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WO2013039202A1 - Nouveau dérivé d'acide acrylique - Google Patents

Nouveau dérivé d'acide acrylique Download PDF

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Publication number
WO2013039202A1
WO2013039202A1 PCT/JP2012/073632 JP2012073632W WO2013039202A1 WO 2013039202 A1 WO2013039202 A1 WO 2013039202A1 JP 2012073632 W JP2012073632 W JP 2012073632W WO 2013039202 A1 WO2013039202 A1 WO 2013039202A1
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group
compound
acceptable salt
pharmacologically acceptable
alkyl group
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PCT/JP2012/073632
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English (en)
Japanese (ja)
Inventor
勉 永田
小林　順
昌倫 岸田
崇 石山
洋成 清水
研吾 野口
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第一三共株式会社
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Publication of WO2013039202A1 publication Critical patent/WO2013039202A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel acrylic acid derivative having excellent TAFIa inhibitory activity.
  • thrombus In vivo, when a failure occurs in a blood vessel, platelets and / or a coagulation cascade are activated to prevent blood leakage, and a thrombus is formed to suppress bleeding.
  • Thrombin generated by the activation of the coagulation cascade cleaves fibrinogen to form insoluble fibrin. Fibrin exists in a mesh form in the thrombus and has a function of strengthening the thrombus. This reaction is called coagulation.
  • the formed fibrin is then degraded by an in vivo reaction. This reaction is fibrinolysis. Under normal conditions, the balance between coagulation and fibrinolysis is regulated and no abnormal amount of thrombus accumulates in the blood vessel.
  • Thrombus formation occurs due to three factors (Virchow's three principles: changes in blood vessel wall properties, changes in blood components, changes in blood flow). Diseases resulting from thrombus formation are one of the most common causes of death among developed countries.
  • TAFI is a carboxypeptidase that is produced in the liver and secreted into the blood.
  • the N-terminal 92-amino acid complex is cleaved by thrombin or thrombin / thrombomodulin residues. Activated.
  • TAFI is also called carboxypeptidase U, carboxypeptidase R, or plasma carboxypeptidase B.
  • TAFIa Activated TAFI is called TAFIa.
  • TAFIa inhibits fibrinolysis by removing the C-terminal Lys or Arg residue of fibrin, which is a major component of thrombus, and fibrin partial degradation products (FDP, Fibrin Degradation Products).
  • FDP Fibrin Degradation Products
  • Two enzymes that induce and promote fibrinolysis, tPA (tissue-type plasminogen activator) and plasminogen bind to fibrin and Lys residues of FDP via their Lys binding sites To do. Subsequently, tPA activates plasminogen on the surface of the fibrin molecule to convert it into plasmin, and initiates fibrinolysis.
  • a Lys or Arg residue appears at the C-terminus of FDP generated by plasmin cleaving fibrin.
  • new plasminogen and tPA bind to the Lys residue of FDP, and further plasmin is generated, so that fibrinolysis proceeds efficiently (positive feedback mechanism of fibrinolysis).
  • TAFIa removes the C-terminal Lys residue of FDP, activation of plasminogen by tPA on the fibrin molecule is inhibited, and an efficient fibrinolytic reaction does not occur.
  • TAFIa suppresses the positive feedback mechanism of fibrinolysis.
  • coagulation As described above, a delicate balance between coagulation and fibrinolysis is established in vivo.
  • coagulation is enhanced due to a disease or the like, blood clots are easily formed, and various diseases develop.
  • diseases include myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome and pulmonary fibrosis. is there.
  • enzymes in the coagulation cascade are often targeted for the treatment of thrombosis. These include activated coagulation factor X (Xa) and thrombin. Inhibitors to these enzymes are at risk for potential side effects such as bleeding. Heparin and low molecular weight heparin cannot be expected to have a medicinal effect when administered orally and must be administered in hospitals. Warfarin can be administered orally, but regular blood tests are necessary for reasons such as interactions with other drugs. Aspirin is an orally administrable drug that inhibits platelet activation and inhibits thrombus formation, but has side effects such as gastric bleeding. One of the goals for further improving the current treatment methods is not to prolong bleeding time while maintaining a high therapeutic effect by drug administration. TAFIa inhibitors are thought to have a low risk for bleeding because they do not affect the process of coagulation and hemostasis by platelets.
  • the fibrinolysis reaction can be made efficient by inhibiting TAFIa and the blood clot can be removed more quickly.
  • it can be expected to exhibit excellent effects in the treatment and prevention of diseases caused by blood clots. So far, several examples of animal experiments that have shown antithrombotic effects by inhibiting TAFIa have been reported.
  • Non-patent Document 2 There is a report that an anti-thrombotic effect was shown in an iron chloride-induced thrombus model by intravenously administering a 39-amino acid polypeptide potatocarboxypeptidase inhibitor (PCI) that inhibits TAFIa to mice.
  • PCI 39-amino acid polypeptide potatocarboxypeptidase inhibitor
  • Non-patent Document 3 In the rabbit venous thrombosis model, the low molecular weight TAFIa inhibitor decreased the thrombus amount by about 35% by intravenous administration (Non-patent Document 3).
  • the low molecular weight TAFIa inhibitor compound is the equivalent of a rat thromboembolism model that reduces the amount of thrombus deposited on the kidney, increases the fibrinolytic marker D-dimer, and reduces the dose of tPA in combination with tPA.
  • the antithrombotic effect was shown (nonpatent literature 4 and 5).
  • Patent Documents 1 to 5 disclose compounds exhibiting TAFIa inhibitory activity.
  • the present inventors have excellent TAFIa inhibitory activity, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation Various synthetic studies were conducted with the aim of acquiring therapeutic agents for syndrome or pulmonary fibrosis. As a result, the inventors have found that an acrylic acid derivative having a specific structure or a pharmacologically acceptable salt thereof exhibits excellent TAFIa inhibitory activity, and has completed the present invention.
  • the present invention provides an acrylic acid derivative exhibiting excellent TAFIa inhibitory activity or a pharmacologically acceptable salt thereof, and a pharmaceutical containing these.
  • R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ⁇ C 8 cycloalkyl group, C 1 ⁇ C 3 alkoxy group, a
  • R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ⁇ C 8 cycloalkyl group, C 1 ⁇ C 3 alkoxy group, a
  • R a is the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 to C 3 alkyl group, a C 3 to C 6 cycloalkyl group, a phenyl group and a phenoxy group.
  • An optionally substituted C 1 -C 6 alkyl group substituted with the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a phenyl group and a phenoxy group; which may be C 2 ⁇ C 6 alkenyl group; a hydroxyl group, a halogen atom, an amino group and a C 1 ⁇ C 3 may be substituted by the same or different 1 to 3 groups selected from alkyl radicals C 3 ⁇ C 8 cycloalkyl group; a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1 ⁇ C 3 alkyl group, a halogeno C 1 ⁇ C 3 alkyl group (said substituents may indicate the same 1 to 3 halogen atoms .), C 1 ⁇ C 3 alkoxy group, C 1 ⁇ C 3 alkylsulfonyl group,
  • R a is a C 3 -C 6 alkyl group; a C 3 -C 6 cycloalkyl group or a C 1 -C 2 alkyl group substituted with a phenyl group; a C 3 -C 7 cycloalkyl
  • R a is a group
  • the compound according to item 1, or a pharmacologically acceptable salt thereof (12) The compound according to any one of (1) to (10) above, wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms, or Its pharmacologically acceptable salts, (13) The compound according to any one of (1) to (12), wherein R 3 and R 9 are both hydrogen atoms, or a pharmacologically acceptable salt thereof, (14) R 9 is a prodrug group, and the prodrug group is the same selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group, and a heterocyclyl group.
  • R 9 is a prodrug group, and the prodrug group includes a phenylalanyl group, an L-norleucyl group, [(5-methyl-2-oxo-1,3-dioxol-4-yl
  • a C 1 -C 6 alkyl group which may be substituted with three groups; or may be substituted with the same or different 1 to 3 groups selected from an oxo group and a C 1 -C 6 alkyl group
  • R 3 is a prodrug group, and the prodrug group is a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group, according to any one of (1) to (12) above
  • a compound, or a pharmacologically acceptable salt thereof (18)
  • the compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of: (19) A medicament comprising the compound according to any one of (1) to (18) above or a pharmacologically acceptable salt thereof as an active ingredient, (20) A TAFIa inhibitor comprising the compound according to any one of (1) to (18) above or a pharmacologically acceptable salt thereof as an active ingredient, (21) A fibrinolysis promoter containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient, (22) A prophylactic agent for a disease caused by inhibition of fibrinolysis comprising the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient, or Therapeutic drugs, (23) Myocardial infarction, angina pectoris (stable angina, unstable angina) containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient Acute coronary syndromes such as cardiomyopathy; venous
  • thrombosis / embolism such as disease (25)
  • Lung diseases such as embolic pulmonary hypertension; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis, acute progressive glomerulonephritis, etc.), kidney diseases such as renal infarction, diabetic nephritis; Liver disease such as liver fibrosis, hepatitis, cirrhosis; eye disease associated with ocular fibrin deposition; organ
  • the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent TAFIa inhibitory activity, and exhibits high oral absorption, plasma concentration and retention in blood. Showed excellent pharmacological action.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is excellent in pharmacokinetics such as distribution in the body, retention in blood, etc., has no prolonged bleeding time, and is highly safe. .
  • the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used as a medicine (especially a prophylactic or therapeutic drug for diseases caused by inhibition of fibrinolysis, Are useful as therapeutic agents), especially acute coronary syndromes such as myocardial infarction and angina (stable angina, unstable angina); venous thromboembolism such as deep vein thrombosis and pulmonary embolism; blood vessels Thrombosis or embolism in the cardiovascular system after surgical operations such as reopening surgery, angioplasty, stent placement, bypass surgery, etc .; Thrombus after artificial joint replacement surgery such as knee replacement surgery and hip replacement surgery Inflammation-related intravascular diseases such as sepsis, disseminated intravascular coagulation syndrome (DIC); Originated / related to peripheral vascular disorders such as peripheral arterial embolism (PAO), arteriosclerosis, diabetes disease; Diseases related to tumors such as shape cancer and blood cancer; or prophylactic drugs
  • the compound of the present invention is a disease caused by contact with a foreign body such as a medical device such as an artificial joint, a vascular catheter, an artificial blood vessel, a vascular stent, or an artificial valve at the time of joint replacement; It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for thrombosis / embolism such as a disease caused by contact of blood with an external medical device such as a cardiopulmonary device or a medical device during hemodialysis.
  • a medical device such as an artificial joint, a vascular catheter, an artificial blood vessel, a vascular stent, or an artificial valve at the time of joint replacement
  • a prophylactic or therapeutic agent preferably a therapeutic agent for thrombosis / embolism
  • an external medical device such as a cardiopulmonary device or a medical device during hemodialysis.
  • the compound of the present invention is used for pulmonary hypertension, adult respiratory urgency syndrome, pulmonary fibrosis, chronic thromboembolic pulmonary hypertension and the like; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis) , Acute progressive glomerulonephritis), kidney diseases such as renal infarction, diabetic nephritis; liver diseases such as liver fibrosis, hepatitis, cirrhosis; eye diseases associated with ocular fibrin deposition; organ transplantation or resection Postoperative organ dysfunction; microcirculatory disturbance due to microthrombosis including thrombotic microangiopathy; or preventive or therapeutic (preferably, therapeutic) for diseases / symptoms associated with cancer cell migration / metastasis It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for diseases associated with thrombosis / embolism or associated with fibrin deposition or the like
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1 -C 6 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group.
  • halogeno C 1 -C 3 alkyl group is the above “C 1 -C 3 alkyl group” substituted with 1 to 3 of the above “halogen atoms”, preferably 1 to 3 A C 1 -C 3 alkyl group substituted with a fluorine atom, and more preferably a trifluoromethyl group.
  • C 3 -C 10 cycloalkyl group means a saturated hydrocarbon ring having 3 to 10 carbon atoms, and is exemplified by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • a polycycloalkyl group such as a bicycloalkyl group or a tricycloalkyl group is also included.
  • bicycloalkyl group examples include a norbornyl group such as an exo-2-norbornyl group, an endo- Such as 2-norbornyl group, 3-pinanyl group, bicyclo [3.1.0] hexyl group, bicyclo [2.2.1] heptyl group, bicyclo [2.2.2] oct-2-yl group, tricyclo
  • the alkyl group examples include an adamantyl group such as a 1-adamantyl group and a 2-adamantyl group.
  • Number 3 is a saturated hydrocarbon ring of ⁇ 8 (C 3 ⁇ C 8 cycloalkyl group), more preferably a saturated hydrocarbon ring having 3 to 7 carbon atoms (C 3 ⁇ C 7 cycloalkyl group), further More preferred is a cyclohexyl group.
  • the “C 1 -C 6 alkoxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert- Examples thereof include a butoxy group, preferably a linear or branched alkyloxy group having 1 to 3 carbon atoms (C 1 -C 3 alkoxy group), and more preferably a methoxy group.
  • halogeno C 1 -C 3 alkoxy group is the above-mentioned “C 1 -C 3 alkoxy group” substituted with the same or different 1 to 3 “halogen atoms”, preferably 1 to 3 A C 1 -C 3 alkoxy group substituted with a fluorine atom, and more preferably a trifluoromethoxy group.
  • C 1 -C 3 alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 3 carbon atoms, and includes a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group. Can be mentioned.
  • Aryl group means an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
  • heterocyclyl group is a monocyclic or bicyclic 3 to 10-membered saturated or unsaturated heterocyclic ring containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom Group, for example, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl Group, pyrazinyl group, benzimidazolyl group, benzoxazolyl group, quinolyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyridyl group, tetrahydropyridyl group, etc., and
  • Aryloxy group means a group composed of the aryl group and an oxy group, and examples thereof include a phenoxy group and a naphthoxy group.
  • C 2 -C 6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, butenyl, 1-propenyl, isopropenyl. Groups and the like.
  • halogenoaryl group is the above “aryl group” substituted with 1 to 3 “halogen atoms” which are the same or different, and examples thereof include a chlorophenyl group and a bromophenyl group.
  • Halogeno unsaturated heterocyclyl group means the above “unsaturated heterocyclyl group” substituted with 1 to 3 of the above “halogen atoms”, and examples thereof include a chlorothienyl group “C 1 -C
  • the “ 6 alkanoyl group” means a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, An isovaleryl group, a pivaloyl group, a hexanoyl group, etc. are mentioned.
  • C 2 -C 6 alkanoyloxy group means a group consisting of a linear or branched alkanoyl group having 2 to 6 carbon atoms and an oxy group, such as an acetyloxy group, propionyloxy group. Group, hexanoyloxy group and the like.
  • (C 3 -C 6 cycloalkyl) carbonyloxy group means a group consisting of a saturated hydrocarbon ring having 3 to 6 carbon atoms and a carbonyloxy group, such as a cyclopropylcarbonyloxy group, a cyclohexylcarbonyloxy group. Etc.
  • the “(C 1 -C 6 alkoxy) carbonyl group” means a group composed of the C 1 -C 6 alkoxy group and a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and an isopropoxycarbonyl group.
  • Heterocyclyloxy group means a group composed of the heterocyclyl group and an oxy group, and examples thereof include a pyrrolidin-3-yloxy group and a pyridin-4-yloxy group.
  • heterocyclylalkyl group means a group consisting of the heterocyclyl group and the C 1 -C 6 alkyl group, and examples thereof include a 1,3-dioxol-4-ylmethyl group.
  • heterocyclylalkyloxycarbonyl group means a group consisting of the heterocyclyl group, the C 1 -C 6 alkoxy group and a carbonyl group, and examples thereof include a 1,3-dioxol-4-ylmethoxycarbonyl group. .
  • the “prodrug group” is a group that can be converted into the compound (I) that is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized or reduced.
  • the prodrug group in R 3 is a prodrug group with respect to a carboxy group, and is preferably the same or selected from a C 2 to C 6 alkanoyloxy group, a (C 3 to C 6 cycloalkyl) carbonyloxy group and an aryl group.
  • C 1 -C 6 alkyl group optionally substituted with 1 to 3 different groups, or 1 to 3 groups selected from the same or different groups selected from oxo group and C 1 -C 6 alkyl group
  • a heterocyclylalkyl group which may be a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group.
  • the prodrug group in R 9 is a prodrug group with respect to an amino group, and preferably from an amino group, a halogeno group, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group, and a heterocyclyl group.
  • a heterocyclylalkyloxycarbonyl group which may be substituted with the same or different 1 to 3 groups selected from An aenylalanyl group, an L-norleucyl group, a [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, a [1- (isobutyryloxy) ethoxy] carbonyl group, [1- A (2,2-di
  • the compound represented by the general formula (I) is preferably a compound represented by the general formula (Ia).
  • R a is preferably selected from (a) a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group and a phenoxy group.
  • C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups; the same or selected from hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group
  • a C 2 -C 6 alkenyl group optionally substituted with 1 to 3 different groups; the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group and a C 1 -C 3 alkyl group;
  • * indicates a bonding position
  • R b is preferably (a) a hydrogen atom or a methyl group, and more preferably (b) a hydrogen atom.
  • R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are each preferably a hydrogen atom (a).
  • R 5 is preferably (a) a hydrogen atom or a methyl group, and more preferably (b) a hydrogen atom.
  • R 3 is preferably (a) a hydrogen atom.
  • R 3 is a prodrug group
  • a prodrug group bonded to the oxygen atom of the carboxyl group preferably (c) a C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cyclo An alkyl) carbonyloxy group and an aryl group, and a C 1 to C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from an aryl group; or an oxo group and a C 1 to C 6 alkyl group Heterocyclylalkyl group which may be substituted with the same or different 1 to 3 groups, more preferably (d) benzyl group or [(isopropoxycarbonyl) oxy] ethyl group.
  • R 9 is preferably (a) a hydrogen atom.
  • R 9 is a prodrug group
  • a prodrug group bonded to the nitrogen atom of the amino group preferably (c) an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, C 1 ⁇ C 6 alkoxy group, the same or different 1 to 3 is substituted with a group optionally C 1 even if ⁇ C 6 alkanoyl group selected from heterocyclyl, an aryl group, and to; C 1 ⁇ C 6 alkyl radical; C 2 ⁇ (C 1 -C 6 alkoxy) carbonyl group optionally substituted by the same or different 1 to 3 groups selected from C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyloxy group and aryl group Or a heterocyclylalkyloxycarbonyl optionally substituted by the same or different 1 to 3 groups
  • R a is a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, and C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from phenoxy group; hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group A C 2 -C 6 alkenyl group which may be substituted with the same or different 1 to 3 groups selected from: a hydroxyl group, a halogen atom, an amino group and a C 1
  • R a is a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are both hydrogen atoms
  • R a is a group
  • R a is a group
  • R b R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms. It is.
  • R 3 is a prodrug group
  • R a is preferably a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms
  • R 3 is a prodrug group bonded to the oxygen atom of the carboxyl group
  • R a is a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is a hydrogen atom
  • R 3 is the same or different 1 to 3 groups selected from a C 2 -C 6 alkanoyloxy group, a (C 3 -C 6 cycloalkyl) carbonyloxy group and an aryl group
  • a C 1 -C 6 alkyl group which may be substituted by: or a heterocycly
  • R 9 is a prodrug group
  • R a is preferably a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms
  • R 9 is a prodrug group bonded to the nitrogen atom of the amino group
  • R a is a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a hydrogen atom
  • R 9 is the same or different one selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group and a heterocyclyl group.
  • C 1 -C 6 alkanoyl group optionally substituted with three groups; C 1 -C 6 alkyl group; C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyloxy group and aryl the same or different 1 to 3 may be substituted by a group (C 1 ⁇ C 6 alkoxy) carbonyl group selected from the group; or, the same or different selected from oxo group and C 1 ⁇ C 6 alkyl group 1 to 3 substituents which may be heterocyclylalkyl alkyloxycarbonyl group with a group that, More preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a hydrogen atom, and R 9 is a phenylalanyl group, an L-norleucyl group,
  • Preferred specific examples of the compound represented by the general formula (I) or (Ia) include the following.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a and R b are the same as described above, and R 10 is substituted with a fluorine atom.
  • An optionally substituted C 1 -C 3 alkyl group or a phenyl group PG 1 represents an amino protecting group, PG 2 represents a hydrogen atom or an amino protecting group, and PG 3 represents a carboxy protecting group. Show.
  • Compound (IV) can be produced by subjecting compound (IIa) and compound (III) to an aldol reaction to produce compound (IV), and the resulting compound (IV) can be subjected to a dehydration reaction.
  • compound (V) can be produced by performing a wittig reaction between compound (IIb) and compound (III).
  • Compound (Ib) can be produced by removing the protecting group of the obtained compound (V).
  • the aldol reaction is a reaction in which compound (IIa) as a CH active compound and compound (III) containing a carbonyl group are combined in the presence of a strong base to form compound (IV).
  • the strong base include carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; Metal alkoxide, alkali metal hydroxide or hydride; alkyllithium such as n-butyllithium, organometallic base represented by dialkylaminolithium such as lithium diisopropylamide; or such as lithium hexamethyldisilazide An organometallic base of bissilylamine can be used.
  • reaction solvent examples include acyclic, cyclic or aromatic hydrocarbons, alcohols, or polar aprotic solvents such as tetrahydrofuran, N, N-dimethylformamide or diethoxyethane, and mixed solvents thereof. Can be used.
  • the reaction temperature is usually about ⁇ 78 ° C. to room temperature.
  • the hydroxyl group of compound (IV) is treated with a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride in an inert solvent at ⁇ 78 ° C. to 50 ° C. in the presence of triethylamine to form a sulfonate ester.
  • a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride in an inert solvent at ⁇ 78 ° C. to 50 ° C. in the presence of triethylamine to form a sulfonate ester.
  • the inert solvent examples include alkyl halide solvents such as methylene chloride, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic solvents such as benzene and toluene; Alternatively, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one and the like, and in addition to these, sulfoxide solvents such as dimethyl sulfoxide and sulfolane may be mentioned; It is also possible to use ketone solvents such as acetone and methyl ethyl ketone; or acetonitrile.
  • alkyl halide solvents such as methylene chloride, chloroform and carbon tetrachloride
  • ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and di
  • pyridine 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) is used. be able to. In some cases, the dehydration reaction may proceed during the aldol reaction.
  • DBU diazabicyclo [5.4.0] undec-7-ene
  • the Wittig reaction is a reaction in which a compound (IIb) having a phosphoryl group and a compound (III) having a carbonyl group are reacted in the presence of a base to produce a compound (V) which is an ⁇ , ⁇ -unsaturated ester.
  • a base sodium hydride, sodium methoxide, potassium carbonate, potassium hexamethylsilazide and the like can be used.
  • a base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylamine and lithium chloride can be used in combination.
  • cyclic ethers such as 18-crown 6-ether can be added as additives.
  • reaction temperature may be selected depending on the substrate, and the reaction can be carried out from ⁇ 78 ° C. under reflux conditions. It can be produced with reference to the following document. 1) Blanchette, M .; A. , Et al. Tetrahedron Lett. 1984, 25, 2183. 2) Still, W .; C. , Et al. Tetrahedron Lett. 1983, 24, 4405.
  • a protecting group usually used as an amino-protecting group in the synthesis of organic compounds, particularly in peptide synthesis may be used.
  • a tert-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group may be used.
  • Alkoxycarbonyl groups such as benzyl groups; arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, para (or ortho) nitrobenzyloxycarbonyl groups; benzyl groups, 4-methoxybenzyl groups, triphenylmethyl groups, etc.
  • alkanoyl group such as a formyl group or an acetyl group; an aroyl group such as a benzoyl group; or an arylsulfonyl group such as a 2,4-dinitrobenzenesulfonyl group or an orthonitrobenzenesulfonyl group.
  • These amino-protecting groups may be selected according to the properties of the compound protecting the amino group, and the reagents and conditions corresponding to the protecting groups may be selected when removing these protecting groups.
  • protecting group for the carboxy group examples include an alkyl group, an aryl group, and an arylalkyl ester group. These protecting groups for the carboxy group may be selected according to the properties of the compound protecting the carboxy group, and the reagents and conditions corresponding to the protecting group may be selected when removing these protecting groups.
  • Compound (I) of the present invention can also be produced by the following method.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , PG 1 , PG 2 and PG 3 are the same as described above, and PG 4 represents a protecting group for an amide group.
  • the cyclization reaction proceeds by keeping the reaction solution neutral to basic, whereby the lactam body (VI) can be produced.
  • the obtained lactam body (VI) is converted to compound (VII) by a dehydration reaction to protect the amide group, and then subjected to a ring-opening reaction to produce compound (IX).
  • Compound (Ic) can be produced by removing the protecting group of compound (IX).
  • the amino group of compound (IV) for example, when PG 1 is a benzyloxycarbonyl group, PG 2 is a hydrogen atom, and PG 3 is a methyl group, the amino group is protected by hydrogenation with a heterogeneous catalyst. It is possible to selectively remove groups. Further, in this case, the subsequent intramolecular cyclization reaction proceeds to produce compound (VI).
  • the solvent for example, water, methanol, ethanol, ethyl acetate, acetic acid and the like can be used.
  • the catalyst palladium-carbon (Pd / C), Pearlman's catalyst (Pd (OH) 2 ), or the like can be used.
  • the reaction temperature can be from room temperature to reflux conditions.
  • the amino group can be selectively deprotected by selecting reagents and conditions according to the protecting group.
  • References include Greene, T .; W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
  • acid hydrolysis is used as the amino group deprotection reaction, an amine salt is formed and the cyclization reaction does not proceed sufficiently, so the reaction system must be neutralized.
  • the hydroxyl group of compound (VI) is treated with a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride at ⁇ 78 ° C. to 50 ° C. in the presence of a base in an inert solvent, and then further treated with a base.
  • a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride
  • the protection of the amide group is a reaction in which compound (VIII) is formed by protecting amide NH on the lactam ring of compound (VII).
  • the protecting group PG 4 is preferably a tert-butoxycarbonyl group. It is possible to protect the amide group by reacting di-tert-butyl dicarbonate under conditions of 0 ° C. to reflux using 4-dimethylaminopyridine as a base in an inert solvent such as dichloromethane or acetonitrile. .
  • an inert solvent such as dichloromethane or acetonitrile.
  • protecting groups for other amide groups for example, Greene, T. et al. W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
  • the ring-opening reaction is a reaction for obtaining compound (IX) by hydrolyzing the lactam ring of compound (VIII).
  • PG 4 is a tert-butoxycarbonyl group
  • lithium hydroxide or the like is allowed to act as a base in a mixed solvent of water and tetrahydrofuran at room temperature.
  • Compound (I) of the present invention can also be produced by the following method.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , PG 1 , PG 2 , PG 3 and PG 4 are the same as above.
  • PG 5 represents an imidazole protecting group.
  • Compound (X) can be produced by a method similar to Production Method 1 and Production Method 2 using Compound (IIc) in which a protecting group is introduced into the nitrogen atom of imidazole as a starting material. After protecting the carboxyl group of compound (X) to obtain compound (XI), only the protecting group for the nitrogen atom of imidazole can be removed to produce compound (XII).
  • Compound (XIII) is produced by alkylating, alkenylating, cycloalkylating, saturated heterocyclylating, arylating or unsaturated heterocyclylating the nitrogen atom of the imidazole moiety of compound (XII) and removing the protecting group Thus, compound (Ic) can be produced.
  • Examples of the protecting group for the nitrogen atom of imidazole include sulfonyl groups such as benzenesulfonyl group and tosyl group; alkoxycarbonyl groups such as t-butoxycarbonyl group and benzyloxycarbonyl group; or trityl group, methoxymethyl group, benzyloxy Examples thereof include alkyl groups such as a methyl group and [2- (trimethylsilyl) ethoxy] methyl group. Among these, a trityl group is preferable.
  • the protecting group for the nitrogen atom of these imidazoles may be selected according to the properties of the compound, and reagents and conditions corresponding to the protecting group may be selected when removing these protecting groups.
  • Protecting / deprotecting amino groups, amide groups, and carboxyl groups is the same as in manufacturing method 1 and manufacturing method 2.
  • Alkylation reaction, cycloalkylation reaction and saturated heterocyclylation reaction are carried out in the presence of a base, for example, elimination of R a -I, R a -Br, R a -OSO 2 CH 3 , R a -OSO 2 CF 3, etc.
  • a compound having a group is reacted with compound (XII) to produce compound (XIII).
  • the reaction solvent an acyclic, cyclic or aromatic hydrocarbon or a polar aprotic solvent can be used.
  • tetrahydrofuran, N, N-dimethylformamide, diethoxyethane, or a mixed solvent thereof can be used. it can.
  • the base for example, cesium carbonate, sodium hydride and the like can be used.
  • the alkenylation reaction, unsaturated heterocyclylation reaction and arylation reaction can be performed by reacting, for example, unsaturated heterocyclylboronic acid or arylboronic acid compound R a -B (OH) 2 with compound (XII). This reaction generates (XIII).
  • a known reaction ((PYS.Lam et al., Tetrahedron Lett., 39, 2941, 1998) can be referred to.
  • the unsaturated heterocyclylation reaction may alternatively be carried out by reacting R a —Br (or R a —I, R a —F, R a —Cl, etc.) with compound (XII) in the presence of copper oxide.
  • XIII can be obtained.
  • WO2003 / 061652 can be referred to.
  • the intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R ⁇ a> , R ⁇ b> , R ⁇ 10 > and PG ⁇ 3 > show the same thing as the above.
  • the nitrogen atom of the imidazole moiety of compound (XVI) that is commercially available or synthesized using well-known methods is alkylated, alkenylated, cycloalkylated, saturated heterocyclylated, arylated, or unsaturated heterocyclyl. It is possible to produce the compound (XVII) by preparing the compound (XVII) by a wittig reaction using the compound (XVIII).
  • Alkylation, alkenylation, cycloalkylation, saturated heterocyclylation, arylation, or unsaturated heterocyclylation is a reaction for synthesizing compound (XV) from compound (XIV) in the same manner as in Production Method 3. .
  • the Wittig reaction in production method 4 is carried out by reacting a compound (XVIII) having a phosphoryl group with a compound (XVII) having a carbonyl group in the presence of a base to produce a compound (XV) which is an ⁇ , ⁇ -unsaturated ester. It is a reaction.
  • a base sodium hydride, sodium methoxide, potassium carbonate and the like can be used.
  • a base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylamine and lithium chloride can be used in combination.
  • reaction temperature may be selected depending on the substrate, and the reaction can be carried out under a condition of ⁇ 78 ° C. to reflux.
  • the reduction reaction is a reaction in which compound (XV) is hydrogenated to compound (IId) by hydrogenation with a heterogeneous catalyst.
  • a heterogeneous catalyst for example, water, methanol, ethanol, ethyl acetate, acetic acid and the like can be used.
  • the catalyst palladium-carbon (Pd / C), Perlman catalyst (Pearlman's catalyst: Pd (OH) 2 ), Raney nickel, Adams catalyst (Adams' catalyst: PtO 2 ), or the like can be used.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a and R b are the same as described above, R 9a represents a prodrug group, and LG 1 represents desorption. Indicates a leaving group.
  • Compound (Ic) can produce a prodrug (Id) by converting an amino group into a prodrug.
  • a prodrug formation of an amino group is a reaction for obtaining a compound (Id) from a compound (Ic) and a compound R 9a —OH by using a condensation reaction.
  • a condensation reaction for example, N, N'- dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, Hydrochloride (EDC.HCl), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride hydrate (DMT-MM), (1H-benzo Triazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU), etc
  • compound (Id) can be obtained by condensing compound (Ic) with compound R 9a -LG 1 which is an active ester.
  • LG 1 includes a p-nitrophenyloxy group, a pentafluorophenyloxy group, a chlorine atom, and the like.
  • a method according to a condensation reaction between a carboxylic acid and an active ester used in usual peptide synthesis can be used.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b and PG 4 are the same as described above, and LG 2 is a leaving group.
  • R 3a represents a prodrug group of a carboxyl group.
  • Compound (Ie) which is a prodrug, can be produced by converting the carboxyl group of compound (IX) into a prodrug and then removing the amino protecting group.
  • a prodrug of a carboxy group is a reaction in which compound (IX) and compound R 3a —OH that is an alcohol are condensed to obtain compound (XIX).
  • the condensing agent N, N′-dicyclohexylcarbodiimide (DCC), N, N′-diisopropylcarbodiimide (DIC), or the like can be used.
  • DCC N, N′-dicyclohexylcarbodiimide
  • DIC N, N′-diisopropylcarbodiimide
  • the reactivity is improved by adding a catalytic amount of 4-dimethylaminopyridine (DMAP).
  • compound (XIX) can be obtained by reacting compound (IX) with compound R 4a -LG 2 which is an alkylating agent under basic conditions.
  • LG 2 includes an iodo group, a bromine atom and the like.
  • an alcohol sulfonate ester eg, R 3a —OSO 2 CH 3 , R 3a —OSO 2 CF 3, etc.
  • R 4a -LG 2 As the reaction solvent, water, tetrahydrofuran, N, N-dimethylformamide, diethoxyethane, or a mixed solvent thereof can be used.
  • the base include alkali metal or alkaline earth metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and potassium hydrogen carbonate.
  • the acrylic acid derivative of the present invention has an excellent TAFIa inhibitory activity, is excellent in pharmacokinetics such as high oral absorption, blood retention and metabolic stability, and is also useful as a pharmaceutical.
  • Particularly useful as a therapeutic agent for myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome, pulmonary fibrosis, etc. is there.
  • it is useful as a therapeutic agent for diseases derived from thromboembolism. It is also useful as a medicine for improving organ function after transplantation.
  • thrombus formation and promotion of thrombus dissolution by filling a blood vessel catheter (indwelling catheter for dialysis), extracorporeal blood circulation device and artificial blood vessel, and filling a TAFIa inhibitor solution in the tube. It is also useful as a therapeutic agent for atherothrombosis, fibrosis (pulmonary fibrosis such as chronic obstructive pulmonary disease, fibrosis after ophthalmic surgery, etc.). It is also useful for improving dysfunction associated with the acute phase of ischemic cerebrovascular disorder.
  • the compound represented by the general formula (I) of the present invention has a basic group such as an amino group, it can be converted to an acid addition salt with a pharmacologically acceptable acid.
  • a pharmacologically acceptable acid examples include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; nitrates, perchlorates, sulfates, phosphates and the like.
  • Inorganic acid salts lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetic acid, malic acid, Organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and amino acid salts such as ornithate, glutamate, aspartate, and halogenated Hydronate or aryl sulfonate is preferred, and hydrochloride, benzene sulfonate, or p-toluene sulfonate is more preferred, and benzene sulfonate or p-toluene is preferred.
  • Nsuruhon salt is even more Preferably, p- toluenesulfonic
  • the compound represented by the general formula (I) since the compound represented by the general formula (I) has an acidic group such as a carboxy group, it is generally possible to form a base addition salt.
  • pharmacologically acceptable salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt and morpholine.
  • phenylglycine alkyl ester salt ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N -Organic amine salts such as-(2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; amino acid salts such as arginine salt; and the like.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may exist as a free form or a solvate, and these solvates are also included in the scope of the present invention.
  • the solvate is not particularly limited as long as it is pharmacologically acceptable. Specifically, a hydrate, an ethanol solvate, and the like are preferable, and a hydrate is more preferable.
  • a nitrogen atom exists in the compound of the present invention represented by the general formula (I), and the nitrogen atom may be an N-oxide, and these solvates and N-oxides are also present. It is included in the scope of the invention.
  • the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof and a production intermediate of the compound of the present invention may be a geometric isomer such as a cis isomer, a trans isomer, etc.
  • various isomers such as optical isomers such as R isomer and S isomer may exist, but the compound of the present invention is not particularly limited, all isomers, stereoisomers and any ratio of these isomers. It also includes isomers and stereoisomer mixtures.
  • the compound of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
  • the atomic isotopes such as deuterium (2 H), tritium (3 H), carbon -13 (13 C), carbon -14 (14 C), nitrogen -15 (15 N), chlorine -37 (37 Cl) or iodine-125 ( 125 I).
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the present invention relates to a compound that is converted into compound (I) which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, Also included in the present invention is a compound that undergoes hydrolysis or the like and is converted to compound (I), or a “pharmaceutically acceptable prodrug compound” that undergoes hydrolysis or the like by gastric acid or the like and is changed to compound (I). .
  • composition containing the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof an appropriate preparation is selected according to the administration method, and methods for preparing various commonly used preparations Can be prepared.
  • a pharmaceutical composition mainly comprising the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof is administered to a mammal (particularly a human), it can be administered systemically or locally, orally or It can be administered parenterally.
  • oral pharmaceutical forms include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
  • These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive.
  • the preparation of the pharmaceutical composition comprises any suitable pharmaceutically acceptable binder, disintegrant, lubricant, swelling agent, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier.
  • coating agents plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffering agents, wetting agents, etc.
  • coating agents plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffering agents, wetting agents, etc.
  • parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and the like.
  • These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive.
  • the preparation of the pharmaceutical composition may be performed as any suitable pharmaceutically acceptable stabilizer, preservative, solubilizer, humectant, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier.
  • Preservatives antioxidants, flavoring agents, gelling agents, neutralizing agents, buffering agents, isotonic agents, surfactants, coloring agents, buffering agents, thickeners, wetting agents, fillers, absorption enhancement It can carry out according to a conventional method using what was suitably selected from an agent, a suspending agent, a binder, etc. as needed.
  • references regarding the above-mentioned pharmaceutically acceptable excipients include, for example, “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and PJ Weller”.
  • the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof can be used in combination with other drugs.
  • Anticoagulant drugs warfarin, heparin, low molecular weight heparin, antithrombin drug, anti-Xa drug, etc.
  • antiplatelet drugs aspirin, ticlopidine, clopidogrel, prasugrel, phosphodiesterase inhibitor, etc.
  • fibrinolysis Enzyme tPA, genetically modified tPA, plasminogen activator such as urokinase, streptokinase, plasmin
  • anticancer drug anti-inflammatory drug, antifibrotic drug, antihypertensive drug, antipulmonary hypertension drug, immunosuppressant drug and so on.
  • the dose of the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight, the kind and dose of drugs administered in combination, etc.
  • the compound (I) equivalent amount is in the range of 0.01 mg to 5000 mg, preferably in the range of 0.1 mg to 1000 mg, more preferably in the range of 1 mg to 200 mg per adult.
  • compound (I) is contained in the range of 0.001 mg / kg to 100 mg / kg, preferably in the range of 0.005 mg / kg to 20 mg / kg, more preferably 0.01 mg / kg to 5 mg. / Kg range.
  • This daily dose may be administered systemically or locally, once a few days to once to several times a day, orally or parenterally, or intravenously in the range of 1-24 hours per day Administer continuously. The daily dose may exceed the above amount if necessary.
  • Triethylamine (9.50 mL) was added dropwise at ⁇ 78 ° C., and the mixture was stirred for 20 minutes, and further stirred at 0 ° C. for 40 minutes.
  • Water was added to the reaction solution, which was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the organic solvent was evaporated under reduced pressure to give the title compound (3.05 g).
  • the aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate.
  • Step 2 3-O-acetyl-5-[(tert-butoxycarbonyl) amino] -2,4,5-trideoxy-2-[(1-trityl-1H-imidazol-4-yl) methyl] pentonic acid
  • methylene chloride 2.0 mL
  • triethylamine 0.0326 mL
  • acetic anhydride 0.100 mL in methylene chloride: 0 0.192 mL was used as a solution dissolved in 900 mL
  • 4-dimethylaminopyridine in methylene chloride (4-dimethylaminopyridine: 4.0 mg dissolved in 0.500 mL of methylene chloride: 0.080 mL was used) and stirred for 7.5 hours.
  • 1,8-diazabicyclo [5.4.0] undec-7-ene (0.0221 mL) was added to the reaction solution, and the mixture was further stirred for 15 hours.
  • Water and methylene chloride were added to the reaction solution to separate it.
  • the aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate.
  • reaction solution was air-cooled, and a methylene chloride-methanol solution (20 v / v) and water were added for liquid separation.
  • a methylene chloride-methanol solution (20 v / v) and water were added for liquid separation.
  • the aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate.
  • Step 4 (2E) -5-amino-2- (imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride
  • the compound obtained in Step 3 (59.0 mg) was suspended in 5N hydrochloric acid, Stir at 85 ° C. for 3 hours. The reaction solution was air-cooled and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (27.8 mg).
  • 1 H NMR (CD 3 OD) ⁇ : 2.67-2.76 (2H, m), 3.05-3.13 (2H, m), 3.79 (2H, s), 6.96 (1H, t, J 7.0 Hz), 7.28 (1H , s), 8.77 (1H, s).
  • reaction solution was cooled to ⁇ 78 ° C., potassium hexamethyldisilazide (0.5 mol / L toluene solution, 0.42 mL) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes.
  • a solution of the compound (18 mg) obtained in Reference Example 1 in tetrahydrofuran (0.5 mL) was added to the reaction solution and stirred for 30 minutes, and then stirred at 0 ° C. for 40 minutes and further at room temperature for 1.5 hours.
  • Aqueous ammonium chloride solution was added to the reaction solution, diluted with methylene chloride, and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • Step 2 (2Z) -5-amino-2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride
  • the compound obtained in Step 1 (39.3 mg) was suspended in 5N hydrochloric acid. And stirred at 85 degrees for 4 hours.
  • the reaction solution was cooled to 0 ° C., and insoluble matters were filtered off.
  • the residue obtained by concentrating the filtrate under reduced pressure was purified by reverse phase HPLC (column: GL sciences Prep-ODS; size: 250 ⁇ 30 mm; flow rate: 15 mL / min; elution solvent: H 2 O), and then lyophilized. This gave the title compound (7.9 mg).
  • 18-Crown-6 (825 mg) was added and cooled to -78 ° C.
  • potassium hexamethyldisilazide 0.5 mol / L toluene solution, 1.72 mL
  • an anhydrous tetrahydrofuran solution (30 mL) of the compound obtained in Reference Example 1 (149 mg) was added dropwise over 40 minutes.
  • Saturated aqueous ammonium chloride solution was added, and the mixture was extracted 3 times with methylene chloride.
  • Step 3 (2E) -5-[(tert-butoxycarbonyl) amino] -2-[(1-propyl-1H-imidazol-4-yl) methyl] penta-2-enoic acid methyl obtained in Step 2
  • the compound (65 mg) was dissolved in N, N-dimethylformamide, 1-bromopropane (21 ⁇ L) and triethylamine (43 ⁇ L) were added to this solution, and the mixture was stirred at 60 to 70 ° C. for 4 days. Furthermore, 1-bromopropane (58 ⁇ L) and triethylamine (173 ⁇ L) were added and stirred for 10 hours.
  • Step 2 (2Z) -5-[(tert-butoxycarbonyl) amino] -2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid methyl obtained in Step 1
  • the compound (127 mg) was dissolved in N, N-dimethylformamide (1.0 mL), triethylamine (84 ⁇ L) and 1-iodopropane (44 ⁇ L) were added to the solution, and the mixture was stirred overnight at room temperature. The mixture was further stirred at 40 ° C. for several hours. Dilute with water and extract several times with ethyl acetate. The organic layer was washed again with water.
  • Step 3 (2Z) -5-amino-2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid dihydrochloride
  • 5N hydrochloric acid aqueous solution (3.0 mL) was added, and the mixture was stirred at 85 ° C. for about 4 hours. After allowing to cool, the operation of adding a small amount of toluene to the residue obtained by concentrating the reaction solution under reduced pressure and azeotroping was repeated several times. The title compound (12.4 mg) was obtained by drying under reduced pressure.
  • Step 2 3-[(1-Propyl-1H-imidazol-4-yl) methyl] -5,6-dihydropyridin-2 (1H) -one
  • the compound obtained in Step 1 (4.0 g) was converted into methylene chloride. (20 mL) and triethylamine (4.7 mL), methanes and sulfonyl chloride (2.0 mL) were added under ice cooling. The reaction solution was stirred for 10 minutes under ice cooling, and then stirred at room temperature for 2 hours. 1,8-diazabicyclo [5.4.0] undec-7-ene (10.1 mL) was added at room temperature, and the mixture was stirred for about 40 hours.
  • Step 3 6-Oxo-5-[(1-propyl-1H-imidazol-4-yl) methyl] -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate
  • Compound obtained in Step 2 (1.8 g) was dissolved in methylene chloride (50 mL), and di-tert-butyl dicarbonate (2.0 g) and 4-dimethylaminopyridine (1.0 g) were added to the solution, and the mixture was stirred at room temperature under a nitrogen atmosphere. Stir all day and night. Di-tert-butyl dicarbonate (3.4 g) was further added, and the mixture was stirred for 32 hours.
  • Step 4 (2Z) -5-amino-2-[(1-propyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid
  • the compound (1.6 g) obtained in Step 3 was converted to tetrahydrofuran. / Water mixed solvent (2/1, 20 mL), lithium hydroxide monohydrate (630 mg) was added to this solution, and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, 5N aqueous hydrochloric acid solution (10 mL) was added to the obtained residue under ice cooling, and the mixture was stirred at the same temperature for 10 min and further at room temperature for 1 hr.
  • the obtained residue was dissolved in a small amount of water and adsorbed on a column containing an ion exchange resin (DOWEX® 50Wx8 / 100-200 Mesh / H form, 20 g).
  • the resin was sufficiently washed with ion-exchanged water until the eluate from the lower part of the column became neutral with pH test paper, and then eluted with a solution obtained by diluting 28% ammonia water 10-fold with ion-exchanged water.
  • the eluate was washed with methylene chloride, and the aqueous layer was concentrated under reduced pressure. Acetone was added to the obtained residue to solidify, and the powder was collected by filtration and dried to obtain the title compound (0.9 g).
  • Step 2 3-[(1-Trityl-1H-imidazol-4-yl) methyl] -5,6-dihydropyridin-2 (1H) -one
  • the title compound (2.43 g) was obtained from the compound (4.22 g) obtained in Step 1.
  • Step 3 6-oxo-5-[(1-trityl-1H-imidazol-4-yl) methyl] -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate Step 3 of Example 5 and Similarly, the title compound (2.82 g) was obtained from the compound (2.43 g) obtained in Step 2 of this example.
  • Step 5 (2Z) -5-[(tert-Butoxycarbonyl) amino] -2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid tert-butyl
  • Step 4 After stirring in 90% acetic acid at 60 ° C. for 2 hours, the reaction solution was neutralized by adding an aqueous sodium hydrogen carbonate solution. Extraction with methylene chloride was performed, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (80.0 mg).
  • Step 6 (2Z) -5-[(tert-butoxycarbonyl) amino] -2- ⁇ [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-ene
  • Sodium hydride (63%, 9.5 mg) was added to a solution of the compound obtained in Step 5 (80.0 mg) in N, N-dimethylformamide (3 mL) with stirring at 0 ° C., followed by reference.
  • a solution of the compound obtained in Example 7 (53.1 mg) in N, N-dimethylformamide (0.5 mL) was added, and the mixture was warmed to room temperature and stirred overnight.
  • Step 7 (2Z) -5-amino-2- ⁇ [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid
  • 5 M hydrochloric acid 3 mL
  • the reaction mixture was concentrated, and the residue was purified by cation exchange resin (DOWEX 50WX8-200, elution solvent: 3% aqueous ammonia) to give the title compound (26.1 mg).
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl ⁇ -4-methylpent-2-enoic acid of Example 5
  • the target product was obtained as a pale yellow solid from the compound obtained in Step 1 of this example (129 mg).
  • Example 9 (2Z) -5-amino-2-[(1-cyclohexyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid Obtained in Reference Example 12 in the same manner as in Example 5. The title compound (343 mg) was obtained from the obtained compound.
  • Example 10 (2Z) -5-amino-2-[(1- ⁇ [5- (5-chloro-2-thienyl) isoxazol-3-yl] methyl ⁇ -1H-imidazol-4-yl) [Methyl] pent-2-enoic acid [Step 1] (2Z) -5-[(tert-butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2- Methyl enoate The compound (3.72 g) obtained in Step 3 of Example 6 was dissolved in tetrahydrofuran (37 mL), and water (20 mL) containing lithium hydroxide monohydrate (0.90 g) was added with stirring at room temperature.
  • Step 3 (2Z) -5-amino-2-[(1- ⁇ [5- (5-chloro-2-thienyl) isoxazol-3-yl] methyl ⁇ -1H-imidazol-4-yl) methyl ] Penta-2-enoic acid hydrochloride
  • the compound obtained in Step 2 of this example (247 mg) and 3- (bromomethyl) -5- (5-chloro-2-thienyl) isoxazole (Journal of Medicinal Chemistry, 2005) 48, 4511) (223 mg)
  • the alkylation reaction was carried out in the same manner as in Step 6 of Example 6.
  • 5M hydrochloric acid 5 mL was added and heated to reflux for 4 hours.
  • Example 11 (2Z) -5-amino-2- ⁇ [1- (3-methylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 8, Reference Example 6 and In the same manner as in Example 5, the title compound (250 mg) was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and (3-methylphenyl) boronic acid.
  • Example 12 (2Z) -5-amino-2- ⁇ [1- (3-methoxyphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 8, Reference Example 6 and In the same manner as in Example 5, the title compound (379 mg) was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and (3-methoxyphenyl) boronic acid.
  • Example 13 (2Z) -5-amino-2-( ⁇ 1- [3- (trifluoromethyl) phenyl] -1H-imidazol-4-yl ⁇ methyl) pent-2-enoic acid
  • Reference Example 8 In the same manner as in Reference Example 6 and Example 5, the target product was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and [3- (trifluoromethyl) phenyl] boronic acid. Obtained as a white solid (366 mg).
  • Example 15 (2Z) -5-amino-2- ⁇ [1- (2-cyclohexylethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Same as Step 3 in Example 10 The title compound (2.0 mg) was obtained using the compound (100 mg) obtained in Step 2 of Example 10 and (2-bromoethyl) cyclohexane (0.056 mL).
  • Example 16 (2Z) -5-amino-2- ⁇ [1- (2-phenylethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid
  • the title compound (3.0 mg) was obtained using the compound (100 mg) obtained in Step 2 of Example 10 and (2-bromoethyl) benzene (0.048 mL).
  • Example 17 (2Z) -5-amino-2- ⁇ [1- (2-cyclopropylethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 6 and Example 5 In the same manner as in the above, the title compound (182 mg) was obtained from the compound obtained in Reference Example 15.
  • Example 19 (2Z) -5-Amino-2- ⁇ [1- (tetrahydro-2H-pyran-4-yl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 6 In the same manner as in Example 5, the title compound (184 mg) was obtained from the compound obtained in Reference Example 17.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-methylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (81.3 mg) was obtained from the compound (161 mg) obtained in Step 1 of this example.
  • Example 24 (2Z) -5-amino-2- ⁇ [1- (cyclohexylmethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 6 and Step 7 of Example 6 Similarly, the title compound (56 mg) was obtained using the compound (200 mg) obtained in Step 5 of Example 6 and (bromomethyl) cyclohexane.
  • Example 25 (2Z) -5-amino-2- ⁇ [1- (3,3-dimethylbutyl) -5-methyl-1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 6 In the same manner as in Example 6 and Example 5, the title compound (121 mg) was obtained from the compound obtained in Reference Example 22.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4,4-dimethylcyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (38 mg) was obtained from the compound (84 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-chlorophenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid
  • the title compound (166 mg) was obtained from the compound (378 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (2-methylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (178 mg) was obtained from the compound (336 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-fluorophenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (144 mg) was obtained from the compound (265 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-methoxyphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (205 mg) was obtained from the compound (370 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (3-thienyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (64.0 mg) was obtained from the compound (113 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-ethylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (214 mg) was obtained from the compound (419 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2-( ⁇ 1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl ⁇ methyl) pent-2-enoic acid
  • Step 6 (2Z) -5-amino-2-( ⁇ 1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl ⁇ methyl) pent-2-enoic acid
  • Example 34 (2Z) -5-amino-2- ⁇ [1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid [Step 1] (2Z ) -5-[(tert-Butoxycarbonyl) amino] -2- ⁇ [1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid tert-butyl Reference Example In the same manner as in Example 8, the title compound (337 mg) was obtained from the compound obtained in Step 5 of Example 6 (500 mg) and 4-tert-butylphenylboronic acid (507 mg).
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (113 mg) was obtained from the compound (337 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2-[(1-pyridin-3-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid
  • the title compound (103 mg) was obtained from the compound (179 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2-[(1-biphenyl-4-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (258 mg) was obtained from the compound (458 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-[(tert-butoxycarbonyl) amino] -2- ⁇ [1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-ene Acid tert-butyl
  • tetrahydrofuran 5 mL
  • TBAF tetrabutylammonium fluoride
  • Step 3 (2Z) -5-amino-2- ⁇ [1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (22 mg) was obtained from the compound (65.8 mg) obtained in Step 2 of this example.
  • Example 40 (2Z) -5-amino-2- ⁇ [1- (4,4-difluorocyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 1 of Example 39 In the same manner as in Step 7 of Example 6, the title compound (20 mg) was obtained.
  • Example 41 (2Z) -5-( ⁇ [1- (isobutyryloxy) ethoxy] carbonyl ⁇ amino) -2- ⁇ [1- (trans-4-methylcyclohexyl) -1H-imidazole-4- Yl] methyl ⁇ pent-2-enoic acid sodium salt
  • the compound obtained in Example 21 (600 mg) and sodium hydrogen carbonate (346 mg) were dissolved in water (10 mL), and stirred at room temperature, isobutyric acid 1-( ⁇ [ A solution of (2,5-dioxopyrrolidin-1-yl) oxy] carbonyl ⁇ oxy) ethyl (WO2005 / 66122) in acetonitrile (5 mL) was added and stirred overnight.
  • TAFI HEPES buffered saline (20 mM HEPES, 150 mM NaCl, pH 7.4, hereinafter HBS) was used for the preparation of the reaction solution.
  • HBS buffered saline
  • TAFIa Ten minutes later, 10 ⁇ L of 100 ⁇ M PPACK (thrombin inhibitor) was added to neutralize thrombin to terminate the activation of TAFI.
  • the produced TAFIa was stored in ice and diluted with 2050 ⁇ L of an HBS solution containing BSA (bovine serum albumin) prepared to a final concentration of 0.1% immediately before use in measurement.
  • BSA bovine serum albumin
  • the compound of the present invention exhibits excellent TAFIa inhibitory activity, and includes myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation. It is useful as a medicament for the treatment of syndrome or pulmonary fibrosis.
  • reaction solution A (13.8 U / mL human thrombin, 170 mM CaCl 2 and 0.9 U / mL thrombomodulin) was added and stirred again, and the absorbance at 405 nm was measured with a plate reader. The temperature was measured every 30 seconds while keeping at 37 ° C., and the degree of coagulation was measured. Of the changes in absorbance, the average value (ABS-ave: [(ABS-max)-(ABS-min)] / 2) of the maximum absorbance (ABS-max) and the minimum absorbance (ABS-min) in the fibrinolysis process is the highest.
  • the time point indicating the near absorbance was set to 1/2 lysis time (1/2 LT), which was used as an index of the fibrinolytic activity of each well. From the relationship between the concentration and 1/2 LT of the test substance, the concentration was calculated for the 1/2 LT 50% as EC 50.
  • compound A the compound of Example 7 in WO 2002/014285 pamphlet was used. The results are shown in Table 2.
  • the compound of the present invention exhibits excellent fibrinolysis promoting activity, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular It is useful as a medicament for the treatment of coagulation syndrome or pulmonary fibrosis.
  • Test Example 3 Evaluation of fibrinolysis-promoting activity in rat thromboembolism model Wistar rats (supplier: Japan SLC) were used. A test substance prepared with a 0.5% methylcellulose solution is orally administered at an arbitrary time point, or a test substance prepared with physiological saline is intravenously administered. After 40 minutes or 4 hours, the jugular vein under thiopental anesthesia Further, PT reagent (Thromboplastin C plus, Sysmex) prepared to 2.25 U / mL with physiological saline was continuously injected (16.8 mL / kg / hr x 20 min). As a positive control group, an overdose TAFIa inhibitor administration group was set.
  • citrate blood was collected from the jugular vein to obtain plasma.
  • the amount of D-dimer contained in plasma is measured using a fully automatic coagulation analyzer ACL-9000 or ACL-TOP500CTS, the ratio to the mean value of the positive control group is calculated, and ED 50 is used as a dose to increase D-dimer by 50 %.
  • ACL-9000 or ACL-TOP500CTS the ratio to the mean value of the positive control group
  • ED 50 is used as a dose to increase D-dimer by 50 %.
  • the compound of the present invention exhibits excellent fibrinolysis promoting activity in vivo, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, dissemination It is useful as a medicine for the treatment of vascular coagulation syndrome or pulmonary fibrosis.
  • Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
  • Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
  • Formulation Example 5 Cream 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% span 20, 0.3% Tween 20 and 41.7% water Prepared by mixing 100 mg of the finely divided compound of Example 5 in 5 g of cream.
  • the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent TAFIa enzyme inhibitory activity, and includes myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, cerebral infarction, It is useful as a therapeutic agent for deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome, pulmonary fibrosis and the like, and as a therapeutic agent for diseases derived from thromboembolism.

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Abstract

Cette invention concerne un composé représenté par la formule générale (I), qui a une activité inhibitrice de l'enzyme TAFIa et est utile à titre d'agent thérapeutique pour l'infarctus du myocarde, l'angine de poitrine, le syndrome coronarien aigu, l'ACV, la thrombose veineuse profonde, l'embolie pulmonaire, ou autre ; ou un sel pharmacologiquement acceptable de celui-ci. (Dans la formule, Ra représente un groupe alkyle éventuellement substitué, un groupe alcényle éventuellement substitué, un groupe cycloalkyle éventuellement substitué, un groupe aryle éventuellement substitué, un groupe hétérocyclyle saturé éventuellement substitué, ou un groupe hétérocyclyle insaturé éventuellement substitué ; Rb représente un atome d'hydrogène ou un groupe alkyle ; R1, R2, R5, et R6 représentent un atome d'hydrogène, un atome de fluor, ou un groupe alkyle ; R4, R7, et R8 représentent un atome d'hydrogène ou un groupe alkyle ; et R3 et R9 représentent un atome d'hydrogène ou un groupe promédicament).
PCT/JP2012/073632 2011-09-15 2012-09-14 Nouveau dérivé d'acide acrylique WO2013039202A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2016104678A1 (fr) * 2014-12-26 2016-06-30 第一三共株式会社 Composition médicale destinée à promouvoir la fibrinolyse

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014285A1 (fr) * 2000-08-17 2002-02-21 Pfizer Limited Imidazoles substitues utilises comme inhibiteurs tafia
WO2011115064A1 (fr) * 2010-03-18 2011-09-22 第一三共株式会社 Dérivé d'imidazole substitué par cycloalkyle

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014285A1 (fr) * 2000-08-17 2002-02-21 Pfizer Limited Imidazoles substitues utilises comme inhibiteurs tafia
WO2011115064A1 (fr) * 2010-03-18 2011-09-22 第一三共株式会社 Dérivé d'imidazole substitué par cycloalkyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BUNNAGE MARK E. ET AL.: "Discovery of Potent & Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor for the Treatment of Thrombosis", J.MED.CHEM., vol. 50, no. 24, 2007, pages 6095 - 6103, XP008165296, DOI: doi:10.1021/jm0702433 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016104678A1 (fr) * 2014-12-26 2016-06-30 第一三共株式会社 Composition médicale destinée à promouvoir la fibrinolyse

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