WO2020111268A1 - （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 - Google Patents

（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 Download PDF

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Publication number
WO2020111268A1
WO2020111268A1 PCT/JP2019/046893 JP2019046893W WO2020111268A1 WO 2020111268 A1 WO2020111268 A1 WO 2020111268A1 JP 2019046893 W JP2019046893 W JP 2019046893W WO 2020111268 A1 WO2020111268 A1 WO 2020111268A1
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Prior art keywords
compound
fluoro
acid
chloro
phenyl
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PCT/JP2019/046893
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English (en)
French (fr)
Japanese (ja)
Inventor
貴之 藤戸
静香 小野
修平 大谷
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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Priority to BR112021010476-3A priority Critical patent/BR112021010476A2/pt
Priority to AU2019390094A priority patent/AU2019390094A1/en
Priority to KR1020217016005A priority patent/KR20210097119A/ko
Priority to EP19888537.8A priority patent/EP3888653A4/en
Priority to NZ776666A priority patent/NZ776666A/en
Priority to SG11202105697SA priority patent/SG11202105697SA/en
Priority to CN201980079268.XA priority patent/CN113226312A/zh
Priority to CA3121447A priority patent/CA3121447A1/en
Priority to MX2021006147A priority patent/MX2021006147A/es
Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Priority to US17/297,649 priority patent/US20210395250A1/en
Priority to JP2020557880A priority patent/JP7196931B2/ja
Publication of WO2020111268A1 publication Critical patent/WO2020111268A1/ja
Priority to IL283481A priority patent/IL283481A/en
Priority to PH12021551219A priority patent/PH12021551219A1/en
Priority to ZA2021/03692A priority patent/ZA202103692B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention provides (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-
  • the present invention relates to a new crystal of (1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one and the like.
  • thromboembolic disease thromboembolic disease
  • a thromboembolic disease occurs when a thrombus is formed at a site of a blood vessel injury, or when the thrombus is released and carried by the bloodstream into another blood vessel to block the blood vessel.
  • thromboembolic diseases include, for example, venous thromboembolism, which is a general term for deep vein thrombosis and pulmonary embolism, stroke, angina, myocardial infarction, and various arterial and venous thrombosis.
  • tissue factor expressed on the blood vessel wall due to the damage of blood vessel becomes the starting point of the blood coagulation cascade and forms a complex with blood coagulation factor VII, which is present in a trace amount in blood.
  • the complex activates blood coagulation factor IX and blood coagulation factor X, which activate prothrombin to thrombin.
  • Thrombin converts fibrinogen to fibrin, which eventually forms insoluble fibrin (early phase).
  • Thrombin produced in this process is thought to promote thrombus formation in the initiation phase and is considered to be important for hemostasis, while activating blood coagulation factor XI to activate activated blood coagulation factor XI (hereinafter also referred to as FXIa). It has been reported that thrombin is increased by causing explosive thrombin production (amplification phase) through the above (see Non-Patent Documents 1-3).
  • anticoagulant drugs are generally used for the treatment and/or prevention of thromboembolic diseases
  • existing anticoagulant drugs have excellent antithrombotic effects, but have serious side effects of bleeding complications. Is a problem, or it does not cause bleeding complications, so it is possible that the dose is limited and that it does not exert a sufficient antithrombotic effect.
  • a therapeutic and/or prophylactic agent for thrombosis and thromboembolism which has a new mechanism of action, that suppresses the growth or increase of pathological thrombus and does not affect the formation of hemostatic thrombus is needed.
  • FXIa has been attracting attention as one of the targets.
  • Blood coagulation factor XI is one of the plasma serine proteases involved in the regulation of blood coagulation and is activated by blood coagulation factor XII, thrombin, or by itself FXIa.
  • FXIa is one of the constituent factors of the blood coagulation pathway called an intrinsic system or a contact system in the classical blood coagulation cascade, and selectively cleaves the peptide bond between Arg-Ala and Arg-Val to Activates coagulation factor IX.
  • the safety of FXIa is supported by the observation in human blood coagulation factor XI deficiency called hemophilia C, which is mainly characterized by mild to moderate bleeding after surgery or trauma.
  • FXIa is a very attractive target with no side effect of bleeding in developing an antithrombotic therapeutic agent and/or preventive agent, and an FXIa inhibitor does not have undesirable side effects such as bleeding, It is expected to be a very powerful and safe antithrombotic therapeutic agent or preventive agent.
  • (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5- Chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one is a selective blood coagulation factor XIa inhibitor, which is effective for treating thromboembolic diseases and the like. It is described to be useful as a therapeutic agent.
  • the dihydrate although formed as crystals, had high hygroscopicity and low oral absorbability, as described later. For these reasons, it has been desired to obtain new drug substance forms (salts, solvates, co-crystals, etc.) that form crystals and are easy to handle as pharmaceuticals.
  • the object of the present invention is (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5- Chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one forms a crystal as a salt, solvate or co-crystal, and further has low hygroscopicity. And/or to provide a drug substance form having excellent oral absorbability.
  • the present inventors have conducted investigations to solve the above-mentioned problems, and have conducted studies on (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazole- 5-yl]-7-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one is among the many coformers It has been found to form crystals with certain coformers, namely ⁇ -resorcinic acid, gentisic acid, nicotinamide and 3-hydroxybenzoic acid.
  • the present invention provides the following embodiments, for example.
  • [2] The compound described in [1] above, which is in a crystalline form; [3] In the powder X-ray diffraction spectrum, about 9.4, about 14.1, about 15.8, about 16.5, about 17.4, about 18.4, about 20.6, and about 22.4.
  • the on-set temperature is about 214° C. or the exothermic peak temperature is about 215° C., and the crystalline form is [2] to [5] or [3-1] to [3-4. ]
  • [8] The compound according to any one of [1] to [7] or [3-1] to [3-4], which is a co-crystal; [9] A pharmaceutical composition containing the compound according to any one of [1] to [8] or [3-1] to [3-4]; [10] The pharmaceutical composition according to the above [9], which is a blood coagulation factor XIa inhibitor; [11] The pharmaceutical composition according to the above [9], which is a prophylactic and/or therapeutic agent for blood coagulation factor XIa-related diseases; [12] The pharmaceutical composition according to the above [11], wherein the blood coagulation factor XIa-related disease is a thromboembolic disease.
  • Thromboembolic disease is arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, arterial cerebral vascular thromboembolic disorder, venous cerebral vascular thromboembolic disorder, or heart chamber or peripheral circulation
  • the thromboembolic disease is thrombosis and/or caused by stroke, cerebral thrombosis, cerebral embolism, venous thrombosis, venous thromboembolism, deep vein thrombosis, or treatment in which blood is exposed to an artificial surface and/or
  • a thromboembolic disease which comprises administering to a mammal an effective amount of the compound according to any one of [1] to [8] or [3-1] to [3-4].
  • a method of preventing and/or treating [16] The compound according to any of the above [1] to [8] or [3-1] to [3-4], which is used for the prevention and/or treatment of thromboembolic diseases. [17] Use of the compound according to any one of [1] to [8] or [3-1] to [3-4] for the manufacture of a prophylactic and/or therapeutic agent for thromboembolic diseases; [18] A method for producing the compound according to any one of the above [1] to [8] or [3-1] to [3-4], characterized by using ethyl acetate in the production step; [19] The following structural formula;
  • the compound according to [20-1] which is a [20-2] crystal.
  • the crystal according to [20-2] which has at least two diffraction peaks at a diffraction angle (2 ⁇ ) of 0.4 degree.
  • powder X-ray diffraction spectrum about 9.4, about 13.3, about 14.1, about 14.7, about 15.1, about 15.8, about 16.5, about 17. 4, about 17.7, about 18.0, about 18.4, about 18.9, about 19.3, about 19.8, about 20.6, about 20.9, about 22.4, about 22. 8, about 23.2, about 24.2, about 25.0, about 25.5, about 25.8, about 26.3, about 27.2, about 27.6, about 27.9, about 28. 6,
  • the crystal according to [20-2] which has diffraction peaks at diffraction angles (2 ⁇ ) of about 29.5 and about 31.0 degrees.
  • [20-5] The crystal according to [20-2], which is characterized by the powder X-ray diffraction spectrum chart shown in FIG. [20-6]
  • [20-7] The crystal according to [20-6], which is characterized by the differential scanning calorimetry chart shown in FIG. 10.
  • [20-8] The compound described in [20-1], which is a co-crystal.
  • [20-10] A pharmaceutical composition comprising the compound according to [20-1] or the crystal according to [20-2].
  • the thromboembolic disease is arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, arterial cerebral vascular thromboembolic disorder, venous cerebral vascular thromboembolic disorder, or heart chamber or The pharmaceutical composition according to [20-13], which is a thromboembolic disorder in peripheral circulation.
  • the thromboembolic disease is thrombosis caused by stroke, cerebral thrombosis, cerebral embolism, venous thrombosis, venous thromboembolism, deep vein thrombosis, or treatment in which blood is exposed to an artificial surface, and The pharmaceutical composition according to [20-13], wherein the pharmaceutical composition is/or thromboembolism.
  • Compound A forms crystals and is useful as a drug substance with low hygroscopicity and/or excellent oral absorption.
  • the powder X-ray-diffraction spectrum chart of the compound of Example 1 (11) is represented (the vertical axis
  • the powder X-ray-diffraction spectrum chart of the compound of Example 2 is represented (the vertical axis
  • the powder X-ray-diffraction spectrum chart of the compound of Example 3 is represented (the vertical axis
  • the powder X-ray-diffraction spectrum chart of the compound of Example 4 is represented (the vertical axis
  • the powder X-ray-diffraction spectrum chart of the compound of Example 5 is shown (a vertical axis
  • the differential scanning calorimetry (DSC) chart of the compound of Example 1 (11) is shown (the vertical axis shows the heat flux (W/g), and the horizontal axis shows the temperature (°C)).
  • the differential scanning calorimetry (DSC) chart of the compound of Example 2 is shown (the vertical axis represents the heat flux (W/g), and the horizontal axis represents the temperature (°C)).
  • the differential scanning calorimetry (DSC) chart of the compound of Example 3 is shown (the vertical axis represents heat flux (W/g), and the horizontal axis represents temperature (°C)).
  • the differential scanning calorimetry (DSC) chart of the compound of Example 4 is shown (the vertical axis shows the heat flux (W/g), and the horizontal axis shows the temperature (°C)).
  • the differential scanning calorimetry (DSC) chart of the compound of Example 5 is shown (the vertical axis represents heat flux (W/g), and the horizontal axis represents temperature (°C)).
  • thermogravimetric measurement (TG) chart of the compound of Example 1 (11) is shown (the horizontal axis represents the rate of change of weight (Weight (%)) in the vertical axis, and the horizontal axis represents the temperature (Temperature (°C)). Represent.).
  • the thermogravimetric (TG) chart of the compound of Example 2 is shown (the horizontal axis represents the rate of change in weight (Weight (%)) on the vertical axis, and the horizontal axis represents the temperature (Temperature (°C))). ..
  • thermogravimetric measurement (TG) chart of the compound of Example 3 is shown (the horizontal axis shows the rate of change in weight (Weight (%)) on the vertical axis, and the horizontal axis shows the temperature (Temperature (°C))). ..
  • the thermogravimetric measurement (TG) chart of the compound of Example 4 is shown (the horizontal axis represents the rate of change of weight (Weight (%)) in the vertical axis, and the horizontal axis represents the temperature (Temperature (°C))). ..
  • the thermogravimetric measurement (TG) chart of the compound of Example 5 is shown (the horizontal axis represents the rate of change in weight (Weight (%)), the horizontal axis represents temperature (Temperature (°C))). ..
  • (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one has the following structural formula
  • the compound represented by the above structural formula is (3S)-3-[2-(6-amino-2-fluoro-3-pyridinyl) as described in Example 2 (10) of Patent Document 1. )-4-Fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydro-5(1H)-indolidinone You can also do it.
  • (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one-3-hydroxybenzoic acid (1/1) is represented by the following structural formula
  • the compound A has a form such as an adduct.
  • An adduct is formed by directly binding (adding) two different molecules (A) and (B) in such a manner that the properties of the bond have changed but neither molecule has an increase or decrease in atoms.
  • Additives include salts and co-crystals.
  • Compound A is (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5- in one embodiment. It is an adduct of chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one with 3-hydroxybenzoic acid.
  • Compound A is (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5- in one embodiment. It is a co-crystal of chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one and 3-hydroxybenzoic acid.
  • Compound A is characterized by at least one physicochemical data in (a) and (b) below. Preferably, it is characterized by both physicochemical data (a) and (b).
  • (A) (i) powder X-ray diffraction spectrum shown in FIG.
  • Compound A may have one or more atoms substituted with an isotope, and isotope-labeled Compound A, for example, Compound A incorporating a radioisotope can be used in studies of tissue distribution of drugs and/or substrates. It is useful. Examples of the isotope include 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I, 125 I and the like can be mentioned.
  • Compound A has a strong FXIa inhibitory activity. Therefore, the compound of the present invention is a thromboembolic disease, for example, arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, arterial cerebral vascular thromboembolic disorder, venous cerebral vascular thromboembolic disorder, and It is useful for the prevention and/or treatment of thromboembolic disorders in the heart chamber or peripheral circulation.
  • thromboembolic disease for example, arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, arterial cerebral vascular thromboembolic disorder, venous cerebral vascular thromboembolic disorder, and It is 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 thrombosis, unstable angina and ischemic complications of non-Q-wave myocardial infarction, medically ST elevation and/or non-ST elevation acute myocardial infarction with controlled or percutaneous coronary intervention, angina such as stable (working) angina, atypical angina, unstable angina Cardiomyopathy, myocardial infarction (first myocardial infarction or recurrent myocardial infarction, etc.), acute myocardial infarction, revascularization and stenosis after coronary artery bypass surgery, percutaneous transluminal angioplasty, cardiac/transcoronary stent placement Examples include re-occlusion and stenosis or sudden ischemic death after thrombolytic therapy for coronary arteries.
  • venous cardiovascular thromboembolic disease for example, in major general surgery, abdominal surgery, hip replacement, knee replacement, hip fracture surgery, multiple fractures, multiple trauma, trauma, spinal cord injury, burns, Alternatively, deep vein thrombosis (DVT) and/or pulmonary embolism (PE) upon admission to a critical care room, DVT and/or PE in patients with acute medical disorders with significantly restricted physical activity, DVT in patients undergoing cancer chemotherapy / Or PE, DVT in stroke patients and/or PE, symptomatic or asymptomatic DVT with or without PE, and the like.
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • the arterial cerebral blood vessel thromboembolic disorder for example, stroke, ischemic stroke, acute stroke, stroke in non-valvular atrial fibrillation or valvular atrial fibrillation patients, cerebral artery thrombosis, cerebral infarction, Transient cerebral ischemic attack (TIA), lacunar infarction, atherosclerotic cerebral infarction, Branchatheromatous disease (BAD), cerebral artery embolism, cerebral thrombosis, cerebrovascular disorder, asymptomatic cerebral infarction or cerebrovascular cognition And the like.
  • TIA Transient cerebral ischemic attack
  • BAD Branchatheromatous disease
  • cerebral artery embolism cerebral thrombosis
  • cerebrovascular disorder asymptomatic cerebral infarction or cerebrovascular cognition And the like.
  • Examples of venous cerebral vascular thromboembolic disorders include intracranial venous thrombosis, cerebral embolism, cerebral thrombosis, cerebral venous sinus thrombosis, intracranial venous sinus thrombosis or cavernous sinus thrombosis.
  • Thromboembolic disorders 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 (DIC), sepsis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease, antiphospholipid antibody syndrome, hepatic embolism, central hepatic vein occlusion (VOD), renal embolism, renal vein thrombosis, renal artery occlusion, refractory nephrosis due to membranous nephropathy or focal glomerulosclerosis, splenic vein thrombosis, superior mesenteric artery occlusion, portal vein thrombosis , Retinal vein occlusion, atherosclerosis, atherosclerosis, peripheral
  • the thromboembolic disease is preferably coronary artery disease, unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction (first myocardial infarction or recurrent myocardial infarction, etc.), sudden ischemic death, transient cerebral ischemia.
  • Stroke 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, renal embolism, portal vein thrombosis, pulmonary embolism, pulmonary infarction, hepatic embolism, central venous occlusion (VOD)/sinusoidal obstruction syndrome (SOS), thrombotic microangiopathy (TMA), disseminated intravascular coagulation (DIC), sepsis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), antiphospholipid antibody syndrome, thrombosis resulting from coronary artery bypass graft (graft) surgery or Examples thereof include thrombosis caused by a treatment in which blood is exposed to the surface of an artifact (medical implant, medical device, catheter, stent,
  • Atrial fibrillation, atherosclerosis or sepsis includes thromboembolic diseases caused by atrial fibrillation, atherosclerosis or sepsis.
  • thromboembolic disease stroke, cerebral thrombosis, cerebral embolism, venous thrombosis, venous thromboembolism, deep venous thrombosis, or thrombosis caused by treatment in which blood is exposed to an artificial surface and/or Or thromboembolism may be mentioned.
  • 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, treatment of deep vein thrombosis and pulmonary thromboembolism and/or suppression of recurrence, lower limb orthopedic surgery (total knee arthroplasty, total hip arthroplasty or hip fracture, etc.) Suppression of onset of VTE in patients undergoing surgery, suppression of onset of DVT and/or PE in patients with acute medical disease whose physical activity is significantly limited, suppression of onset of VTE in patients undergoing abdominal surgery and/or after surgery, cancer chemistry Inhibition of DVT and/or PE in patients undergoing therapy is included.
  • ischemic stroke For the prevention and/or treatment of ischemic stroke, suppression and/or treatment of ischemic stroke and systemic embolism in non-valvular atrial fibrillation patients, and embolic stroke (ESUS) patients in which the source of embolism cannot be identified
  • Suppression and/or treatment of recurrent stroke and systemic embolism suppression and/or treatment of ischemic stroke and systemic embolism in patients with atrial fibrillation complicated with acute coronary syndrome (ACS), chronic kidney disease (CKD) or the prevention and/or treatment of ischemic stroke and systemic embolism in patients with atrial fibrillation with end-stage renal failure, the suppression and/or treatment of recurrent Branch atheromatous disease (BAD), and the ischemic stroke (cardiogenic) Recurrence suppression and/or treatment after (except for cerebral embolism).
  • ACS acute coronary syndrome
  • CKD chronic kidney disease
  • BAD recurrent Branch atheromatous disease
  • BAD ischemic stroke (cardiogenic) Recurrence suppression
  • the prevention and/or treatment of thromboembolic diseases caused by the treatment in which blood is exposed to the surface of an artifact that promotes thrombus formation includes the prevention and/or treatment of thromboembolic diseases in patients undergoing artificial valve replacement and transplantation. And/or treatment of thromboembolic disease in patients with auxiliary artificial hearts such as implantable type, total replacement type, percutaneous type, or external type, prevention and/or treatment of thromboembolic disease in patients with coronary artery stent implantation Is included.
  • ACS acute coronary syndrome
  • ACS acute coronary syndrome
  • peripheral artery disease suppression of cardiovascular events in patients with acute coronary syndrome
  • ACS suppression of cardiovascular events in patients with coronary artery disease or peripheral artery disease
  • Suppression of cardiovascular events in diabetic patients (and more preferably type 2 diabetic patients) at high cardiovascular risk is included.
  • compound A since compound A has a plasma kallikrein inhibitory action, it is useful for the prevention and/or treatment of diseases associated with plasma kallikrein.
  • diseases involving plasma kallikrein include, for example, retinopathy, diabetic retinopathy, hypertensive retinopathy, proliferative and non-proliferative retinopathy, age-related macular degeneration (AMD), and/or treatment of hematoma.
  • AMD age-related macular degeneration
  • HAE hereditary angioedema
  • DME diabetic macular edema
  • CSME clinically significant macular edema
  • CME cystoid macular edema
  • retina Edema glial-related edema, cerebral edema, lymphedema, angioedema, traumatic brain injury, hemorrhagic stroke, intracerebral hemorrhage, cerebral aneurysm, arteriovenous malformation, spinal cord injury, ischemia-reperfusion injury, ischemia, brain dysfunction Blood, pain, disorders with inflammatory components, encephalitis, multiple sclerosis, pruritus, arthritis, inflammatory bowel disease, gout, psoriasis, astrocyte activation-related diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis , Creutzfeldt-Jakob disease, epilepsy, essential hypertension
  • the disease involving plasma kallikrein is preferably edema-related disease, inherited angioedema, macular edema, cerebral edema, retinopathy, edema formation associated with ischemia-reperfusion injury, during surgery such as cardiopulmonary bypass or coronary artery bypass grafting. Blood loss is included.
  • the compound of the present invention is used as a single agent but also, for example, (1) Complementation and/or enhancement of its preventive, therapeutic and/or symptom improving effect, In order to (2) improve its kinetics/absorption, reduce the dose, and/or (3) reduce its side effects, it may be used in combination with other active ingredients such as the drugs listed below. ..
  • examples of the drug used in combination with compound A include anticoagulants, antiplatelets, thrombolytic agents, fibrinolytic agents, serine protease inhibition. Agents, elastase inhibitors, steroids or combinations thereof and the like.
  • thrombin inhibitors As anticoagulants, thrombin inhibitors, antithrombin III activators, heparin cofactor II activators, other FXIa inhibitors, plasma and/or tissue kallikrein inhibitors, plasminogen activator inhibitors (PAI-1) inhibitors Agent, thrombin activation fibrinolysis inhibitor (TAFI) inhibitor, factor VIIa inhibitor, factor VIIIa inhibitor, factor IXa inhibitor, factor Xa inhibitor, factor XIIa inhibitor, or a combination thereof Is mentioned.
  • PAI-1 plasminogen activator inhibitors
  • TAFI thrombin activation fibrinolysis inhibitor
  • factor VIIa inhibitor As anticoagulants, thrombin inhibitors, antithrombin III activators, heparin cofactor II activators, other FXIa inhibitors, plasma and/or tissue kallikrein inhibitors, plasminogen activator inhibitors (PAI-1) inhibitors Agent, thrombin activation fibrinolysis inhibitor (TAFI) inhibitor, factor VIIa inhibitor
  • a GPII/IIIa blocker As an antiplatelet agent, a GPII/IIIa blocker, a protease activated receptor (PAR-1) antagonist, a PAR-4 antagonist, a phosphodiesterase III inhibitor, another phosphodiesterase inhibitor, a P2X1 antagonist, a P2Y1 receptor antagonist, a P2Y12 antagonist, 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) Antagonists, GAS6 antagonists, aspirin, or combinations thereof and the like.
  • PAR-1 protease activated receptor
  • PAR-4 antagonist As an antiplatelet agent, a GPII/IIIa blocker, a protease activated receptor (PAR-1) antagonist, a PAR-4 antagonist, a
  • the drug used in combination with Compound A is preferably an antiplatelet agent.
  • Preferred antiplatelet agents include clopidogrel, prasugrel, ticagrelol, cangrelor, erynogrel, cilostazol, sarpogrelate, iloprost, beraprost, limaprost and/or aspirin, or a combination thereof.
  • the drug used in combination with Compound A is preferably warfarin, unfractionated heparin, low molecular weight heparin, enoxaparin, dalteparin, bemiparin, tinzaparin, semuloparin sodium (AVE-5026), danapaloid, synthetic pentasaccharide, fondaparinux, Hirudin, Disulfatohirudin, Lepirudin, Bivalirudin, Decyludine, Argatroban, Aspirin, Ibuprofen, Naproxen, Sulindac, Indomethacin, Mefenamate, Droxicam, Diclofenac, Sulfinpyrazone, Piroxicam, Ticlopiridine, Clopidogrel, Prasugrelol, Ticagrelor, Ticagrelor, Ticagrelor, Ticagrelor, Ticagrelor.
  • the drug used in combination with Compound A includes, for example, potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchange transporter inhibitors, antiarrhythmic agents, antiarteriosclerotic agents.
  • Agents anti-inflammatory agents, antioxidants, angiogenesis modulators, osteoporosis therapeutic agents, hormone replacement therapy, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, anxiolytics, antipsychotics, antiproliferatives , Anti-tumor agents, anti-ulcer and gastroesophageal reflux agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infect
  • the drug used in combination with the compound A includes, for example, an antiarrhythmic drug, an antihypertensive drug, an anticoagulant drug, an antiplatelet drug, a thrombolytic drug, a fibrinolytic drug, a calcium channel blocker,
  • an antiarrhythmic drug for example, an antiarrhythmic drug, an antihypertensive drug, an anticoagulant drug, an antiplatelet drug, a thrombolytic drug, a fibrinolytic drug, a calcium channel blocker
  • examples include potassium channel blockers, 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 drug used in combination with Compound A is an antiplatelet agent or a combination thereof.
  • the drug to be used in combination with Compound A may be administered in the form of a combination drug containing both components in one preparation, or may be in the form of separate preparations administered by the same administration route or different administration routes. .. When separate formulations are administered, they need not necessarily be administered simultaneously, and administration may be staggered as necessary. In addition, when there is a time lag in administration, the order of administration is not particularly limited and may be appropriately adjusted so as to obtain the desired drug effect.
  • the dose of these other drugs used in combination with Compound A can be appropriately increased or decreased based on the clinically used dose of the drug or a similar drug.
  • the compounding ratio of the compound of the present invention and the other drug 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. Further, the other drug may be a drug having the same mechanism as that other than those listed above. Such drugs include those that have been found to date, as well as those that will be found in the future.
  • Compound A is usually administered systemically or locally in oral or parenteral form.
  • oral preparation examples include liquid preparations for oral administration (eg, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for oral administration (eg, tablets (sublingual tablets, buccal tablets) Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, troches) and the like.
  • parenteral agents include liquids (for example, injections (intravitreal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip, etc.), eye drops (for example, aqueous solution).
  • 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 eg, , Ointments (eye ointments, etc.), ear drops and the like.
  • These preparations may be release controlling agents such as immediate release preparations and sustained release preparations.
  • These preparations can be produced by a known method, for example, the method described in the Japanese Pharmacopoeia.
  • a liquid preparation for oral use as an oral preparation is produced, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (eg, purified water, ethanol or a mixed solution thereof).
  • this liquid agent may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent and the like.
  • the solid preparation for oral administration 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, hydroxypropyl cellulose, polyvinylpyrrolidone, aluminometasilicate).
  • an excipient for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.
  • a binder for example, hydroxypropyl cellulose, polyvinylpyrrolidone, aluminometasilicate.
  • Magnesium acid etc. disintegrating agent
  • lubricant eg magnesium stearate etc.
  • stabilizer dissolution aid
  • dissolution aid glutamic acid, aspartic acid etc.
  • a coating agent for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • the external preparation as a parenteral preparation is manufactured by a known method or a commonly used formulation.
  • an ointment is produced by grinding or melting the active ingredient in a base.
  • the ointment base is selected from known or commonly used ointment bases.
  • higher fatty acids or higher fatty acid esters eg, 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 Eg, beeswax, spermaceti, ceresin, etc.
  • surfactant eg, polyoxyethylene alkyl ether phosphate, etc.
  • higher alcohol eg, cetanol, stearyl alcohol, cetostearyl alcohol, etc.
  • silicone oil eg, Dimethyl polysiloxane etc.
  • hydrocarbons eg hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin etc.
  • glycols eg ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol etc.
  • vegetable oils eg , Castor
  • Parenteral injections include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use.
  • the injection is used, for example, by dissolving, suspending or emulsifying the 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 the like, and combinations thereof are used.
  • this injection contains stabilizers, solubilizers (eg glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. Good.
  • an aseptic solid agent for example, a freeze-dried product, and use it by dissolving it in aseptic or aseptic distilled water for injection or other solvent before use.
  • Compound A or Compound A and another drug are usually administered systemically or locally, orally or parenterally.
  • the dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once per adult in the range of 1 ng to 1000 mg once a day. Alternatively, it may be parenterally administered once per day in the range of 0.1 ng to 10 mg once per adult, or continuously in the range of 1 hour to 24 hours per day.
  • a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases.
  • (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one, or a salt, solvate, co-crystal or the like thereof can be obtained according to, for example, the Examples described below or these. It can be manufactured according to the method. Note that the seed crystal may or may not be used when performing recrystallization.
  • Solvents in parentheses shown in the chromatographic separation and TLC indicate the elution solvent or developing solvent used, and the ratios indicate volume ratios.
  • the solvent in the parentheses shown in the NMR part indicates the solvent used for the measurement.
  • the compound name used in the present specification is generally a computer program for naming according to the rules of IUPAC, ACD/Name (registered trademark) of Advanced Chemistry Development, or is named according to the IUPAC nomenclature. It is a thing.
  • Example 1 6-Fluoro-5-iodo-2-pyridinamine N-iodosuccinimide (56.5 g) was cooled with ice to give 6-fluoro-2-pyridinamine (25.6 g) N,N-dimethylformamide ( 200 mL) was added to the solution in divided portions (3 times). After stirring at room temperature for 3 hours, city water (0.5 L) was added to the reaction solution. Extracted 3 times with ethyl acetate/hexane (1/1, 300 mL), and the organic layer was saturated aqueous sulfite solution (0.5 L), saturated aqueous sodium carbonate solution (0.5 L, twice), city water (0.5 L), saturated saline solution.
  • Example 1(2) Bis(2-methyl-2-propanyl)(6-fluoro-5-iodo-2-pyridinyl) imidodicarbonate
  • Compounds (36.7g) and 4 prepared in Example 1(1) A solution of di-tert-butyldicarbonate (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.
  • 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 obtained 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 1(5) 2-Methyl-2-propanyl (5- carbamimidoyl -6-fluoro-2-pyridinyl)carbamate acetate Salt of the compound (1.93 g) prepared in Example 1(4) in acetic acid (10 mL) ) Acetic anhydride (0.75 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. Palladium (II) hydroxide (20%, 250 mg) was added to the reaction solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude title compound (2.99 g) having the following physical data. LC / MS t R 0.59 min; MS (ES +) m / z 255 (M + H) ( condition a).
  • Example 1(6) 2-Methyl-2-propanyl (5-carbamimidoyl-6-fluoro-2-pyridinyl)carbamate hydrochloride
  • a 10% hydrogen chloride/methanol (6.5 mL) solution was added to the solution, and the mixture was stirred at room temperature for 10 minutes.
  • Toluene was added to the reaction mixture and the mixture was concentrated to give the crude title compound (2.63 g) having the following physical data.
  • Example 1(7) (3S)-3-(chloroacetyl)-7-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydro-5(1H)- Indolidinone (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 WO 2013/093484 pamphlet
  • dichloromethane 15 mL
  • 1-chloro-N,N,2-trimethyl-1-propene-1- Amine (1.33 mL) was added under ice cooling, and the mixture was stirred at 0°C for 40 minutes.
  • Trimethylsilyldiazomethane (2M hexane solution, 8.4 mL) was added, and the mixture was further stirred at 0° C. for 1 hr.
  • Concentrated hydrochloric acid (0.87 mL) was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes.
  • Example 1(8) 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
  • Compound (1.5 g) prepared in Example 1(6) and Example 1(7) Potassium carbonate (0.70 g) was added to a solution of the compound (1.0 g) produced in 1. 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.
  • the retention times of the title compound upon optical resolution under the above conditions were 13 minutes (S-form compound of Example 1(9)) and 9.5 minutes (R-form compound of Example 1(9)), respectively. there were.
  • Example 1 (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
  • Example 1 The compound (100 mg) of Example 1 (10) was dissolved in acetonitrile (1.0 mL) and water (0.018 mL) at 75° C. by heating, and then the mixture was stirred at 40° C. for 2 hours and at room temperature for 30 minutes to produce a product. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (76 mg).
  • the R-form compound of Example 1(9) The same operation as in Example 1(10) was performed using to obtain the title compound having the following physical properties.
  • Example 1 (13) (3R)-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 1(12) was used.
  • the same operation as in Example 1 (11) was performed using to obtain the title compound having the following physical properties.
  • the crystallization method three conditions of the slurry method (25°C and 40°C), the precipitation method (room temperature deposition), and the evaporative concentration method (40°C or 80°C heating, room temperature evaporation) are set, and the solvent/crystallization method is combined Then, 576 crystallization conditions were set for each salt.
  • Example 1 (13) As a result of this examination, only dihydrate (Example 1 (13)) was obtained as a crystal with good crystallinity as Example 1 (12). From this data, even in the compound of Example 1(10), which is this enantiomer, the only crystal having good crystallinity is the dihydrate (Example 1(11)). Since the compound has high hygroscopicity and low oral absorption as described later, it was found that the compound cannot be selected as it is as a drug substance for a drug. Since crystals that meet the problem could not be obtained by the above-described salt and free form studies, further crystallization studies of the co-crystal of the compound of Example 1 (10) were performed as follows.
  • Example 1 Using the compound of Example 1 (13), the possibility of crystallization of a co-crystal was examined.
  • 60 types of reagents oxalic acid, fumaric acid, adipic acid, L-tartaric acid, D-tartaric acid, benzoic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid , 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, saccharin, orotic acid, 1-hydroxy-2-naphthoic acid, L-pyro Glutamic acid, D-pyroglutamic acid, benzamide, ethyl maltol, nicotinamide, glycolic acid, sorbic acid, L-camphoric acid, D-camphoric acid, urea, taurine, malonic acid, L-mandelic acid, D-man
  • Example 2 (3R)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one- ⁇ -resorcinic acid (2/1) ⁇ -Resorcinic acid (2.83 mg) and acetonitrile (100 ⁇ L) were added to the compound (20 mg) of Example 1 (13), and the mixture was stirred at 25° C. for 1 day. The resulting precipitate was collected by filtration and dried in a fume hood to give crystals of the title compound having the following physical properties.
  • Example 3 (3R)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one-gentisic acid (2/1)
  • gentisic acid (2.83 mg)
  • acetonitrile 100 ⁇ L
  • Example 4 (3S)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one-nicotinamide (2/1)
  • the compound (500 mg) of Example 1 (11) was mixed with nicotinamide (56.1 mg) and acetonitrile (5 mL), and the mixture was stirred at 25°C for 1 day. The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (465 mg) having the following physical data.
  • Example 1 The compound (500 mg) of Example 1 (11) was mixed with 3-hydroxybenzoic acid (127.0 mg) and ethyl acetate (5 mL), and the mixture was stirred at 25°C for 1 day. The resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (529 mg) having the following physical data.
  • Example 6 (3R)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one-3-hydroxybenzoic acid (2/1)
  • the compound of Example 1 (12) (500 mg) was mixed with 3-hydroxybenzoic acid (63.5 mg) and acetonitrile (5 mL), and the mixture was stirred at 25°C for 1 day. The formed precipitate was collected by filtration and dried under reduced pressure to give the title compound (508 mg) having the following physical data.
  • the diffraction angle (2 ⁇ ) and the overall pattern are important in recognizing the crystal identity, and the relative intensity is the crystal growth direction and particle size. , It may be changed depending on the measurement conditions. Also in the DSC data, the overall pattern is important in recognizing the identity of crystals, and may slightly change depending on the measurement conditions. Therefore, in the compound of the present invention, those having a pattern similar to that of the powder X-ray diffraction spectrum or DSC in total are included in the compound of the present invention.
  • the description of the diffraction angle (2 ⁇ (degree)) in the powder X-ray diffraction pattern and the temperature (° C.) in the DSC analysis means that the error range usually accepted in the data measurement method is included, and is approximately It is the diffraction angle and the temperature.
  • the “about” or “substantially the same” of the diffraction angle (2 ⁇ (degree)) in powder X-ray diffraction is ⁇ 0.2 degrees in one embodiment, and ⁇ 0. It is once.
  • “About” of the onset temperature (° C.) and the endothermic peak temperature (° C.) in the DSC analysis is ⁇ 10° C. in one embodiment, ⁇ 5° C. in another embodiment, and ⁇ in another embodiment. 2°C.
  • the powder X-ray diffraction spectrum shown in FIG. the powder X-ray diffraction spectrum shown in FIG.
  • the diffraction angle (2 ⁇ ) and relative intensity shown in Table 2 are shown.
  • Example 2 (3R)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-
  • the data powder X-ray diffraction spectrum of (1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one- ⁇ -resorcinic acid (2/1) is shown in FIG.
  • the powder X-ray diffraction spectrum, the diffraction angle (2 ⁇ ) and the relative intensity shown in Table 3 are shown.
  • the differential scanning calorimetry as shown in the chart in FIG.
  • thermogravimetric measurement as shown in the chart of FIG. 12, a weight loss of about 1.1% was exhibited from about room temperature to about 63° C.
  • Example 3 (3R)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one-gentisic acid (2/1)
  • Data Powder X-ray diffraction spectrum shows powder X shown in FIG.
  • the line diffraction spectrum, the diffraction angle (2 ⁇ ) and the relative intensity shown in Table 4 are shown.
  • a broad endotherm in the range of about room temperature to about 100° C. and an endotherm and an exotherm from about 155° C. were exhibited.
  • thermogravimetric measurement as shown in the chart of FIG. 13, a weight loss of about 1.0% was exhibited from about room temperature to about 56°C.
  • Example 4 (3S)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2- (1H-Tetrazol-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one-nicotinamide (2/1) in the data powder X-ray diffraction spectrum, powder X shown in FIG. The line diffraction spectrum, the diffraction angle (2 ⁇ ) and the relative intensity shown in Table 5 are shown. In the differential scanning calorimetry, as shown in the chart in FIG. 9, it showed endotherm and heat generation from about 144° C. In the thermogravimetric measurement, as shown in the chart of FIG. 14, a weight loss of about 0.4% (less than 1%) was exhibited from about room temperature to about 65° C.
  • Example 5 (3S)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-
  • Data powder X-ray diffraction spectrum of (1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one-3-hydroxybenzoic acid (1/1) is shown in FIG.
  • the powder X-ray diffraction spectrum, the diffraction angle (2 ⁇ ) and the relative intensity shown in Table 6 are shown.
  • heat generation was observed in the range of about 200° C. to about 234° C.
  • the onset temperature was 213.6°C and the exothermic peak temperature was 214.7°C.
  • thermogravimetric measurement as shown in the chart of FIG. 15, no weight reduction was observed from about room temperature to about 156° C.
  • the collected liquid was filtered with a filter, and the filtrate was diluted with acetonitrile twice.
  • the diluted solution of artificial intestinal fluid was centrifuged at 3000 rpm for 5 minutes, and the supernatant was used as a sample solution.
  • the dilution itself was used as a sample solution, and the solubility was calculated by a high performance liquid chromatography method.
  • the solubility of the compound of Example 1 (11) in pharmacopoeia I is 41 ⁇ g/mL, and the solubilities of the compounds of Examples 4 and 5 in pharmacopoeia I are 77 ⁇ g/mL and 75 ⁇ g/mL, respectively. there were.
  • the solubility of the compound of Example 1 (11) in artificial intestinal fluid was 47 ⁇ g/mL, and the solubility of the co-crystals of the compounds of Examples 4 and 5 in artificial intestinal fluid was 60 ⁇ g/mL.
  • Example 1 (11), Example 4 and Example 5 were prepared.
  • the suspension was adjusted to 0.33 mg/mL (as free base) with a 0.5% aqueous methyl cellulose solution.
  • Each suspension was forcibly administered intragastrically using a sonde to a monkey (cynomolgus monkey/male) that had been fasted from the previous day.
  • the dose was adjusted to 1 mg/kg according to the monkey body weight. 0.25, 0.5, 1, 2, 4, 7, and 24 hours after the administration of the suspension (medicine solution), blood was injected from the cephalic vein (tosokuhijomyaku) using a heparin-added syringe. 5 mL was collected.
  • the collected blood was centrifuged at 10,000 G for 5 minutes to collect plasma.
  • the oral absorption rate (%) was calculated by multiplying the value obtained by dividing the AUC (area under the blood concentration-time curve) at the time of oral administration by the AUC at the time of intravenous administration by 100.
  • LC/MS/MS The analysis by LC/MS/MS was performed under the following conditions.
  • Measuring device API-5000 (manufactured by Applied Biosystems/MDS SCIEX)
  • Analytical column Cadenza CD-C18 (2.0 mm ID ⁇ 100 mm, 3 ⁇ m)
  • Flow rate 0.4 mL/min
  • Mobile phase component 0.1% formic acid aqueous solution/acetonitrile (0 min: 65/35, 4.0 min: 65/35, 4.1 min: 10/90, 5.0 min: 10/90, 5.1 minutes: 65/35, 7.0 minutes: 65/35)
  • Scan type MRM (Multiple Reaction Monitoring) Polarity: Positive
  • Formulation Example 1 Compound A 5 mg-containing tablet The following components were admixed in a conventional method and punched out to give 10,000 tablets each containing 5 mg of active ingredient. .(3S)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-(1H- Tetrazol-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one-3-hydroxybenzoic acid (1/1): 50 g ⁇ Carboxymethyl cellulose calcium (disintegrant): 20 g ⁇ Magnesium stearate (lubricant): 10 g ⁇ Microcrystalline cellulose: 920 g
  • Formulation Example 2 Injection containing Compound A (20 mg) The following components are mixed by a conventional method, the solution is sterilized by a conventional method, 5 mL each is filled in an ampoule, and lyophilized by a conventional method, and 20 mg of the active ingredient is contained in one ampoule. Obtain 10,000 ampoules.
  • Compound A has very strong blood coagulation factor XIa inhibitory activity, excellent hygroscopicity, and excellent oral absorption, and is very useful as a drug substance for pharmaceuticals.

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PCT/JP2019/046893 2018-11-30 2019-11-29 （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 Ceased WO2020111268A1 (ja)

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MX2021006147A MX2021006147A (es) 2018-11-30 2019-11-29 Nuevo cristal de (3s)-3-[2-(6-amino-2-fluoropiridin-3-il)-4-fluoro -1h-imidazol-5-il]-7-[5-cloro-2-(1h-tetrazol-1-il)fenil]-2,3-dihi droindolizin-5(1h)-ona.
KR1020217016005A KR20210097119A (ko) 2018-11-30 2019-11-29 (3s)-3-[2-(6-아미노-2-플루오로피리딘-3-일)-4-플루오로-1h-이미다졸-5-일]-7-[5-클로로-2-(1h-테트라졸-1-일)페닐]-2,3-디히드로인돌리진-5(1h)-온의 신규 결정
EP19888537.8A EP3888653A4 (en) 2018-11-30 2019-11-29 NOVEL CRYSTAL OF (3S)-3-[2-(6-AMINO-2-FLUOROPYRIDIN-3-YL)-4-FLUORO-1H-IMIDAZOLE-5-YL]-7-[5-CHLORO-2-(1H -TETRAZOLE-1-YL)PHENYL]-2,3-DIHYDROINDOLIZINE-5(1H)-ONE
NZ776666A NZ776666A (en) 2018-11-30 2019-11-29 Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1h-imidazol-5-yl]-7-[5-chloro-2-(1h-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1h)-one
SG11202105697SA SG11202105697SA (en) 2018-11-30 2019-11-29 Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1h)-one
CN201980079268.XA CN113226312A (zh) 2018-11-30 2019-11-29 (3s)-3-[2-(6-氨基-2-氟吡啶-3-基)-4-氟-1h-咪唑-5-基]-7-[5-氯-2-(1h-四唑-1-基)苯基]-2,3-二氢吲哚嗪-5(1h)-酮的新型晶体
CA3121447A CA3121447A1 (en) 2018-11-30 2019-11-29 Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1h-imidazol-5-yl]-7-[5-chloro-2-(1h-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1h)-one
BR112021010476-3A BR112021010476A2 (pt) 2018-11-30 2019-11-29 Novo cristal de (3s)-3-[2-(6-amino-2-fluoropiridin-3-il)-4-fluoro-1h-imidazol-5-il]-7-[5-cloro-2-(1h-tetrazol-1-il)fenil]-2,3-dihidroindolizin-5(1h)-ona
US17/297,649 US20210395250A1 (en) 2018-11-30 2019-11-29 Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1h-imidazol-5-yl]-7-[5-chloro-2-(1h-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1h)-one
AU2019390094A AU2019390094A1 (en) 2018-11-30 2019-11-29 Novel crystal of (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1h)-one
JP2020557880A JP7196931B2 (ja) 2018-11-30 2019-11-29 （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
IL283481A IL283481A (en) 2018-11-30 2021-05-26 A new crystal of (3s)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1h-imidazol-5-yl]-7-[5-chloro-2-(1h -tetrazol-1-yl)phenyl]-3,2-dihydroindolizin-5(1h)-one
PH12021551219A PH12021551219A1 (en) 2018-11-30 2021-05-27 Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1himidazol- 5-yl]-7-[5-chloro-2-(1h-tetrazol-1-yl)phenyl]-2,3- dihydroindolizin-5(1h)-one
ZA2021/03692A ZA202103692B (en) 2018-11-30 2021-05-28 Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1h)-one

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022125869A1 (en) * 2020-12-11 2022-06-16 Board Of Regents, The University Of Texas System Compositions and methods of making cocrystals using dielectric heating with dispersive and distributive mixing
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 (1)

* Cited by examiner, † Cited by third party
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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 (3)

* Cited by examiner, † Cited by third party
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
WO2016093285A1 (ja) 2014-12-10 2016-06-16 小野薬品工業株式会社 ジヒドロインドリジノン誘導体
JP2017218449A (ja) * 2016-06-06 2017-12-14 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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016093285A (ja) 2014-11-13 2016-05-26 株式会社ユニバーサルエンターテインメント 遊技機

Patent Citations (4)

* Cited by examiner, † Cited by third party
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
JP2015500868A (ja) * 2011-12-21 2015-01-08 小野薬品工業株式会社 第ＸＩａ因子阻害剤としての新規ピリジノンおよびピリミジノン誘導体
WO2016093285A1 (ja) 2014-12-10 2016-06-16 小野薬品工業株式会社 ジヒドロインドリジノン誘導体
JP2017218449A (ja) * 2016-06-06 2017-12-14 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

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BIOLOGICAL & PHARMACEUTICAL BULLETIN, vol. 34, 2011, pages 401 - 407
BLOOD COAGULATION AND FIBRINOLYSIS, vol. 17, 2006, pages 251 - 257
BLOOD, vol. 102, 2003, pages 953 - 955
BLOOD, vol. 113, 2009, pages 936 - 944
BLOOD, vol. 119, 2012, pages 2401 - 2408
DOLOMANOV, O.VBOURHIS, L.J.GILDEA, R.JHAWARD, J.A.K.PUSCHMANN, H., J. APPL. C YST., vol. 42, 2009, pages 339 - 341
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 3, 2005, pages 695 - 702
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 4, 2006, pages 1496 - 1501
MOL PHARM, vol. 4, no. 3, May 2007 (2007-05-01), pages 323 - 38
PHARMACEUTICAL RESEARCH, vol. 20, 2003, pages 1674 - 1680
SCIENCE, vol. 253, 1991, pages 909 - 912
See also references of EP3888653A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022125869A1 (en) * 2020-12-11 2022-06-16 Board Of Regents, The University Of Texas System Compositions and methods of making cocrystals using dielectric heating with dispersive and distributive mixing
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

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BR112021010476A2 (pt) 2021-08-24
EP3888653A1 (en) 2021-10-06
IL283481A (en) 2021-07-29
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