WO2007007588A1 - Compose comportant un groupe cyclique ayant un noyau plan - Google Patents

Compose comportant un groupe cyclique ayant un noyau plan Download PDF

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Publication number
WO2007007588A1
WO2007007588A1 PCT/JP2006/313290 JP2006313290W WO2007007588A1 WO 2007007588 A1 WO2007007588 A1 WO 2007007588A1 JP 2006313290 W JP2006313290 W JP 2006313290W WO 2007007588 A1 WO2007007588 A1 WO 2007007588A1
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group
substituent
compound
oxo
represented
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PCT/JP2006/313290
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Japanese (ja)
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Kazuhiko Torisu
Masaru Sakai
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Ono Pharmaceutical Co., Ltd.
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Publication of WO2007007588A1 publication Critical patent/WO2007007588A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound having a planar cyclic group as a mother nucleus.
  • a compound having a planar cyclic group as a mother nucleus For details, refer to General Formula
  • the blood coagulation reaction is one of the ecological defense reactions triggered in response to stimulation of endotoxin and other foreign substances as well as vascular damage. This reaction also acts as a cascading mechanism that proceeds in the presence of calcium ions on the platelet aggregated at the injury site or on the membrane of damaged endothelial cells.
  • the blood coagulation system is also composed of various serine protease precursors, protein cofactors and fibrous tampa fibrinogen isotopes. Thrombin generated in the coagulation cascade converts soluble fibrinogen to insoluble fibrin, causing blood clotting.
  • the blood coagulation cascade is roughly divided into two types, an extrinsic system and an intrinsic system.
  • the extrinsic system begins with the formation of a complex with the activated blood coagulation factor VII by the tissue factor exposed by vascular disruption and endotoxin stimulation, and activates factor X.
  • the endogenous system leads to the activation of factor X through a multi-stage enzymatic reaction after the activation of the contact factor.
  • These extrinsic and intrinsic systems merge at factor X, and activated factor X (blood coagulation factor Xa, hereinafter abbreviated as FXa) activates prothrombin to thrombin and is soluble.
  • activated factor X blood coagulation factor Xa, hereinafter abbreviated as FXa
  • FXa located at the confluence of extrinsic and intrinsic systems, is upstream of thrombin, and FXa inhibitors may be more efficient and specific anticoagulants than thrombin inhibitors.
  • anti-coagulant drugs such as sulfarin and thrombin inhibitors are used.
  • sulfarin which is widely used as an oral preparation, often interacts with meals and other concomitant drugs, requiring complicated anticoagulant tests for patients.
  • thrombin inhibitors, heparin and the like have side effects such as bleeding because of their low specificity for the enzyme.
  • selective thrombin inhibitors also inhibit platelet aggregation by thrombin and the production of protein C, which is a coagulation regulator, so that the deviation from bleeding action is narrow and likely.
  • an FXa inhibitor can be an effective anticoagulant because it inhibits the confluence of the extrinsic system and the intrinsic system.
  • FXa selective inhibitors that do not have thrombin inhibitory activity should not have direct platelet aggregation inhibitory activity or protein C production inhibitory activity. It can be an ideal anticoagulant
  • Patent Document 1 discloses a general formula (Y)
  • Ar 1Y is a cyclic group which may be substituted with 1 to 5 groups
  • L 1Y is a bond or a divalent linker having 1 to 10 atoms in the main chain
  • Ar 2Y is a 5-membered monocyclic aromatic heterocyclic ring which may be substituted with 1 to 3 groups
  • Ar 3Y may be substituted with 1 to 3 groups 6
  • L 2Y is a divalent linker having 1 to 10 atoms in the main chain
  • Q Y is a basic group or NR 1Y R 2Y (Excerpts only necessary parts).
  • Patent Document 2 includes a general formula (Z).
  • a z represents benzene, 13-membered heterocyclic ring containing 3 nitrogen atoms or 14-membered heterocyclic ring containing 14 nitrogen atoms, oxygen atoms or sulfur atoms
  • R z represents hydrogen atom and C 14 selected from the group consisting of 4 alkyls
  • R 1Z is selected from the group forces of halogen atoms, Cl 8 alkyls, C2 8 alkyls and C2 8 alkyls
  • R 2Z is a hydrogen atom, Cl 8 alkyls, X Z — OR 2aZ — X Z — SR 2aZ — X Z — COR 2aZ — XZ— CO R 2aZ
  • W z is
  • NZ represents an integer of 0 3
  • mZ represents an integer of 0 1
  • R 4Z is a halogen atom
  • OR 4aZ NR 4aZ R 4bz — SR 4aZ — R 4eZ equal force
  • Group force is selected
  • R 4aZ is also selected
  • R 4aZ and R 4bz each independently represent a hydrogen atom or Cl 8 alkyl
  • R 4eZ is Cl 8 alkyl, C3 6 hetero Cycloalkyl, aryl, heteroaryl, etc.
  • Group power is selected. The definition of the group extracted the necessary parts.
  • a disubstituted thiophene derivative compound represented by the formula (1) and a pharmaceutically acceptable salt thereof are useful as FXa inhibitors.
  • R 2Z is a compound in which a carbamoyl group or an alkylsulfonyl group is substituted with an alkyl group.
  • Patent Document 1 Pamphlet of International Publication No. 03Z97047.
  • Patent Document 2 International Publication No. 2006Z002099 pamphlet.
  • Thrombotic diseases in which the blood coagulation mechanism is activated for example, thrombosis associated with cardiovascular disease 'embolism, thrombosis associated with cerebrovascular disease, embolism associated with venous vascular disease, embolism , And Z or systemic and Z or peripheral thrombosis / embolism prevention and Z or treatment, anticoagulants that are powerful, safe, do not require immediate use, do not require immediate monitoring, and have few side effects are desired And Providing it is the subject of the present invention.
  • a compound having a strong FXa inhibitory activity i.e., a cyclic group represented by ring A, an atom bonded to ring A in X, and an atom bonded to ring A in B are coplanar.
  • a strong FXa inhibitory activity i.e., a cyclic group represented by ring A, an atom bonded to ring A in X, and an atom bonded to ring A in B are coplanar.
  • the present invention provides:
  • ring A represents a cyclic group having planarity which may be substituted by a substituent
  • B represents a cyclic group which may be substituted by a substituent
  • R 1 represents a substituent
  • X may be further substituted with a substituent, and represents a spacer having 1 to 5 atoms in the main chain.
  • the planar cyclic group represented by ring A is a C4-15 monocyclic, fused bicyclic or fused tricyclic carbocyclic ring having planarity, or a planar oxygen atom, nitrogen atom, and
  • R 2 represents a substituent
  • ring Y represents a 3- to 8-membered nitrogen-containing heterocyclic ring in which a carbocarbon adjacent to the nitrogen atom is present in the ring
  • n represents 0 or 1 to 8 Represents an integer
  • the arrow pointing to the left represents binding to B.
  • R 2 may be the same or different.
  • R 3 , R 4 and R 5 each independently represents a hydrogen atom or a substituent
  • X 1 represents CO— or SO 2
  • the left-pointing arrow represents binding to R 1
  • the direction arrow indicates binding to ring A.
  • Z represents an optionally substituted nitrogen atom, oxygen atom or sulfur atom.
  • R 4 or R 5 may have an alkyl group which may have a substituent, may have a substituent, V, a carbocyclic group, or may have a substituent! /, Or may! / , Rubamoyl group or alkoxy carbo
  • R 41 represents a hydrogen atom, an optionally substituted rubamoyl group or an alkyl group substituted with an alkylsulfonyl group
  • R 51 may have a hydrogen atom or a substituent.
  • This represents an alkyl group substituted by a strong rubamoyl group or an alkylsulfol group, and other symbols have the same meaning as described above.
  • R 6 and R 7 each independently represent a substituent, and the arrow pointing to the right represents binding to X.
  • a pharmaceutical thread composition comprising as an active ingredient a compound represented by the general formula (I) according to [1], a salt, a solvate thereof, or a prodrug thereof,
  • Blood coagulation factor Xa mediated by administering an effective amount of a compound represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof according to [1] above to a mammal Prevention and Z or treatment methods for sexually transmitted diseases,
  • blood coagulation factor Xa-mediated disease refers to a disease in which blood coagulation factor Xa is involved in any process of disease formation, exacerbation, or continuation.
  • Examples of the Xa-mediated disease include thromboembolism.
  • thrombosis, embolism refers to thrombosis and Z or thromboembolism, and This refers to all the diseases that accompany these, and “thrombosis / embolism” includes, for example, “thrombosis / embolism associated with cardiovascular disease”, “thrombosis / embolism associated with cerebrovascular disease”, “ Thrombus / embolism associated with venous vascular disease ”and Z or“ systemic and Z or peripheral thrombosis / embolism ”are included.
  • thrombosis associated with cardiovascular disease embolism, for example, stable angina, atypical angina, unstable angina, etc., acute myocardial infarction , Myocardial infarction, acute coronary syndrome, asymptomatic myocardial ischemia, coronary artery thrombosis, reocclusion and restenosis after coronary artery bypass surgery, coronary artery interpension such as percutaneous transluminal coronary angioplasty 'stent placement Reocclusion and restenosis, cardiomyopathy, acute heart failure, congestive chronic heart failure, valvular disease, reocclusion and restenosis associated with coronary thrombolysis.
  • thrombosis / embolism associated with cerebrovascular disease includes, for example, ischemic cerebral vascular disorder, acute cerebral infarction, lacunar infarction, atherothrombotic cerebral infarction, cerebral artery embolism , Cerebral thrombosis, cerebrovascular disorder, disease associated with stroke, Alzheimer's disease, cerebrovascular dementia, dementia, reocclusion and restenosis after intracranial and internal artery bypass surgery, percutaneous transluminal arterioplasty Re-occlusion and restenosis after inter-pension such as stent placement, re-occlusion and restenosis associated with arterial hemolysis, cerebral infarction such as asymptomatic cerebral infarction, recurrence after onset of cerebral infarction, basilar, vertebral artery syndrome Transient cerebral ischemic attack (TIA), including basilar, vertebral artery syndrome, cerebral embolism, cardiogenic and Z or non-cardiogenic cerebral embolism.
  • TIA Transient cerebral ischemic attack
  • examples of “thrombosis / embolism associated with venous vascular disease” include, for example, economy class syndrome, deep vein thrombosis, acute pulmonary thromboembolism, pulmonary thromboembolism, pulmonary infarction, artificial Total knee arthroplasty ⁇ Joint surgery including total hip arthroplasty, fracture and spine surgery including femoral neck fracture surgery ⁇ Orthopedic surgery ⁇ plastic surgery ⁇ general surgery including cesarean section During surgery such as obstetrics and gynecology surgery 'post-operative venous thromboembolism, thrombosis associated with acute medical disease' embolism, vena cava filter placement and thrombosis associated with Z or prosthetic valve replacement
  • systemic and Z or peripheral thrombus'embolism includes, for example, arteriosclerosis, limb arteriosclerosis, obstructive arteriosclerosis, peripheral arterial occlusion, disease
  • Obstructive thromboangitis chronic arterial occlusion, chronic arterial occlusion and ischemic symptoms such as ulcer, pain and cold feeling based on Z or obstructive embolization vasculitis, intermittent claudication, antiphospholipid antibody syndrome , Sores, generalized intravascular coagulation syndrome (DIC), systemic lupus erythematosus, thrombosis associated with cancer 'leukemia', embolism, sepsis, organ failure, heparin-induced thrombocytopenia (HIT), associated with organ transplantation Thromboembolism, coagulation of perfused blood during blood extracorporeal circulation (hemodialysis), peripheral vascular bypass surgery, vascular grafting, post-artificial vascularization and thrombosis associated with Z or prosthetic valve replacement, peripheral vascular inter-pension Re-occlusion and restenosis, non-valvular glomerulonephritis, chronic glomerulonephritis, IgA
  • blood coagulation factor Xa-mediated disease is preferably “thrombosis, embolism”, and “thromboembolism” is preferably “thrombosis associated with cardiovascular disease” ”,“ Thrombosis, embolism associated with cerebrovascular disease ”,“ thrombosis, embolism associated with venous vascular disease ”, and Z or“ systemic and Z or peripheral thrombus' embolism ”, more preferred Is "thrombosis associated with venous vascular disease 'embolism”.
  • thrombosis / embolism associated with venous vascular disease is preferably deep vein thrombosis, pulmonary thromboembolism, pulmonary infarction, total knee replacement, total hip replacement Including joint surgery, fractures including femoral neck fracture, spine surgery, abdominal surgery, orthopedic surgery including cesarean section, plastic surgery, general surgery, gynecological surgery, etc.
  • Embolism embolism associated with rheumatic heart disease and atrial fibrillation
  • cerebral embolism and systemic embolism associated with valvular and Z or non-valvular atrial fibrillation recurrent venous thromboembolism
  • Congenital antithrombin (AT) deficiency associated with recurrent thrombus and cerebral vein occlusion, more preferably deep vein thrombosis and pulmonary thromboembolism.
  • the “cyclic group having planarity” in the “cyclic group having planarity which may be substituted by a substituent” represented by ring A means a carbon atom having sp 2 hybrid orbital, acid Represents a cyclic group composed of 4 to 15 atoms selected from the group consisting of elementary atom, nitrogen atom and sulfur nuclear power, and examples of the “cyclic group having planarity” include “planarity C4 ⁇ 15 monocyclic, fused bicyclic or fused tricyclic carbocycles ”or“ planar oxygen atoms, nitrogen atoms and sulfur atom 1 to 5 selected from the group consisting of nuclear atoms. 5-15 membered monocyclic, fused bicyclic or fused tricyclic heterocycle "
  • planar C4-15 monocyclic, condensed bicyclic or condensed tricyclic carbocyclic ring include, for example, cyclobutadiene, benzene, pentalene, azulene, naphthalene, Examples include heptalene, biphenylene, as-indacene, s-indacene, isanaphthylene, phenanthrene, and anthracene ring.
  • a 5- to 15-membered monocyclic or condensed bicyclic ring containing 1 to 5 heteroatoms selected from the group consisting of a planar oxygen atom, nitrogen atom and sulfur atom
  • Specific examples of the ⁇ fused tricyclic heterocycle '' include, for example, pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, furazane, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine, and pyrazole.
  • the ring ⁇ represents "a planar oxygen atom, a nitrogen atom and a sulfur atom selected from the group consisting of 1 and 5 heteroatoms, and a 5-membered monocycle"
  • the “heterocycle” include pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, furazane, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole ring and the like.
  • examples of the “substituent” in the “cyclic group having planarity which may be substituted by a substituent” represented by ring A include (1) A good alkyl group, (2) an optionally substituted alkyl group, (3) an optionally substituted alkyl group, and (4) an optionally substituted group.
  • Carbocyclic group (5) optionally substituted heterocyclic group, (6) optionally protected hydroxyl group, (7) optionally protected mercapto group, (8) protected An optionally substituted amino group, (9) a rubamoyl group optionally having a substituent, (10) a sulfamoyl group optionally having a substituent, (11) a carboxyl group, (12) an alkoxycarbole A group (for example, a Cl-6 alkoxy carbo ol group such as a methoxy carbo ol, an ethoxy carbo ol, a tert-butoxycarbonyl group, etc.), 13) sulfo group (one SO H), (14) sulfino
  • Alkyl sulfiel groups that may have (for example, Cl to 4 alkyl sulfiel groups such as methyl sulfiel and ethyl sulfiel groups), (23) aryl sulfyl groups that may have a substituent (For example, C6-10 arylsulfyl group such as a phenylsulfuryl group), (24) an alkylsulfonyl group which may have a substituent (for example, a methylsulfonyl group, an ethylsulfyl group, etc.) Cl-25 alkylsulfol group, etc.) (25) may have a substituent, but may be an arylsulfol group (for example, a C6-10 arylsulfol group such as a phenolsulfol group, or a pyridinylsulfol group).
  • arylsulfol group for example, a C6
  • a C6-10 aryl group such as a benzoyl group, a 5- to 10-membered heteroaryl carbonyl group such as a pyridylcarbol group, etc.
  • acyl group for example, C 1-6 such as formyl, acetyl, propanoyl, bivaloyl group, etc.
  • Arkanol for example, a C6-10 aryl
  • alkyl group in the “alkyl group” as the substituent may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , Pentinole, hexyl, heptyl, octinole, noninore, decinole, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl groups, etc. -20 alkyl groups and the like.
  • the "acyl group” in the “acylamino group” and the “N-acyl N-alkylamino group” as the substituent of the alkyl group is "the protected hydroxyl group as a substituent which will be described later. ”,“ Protected, may be a mercapto group ”and“ protected, may be an amino group ”and have the same meaning as the“ acyl group ”as a protecting group.
  • N acyl N alkylamino group examples include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, Examples thereof include linear or branched Cl-20 alkyl groups such as dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl groups.
  • the “carbocycle” as the substituent of the alkyl group includes, for example, “a part or all of which is saturated! / ⁇ may be! / ⁇ C3-15 monocyclic, condensed bicyclic or condensed tricyclic. Cyclic carbocycle "and the like. Examples of the “C3-15 monocyclic, condensed bicyclic or condensed tricyclic carbocyclic ring which may be partially or fully saturated” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexane, and the like.
  • a C3-15 monocyclic, fused bicyclic or fused tricyclic carbocycle which may be partially or fully saturated, includes a spiro-bonded bicyclic carbocycle and a bridge. Also included are fused bicyclic carbocycles such as spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2.2.1] heptane, bicyclo [ 2. 2. 1] Hepter 2—Yen, Bicyclo [3. 1. 1] Heptane, Bicyclo [3. 1. 1] Hepter 2—Yen, Bicyclo [2. 2. 2] Octane, Bicyclo [2. 2. 2] Octa 2-en, adamantane, noradamantan ring and so on.
  • fused bicyclic carbocycles such as spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2.2.1] h
  • the “substituent” of the carbocyclic ring as the substituent of the alkyl group includes a Cl-8 alkyl group.
  • heterocycle as the substituent of the alkyl group include, for example, part or all of 1 to 5 heteroatoms selected from the group consisting of "oxygen atom, nitrogen atom and sulfur nuclear atom” May be saturated 3 to 15 membered monocyclic, fused bicyclic or fused tricyclic heterocycle ".
  • ⁇ fused bicyclic or fused tricyclic heterocycle '' include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, Oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxazizepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, thiadiazepine
  • the “substituent” of the heterocyclic ring as the substituent of the alkyl group includes Cl-8 alkyl groups (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl).
  • alkaryl group in "having a substituent, which may have a substituent” as the substituent examples include, for example, etule, probe, buture, pentale, and Examples thereof include straight chain or branched C2-20 alkenyl groups such as a xel group.
  • the substituent of the alkenyl group has the same meaning as the substituent in the above-mentioned “alkyl group optionally having substituent (s)”.
  • Examples of the alkyl group in the "having an alkyl group, which may have a substituent" as a substituent include, for example, an etul, propiel, butur, pentyl, hexyl group and the like. And a straight chain or branched chain C2-20 alkyl group.
  • the substituent of the alkynyl group has the same meaning as the substituent in the aforementioned “alkyl group optionally having substituent (s)”.
  • Examples of the carbocycle in the "having a substituent, or a carbocyclic group" as a substituent include, for example, "C3-15 monocyclic ring which may be partially or fully saturated, A fused bicyclic or fused tricyclic carbocycle "and the like.
  • Examples of the “C3-C15 monocyclic, condensed bicyclic or condensed tricyclic carbocyclic ring, which may be partially or fully saturated” include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • a Cl-4 alkyl group eg, methyl, ethyl, propyl, butyl group, etc.
  • a C2-4 alkenyl group eg, etyr, pro Penyl, butyr group, etc.
  • C2-4 alkyl group eg, ethynyl, probule, butynyl group, etc.
  • hydroxyl group Cl-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy group, etc.)
  • Cl— 6Alkoxycarbon groups for example, methoxycarbol, ethoxycarbol, tert-butoxycarbol group, etc.
  • mercapto groups for example, methoxycarbol, ethoxycarbol, tert-butoxycarbol group, etc.
  • mercapto groups for example, methoxycarbol, ethoxycarbol, tert-butoxycarbol group, etc.
  • mercapto groups Cl-4 alkyl
  • having a substituent may be a carbocyclic group" as a substituent
  • “having a substituent may be a cyclic group” as a substituent of a carbocyclic ring. Is shown as a substituent of ring A above.
  • the same meaning as “carbocycle” in a carbocyclic group which may have a substituent, or “heterocycle” in a heterocyclic group which may have a substituent is represented.
  • the "having a substituent, which may be a carbocyclic group” as the substituent the "having a substituent, which may be a cyclic group”
  • the “substituent” has the same meaning as the substituent of the carbocyclic ring as the substituent of the “alkyl group” as the substituent of the “substituent”, and these optional substituents are substituted. You can replace 1 and 4 in the possible positions.
  • heterocycle in the "having a substituent, which may have a substituent," as a substituent is, for example, 1 to 5 selected from the group consisting of "oxygen atom, nitrogen atom and sulfur nuclear atom” A 3 to 15-membered monocyclic, fused bicyclic or fused tricyclic heterocycle containing one heteroatom, which may be partially or wholly saturated.
  • Oxygen atom, nitrogen atom and sulfur nuclear power are also selected from the group consisting of 1 to 5 heteroatoms, part or all of which may be saturated 3-15 membered monocyclic, condensed bicyclic
  • ⁇ fused tricyclic heterocycle '' include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, age xepin, thiophene, thiopyran, and chepin.
  • the “substituent” of the heterocyclic ring has the same meaning as the substituent in the aforementioned “carbocyclic group, which may have a substituent,” and these optional substituents can be substituted. 1 to 4 positions may be substituted.
  • Protected group in “Protected !, may be a hydroxyl group", “Protected, may be a mercapto group” and “Protected, may be an amino group” as a substituent As, for example, it may have a substituent, may be an alkyl group (having the same meaning as the above-mentioned “having a substituent, may be an alkyl group”), and may have a substituent.
  • a carbocyclic group (which has the same meaning as the above-mentioned “carbocyclic group which may have a substituent”), a heterocyclic group which may have a substituent (the above “having a substituent” And an alkylsulfonyl group (for example, a Cl-6 alkylsulfol group such as a methylsulfol or ethylsulfol group), an arylsulfol group (for example, a phenyl group).
  • -Sulfol group etc. C6-10 aryl sulfonyl group etc. acyl group etc. That.
  • acyl group (1) having a substituent may be an alkyl carbo group, and (2) having a substituent! /, May! /, An alkenyl carbonyl group. (3) an alkynylcarbonyl group which may have a substituent, (4) a substituent ! And carbocyclic group, (5) having a substituent! /, May! /, And a heterocyclic carbonyl group. These optional substituents may be substituted. 1 or 4 may be substituted.
  • the “having a substituent! /, Even the alkyl” in the “having a substituent, may be an alkyl carbo group” means the above-mentioned “having a substituent, It has the same meaning as “alkyl group”.
  • V having a substituent may be a alkenyl” in “Alkalcarbon group having a substituent” may be the same as the above “having a substituent. It represents the same meaning as the “alkell group”.
  • the “having a substituent! / May be an alkyl” in the “having a substituent, may be an alkyl carbonyl group” means the above-mentioned “having a substituent, It has the same meaning as “alkyl group”.
  • the “carbocycle having a substituent” may be the “carbocycle having a substituent” or the “carbocycle” in the “carbocyclic carbocycle group”. It has the same meaning as “carbocyclic group”. In the “having a substituent, it may be a heterocyclic carbocyclic group”, “having a substituent! /, Or a heterocycle” may be the above-mentioned “having a substituent, It represents the same meaning as “heterocyclic group”.
  • Examples of the "substituent may have a rubamoyl group" as a substituent include, for example, an unsubstituted rubamoyl group, an N-mono-Cl-4 alkyl rubamoyl group (for example, N- Methylcarbamoyl, N-ethylcarbamoyl, N-propyl rubamoyl, N-isopropyl pill rubamoyl, N-butylcarbamoyl, etc.), N, N-diCl-4 alkyl rubamoyl (eg, N, N -Dimethylcarbamoyl, N, N-jetylcarbamoyl, N, N-dipropyl-powered rubamoyl, N, N-dibutylcarbamoyl group, etc.), 1-piperidylcarbol group and the like.
  • an unsubstituted rubamoyl group for example, N- Methy
  • a sulfamoyl group as a substituent includes, for example, an unsubstituted sulfamoyl group, an N-mono-Cl-4 alkylsulfamoyl group (for example, N-methyl).
  • N-ethylsulfamoyl N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl groups, etc.
  • N, N-diCl-4 alkylsulfamoyl groups for example, N, N-dimethylsulfamoyl, N, N-jetylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl group, etc.
  • substituent may be an alkyl sulfier group", “having a substituent, may be an aryl sulfier group", “having a substituent
  • substituent in the “alkylsulfonyl group”, “having a substituent, may be an arylsulfonyl group”, and “an acyl group optionally having a substituent”
  • Cl to 4 alkyl groups for example, methyl, ethyl, propyl, butyl groups, etc.
  • C2-4 alkyl groups for example, etul, probe base, butyr groups, etc.
  • C2 to 4 alkyl groups Group for example, ethynyl, propier, butynyl group, etc.
  • hydroxyl group Cl-4 alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy group, etc.), Cl-6 alkoxy carbo group
  • the “cyclic group” in the “cyclic group optionally substituted by a substituent” represented by B represents “having a substituent” as the substituent of the ring A. It represents the same meaning as “carbocycle” in “carbocycle” or “heterocycle” in “heterocycle”.
  • examples of the “substituent” in the “cyclic group optionally substituted by a substituent” represented by B include (1) an alkyl group which may have a substituent, ( 2) an optionally substituted alkyl group, (3) an optionally substituted alkyl group, and (4) a substituted group.
  • a heterocyclic group which may have a substituent (6) a hydroxyl group which may be protected, (7) a mercapto group which may be protected, (8) an amino group which may be protected, (9) a carboxyl group, (10) an alkoxy carbo group (for example, Cl such as methoxy carbo yl, ethoxy carb, tert-butoxy carbo ⁇ 6 alkoxy carbo group, etc.), (11) sulfo group (one SO H), (12) sulfino group, (13) phosphono group, (14) nitro group, (15)
  • alkylsulfinyl group for example, a Cl to 4 alkylsulfuric group such as a methylsulfuryl group, an ethylsulfuric group, etc.
  • an arylsulfifer group optionally having a substituent for example, a C6-10 arylsulfier group such as a phenylsulfiel group
  • Alkylsulfol groups for example, C1-6 alkylsulfonyl groups such as methylsulfol and ethylsulfol groups
  • arylaryl groups which may have a substituent (for example, phenylsulfo- A C6-10 aryl group such as an alkyl group),
  • an optionally substituted acyl group for example, a Cl-6 alkanoyl group such as
  • any one of these optional substituents may be substituted at substitutable positions.
  • alkyl group in the “alkyl group” as the substituent of B for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, heptyl, octyl, nonyl, decyl And linear or branched C1-20 alkyl groups such as undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl groups.
  • the “substituent” of the alkyl group a hydroxyl group, a force carboxyl group, a nitro group, an azide group, a Cl-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, hexyloxy group, etc.), C3-7 Cycloalkyl-Cl-6 alkoxy group (for example, cyclohexylmethyloxy, cyclopentylethyloxy group, etc.), C3-7 cycloalkyloxy group (for example, cyclohexyloxy group, etc.), C7-15 aralkyloxy group (E.g., benzyloxy, phenethyloxy, phenylpropyloxy, naphthylmethyloxy, naphthylethyloxy groups, etc.), phenoxy groups, Cl-6 alkoxy carbo yl groups (e.g., methoxy carbo yl, ethoxy carbo
  • 6 to 10 ⁇ reel carbonyl group such Benzoiru group
  • Okiso group which may have a substituent carbocyclic group, and It may have a substituent, and examples thereof include a heterocyclic group, and these optional substituents may be substituted at 1 or 4 positions.
  • Examples of the “carbocyclic group” as the substituent of the “alkyl group” as the “substituent” of B include, for example, “C3-15 monocyclic, condensed bicyclic or optionally partially or fully saturated” A fused tricyclic carbocycle ".
  • Examples of the “C3-15 monocyclic, condensed bicyclic or condensed tricyclic carbocyclic ring which may be partially or fully saturated” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, Cycloheptane, Cyclooctane, Cyclononane, Cyclodecane, Cycloundecane, Cyclododecane, Cyclotridecane, Cyclotetradecane, Cyclopentadecane, Cyclopentene, Cyclohexene, Cycloheptene, Cyclooctene, Cyclopentagen, Cyclohexagen, Cyclo Butadiene, cyclotaktage , Benzene, pentalene, nohydropentalene, azulene, nohydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydron
  • a C3-15 monocyclic, fused bicyclic or fused tricyclic carbocycle which may be partially or fully saturated includes a spiro-bonded bicyclic carbocycle and a bridged fused bicyclic carbon. Rings are also included, for example, spiro [4. 4] nonane, spiro [4. 5] decane, spiro [5. 5] undecane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] hepter 2—Yen, bicyclo [3. 1. 1] heptane, bicyclo [3. 1. 1] Hepter 2—Yen, bicyclo [2. 2.
  • the “substituent” of the “carbocyclic group” is a Cl-8 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl).
  • heterocyclic group as the substituent of the “alkyl group” as the “substituent” of B include, for example, “oxygen atom and 1 to 5 heteroatoms selected from Z or sulfur nuclear power, A 3 to 15 membered monocyclic, fused bicyclic or fused tricyclic heterocycle which may be partially or wholly saturated.
  • Oxygen atoms and Z or sulfur nuclear power is selected 1 !, including 5 heteroatoms, partially or fully saturated, 3-15 membered monocyclic, fused bicyclic or Examples of the ⁇ fused tricyclic heterocycle '' include, for example, furan, pyran, oxepin, thiophene, diapyran, chepin, benzofuran, isobenzofuran, benzoti.
  • Phen isobenzothiene, dithianaphthalene, chromene, benzoxepin, benzochopine, dibenzofuran, xanthene, dibenzothiophene, phenoxathiin, thianthrene, oxsilane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydro Xepin, tetrahydroxepin, perhydroxepin, thiirane, chetan, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrochepin, tetrahydrochepin, perhydrochepine, o Xanthian, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzo
  • a Cl to 8 alkyl group for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, Octyl group, etc.
  • hydroxyl group carboxyl group, nitro group
  • Cl-6 alkoxy group for example, methoxy, ethoxy, propoxy, hexyloxy group, etc.
  • C1-6 alkoxycarbonyl group for example, methoxycarbol, ethoxy) Carboyl, tert-butoxycarbol group, etc.
  • Cl-6 alkyl carboxyloxy group for example, acetoxy, ethylcarboxoxy group, etc.
  • Cl-4 alkylthio group for example, methylthio, ethylthio, propylthio, Ptyl
  • alkenyl group in the “alkenyl group which may have a substituent” as the substituent of B examples include, for example, ethenyl, probe, butenyl, pentyl, hexyl. And straight-chain or branched C2-20 alkenyl groups such as groups.
  • the substituent of the alkenyl group has the same meaning as the substituent in the “substituent, may be substituted alkyl group” as the substituent of B.
  • Examples of the alkyl group in the "having an alkyl group, which may have a substituent" as the substituent of B include, for example, ethynyl, probule, butyur, pentyl, hexynyl group and the like. And a linear or branched C2-20 alkyl group.
  • the substituent of the alkyl group has the same meaning as the substituent in the “substituent, may be substituted alkyl group” as the substituent of B.
  • Examples of the "carbocyclic group" in the "having a substituent, or a carbocyclic group” as the substituent of B include, for example, “part or all of which may be saturated C3- 15 monocyclic, fused bicyclic or fused tricyclic carbocycles ”. “Some or all may be saturated!
  • C3-15 monocyclic, fused bicyclic or fused tricyclic carbocycle includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane , Cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclootaten, cyclopentagen, cyclohexagen, cyclohexabutadiene, Cyclotagen, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydr
  • some or all of which may be saturated C3-15 monocyclic, fused bicyclic or fused tricyclic carbocycles may be spiro-bonded bicyclic carbocycles and bridged fused bicyclic carbons. Rings are also included, such as spiro [4.4] nonane, spiro [4. 5] decane, spiro [5.5] undecane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] hepter 2—Yen, bicyclo [3. 1. 1] heptane, bicyclo [3. 1. 1] hepter 2—Yen, bicyclo [2. 2. 2] octane, bicyclo [2.2.2] Otter 2— Nen, adamantane, noradamantan ring and the like.
  • a Cl to 4 alkyl group for example, methyl, ethyl, propyl, butyl group, etc.
  • a C2 to 4 alkenyl group for example, etul, Propenyl, butyr group, etc.
  • C2-4 alkyl group eg, ethynyl, probule, butynyl group, etc.
  • hydroxyl group Cl-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy) Group)
  • Cl-6 alkoxy carbo group for example, methoxy carbo yl, ethoxy carb, tert-butoxy carbo ol group, etc.
  • mercapto group for example, Cl-4 alkylthio group (eg methylthio, ethylthio) , Propylthio, butylthio group, etc.), oxo group, halogen atom
  • heterocyclic group in the "having a substituent, which may have a substituent” as the substituent of B is selected from the group consisting of, for example, "oxygen atom, nitrogen atom and sulfur nuclear atom” Or a 3 to 15 membered monocyclic, fused bicyclic or fused tricyclic heterocycle containing 1 or 5 heteroatoms, which may be partially or fully saturated.
  • Examples of the ⁇ ring or fused tricyclic heterocycle '' include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, Oxazonole, isoxazonole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxazazine, oxazepine, oxadiazepine, thiadiazonole, thiazine, thiadiazine, thiazepine, thiadia
  • the "substituent" of the "heterocyclic group” has the same meaning as the substituent in the "substituent having a substituent, and may be! / ⁇ carbocyclic group" as the substituent of B, These optional substituents can be substituted at the substitutable position by 1 or 4!
  • substituent of B may be a hydroxyl group
  • Protected may be a mercapto group
  • Protected group May have a substituent, for example, or may be an alkyl group (represents the same meaning as the" optionally substituted alkyl group "as the substituent of B)
  • a carbocyclic group which may have a group (the above The same meaning as “having a substituent and a carbocyclic group” as a substituent of B is represented.
  • a heterocyclic group (the same meaning as the “optionally substituted heterocyclic group” as the substituent of the “alkyl group” as the substituent of B) ), Alkoxy carbo groups (for example, Cl-6 alkoxy carbo groups such as methoxy carbo yl, ethoxy carbo ol, tert-butoxy carbo ol etc.), alkyl sulfonate groups (eg , Cl-6 alkylsulfol groups such as methylsulfol and ethylsulfol groups), arylsulfol groups (eg C6-10 arylsulfol groups such as phenylsulfol groups), And an acyl group and a piperidyl group.
  • Alkoxy carbo groups for example, Cl-6 alkoxy carbo groups such as methoxy carbo yl, ethoxy carbo ol, tert-butoxy carbo ol etc.
  • acyl group (1) having a substituent may be an alkyl carbo group, and (2) having a substituent! /, May! /, An alkenyl carbonyl group. (3) an optionally substituted alkyl carbonyl group, (4) a substituted group! /, A carbocyclic carbonyl group, (5) a substituted group
  • examples thereof include a heterocyclic carbonyl group, and these optional substituents may be substituted by 1 or 4 at substitutable positions.
  • alkyl in “having a substituent, which may be an alkylcarbo- ral group” means "substituent” Even if it has a group, it represents the same meaning as the “alkyl group”.
  • Alkal having a substituent may be used as the substituent of the above-mentioned “having a substituent. In this case, it means the same as “alkenyl group”.
  • the “having a substituent! /, May! /, Alkyl” in the “having a substituent may be V, an alkyl carbonyl group” is a substituent of the above-mentioned B.
  • the “carbocycle” having a substituent in the “carbocyclic carbocycle group having a substituent” is the “substituent having a substituent”. It may have the same meaning as “carbocyclic group”.
  • the heterocycle” in the “having a substituent, may be a heterocyclic carbocycle group” means the “substituent having a substituent” as the substituent of B. It has the same meaning as “! /! Heterocyclic group”.
  • an optionally substituted alkylsulfier group having a substituent! / May be an arylsulfier group
  • substituted alkyl sulfo group having a substituent
  • substituted alkylsulfier group having a substituent! / May be an arylsulfier group
  • substituted Has! /, May! /, Alkyl sulfo group “ has a substituent
  • the “substituent” in the “acyl group” may be, for example, a Cl to 4 alkyl group (for example, methyl, ethyl, propyl, butyl group, etc.), a C2 to 4 alkenyl group (for example, ethyl).
  • the "substituent" represented by R 1 is the “substituent” in the "cyclic group having planarity" which is substituted by the substituent represented by the ring A. "Means the same.
  • One means an interval of 1 to 5 main chain atoms.
  • “the number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • Examples of the “spacer having 1 to 5 atoms in the main chain” include, for example, a methylene group (one CH—) which may have one or two substituents, and a substituent.
  • Nitrogen atoms that may have (—NH—), —CO—, —O—, —S—, —SO—, —SO
  • C2-5 alkylene group which may replace one oxygen atom, nitrogen atom or sulfur atom includes C2-5 linear or branched groups such as ethylene, propylene, isopropylene, butylene, isobutylene and pentylene groups. Examples thereof include a branched alkylene group or a C2-5 alkylene group in which one carbon atom in an ethylene, propylene, isopropylene, butylene, isobutylene, or pentylene group is replaced with an oxygen atom, a nitrogen atom, or a sulfur atom.
  • the remaining bond of the nitrogen atom is a hydrogen atom, a Cl-6 alkyl group, a C2-6 acyl group, or a Cl-6 alkoxycarbonyl group (for example, methoxycarbon, ethoxycarbonyl, tert-butoxycarbon). Group).
  • the C2-5 alkylene group may be substituted with a substituent.
  • Cl-8 alkyl group for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl group, etc.
  • Hydroxyl group amino group, force ruboxyl group, nitro group, mono- or di-Cl-6 alkylamino group (for example, methylamidoethylamino, propylamidodimethylamidojetylamino group, etc.), Cl-67 alkoxy group (eg, methoxy, Ethoxy, propoxy, hexyloxy groups, etc.), Cl-6 alkoxy carbo yl groups (for example, methoxy carbo ol, ethoxy carbo ol, tert-butoxy carbo ol groups, etc.), Cl-6 alkyl carboxy groups (for example, methoxy carbo ol,
  • C2-5 alkylene group examples include — (CH 2) —, — (CH 2) ⁇ , One (CH) ⁇ ,-(CH) ⁇ , -O-CH ⁇ , -O- (CH) ⁇ , O- (CH) one,
  • Cl-6 alkylidene group in the “optionally Cl-6 alkylidene group” examples include methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene group and the like.
  • a hydroxyl group an amino group, a carboxyl group, a nitro group, an azido group, a mono- or di-C 1-6 alkylamino group (for example, , Methylamino, ethylamino, propylamino-containing dimethylamino-containing ketylamino groups, etc.), N-arylamino groups (eg, N-phenylamino groups, etc.), N-aryl-N alkylamino groups (eg, N-phenol-N-methylamino) N-phenol-N ethylamino, N-phenyl-N with propylamino N-phenyl-N-butylamino-containing N-ferro-N-pentylamino-containing N-phenol-hexylamino groups, etc., Cl-6 Alkoxy groups (for example, methoxy, ethoxy,
  • Cl-6 alkylsulfol groups such as methylsulfol and ethylsulfyl groups
  • arylsulfol groups eg, C6-10 arylsulfol groups such as phenylsulfol groups
  • acyl groups for example, Cl-6 alkanoyl groups such as formyl, acetyl, propanoyl, bivaloyl groups, etc., for example, C6-10 aryl carbonate groups such as benzoyl group, etc., etc., and any of these substituents can be substituted.
  • 1 to 4 may be substituted at any position.
  • the like for example, Cl-6 alkylsulfol groups such as methylsulfol and ethylsulfyl groups
  • arylsulfol groups eg, C6-10 arylsulfol groups such as phenylsulfol groups
  • acyl groups for example,
  • ring Y further includes an oxygen atom, a nitrogen atom and a sulfur atom.
  • 1 to 5 heteroatoms selected from the group consisting of atoms, which may be partially or fully saturated 3 to 8 membered at least one nitrogen atom
  • ⁇ 2 , ⁇ 3 , 4 , ⁇ 5 or ⁇ 6 each independently represents a bond, a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom, provided that ⁇ 2 , ⁇ 3 , ⁇ 4 , ⁇ ⁇ 5 and ⁇ 6 do not represent joints at the same time, and the arrow pointing to the left represents joining with ⁇
  • [Chemical Formula 16] is a force that represents a single bond or a double bond. ), Specifically, for example,
  • substituted represented by R 2 has the same meaning as the “substituent” in the “cyclic group” which may be substituted by the substituent represented by B.
  • the “substituent” represented by R 3 , R 4 , R 5 , R 6 or R 7 is the “substituent substituted by the substituent represented by the ring A”. It represents the same meaning as “substituent” in “cyclic group having”.
  • the "cyclic group having planarity" in the "cyclic group having planarity which may be substituted by a substituent" represented by ring A is preferably "planarity" 1 to 5 heteroatoms selected from the group consisting of a C 4-15 monocyclic, fused bicyclic or fused tricyclic carbocyclic ring having or a planar oxygen atom, nitrogen atom and sulfur atomic energy. 5- to 15-membered monocyclic, fused bicyclic or fused tricyclic heterocycle ".
  • the “planar C4-15 monocyclic, condensed bicyclic or condensed tricyclic carbocyclic ring” is preferably “planar C6-10 monocyclic or condensed bicyclic.
  • a 5- to 15-membered monocyclic, condensed, containing 1 to 5 heteroatoms selected from the group consisting of planar oxygen, nitrogen and sulfur atoms The bicyclic or fused tricyclic heterocycle preferably contains “one or more heteroatoms selected from the group consisting of planar oxygen, nitrogen and sulfur atoms”. , 5-membered monocyclic complex ring ”.
  • a 5-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from the group consisting of a planar oxygen atom, nitrogen atom and sulfur atom Preferably Is a pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, furazane, oxadiazole, thiophene, thiazole, isothiazole, or thiadiazole ring, more preferably pyrazole, triazole, oxazole, isoxazole, oxaziazole, thiazole.
  • Isothiazole, or thiadiazole ring and most preferably an oxazole, isoxazole, or oxaziazole ring.
  • oxazole, isoxazole, 1,2,4 oxaziazole, or 1,3,4-oxaziazole ring are especially preferred.
  • Z preferably has a substituent! /, But may be a nitrogen atom, an oxygen atom or a sulfur atom, more preferably an oxygen atom or a sulfur atom. Most preferred is an oxygen atom.
  • the "substituent" of the "nitrogen atom" which may be represented by Z is preferably an alkyl group which may have a substituent.
  • the “cyclic group” in the “cyclic group substituted by a substituent” represented by B is preferably “partially or partially saturated”.
  • the “substituent” in the “cyclic group that may be substituted by a substituent” represented by B is preferably a carbocyclic group that may have a substituent, A heterocyclic group which may have a group, a hydroxyl group which may be protected, a mercapto group which may be protected, an alkylsulfonyl group which may have a substituent, and a substituent. May be an acyl group, or
  • a heterocyclic group which may have a substituent, a hydroxyl group which may be protected, an alkylsulfonyl group which may have a substituent, and a substituent.
  • it may be a perhydrodiazepinel group, a piperidyl-loxy group, a methylsulfol group, a pyrrolidylcarbol group, or a group which may have a substituent.
  • the “substituent” in the “cyclic group optionally substituted by a substituent” represented by B is preferably 1 to 5, at least one of which is preferred.
  • the “3- to 8-membered nitrogen-containing heterocyclic ring in which a carbocyclic carbon adjacent to the nitrogen atom is present in the ring” represented by ring Y is preferably
  • n is preferably 0.
  • the “substituent” represented by R 1 is preferably a carbocyclic group which may have a substituent, or a heterocyclic group which may have a substituent, more preferably An optionally substituted heterocyclic group, and most preferably 1 to 5 heteroatoms selected from the group of optionally substituted oxygen atoms, nitrogen atoms and sulfur atomic energy. It is a 3- to 15-membered monocyclic, fused bicyclic or fused tricyclic heterocycle which may be partially or wholly saturated including atoms. Particularly preferably, part or all may be saturated, including 1 to 5 heteroatoms selected from the group consisting of optionally substituted oxygen atom, nitrogen atom and sulfur nuclear atom.
  • LO member monocyclic or condensed bicyclic bicyclic ring particularly preferably a thiophene ring which may have a substituent, a pyridine ring which may have a substituent, Or it may have a substituent! /, May! /, An indole ring.
  • R 6 and R 7 each independently represent a substituent, and the arrow pointing to the right represents binding to X.
  • a 3-substituted thiophene ring more preferably
  • R 6 is preferably a halogen atom, more preferably a chlorine atom.
  • R 7 is preferably a halogen atom, more preferably a fluorine atom.
  • the "spacer having 1 to 5 atoms in the main chain which may be further substituted with a substituent" represented by X preferably has 1 or 2 substituents. ! /, Methylene group (one CH-), optionally substituted nitrogen atom (one NH-), -CO-
  • 1 O-, 1 S-, 1 SO-, -SO- forces are also selected 1 to 5 divalent groups, and more
  • X 1 is preferably CO— or so—, more preferably
  • R 3 is preferably a hydrogen atom or a Cl-6 alkyl group, and more preferably a hydrogen atom.
  • R 4 is preferably a hydrogen atom, a Cl-6 alkyl group, a force rubamoyl group in which Cl-6 alkyl group is substituted 1 or 2, or a Cl-6 alkylsulfol group substituted.
  • a Cl-6 alkyl group more preferably a hydrogen atom, a dimethylaminocarbol group, a methylsulfo-ruethyl group, or an ethylsulfo-ruethyl group.
  • R 5 is preferably a hydrogen atom, a Cl-6 alkyl group, a force rubamoyl group in which Cl-6 alkyl group is substituted by 1 or 2, or a Cl-6 alkylsulfol group substituted.
  • a Cl-6 alkyl group more preferably a hydrogen atom, a dimethylaminocarbol group, a methylsulfo-ruethyl group, or an ethylsulfo-ruethyl group.
  • the compound represented by the general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof is preferably represented by the general formula (I 1)
  • an alkyl group, an alkyl group, an alkyl group, an alkoxy group, an alkylthio group, an alkylene group, an alkylene group, and an alkylene group include straight-chain and branched-chain groups.
  • the compound represented by the general formula (I) is converted into a salt by a known method.
  • the salt is preferably a water-soluble salt which is preferably a pharmaceutically acceptable salt.
  • Suitable salts include, for example, salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetra Methyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D— Salts with glucamine, etc., and acid addition salts (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, inorganic acid salt, or a
  • the compound represented by the general formula (I) and a salt thereof can be converted into a solvate. It is preferable that the solvate has low toxicity and water solubility. Suitable solvates include, for example, solvates with water and alcohol solvents (eg ethanol).
  • the prodrug of the compound represented by the general formula (I) is a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like in vivo.
  • the compound represented by the general formula (I) when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, In general, the amino group of the compound represented by the formula (I) is converted to eicosanolation, alanylation, pentylamino force grouping, (5-methyl-2-oxo-1,3-dioxolene 4-yl) methoxycarbonylation, tetrahydrofuranyl , Pyrrolidylmethylation, bivalyloxymethylation, acetomethylation, tert-butylated compounds, etc.); when the compound represented by the general formula (I) has a hydroxyl group, Is an acylated, alkylated, phosphorylated, borated compound (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, propano
  • the carboxy group of the compound represented by the general formula (I) is ethyl ester, isopropyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester) , Ethoxycarbonyloxetyl ester, phthalidyl esterification, (5-methyl-2-oxo-1,3 dioxolene-4-yl) methyl esterification, cyclohexyloxycarboxyl esterification, methyl amide
  • a compound represented by the general formula (I) having a carboxy group examples thereof include compounds in which a carboxy group is substituted with a hydroxymethyl group. These compounds can be produced by known methods.
  • the prodrug of the compound represented by the general formula (I) may be a solvate or a non-solvate.
  • the compound of the present invention represented by the general formula (I) can be produced, for example, according to the method shown below, a method analogous thereto or the method shown in Examples.
  • the salt of the general formula (I) may be mentioned as a salt that the raw material compound may be used as a salt.
  • R 1_ the chi [pi and beta [pi, respectively, carboxy groups contained in the groups represented by X and the force R 1 representing the same meaning as beta "11, X 11 and beta [pi, hydroxyl, our amino group And the mercapto group shall be protected as necessary.
  • the compound represented by the above can be prepared by subjecting it to a cyclization reaction and further subjecting it to a deprotection reaction of a protecting group, if necessary.
  • the compound represented by the general formula (II) is converted into an organic solvent (benzene, toluene, xylene, nitrobenzene, acetonitrile, dioxane, tetrahydrofuran, Carbon chloride, chlorophenol, dichloromethane, dichloroethane, etc., or a mixed solvent of any ratio thereof) or without solvent, with or without microwave irradiation, in the presence of a metal catalyst (eg, zirconium chloride) or In the absence, dehydrating agents (for example, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentoxide, chloride salt, Burgess reagent [Burgess Reagent: methyl N- (triethylammosulfol) strength rubamate], Polyphosphoric acid, trifluoroacetic anhydride, acetic anhydride
  • the deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) in an alkali metal hydroxide (sodium hydroxide, sodium hydroxide, lithium hydroxide, lithium hydroxide). Etc.), alkaline earth metal hydroxides (barium hydroxide, hydroxide power, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof, about 0 Performed at a temperature of ⁇ 40 ° C.
  • an organic solvent methanol, tetrahydrofuran, dioxane, etc.
  • alkali metal hydroxide sodium hydroxide, sodium hydroxide, lithium hydroxide, lithium hydroxide.
  • Etc. alkaline earth metal hydroxides
  • barium hydroxide, hydroxide power, etc. or carbonates (sodium carbonate, potassium carbonate, etc.) or their a
  • the deprotection reaction under acidic conditions can be carried out, for example, using an organic acid (acetic acid, trifluoroacetic acid, methane) in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, azole, etc.).
  • organic acid acetic acid, trifluoroacetic acid, methane
  • organic solvent dichloromethane, chloroform, dioxane, ethyl acetate, azole, etc.
  • Deprotection reaction by hydrogenolysis includes, for example, a solvent (ether type (tetrahydrofuran, dioxane, dimethoxyethane, jetyl ether, etc.), alcohol type (methanol, ethanol, etc.), benzene type (benzene , Toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof, About 0 ⁇ in the presence of a catalyst (palladium-carbon, black black, palladium hydroxide carbon, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere under normal pressure or under pressure, or in the presence of ammonium formate. Performed at a temperature of 200 ° C.
  • a solvent ether type (tetrahydrofuran, dioxan
  • the desilylation reaction is carried out at a temperature of about 0 to 40 ° C., for example, using tetraptylammonium fluoride in an organic solvent miscible with water (tetrahydrofuran, acetonitrile, etc.). Be made.
  • the deprotection reaction using a metal is carried out, for example, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof with an organic solvent such as tetrahydrofuran). In the presence, it is carried out at a temperature of about 0 to 40 ° C with ultrasonication if necessary.
  • an acidic solvent acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof with an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex is carried out, for example, by using an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof with a trap reagent (hydrogen Tryptyl tin, triethyl silane, dimedone, morpholine, jetylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and Z or organic acid salts (sodium 2-ethylhexanoate, 2-ethyl) Metal complexes (tetrakistriphenylphosphine palladium (0), disodium bisbis (triphenylphosphine)) in the presence or absence of phosphine reagents (triphenylphosphine, etc.
  • the deprotection reaction can be performed by the method described in, for example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
  • Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, an aryl group, a tert-butyl group, a trichlorodiethyl group, a benzyl (Bn) group, a phenacyl group, a p-methoxybenzyl group, a trityl group, Examples thereof include a solid support having a 2-chlorotrityl group or a structure thereof bound thereto.
  • hydroxyl-protecting group examples include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, and 2-tetrahydrovinyl (THP).
  • TMS Trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • acetyl Ac
  • pivaloyl benzoyl
  • benzyl (Bn) Group p-methoxybenzyl group, aryloxycarboro (Alloc) group, 2,2,2-trichloro-orthoethoxycarboro (Troc) group, and the like.
  • Examples of the protecting group for the amino group include a benzyloxycarbol group, a tert-butoxycarboxyl group (Boc), an aryloxycarbol (Alloc) group, and 1-methyl-1- (4 -Biphenyl) ethoxycarboro (Bpoc) group, trifluoroacetyl group, 9 fluoromethoxycarbole (Fmoc) group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxime And til (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) group, and the like.
  • Examples of protecting groups for mercapto groups include benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydrovinyl (THP), diphenylmethyl, and acetyl (Ac) groups. Can be mentioned.
  • the protecting group for a carboxyl group, a hydroxyl group, an amino group, or a mercapto group is not particularly limited as long as it is a group that can be easily and selectively eliminated.
  • those described in T. W. Greene, Protective uroups in Organic Synthesis, Wiley, New York, 1999 are used.
  • the objective compound of the present invention can be easily produced by using and separating these deprotection reactions.
  • the compound represented by the general formula (II) can be produced by the method represented by the reaction process formula 1.
  • the method of using acid and lide includes, for example, using a carboxylic acid represented by the general formula (IV) as an organic solvent (black mouth form, dichloromethane, jetyl ether, tetrahydrofuran, dimethoxyethane, N, N-dimethylformamide, etc. ) In or without solvent, it is reacted with an acid halide agent (eg oxalyl chloride, salt thiothionyl, etc.) at about ⁇ 20 ° C.
  • an acid halide agent eg oxalyl chloride, salt thiothionyl, etc.
  • the obtained acid chloride is used in an organic solvent (dioxane, tetrahydrofuran, dichloromethane, etc.) in a phase transfer catalyst (tetraptyl ammonium chloride, triethylbenzyl ammonium chloride, trioctylmethyl ammonium chloride, trimethyl decyl ammonium- Quaternary ammonium salts such as um chloride, tetramethyl ammonium bromide, etc.) in the presence or absence of an alkaline aqueous solution (sodium bicarbonate aqueous solution or sodium hydroxide aqueous solution, etc.)
  • a hydrazide compound represented by
  • the method using a mixed acid anhydride is, for example, a method in which the carboxylic acid represented by the general formula (IV) is used in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran) or without solvent.
  • an organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran
  • a method using a condensing agent includes, for example, a hydrazide compound represented by the general formula ( ⁇ ) and a carboxylic acid represented by the general formula (IV) in an organic solvent (black form, dichloromethane).
  • N, N-dimethylformamide, jetyl ether, tetrahydrofuran, etc.) or without solvent In the presence or absence of a base (pyridine, triethylamine, N, N dimethylamino-line, N, N dimethylaminopyridine, etc.), a condensing agent (1,3 dicyclohexylenorenoreimide (DCC), 1-ethyl-3- [3 (Dimethylamino) propyl] carbodiimide (EDC), 1, 1, monocarbodiimidazole (CDI), 2-chloro-1-methylpyridyl-mu-iodine, 1-propanephosphonic acid cyclic anhydride, PPA) and the like, and 1-hydroxybenztriazole (HOBt) or N-hydroxysuccinimide (HOSu) is used or not! /, And the reaction is carried out at about 0 to 40 ° C.
  • a base pyridine, triethyl
  • the reactions (1), (2) and (3) are all desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • inert gas argon, nitrogen, etc.
  • the amidy reaction of the carboxylic acid compound represented by the general formula (V) in the reaction process formula 1 and the hydrazide compound represented by the general formula (VI) is represented by the general formula (IV). It can be carried out by the same method as the amidy reaction between a carboxylic acid compound and a hydrazide compound represented by the general formula ( ⁇ ).
  • reaction scheme 1 the compounds represented by the general formulas (III), (IV), (V) and (VI) used as starting materials may be known ones, or may be known methods, For example, it can be easily produced by using the method described in “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)”.
  • reaction involving heating can be performed using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.
  • a solid-supported reagent supported on a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • the reaction product is obtained by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion It can be purified by exchange resin, scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • the compound of the present invention represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof hereinafter abbreviated as “the compound of the present invention represented by the general formula (I)” or simply “the compound of the present invention”.
  • the toxicity is very low and it is safe enough to use as a medicine.
  • the compound of the present invention represented by the general formula (I) has an FXa inhibitory action and suppresses the extrinsic and intrinsic coagulation cascades, so that the blood coagulation mechanism is activated. Useful for prevention and Z or treatment of embolism.
  • thrombosis / embolism examples include ⁇ thrombosis / embolism associated with cardiovascular diseases (angina pectoris such as stable exertion angina, variant angina, unstable angina, acute myocardial infarction, myocardial infarction, Acute coronary syndromes, asymptomatic myocardial ischemia, coronary artery thrombosis, reocclusion and restenosis after coronary artery bypass surgery, reocclusion and resuscitation associated with coronary artery interpension such as percutaneous transluminal coronary angioplasty 'stent placement Stenosis, cardiomyopathy, acute heart failure, congestive chronic heart failure, valvular disease, reocclusion and restenosis associated with coronary thrombolysis), "thrombosis associated with cerebrovascular disease, embolism (ischemic cerebrovascular disorder) Cerebral infarction acute phase, lacunar infarction, atherothrombotic cerebral infarction, cerebral artery embolism, cerebral
  • thrombus associated with acute medical illness ⁇ embolism, vena cava Thrombosis associated with filter placement and z or prosthetic valve replacement, embolism associated with rheumatic heart disease and atrial fibrillation, cerebral infarction and systemic involvement associated with valvular and Z or non-valvular atrial fibrillation Embolism, recurrent venous thromboembolism, congenital antithrombin (AT) deficiency with recurrent thrombus, cerebral venous occlusion, etc.) "and Z or" systemic and Z or peripheral thrombus, Embolism (arteriosclerosis, limb arteriosclerosis, obstructive arteriosclerosis, Treetop arterial occlusion, Birja's disease, obstructive thromboangiitis, chronic arterial occlusion, chronic arterial occlusion and ulcers based on Z or obstructive thromboangi
  • Ratio of thrombin inhibitory activity value (Ki value) and FXa inhibitory activity value (Ki value) of the compound of the present invention represented by the general formula (I) (thrombin inhibitory activity value (Ki value) ZFXa inhibitory activity value (Ki value))
  • thrombin inhibitory activity value (Ki value) ZFXa inhibitory activity value (Ki value)
  • ⁇ is about 10 to 1,000,000, more preferred ⁇ is about 100 to 1,000,000, and more preferred ⁇ is about 500 to 1,000,000.
  • the Ki value is calculated by a known method.
  • the method for calculating the Ki value is described, for example, in “Enzyme Experiment Method I” (Shunnori Ohno, Fumio Sakiyama, Kenji Takahashi, 1st edition, pages 392-394, Yodogawa Shoten).
  • the in vivo antithrombotic activity of the compounds of the present invention is described in, for example, Thrombosis Research 87-4, 353-357, (1997); Thromb Haemost 79-3, 656-662, (1998) It can be evaluated by the method or a method obtained by improving the method.
  • the compound of the present invention represented by the general formula (I) is: (1) supplementation and Z or enhancement of preventive and Z or therapeutic effect of the compound of the present invention, (2) kinetics of the compound of the present invention 'improvement of absorption, dosage In combination with other drugs, it may be administered as a concomitant drug.
  • the combined use of the compound of the present invention represented by the general formula (I) and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be in separate preparations.
  • the dosage form may be taken.
  • simultaneous administration and administration with a time difference are included.
  • administration at a time interval may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later.
  • Each administration method may be the same or different.
  • the preventive and Z or therapeutic effects are not particularly limited by the above combination drug.
  • Any disease that complements and enhances or enhances the preventive and Z or therapeutic effects of the compound of the present invention may be used.
  • drugs for preventing and / or complementing or enhancing Z or therapeutic effects of thrombotic diseases in which the blood coagulation mechanism of the compound of the present invention represented by the general formula (I) is activated include, for example, lowering blood pressure Drugs, antihyperlipidemic drugs, antiplatelet drugs, anticoagulants, thrombolytic drugs, vasodilators, brain function improving drugs, nootropics, antitumor drugs, hypoglycemic drugs, antiobesity drugs, etc. It is done.
  • antihypertensive agents include enalapril maleate, benazepril hydrochloride, arasepril, cilazapril, trandolapril, lisinopril, imidapril hydrochloride, quinapril hydrochloride, temocapril hydrochloride, delapril hydrochloride, captopril, and perindopril elpmin Hexamethonium bromide, hydralazine hydrochloride, hydrazinophthalazine hydrochloride, labetalol hydrochloride, cripine hydrochloride, candesartan 'cilexetil (TCV_116), candesartan (CV-1197 4), methinoredopa, rosanoletane potassium, oral sultan, valsartan, Eprosartan, e Posartan, ilbesartan, tasos
  • Antihyperlipidemic drugs include HMG-CoA reductase inhibitors (for example, pravastatin or its sodium salt, simvastatin, flupastatin, ripankle, cerivastatin, cerivastatin sodium, itapastatin, atorvastatin or its calcium hydrate, oral Pastatin, ZD-4522 or salts thereof), fibrates (eg, becloclobrate, vinyl fibrate, ciprofibrate, symfibrate, clofibrate, clofibrate aluminum, clofibric acid, bezafibrate, clinofibrate, Etofibrate, Gemfib Mouth Jill, Pilifibrate, Nicofibrate, Ronfibrate, Simfibrate, Theofibrate, Phenofibrate, Fuenofibric Acid, etc.), Yio Exchange fats (eg, cholestyramine), nicotinic acid drugs (eg
  • LDL receptor carotenatives LDL receptor carotenatives
  • cholesterol absorption inhibitors eg ezetimibe
  • MTP inhibitors ileal bile acid transporter Inhibitor
  • SCAP ligand SCAP ligand
  • FXR ligand FXR ligand
  • antiplatelet agents include cycloxygenase inhibitors, thromboxane synthase inhibitors, thromboxane receptor antagonists, thrombin receptor antagonists, adenosine-2-phosphate receptor antagonists. , Serotonin receptor antagonists, phosphodiesterase inhibitors, phosphinocytide 3-kinase inhibitors, prostaglandins, GPIIbZlIIa antagonists, GPVI signal inhibitors including anti-GPVI antibodies, GPIb signal inhibitors including anti-GPIb antibodies, etc. Is mentioned.
  • aspirin SCH530348, E5555, ticlovidin hydrochloride, clopidogrel sulfate, prasdarrel (CS-747), AZD6140, INS—5058 9, AR-C69931MX, YM337, YM028, dipyridamole, DZ-697b, cilostazol And beraprost sodium, NM-702, sarpodalelate hydrochloride, ozadaler sodium, abciximab, tirofiban, loxifiban, eptifibatide, CBL1309 and the like.
  • Anticoagulants include, for example, henolines (eg, heno ⁇ phosphate sodium, dalteparin sodium, heparin calcium, parnaparin sodium, leviparin sodium, octaparine, etc.), henoline analogues ( For example, danaparoid sodium, enoxaparin, nadroparin, bemiparin, leviparin, tinzaparin and other low molecular weight heparins, idranolinettus, fondoperinutus, etc.), sulfarin potassium, thrombin inhibitors (for example, argatroban) , Ximelagatran, melagatran, AZD0837, dabigatran, pinorildin (Hirlog), revirdin, hirudin, decylzine, SSR-182289A, SR-123781A, S-18326, AZD-0837, LB-30870, L-37537
  • thrombolytic agents include t-PA (tissue-type plasminogen activity factor), urokinase, prourokinase, thisokinase, anoleteplase, natepase, monteplase, pamiteplase, streptokinase, alfimeplase, AZD9684 and other ruboxypeptidase U (TAFIa) inhibitors and plasminogen activator inhibitors 1 (PAI-1) inhibitors.
  • t-PA tissue-type plasminogen activity factor
  • vasodilator examples include alprostadil alpha detas, alprostadil, limaprostanolefadetas, limaprostat, epoprostenol sodium, hep mouth-cart, isotaspurin hydrochloride, trazoline hydrochloride , Dipyridamole, combined use with aspirin or dipyridamole sustained-release agent including a combination.
  • Examples of the brain function improving drug include astrocyte function improving drug (for example, (2R) -2-propylpyruocanoic acid, etc.), brain function stimulating drug (for example, aracetam, -sergoline, etc.), Drugs that improve cerebral circulation metabolism (e.g., idebenone, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate, pyrithoxine hydrochloride, ⁇ -aminobutyric acid, bifumelan hydrochloride, lisuride maleate, indeloxazine hydrochloride,- Sergoline, propentophilin, ifenprodil tartrate, cytochrome C, cardiochrome, citicoline, disodium adenosine triphosphate, fasudyl hydrate, fumaric acid-zofunonone, etc.), dopamine receptor agonists (for example, L
  • antidementia drug examples include donepezil hydrochloride.
  • Antitumor agents include, for example, alkyl glazes (nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, thiotepa, carbocon, busulfan, etc.), nitrosourea derivatives (dimustine hydrochloride, ranimustine, etc.) Antimetabolite (methotrexate, mercaptopurine, 6-mercapropurine boside, fluorouracil, tegafur, UFT, carmofur, doxyfluridine, cytarabine, enocitabine, gemcitabine, hydroxycarbamide, procarbazine hydrochloride, etc.
  • alkyl glazes nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, thiotepa, carbocon, busulfan, etc.
  • nitrosourea derivatives dimustine hydrochloride, ranimustine,
  • Antibiotics idarubicin hydrochloride, epirubicin hydrochloride, actinomycin D, mitomycin C, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, neocalcinostatin, pirarubicin, epirubici , Idarubicin, chromomycin A3, bleomycin, hepromycin sulfate, etc., plant alkaloids and hormones (irinotecan hydrochloride, docetaxel, paclitaxel, etoposide, goserelin acetate, estramustine sodium phosphate, mepitiostan, epitiostanol) Tamoxifen taenoate, toremifene taenoate, fuadorzol hydrochloride hydrate, vinorelbine tartrate, jetylstilbestrol phosphate, medroxyprogesterone acetate, bunblastine
  • hypoglycemic agents include insulin preparations (eg, urine, animal insulin preparations extracted from porcine spleen; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast; Protamine insulin submucosa; insulin fragments or derivatives (eg INS-1 etc.), etc., insulin sensitizers (eg pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614, etc., a Dalcosidase inhibitor (eg, voglibose, akanolevose, miglitonore, emidalitate, etc.), biguanide (eg, phenformin, metformin, Buformin, etc.), insulin secretagogues (sulfo-lureas such as tolptamide, da
  • Peptidyl peptidase IV inhibitor eg, NVP-DPP-278, PT-100, sitagliptin, vildagliptin, etc.
  • ⁇ 3 agonist eg, CL-316243, SR-58611-A, UL-TG-307 SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.
  • amylinagost eg, pramlintide
  • phosphotyrosine phosphatase inhibitor eg, vanadic acid
  • gluconeogenesis inhibitor eg, glycogen phosphorylase
  • Inhibitor fructose-1, 6-bisphosphatase inhibitor, glucose mono-6-phosphatase inhibitor, Gon antagonists etc.
  • SGLUT sodium-glucose cotransporter
  • inhibitors e.g., AVE- 2268, KGT-1251, T-1095 etc.
  • Anti-obesity drugs include, for example, central anti-obesity drugs (for example, dexfenfluramine, fenfuneramine, fuentenoremine, sibutramine, amphepramone, dexamphetamine, mazindol, phenolpropanolamine, Benzolex, etc.), spleen lipase inhibitors (eg, orlistat), ⁇ 3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085 etc.), peptidic appetite suppressants (eg, lebutin, CNTF (ciliary neurotrophic factor) etc.), cholecystocynagost (eg, linchtripto, FPL-15849 etc.) It is done.
  • central anti-obesity drugs for example, dexfenfluramine, fenfuneramine, fuentenoremine, sibutramine,
  • the weight ratio of the compound of the present invention represented by the general formula (I) to other drugs is not particularly limited. Other drugs may be administered in combination of any two or more.
  • the dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually in the range of lmg to lOOOmg once per adult, several times once a day.
  • Oral administration or parenteral administration preferably nasal drops, eye drops, patches or ointments
  • parenteral administration preferably nasal drops, eye drops, patches or ointments
  • As a force administered intravenously in the range of 1 to 24 hours per day, or injected subcutaneously in the range of 1 to 5 times per day.
  • the dose varies depending on various conditions, and therefore, a dose smaller than the above dose may be sufficient, or may be necessary beyond the range.
  • a solid preparation for internal use for oral administration a liquid for internal use, an injection for external administration, an external preparation, Used as suppositories, eye drops, inhalants and the like.
  • Solid preparations for internal use for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • Tablets include sublingual tablets, buccal adhesive tablets, buccal quick disintegrating tablets and the like.
  • one or more of the active substances can be used as it is in the strength or excipients (latatose, mannitol, glucose, microcrystalline cellulose, denpun etc.), binders (hydroxylpropylcellulose, (Bulpyrrolidone, magnesium metasilicate aluminate, etc.), disintegrating agent (calcium glycol glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, solubilizer (glutamic acid, aspartic acid, etc.), etc. And is formulated and used according to conventional methods.
  • coating agents sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethylcellulose
  • sphthalate hydroxylpropylcellulose
  • capsules of absorbable substances such as gelatin are also included.
  • Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions' emulsions, syrups, elixirs and the like.
  • a solution one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (purified water, ethanol or a mixture thereof).
  • 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.
  • dosage forms for external use for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops, And nasal drops. These contain one or more active substances and are produced and prepared by known methods or commonly used formulations.
  • buffers that provide isotonicity with stabilizers such as sodium hydrogen sulfite, such as sodium chloride salt, It may contain an isotonic agent such as sodium nitrate or citrate. Further, it may be used as an aerosol agent.
  • injections for parenteral administration include solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent at the time of use.
  • An injection is used by dissolving, suspending or emulsifying one or more active substances 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 may contain stabilizers, solubilizers (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. Good.
  • a sterile solid preparation such as a lyophilized product can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.
  • compositions for parenteral administration include suppositories and vaginal suppositories that contain one or more active substances and are formulated in a conventional manner.
  • the compound of the present invention is a compound excellent in selectivity that specifically inhibits FXa and has a weak inhibitory effect on other enzymes (for example, thrombin).
  • the compound of the present invention is a compound having excellent solubility and absorbability.
  • the compound of the present invention is a compound having a very weak inhibitory action on drug metabolizing enzymes.
  • the compound of the present invention is a compound that avoids side effects such as phospholibidosis, cardiotoxicity (for example, QT prolongation, etc.), or liver toxicity. These are the most demanding physical, chemical, and pharmaceutical properties for drug development [The Merck Manual of Diagnosis and Therapy (17 Ed), Merck & Co. publication], and the compounds of the present invention are excellent. It has the conditions to become a medicine.
  • the solvent in Katsuko shown in the place of separation by chromatography and the place of TLC indicates the elution solvent or developing solvent used. Unless otherwise specified, all solvent ratios represent volume ratios.
  • the solvent in the box in the location of NMR shows the solvent used for the measurement.
  • Ethyl 2- (4 bromophenol) -1,3-oxazole-4-carboxylate (A STATECH, Catalog No. E58636) (l.OOg) in dioxane (5 mL) at room temperature (approximately 20 mL). -25 ° C, the same shall apply below) 2 Piberidinone (402 mg), Cesium carbonate (1.54 g), Xantphos (4,5 Bis (diphenylphosphino) — 9, 9 Dimethylxa N) (147 mg) followed by tris (dibenzylideneacetone) dipalladium (0) (77 mg). The reaction solution was stirred at 95 ° C. for 16 hours.
  • This ester derivative (3.20 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and methanol (10 mL). The reaction mixture was charged with 2N aqueous sodium hydroxide solution (9.7 mL) at room temperature and stirred for 20 hours. 1N Hydrochloric acid (about 30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of hexane and ethyl acetate to give the title compound (2.78 g) having the following physical data.
  • Example 14 To a solution of the compound prepared in Example 14 (120 mg) in methylene chloride (5 mL) at room temperature under an argon atmosphere, the compound prepared in Example 11 (124 mg), triethylamine (188 / z L), 1-hydroxybenztriazole-hydrate (124 mg) and 1-ethyl 3--3-dimethylamino) propyl] carposimide hydrochloride (155 mg) were added and stirred. The reaction mixture was further stirred at 40 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. Concentrated.
  • the obtained residue was recrystallized from ethyl acetate and hexane.
  • the purified product was recrystallized from methylene chloride and ethyl acetate to give the title compound (134 mg) having the following physical data.
  • Example 16 To a solution of the compound prepared in Example 16 (53 mg) in methanol (2 mL) was added 5% palladium carbon (10 mg) at room temperature under an argon atmosphere. The reaction mixture was stirred vigorously for 4 hours under hydrogen atmosphere. The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give the title compound (34 mg) having the following physical data.
  • Example 8 The title compound having the following physical data was obtained in the same manner as in Example 7 ⁇ Example 8, except that 4-trobenzaldehyde was used instead of the compound produced in Example 6.
  • Example 21 To a suspension of the compound prepared in Example 21 (85 mg) in methylene chloride (3 mL) was added pyridine (0.04 mL) at room temperature. To the reaction mixture, a solution of the compound (60 mg) prepared in Example 19 in salt methylene chloride (1 mL) was added dropwise and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and methanol. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The organic layer was washed successively with 2N aqueous sodium hydroxide, water and saturated brine, and concentrated under reduced pressure.
  • the precipitated solid was collected by filtration, washed with water, and dissolved in a mixed solvent of methanol and tetrahydrofuran. The solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain the title compound (62 mg) having the following physical property values.
  • the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 4- (1-pyrrolidylcarbol) benzoate d. 7g ) Got.
  • the obtained ester derivative was dissolved in a mixed solvent of methanol (15 mL) and dimethoxyethane (15 mL). To the mixture was added 1N sodium hydroxide aqueous solution (10 mL), and the mixture was stirred at 25 ° C. for 1 hour. Methyl tert-butyl ether was added to the reaction mixture, and back extraction was performed.
  • Example 23 Using the compound produced in Example 23 instead of the compound produced in Example 11, the title compound having the following physical property values was obtained in the same manner as in Example 15.
  • Example 25 Using the compound prepared in Example 25 instead of the compound prepared in Example 16, the title compound having the following physical properties was obtained in the same manner as in Example 17 ⁇ Example 18. .
  • TLC: Rf 0.46 (methylene chloride Z methanol 9Zl);
  • This amine derivative was dissolved in a mixed solvent of dioxane (10 mL) and water (10 mL). To this solution, triethylamine (3.05 mL), di-tert-butyl dicarbonate (1.05 g) and 2N aqueous sodium hydroxide solution (4.4 mL) were added, and the mixture was stirred overnight at room temperature. Water and methyl tert-butyl ether were added to the reaction mixture, and the phases were separated. Acidify the aqueous layer with 2N hydrochloric acid (16mL) And extracted with ethyl acetate.
  • Example 27 Using the compound prepared in Example 27 instead of the compound prepared in Example 23, the title having the following physical property values was obtained in the same manner as in Example 24 ⁇ Example 25 ⁇ Example 26. A compound was obtained.
  • Example 28 To a solution of the compound prepared in Example 28 (50 mg) in dioxane (2 mL) was added 4N hydrogen chloride. Dioxane solution (2 mL) was added and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (46 mg) having the following physical data.
  • Example 25 Using 4-torobenzoic acid instead of the compound prepared in Example 23, the title compound having the following physical property values was obtained in the same manner as in Example 24 ⁇ Example 25 ⁇ Example 26.
  • TLC: Rf 0.55 (methylene chloride Zmethanol 9Zl).
  • Example 31 Using the compound prepared in Example 31 instead of the compound prepared in Example 21, the title compound having the following physical property values was obtained in the same manner as in Example 22.
  • Example 34 Using the compound prepared in Example 34 instead of the compound prepared in Example 23, benzyl [2- ⁇ 3 [(tert-butoxycarbox] in the same manner as in Example 24 ⁇ Example 25. -Le) amino] propoxy ⁇ — 4— (methylsulfuryl) phenol] — 1, 3, 4-oxa Diazol 2-yl ⁇ methyl carbamate was obtained.
  • To a solution of methylsulfur derivative (0.33 g) in black mouth form (10 mL) was added 3 black mouth perbenzoic acid (0.26 g) under ice cooling, and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 35 In the same manner as in Example 34 ⁇ Example 35, using tert-butyl 4-hydroxy 1-piperidinecarboxylate instead of tert-butyl 3-hydroxypropylcarbamate, the following physical properties were obtained.
  • the title compound having
  • Example 11 To a solution of the compound prepared in Example 11 (440 mg) in methylene chloride (10 mL) was added tert-butoxycarbohydrazide (400 mg), 1-hydroxybenztriazole-hydrate (324 mg), triethylamine at room temperature under an argon atmosphere. (1.25 mL) and 1-ethyl 3- [3- (dimethylamino) propyl] carposimide hydrochloride (575 mg) were added and stirred for 24 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 37 Using the compound prepared in Example 37 instead of the compound prepared in Example 16, the title compound having the following physical property values was obtained in the same manner as in Example 17 ⁇ Example 18. .
  • TLC: Rf 0.21 (Ethyl acetate Zmethanol 30Zl);
  • Example 39 Using the compound prepared in Example 39 instead of the compound prepared in Example 16, the same procedure as in Example 17 ⁇ Example 18 was performed, and the title compound having the following physical property values was obtained. Got a compound
  • Example 41 Using the compound produced in Example 41 instead of the compound produced in Example 24, the same procedure as in Example 25 ⁇ Example 26 was performed, and the title having the following physical property values was obtained. A compound was obtained.
  • Example 43 Using the corresponding amine instead of dimethylamine monohydrochloride, the same procedure as in Example 43 was performed to give the title compound having the following physical data.
  • Example 43 (9) 5 Black mouth N— [3-Oxo 1— 1 [4— (2-Oxo 1-piberidyl) phenol] 1, 3, 4-Oxadiazole 1- 2-yl ⁇ 3— (Tetrahydro 1H pyran 1 4-ylamino) propyl] 2-thiophenecarboxamide
  • Example 42 Using the corresponding amino acid derivative instead of Z-aspartic acid beta tert butyl ester, the same operation as in Example 41 ⁇ Example 42 was performed to obtain the title compound having the following physical property values.
  • Example 44 Using the compound prepared in Example 44 instead of the compound prepared in Example 42, the same operation as in Example 43 was performed to obtain the title compound having the following physical property values. .
  • Example 45 Using the corresponding amine instead of dimethylamine monohydrochloride, the same operation as in Example 45 was performed to obtain the title compound having the following physical properties.
  • Example 42 Using the corresponding amino acid derivative instead of Z-aspartic acid beta tert butyl ester, the same operation as in Example 41 ⁇ Example 42 was performed to obtain the title compound having the following physical property values.
  • Example 47 The same procedure as in Example 47 was carried out using the corresponding acid halide in place of salt acetyl chloride to give the title compound having the following physical properties.
  • Example 42 Using the corresponding amino acid derivative instead of aspartic acid beta tert butyl ester, the same operation as in Example 41 ⁇ Example 42 was performed to obtain the title compound having the following physical property values.
  • Example 42 Using the corresponding amino acid derivative instead of aspartic acid beta tert butyl ester, the same operation as in Example 41 ⁇ Example 42 was performed to obtain the title compound having the following physical property values.
  • Example 48 (1) 5 Black mouth N— (l—Methyl 1— 1 [4— (2-oxo 1-piveridyl) pheyl] -1, 3, 4 oxadiazo 1 ro 2—yl ⁇ ethyl) 2 Thiophencarbox Samide,
  • Example 42 Using the corresponding amino acid derivative instead of aspartic acid beta tert butyl ester, the same operation as in Example 41 ⁇ Example 42 was performed to obtain the title compound having the following physical property values.
  • Example 49 To a solution of the compound prepared in Example 49 (250 mg) in methylene chloride (10 mL) was added 3 ° C. perbenzoic acid (149 mg) at 0 ° C. under an argon atmosphere, and the mixture was stirred for 2 hours. Further, 3-chloroperbenzoic acid (35 mg) was added and stirred for 1 hour. Three-clonal perbenzoic acid (26 mg) was added again and stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine.
  • Example 50 The title compound having the following physical data was obtained by conducting the same operation as in Example 50 using the corresponding sulfide in place of the compound prepared in Example 49.
  • Example 14 Benzyl hydrazinecarboxylate was used in place of the compound prepared in Example 14, V, and 4- [(tert-butoxycarbol) amino] benzoic acid was used in place of the compound prepared in Example 11. Then, a reaction similar to that in Example 15 ⁇ Example 17 was performed to obtain a hydrazide.
  • Example 41 Using this hydrazide and Boc-DL-methionine, Example 41 ⁇ Example 25 ⁇ Example 29-> The same procedure as in Example 8 was performed to obtain an arline form.
  • Example 50 The title compound having the following physical data was obtained by the same procedures as in Example 22 ⁇ Example 50, using this phosphide and the compound prepared in Example 19.
  • Example 51 Using the corresponding amino acid derivative instead of Boc-DL methionine, the same operation as in Example 51 was performed to obtain the title compound having the following physical property values.
  • Example 15 ⁇ tert-butyl hydrazinecarboxylate was used in place of the compound prepared in Example 14, and 2 fluoro 4-trobenzoic acid was used in place of the compound prepared in Example 11. Reaction similar to Example 29 was performed and the hydrazide body was obtained.
  • Example 15 Using this hydrazide and Boc-DL-methionine, the title compound having the following physical property values was obtained in the same manner as in Example 15 ⁇ Example 25 ⁇ Example 29 ⁇ Example 8 ⁇ Example 21. Got.
  • Example 52 Using the compound manufactured in Example 52 instead of the compound manufactured in Example 21, the same procedure as in Example 22 ⁇ Example 50 was performed, and the title having the following physical property values was obtained. A compound was obtained.
  • Example 54 Using the compound prepared in Example 54 instead of Z-aspartic acid-beta-tert-butyl ester, the same operation as in Example 41 ⁇ Example 42 was performed to obtain the title compound having the following physical property values. It was.
  • Jetyl 2- [(tert-butoxycarbol) amino] malonate (15.0g) in tetrahydrofuran Z ethanol (50mLZ50mL)
  • 5N sodium hydroxide aqueous solution (12mL) at room temperature and stir for 30 minutes did.
  • the reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine.
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 25 Example 29 ⁇ Example 8 ⁇ Example 22
  • the title compound having the following physical data was obtained in the same manner as in Example 22.

Abstract

L'invention concerne un composé ayant un effet anti-Fxa, utile pour prévenir et/ou traiter les maladies thrombotiques ayant un mécanisme de coagulation du sang activée, telle qu'une thrombose/embolie associée avec une maladie cardiovasculaire, une thrombose/embolie associée avec une maladie cérébrovasculaire et une thrombose/embolie associée avec une maladie veineuse. L'invention concerne donc un composé représenté par la formule générale (I), un sel ou un solvate de ce composé, ou un promédicament de ce composé, sel ou solvate : (I) où le cycle A représente un groupe cyclique dont le plan peut être substitué ; B représente un groupe cyclique pouvant être substitué ; R1 représente un substituant ; et X représente un espaceur pour la chaîne principale ayant de 1 à 5 atomes et pouvant également être substitué.
PCT/JP2006/313290 2005-07-08 2006-07-04 Compose comportant un groupe cyclique ayant un noyau plan WO2007007588A1 (fr)

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US7763608B2 (en) 2006-05-05 2010-07-27 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
JP2010526319A (ja) * 2007-05-03 2010-07-29 アキュメトリックス インコーポレイテッド トロンビンレセプターアンタゴニストによる血小板凝集阻害を測定する方法
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide
US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
US8048902B2 (en) 2008-12-15 2011-11-01 Amira Pharmaceuticals, Inc. Antagonists of lysophosphatidic acid receptors
US8058300B2 (en) 2009-06-03 2011-11-15 Amira Pharmaceuticals, Inc. Polycyclic antagonists of lysophosphatidic acid receptors
US8153670B2 (en) 2004-06-18 2012-04-10 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
WO2012054510A1 (fr) * 2010-10-19 2012-04-26 Comentis, Inc. Composés oxadiazole qui inhibent l'activité de la bêta-secrétase, et leurs procédés d'utilisation
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
US8217066B2 (en) 2009-10-01 2012-07-10 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8455499B2 (en) 2008-12-11 2013-06-04 Amira Pharmaceuticals, Inc. Alkyne antagonists of lysophosphatidic acid receptors
US8530501B2 (en) 2009-12-17 2013-09-10 Millennium Pharmaceuticals, Inc. Salts and crystalline forms of a factor Xa inhibitor
US8541587B2 (en) 2011-04-05 2013-09-24 Amira Pharmaceuticals, Inc. Lysophosphatidic acid receptor antagonists
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US8592402B2 (en) 2009-08-04 2013-11-26 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8664220B2 (en) 2009-10-01 2014-03-04 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US8742120B2 (en) 2009-12-17 2014-06-03 Millennium Pharmaceuticals, Inc. Methods of preparing factor xa inhibitors and salts thereof
US9506938B2 (en) 2003-07-08 2016-11-29 Accumetrics, Inc. Methods for measuring platelet reactivity of individuals treated with drug eluting stents
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds

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US8574828B2 (en) 2003-07-08 2013-11-05 Accumetrics, Inc. Controlled platelet activation to monitor therapy of ADP antagonists
US9341637B2 (en) 2003-07-08 2016-05-17 Accumetrics Inc. Controlled platelet activation to monitor therapy of ADP antagonists
US9506938B2 (en) 2003-07-08 2016-11-29 Accumetrics, Inc. Methods for measuring platelet reactivity of individuals treated with drug eluting stents
US8377974B2 (en) 2004-06-18 2013-02-19 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8153670B2 (en) 2004-06-18 2012-04-10 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8063077B2 (en) 2006-05-05 2011-11-22 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8349873B2 (en) 2006-05-05 2013-01-08 Millennium Pharmaceuticals, Inc. Factor XA inhibitors
US7767697B2 (en) 2006-05-05 2010-08-03 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7763608B2 (en) 2006-05-05 2010-07-27 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
WO2008111299A1 (fr) * 2007-03-09 2008-09-18 Daiichi Sankyo Company, Limited Nouveau dérivé de diamide
JP2010526319A (ja) * 2007-05-03 2010-07-29 アキュメトリックス インコーポレイテッド トロンビンレセプターアンタゴニストによる血小板凝集阻害を測定する方法
US7994179B2 (en) 2007-12-20 2011-08-09 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
US8455499B2 (en) 2008-12-11 2013-06-04 Amira Pharmaceuticals, Inc. Alkyne antagonists of lysophosphatidic acid receptors
US8048902B2 (en) 2008-12-15 2011-11-01 Amira Pharmaceuticals, Inc. Antagonists of lysophosphatidic acid receptors
US8440707B2 (en) 2008-12-15 2013-05-14 Amira Pharmaceuticals, Inc. Antagonists of lysophosphatidic acid receptors
US8058300B2 (en) 2009-06-03 2011-11-15 Amira Pharmaceuticals, Inc. Polycyclic antagonists of lysophosphatidic acid receptors
US8273780B2 (en) 2009-06-03 2012-09-25 Amira Pharmaceuticals, Inc. Polycyclic antagonists of lysophosphatidic acid receptors
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
WO2011007819A1 (fr) 2009-07-17 2011-01-20 塩野義製薬株式会社 Produit pharmaceutique contenant un composé lactame ou benzène sulfonamide
US8592402B2 (en) 2009-08-04 2013-11-26 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8778983B2 (en) 2009-10-01 2014-07-15 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US8664220B2 (en) 2009-10-01 2014-03-04 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US9090573B2 (en) 2009-10-01 2015-07-28 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8217066B2 (en) 2009-10-01 2012-07-10 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US9624182B2 (en) 2009-10-01 2017-04-18 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US10000456B2 (en) 2009-10-01 2018-06-19 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US8742120B2 (en) 2009-12-17 2014-06-03 Millennium Pharmaceuticals, Inc. Methods of preparing factor xa inhibitors and salts thereof
US8530501B2 (en) 2009-12-17 2013-09-10 Millennium Pharmaceuticals, Inc. Salts and crystalline forms of a factor Xa inhibitor
WO2012054510A1 (fr) * 2010-10-19 2012-04-26 Comentis, Inc. Composés oxadiazole qui inhibent l'activité de la bêta-secrétase, et leurs procédés d'utilisation
US8541587B2 (en) 2011-04-05 2013-09-24 Amira Pharmaceuticals, Inc. Lysophosphatidic acid receptor antagonists
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

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