by the same procedures as in Example 2 (8).
- Optical resolution (DAICEL, CHIRALFLASH® IC column, (particle diameter: 20 ⁇ m; column length: 100 ⁇ 30 mm ID) flow rate: 24 mL / min; column temperature: room temperature; mobile phase: acetonitrile; detector: UV
- the retention time of the title compound when Yamazen UV-254W UV-Detector was used was 13.7 minutes (S-form compound of Example 3 (3)) and 8.1 minutes (R-form of Example 3 (3)), respectively. Compound).
- Example 3 (4): (6S) -6- [2- (6-Amino-2-fluoro-3-pyridinyl) -4-fluoro-1H-imidazol-5-yl] -2- [5-chloro- 2- (1H-tetrazol-1-yl) phenyl] -7,8-dihydropyrrolo [1,2-a] pyrimidin-4 (6H) -one
- 6S 6- [2- (6-Amino-2-fluoro-3-pyridinyl) -4-fluoro-1H-imidazol-5-yl] -2- [5-chloro- 2- (1H-tetrazol-1-yl) phenyl] -7,8-dihydropyrrolo [1,2-a] pyrimidin-4 (6H) -one
- the title compound having the following physical data was obtained by the same procedures as in Example 2 (10).
- Example 3 (6R) -6- [2- (6-Amino-2-fluoro-3-pyridinyl) -4-fluoro-1H-imidazol-5-yl] -2- [5-chloro- 2- (1H-tetrazol-1-yl) phenyl] -7,8-dihydropyrrolo [1,2-a] pyrimidin-4 (6H) -one dihydrochloride
- the title compound having the following physical data was obtained by conducting the same operations as in Example 2 (11) using the R compound of Example 3 (3).
- Compound obtained by performing the same operation as in Example 2 (8) ⁇ Comparative Example 2 (2) using the compound synthesized in Example 3 (1) and the compound described in Example 237 of Patent Document 6. Was optically resolved to give the title compound.
- Example 4 Ethyl (3S) -7- (2-azido-5-chlorophenyl) -5-oxo-1,2,3,5-tetrahydro-3-indolizinecarboxylate ethyl (3S) -7 -(2-amino-5-chlorophenyl) -5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylate (described in Example 7 of Patent Document 6) (2.0 g) in acetonitrile solution ( To 15 mL), trimethylsilyl azide (1.39 g) and amyl nitrite (1.41 g) were added under cooling (0 ° C.).
- 5M hydrochloric acid 5 mL
- 5 M aqueous sodium hydroxide solution 5 mL
- the organic layer was dried and concentrated to give the title compound (61.7 mg) having the following physical data.
- Example 4 2- [4-( ⁇ [(2-methyl-2-propanyl) oxy] carbonyl ⁇ amino) phenyl] -2-oxoethyl (3S) -7- [2- (4-carbamoyl- 1H-1,2,3-triazol-1-yl) -5-chlorophenyl] -5-oxo-1,2,3,5-tetrahydro-3-indolizine carboxylate
- Compound prepared in Example 4 (3) (6.10 g) in N, N-dimethylformamide (61 mL) was added tert-butyl N- [4- (2-bromoacetyl) phenyl] carbamate (7.19 g) and N, N-diisopropylethylamine (5.3 mL).
- Example 4 2-methyl-2-propanyl [4- (2- ⁇ (3S) -7- [2- (4-carbamoyl-1H-1,2,3-triazol-1-yl)- 5-chlorophenyl] -5-oxo-1,2,3,5-tetrahydro-3-indolidinyl ⁇ -1H-imidazol-5-yl) phenyl] carbamate
- the compound prepared in Example 4 (4) (3.93 g) Dissolved in toluene (79 mL) and glacial acetic acid (3.9 mL), ammonium acetate (9.57 g) was added. The mixture was stirred for 4 hours under heating to reflux, and water and ethyl acetate were added.
- N, N-diisopropylethylamine (0.87 mL
- 2- (trimethylsilyl) Ethoxymethyl chloride (0.66 mL) was added.
- Example 4 2-methyl-2-propanyl [4- (2- ⁇ (3S) -7- [5-chloro-2- (4-cyano-1H-1,2,3-triazole-1] -Yl) phenyl] -5-oxo-1,2,3,5-tetrahydro-3-indolidinyl ⁇ -5-fluoro-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-imidazol-4-yl ) Phenyl] carbamate
- the compound (560 mg) prepared in Example 4 (7) was dissolved in tetrahydrofuran (5.6 mL) and acetonitrile (2.8 mL), and sodium carbonate (205 mg) and 1-chloromethyl-4 were dissolved at ⁇ 10 ° C.
- Example 4 2-methyl-2-propanyl [4- (2- ⁇ (3S) -7- [5-chloro-2- (4-cyano-1H-1,2,3-triazole-1] -Yl) phenyl] -5-oxo-1,2,3,5-tetrahydro-3-indolidinyl ⁇ -4-fluoro-1H-imidazol-5-yl) phenyl] carbamate
- Compound prepared in Example 4 (8) To a solution of (427 mg) in 1,4-dioxane (4.3 mL) was added 5M aqueous hydrochloric acid (0.43 mL).
- Example 4 10- (2- ⁇ (3S) -3- [5- (4-aminophenyl) -4-fluoro-1H-imidazol-2-yl] -5-oxo-1,2, 3,5-tetrahydro-7-indolidinyl ⁇ -4-chlorophenyl) -1H-1,2,3-triazole-4-carbonitrile
- Trifluoroacetic acid (0.96 mL) was added to a dichloromethane solution (6.4 mL) of the compound (320 mg) prepared in Example 4 (9). The mixture was stirred at room temperature for 45 minutes, then toluene was added and concentrated.
- Biological Example 1 (1) In vitro assay The human blood coagulation factor XIa, factor VIIa, factor IXa, factor Xa, factor XIIa, plasma kallikrein and thrombin inhibitory activity of the compounds of the present invention were evaluated. A chromogenic substrate solution was added to each enzyme solution, and the absorbance at 405 nm was measured continuously at 37 ° C. at 15 second intervals for 5 minutes to determine the substrate degradation rate (mOD / min). The 50% inhibitory concentration (IC50) for each enzyme of the compound of the present invention was calculated by performing linear regression by the least square method from the natural logarithm conversion value of the concentration of the compound of the present invention and the enzyme inhibition rate determined according to the following equation. The enzyme inhibition rate (%) of the compound of the present invention was calculated using the following formula. :
- Human blood coagulation factor XIa (Haematologic Technologies Inc.) inhibitory activity was 0.1 U / buffer with a buffer containing 300 mM NaCl, 10 mM KCl, 2 mg / mL PEG6000, 100 mM HEPES-NaOH (pH 7.4). The measurement was performed using an enzyme solution adjusted to mL and S-2366 (pyroglulu-Pro-Arg-pNA, CHROMOGENIX) adjusted to 1 mM with distilled water.
- Human blood coagulation factor Xa (Sekisui Diagnostics LLC.) Inhibitory activity and human thrombin (Sigma) inhibitory activity were respectively in a buffer containing 300 mM NaCl, 4 mg / mL PEG6000, 100 mM Tris-HCl (pH 7.4). Each enzyme solution adjusted to 0.5 U / mL or 0.25 U / mL and S-2222 [Bz-Ile-Glu ( ⁇ -OR) -Gly-Arg-pNA ⁇ adjusted to 1 mM with distilled water, respectively.
- Human blood coagulation factor IXa inhibitory activity Human blood coagulation factor IXa (Sekisui Diagnostics LLC.) Inhibitory activity was increased to 30 U / mL with a buffer solution containing 200 mM NaCl, 10 mM CaCl 2 , 60% ethylene glycol, 100 mM Tris-HCl (pH 7.4). The measurement was performed using Spectrozix FIXa (HD-Leu-Ph'Gly-Arg-pNA ⁇ 2AcOH, Sekisui Diagnostics LLC.) Adjusted to 10 mM with the prepared enzyme solution and distilled water.
- Human blood coagulation factor VIIa inhibitory activity Human blood coagulation factor VIIa (Sekisui Diagnostics LLC.) Inhibitory activity was 300 mM NaCl, 10 mM CaCl 2 , 10 mg / mL PEG6000, 100 mM HEPES-NaOH (pH 7.4), recombinant human tissue factor (Arireza R). Adjusted to 200 U / mL with a buffer containing the method of Riesier et al. (Manufactured according to Protein Expression and Purification, 1992, Vol. 3, No. 6, pp. 453-460) The measurement was performed using S-2288 (HD-Ile-Pro-Arg-pNA, CHROMOGENIX) adjusted to 10 mM with an enzyme solution and distilled water.
- S-2288 HD-Ile-Pro-Arg-pNA, CHROMOGENIX
- APTT activated partial thromboplastin time
- PT prothrombin time
- the anticoagulant activity (APTT ⁇ 2 or PT ⁇ 2) of the compounds of the present invention was expressed as the concentration required to double the clotting time in the vehicle (1% DMSO) group.
- APTT ⁇ 2 or PT ⁇ 2 was determined by plotting the concentration of the compound of the invention against the increase in clotting time in fold.
- the compound of the present invention has strong FXIa inhibitory activity and anticoagulant activity.
- the human blood coagulation factor Xa, factor XIIa, factor IXa, factor VIIa and human thrombin inhibitory activity of the compound of the present invention were sufficiently weak.
- Biological Experimental Example 2 Pharmacokinetic (PK) test in rats A single dose of the compound of the present invention 0.1 mg / kg, i. v. Administered intravenously as a dose (vehicle: 20% HP- ⁇ -CD solution), and 1 mg / kg, p. o. Fasted male Crj: CD (SD) rats were given as a dose (vehicle: 0.5% methylcellulose solution) by oral gavage. 0.08, 0.25, 0.5, 1, 3, 7 hours after intravenous administration or 0.08, 0.25, 0.5, 1, 2, 4, 6 after oral administration At 8, 24 hours, blood samples were collected from the jugular vein into heparinized syringes. Plasma was obtained by centrifugation and stored at ⁇ 20 ° C. until measurement of plasma concentration.
- deproteinization of the plasma sample was performed using acetonitrile, and the protein was filtered using a filter, diluted with purified water, and analyzed by LC / MS / MS.
- An analytical column (Shim-pack XR-ODSII, 2.0 mm ⁇ 75 mm, 2.2 ⁇ m) and a mobile phase (0.1% formic acid in water and 0.1% formic acid in acetonitrile, flow rate 0.5 mL / min) were used. .
- This system was used in multiple reaction monitoring (MRM) mode with positive ion detection.
- MRM multiple reaction monitoring
- AUC blood concentration-time curve
- BA bioavailability
- APTT ⁇ 2 maintenance time the time when the plasma compound concentration of the compound of the present invention exceeded APTT ⁇ 2 (APTT ⁇ 2 maintenance time) was calculated. .
- Example 2 10
- Example 4 10
- Comparative Example 2 (3) APTT ⁇ 2
- the compound of the present invention exhibits good blood dynamics.
- the compound of the present invention exhibited one or more C8h / APTT ⁇ 2 when orally administered at a dose of 1 mg / kg.
- the compound of the present invention maintained a plasma concentration of APTT ⁇ 2 or more for 8 hours or more, while the APTT ⁇ 2 maintenance time of the comparative compounds was all less than 2 hours.
- the compound of the present invention has both good blood dynamics and strong anticoagulant activity, and can exhibit anticoagulant activity for a long time after oral administration.
- Biological Experiment Example 3 Drug Interaction (1) CYP Inhibitory Activity Competitive inhibitory activity Midazolam and the compound of the present invention were added to human-derived liver microsome suspension and shaken at 37 ° C. for 3 minutes, and then the concentration of 1′-hydroxymidazolam in the sample was analyzed by LC / MS / MS did.
- Time-dependent inhibition (TDI) activity The compound of the present invention was added to human-derived liver microsome suspension, shaken at 37 ° C. for 30 minutes, added with midazolam, further shaken for 3 minutes, and 1 ′ in the sample after shaking. -Hydroxymidazolam concentration was analyzed by LC / MS / MS.
- Both competitive inhibitory activity and TDI activity are analytical columns (Shim-pack XR-ODSII, 2.0 mm ⁇ 75 mm, 2.2 ⁇ m) and mobile phase (0.1% formic acid in water and 0.1% formic acid in acetonitrile, flow rate 0. 5 mL / min) was used.
- This system was used in multiple reaction monitoring (MRM) mode with positive ion detection.
- concentration of the compound of the present invention in the sample any one of 1, 3, 10, 15, 30, 50 ⁇ mol / L was used, and IC50 value was calculated according to the following formula as an index of competitive inhibition and CDI inhibitory activity of TDI. .
- the IC50 value is ⁇ 1 or ⁇ 5 ⁇ mol / L, and the maximum concentrations are 10, 30, 50 ⁇ mol / L.
- the IC50 values when the inhibition rate was 50% or less were>10,> 30, and> 50 ⁇ mol / L, respectively.
- the concentration of the compound of the present invention was defined as D ( ⁇ mol / L).
- CYP IC50 value (TDI) / APTT ⁇ 2 was calculated as an index of deviation between the concentration capable of exhibiting anticoagulant activity and CYP inhibitory activity.
- the compound of the present invention is a powerful FXIa inhibitor, which has excellent oral absorption and blood kinetics, exhibits strong anticoagulant activity for a long time after oral administration, and has anticoagulant activity and CYP inhibitory activity. It was confirmed that the compound had a gap between them.
- hERG inhibitory activity The hERG inhibitory activity of the compound of the present invention was measured by the following procedure. Using hERG-transfected CHO-K1 cells, stimulation pulse-induced hERG channel current (IKr) was measured by the amphotericin perforated patch clamp method using a fully automatic patch clamp system. The stimulation pulse was a holding voltage: ⁇ 80 mV, a depolarization voltage: +40 mV (2 seconds), a repolarization voltage: ⁇ 50 mV (2 seconds), and the maximum tail current induced after the repolarization voltage was measured.
- IKr stimulation pulse-induced hERG channel current
- the stimulation pulse was applied twice before the addition of the compound of the present invention and 5 minutes after the addition, and the change rate of the maximum tail current with respect to before the addition was determined.
- the compound of the present invention was made into a dimethyl sulfoxide (DMSO) solution and added to the extracellular solution at a concentration of 1%.
- the inhibition rate (%) of the hERG channel was determined by correcting the change rate of the maximum tail current before and after the addition of the compound of the present invention with the change rate in the vehicle treatment group.
- the hERG inhibition rate was less than 51% when the concentration of the compound of the present invention added to the cells was 10 ⁇ M. From the above, it was confirmed that the compound of the present invention was a compound having low hERG inhibitory activity and excellent safety.
- the steatosis inducing action of the compound of the present invention was measured by the following procedure. 1% of the compound DMSO solution of the present invention having a concentration of 6.25, 12.5, 25, 50, 100 ⁇ M was added to the human immortalized hepatocyte cell line Fa2N-4, and after 72 hours of exposure, Nile Red was added. The fluorescence intensity of the cells was measured at an excitation wavelength of 485 nm and a fluorescence wavelength of 570 nm. When the fluorescence measurement value was 160% or more of the vehicle treatment, it was determined that there was a steatosis-inducing action.
- the fluorescence measurement value when the concentration of the compound of the present invention in the medium was 25 ⁇ M was less than 160% of the fluorescence measurement value during the medium treatment. From the above, it was confirmed that the compound of the present invention was a compound having a low steatosis action and excellent safety.
- Formulation Example 1 The following components are mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of the active ingredient.
- Formulation Example 2 The following components are mixed by a conventional method, filtered through a dust filter, filled in 5 ml aliquots, and heat sterilized in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient in one ampule.
- the compound of the present invention has a strong FXIa inhibitory activity, it is useful for the prevention and / or treatment of thromboembolic diseases.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
[1]一般式(I)
XはCHまたはNを表す。]
で示される化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ、
[2]一般式(I)で示される化合物が、(3S)-3-[5-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-2-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノンである前記[1]記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ、
[3]一般式(I)で示される化合物が、(3S)-3-[2-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-5-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノンである前記[1]記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ、
[4]一般式(I)で示される化合物が、(6S)-6-[2-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-5-イル]-2-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-7,8-ジヒドロピロロ[1,2-a]ピリミジン-4(6H)-オンである前記[1]記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ、
[5]一般式(I)で示される化合物が、1-(2-{(3S)-3-[5-(4-アミノフェニル)-4-フルオロ-1H-イミダゾール-2-イル]-5-オキソ-1,2,3,5-テトラヒドロ-7-インドリジニル}-4-クロロフェニル)-1H-1,2,3-トリアゾール-4-カルボニトリルである前記[1]記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ、
[6]前記[1]~[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを有効成分として含有する医薬組成物、
[7]前記[1]~[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを有効成分として含有するFXIa阻害剤、
[8]前記[1]~[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを有効成分として含有する血栓塞栓性疾患の予防および/または治療剤、
[9]血栓塞栓性疾患が、動脈性心血管血栓塞栓性障害、静脈性心血管血栓塞栓性障害、動脈性脳血管血栓塞栓性障害、静脈性脳血管血栓塞栓性障害、または心腔もしくは末梢循環における血栓塞栓性障害である前記[8]に記載の剤、
[10]血栓塞栓性疾患が、冠動脈疾患、不安定狭心症、急性冠症候群、心房細動、心筋梗塞、虚血性突然死、一過性脳虚血発作、脳卒中、末梢動脈疾患、アテローム性動脈硬化症、末梢閉塞性動脈疾患、静脈血栓症、静脈血栓塞栓症、深部静脈血栓症、血栓性静脈炎、動脈塞栓症、冠状動脈血栓症、大脳動脈血栓症、脳塞栓症、腎臓塞栓症、門脈血栓症、肺塞栓症、肺梗塞、肝塞栓症、肝中心静脈閉塞症/類洞閉塞症候群、血栓性微小血管障害症、播種性血管内凝固症候群、敗血症、急性呼吸窮迫症候群、急性肺損傷、抗リン脂質抗体症候群、冠動脈バイパス移植手術に起因する血栓症または血栓形成を促進する人工物表面に血液が曝露される治療により引き起こされる血栓症である、前記[8]または[9]のいずれか1つに記載の剤、
[11]血栓塞栓性疾患が、静脈血栓塞栓症、虚血性脳卒中、血栓形成を促進する人工物表面に血液が暴露される治療により引き起こされる血栓塞栓性疾患、急性冠症候群、冠動脈疾患または末梢動脈疾患である、前記[8]~[10]のいずれかに記載の剤、
[12]血栓塞栓性疾患を予防および/または治療するための前記[1]~[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ、
[13]血栓塞栓性疾患の予防および/または治療剤を製造するための前記[1]~[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグの使用、および
[14]血栓塞栓性疾患の予防および/または治療が必要な患者に有効投与量の前記[1]~[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを投与することからなる該疾患の予防および/または治療方法等に関する。
本発明化合物は、公知の方法、例えば、以下に示す方法、実施例に記載した方法あるいは、Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999に記載された方法等を適宜改良し、組み合わせて用いることで製造することができる。
本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
本発明化合物は、強力なFXIa阻害活性を有する。したがって、本発明化合物は血栓塞栓性疾患、例えば、動脈性心血管血栓塞栓性障害、静脈性心血管血栓塞栓性障害、動脈性脳血管血栓塞栓性障害、静脈性脳血管血栓塞栓性障害、および心腔または末梢循環における血栓塞栓性障害の予防および/または治療に有用である。
(1)その予防、治療および/または症状改善効果の補完および/または増強、
(2)その動態・吸収改善、投与量の低減、および/または
(3)その副作用の軽減のために、他の有効成分、例えば、以下に列挙するような薬剤等と組み合わせ、併用剤として用いてもよい。
条件a.カラムYMC-Triart C18、2.0mmx30mm、1.9μm;カラム温度30℃;移動相(A液)0.1%トリフルオロ酢酸水溶液および(B液)0.1%トリフルオロ酢酸アセトニトリル溶液;流速1.0mL/min;分析時間1.5分;グラジエント:0分(A液/B液=95/5)、0.1分(A液/B液=95/5)、1.2分(A液/B液=5/95)、1.4分(A液/B液=5/95)、1.41分(A液/B液=95/5),1.5分(A液/B液=95/5)
条件b.カラムWaters ACQUITY UPLC(登録商標) BEH C18、 2.1mm x 30mm、 1.7 μm;カラム温度40℃;移動相(A液)0.1%ギ酸水溶液および(B液)0.1%ギ酸アセトニトリル溶液;流速1.0mL/min;分析時間1.5分;グラジエント:0分(A液/B液=95/5)、0.1分(A液/B液=95/5)、1.2分(A液/B液=5/95)、1.4分(A液/B液=5/95)、1.41分(A液/B液=95/5),1.5分(A液/B液=95/5)
実施例1(1):2-メチル-2-プロパニル (6-フルオロ-5-ヨード-2-ピリジニル)カルバマート
6-フルオロ-5-ヨードピリジン-2-アミン(17g)のアセトニトリル(150mL)溶液にジ-tert-ブチルジカーボネート(17.14g)および4-ジメチルアミノピリジン(0.87g)を加え、混合物を室温にて2時間撹拌した。さらにジ-tert-ブチルジカーボネート(7.8g)を加え、室温にてさらに2時間撹拌した。反応混合物に、飽和塩化アンモニウム水溶液と酢酸エチルを加え、不溶物を除去した。併せた有機層を飽和食塩水で洗浄し、乾燥後、濃縮した。残渣を2回のカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100→25:75)、(アミノシリカ、酢酸エチル:ヘキサン=10:90→50:50にて精製し、以下の物性値を有する標題化合物(9.2g)を得た。
TLC:Rf 0.69(酢酸エチル:ヘキサン=25:75)。
実施例1(1)で製造した化合物(40g)のN,N-ジメチルホルムアミド溶液(200mL)にトリブチル(1-エトキシエテニル)すず(50g)を加えた。混合物をアルゴンで脱気し、テトラキス(トリフェニルホスフィン)パラジウム(0)(3.24g)を加え、混合物を100℃で16時間撹拌した。反応混合物を酢酸エチル(200mL)で希釈し、1Mフッ化カリウム水溶液(500mL)に注いだ。混合物を30分撹拌した後、セライト(登録商標)を通して濾過し、ろ液を酢酸エチルで抽出した。併せた有機層を水および飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(アミノシリカ、酢酸エチル:ヘキサン=3:97→5:95)にて精製し、以下の物性値を有する標題化合物(34.4g)を得た。
LC/MS tR 1.15 分: MS (ES+) m/z 227 [M-CH2C(CH3)2)+H] (条件a)。
実施例1(2)で製造した化合物(34.4g)をテトラヒドロフラン(150mL)と水(50mL)に溶解し、氷冷下N-ブロモコハク酸イミド(21.7g)を加えた。混合物を氷冷下30分撹拌した後、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で2回洗浄した。有機層を飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=10:90→30:70)にて精製し、以下の物性値を有する標題化合物(27.58g)を得た。
TLC:Rf 0.26(酢酸エチル:ヘキサン=10:90)。
(3S)-7-[5-クロロ-2-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-5-オキソ-1,2,3,5-テトラヒドロインドリジン-3-カルボン酸(特許文献6の実施例9に記載)(27.58g)と実施例1(3)で製造した化合物(25.68g)のN-メチルピロリドン溶液(200mL)に氷冷下N,N-ジイソプロピルエチルアミン(26.7mL)を加えた。室温にて30分撹拌した後、反応混合物を酢酸エチル(200mL)で希釈し飽和塩化アンモニウム水溶液(500mL)で洗浄した。水層を酢酸エチルで抽出し、合わせた有機層を水(500mL)、飽和食塩水(500mL)で洗浄し、乾燥後濃縮した。残渣をトルエン(500mL)と氷酢酸(50mL)に溶解し、酢酸アンモニウム(59.4g)を加え、混合物を100℃で3時間撹拌した。混合物を減圧濃縮し、酢酸エチルで希釈し、飽和炭酸カリウム水溶液(500mL)にて洗浄した。水層を酢酸エチルで抽出し、合わせた有機層を乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=50:50→100:0)にて精製し、以下の物性値を有する標題化合物(33.5g)を得た。
LC/MS tR 0.84分: MS (ES+) m/z 590 (M+H) (条件a)。
実施例1(4)で製造した化合物(350mg)をテトラヒドロフラン(1.2mL)とアセトニトリル(3.6mL)に溶解し、ピリジン(0.14mL)を加え、-18oCにて1-クロロメチル-4-フルオロ-1,4-ジアゾニアビシクロ[2.2.2]オクタン ビス(テトラフルオロボラート)(315mg)を加え、2時間撹拌した。反応混合物を酢酸エチルで希釈し、亜硫酸ナトリウム水溶液を加え撹拌した。水を加え分液し、水層を酢酸エチルで抽出した。有機層を合わせ、塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70→100:0)にて精製し、以下の物性値を有する標題化合物(138mg)を得た。
TLC:Rf 0.51(酢酸エチル:ヘキサン=80:20)。
TLC:Rf 0.48(酢酸エチル);
1H-NMR (CD3OD): δ 9.34 (s, 1H), 7.76 - 7.62 (m, 4H), 6.45 (dd, 1H), 6.13 (s, 1H), 6.07 (s, 1H), 5.71 (d, 1H), 3.42 (m, 1H), 3.06 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H)。
N-ヨードスクシンイミド(56.5g)を氷冷下、6-フルオロ-2-ピリジナミン(25.6g)のN,N-ジメチルホルムアミド(200mL)溶液に分割投入(3回)した。室温で3時間撹拌した後、反応液に市水(0.5L)を加えた。酢酸エチル/ヘキサン(1/1、300mL)で3回抽出し、有機層を飽和亜硫酸水溶液(0.5L)、飽和炭酸ナトリウム水溶液(0.5L、2回)、市水(0.5L)、飽和食塩水(0.5L)で洗浄し、乾燥後、濃縮した。得られた残渣にヘキサン/酢酸エチル(3/1、150mL)を加え、室温下スラリー洗浄し、ろ過した。得られた固体を乾燥し、以下の物性値を有する標題化合物(36.7g)を得た。
TLC:Rf 0.56(酢酸エチル:ヘキサン=1:2)。
実施例2(1)で製造した化合物(36.7g)と4-ジメチルアミノピリジン(0.9g)のアセトニトリル(300mL)溶液にジ-tert-ブチルジカーボネート(74.0g)のアセトニトリル(100mL)溶液を加え、室温で3時間撹拌した。反応溶液を濃縮し、得られた残渣を酢酸エチル(500mL)に溶解し、飽和塩化アンモニウム水溶液(400mL)で洗浄し、水層を酢酸エチル(200mL)で抽出した。合わせた有機層を乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=5:95→10:90)し、以下の物性値を有する標題化合物(45.06g)を得た。
1H-NMR (CDCl3): δ 8.14 (t, 1H), 7.03 (dd, 1H), 1.47 (s, 18H)。
実施例2(2)で製造した化合物(9.1g)、シアン化亜鉛(II)(7.32g)、テトラキス(トリフェニルホスフィン)パラジウム(0)(1.2g)の1-メチル-2-ピロリジノン(60mL)溶液を減圧下脱気した。マイクロウェーブ照射下、130℃で1時間撹拌した後、放冷した。反応溶液を酢酸エチル(100mL)で希釈した後、セライトろ過により不溶物を除去し、不溶物を酢酸エチル(50mL)で洗浄した。ろ液を分液し、水層を酢酸エチル(100mL)で再抽出した。有機層を合わせ、乾燥後、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=5:95→80:20)することで以下の物性値を有する標題化合物(2.1g)を得た。
TLC:Rf 0.25(酢酸エチル:ヘキサン=10:90)。
実施例2(3)で製造した化合物(1.56g)とヒドロキシルアミン塩酸塩(0.91g)のエタノール(40mL)溶液にN,N-ジイソプロピルエチルアミン(2.84mL)を加え、40℃で終夜撹拌した。反応溶液を濃縮し、得られた残渣を酢酸エチル(50mL)に溶解した。市水(50mL)を加え、洗浄した後、有機層を乾燥後、濃縮し、以下の物性値を有する未精製の標題化合物(1.93g)を得た。
LC/MS tR 0.60分; MS (ES+) m/z 271 (M+H) (条件a)。
実施例2(4)で製造した化合物(1.93g)の酢酸(10mL)溶液に無水酢酸(0.75mL)を加え、室温で1時間撹拌した。反応液に水酸化パラジウム(II)(20%、250mg)を加え、水素雰囲気下、室温で3時間撹拌した。反応液をセライトろ過し、ろ液を減圧濃縮し、以下の物性値を有する未精製の標題化合物(2.99g)を得た。
LC/MS tR 0.59分; MS (ES+) m/z 255 (M+H) (条件a)。
実施例2(5)で製造した化合物(2.6g)のメタノール(10mL)溶液に10%塩化水素/メタノール(6.5mL)溶液を加え、室温で10分間撹拌した。反応液にトルエンを加え濃縮し、以下の物性値を有する未精製の標題化合物(2.63g)を得た。
LC/MS tR 0.58分; MS (ES+) m/z 255 (M+H) (条件a)。
(3S)-7-[5-クロロ-2-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-5-オキソ-1,2,3,5-テトラヒドロインドリジン-3-カルボン酸(特許文献6の実施例9に記載)(3.0g)のジクロロメタン(15mL)溶液に、1-クロロ-N,N,2-トリメチル-1-プロペン-1-アミン(1.33mL)を氷冷下加え、0℃にて40分間撹拌した。トリメチルシリルジアゾメタン(2Mヘキサン溶液、8.4mL)を加えた後、さらに0℃で1時間撹拌した。濃塩酸(0.87mL)を氷冷下加え、室温で20分撹拌した。反応液に市水(50mL)を加え、ジクロロメタン(50mL)で2回抽出した。有機層を乾燥後、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=40:60→100:0)し、以下の物性値を有する標題化合物(2.32g)を得た。
LC/MS tR 0.80分; MS (ES+) m/z 390 (M+H) (条件a)。
実施例2(6)で製造した化合物(1.5g)および実施例2(7)で製造した化合物(1.0g)のアセトニトリル(50mL)溶液に炭酸カリウム(0.70g)を加え、80℃で17時間撹拌した。反応溶液を酢酸エチル(100mL)で希釈した後、市水(100mL)、飽和食塩水(200mL)で洗浄し、乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=50:50→100:0、続いてメタノール:酢酸エチル=5:95)し、以下の物性値を有する標題化合物(1.11g)を得た。
LC/MS tR 0.81分; MS (ES+) m/z 590 (M+H) (条件a)。
実施例2(8)で製造した化合物(264mg)および炭酸ナトリウム(118mg)のアセトニトリル(10mL)/テトラヒドロフラン(5mL)懸濁液に、1-クロロメチル-4-フルオロ-1,4-ジアゾニアビシクロ[2.2.2]オクタン ビス(テトラフルオロボラート)(selectfluor(登録商標))(95mg)を加え氷/食塩浴にて冷却下で3時間撹拌した。反応溶液を酢酸エチル(20mL)で希釈し、亜硫酸ナトリウム水溶液(40mL)を加えた。水層を酢酸エチル(50mL)で2回抽出し、合わせた有機層を乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(アミノシリカ、酢酸エチル:ヘキサン=50:50→100:0、続いてメタノール:酢酸エチル=5:95)し、実施例2(9)のS体化合物とR体化合物の混合物(71.2mg)を得た。得られた混合物(20mg)を光学分割(DAICEL、CHIRALFLASH(登録商標)IC カラム、(粒子径:20μm;カラム長:100 x 30 mm I.D.)流速:24mL/min;カラム温度:室温;移動相(A):アセトニトリル;移動相(B):メタノール;イソクラティック(移動相(A):移動相(B)=90:10)20分;検出器:UV Yamazen UV-254W UV-Detector)によって精製し、標題化合物(実施例2(9)のS体化合物:7.9mg、実施例2(9)のR体化合物:7.7mg)を得た。なお、上記条件により光学分割した際における標題化合物の保持時間は、それぞれ13分(実施例2(9)のS体化合物)および9.5分(実施例2(9)のR体化合物)であった。
それぞれの標題化合物を下記括弧内の液体クロマトグラフィー条件により分析した際における物性値を以下に示す。
実施例2(9)のS体化合物:
LC tR 10.4分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相アセトニトリル/メタノール=90/10、流速1.0mL/min)。
実施例2(9)のR体化合物:
LC tR 7.95分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相アセトニトリル/メタノール=90/10、流速1.0mL/min)。
TLC:Rf 0.60(メタノール:酢酸エチル=5:95);
1H-NMR (CD3OD): δ 9.31 (s, 1H), 7.91 (dd, 1H), 7.74 - 7.65 (m, 3H), 6.44 (dd, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 5.83 (dd, 1H), 3.39-3.06 (m, 2H), 2.62 - 2.48 (m, 2H);
LC tR 22.5分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相ヘキサン/酢酸エチル=30/70、流速1.0mL/min);
[α]25 D=+44.1°(CH3OH、c=1.00)。
LC/MS tR 0.83分;MS(ES+) m/z 508(M+H) (条件a);
1H-NMR (d6-DMSO): δ 11.7 (brs, 1H), 9.64 (s, 1H), 7.87 (dd, 1H), 7.79 (brs, 2H), 7.75 (brs, 1H), 6.38 (dd, 1H), 6.00 (s, 1H), 5.92 (s, 1H), 5.69 (d, 1H), 3.23 - 2.96 (m, 2H), 2.58-2.22 (m, 2H)。
1H-NMR (CD3OD): δ 9.31 (s, 1H), 7.91 (dd, 1H), 7.74 - 7.65 (m, 3H), 6.44 (dd, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 5.83 (dd, 1H), 3.39 - 3.06 (m, 2H), 2.62 - 2.48 (m, 2H);
LC tR 13.6分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相ヘキサン/酢酸エチル=30/70、流速1.0mL/min);
[α]23 D= -39.6°(CH3OH、c=1.00)。
1H-NMR (CD3OD): δ 9.31 (s, 1H), 7.91 (dd, 1H), 7.74 - 7.65 (m, 3H), 6.44 (dd, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 5.83 (dd, 1H), 3.39 - 3.06 (m, 2H), 2.62 - 2.48 (m, 2H);
LC/MS tR 0.82分;MS(ES+) m/z 508(M+H) (条件a)。
実施例2(8)で製造した化合物(1.47g)のTHF(28mL)溶液を0℃に冷却し、1,3-ジクロロ-5,5-ジメチルヒダントイン(491mg)を加え、30分間撹拌した。反応混合物に亜硫酸ナトリウム水溶液を加えて試薬を分解し、水を加え、酢酸エチルで抽出した。得られた有機層を水、1M水酸化ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=70:30→100:0)し、標題化合物(1.10g)を得た。
実施例2(1)で製造した化合物の代わりに6-アミノニコチノニトリルを用いて、実施例2(2)→実施例2(4)→実施例2(5)→実施例2(6)と同様の操作を行うことにより、標題化合物を得た。
(6S)-2-[5-クロロ-2-(1H-1,2,3,4-テトラゾール-1-イル)フェニル]-4-オキソ-4H,6H,7H,8H-ピロロ[1,2-a]ピリミジン-6-カルボン酸(特許文献6の実施例336に記載)を用いて、実施例2(7)と同様の操作を行うことで、以下の物性値を有する標題化合物を得た。
LC/MS tR 0.75分;MS(ES+) m/z 391(M+H) (条件a)。
実施例2(6)で製造した化合物と実施例3(1)の化合物を用いて、実施例2(8)と同様の操作を行うことで、以下の物性値を有する標題化合物を得た。
LC/MS tR 0.79分; MS (ES+) m/z 591 (M+H) (条件a)。
実施例3(2)で製造した化合物を用いて、実施例2(9)と同様の操作を行うことで、以下の物性値を有する標題化合物を得た。なお、光学分割(DAICEL、CHIRALFLASH(登録商標)IC カラム、(粒子径:20μm;カラム長:100 x 30 mm I.D.)流速:24mL/min;カラム温度:室温;移動相:アセトニトリル;検出器:UV Yamazen UV-254W UV-Detector)した際における標題化合物の保持時間は、それぞれ13.7分(実施例3(3)のS体化合物)および8.1分(実施例3(3)のR体化合物)であった。
実施例3(3)のS体化合物:
LC tR 4.15分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min)。
実施例3(3)のR体化合物:
LC tR 3.75分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min)。
TLC:Rf 0.65(メタノール:酢酸エチル=5:95);
1H-NMR (CD3OD): δ 9.40 (s, 1H), 7.95 - 7.86 (m,2H), 7.76 (dd, 1H), 7.68 (d, 1H), 6.44 (dd, 1H), 6.41 (s, 1H), 5.78 (dd, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 2.62 (m, 1H) 2.41 (m, 1H);
LC tR 4.23分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min);
[α]25 D=+74.6°(CH3OH、c=1.00)。
1H-NMR (CD3OD): δ 9.44 (s, 1H), 7.95 - 7.85 (m,2H), 7.78 (dd, 1H), 7.71 (d, 1H), 6.50 (dd, 1H), 6.42 (s, 1H), 5.80 (dd, 1H), 3.13 (m, 1H), 2.98 (m, 1H), 2.72 (m, 1H) 2.43 (m, 1H);
LC tR 4.63分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min)。
エチル (3S)-7-(2-アミノ-5-クロロフェニル)-5-オキソ-1,2,3,5-テトラヒドロインドリジン-3-カルボキシレート(特許文献6の実施例7に記載)(2.0g)のアセトニトリル溶液(15mL)に、冷却(0℃)下、トリメチルシリルアジド(1.39g)および亜硝酸アミル(1.41g)を加えた。混合物を室温にて1時間撹拌した後、濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=10:90→100:0)にて精製し、以下の物性値を有する標題化合物(1.89g)を得た。
TLC:Rf 0.75 (メタノール:酢酸エチル=5:95)。
実施例4(1)で製造した化合物(15.0g)のN,N-ジメチルホルムアミド溶液(45mL)に、プロピオルアミド(3.18g)、(R)-3,4-ジヒドロキシ-5-((S)-1,2-ジヒドロキシエチル)フラン-2(5H)-オン(1.47g)および硫酸銅(II)(0.33g)を加えた。混合物を50℃にて10分撹拌した後、水を加えた。析出物を濾取し、水で洗浄後、乾燥し、以下の物性値を有する標題化合物(17.5g)を得た。
LC/MS tR 0.69 分: MS (ES+) m/z 428 (M+H) (条件b)。
実施例4(2)で製造した化合物(100mg)の1,4-ジオキサン溶液(10mL)に、5M塩酸(5 mL)を加えた。混合物を60℃にて5時間撹拌した後、室温にて5M 水酸化ナトリウム水溶液(5mL)を加え、酢酸エチルで抽出した。有機層を乾燥後濃縮し、以下の物性値を有する標題化合物(61.7mg)を得た。
LC/MS tR 0.60 分: MS (ES+) m/z 400 (M+H) (条件b)。
実施例4(3)で製造した化合物(6.10g)のN,N-ジメチルホルムアミド溶液(61mL)に、tert-ブチル N-[4-(2-ブロモアセチル)フェニル]カルバマート(7.19g)およびN,N-ジイソプロピルエチルアミン(5.3mL)を加えた。混合物を室温にて3日間撹拌した後、水と酢酸エチルを加えた。析出物を濾過にて集めて水で洗浄後、乾燥し、以下の物性値を有する標題化合物(3.93g)を得た。
LC/MS tR 0.90分: MS (ES+) m/z 633 (M+H) (条件b)。
実施例4(4)で製造した化合物(3.93g)をトルエン(79mL)と氷酢酸(3.9mL)に溶解し、酢酸アンモニウム(9.57g)を加えた。混合物を加熱還流下、4時間撹拌した後、水と酢酸エチルを加えた。有機層を水で洗浄後、乾燥し、以下の物性値を有する標題化合物(3.98g)を得た。
LC/MS tR 0.73分: MS (ES+) m/z 613 (M+H) (条件b)。
実施例4(5)で製造した化合物(3.81g)のピリジン溶液(76mL)に、冷却(0℃)下、無水トリフルオロ酢酸(4.3mL)を加えた。混合物を0℃にて2時間撹拌した後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥して濃縮し、得られた残渣をテトラヒドロフランに溶解し、アンモニア水を加え、30分撹拌した。混合物を濃縮し、残渣をカラムクロマトグラフィー(ジオールシリカゲル、酢酸エチル:ヘキサン=50:50→80:20)(アミノシリカゲル、酢酸エチル:ヘキサン=50:50→80:20)にて精製し、以下の物性値を有する標題化合物(2.39g)を得た。
LC/MS tR 0.83 分: MS (ES+) m/z 595 (M+H) (条件b)。
実施例4(6)で製造した化合物(2.00g)のN,N-ジメチルホルムアミド溶液(20mL)に、冷却(0℃)下、N,N-ジイソプロピルエチルアミン(0.87mL)および2-(トリメチルシリル)エトキシメチルクロリド(0.66mL)を加えた。混合物を室温にて8時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥し濃縮した。残渣をカラムクロマトグラフィー(ジオールシリカゲル、酢酸エチル:ヘキサン=30:70→50:50)にて精製し、以下の物性値を有する標題化合物(2.27g)を得た。
LC/MS tR 1.17分: MS (ES+) m/z 725 (M+H) (条件b)。
実施例4(7)で製造した化合物(560mg)をテトラヒドロフラン(5.6mL)とアセトニトリル(2.8mL)に溶解し、-10℃にて炭酸ナトリウム(205mg)および1-クロロメチル-4-フルオロ-1,4-ジアゾニアビシクロ[2.2.2]オクタン ビス(テトラフルオロボラート)(219mg)を加え、6時間撹拌した。反応混合物を酢酸エチルで希釈し、水を加え分液し、水層を酢酸エチルで抽出した。有機層を合わせ、飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70→50:50)にて精製し、以下の物性値を有する標題化合物(277mg)を得た。
LC/MS tR 1.30 分: MS (ES+) m/z 743 (M+H) (条件a)。
実施例4(8)で製造した化合物(427mg)の1,4-ジオキサン溶液(4.3mL)に、5M塩酸水溶液(0.43mL)を加えた。混合物を室温にて30分撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥し濃縮した。残渣をカラムクロマトグラフィー(ジオールシリカゲル、酢酸エチル:ヘキサン=35:65→50:50)にて精製し、以下の物性値を有する標題化合物(320mg)を得た。
LC/MS tR 1.11 分: MS (ES+) m/z 613 (M+H) (条件a)。
LC/MS tR 0.79 分: MS (ES+) m/z 513 (M+H) (条件a);
1H NMR (300 MHz, methanol-d4); δ 8.88 (s, 1H), 7.73-7.65 (m, 3H), 7.30 (d, 2H), 6.75 (d, 2H), 6.11 (s, 1H), 6.08 (s, 1H), 5.70 (d, 1H), 3.42 (m, 1H), 3.10 (m, 1H), 2.61 (m, 1H), 2.39 (m, 1H)。
(3S)-3-[5-(6-アミノ-2-フルオロ-3-ピリジニル)-1H-イミダゾール-2-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノン(比較例1(1)とする。):
(1)in vitroアッセイ
本発明化合物のヒト血液凝固第XIa因子、第VIIa因子、第IXa因子、第Xa因子、第XIIa因子、血漿カリクレインおよびトロンビン阻害活性を評価した。各酵素液に発色基質液を添加し、405nmの吸光度を37℃で15秒間隔に連続的に5分間測定し、基質分解速度(mOD/min)を求めた。本発明化合物の各酵素に対する50%阻害濃度(IC50)は、本発明化合物の濃度の自然対数変換値と下記方程式に従って求めた酵素阻害率から、最小二乗法による直線回帰を行い、算出した。
本発明化合物の酵素阻害率(%)は、以下の式を用いて算出した。:
ヒト血液凝固第XIa因子(Haematologic Technologies Inc.)阻害活性は、300 mM NaCl、10 mM KCl、2 mg/mL PEG6000、100 mM HEPES-NaOH(pH7.4)を含む緩衝液で0.1 U/mLに調整した酵素液および蒸留水で1 mMに調整したS-2366(pyroglu-Pro-Arg-pNA、CHROMOGENIX)を用いて測定した。
ヒト血漿カリクレイン(Enzyme Research Laboratories Ltd.)阻害活性は、400 mM NaCl、10 mg/mL PEG6000および200 mMリン酸緩衝液(pH7.4)を含む緩衝液で20 mU/mLに調整した酵素液および蒸留水で500 μMに調整したS-2302(H-D-Pro-Phe-Arg-pNA、CHROMOGENIX)を用いて測定した。
ヒト血液凝固第Xa因子(Sekisui Diagnostics LLC.)阻害活性およびヒトトロンビン(Sigma)阻害活性は、300 mM NaCl、4 mg/mL PEG6000、100 mM トリス-HCl(pH7.4)を含む緩衝液でそれぞれ0.5 U/mLまたは0.25 U/mLに調整した各酵素液および蒸留水でそれぞれ1 mMに調整したS-2222[Bz-Ile-Glu(γ-OR)-Gly-Arg-pNA・HCl,R=H(50%) and R=CH3(50%)、CHROMOGENIX]またはS-2366を用いて測定した。
ヒト血液凝固第XIIa因子(Enzyme Research Laboratories Ltd.)阻害活性は、300 mM NaCl、100 mM トリス-HCl(pH7.4)を含む緩衝液で0.78 U/mLに調整した酵素液および蒸留水で1mMに調整したS-2302を用いて測定した。
ヒト血液凝固第IXa因子(Sekisui Diagnostics LLC.)阻害活性は、200 mM NaCl、10 mM CaCl2、60%エチレングリコール、100 mM トリス-HCl(pH7.4)を含む緩衝液で30 U/mLに調整した酵素液および蒸留水で10 mMに調整したSpectrozume FIXa(H-D-Leu-Ph’Gly-Arg-pNA・2AcOH、Sekisui Diagnostics LLC.)を用いて測定した。
ヒト血液凝固第VIIa因子(Sekisui Diagnostics LLC.)阻害活性は、300 mM NaCl、10 mM CaCl2、10 mg/mL PEG6000、100 mM HEPES-NaOH(pH7.4)、組換えヒト組織因子(アリレザ R.リザイエらの方法(プロテイン エクスプレッション アンド ピューリフィケーション(Protein expression and purification)、1992年、第3巻、第6号、453~460頁)に従って製造した)を含む緩衝液で200U/mLに調整した酵素液および蒸留水で10mMに調整したS-2288(H-D-Ile-Pro-Arg-pNA、CHROMOGENIX)を用いて測定した。
全自動血液凝固測定装置(CA-1500、Sysmex Corporation)を用いて、活性化部分トロンボプラスチン時間(APTT)およびプロトロンビン時間(PT)を測定した。APTTまたはPT測定に対して、血液凝固試験用標準ヒト血漿(Siemens Healthcare Diagnostics GmbH)を本発明化合物希釈液と混合し、その後、血塊形成を開始させるために、APTT試薬(Siemens Healthcare Diagnostics GmbH)および0.02M塩化カルシウムまたはPT試薬(Siemens Healthcare Diagnostics GmbH)の自動添加を行った。本発明化合物の抗凝固活性(APTT×2またはPT×2)は、ビヒクル(1%DMSO)群における凝固時間を倍にするために必要な濃度として表した。APTT×2またはPT×2は、凝固時間の倍単位での増加に対して本発明の化合物の濃度をプロットすることによって決定した。
本発明化合物を単回0.1mg/kg、i.v.用量(媒体:20%HP-β-CD溶液)として静脈内注射投与、及び1mg/kg、p.o.用量(媒体:0.5%メチルセルロース溶液)として強制経口投与により絶食オスCrj:CD(SD)ラットに与えた。静脈内注射投与後、0.08、0.25、0.5、1、3、7時間で、または経口投与後、0.08、0.25、0.5、1、2、4、6、8、24時間で、ヘパリン処理シリンジに、頸静脈から血液試料を採取した。遠心によって血漿を得て、血漿濃度の測定まで-20℃で保管した。
(1)CYP阻害活性
競合阻害活性
ミダゾラム及び本発明化合物をヒト由来肝ミクロソーム懸濁液に添加し37℃で3分間振盪させた後、試料中の1’-ヒドロキシミダゾラム濃度をLC/MS/MSによって分析した。
本発明化合物をヒト由来肝ミクロソーム懸濁液に添加し37℃で30分間振盪させた後ミダゾラムを添加し、更に3分間振盪させ、振盪後の試料中の1’-ヒドロキシミダゾラム濃度をLC/MS/MSによって分析した。
本発明化合物をヒト血清で懸濁したヒト由来肝細胞懸濁液に添加し37℃で10分間振盪させた後、ミダゾラムを添加し更に90分間振盪させ、振盪後の試料中の1’-ヒドロキシミダゾラム濃度をLC/MS/MSによって分析した。分析用カラム(Shim-pack XR-ODSII、2.0mm×75mm、2.2μm)および移動相(水中0.1%ギ酸およびアセトニトリル中0.1%ギ酸、流速0.5mL/分)を使用した。陽イオン検出により、多重反応モニタリング(MRM)モードでこの系を使用した。本発明化合物の試料中濃度は10μmol/L、30μmol/L、100μmol/Lとした。
(1)hERG阻害作用
本発明化合物のhERG阻害活性を、以下の手順により測定した。
hERGの遺伝子導入CHO-K1細胞を使用し、刺激パルスにより誘導されるhERGチャンネル電流(IKr)を、アンフォテリシン穿孔パッチクランプ法によって全自動パッチクランプシステムを用いて測定した。刺激パルスは保持電圧:-80mV、脱分極電圧:+40mV(2秒間)、再分極電圧:-50mV(2秒間)とし、再分極電圧後に誘導される最大tail電流を測定した。刺激パルスは本発明化合物の添加前および添加5分後の2回適用し、添加前に対する最大tail電流の変化率を求めた。本発明化合物はジメチルスルホキシド(DMSO)溶液とし、1%の濃度で細胞外液に添加した。hERGチャンネルの阻害率(%)は本発明化合物の添加前後の最大tail電流の変化率を媒体処置群での変化率で補正することにより求めた。
本発明化合物のステアトーシス誘導作用を、以下の手順により測定した。
ヒト不死化肝細胞株Fa2N-4に培地に6.25、12.5、25、50、100μMの濃度の本発明化合物DMSO溶液を1%添加し、72時間暴露させた後、Nile Redを添加し、励起波長485nm、蛍光波長570nmで細胞の蛍光強度を測定した。蛍光測定値が媒体処置の160%以上の値を示した場合、ステアトーシス誘導作用ありと判定した。
製剤例1
以下の各成分を常法により混合した後打錠して、一錠中に10mgの活性成分を含有する錠剤1万錠を得る。
・(3S)-3-[5-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-2-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノン…100g
・カルボキシメチルセルロースカルシウム … 20g
・ステアリン酸マグネシウム … 10g
・微結晶セルロース … 870g
以下の各成分を常法により混合した後、除塵フィルターでろ過し、5mlずつアンプルに充填し、オートクレーブで加熱滅菌して、1アンプル中20mgの活性成分を含有するアンプル1万本を得る。
・(3S)-3-[5-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-2-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノン…200g
・マンニトール … 20g
・蒸留水 … 50L
Claims (14)
- 一般式(I)で示される化合物が、(3S)-3-[5-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-2-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノンである請求項1記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ。
- 一般式(I)で示される化合物が、(3S)-3-[2-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-5-イル]-7-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-2,3-ジヒドロ-5(1H)-インドリジノンである請求項1記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ。
- 一般式(I)で示される化合物が、(6S)-6-[2-(6-アミノ-2-フルオロ-3-ピリジニル)-4-フルオロ-1H-イミダゾール-5-イル]-2-[5-クロロ-2-(1H-テトラゾール-1-イル)フェニル]-7,8-ジヒドロピロロ[1,2-a]ピリミジン-4(6H)-オンである請求項1記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ。
- 一般式(I)で示される化合物が、1-(2-{(3S)-3-[5-(4-アミノフェニル)-4-フルオロ-1H-イミダゾール-2-イル]-5-オキソ-1,2,3,5-テトラヒドロ-7-インドリジニル}-4-クロロフェニル)-1H-1,2,3-トリアゾール-4-カルボニトリルである請求項1記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ。
- 請求項1~5のいずれか1項記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを有効成分として含有する医薬組成物。
- 請求項1~5のいずれか1項記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを有効成分として含有するFXIa阻害剤。
- 請求項1~5のいずれか1項記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを有効成分として含有する血栓塞栓性疾患の予防および/または治療剤。
- 血栓塞栓性疾患が、動脈性心血管血栓塞栓性障害、静脈性心血管血栓塞栓性障害、動脈性脳血管血栓塞栓性障害、静脈性脳血管血栓塞栓性障害、または心腔もしくは末梢循環における血栓塞栓性障害である請求項8に記載の剤。
- 血栓塞栓性疾患が、冠動脈疾患、不安定狭心症、急性冠症候群、心房細動、心筋梗塞、虚血性突然死、一過性脳虚血発作、脳卒中、末梢動脈疾患、アテローム性動脈硬化症、末梢閉塞性動脈疾患、静脈血栓症、静脈血栓塞栓症、深部静脈血栓症、血栓性静脈炎、動脈塞栓症、冠状動脈血栓症、大脳動脈血栓症、脳塞栓症、腎臓塞栓症、門脈血栓症、肺塞栓症、肺梗塞、肝塞栓症、肝中心静脈閉塞症/類洞閉塞症候群、血栓性微小血管障害症、播種性血管内凝固症候群、敗血症、急性呼吸窮迫症候群、急性肺損傷、抗リン脂質抗体症候群、冠動脈バイパス移植手術に起因する血栓症または血栓形成を促進する人工物表面に血液が曝露される治療により引き起こされる血栓症である、請求項8または9のいずれか一項に記載の剤。
- 血栓塞栓性疾患が、静脈血栓塞栓症、虚血性脳卒中、血栓形成を促進する人工物表面に血液が暴露される治療により引き起こされる血栓塞栓性疾患、急性冠症候群、冠動脈疾患または末梢動脈疾患である、請求項8~10のいずれか一項に記載の剤。
- 血栓塞栓性疾患を予防および/または治療するための請求項1~5のいずれか1項記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグ。
- 血栓塞栓性疾患の予防および/または治療剤を製造するための請求項1~5のいずれか1項記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグの使用。
- 血栓塞栓性疾患の予防および/または治療が必要な患者に有効投与量の請求項1~5のいずれか1項記載の化合物、その塩、その溶媒和物、そのN-オキシド体またはそのプロドラッグを投与することからなる該疾患の予防および/または治療方法。
Priority Applications (25)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SG11201704708QA SG11201704708QA (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
DK15867764.1T DK3231803T3 (da) | 2014-12-10 | 2015-12-09 | Dihydroindolizinonderivat |
CN201580066685.2A CN107001363B (zh) | 2014-12-10 | 2015-12-09 | 二氢吲嗪酮衍生物 |
PL15867764T PL3231803T3 (pl) | 2014-12-10 | 2015-12-09 | Pochodna dihydroindolizynonu |
EP20170445.9A EP3702357B1 (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
ES15867764T ES2814098T3 (es) | 2014-12-10 | 2015-12-09 | Derivado de dihidroindolizinona |
AU2015362422A AU2015362422B2 (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
MX2017007551A MX2017007551A (es) | 2014-12-10 | 2015-12-09 | Derivado de dihidroindolizinona. |
CA2970233A CA2970233C (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
EP15867764.1A EP3231803B1 (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
RU2017124150A RU2707887C2 (ru) | 2014-12-10 | 2015-12-09 | Производное дигидроиндолизинона |
KR1020177015619A KR102525392B1 (ko) | 2014-12-10 | 2015-12-09 | 디히드로인돌리지논 유도체 |
MYPI2017702113A MY194106A (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
JP2016563720A JP6610562B2 (ja) | 2014-12-10 | 2015-12-09 | ジヒドロインドリジノン誘導体 |
BR112017012146-8A BR112017012146B1 (pt) | 2014-12-10 | 2015-12-09 | Composto derivado de di-hidroindolizinona, seu uso, composição farmacêutica e inibidor de fxia |
US15/534,247 US10065955B2 (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
NZ733574A NZ733574A (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
PH12017501067A PH12017501067A1 (en) | 2014-12-10 | 2017-06-08 | Dihydroindolizinone derivative |
IL252777A IL252777B (en) | 2014-12-10 | 2017-06-08 | A dihydroindolizinone derivative |
ZA2017/04602A ZA201704602B (en) | 2014-12-10 | 2017-07-07 | Dihydroindolizinone derivative |
US16/050,266 US10407426B2 (en) | 2014-12-10 | 2018-07-31 | Dihydroindolizinone derivative |
US16/527,489 US10550119B2 (en) | 2014-12-10 | 2019-07-31 | Dihydroindolizinone derivative |
US16/720,486 US10815233B2 (en) | 2014-12-10 | 2019-12-19 | Dihydroindolizinone derivative |
US17/027,922 US11566027B2 (en) | 2014-12-10 | 2020-09-22 | Dihydroindolizinone derivative |
US18/088,045 US20230138003A1 (en) | 2014-12-10 | 2022-12-23 | Dihydroindolizinone derivative |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014249822 | 2014-12-10 | ||
JP2014-249822 | 2014-12-10 | ||
JP2014-263251 | 2014-12-25 | ||
JP2014263251 | 2014-12-25 | ||
JP2015-046150 | 2015-03-09 | ||
JP2015046150 | 2015-03-09 | ||
JP2015-160632 | 2015-08-17 | ||
JP2015160632 | 2015-08-17 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/534,247 A-371-Of-International US10065955B2 (en) | 2014-12-10 | 2015-12-09 | Dihydroindolizinone derivative |
US16/050,266 Continuation US10407426B2 (en) | 2014-12-10 | 2018-07-31 | Dihydroindolizinone derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016093285A1 true WO2016093285A1 (ja) | 2016-06-16 |
Family
ID=56107463
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2015/084573 WO2016093285A1 (ja) | 2014-12-10 | 2015-12-09 | ジヒドロインドリジノン誘導体 |
Country Status (23)
Country | Link |
---|---|
US (6) | US10065955B2 (ja) |
EP (2) | EP3702357B1 (ja) |
JP (3) | JP6610562B2 (ja) |
KR (1) | KR102525392B1 (ja) |
CN (1) | CN107001363B (ja) |
AU (1) | AU2015362422B2 (ja) |
BR (1) | BR112017012146B1 (ja) |
CA (1) | CA2970233C (ja) |
DK (1) | DK3231803T3 (ja) |
ES (2) | ES2927307T3 (ja) |
HU (1) | HUE051080T2 (ja) |
IL (1) | IL252777B (ja) |
MX (2) | MX2017007551A (ja) |
MY (1) | MY194106A (ja) |
NZ (1) | NZ733574A (ja) |
PH (1) | PH12017501067A1 (ja) |
PL (1) | PL3231803T3 (ja) |
PT (1) | PT3231803T (ja) |
RU (1) | RU2707887C2 (ja) |
SG (1) | SG11201704708QA (ja) |
TW (1) | TWI696620B (ja) |
WO (1) | WO2016093285A1 (ja) |
ZA (1) | ZA201704602B (ja) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
US9777001B2 (en) | 2014-01-31 | 2017-10-03 | Bristol-Myers Squibb Company | Macrocycles with aromatic P2′ groups as factor xia inhibitors |
US10081623B2 (en) | 2014-09-04 | 2018-09-25 | Bristol-Myers Squibb Company | Diamide macrocycles that are FXIa inhibitors |
US10273236B2 (en) | 2014-01-31 | 2019-04-30 | Bristol-Myers Squibb | Macrocyclic factor XIa inhibitors bearing heterocyclic groups |
WO2020111268A1 (ja) | 2018-11-30 | 2020-06-04 | 小野薬品工業株式会社 | (3s)-3-[2-(6-アミノ-2-フルオロピリジン-3-イル)-4-フルオロ-1h-イミダゾール-5-イル]-7-[5-クロロ-2-(1h-テトラゾール-1-イル)フェニル]-2,3-ジヒドロインドリジン-5(1h)-オンの新規結晶 |
CN114026087A (zh) * | 2019-06-28 | 2022-02-08 | 上海济煜医药科技有限公司 | 三并环类化合物及其制备方法和用途 |
WO2023002984A1 (ja) * | 2021-07-20 | 2023-01-26 | 小野薬品工業株式会社 | イミダゾール化合物の製造方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6992284B2 (ja) * | 2016-06-06 | 2022-01-13 | 小野薬品工業株式会社 | ジヒドロインドリジノン誘導体を含有する医薬組成物 |
KR102242187B1 (ko) * | 2019-06-04 | 2021-04-20 | 주식회사 우정바이오 | 실내 표면 및 공기 살균 정화 장치 |
TWI833610B (zh) * | 2022-03-21 | 2024-02-21 | 大陸商上海濟煜醫藥科技有限公司 | 三并環類化合物製備方法及其中間體 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013093484A1 (en) * | 2011-12-21 | 2013-06-27 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
WO2015120777A1 (zh) * | 2014-02-14 | 2015-08-20 | 四川海思科制药有限公司 | 一种吡啶酮或嘧啶酮衍生物、及其制备方法和应用 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL61385A (en) * | 1979-12-06 | 1984-11-30 | Labaz Sanofi Nv | 3-(4-(dialkylaminoalkyl)-oxy-benzoyl)-indolizine derivatives,their preparation and pharmaceutical compositions containing them |
EP0407342A3 (en) | 1989-07-06 | 1991-07-10 | Ciba-Geigy Ag | Pyrimidine derivatives |
DE4221583A1 (de) | 1991-11-12 | 1993-05-13 | Bayer Ag | Substituierte biphenylpyridone |
DE4407488A1 (de) | 1994-03-07 | 1995-09-14 | Bayer Ag | Verwendung von Biphenyl- und Pyridylmethylpyridonen |
IT1277405B1 (it) * | 1995-08-01 | 1997-11-10 | Menarini Farma Ind | Derivati di lattami biciclici come inibitori della trombina |
ES2334990T3 (es) | 2002-02-14 | 2010-03-18 | Pharmacia Corporation | Piridinonas sustituidas como moduladores de p38 map quinasa. |
FR2838123B1 (fr) * | 2002-04-04 | 2005-06-10 | Sanofi Synthelabo | Nouveaux derives d'indolozine-1,2,3 substituee, inhibiteurs selectifs du b-fgf |
US7579357B2 (en) | 2003-08-13 | 2009-08-25 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
GB0420722D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
ATE511502T1 (de) | 2005-12-14 | 2011-06-15 | Bristol Myers Squibb Co | Arylpropionamid-, arylacrylamid-, arylpropinamid- oder arylmethylharnstoffanaloge als faktor-xia- inhibitoren |
US7803940B2 (en) | 2006-11-24 | 2010-09-28 | Takeda Pharmaceutical Company Limited | Heteromonocyclic compound or a salt thereof having strong antihypertensive action, insulin sensitizing activity and the like production thereof and use thereof for prophylaxis or treatment of cardiovascular diseases, metabolic diseases and/or central nervous system diseases |
CA2670404A1 (en) | 2006-11-24 | 2008-05-29 | Takeda Pharmaceutical Company Limited | Heteromonocyclic compound and use thereof |
CN101605779B (zh) | 2006-12-15 | 2013-11-20 | 百时美施贵宝公司 | 作为凝血因子xia抑制剂的芳基丙酰胺、芳基丙烯酰胺、芳基丙炔酰胺或芳基甲基脲类似物 |
CA2708151A1 (en) | 2007-12-11 | 2009-06-18 | Schering Corporation | Gamma secretase modulators |
PE20140239A1 (es) | 2010-10-07 | 2014-03-07 | Takeda Pharmaceutical | Derivados de 1,4-oxazepano |
TW201319068A (zh) * | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為xia因子抑制劑之環狀p1接合劑 |
GB2497806A (en) * | 2011-12-21 | 2013-06-26 | Ono Pharmaceutical Co | Pyridinone and pyrimidinone derivatives as factor XIa inhibitors |
WO2016011940A1 (zh) * | 2014-07-25 | 2016-01-28 | 江苏恒瑞医药股份有限公司 | 氮茚-酰胺类衍生物、其制备方法及其在医药上的应用 |
-
2015
- 2015-12-09 US US15/534,247 patent/US10065955B2/en active Active
- 2015-12-09 SG SG11201704708QA patent/SG11201704708QA/en unknown
- 2015-12-09 MY MYPI2017702113A patent/MY194106A/en unknown
- 2015-12-09 BR BR112017012146-8A patent/BR112017012146B1/pt active IP Right Grant
- 2015-12-09 ES ES20170445T patent/ES2927307T3/es active Active
- 2015-12-09 JP JP2016563720A patent/JP6610562B2/ja active Active
- 2015-12-09 KR KR1020177015619A patent/KR102525392B1/ko active IP Right Grant
- 2015-12-09 NZ NZ733574A patent/NZ733574A/en unknown
- 2015-12-09 PL PL15867764T patent/PL3231803T3/pl unknown
- 2015-12-09 CN CN201580066685.2A patent/CN107001363B/zh active Active
- 2015-12-09 DK DK15867764.1T patent/DK3231803T3/da active
- 2015-12-09 EP EP20170445.9A patent/EP3702357B1/en active Active
- 2015-12-09 RU RU2017124150A patent/RU2707887C2/ru active
- 2015-12-09 ES ES15867764T patent/ES2814098T3/es active Active
- 2015-12-09 WO PCT/JP2015/084573 patent/WO2016093285A1/ja active Application Filing
- 2015-12-09 EP EP15867764.1A patent/EP3231803B1/en active Active
- 2015-12-09 CA CA2970233A patent/CA2970233C/en active Active
- 2015-12-09 AU AU2015362422A patent/AU2015362422B2/en active Active
- 2015-12-09 HU HUE15867764A patent/HUE051080T2/hu unknown
- 2015-12-09 PT PT158677641T patent/PT3231803T/pt unknown
- 2015-12-09 TW TW104141268A patent/TWI696620B/zh active
- 2015-12-09 MX MX2017007551A patent/MX2017007551A/es unknown
-
2017
- 2017-06-08 IL IL252777A patent/IL252777B/en active IP Right Grant
- 2017-06-08 MX MX2021005869A patent/MX2021005869A/es unknown
- 2017-06-08 PH PH12017501067A patent/PH12017501067A1/en unknown
- 2017-07-07 ZA ZA2017/04602A patent/ZA201704602B/en unknown
-
2018
- 2018-07-31 US US16/050,266 patent/US10407426B2/en active Active
-
2019
- 2019-07-31 US US16/527,489 patent/US10550119B2/en active Active
- 2019-10-25 JP JP2019194671A patent/JP6791338B2/ja active Active
- 2019-12-19 US US16/720,486 patent/US10815233B2/en active Active
-
2020
- 2020-09-22 US US17/027,922 patent/US11566027B2/en active Active
- 2020-11-05 JP JP2020185297A patent/JP2021011506A/ja active Pending
-
2022
- 2022-12-23 US US18/088,045 patent/US20230138003A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013093484A1 (en) * | 2011-12-21 | 2013-06-27 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
WO2015120777A1 (zh) * | 2014-02-14 | 2015-08-20 | 四川海思科制药有限公司 | 一种吡啶酮或嘧啶酮衍生物、及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3231803A4 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10273236B2 (en) | 2014-01-31 | 2019-04-30 | Bristol-Myers Squibb | Macrocyclic factor XIa inhibitors bearing heterocyclic groups |
US9777001B2 (en) | 2014-01-31 | 2017-10-03 | Bristol-Myers Squibb Company | Macrocycles with aromatic P2′ groups as factor xia inhibitors |
US10081623B2 (en) | 2014-09-04 | 2018-09-25 | Bristol-Myers Squibb Company | Diamide macrocycles that are FXIa inhibitors |
US11053247B2 (en) | 2014-10-01 | 2021-07-06 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIA inhibitors |
US10336754B2 (en) | 2014-10-01 | 2019-07-02 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
WO2020111268A1 (ja) | 2018-11-30 | 2020-06-04 | 小野薬品工業株式会社 | (3s)-3-[2-(6-アミノ-2-フルオロピリジン-3-イル)-4-フルオロ-1h-イミダゾール-5-イル]-7-[5-クロロ-2-(1h-テトラゾール-1-イル)フェニル]-2,3-ジヒドロインドリジン-5(1h)-オンの新規結晶 |
JPWO2020111268A1 (ja) * | 2018-11-30 | 2021-10-14 | 小野薬品工業株式会社 | (3s)−3−[2−(6−アミノ−2−フルオロピリジン−3−イル)−4−フルオロ−1h−イミダゾール−5−イル]−7−[5−クロロ−2−(1h−テトラゾール−1−イル)フェニル]−2,3−ジヒドロインドリジン−5(1h)−オンの新規結晶 |
JP7196931B2 (ja) | 2018-11-30 | 2022-12-27 | 小野薬品工業株式会社 | (3s)-3-[2-(6-アミノ-2-フルオロピリジン-3-イル)-4-フルオロ-1h-イミダゾール-5-イル]-7-[5-クロロ-2-(1h-テトラゾール-1-イル)フェニル]-2,3-ジヒドロインドリジン-5(1h)-オンの新規結晶 |
TWI826599B (zh) * | 2018-11-30 | 2023-12-21 | 日商小野藥品工業股份有限公司 | (3s)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1h-咪唑-5-基]-7-[5-氯-2-(1h-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1h)-酮的新穎結晶 |
CN114026087A (zh) * | 2019-06-28 | 2022-02-08 | 上海济煜医药科技有限公司 | 三并环类化合物及其制备方法和用途 |
JP2022530718A (ja) * | 2019-06-28 | 2022-06-30 | シャンハイ ジェミンケア ファーマシューティカルズ カンパニー、リミテッド | 三環式化合物及びその製造方法と使用 |
JP7222123B2 (ja) | 2019-06-28 | 2023-02-14 | シャンハイ ジェミンケア ファーマシューティカルズ カンパニー、リミテッド | 三環式化合物及びその製造方法と使用 |
WO2023002984A1 (ja) * | 2021-07-20 | 2023-01-26 | 小野薬品工業株式会社 | イミダゾール化合物の製造方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6610562B2 (ja) | ジヒドロインドリジノン誘導体 | |
JP6992284B2 (ja) | ジヒドロインドリジノン誘導体を含有する医薬組成物 | |
JP7196931B2 (ja) | (3s)-3-[2-(6-アミノ-2-フルオロピリジン-3-イル)-4-フルオロ-1h-イミダゾール-5-イル]-7-[5-クロロ-2-(1h-テトラゾール-1-イル)フェニル]-2,3-ジヒドロインドリジン-5(1h)-オンの新規結晶 | |
JP2021521132A (ja) | 置換オキソピリジン誘導体 | |
WO2020059812A1 (ja) | 4-({(4s)-1-(4-カルバムイミドイルベンゾイル)-4-[4-(メチルスルホニル)ピペラジン-1-イル]-l-プロリル}アミノ)安息香酸の新規塩およびその新規結晶形 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15867764 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2016563720 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2970233 Country of ref document: CA Ref document number: 20177015619 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11201704708Q Country of ref document: SG Ref document number: 15534247 Country of ref document: US Ref document number: 12017501067 Country of ref document: PH Ref document number: MX/A/2017/007551 Country of ref document: MX Ref document number: 252777 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112017012146 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2017124150 Country of ref document: RU Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2015867764 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2015362422 Country of ref document: AU Date of ref document: 20151209 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112017012146 Country of ref document: BR Kind code of ref document: A2 Effective date: 20170608 |