WO2007083689A1 - Plasminogen activator inhibitor-1 inhibitor - Google Patents

Plasminogen activator inhibitor-1 inhibitor Download PDF

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Publication number
WO2007083689A1
WO2007083689A1 PCT/JP2007/050666 JP2007050666W WO2007083689A1 WO 2007083689 A1 WO2007083689 A1 WO 2007083689A1 JP 2007050666 W JP2007050666 W JP 2007050666W WO 2007083689 A1 WO2007083689 A1 WO 2007083689A1
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group
carboxylic acid
compound
carboxy
chemical
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PCT/JP2007/050666
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French (fr)
Japanese (ja)
Inventor
Kiyoshi Kurokawa
Toshio Miyata
Noriaki Hirayama
Nagahisa Yamaoka
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Renascience Co., Ltd.
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Priority to JP2007554938A priority Critical patent/JPWO2007083689A1/en
Publication of WO2007083689A1 publication Critical patent/WO2007083689A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A61P9/06—Antiarrhythmics
    • 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 plasminogen inhibitor inhibitor (hereinafter also referred to as "PAI-1") inhibitor.
  • PAI-1 plasminogen inhibitor inhibitor
  • the present invention also relates to a pharmaceutical composition that has an action of inhibiting PAI-1 activity and is effective in preventing or treating various diseases in which PAI-1 activity is involved in the onset.
  • the present invention relates to a novel compound having PAI-1 inhibitory activity.
  • Thrombus ischemic heart disease such as cerebral embolism, cerebral infarction, ischemic cerebrovascular disorder such as transient ischemic attack, angina, myocardial infarction, intra-atrial thrombus in atrial fibrillation, heart failure
  • ischemic cerebrovascular disorder such as transient ischemic attack, angina, myocardial infarction, intra-atrial thrombus in atrial fibrillation, heart failure
  • Blood circulation requires fluidity to transport oxygen and nutrients to body tissues and collect unwanted materials, but also requires coagulation to stop blood and prevent blood loss during trauma. .
  • coagulation to stop blood and prevent blood loss during trauma.
  • the fibrinolysis system plays an important role in thrombolysis, tissue destruction and repair, cell migration, and the like.
  • the fibrinolytic system is activated by a plasminogen activator (hereinafter referred to as “PA”) by converting plasminogen to plasmin.
  • PA plasminogen activator
  • PAI-1 plasminogen activator inhibitor 1
  • tissue plasminogen activator converts plasminogen, which is a precursor of plasmin, into plasmin. Plasmin breaks down fibrin into a fibrin degradation product.
  • PAI-1 is a serine protease inhibitor that specifically inhibits tPA and urokinase-type plasminogen activator (hereinafter referred to as "u-PAj”), and suppresses the production of plasmin. In turn, it inhibits fibrin degradation.
  • u-PAj urokinase-type plasminogen activator
  • PAI 1 has an active form that exhibits PA inhibitory activity due to a difference in three-dimensional structure
  • L PAI-1 exists and is produced by hepatocytes, megakaryocytes, and adipocytes in addition to vascular endothelial cells, which are the main production cells.
  • PAI-1 is an acute phase protein, and its production is increased by various site force-in and growth factors, causing causes of ischemic organ damage in sepsis and disseminated intravascular coagulation syndrome (DIC) It is considered as one of
  • genetic polymorphism by single base substitution of PAI-1 gene promoter is known, and it has been clarified that plasma PAI-1 concentration increases due to the genetic polymorphism.
  • PAI-1 is considered to be involved in the formation and progression of various pathologies such as various thrombosis, cancer, diabetes, and arteriosclerosis. Therefore, the activity of PAI-1
  • the inhibitory compound is useful as a prophylactic and therapeutic agent for diseases related to decreased fibrinolytic activity such as thrombosis, cancer, diabetic complications, and arteriosclerosis (Non-patent Document 5).
  • tissue fibrosis occurs in many tissues and organs such as the lung, heart, blood vessels, liver, and kidneys.
  • Corticosteroids such as steroids, and cytotoxic drugs such as cyclophosphamide (an alkylating agent) Nazathioprine (antimetabolite, immunosuppressive agent) are currently being used for symptomatic treatment. .
  • Non-Patent Literature l Aya N, et al. (Aya'enu et al.), J. Pathol. (The 'Journal' Ob 'Pathology), 166, 289-295, 1992
  • Non-Patent Document 2 Yoshida Y, et al. (Yoshida 'Wai et al.), Nephron, 88, 24-29, 200 1
  • Non-Patent Document 3 WA Border, et al. (W ⁇ ⁇ E ⁇ ⁇ Border et al.), J. Clin. Invest. (The 'Journal' of 'Tari-Cal' investigation), 112 , 379, 2003
  • Non-patent document 4 WA Border, et al. (W ⁇ ⁇ E ⁇ ⁇ ⁇ Border et al.), Kidney Int. (Kidney's International), 59, 246, 2001
  • Non-Patent Document 5 Egelund R, et al. (Igelund et al.), J. Biol. Chem. (The 'Journal' Ob • Biological 'Chemistry), 276, 13077-13086, 2001
  • u-PA urokinase
  • fibrinolytic promoter which has been obtained by purifying human urine mosquito, and that production efficiency and safety are never high.
  • Ena urokinase is a high molecular compound having a molecular weight of about 54,000.
  • Other fibrinolytic promoters include tisokinase, alteplase (genetical recombination), nasarplase (cell culture), nateplase (genetic recombination), monteplase (genetical recombination), pamitepase (genetic recombination), and batroxobin.
  • the deviation is also a polymer compound. Accordingly, there is a demand for a low molecular weight compound-derived drug that can be synthesized in large quantities and has high safety as a fibrinolytic promoter. In addition, radically treat tissue fibrosis. There is also a need for the development of effective drugs that treat and improve.
  • the present invention has been made in view of the conventional problems that are encouraging, and as a highly safe pharmaceutical composition, particularly as a fibrinolytic promoter or antifibrosis agent, comprising a low-molecular compound capable of mass synthesis as an active ingredient.
  • An object is to provide a useful pharmaceutical composition. It is another object of the present invention to provide a novel compound useful as an active ingredient of a pharmaceutical composition such as a fibrinolytic agent or an antifibrotic agent.
  • the inventors of the present invention also include compounds represented by the formula (3) described below (hereinafter referred to collectively as “compound (3) of the present invention” or “compound ( 3) ”), in particular, it was confirmed that compounds (4) to (16) were novel compounds not yet published in literature. The present invention has been completed based on such knowledge.
  • the present invention includes the following aspects:
  • R is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms
  • R and R may be bonded to each other to form a 5- to 6-membered ring;
  • A is a straight-chain or branched alkylene having 1 to 7 carbon atoms, alkene or alkylene, cycloalkylene having 3 to 8 carbon atoms, or a single bond;
  • R is a hydrogen atom,
  • a phenyl group or a furyl group which may have a substituent, or the following formula (2);
  • R is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms
  • R represents a hydrogen atom or a substituent.
  • A is a linear or branched alkylene having 1 to 7 carbon atoms, or a cycloalkylene having 3 to 8 carbon atoms;
  • R is represented by the following formula (2) ;
  • R is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms;
  • R represents a hydrogen atom or a substituent.
  • a PAI-1 inhibitor according to Item 1 comprising a compound represented by the above or a salt thereof, or a solvate thereof as an active ingredient.
  • a 2-chael group a force that is CH 2 CH 2 (CH 3), or the same or different, R and R
  • Item 2 3 2 2 3 or R 1 and R are bonded to each other to form a condensed 6-membered ring,
  • R and R ′ 1S are the same or different and are each a hydrogen atom, a straight chain having 1 to 3 carbon atoms, or
  • Item 4 The PAI-1 inhibitor according to any one of Items 1 to 3, which is a branched alkyl group, a phenol group, or a halogen atom.
  • A is a linear alkylene having 3 to 5 carbon atoms, —CH—C (CH) —CH —,
  • Item 2 The PAI-1 inhibitor according to any one of Items 1 to 4, which is cyclohexylene.
  • R is a hydrogen atom, and R and R 'are a phenyl group or a 2-chael group.
  • Item 6 The PAI-1 inhibitor according to any one of Items 1 to 5, wherein A is butylene.
  • Item 7 A pharmaceutical composition comprising the PAI-1 inhibitor according to any one of Items 1 to 6, and a pharmaceutically acceptable carrier or additive.
  • a pharmaceutical composition comprising a compound represented by the above general formula (1) or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier or additive.
  • Item 8 The pharmaceutical composition according to Item 7, which is a prophylactic or therapeutic agent for a disease associated with the onset of PAI-1 activity.
  • Item 9 The pharmaceutical composition according to Item 7 or 8, which is a fibrinolytic promoter.
  • Item 10 Disease power related to the onset of PAI-1 activity Angina, myocardial infarction or atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary embolism Embolism, deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or percutaneous coronary angioplasty Item 10.
  • Item 11 The disease composition in which PAI-1 activity is involved in the onset
  • Item 12 The pharmaceutical composition according to Item 11, wherein the disease associated with tissue fibrosis is pulmonary fibrosis.
  • Item 13 The pharmaceutical composition according to any one of Items 7 to 12, which has an oral dosage form.
  • R and R ′ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms;
  • R 2 ′ is the same or different and is a hydrogen atom, an optionally substituted phenyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms;
  • R and R ′ are the same or Differently, a hydrogen atom, an optionally substituted phenyl group,
  • R and R are phenyl groups having no substituent and R and R ′ are
  • A is either butylene or CH 2 -C (CH 2) 2 -CH 1
  • A is not butylene.
  • Item 15 A compound represented by any one of the following formulas (4) to (16) or a salt thereof:
  • a pharmaceutical composition comprising as an active ingredient at least one selected from the compound or the pharmaceutically acceptable salt thereof according to item 16. or the pharmaceutically acceptable salt thereof, or the solvate power thereof.
  • the use of the pharmaceutical composition is not particularly limited, and is not limited to those based on PAI-1 inhibitory action such as prevention or treatment of diseases in which PAI-1 activity is involved in onset. .
  • a pharmaceutical composition comprising a low-molecular compound that can be synthesized in large quantities and has high safety as an active ingredient.
  • the pharmaceutical composition comprises a compound having a high inhibitory action on PAI-1 (PAI-1 inhibitor) as an active ingredient, and prevents or prevents various diseases caused by PAI-1 activity. It can be used effectively as a therapeutic agent.
  • the pharmaceutical composition of the present invention is used as a fibrinolytic promoter as an angina pectoris, myocardial infarction or atrial thrombosis in atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary embolism , Deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or percutaneous coronary angioplasty (PTCA) ) Useful for the prevention or treatment of later restenosis.
  • the pharmaceutical composition of the present invention is useful as an antifibrotic agent for the prevention or treatment of various diseases associated with tissue fibrosis, particularly pulmonary fibrosis.
  • the PAI-1 inhibitor provided by the present invention has the following formula (1)
  • R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
  • alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and ter-butyl group.
  • R represents a hydrogen atom, an optionally substituted phenyl group or a chanel.
  • a straight-chain or branched alkyl group having 1 to 6 carbon atoms Preferred are a phenyl group, a chael group, a methyl group, an isobutyl group, an isopropyl group, or a hydrogen atom, which may have a substituent, and more preferred are a chael group, a phenyl group, and an isobutyl group.
  • Preferred examples of the chael group include a 2-chael group.
  • substituent of the phenyl group or the phenyl group include a carboxyl group, an amino group, a halogen atom, and a heterocyclic group.
  • a halogen atom for example, a chlorine atom, a fluorine atom, an iodine atom, etc. is preferred.
  • linear or branched alkyl group having 1 to 6 carbon atoms examples include methyl group, ethyl group, n propyl group, isopropyl group, n butyl group, isobutyl group, sec butyl group, ter-butyl group, pentyl group , Isopentyl group, neopentyl group, ter pentyl group, hexyl group, isohexyl group, neohexyl group, and ter-hexyl group.
  • Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably A til group, an isopropyl group and an isobutyl group;
  • R and R are bonded to each other together with the carbon atom to which they are bonded to form a 5-6 membered
  • a ring may be formed.
  • Such 5- to 6-membered rings can include cyclohexane, cyclohexene, 1,3 cyclohexagen, cyclopentane, cyclopentene and benzene. Preferred is cyclohexane.
  • R may have a hydrogen atom or a substituent! /, A full group, or a straight chain of 1 to 6 carbon atoms.
  • it may be a branched alkyl group or a halogen atom.
  • substituent of the phenyl group include a carboxyl group, an amino group, a halogen atom, and a heterocyclic group as described above.
  • linear or branched alkyl group having 1 to 6 carbon atoms are the same as those described above.
  • R is preferably a hydrogen atom or phenyl
  • a group, a methyl group, an isopropyl group, and a halogen atom A group, a methyl group, an isopropyl group, and a halogen atom.
  • A is a single bond; a linear or branched alkylene, alkylene, or alkylene having 1 to 7 carbon atoms; a cycloalkylene having 3 to 8 carbon atoms.
  • Preferred are linear or branched alkylene having 2 to 5 carbon atoms, cycloalkylene having 6 carbon atoms (cyclohexanediyl), and beylene.
  • Specific examples of the linear or branched alkylene having 2 to 5 carbon atoms include an ethylene group, a propylene group, a butylene group, a pentylene group, and CH 2 C (CH 3) 2 CH 3.
  • R is a hydrogen atom, a phenyl group which may have a substituent, or
  • the furyl group is preferably a 2-furyl group.
  • the substituent includes a chlorine atom, an iodine atom, a bromine atom or a halogen atom of a fluorine atom; a linear or branched chain having 1 to 6 carbon atoms
  • the alkyl group of can be mentioned.
  • a halogen atom is preferably a fluorine atom or a chlorine atom.
  • Specific examples of the linear or branched alkyl group having 1 to 6 carbon atoms include those described above, preferably a ter butyl group and an n-butyl group.
  • R can be a group represented by the following formula (2):
  • R ′ and R may be different, but are preferably the same.
  • R ' as in R described above, a hydrogen atom or a substituent optionally having a substituent may be used.
  • compound (1) has the above group (2) as R, R ′ and R
  • R ' is also a hydrogen atom, a phenyl group which may have a substituent, a carbon atom, as in R described above.
  • It may be a linear or branched alkyl group having 1 to 6 prime numbers or a halogen atom, and together with R ′, these atoms are bonded to each other together with the carbon atom to which they are bonded.
  • R and R ' may be different, but it is preferred that they are identical, and at the same time mutually
  • R and R may form a 5- to 6-membered ring.
  • A is a linear or branched alkylene having 1 to 7 carbon atoms, or a cycloalkylene having 3 to 8 carbon atoms, and R is the above group.
  • R and R ′ In which R is a hydrogen atom, and R and R ′ are the same or different and are ter-butyl groups. More preferably, R and R ′ have a hydrogen atom or a substituent.
  • A is ethylene, propylene, butylene, pentylene, CH—C (CH 2) —CH 2 —, or cyclohexane.
  • R, R ′, R and R are all hydrogen atoms, and R and R are each a phenyl group.
  • A is butylene or CH— C (CH) CH—
  • These compounds (1) targeted by the present invention may have a free form as described above, or may have a salt form.
  • the salt include pharmaceutically acceptable salts such as salts with inorganic bases or organic bases, salts with basic amino acids, and the like.
  • the inorganic base include alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; aluminum and ammonia.
  • Organic bases include, for example, primary amines such as ethanolamine; secondary amines such as jetylamine, diethanolamine, dicyclohexylamine, N, N 'dibenzylethylenediamine; trimethylamine, triethylamine. And tertiary amines such as pyridine, picoline and triethanolamine.
  • basic amino acids include arginine, lysine, orthine and the like.
  • suitable compound (1) targeted by the present invention include the following compounds a to n and o to zz.
  • These compounds a to n and o to zz are all included in the compound (1) represented by the general formula (1), and among them, the compounds a, b, c, d, e , H, j, k, o to zz are compounds included in the compound represented by the general formula (17).
  • compounds a, b, c, d, e, g, h, i, j, k, 1, s, t, v and r are more preferable, and more preferably the compound a , B, d, e, h, s and t, particularly preferably compounds a, b, d and h.
  • the compound (1) targeted by the present invention may be a solvate of a free substance or a salt thereof.
  • Powerful solvates include hydrates.
  • Compound (1) particularly compounds a to n, are commercially available, and can be produced by a method known per se.
  • R represents a group represented by the formula (2)
  • a compound having can be produced by the following production method (A) 1 or a method analogous thereto.
  • A production method
  • compounds o to zz are novel compounds not yet described in the literature, and their production methods will be described in detail in Production Examples 5 to 17.
  • R is a linear or branched alkyl group having 1 to 4 carbon atoms, and R and R are
  • a compound represented by a hydrogen atom (IX, particularly compound (17)) is produced.
  • R may have a hydrogen atom or a substituent, and may be a phenyl group or a furyl group.
  • A is as defined above, X is a leaving group, R is a hydrogen atom, and has a substituent.
  • a fur group or a furyl group which may be present which may be present.
  • examples of the leaving group represented by X include a halogen atom.
  • the halogen atom include a fluorine atom, a chlorine atom, an fluorine atom, and an iodine atom.
  • it is chlorine.
  • the reaction of the compound (18) and the compound (19) or the compound (18) and the compound (20) is carried out according to a conventional acylation reaction known to those skilled in the art, and is appropriately performed in an appropriate solvent.
  • a simple base As the base, an organic base such as triethylamine or pyridine can be suitably used.
  • the target compound (1) amide-carboxylic acid body in which R is hydrogen can be produced.
  • This alkaline hydrolysis reaction can be carried out by an ordinary method known to those skilled in the art. Examples of the alkali used include potassium hydroxide, sodium hydroxide, barium hydroxide and the like.
  • the PAI-1 inhibitory activity of the compound (1) can be evaluated by an in vitro assay system.
  • an in vitro assay system for example, a method for measuring a change in the activity of PAI-1 with respect to tissue plasminogen activator (tPA) in the presence of compound (1) can be mentioned.
  • the active fluctuation of PAI-1 can be measured by using the reaction product generated by the action of t-PA on the substrate as an index.
  • the activity variation of PAI-1 is measured using the amount of p-12 troanilide (reaction product) generated by the action of tPA on the chromogenic substrate (S-2288) as an index.
  • the Vitro Atssey system is illustrated. It can be judged that the smaller the amount of reaction product produced, the higher the PAI-1 inhibitory activity.
  • the PAI-1 inhibitory activity of the compound (1) is in the presence of the compound (1) in the complex of PAI-1 and tPA (t-1 / t-PA complex). Variation in formation can also be evaluated by measuring, for example, by Western blotting (see, for example, Experimental Example 2). Here, it can be judged that the smaller the amount of P ⁇ -1 / t-PA complex formed ( ⁇ -1 / t-PA complex formation inhibition), the higher the PAI-1 inhibitory activity.
  • Compound (1) has an action of inhibiting the activity of PAI-1.
  • compounds a to l preferably compounds a, b, d, e and h, particularly preferably compounds a, b, d and h are described later.
  • it has an excellent PAI-1 activity inhibitory action. This action can enhance fibrin degradation and fibrinogen degradation by plasmin, promote the biological fibrinolytic system, and improve the degradation of the biological fibrinolytic system.
  • compound (1) can prevent or ameliorate tissue fibrosis and diseases related to tissue fibrosis based on the action of inhibiting the activity of PAI-1.
  • the PAI-1 inhibitor of the present invention comprises such a compound (1) as an active ingredient.
  • the PAI-1 inhibitor of the present invention may be compound (1) 100% potent, or otherwise contains an effective amount of compound (1) that exhibits PAI-1 inhibitory action. It only has to do. But are not limited to, the PAI 1 inhibitor, usually the compound (1) is 0.1 to 99 wt%, good Mashiku comprises in the range of 1 to 80 weight 0/0.
  • the present invention provides a pharmaceutical composition containing the aforementioned PAI-1 inhibitor as an active ingredient.
  • the pharmaceutical composition of the present invention contains the compound (1) described above as an active ingredient.
  • the pharmaceutical composition of the present invention has a PAI-1 inhibitory action by containing an effective amount of the compound (1).
  • fibrin is degraded by plasmin and fibrinogen is degraded. It enhances and promotes the fibrinolytic system of the living body, or improves the lowered fibrinolytic system of the living body.
  • the pharmaceutical composition of the present invention can be used as a fibrinolytic promoter.
  • the pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for thrombotic diseases and conditions in which PAI-1 activity is involved in the onset, or diseases and conditions caused by a decrease in fibrinolytic system.
  • Possible diseases or conditions include, for example, angina pectoris, myocardial infarction, intra-atrial thrombus in atrial fibrillation, ischemic heart disease such as heart failure, cerebral embolism, cerebral infarction, transient ischemic attack, etc. Ischemic cerebrovascular disease, arteriosclerosis, pulmonary embolism, deep vein thrombosis during surgery (
  • DVT disseminated intravascular coagulation syndrome
  • DIC disseminated intravascular coagulation syndrome
  • angiopathy neuropathy, retinopathies, nephropathy, etc.
  • thrombus formation such as restenosis after percutaneous coronary angioplasty (PTCA) Mention may be made of the various diseases or conditions involved.
  • the pharmaceutical composition of the present invention comprises a PAI-1 inhibitory action by containing an effective amount of compound (1).
  • the pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for diseases and pathologies related to tissue or organ fibrosis caused by PAI-1 activity. Examples of such diseases or conditions include pulmonary fibrosis, tissue fibrosis associated with myocardial infarction, tissue fibrosis associated with nephropathy, and the like.
  • the pharmaceutical composition of the present invention usually contains a pharmaceutically acceptable carrier or additive in addition to an effective amount of the compound (1) for promoting (or improving) the fibrinolytic system or antifibrosis. It is prepared as follows.
  • the compounding amount of the compound (1) in the pharmaceutical composition is appropriately selected according to the type of disease or pathology to be administered and the administration form.
  • the entire pharmaceutical composition It can be 0.001 to 50% by weight, particularly 0.01 to 10% by weight of the weight (100% by weight).
  • the administration method of the pharmaceutical composition of the present invention includes oral administration and parenteral administration such as intravenous administration, intramuscular administration, subcutaneous administration, transmucosal administration, transdermal administration, and rectal administration. be able to. Oral administration and intravenous administration are preferred, and oral administration is more preferred.
  • the pharmaceutical composition of the present invention can be prepared into various forms of preparations (dosage forms) according to the powerful administration method. In the following, each formulation (drug form) will be described, but the dosage form used in the present invention is not limited to these, and various dosage forms commonly used in the pharmaceutical formulation field can be used. .
  • Examples of dosage forms for oral administration include powders, granules, capsules, pills, tablets, elixirs, suspensions, emulsions, and syrups. can do.
  • these formulations can be modified such as sustained release, stabilization, easy disintegration, hard disintegration, entericity, easy absorption, and the like.
  • dosage forms for intravenous administration, intramuscular administration, or subcutaneous administration include injections and infusions (including dry products prepared at the time of use), and can be appropriately selected.
  • dosage forms for transmucosal administration, transdermal administration, or rectal administration include mastication agents, sublingual agents, buccal agents, troches, ointments, patches, liquids, etc. You can choose here depending on the location. These formulations can also be modified such as sustained release, stabilization, easy disintegration, difficulty disintegration, and easy absorption.
  • the pharmaceutical composition of the present invention may contain pharmaceutically acceptable carriers and additives depending on the dosage form (oral administration or various parenteral administration dosage forms).
  • Pharmaceutically acceptable carriers and additives include solvents, excipients, coating agents, bases, binders, lubricants, disintegrants, solubilizers, suspending agents, thickeners, emulsifiers. , Stabilizers, buffers, isotonic agents, soothing agents, preservatives, flavoring agents, fragrances, and coloring agents. Specific examples of pharmaceutically acceptable carriers and additives are listed below, but the present invention is not limited thereto.
  • Examples of the solvent include purified water, sterilized purified water, water for injection, physiological saline, laccase oil, ethanol, glycerin and the like.
  • Excipients include starches (eg, potato starch, wheat starch, corn starch), lactose, glucose, sucrose, crystalline cellulose, calcium sulfate, calcium carbonate, sodium bicarbonate, sodium chloride salt, tark, oxidized Titanium, trehalose, xylitol and the like can be mentioned.
  • binders starch and derivatives thereof, cellulose and derivatives thereof (for example, methinoresenorelose, ethinoresenorelose, hydroxypropinoresenorelose, canoleboxymethylcellulose), gelatin, sodium alginate, tragacanth, arabian
  • natural polymer compounds such as rubber, synthetic polymer compounds such as polyvinyl pyrrolidone and polybutyl alcohol, dextrin and hydroxypropyl starch.
  • Lubricants include light anhydrous carboxylic acid, stearic acid and its salts (eg, magnesium stearate), talc, waxes, wheat starch, macrogol, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol, Examples include silicone oil.
  • Disintegrants include starch and derivatives thereof, agar, gelatin powder, sodium hydrogen carbonate, calcium carbonate, cellulose and derivatives thereof, hydroxypropyl starch, strength ruboxymethyl cellulose and salts thereof, and cross-linked products thereof, low substitution And hydroxypropylcellulose.
  • solubilizer examples include cyclodextrin, ethanol, propylene glycol, and polyethylene glycol.
  • Suspending agents include sodium carboxymethyl cellulose, polypyrrole pyrrolidone, gum arabic, tragacanth, sodium alginate , Aluminum monostearate, citrate, various surfactants and the like.
  • thickeners examples include sodium carboxymethylcellulose, polypyrrole pyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, tragacanth.
  • emulsifier examples include gum arabic, cholesterol, tragacanth, methylcellulose, lecithin, various surfactants (for example, polyoxyl 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate).
  • Stabilizers include tocopherols, chelating agents (eg EDTA, thioglycolic acid), inert gases (eg nitrogen, diacid-carbon), reducing substances (eg sodium hydrogen sulfite, sodium thiosulfate, ascorbine) Acid, longalite) and the like.
  • chelating agents eg EDTA, thioglycolic acid
  • inert gases eg nitrogen, diacid-carbon
  • reducing substances eg sodium hydrogen sulfite, sodium thiosulfate, ascorbine
  • Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium citrate, boric acid and the like.
  • Examples of isotonic agents include sodium chloride salt and glucose.
  • Examples of soothing agents include local anesthetics (pro-in hydrochloride, lidocaine), pendyl alcohol, glucose, sorbitol, amino acids and the like.
  • Examples of the corrigent include sucrose, saccharin, licorice extract, sorbitol, xylitol, dariserine and the like.
  • Examples of the fragrances include spruce tincture and rose oil.
  • Examples of the colorant include water-soluble food dyes and lake dyes.
  • preservative examples include benzoic acid and its salts, para-benzoic acid esters, chlorobutanol, reverse soap, benzyl alcohol, phenol, tiromesal, dehydroacetic acid, boric acid and the like.
  • Coating agents include sucrose, hydroxypropylcellulose (HPC), shellac, gelatin, glycerin, sorbitol, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polybutylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate ( HPMCP), cellulose acetate phthalate (CAP), methyl methacrylate, methacrylic acid copolymer, and the polymers described above.
  • HPMC hydroxypropylmethylcellulose
  • HPMCP polybutylpyrrolidone
  • HPMCP hydroxypropylmethylcellulose phthalate
  • CAP cellulose acetate phthalate
  • Bases include petrolatum, liquid paraffin, carnauba wax, beef tallow, hydrogenated oil, beef wax, beeswax, vegetable oil, macrogol, macrogol fatty acid ester, stearic acid, cal Sodium boxymethylcellulose, bentonite, cacao butter, wittebuzole, gelatin, stearyl alcohol, hydrolanolin, cetanol, light liquid paraffin, hydrophilic salmon, single ointment, white ointment, hydrophilic ointment, macrogol ointment, hard fat, oil-in-water Type emulsion base and water-in-oil type emulsion glaze.
  • DDS drug delivery system
  • the DDS preparations referred to in this specification include sustained release preparations, topical preparations (troches, buccal tablets, sublingual tablets, etc.), drug release control preparations, enteric preparations and gastric preparations, etc., administration routes, bioavailability
  • it is a drug product in the optimal drug product form taking into account side effects.
  • the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic agent for a disease state associated with a decrease in fibrinolytic system (thrombosis)
  • its oral dose is converted to the amount of compound (1).
  • 03-300 mgZkg body weight range force more preferably 0.1-50 mgZkg body weight.
  • a dose such that the effective blood concentration of compound (1) is in the range of 0.2 to 50 gZmL, more preferably 0.5 to 20 / ⁇ 8 ⁇ can be mentioned.
  • the oral dose is 0.03 to 300 mgZkg in terms of the amount of compound (1). Range of body weight More preferably, it is 0.1 to 50 mgZkg body weight.
  • the dosage should be such that the effective blood concentration of compound (1) is in the range of 0.2-50; ⁇ ⁇ , more preferably 0.5-20 / ⁇ 8 8 ⁇ . be able to. These dosages may vary depending on age, sex, body type, and the like.
  • R and R ′ may be the same or different and each may have a hydrogen atom or a substituent.
  • R and R are phenyl groups having no substituent and R and R ′ are
  • A is either butylene or CH 2 -C (CH 2) 2 -CH 1
  • A is not butylene.
  • the present invention provides a powerful new compound.
  • Examples of the novel compound (3) targeted by the present invention include those in which R and R'1S are the same or different and are a hydrogen atom or a ter-butyl group.
  • R and R ′ are hydrogen atoms.
  • R and R ' are hydrogen atoms.
  • 3 3 or different may be a hydrogen atom, a methyl group, an isopropyl group, a phenol group, or a halogen atom.
  • A examples include propylene, butylene, pentylene, -CH 2 -C (CH 2) 2 -CH 1, and cyclohexylene.
  • novel compound (3) include the following compounds o to zz. The production method of such a compound will be described in detail in Production Examples 5-17.
  • PAI-1 inhibitory action as described above, and diseases and pathologies related to the onset of PAI-1 such as pathological conditions related to decreased fibrinolytic system (thrombosis). It is also useful as an active ingredient in prophylactic or therapeutic agents (pharmaceutical compositions) for pathological conditions related to tissue fibrosis.
  • prophylactic or therapeutic agents pharmaceutical compositions
  • compounds o to zz compounds o to x are preferable, compounds s, t, r, q, and w are more preferable, and compounds s, t, and r are more preferable. .
  • the present invention comprises the above compound (3), particularly the compounds o to zz (preferably compounds o to x) or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • a pharmaceutical composition is provided.
  • the pharmaceutical composition can be prepared in an appropriate formulation form according to the dosage form by a conventional method according to the description in (II).
  • R is a phenyl group or a 2-chael group.
  • the compound in which R is a phenol group is 2- [3- (3'-carboxy-4'-phenylthiophene-2'-ylcarbamoyl) -pentanoylamino] -4 -Phenolthiophene-3-carboxylic acid, hereinafter also referred to as “compound a”.
  • compounds in which R and R ′ are 2-chenyl groups are 2- [3- (3'-carboxy-4'-phenylthiophene-2'-ylcarbamoyl) -pentanoylamino] -4 -Phenolthiophene-3-carboxylic acid, hereinafter also referred to as “compound a”.
  • compounds in which R and R ′ are 2-chenyl groups
  • Step 3 Synthesis of amide-carboxylic acid (6) (compounds a and b) Dissolve the salt (5) obtained above in a mixture of THFZH 2 O (150 ml Z 200 ml) and add 20% vinegar.
  • the title compound was prepared by converting compound d (Specs, The Netherlands) to the disodium salt using aqueous NaOH in THF.
  • the title compound was prepared by converting Compound h (Specs, The Netherlands) to the disodium salt using aqueous NaOH in THF.
  • the obtained residue was stirred while adding 100 ml of DMF, 2.83 g (88.2 mmol) of sulfur and 7.68 g (88.2 mmol) of morpholine. Thereafter, ethyl acetate was added to the reaction solution, followed by washing with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain 2.69 g of 2-amino-5-phenolphen-3-carboxylic acid tert-butyl ester (yield 11.1%).
  • Step 1 54 ml (430 mmol) 4-methyl-2-pentanone, 25 ml (285 mol) methyl cyanoacetate, 3.5 ml (61 mmol) acetic acid and 1.5 g (19 mmol) ammonium acetate in 90 ml toluene. The mixture was dehydrated and refluxed for an hour. After cooling, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and aqueous NaCl. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • a 1.25 mM S-2288 synthetic substrate (Chromogenix (Italy), the same applies hereinafter) as a chromogenic substrate was added thereto.
  • the final mixture was lOOmM Tris-HCl (pH 8), 30 mM NaCl, 1% DMSO, 0.1% Tween 80, 67 nM PA to 1, 9.8 nM t—PA ⁇ lm M S-2288 and each test compound a or b (20 35, 50 or 100 M).
  • P 2 troanilide cleaved from the chromogenic substrate (S-2288) by the action of tPA was measured at an absorbance of 405 nm every 5 minutes for 30 minutes using a spectrophotometer. The same test was conducted for the system without the test compound, and the PAI-1 activity after 30 minutes of this system (control system) was taken as 100%, and the PAI-1 activity when each test compound was added. Evaluated.
  • FIGS. 4 (A) to (C) are the compounds a [2- [3- (3'-carboxy-4'-phenolthiophene-2-silylcarbamoyl) -pentanoylamino]- 4-phenylthiophene-3-carboxylic acid] (concentration 20, 35, 50, 100 ⁇ ), compound b [2- [3- (3'-carboxy-4'-cherthiophene-2 Rucarbamoyl) -pentanoylamino] -4-chelthiophene-3-carboxylic acid] (concentration 20, 35, 50, 100 M), and tiplaxtinin (comparative compound) (concentration 20, 35, M) were added.
  • test compound (compounds a and b) was tested for the inhibitory activity of PAI-1 and t-PA complex formation (—-1 / t-PA complex) by Western blotting.
  • the electrophoresed protein is transferred to a polyvinylidene difluoride membrane (PVDF membrane, manufactured by Biorad) (100V for 1 hour), and then the PVDF membrane is shaken with Block Ace (Snow Brand Milk Products) for 2 hours at room temperature. Finally, it blocked. Thereafter, the mixture was reacted with a 1000-fold diluted t-PA antibody (Cedarlane Laboratories Ltd. (Canada)) at 4 ° C. Thereafter, alkaline phosphatase labeled Hedge IgG antibody was added, reacted for 1 hour at room temperature, and then developed with NBT-BCIP solution.
  • PVDF membrane polyvinylidene difluoride membrane
  • lane 1 is an electrophoretic image of t-PA
  • lanes 2 and 3 are electrophoretic images of sample solutions when compounds a and b are used as test compounds, respectively
  • lane 4 is a test compound
  • thrombin (10NIH U / ml: manufactured by Mochida Pharmaceutical) dissolved in 0.2 ml of physiological saline was used for fibrinogen (produced by Organon Teknica) at a rate of 1.5 mgZml on a 9 cm plate.
  • Aqueous solution 25 mM sodium valpital, 50 mM NaCl, and 25 mM CaCl
  • each test compound was added in an excess amount corresponding to 6000 to 60000 times in molar ratio to AP (Sigma-Aldrich Co.) adjusted to 0.2 pmolZ ⁇ L, and 0.1% Tween80 was included. Incubation was carried out in 20 mM Tris-HCl (pH 7.8) at 37 ° C for 15 minutes. Thereafter, the mixture was reacted with plasmin adjusted to 0.2 pmol / ⁇ L at 37 ° C for 15 minutes.
  • plasmin synthetic substrate Peptide Laboratories, Japan
  • AMC 7-amino-4-methylcoumarin released from the above substrate by plasmin cleaving action was detected at a fluorescence wavelength of 380 nm and an excitation wavelength of 460. Measured every minute for 30 minutes.
  • the same test was performed on a system not containing the test compound, and the AP inhibitory effect of each test compound was evaluated with the AP activity 30 minutes after the reaction as 100%.
  • the reaction solution was mixed with loading buffer (Daiichi Kagaku) and heated at 100 ° C for 5 minutes to obtain a sample solution.
  • the sample solution was electrophoresed on a 4-20% polyacrylamide gel (Daiichi Chemical) using an electrophoresis apparatus (Daiichi Chemical) and Tris-Glycine buffer (Daiichi Chemical). .
  • the band was detected by the usual staining method (Coomassie 'Brilliant' Blue). The results are shown in FIG. In Fig.
  • lanes 1 to 3 are electrophoresis images of plasmin, antiplasmin (AP), and PAI-1, respectively, and lane 4 is a reaction of plasmin and antiplasmin without using compound b.
  • Electrophoresis image of sample solution lanes 5 and 6 are electrophoretic images of sample solution obtained by reacting plasmin and antiplasmin using compound b in molar ratios of 3,000 and 15,000 times, respectively, and lane 7 is compound b.
  • Electrophorograms of sample solutions of plasmin and PAI-1 reaction without using lanes, lanes 8 and 9 are plasmin and PAI-1 using compound b in molar ratios of 3,000 and 15,00 0 respectively. Electrophoresis images of the sample solutions reacted with are shown respectively.
  • Example 7 Evaluation of effects on bleomycin-induced pulmonary fibrosis
  • a model animal mouse
  • pulmonary fibrosis was artificially induced with bleomycin.
  • mice Male, body weight: 21-21 g
  • mice Ten mice were used for control.
  • the test subject mice received Compound b (2- [3- (3'-carboxy-4'-cherthiophene-2-sylcarbamoyl) -pentanoylamino] -4-chelylthiophene-3-carboxylic acid (200 mg / kg) was forcibly administered orally .
  • Compound b (2- [3- (3'-carboxy-4'-cherthiophene-2-sylcarbamoyl) -pentanoylamino] -4-chelylthiophene-3-carboxylic acid (200 mg / kg) was forcibly administered orally .
  • lung tissues of these control mice and test mice were subjected to histological analysis, and the amount of hydroxyproline was measured.
  • the amount of hydroxyproline in the lung tissue was measured as the amount in the hydrolyzate of lung tissue according to the method of Kivirikko et al.
  • Fig. 9 (a is the fibrosis score, b is the tissue-stained image), and the amount of hydroxyproline in the lung tissue and plasma PAI-1 activity are shown in Table 3.
  • pulmonary fibrosis induced by bleomycin administration (fibrosis score: 4.7 ⁇ 0.17, control group: 0.5 ⁇ 0.17, P ⁇ 0.001) is caused by administration of compound b.
  • Significantly improved (fibrosis score: 2.9 ⁇ 0.42, P 0.01), consistent with the above PAI-1 activity results.
  • a rat AV shunt model which is a thrombus model animal, was used to produce 2- [3- (3′-carboxy-4′-chelthiophene-2, -Ylcarbamoyl) -pentanoylamino] -4-Chelthiophene-3-carboxylic acid (a compound a) was examined for antithrombotic activity. In addition to this, a blood coagulation test was also performed in parallel. [0343] It should be noted that the AV shunt model test here is a well-known literature (RFPeters, et al.
  • test compound in addition to the compound a of the present invention, ⁇ farin (manufactured by Wako Pure Chemical Industries, Ltd.) and ticlovidin hydrochloride (manufactured by Sigma-Aldrich Co.) were used as comparative compounds (positive control compounds). .
  • test compounds consist of carboxymethyl cellulose (manufactured by Nacalai Testa Co., Ltd.) (hereinafter, rCMC-Naj t), 0.5 g CMC, dissolved in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) in lOOmL.
  • the solution was suspended in Na solution.
  • Compound a is suspended in a 0.5% CMC-Na solution at a concentration of 75 mg / mL
  • ticlovidin hydrochloride is suspended in a 0.5% CMC-Na solution at a concentration of 142.3 mg / mL.
  • the dosing solution was prepared by suspending it, and suspending fufarin in a 0.5% CMC-Na solution to a concentration of 0.3 mg / mL.
  • each test compound was administered to the test animal so that the maximum blood concentration was reached at the time of performing the AV shunt procedure.
  • test compound a was administered at a rate of 300 mg / kg 17.5 hours before anesthesia and shunt surgery, ⁇ farin at a rate of 1.2 mg / kg 23.5 hours before, and ticlovidin hydrochloride at a rate of 500 mg / kg 1.5 hours before.
  • the AV shunt model was performed when the maximum blood concentration was reached, considering the pharmacokinetics of each test compound.
  • the operation for creating the AV shunt model was performed according to the following method.
  • a shunt catheter was created. A film was wrapped around the connection through the silk thread to prevent blood from leaking.
  • Rats were anesthetized with pentobarbital (manufactured by Dainippon Sumitomo Pharma Co., Ltd.) intraperitoneally at a rate of 50 mg / kg, filled with physiological saline in the catheter, and both ends of the catheter on the right Blood was perfused by insertion into the carotid artery and left jugular vein. Thirty minutes after the start of perfusion, the catheter was clamped with forceps to stop blood flow, and the tube part through which silk thread was passed was cut out. Subsequently, the weight of the thrombus formed by blood perfusion was measured. Specifically, the cut tube force was also carefully taken out of the silk thread, the liquid phase was removed with filter paper, the remaining wet weight was measured, and the weight of the silk thread of 6.5 cm was further subtracted from this to determine the thrombus weight. did.
  • pentobarbital manufactured by Dainippon Sumitomo Pharma Co., Ltd.
  • the tube was cut out, and blood was collected for abdominal aortic force coagulation test.
  • 1.8 mL of whole blood was added to a vacuum blood collection tube containing 3.13% citrate and centrifuged to obtain plasma.
  • 0.5 mL of whole blood was added to a micro blood collection tube containing a serum separating agent and a coagulation promoter to obtain serum.
  • APTT activated partial thromboplastin time
  • PT prothrombin time
  • Table 4 shows the thrombus weight obtained for the vehicle administration group and each test compound administration group (Groups 1 to 4).
  • the thrombus weight of the compound a administration group of the present invention is the same as that of the positive control compound ( ⁇ -farin, ticlobidine hydrochloride) administration group, in the vehicle administration group. Compared with significantly decreased.
  • the prothrombin time (PT) and the active ⁇ partial thromboplastin time ( ⁇ ) did not significantly change in the compound a administration group of the present invention compared to the vehicle administration group.
  • the hufarin administration group decreased the thrombus weight and prolonged PT and APTT.
  • the ticlovidin hydrochloride administration group reduced the thrombus weight, but did not show any effect on PT and APTT in the same manner as the compound a of the present invention.
  • PT and APTT are both indicators for determining the coagulation system. That is, in this test, the result that the compound a of the present invention did not affect both PT and APTT means that the compound a is a compound having a property different from that of the anticoagulant.
  • LDH lactate dehydrogenase
  • Compounds a and b of the present invention were added to HeLa cells (cervical cancer-derived epithelial cell line) at a rate of 250 ⁇ ⁇ , 125 ⁇ , or 50 ⁇ , and the cell force was also eluted.
  • the cytotoxicity of compounds a and b was tested by subjecting LDH to an enzyme reaction with INT (tetrazolium salt) for 30 minutes and quantifying red formazan converted from INT at 490 ⁇ m.
  • INT tetrazolium salt
  • a similar test was performed using 0.5% DMSO instead of compounds a and b.
  • the compounds a and b of the present invention were both strong enough to show no cytotoxicity up to 250 M.
  • Cmax maximum blood concentration
  • T1 / 2 half-life
  • FIG. 1 is a diagram showing a synthesis scheme of compound (1) of the present invention (particularly compounds a and b).
  • NMR data of compound a of the present invention ( ⁇ , ⁇ ′-bis [3,3, -carboxy-4,4, -phenol-2,2-phenyl] hexanedicarboxamide) Indicates.
  • FIG. 3 Compound b of the present invention (b, ⁇ , -bis [3,3, -carboxy-4,4,-(2,2, -chael) -2,2'-chael]
  • the NMR data of xanthodicarboxamide are shown.
  • FIG. 5 is an electrophoretic image showing the inhibitory effect on complex formation between tissue plasminogen activator (tPA) and PAI-1 of each compound by Western blotting (Experimental Example 2).
  • FIG. 6 shows the PAI-1 inhibitory effect of each compound by the fibrin plate method (natural substrate method) (Experimental Example 3).
  • FIG. 7 N, N, -Bis [3,3, 1-carboxy-1,4,4, 1-Fel 2,2,1 chael] hexanedicarboxamide (compound a) (Fig. (A )), And ⁇ ,-, -bis [3,3, one carboxy, one 4,
  • Compound b is an electrophoretic image showing the inhibitory effect of plasmin and antiplasmin complex formation.

Abstract

Disclosed are a PAI-1 inhibitor and a pharmaceutical composition which contain a compound represented by the formula (1) below or a salt thereof as an active ingredient. [Chemical formula 1] (1) [In the formula, R1 represents a hydrogen atom, or a linear or branched alkyl group having 1-4 carbon atoms; R2 represents an optionally substituted phenyl group or thienyl group, or a linear or branched alkyl group having 1-6 carbon atoms, R3 represents a hydrogen atom, or alternatively R2 and R3 combine together to form a five- or six-membered ring; A represents a linear or branched alkylene, alkenylene or alkynylene having 1-7 carbon atoms, or a single bond; and R4 represents a hydrogen atom, an optionally substituted phenyl group or furyl group, or a group represented by the following formula (2): [Chemical formula 2] (2) (wherein R1’, R2’ and R3’ represent the same as R1, R2 and R3, respectively).]

Description

明 細 書  Specification
プラスミノーゲンァクチべ一ターインヒビタ一一 1阻害剤  Plasminogen activator inhibitor 1 inhibitor
技術分野  Technical field
[0001] 本発明は、プラスミノーゲンァクチべ一ターインヒビタ一一 1 (以下、「PAI— 1」ともい う）阻害剤に関する。また本発明は、 PAI— 1活性を阻害する作用を有し、 PAI— 1活 性が発症に関わっている各種疾患の予防または治療に有効な医薬組成物に関する 。さらに本発明は、 PAI—1阻害活性を有する新規ィ匕合物に関する。  [0001] The present invention relates to a plasminogen inhibitor inhibitor (hereinafter also referred to as "PAI-1") inhibitor. The present invention also relates to a pharmaceutical composition that has an action of inhibiting PAI-1 activity and is effective in preventing or treating various diseases in which PAI-1 activity is involved in the onset. Furthermore, the present invention relates to a novel compound having PAI-1 inhibitory activity.
背景技術  Background art
[0002] 血栓は、脳塞栓症、脳梗塞、一過性脳虚血発作等の虚血性脳血管障害、狭心症、 心筋梗塞、心房細動における心房内血栓、心不全等の虚血性心疾患の病因となり 得る。血液循環には、体内組織に酸素や栄養を運搬し、不要物を回収するための流 動性が求められる一方で、外傷時等に止血して血液の損失を防ぐ凝固性も必要であ る。この流動性と凝固性という相反する機能がアンバランスとなり凝固側に傾いたとき 、血管内に血栓が生じ、虚血性の脳血管障害や心疾患が生じると考えられている。  [0002] Thrombus ischemic heart disease such as cerebral embolism, cerebral infarction, ischemic cerebrovascular disorder such as transient ischemic attack, angina, myocardial infarction, intra-atrial thrombus in atrial fibrillation, heart failure Can be the etiology of Blood circulation requires fluidity to transport oxygen and nutrients to body tissues and collect unwanted materials, but also requires coagulation to stop blood and prevent blood loss during trauma. . When the contradictory functions of fluidity and coagulation become imbalanced and tilted toward the coagulation side, it is thought that a thrombus occurs in the blood vessel, resulting in ischemic cerebrovascular disorder and heart disease.
[0003] 線維素溶解系（以下、「線容系」と称する）は、血栓溶解、組織の破壊や修復、細胞 移動などに重要な役割を果たしている。線溶系は、プラスミノーゲンァクチべ一ター（ 以下、「PA」と称する）がプラスミノーゲンをプラスミンに変換することにより活性ィ匕され る。一方、プラスミノーゲンァクチべ一ターインヒビタ一一 1 (PAI— 1)は、 PAを阻害 する。  [0003] The fibrinolysis system (hereinafter referred to as "dietary system") plays an important role in thrombolysis, tissue destruction and repair, cell migration, and the like. The fibrinolytic system is activated by a plasminogen activator (hereinafter referred to as “PA”) by converting plasminogen to plasmin. On the other hand, plasminogen activator inhibitor 1 (PAI-1) inhibits PA.
[0004] 組織プラスミノーゲンァクチべ一ター（以下、「t—PA」と称する）は、プラスミンの前 駆体であるプラスミノーゲンをプラスミンに変換する。プラスミンはフイブリンを分解して フイブリン分解産物に変える。  [0004] A tissue plasminogen activator (hereinafter referred to as “t-PA”) converts plasminogen, which is a precursor of plasmin, into plasmin. Plasmin breaks down fibrin into a fibrin degradation product.
[0005] PAI— 1は、 t PAおよびゥロキナーゼ型プラスミノーゲンァクチべ一ター（以下、「 u-PAjと称する）を特異的に阻害するセリンプロテアーゼインヒビターであり、プラス ミンの生成を抑制し、ひいてはフイブリンの分解を阻害する。 [0005] PAI-1 is a serine protease inhibitor that specifically inhibits tPA and urokinase-type plasminogen activator (hereinafter referred to as "u-PAj"), and suppresses the production of plasmin. In turn, it inhibits fibrin degradation.
[0006] PAI 1には、立体構造の違!、により、 PA阻害活性を示す活性型（active form)と、[0006] PAI 1 has an active form that exhibits PA inhibitory activity due to a difference in three-dimensional structure,
PA阻害活性を示さない潜在型（latent form)とがある。通常、血漿中には 20ngZm Lの PAI— 1が存在し、主要な産生細胞である血管内皮細胞の他、肝細胞、巨核球（ megakaryocyte)、および脂肪細胞で産生されることも知られている。 There is a latent form that does not show PA inhibitory activity. Usually 20ngZm in plasma It is known that L PAI-1 exists and is produced by hepatocytes, megakaryocytes, and adipocytes in addition to vascular endothelial cells, which are the main production cells.
[0007] PAI—1は、急性期タンパク質であり、種々のサイト力インや増殖因子により産生が 亢進して、敗血症や播種性血管内凝固症候群 (DIC)における虚血性臓器障害を引 き起こす原因の一つとして考えられている。また、 PAI— 1遺伝子プロモーターの一 塩基置換による遺伝子多型が知られており、当該遺伝子多型に起因して血漿 PAI— 1濃度が増加することが明らかにされている。  [0007] PAI-1 is an acute phase protein, and its production is increased by various site force-in and growth factors, causing causes of ischemic organ damage in sepsis and disseminated intravascular coagulation syndrome (DIC) It is considered as one of In addition, genetic polymorphism by single base substitution of PAI-1 gene promoter is known, and it has been clarified that plasma PAI-1 concentration increases due to the genetic polymorphism.
[0008] また、糖尿病に関しては、動脈硬化の促進および細小血管合併症が、糖尿病の重 要な合併症である虚血性心疾患、糖尿病性網膜症および腎障害の原因になると考 えられている。たとえば糖尿病性腎症では、糸球体内の細胞外基質の増加と間質の 線維化が特徴的に認められ、糸球体と尿細管における PAI— 1の発現が増強される 。近位尿細管培養では、高血糖条件下で PAI—1の産生増加が認められる。また、 腎間質線維化モデルマウスを用いた実験では、 PAI— 1の腎組織内発現とマクロファ ージ浸潤との相関性が確認されて 、る (非特許文献 1参照)。  [0008] In addition, regarding diabetes, acceleration of arteriosclerosis and microvascular complications are thought to cause ischemic heart disease, diabetic retinopathy and kidney damage, which are important complications of diabetes. . For example, diabetic nephropathy is characterized by increased extracellular matrix in the glomeruli and fibrosis of the interstitium, and enhanced expression of PAI-1 in the glomeruli and tubules. Proximal tubular cultures show increased production of PAI-1 under hyperglycemic conditions. Further, in an experiment using a renal interstitial fibrosis model mouse, the correlation between the expression of PAI-1 in the renal tissue and macrophage infiltration has been confirmed (see Non-Patent Document 1).
[0009] またネフローゼ症候群患者の一日蓄尿を濃縮して尿中 PAI— 1量を測定した結果 から、ネフローゼ症候群患者の尿中 PAI— 1濃度は高値であることが報告されている (非特許文献 2参照)。  [0009] Further, the concentration of urinary PAI-1 in patients with nephrotic syndrome was measured and the urinary PAI-1 concentration was measured, and it was reported that the concentration of urinary PAI-1 in patients with nephrotic syndrome was high (non-patented) (Ref. 2).
[0010] Thy— 1腎炎モデルに、 PAI— 1拮抗剤として不活性 PAI— 1ミュータント（非特許 文献 3)や t— PA (非特許文献 4)を投与した結果、炎症 (細胞浸潤)の軽減、 TGF- βの低下、およびメサンギゥム基質の減少が確認され、 Thy— 1腎炎の改善が認めら れたとの報告もある。  [0010] Reduction of inflammation (cell infiltration) as a result of administration of inactive PAI-1 mutant (Non-patent document 3) or t-PA (Non-patent document 4) as a PAI-1 antagonist to the Thy-1 nephritis model In addition, a decrease in TGF-β and a decrease in mesangial substrate have been confirmed, and it has been reported that an improvement in Thy-1 nephritis has been observed.
[0011] PAI— 1の血漿濃度の増加による線溶活性の低下は、深部静脈血栓症、虚血性心 疾患および糖尿病性血管障害と関係している。線溶活性の低下に加え、過凝血性 および血小板過凝集性を含む!/、くつかの他の血栓形成性の異常もまた、糖尿病患 者において示されており、これらは微小血栓形成に寄与し、糖尿病性細小血管障害 や糖尿病性大血管障害の進行に重要な役割を果たしている。  [0011] Decreased fibrinolytic activity due to increased plasma concentration of PAI-1 is associated with deep vein thrombosis, ischemic heart disease and diabetic vasculopathy. In addition to reduced fibrinolytic activity, including hypercoagulability and platelet hyperaggregation! /, Several other thrombogenic abnormalities have also been shown in diabetics, which contribute to microthrombus formation It plays an important role in the progression of diabetic microangiopathy and diabetic macroangiopathy.
[0012] このように、 PAI— 1は、種々の血栓症、癌、糖尿病、および動脈硬化症等の各種 の病態の形成や進展に関与していると考えられている。このため、 PAI— 1の活性を 阻害する化合物は、血栓症を始め、癌、糖尿病合併症、および動脈硬化症等の、線 溶活性の低下に関係する疾患の予防および治療剤として有用である（非特許文献 5[0012] Thus, PAI-1 is considered to be involved in the formation and progression of various pathologies such as various thrombosis, cancer, diabetes, and arteriosclerosis. Therefore, the activity of PAI-1 The inhibitory compound is useful as a prophylactic and therapeutic agent for diseases related to decreased fibrinolytic activity such as thrombosis, cancer, diabetic complications, and arteriosclerosis (Non-patent Document 5).
) o ) o
[0013] また、組織の線維化は、肺を始め、心臓、血管、肝臓および腎臓など多くの組織や 器官で生じるが、それを根本的に治療する薬剤は未だなぐ経験的にプレドニゾロン やコルチコステロイドなどの副腎皮質ホルモン、ならびにシクロホスフアミド（アルキル ィ匕剤)ゃァザチォプリン (代謝拮抗剤、免疫抑制剤)などの細胞障害性薬剤が、対症 療法的に使用されて 、るのが現状である。  [0013] In addition, tissue fibrosis occurs in many tissues and organs such as the lung, heart, blood vessels, liver, and kidneys. However, there is no empirical treatment for prednisolone or cortico. Corticosteroids such as steroids, and cytotoxic drugs such as cyclophosphamide (an alkylating agent) Nazathioprine (antimetabolite, immunosuppressive agent) are currently being used for symptomatic treatment. .
非特許文献 l :Aya N, et al. (アヤ'ェヌら）， J. Pathol. (ザ'ジャーナル'ォブ 'パソロジ 一）， 166, 289-295, 1992  Non-Patent Literature l: Aya N, et al. (Aya'enu et al.), J. Pathol. (The 'Journal' Ob 'Pathology), 166, 289-295, 1992
非特許文献 2 :Yoshida Y, et al. (ヨシダ'ワイら）， Nephron (ネフロン）， 88, 24-29, 200 1  Non-Patent Document 2: Yoshida Y, et al. (Yoshida 'Wai et al.), Nephron, 88, 24-29, 200 1
非特許文献 3 : W. A. Border, et al. (ダブリュ^ ~·エ^ ~·ボーダーら）， J. Clin. Invest. ( ザ'ジャーナル'ォブ 'タリ-カル 'インべスティゲーシヨン）， 112, 379, 2003 非特許文献 4 : W. A. Border, et al. (ダブリュ^ ~·エ^ ~·ボーダーら） , Kidney Int. (キ ドニ一'インターナショナル）， 59, 246, 2001  Non-Patent Document 3: WA Border, et al. (W ^^ · E ^ ~ Border et al.), J. Clin. Invest. (The 'Journal' of 'Tari-Cal' investigation), 112 , 379, 2003 Non-patent document 4: WA Border, et al. (W ^^ · E ^ ~ · Border et al.), Kidney Int. (Kidney's International), 59, 246, 2001
非特許文献 5 : Egelund R, et al. (ィゲルンドら）， J. Biol. Chem. (ザ'ジャーナル'ォブ •バイオロジカル 'ケミストリー）， 276, 13077-13086, 2001  Non-Patent Document 5: Egelund R, et al. (Igelund et al.), J. Biol. Chem. (The 'Journal' Ob • Biological 'Chemistry), 276, 13077-13086, 2001
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0014] これまで、線溶系促進薬としては u—PAであるゥロキナーゼが知られている力 こ れはヒト尿カも精製して得られており、生産効率や安全性は決して高 、とは 、えな ヽ 。さらに、ゥロキナーゼは、分子量約 54,000の高分子化合物である。そのほかの線 溶系促進薬としては、チソキナーゼ、アルテプラーゼ (遺伝子組換え）、ナサルプラー ゼ (細胞培養）、ナテプラーゼ (遺伝子組換え）、モンテプラーゼ (遺伝子組換え）、パ ミテプラーゼ (遺伝子組換え）およびバトロキソビンが知られて 、るが、 、ずれも高分 子化合物である。従って、線溶系促進薬として、大量合成が可能であり安全性の高 い低分子化合物由来の薬物が求められている。また、組織の線維化を根本的に治 療し改善する有効な薬物の開発も求められて 、る。 [0014] To date, u-PA, urokinase, is known as a fibrinolytic promoter, which has been obtained by purifying human urine mosquito, and that production efficiency and safety are never high. , Ena. Furthermore, urokinase is a high molecular compound having a molecular weight of about 54,000. Other fibrinolytic promoters include tisokinase, alteplase (genetical recombination), nasarplase (cell culture), nateplase (genetic recombination), monteplase (genetical recombination), pamitepase (genetic recombination), and batroxobin. As a result, the deviation is also a polymer compound. Accordingly, there is a demand for a low molecular weight compound-derived drug that can be synthesized in large quantities and has high safety as a fibrinolytic promoter. In addition, radically treat tissue fibrosis. There is also a need for the development of effective drugs that treat and improve.
[0015] 本発明は、力かる従来の問題に鑑み、大量合成が可能な低分子化合物を有効成 分とする安全性の高!ヽ医薬組成物、特に線溶系促進薬または抗線維症剤として有 用な医薬組成物を提供することを目的とする。また、線溶系促進薬または抗線維症 剤などの医薬組成物の有効成分として有用な新規化合物を提供することを目的とす る。  [0015] The present invention has been made in view of the conventional problems that are encouraging, and as a highly safe pharmaceutical composition, particularly as a fibrinolytic promoter or antifibrosis agent, comprising a low-molecular compound capable of mass synthesis as an active ingredient. An object is to provide a useful pharmaceutical composition. It is another object of the present invention to provide a novel compound useful as an active ingredient of a pharmaceutical composition such as a fibrinolytic agent or an antifibrotic agent.
課題を解決するための手段  Means for solving the problem
[0016] 本発明者らは、上記課題を解決するために鋭意研究を進めた結果、下式（1)で示 される化合物若しくはその塩、またはこれらの溶媒和物（以下、これらを総称して「本 発明の化合物（1)」または「ィ匕合物（1)」という。）が、プラスミノーゲンァクチべ一ター インヒビタ一一 1 (PAI— 1)に対して高い阻害活性を有することを見出し、さらにこれ が PAI— 1阻害剤として線溶系促進薬の有効成分として有用であることを確認した。 また本発明者らは、 PAI— 1が組織線維化、特に肺線維症の主原因であることを見 出し、本発明の化合物（1)によってこの組織線維化が有意に改善することを確認した 。また、本発明者らは、力かる化合物（1)の中でも後述する式 (3)で示される化合物（ 以下、これらを総称して「本発明の化合物（3)」または「ィ匕合物（3)」という。）、特に化 合物 (4)〜（16)は、文献未収載の新規ィ匕合物であること確認した。本発明はかかる 知見に基づいて完成したものである。  [0016] As a result of diligent research to solve the above-mentioned problems, the present inventors have found that the compound represented by the following formula (1) or a salt thereof, or a solvate thereof (hereinafter, these are generically named). ("Compound (1) of the present invention" or "Compound (1)") has a high inhibitory activity against plasminogen activator inhibitor 1 (PAI-1). In addition, it was confirmed that it is useful as an active ingredient of a fibrinolytic promoter as a PAI-1 inhibitor. The present inventors also found that PAI-1 is the main cause of tissue fibrosis, particularly pulmonary fibrosis, and confirmed that this tissue fibrosis was significantly improved by the compound (1) of the present invention. . In addition, the inventors of the present invention also include compounds represented by the formula (3) described below (hereinafter referred to collectively as “compound (3) of the present invention” or “compound ( 3) ”), in particular, it was confirmed that compounds (4) to (16) were novel compounds not yet published in literature. The present invention has been completed based on such knowledge.
[0017] すなわち、本発明には下記の態様が含まれる：  That is, the present invention includes the following aspects:
(I)プラスミノーゲンァクチべ一ターインヒビタ一一 1 (PAI— 1)阻害剤  (I) Plasminogen activity inhibitor 1 (PAI-1) inhibitor
項 1.下式 (1) :  Item 1.Formula (1):
[0018] [化 1]  [0018] [Chemical 1]
Figure imgf000006_0001
Figure imgf000006_0001
[0019] 〔式中、 Rは水素原子または炭素数 1〜4の直鎖または分枝鎖状のアルキル基; R は水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル基、または炭素 数 1〜6の直鎖または分枝鎖状のアルキル基; Rは水素原子、置換基を有していても [Wherein, R is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R Is a hydrogen atom, a phenyl group or a chaer group which may have a substituent, or a linear or branched alkyl group having 1 to 6 carbon atoms; R has a hydrogen atom or a substituent Even
3  Three
よいフエニル基、炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロゲン 原子を示す。また Rおよび Rは互いに結合して 5〜6員の環を形成していてもよい；  A good phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a halogen atom. R and R may be bonded to each other to form a 5- to 6-membered ring;
2 3  twenty three
Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、ァルケ-レン若しくはアルキ 二レン、炭素数 3〜8のシクロアルキレン、またはシングルボンド; Rは水素原子、置  A is a straight-chain or branched alkylene having 1 to 7 carbon atoms, alkene or alkylene, cycloalkylene having 3 to 8 carbon atoms, or a single bond; R is a hydrogen atom,
4  Four
換基を有していてもよいフエ-ル基またはフリル基、または、下式（2)；  A phenyl group or a furyl group which may have a substituent, or the following formula (2);
[0020] [化 2]  [0020] [Chemical 2]
Figure imgf000007_0001
Figure imgf000007_0001
[0021] (式中、 R，は水素原子または炭素数 1〜4の直鎖または分枝鎖状のアルキル基; R  [In the formula, R, is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R
1 2 1 2
'は水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル基、または炭 素数 1〜6の直鎖または分枝鎖状のアルキル基; R，は水素原子、置換基を有してい 'Represents a hydrogen atom, an optionally substituted phenyl group or a chaer group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R, represents a hydrogen atom or a substituent. Have
3  Three
てもよいフエニル基、炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロ ゲン原子を示す。また R，および R，は互いに結合して 5〜6員の環を形成していても  An optionally substituted phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a halogen atom; R and R may be bonded to each other to form a 5- to 6-membered ring.
2 3  twenty three
よい。）を示す。〕  Good. ). ]
で示される化合物若しくはその塩、またはこれらの溶媒和物を有効成分とする、 PAI 1阻害剤。  Or a salt thereof or a solvate thereof as an active ingredient.
[0022] 項 2.—般式（1)中、 Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、または 炭素数 3〜8のシクロアルキレン; Rは、下式（2)；  Item 2.—In the general formula (1), A is a linear or branched alkylene having 1 to 7 carbon atoms, or a cycloalkylene having 3 to 8 carbon atoms; R is represented by the following formula (2) ;
4  Four
[0023] [化 3]  [0023] [Chemical 3]
Figure imgf000007_0002
Figure imgf000007_0002
[0024] (式中、 R，は水素原子または炭素数 1〜4の直鎖または分枝鎖状のアルキル基; R 'は水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル基、または炭 素数 1〜6の直鎖または分枝鎖状のアルキル基; R，は水素原子、置換基を有してい [Wherein, R, is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R 'Represents a hydrogen atom, an optionally substituted phenyl group or a chaer group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R, represents a hydrogen atom or a substituent. Have
3  Three
てもよいフエニル基、炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロ ゲン原子を示す。また R，および R，は互いに結合して 5〜6員の環を形成していても  An optionally substituted phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a halogen atom; R and R may be bonded to each other to form a 5- to 6-membered ring.
2 3  twenty three
よい。 )  Good. )
で示される化合物若しくはその塩、またはこれらの溶媒和物を有効成分とする、項 1 記載の PAI— 1阻害剤。  Item 2. A PAI-1 inhibitor according to Item 1, comprising a compound represented by the above or a salt thereof, or a solvate thereof as an active ingredient.
[0025] 項 3. Rおよび R，力 同一または異なって、置換基を有していてもよいフエ-ル基 [0025] Item 3. R and R, force The same or different, a phenyl group which may have a substituent
2 2  twenty two
、 2—チェ-ル基、 CH CH (CH )である力、または同一または異なって、 Rと R  A 2-chael group, a force that is CH 2 CH 2 (CH 3), or the same or different, R and R
2 3 2 2 3 もしくは R，と R，がそれぞれ結合して縮合 6員環を形成している、項 1または 2に記載  Item 2 3 2 2 3 or R 1 and R are bonded to each other to form a condensed 6-membered ring,
2 3  twenty three
の PAI— 1阻害剤。  PAI-1 inhibitor.
[0026] 項 4. Rおよび R ' 1S 同一または異なって、水素原子、炭素数 1〜3の直鎖または  [0026] Item 4. R and R ′ 1S are the same or different and are each a hydrogen atom, a straight chain having 1 to 3 carbon atoms, or
3 3  3 3
分枝鎖状のアルキル基、フエ-ル基、またはハロゲン原子である、項 1乃至 3のいず れかに記載の PAI— 1阻害剤。  Item 4. The PAI-1 inhibitor according to any one of Items 1 to 3, which is a branched alkyl group, a phenol group, or a halogen atom.
[0027] 項 5. Aが、炭素数 3〜5の直鎖状のアルキレン、—CH—C (CH ) —CH —、ま [0027] Item 5. A is a linear alkylene having 3 to 5 carbon atoms, —CH—C (CH) —CH —,
2 3 2 2 たはシクロへキシレンである、項 1乃至 4のいずれかに記載の PAI— 1阻害剤。  Item 2. The PAI-1 inhibitor according to any one of Items 1 to 4, which is cyclohexylene.
[0028] 項 6. Rが水素原子であり、 Rおよび R 'がフエ-ル基または 2 チェ-ル基であり [0028] Item 6. R is a hydrogen atom, and R and R 'are a phenyl group or a 2-chael group.
1 2 2  1 2 2
、 Aがブチレンである、項 1乃至 5のいずれかに記載の PAI— 1阻害剤。  Item 6. The PAI-1 inhibitor according to any one of Items 1 to 5, wherein A is butylene.
[0029] (II)医薬組成物 [0029] (II) Pharmaceutical composition
項 7.項 1乃至 6のいずれかに記載する PAI— 1阻害剤、および薬学的に許容され る担体または添加剤を含む医薬組成物。言い換えれば、上記一般式（1)に記載する 化合物若しくはその塩またはこれらの溶媒和物、および薬学的に許容される担体ま たは添加剤を含む医薬組成物。  Item 7. A pharmaceutical composition comprising the PAI-1 inhibitor according to any one of Items 1 to 6, and a pharmaceutically acceptable carrier or additive. In other words, a pharmaceutical composition comprising a compound represented by the above general formula (1) or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier or additive.
[0030] 項 8. PAI— 1活性が発症に関わって 、る疾患の予防または治療薬である項 7記載 の医薬組成物。 [0030] Item 8. The pharmaceutical composition according to Item 7, which is a prophylactic or therapeutic agent for a disease associated with the onset of PAI-1 activity.
[0031] 項 9.線溶系促進薬である項 7または 8記載の医薬組成物  [0031] Item 9. The pharmaceutical composition according to Item 7 or 8, which is a fibrinolytic promoter.
項 10. PAI—1活性が発症に関わっている疾患力 狭心症、心筋梗塞もしくは心房 細動における心房内血栓、虚血性心疾患、虚血性脳血管障害、動脈硬化症、肺塞 栓症、外科手術時の深部静脈血栓症 (DVT)、播種性血管内凝固症候群 (DIC)、 糖尿病合併症としての血管障害、神経障害、網膜症もしくは腎症、または経皮的冠 動脈形成術 (PTCA)後の再狭窄である、項 9に記載する医薬組成物。 Item 10. Disease power related to the onset of PAI-1 activity Angina, myocardial infarction or atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary embolism Embolism, deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or percutaneous coronary angioplasty Item 10. The pharmaceutical composition according to Item 9, which is restenosis after (PTCA).
[0032] 項 11. PAI—1活性が発症に関わっている疾患力 組織線維化を伴う疾患である 項 8に記載する医薬組成物。  [0032] Item 11. The disease composition in which PAI-1 activity is involved in the onset The pharmaceutical composition according to Item 8, wherein the disease is accompanied by tissue fibrosis.
[0033] 項 12.組織線維化を伴う疾患が肺線維症である項 11に記載する医薬組成物。  [0033] Item 12. The pharmaceutical composition according to Item 11, wherein the disease associated with tissue fibrosis is pulmonary fibrosis.
[0034] 項 13.経口投与形態を有する項 7乃至 12のいずれかに記載する医薬組成物。  [0034] Item 13. The pharmaceutical composition according to any one of Items 7 to 12, which has an oral dosage form.
[0035] 項 14.下式（3) :  [0035] Item 14. The following equation (3):
[0036] [化 4]  [0036] [Chemical 4]
Figure imgf000009_0001
Figure imgf000009_0001
[0037] 〔式中、 Rと R 'は、同一または異なって、水素原子または炭素数 1〜4の直鎖または 分枝鎖状のアルキル基; R  [In the formula, R and R ′ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R
2と R  2 and R
2 'は、同一または異なって、水素原子、置換基を有し ていてもよいフエニル基、または炭素数 1〜6の直鎖または分枝鎖状のアルキル基; R と R 'は、同一または異なって、水素原子、置換基を有していてもよいフエニル基、 2 ′ is the same or different and is a hydrogen atom, an optionally substituted phenyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R and R ′ are the same or Differently, a hydrogen atom, an optionally substituted phenyl group,
3 3 3 3
炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロゲン原子; Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、または炭素数 3〜8のシクロアルキレンを 示す。但し、 Rおよび R，が置換基を有さないフエ-ル基であり且つ Rおよび R 'が  A linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom; A represents a linear or branched alkylene having 1 to 7 carbon atoms or a cycloalkylene having 3 to 8 carbon atoms . Provided that R and R are phenyl groups having no substituent and R and R ′ are
2 2 3 3 水素原子であるとき、 Aはブチレンおよび CH -C (CH ) -CH一のいずれでも  When 2 2 3 3 is a hydrogen atom, A is either butylene or CH 2 -C (CH 2) 2 -CH 1
2 3 2 2  2 3 2 2
なぐまた Rおよび R，がイソブチル基であり且つ Rおよび R，が水素原子であるとき  When R and R are isobutyl groups and R and R are hydrogen atoms
2 2 3 3  2 2 3 3
、 Aはブチレンではない。〕  A is not butylene. ]
で示される化合物またはその塩。  Or a salt thereof.
[0038] 項 15.下式 (4)〜（16)のいずれかに示される化合物またはその塩：  Item 15. A compound represented by any one of the following formulas (4) to (16) or a salt thereof:
[0039] 2-[5-(3， -カルボキシ- 4， -(P-クロ口フエ-ル)チォフェン- 2， -ィルカルバモイル)-ペン タノィルァミノ] -4-(p-クロ口フエ-ル)チォフェン- 3-カルボン酸  [0039] 2- [5- (3, -Carboxy-4,-(P-chrome mouth file) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (p-black mouth file) Thiophene-3-carboxylic acid
[0040] [化 5]
Figure imgf000010_0001
[0040] [Chemical 5]
Figure imgf000010_0001
[0041] 2-[4-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2 ' -ィルカルバモイル)-ブチリルアミ ノ] -4-イソブチルチオフェン- 3-カルボン酸 [0041] 2- [4- (3′-carboxy-4′-isobutylthiophene-2′-ylcarbamoyl) -butyrylamino] -4-isobutylthiophene-3-carboxylic acid
[0042] [化 6] [0042] [Chemical 6]
( 5)( Five)
Figure imgf000010_0002
Figure imgf000010_0002
[0043] 2-[4-(3， -力ルポキシ- 4' -イソプチルチオフェン- 2， -ィルカルバモイル)- 3,3-ジメチル ブチリルァミノ] -4-イソブチルチオフェン- 3-カルボン酸  [0043] 2- [4- (3, -Strong Lupoxy-4'-Isoptylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino] -4-isobutylthiophene-3-carboxylic acid
[0044] [化 7] [0044] [Chemical 7]
Figure imgf000010_0003
Figure imgf000010_0003
[0045] 2-[6-(3， -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-へキサノィルァ ミノ] -4-フエ-ルチオフェン- 3-カルボン酸 [0045] 2- [6- (3, -Carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -hexanoylamino] -4-phenolthiophene-3-carboxylic acid
[0046] [化 8] [0046] [Chemical 8]
Figure imgf000010_0004
Figure imgf000010_0004
[0047] 2-[5-(3， -カルボキシ -5， -メチル -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-ぺ ンタノィルァミノ] -5-メチル -4-フエ-ルチオフェン- 3-カルボン酸 [0047] 2- [5- (3, -Carboxy-5, -methyl-4, -phenylthiophene-2, -ylcarbamoyl) -pe Antanoylamino] -5-methyl-4-phenolthiophene-3-carboxylic acid
[0048] [化 9] [0048] [Chemical 9]
Figure imgf000011_0001
Figure imgf000011_0001
[0049] 2-[5-(3 ' -カルボキシ -5， -フエ-ルチオフェン- 2， -ィルカルバモイル)-ペンタノィルァ ミノ] -5-フエ-ルチオフェン- 3-カルボン酸 [0049] 2- [5- (3'-carboxy-5, -phenylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-phenolthiophene-3-carboxylic acid
[0050] [化 10]  [0050] [Chemical 10]
Figure imgf000011_0002
Figure imgf000011_0002
[0051] 2-[5-(3， -カルボキシ- 5， -クロロチォフェン- 2， -ィルカルバモイル) - ンタノィルァミノ ]-5-クロロチォフェン- 3-カルボン酸 [0051] 2- [5- (3, -Carboxy-5, -chlorothiophene-2, -ylcarbamoyl) -tertylamino] -5-chlorothiophene-3-carboxylic acid
[0052] [化 11]  [0052] [Chemical 11]
Figure imgf000011_0003
Figure imgf000011_0003
[0053] 2-[4-(3， -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-シクロへキシル カルボ-ルァミノ] -4-フ -ルチオフェン- 3-カルボン酸 [0053] 2- [4- (3, -Carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -cyclohexylcarbolamino] -4-furthiophene-3-carboxylic acid
[0054] [化 12]  [0054] [Chemical 12]
Figure imgf000011_0004
[0055] 2-[5-(3， -カルボキシ -5， -イソプロピル- 4' -メチルチオフェン- 2， -ィルカルバモイル) - ペンタノィルァミノ] -4-イソブチルチオフェン- 3-カルボン酸
Figure imgf000011_0004
[0055] 2- [5- (3, -Carboxy-5, -isopropyl-4'-methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0056] [化 13] [0056] [Chemical 13]
Figure imgf000012_0001
Figure imgf000012_0001
[0057] 2-[3-(3， -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバモイル)-プロパノィル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸 [0057] 2- [3- (3, -Carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -propanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0058] [化 14] [0058] [Chemical 14]
Figure imgf000012_0002
Figure imgf000012_0002
[0059] 2-[5-(3， -カルボキシ- 4， -イソプロピルチオフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -4-イソプロピルォフェン- 3-カルボン酸 [0059] 2- [5- (3, -Carboxy-4, -isopropylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isopropylophene-3-carboxylic acid
[0060] [化 15] [0060] [Chemical 15]
Figure imgf000012_0003
Figure imgf000012_0003
[0061] 2-[5-(3， -カルボキシ -5， -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィルアミ ノ] -5-メチルチオフェン- 3-カルボン酸 [0061] 2- [5- (3, -Carboxy-5, -methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-methylthiophene-3-carboxylic acid
[0062] [化 16] [0062] [Chemical 16]
Figure imgf000012_0004
Figure imgf000012_0004
[0063] 2-[5-(3， -tert-ブトキシカルボ-ル -5， -メチルチオフェン- 2， -ィルカルバモイル)-ぺ ンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸 [0063] 2- [5- (3, -tert-Butoxycarbol-5, -methylthiophene-2, -ylcarbamoyl) -pe Antanoylamino] -5-methylthiophene-3-carboxylic acid
[0064] [化 17] [0064] [Chemical 17]
Figure imgf000013_0001
Figure imgf000013_0001
[0065] 項 16.項 14または 15に記載する化合物若しくはその薬学的に許容される塩、また はこれらの溶媒和物力 なる群力 選択される少なくとも 1つを有効成分とする医薬 組成物。  [0065] A pharmaceutical composition comprising as an active ingredient at least one selected from the compound or the pharmaceutically acceptable salt thereof according to item 16. or the pharmaceutically acceptable salt thereof, or the solvate power thereof.
[0066] なお、当該医薬組成物の用途は特に限定されず、 PAI— 1活性が発症に関わって いる疾患の予防または治療用途などの PAI— 1阻害作用に基づくものに限定される わけではない。  [0066] The use of the pharmaceutical composition is not particularly limited, and is not limited to those based on PAI-1 inhibitory action such as prevention or treatment of diseases in which PAI-1 activity is involved in onset. .
発明の効果  The invention's effect
[0067] 本発明により、大量合成が可能であり安全性の高い低分子化合物を有効成分とす る医薬組成物を提供することができる。当該医薬組成物は、 PAI—1に対して高い阻 害作用を有する化合物（PAI— 1阻害剤）を有効成分とするものであり、 PAI— 1活性 に起因して生じる各種の疾患の予防または治療剤として有効に用いることができる。 特に、本発明の医薬組成物は、線溶系促進薬として、狭心症、心筋梗塞もしくは心 房細動における心房内血栓、虚血性心疾患、虚血性脳血管障害、動脈硬化症、肺 塞栓症、外科手術時の深部静脈血栓症 (DVT)、播種性血管内凝固症候群 (DIC) 、糖尿病合併症としての血管障害、神経障害、網膜症もしくは腎症、または経皮的冠 動脈形成術 (PTCA)後の再狭窄の予防または治療に有用である。また本発明の医 薬組成物は、抗線維症薬として、組織線維化に関連する各種の疾患、特に肺線維 症の予防または治療に有用である。  [0067] According to the present invention, it is possible to provide a pharmaceutical composition comprising a low-molecular compound that can be synthesized in large quantities and has high safety as an active ingredient. The pharmaceutical composition comprises a compound having a high inhibitory action on PAI-1 (PAI-1 inhibitor) as an active ingredient, and prevents or prevents various diseases caused by PAI-1 activity. It can be used effectively as a therapeutic agent. In particular, the pharmaceutical composition of the present invention is used as a fibrinolytic promoter as an angina pectoris, myocardial infarction or atrial thrombosis in atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary embolism , Deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or percutaneous coronary angioplasty (PTCA) ) Useful for the prevention or treatment of later restenosis. In addition, the pharmaceutical composition of the present invention is useful as an antifibrotic agent for the prevention or treatment of various diseases associated with tissue fibrosis, particularly pulmonary fibrosis.
[0068] また本発明によれば、 PAI- 1に対して高 ヽ阻害作用を有する新規化合物を提供 することができる。力かる化合物は、 PAI—1活性に起因して生じる各種の疾患の予 防または治療剤など、医薬組成物の有効成分として有用である。  [0068] Further, according to the present invention, it is possible to provide a novel compound having an inhibitory effect on PAI-1. Powerful compounds are useful as active ingredients in pharmaceutical compositions, such as prophylactic or therapeutic agents for various diseases caused by PAI-1 activity.
発明を実施するための最良の形態 [0069] (I) PAI— 1阻害剤 BEST MODE FOR CARRYING OUT THE INVENTION [0069] (I) PAI-1 inhibitor
本発明が提供する PAI— 1阻害剤は、下式（1)  The PAI-1 inhibitor provided by the present invention has the following formula (1)
[0070] [化 18] [0070] [Chemical 18]
Figure imgf000014_0001
Figure imgf000014_0001
[0071] で示される化合物またはその塩を有効成分とするものである。 [0071] or a salt thereof as an active ingredient.
[0072] 式（1)中、 Rは水素原子または炭素数 1〜4の直鎖または分枝鎖状のアルキル基 で示される。ここで、炭素数 1〜4のアルキル基としては、メチル基、ェチル基、 n—プ 口ピル基、イソプロピル基、 n—ブチル基、イソブチル基、 sec-ブチル基、および ter- ブチル基などの直鎖または分枝鎖状のアルキル基を挙げることができる力 Rとして [0072] In the formula (1), R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Here, examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and ter-butyl group. A force R that can mention a linear or branched alkyl group
1 好ましくは水素原子および t-ブチル基である。  1 Preferred are a hydrogen atom and a t-butyl group.
[0073] 式（1)中、 Rは、水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル  In the formula (1), R represents a hydrogen atom, an optionally substituted phenyl group or a chanel.
2  2
基、または炭素数 1〜6の直鎖または分枝鎖状のアルキル基である。好ましくは置換 基を有していてもよいフエ-ル基、チェ-ル基、メチル基、イソブチル基、イソプロピ ル基、または水素原子であり、より好ましくはチェ-ル基、フエニル基、およびイソブ チル基である。  Or a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Preferred are a phenyl group, a chael group, a methyl group, an isobutyl group, an isopropyl group, or a hydrogen atom, which may have a substituent, and more preferred are a chael group, a phenyl group, and an isobutyl group. A til group.
[0074] チェ-ル基としては好適には 2 チェ-ル基を挙げることができる。これらフエニル 基またはチェニル基の置換基としてはカルボキシル基、アミノ基、ハロゲン原子、へ テロ環基を挙げることができる。好ましくはハロゲン原子 (例えば、塩素原子、フッ素 原子、ヨウ素原子など)である。  [0074] Preferred examples of the chael group include a 2-chael group. Examples of the substituent of the phenyl group or the phenyl group include a carboxyl group, an amino group, a halogen atom, and a heterocyclic group. A halogen atom (for example, a chlorine atom, a fluorine atom, an iodine atom, etc.) is preferred.
炭素数 1〜6の直鎖または分枝鎖状のアルキル基としては、メチル基、ェチル基、 n プロピル基、イソプロピル基、 n ブチル基、イソブチル基、 sec ブチル基、 ter— ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、 ter ペンチル基、へキ シル基、イソへキシル基、ネオへキシル基、 ter—へキシル基を挙げることができる。 好ましくは炭素数 1〜4の直鎖または分枝鎖状のアルキル基であり、より好ましくはメ チル基、イソプロピル基、イソブチル基である。 Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n propyl group, isopropyl group, n butyl group, isobutyl group, sec butyl group, ter-butyl group, pentyl group , Isopentyl group, neopentyl group, ter pentyl group, hexyl group, isohexyl group, neohexyl group, and ter-hexyl group. Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably A til group, an isopropyl group and an isobutyl group;
[0075] 式（1)中、 Rと Rは、これらが結合する炭素原子とともに互いに結合して 5〜6員の [0075] In the formula (1), R and R are bonded to each other together with the carbon atom to which they are bonded to form a 5-6 membered
2 3  twenty three
環を形成したものであってもよい。かかる 5〜6員環としては、シクロへキサン、シクロ へキセン、 1, 3 シクロへキサジェン、シクロペンタン、シクロペンテンおよびべンゼ ンを挙げることができる。好ましくはシクロへキサンである。  A ring may be formed. Such 5- to 6-membered rings can include cyclohexane, cyclohexene, 1,3 cyclohexagen, cyclopentane, cyclopentene and benzene. Preferred is cyclohexane.
[0076] また、 Rは、水素原子、置換基を有して!/、てもよ 、フ -ル基、炭素数 1〜6の直鎖 [0076] R may have a hydrogen atom or a substituent! /, A full group, or a straight chain of 1 to 6 carbon atoms.
3  Three
または分枝鎖状のアルキル基、またはハロゲン原子であることもできる。フエ-ル基の 置換基としては前述するようにカルボキシル基、アミノ基、ハロゲン原子、ヘテロ環基 を挙げることができる。また炭素数 1〜6の直鎖または分枝鎖状のアルキル基としても 、前述するものを同様に挙げることができる。 Rとして、好ましくは水素原子、フエニル  Alternatively, it may be a branched alkyl group or a halogen atom. Examples of the substituent of the phenyl group include a carboxyl group, an amino group, a halogen atom, and a heterocyclic group as described above. Examples of the linear or branched alkyl group having 1 to 6 carbon atoms are the same as those described above. R is preferably a hydrogen atom or phenyl
3  Three
基、メチル基、イソプロピル基、およびハロゲン原子である。  A group, a methyl group, an isopropyl group, and a halogen atom.
[0077] Aは、シングルボンド；炭素数 1〜7の直鎖または分枝鎖状のアルキレン、ァルケ- レン、またはアルキ-レン；炭素数 3〜8のシクロアルキレンである。好ましくは、炭素 数 2〜5の直鎖または分枝鎖状のアルキレン、炭素数 6のシクロアルキレン（シクロへ キサンジィル）、およびビ-レンである。炭素数 2〜5の直鎖または分枝鎖状のアルキ レンとして具体的には、エチレン基、プロピレン基、ブチレン基、ペンチレン基、 CH C (CH ) CH を挙げることができる。好ましくはブチレン基、 -CH C (CH ) CH[0077] A is a single bond; a linear or branched alkylene, alkylene, or alkylene having 1 to 7 carbon atoms; a cycloalkylene having 3 to 8 carbon atoms. Preferred are linear or branched alkylene having 2 to 5 carbon atoms, cycloalkylene having 6 carbon atoms (cyclohexanediyl), and beylene. Specific examples of the linear or branched alkylene having 2 to 5 carbon atoms include an ethylene group, a propylene group, a butylene group, a pentylene group, and CH 2 C (CH 3) 2 CH 3. Preferably a butylene group, -CH C (CH) CH
2 3 2 2 2 3 2 一、シクロへキサンジィルである。 2 3 2 2 2 3 2 This is cyclohexanediyl.
2  2
[0078] 式（1)中、 Rとしては、水素原子、または置換基を有していてもよいフエ-ル基また  In the formula (1), R is a hydrogen atom, a phenyl group which may have a substituent, or
4  Four
はフリル基を挙げることができる。  May include a furyl group.
[0079] ここで、フリル基としては 2 フリル基が好ましい。フエ-ル基またはフリル基が置換 基を有する場合、当該置換基としては、塩素原子、ヨウ素原子、臭素原子またはフッ 素原子のハロゲン原子;炭素数 1〜6の直鎖状または分枝鎖状のアルキル基を挙げ ることができる。ハロゲン原子として好ましくはフッ素原子または塩素原子である。炭 素数 1〜6の直鎖状または分枝鎖状のアルキル基としては、具体的には前述するも のを挙げることができる力 好ましくは ter ブチル基、 n—ブチル基である。  [0079] Here, the furyl group is preferably a 2-furyl group. When the phenol group or the furyl group has a substituent, the substituent includes a chlorine atom, an iodine atom, a bromine atom or a halogen atom of a fluorine atom; a linear or branched chain having 1 to 6 carbon atoms The alkyl group of can be mentioned. A halogen atom is preferably a fluorine atom or a chlorine atom. Specific examples of the linear or branched alkyl group having 1 to 6 carbon atoms include those described above, preferably a ter butyl group and an n-butyl group.
[0080] また、 Rは、下式（2)で示される基であることができる：  [0080] R can be a group represented by the following formula (2):
4  Four
[0081] [化 19]
Figure imgf000016_0001
[0081] [Chemical 19]
Figure imgf000016_0001
[0082] ここで、 'としては、前述する と同様に、水素原子または炭素数 1〜4の直鎖ま たは分枝鎖状のアルキル基を挙げることができる。化合物（1)が Rとして上記の基（2  [0082] Here, as described above, as described above, a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms can be exemplified. Compound (1) is a group represented by the above group (2
4  Four
)を有する場合、 R 'と Rとは異なっていてもよいが、同一であることが好ましい。  ), R ′ and R may be different, but are preferably the same.
[0083] また、 R 'としては、前述する Rと同様に、水素原子、置換基を有していてもよいフ [0083] Further, as R ', as in R described above, a hydrogen atom or a substituent optionally having a substituent may be used.
2 2  twenty two
ェニル基若しくはチェ-ル基、または炭素数 1〜6の直鎖または分枝鎖状のアルキル 基を挙げることができる。化合物（1)が Rとして上記の基 (2)を有する場合、 R 'と R  Examples thereof include a phenyl group, a chaer group, and a linear or branched alkyl group having 1 to 6 carbon atoms. When compound (1) has the above group (2) as R, R ′ and R
4 2 2 とは異なって 、てもよ 、が、同一であることが好まし!/、。  Unlike 2 2 2, but it is preferred that they are the same! /.
[0084] R 'も、前述する Rと同様に、水素原子、置換基を有していてもよいフ ニル基、炭 [0084] R 'is also a hydrogen atom, a phenyl group which may have a substituent, a carbon atom, as in R described above.
3 3  3 3
素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロゲン原子であってもよ!/ヽ し、また R 'とともに、これらが結合する炭素原子とともに互いに結合して 5〜6員の環  It may be a linear or branched alkyl group having 1 to 6 prime numbers or a halogen atom, and together with R ′, these atoms are bonded to each other together with the carbon atom to which they are bonded. Ring
2  2
を形成してなるものであってもよい。化合物（1)が Rとして上記の基（2)を有する場合  May be formed. When compound (1) has the above group (2) as R
4  Four
、 Rと R 'とは異なっていてもよいが、同一であることが好ましぐまた、互いに同時に , R and R 'may be different, but it is preferred that they are identical, and at the same time mutually
3 3 3 3
Rと R，ととも 5〜6員の環を形成していてもよい。  R and R may form a 5- to 6-membered ring.
2 2  twenty two
[0085] 好適な化合物としては、式（1)において、 Aが炭素数 1〜7の直鎖または分枝鎖状 のアルキレン、または炭素数 3〜8のシクロアルキレンであり、また Rとして上記基（2)  [0085] As a preferred compound, in the formula (1), A is a linear or branched alkylene having 1 to 7 carbon atoms, or a cycloalkylene having 3 to 8 carbon atoms, and R is the above group. (2)
4  Four
を有するものである。力かる好適な化合物として、下式（17)に示すィ匕合物を挙げるこ とができる：  It is what has. Examples of preferred compounds that can be used include compounds represented by the following formula (17):
[0086] [化 20] [0086] [Chemical 20]
Figure imgf000016_0002
Figure imgf000016_0002
(式中、1^、1^、1^、1^ '、1^，および R，は前記と同意義である。 ) (In the formula, 1 ^, 1 ^, 1 ^, 1 ^ ', 1 ^, and R are as defined above.)
1 2 3 1 2 3  1 2 3 1 2 3
本発明が対象とする化合物（1) (特に化合物（17) )として、好ましくは Rおよび R ' が水素原子であるもの、および Rおよび R 'が同一または異なって ter-ブチル基であ るものを挙げることができる。より好ましくは、 Rおよび R 'が、水素原子、置換基を有 As the compound (1) (particularly the compound (17)) targeted by the present invention, preferably R and R ′ In which R is a hydrogen atom, and R and R ′ are the same or different and are ter-butyl groups. More preferably, R and R ′ have a hydrogen atom or a substituent.
2 2  twenty two
するかまたは置換を有しないフエニル基、 2—チェニル基、イソプロピル基、イソブチ ル基〔一 CH CH (CH ) 〕である力、または Rと Rおよび R，と R，がそれぞれ互い  Or a force that is a phenyl group, 2-phenyl group, isopropyl group, isobutyl group [one CH CH (CH 2)], or R and R and R and R are
2 3 2 2 3 2 3 に結合して 6員環を形成しているものである。また更に好ましくは、 Aがエチレン、プロ ピレン、ブチレン、ペンチレン、 CH— C (CH ) — CH —、またはシクロへキサン  It is bonded to 2 3 2 2 3 2 3 to form a 6-membered ring. Even more preferably, A is ethylene, propylene, butylene, pentylene, CH—C (CH 2) —CH 2 —, or cyclohexane.
2 3 2 2  2 3 2 2
ジィルであるものである。より好ましい本発明の化合物（1) (特に化合物（17) )として は、 R、 R '、 Rおよび R，がいずれも水素原子であり、 Rおよび R，がフエ-ル基ま It is what is a jill. As a more preferred compound (1) (especially compound (17)) of the present invention, R, R ′, R and R are all hydrogen atoms, and R and R are each a phenyl group.
1 1 3 3 2 2 たは 2—チェ二ノレ基であり、 Aがブチレンまたは CH— C (CH ) CH—である 1 1 3 3 2 2 or 2-Chechinole group, A is butylene or CH— C (CH) CH—
2 3 2 2 化合物を挙げることができる。  2 3 2 2 compounds.
[0088] なお、本発明が対象とするこれらの化合物（1)は、前述するように遊離の形態を有 するものであってもよいが、塩の形態を有するもののであってもよい。ここで塩として は、通常、医薬上許容される塩、たとえば無機塩基または有機塩基との塩、または塩 基性アミノ酸との塩などを挙げることができる。無機塩基としては、たとえば、ナトリウム やカリウム等のアルカリ金属；カルシウムやマグネシウム等のアルカリ土類金属；アル ミニゥムゃアンモ-ゥム等を挙げることができる。有機塩基としては、たとえば、ェタノ ールァミン等の第一級ァミン；ジェチルァミン、ジエタノールァミン、ジシクロへキシル ァミン、 N, N' ジベンジルエチレンジァミン等の第二級ァミン；トリメチルァミン、トリ ェチルァミン、ピリジン、ピコリン、トリエタノールァミン等の第三級アミン等を挙げること ができる。塩基性アミノ酸としては、たとえば、アルギニン、リジン、オル-チン等を挙 げることができる。  [0088] These compounds (1) targeted by the present invention may have a free form as described above, or may have a salt form. Examples of the salt include pharmaceutically acceptable salts such as salts with inorganic bases or organic bases, salts with basic amino acids, and the like. Examples of the inorganic base include alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; aluminum and ammonia. Organic bases include, for example, primary amines such as ethanolamine; secondary amines such as jetylamine, diethanolamine, dicyclohexylamine, N, N 'dibenzylethylenediamine; trimethylamine, triethylamine. And tertiary amines such as pyridine, picoline and triethanolamine. Examples of basic amino acids include arginine, lysine, orthine and the like.
[0089] 本発明が対象とする好適な化合物（1)として、具体的には下記の化合物 a〜nおよ び o〜zzを挙げることができる。  [0089] Specific examples of suitable compound (1) targeted by the present invention include the following compounds a to n and o to zz.
[0090] 化合物 a [0090] Compound a
2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモイル)-ペンタノィルァ ミノ] -4-フエ-ルチオフェン- 3-カルボン酸  2- [3- (3'-Carboxy-4'-phenylthiophene-2-silylcarbamoyl) -pentanoylamino] -4-phenolthiophene-3-carboxylic acid
[0091] [化 21]
Figure imgf000018_0001
[0091] [Chemical 21]
Figure imgf000018_0001
[0092] 化合物 bおよびその塩 [0092] Compound b and its salt
2- [5- (3， -カルボキシ- 4， -(2-チェニル)チォフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -4-(2-チェ-ル)チォフェン- 3-カルボン酸  2- [5- (3, -Carboxy-4,-(2-Cenyl) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (2-Chel) thiophene-3-carboxylic acid
[0093] [化 22]  [0093] [Chemical 22]
Figure imgf000018_0002
Figure imgf000018_0002
[0094] 2-[5-(3， -カルボキシ- 4， -(2-チェニル)チォフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -4-(2-チェニル)チォフェン- 3-カルボン酸 ジナトリウム塩 [0094] 2- [5- (3, -Carboxy-4,-(2-Cenyl) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (2-Cenyl) thiophene-3-carboxylic acid disodium salt
[0095] [化 23]  [0095] [Chemical 23]
Figure imgf000018_0003
Figure imgf000018_0003
[0096] 化合物 c [0096] Compound c
2- [3- (3'-カルボキシ- 4'，5'，6',7'-テトラヒドロ-ベンゾ [b]チォフェン- 2'-ィルカルパモ イル)-ペンタノィルァミノ] - 4,5,6,7-テトラヒドロ-ベンゾ [b]チォフェン- 3-カルボン酸 2- [3- (3'-Carboxy-4 ', 5', 6 ', 7'-tetrahydro-benzo [b] thiophene-2'-ilcarpamoyl) -pentanoylamino]-4,5,6, 7-Tetrahydro-benzo [b] thiophene-3-carboxylic acid
[0097] [化 24] [0097] [Chemical 24]
Figure imgf000018_0004
[0098] 化合物 dおよびその塩
Figure imgf000018_0004
[0098] Compound d and its salt
2-[5-(3，カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバモイル)-ペンタノィル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [5- (3, Carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0099] [化 25] [0099] [Chemical 25]
Figure imgf000019_0001
Figure imgf000019_0001
[0100] 2-[5-(3， -カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバモイル)-ペンタノィル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸 ジナトリウム塩 [0100] 2- [5- (3, -Carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carboxylic acid disodium salt
[0101] [化 26] [0101] [Chemical 26]
）)
Figure imgf000019_0002
Figure imgf000019_0002
[0102] 化合物 e [0102] Compound e
2- [3- (3'-カルボキシ- 4'，5'，6'，7'-テトラヒドロ [b]チォフェン- 2しィルカルバモイル)-プ ロパノィルァミノ]- 4,5,6,7-テトラヒドロ-ベンゾ [b]チォフェン- 3-カルボン酸  2- [3- (3'-Carboxy-4 ', 5', 6 ', 7'-tetrahydro [b] thiophene-2-silylcarbamoyl) -propanoylamino]-4,5,6,7-tetrahydro-benzo [b] Thiophene-3-carboxylic acid
[0103] [化 27] [0103] [Chemical 27]
Figure imgf000019_0003
Figure imgf000019_0003
[0104] 化合物 f [0104] Compound f
2-へキサノィルァミノ- 4-p-トリルチオフェン- 3-カルボン酸  2-Hexanoylamino-4-p-tolylthiophene-3-carboxylic acid
[0105] [化 28]
Figure imgf000020_0001
[0105] [Chemical 28]
Figure imgf000020_0001
[0106] ィ [0106]
2-(3-フラン- 2-ィル -アタリロイルァミノ) -4一（2 チェニル） 3 カルボン酸  2- (3-furan-2-yl-atallyloylamino) -4 mono (2 cenyl) 3 carboxylic acid
[0107] [化 29]  [0107] [Chemical 29]
Figure imgf000020_0002
Figure imgf000020_0002
[0108] ィ k合物 hおよびその塩 [0108] i k compound h and its salt
2-[4-(3しカルボキシ -4し (2-チェニル)チォフェン- 2しィルカルバモイル) - 3,3-ジメチ ルブチリルァミノ] -4-(2-チェニル)チォフェン- 3-カルボン酸  2- [4- (3) carboxy-4 (2-phenyl) thiophene-2-ylcarbamoyl) -3,3-dimethylbutyrylamino] -4- (2-phenyl) thiophene-3-carboxylic acid
[0109] [化 30]  [0109] [Chemical 30]
Figure imgf000020_0003
Figure imgf000020_0003
[0110] 2- [4- (3'-カルボキシ- 4し (2-チェ-ル)チォフェン- 2しィルカルバモイル)- 3,3- ルブチリルァミノ] -4-(2-チェニル)チォフェン- 3-カルボン酸 ジナトリウム塩 [0110] 2- [4- (3'-Carboxy-4 (2-Chel) thiophene-2-Silbcarbamoyl) -3,3-Rubutylylamino] -4- (2-Cenyl) thiophene-3-Carbon Acid disodium salt
[0111] [化 31] [0111] [Chemical 31]
Figure imgf000020_0004
Figure imgf000020_0004
[0112] 化合物 i 4 -イソブチル -2-シンナモイルチオフェン- 3-カルボン酸 [0112] Compound i 4-Isobutyl-2-cinnamoylthiophene-3-carboxylic acid
[0113] [化 32] [0113] [Chemical 32]
Figure imgf000021_0001
Figure imgf000021_0001
[0114] 化合物 i [0114] Compound i
2 - [4- (3'-カルボキシ- 4',5', 6', 7'-テトラヒドロ-ベンゾ [b]チォフェン- 2-ィルカルバモ ィル) - 3，3-ジメチル]-ブチリルァミノ) -4,5,6,7-テトラヒドロ-ベンゾ [b]チォフェン- 3-力 ルボン酸  2-[4- (3'-carboxy-4 ', 5', 6 ', 7'-tetrahydro-benzo [b] thiophen-2-ylcarbamoyl)-3,3-dimethyl] -butyrylamino) -4, 5,6,7-tetrahydro-benzo [b] thiophene-3-force rubonic acid
[0115] [化 33] [0115] [Chemical 33]
Figure imgf000021_0002
Figure imgf000021_0002
[0116] 化合物 k [0116] Compound k
2- [5- (3 '-カルボキシ- 4'-フエ-ルチオフェン- 2 '-ィルカルバモイル)- (3， 3-ジメチル) )ブチルァミノ] -4-フエニル-チォフェン- 3-カルボン酸  2- [5- (3'-Carboxy-4'-phenylthiophene-2'-ylcarbamoyl)-(3,3-dimethyl)) butyramino] -4-phenyl-thiophene-3-carboxylic acid
[0117] [化 34] [0117] [Chemical 34]
Figure imgf000021_0003
Figure imgf000021_0003
[0118] 化合物 1 [0118] Compound 1
2- (4- tert-ブチル ミンゾィルァミノ) -4一（2 チェ-ル） 3 力ルボン酸  2- (4- tert-butyl minzoylamino) -4 one (2 chael) 3 strength rubonic acid
[0119] [化 35] [0119] [Chemical 35]
Figure imgf000022_0001
Figure imgf000022_0001
[0120] 化合物 m [0120] Compound m
2- (3-フエ-ルプロピオ-ルァミノ)- 4— (2 チェ-ル）—3—カルボン酸 2- (3-Ferpropio-Lamino)-4— (2 chails) —3-carboxylic acid
[0121] [化 36] [0121] [Chemical 36]
Figure imgf000022_0002
Figure imgf000022_0002
[0122] 化合物 n [0122] Compound n
2- (4-フルォ口べンゾィルァミノ)- 4- (2 チェ-ル） 3 カルボン酸  2- (4-Fluorobenzoylamino) -4- (2 chails) 3 Carboxylic acid
[0123] [化 37] [0123] [Chemical 37]
Figure imgf000022_0003
Figure imgf000022_0003
[0124」 化合物 o [0124] Compound o
2- [5- (3， -カルボキシ- 4， -(p-クロ口フエ-ル)チォフェン- 2， -ィルカルバモイル)-ペン タノィルァミノ] -4-(p-クロ口フエ-ル)チォフェン- 3-カルボン酸  2- [5- (3, -Carboxy-4,-(p-chrome phthalate) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (p-chrome phthalate) thiophene-3 -carboxylic acid
[0125] [化 38]
Figure imgf000023_0001
[0125] [Chemical 38]
Figure imgf000023_0001
( θ )  (θ)
[0126] 化合物 p [0126] Compound p
2-[4-(3 ' -カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバモイル)-ブチリルアミ ノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [4- (3'-carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -butyrylamino] -4-isobutylthiophene-3-carboxylic acid
[0127] [化 39] [0127] [Chemical 39]
Figure imgf000023_0002
Figure imgf000023_0002
( P ) (P)
[0128] 化合物 α [0128] Compound α
2-[4-(3 ' -カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバモイル)- 3,3-ジメチル ブチリルァミノ-ジメチルブチリルァミノ] -4-イソブチルチオフェン- 3 -力ルボン酸  2- [4- (3'-Carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino-dimethylbutyrylamino] -4-isobutylthiophene-3-strong rubonic acid
[0129] [化 40] [0129] [Chemical 40]
Figure imgf000023_0003
Figure imgf000023_0003
(q )  (q)
[0130] 化合物 r [0130] Compound r
2-[6-(3， -カルボキシ- 4， -フエ-ルチオフェン- 2， -ィルカルバモイル) - 、キサノィルァ ミノ] -4-フエ-ルチオフェン- 3-カルボン酸  2- [6- (3, -Carboxy-4, -phenylthiophene-2, -ylcarbamoyl)-, xanoylamino] -4-phenolthiophene-3-carboxylic acid
[0131] [化 41]
Figure imgf000024_0001
[0131] [Chemical 41]
Figure imgf000024_0001
( r ) (r)
[0132] ィ [0132]
2-[5-(3， -カルボキシ -5， -メチル -4， -フエ-ルチオフェン- 2， -ィルカルバモイル) - ンタノィルァミノ] -5-メチル -4-フエ二ルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -methyl-4, -phenylthiophene-2, -ylcarbamoyl) -tertylamino] -5-methyl-4-phenylthiophene-3-carboxylic acid
[0133] [化 42]  [0133] [Chemical 42]
Figure imgf000024_0002
Figure imgf000024_0002
( s )  (s)
[0134] ィ ί^ [0134] i ί ^
2- [5- (3， -カルボキシ -5， -フエ-ルチオフェン- 2， -ィルカルバモイル) - ンタノィルァ ミノ] -5-フエ-ルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -phenylthiophene-2, -ylcarbamoyl) -tertylamino] -5-phenylthiophene-3-carboxylic acid
[0135] [化 43]  [0135] [Chemical 43]
Figure imgf000024_0003
Figure imgf000024_0003
( t ) (t)
[0136] 化合物 u [0136] Compound u
2-[5-(3， -カルボキシ- 5 ' -クロロチォフェン- 2， -ィルカルバモイル) - ンタノィルァミノ ]-5-クロロチォフェン- 3 -力ルボン酸 [0137] [化 44] 2- [5- (3, -Carboxy-5'-chlorothiophene-2, -ylcarbamoyl) -tanoylamino] -5-chlorothiophene-3-strong rubonic acid [0137] [Chemical 44]
Figure imgf000025_0001
Figure imgf000025_0001
( u)  (u)
[0138] ィ [0138]
2-[4-(3， -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-シクロへキシノレ カルボ-ルァミノ] -4-フエ-ルチオフ-ン -3-カルボン酸  2- [4- (3, -Carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -cyclohexenolecarbolamino] -4-phenolthiophene-3-carboxylic acid
[0139] [化 45]  [0139] [Chemical 45]
Figure imgf000025_0002
Figure imgf000025_0002
( V)  (V)
[0140] ィ 合物 w  [0140] i Compound w
2-[5-(3， -カルボキシ -5， -イソプロピル- 4， -メチルチオフェン- 2， -ィルカルバモイル) - ペンタノィルァミノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -isopropyl-4, -methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0141] [化 46]  [0141] [Chem 46]
Figure imgf000025_0003
Figure imgf000025_0003
(w) (w)
[0142] ィ ·χ [0142] ii · χ
2-[3-(3' -カルボキシ -4， -イソブチルチオフェン- 2' -ィルカルバモイル) -プロパノィル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [3- (3'-carboxy-4, -isobutylthiophene-2'-ylcarbamoyl) -propanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0143] [化 47]
Figure imgf000026_0001
[0143] [Chemical 47]
Figure imgf000026_0001
( x)  (x)
[0144] ィ [0144]
2-[5-(3 ' -カルボキシ -4' -イソプロピルチオフェン- 2 ' -ィルカルバモイル) - ンタノィ ルァミノ] -4-イソプロピルォフェン- 3-カルボン酸  2- [5- (3'-Carboxy-4'-isopropylthiophene-2'-ylcarbamoyl) -tertanoylamino] -4-isopropylophen-3-carboxylic acid
[0145] [化 48]  [0145] [Chemical 48]
Figure imgf000026_0002
Figure imgf000026_0002
( y)  (y)
[0146] ィ ·ζ  [0146] B
2-[5-(3 ' -カルボキシ -5 ' -メチルチオフェン- 2， -ィルカルバモイル) - ノタノィルア ノ] -5-メチルチオフェン- 3-カルボン酸  2- [5- (3'-Carboxy-5'-methylthiophene-2, -ylcarbamoyl) -notanoylano] -5-methylthiophene-3-carboxylic acid
[0147] [化 49]  [0147] [Chemical 49]
Figure imgf000026_0003
Figure imgf000026_0003
( z ) (z)
[0148] 化合物 zz [0148] Compound zz
2-[5-(3， - tert-ブトキシカルボ-ル -5， -メチルチオフェン- 2， -ィルカルバモイル) - ンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸  2- [5- (3, -tert-Butoxycarbol-5, -methylthiophene-2, -ylcarbamoyl) -tertanoylamino] -5-methylthiophene-3-carboxylic acid
[0149] [化 50]
Figure imgf000027_0001
[0149] [Chemical 50]
Figure imgf000027_0001
[0150] これらの化合物 a〜nおよび o〜zzはいずれも一般式（1)で示される化合物（1)に包 含されるものであるが、なかでも化合物 a、 b、 c、 d、 e、 h、 j、 k、 o〜zzは、一般式（17) で示される化合物に包含される化合物である。化合物（1)のうち好ましくは、化合物 a 、 b、 c、 d、 e、 g、 h、 i、 j、 k、 1、 s、 t、 vおよび rであり、より好ましくはィ匕合物 a、 b、 d、 e、 h、 sおよび tであり、特に好ましくは化合物 a、 b、 d、および hである。 [0150] These compounds a to n and o to zz are all included in the compound (1) represented by the general formula (1), and among them, the compounds a, b, c, d, e , H, j, k, o to zz are compounds included in the compound represented by the general formula (17). Of the compounds (1), compounds a, b, c, d, e, g, h, i, j, k, 1, s, t, v and r are more preferable, and more preferably the compound a , B, d, e, h, s and t, particularly preferably compounds a, b, d and h.
[0151] また、本発明が対象とする化合物（1)は、遊離物またはその塩が溶媒和してなるも のであってもよい。力かる溶媒和物には水和物が含まれる。  [0151] Further, the compound (1) targeted by the present invention may be a solvate of a free substance or a salt thereof. Powerful solvates include hydrates.
[0152] 化合物（1)、特に化合物 a〜nは商業的に入手可能であり、また自体公知の方法に より製造することができる。例えば、化合物（1)のうち、 Rとして、式（2)で示される基  [0152] Compound (1), particularly compounds a to n, are commercially available, and can be produced by a method known per se. For example, in the compound (1), R represents a group represented by the formula (2)
4  Four
を有する化合物は、下記 (A)の製法 1、またはこれに準じた方法で製造することがで きる。なお、化合物（1)中、化合物 o〜zzは、文献未収載の新規化合物であり、その 製造方法は製造例 5〜17にて詳細に説明する。  A compound having can be produced by the following production method (A) 1 or a method analogous thereto. In compound (1), compounds o to zz are novel compounds not yet described in the literature, and their production methods will be described in detail in Production Examples 5 to 17.
[0153] (A)製法 1  [0153] (A) Manufacturing method 1
式（18) :  Formula (18):
[0154] [化 51]  [0154] [Chemical 51]
Figure imgf000027_0002
Figure imgf000027_0002
[0155] (式中、 R は炭素数 1〜4の直鎖または分枝鎖状のアルキル基、 Rおよび Rは、上 [Wherein R is a linear or branched alkyl group having 1 to 4 carbon atoms, and R and R are
1 2 3 記で定義した通りである。 )  1 2 3 As defined above. )
で示される化合物を、式（19) [0156] [化 52]
Figure imgf000028_0001
A compound represented by formula (19) [0156] [Chemical 52]
Figure imgf000028_0001
[0157] (式中、 Aは上記で定義した通りであり、 Xは脱離基である。 ) [Wherein A is as defined above, and X is a leaving group.]
で示される化合物と反応させ、次いで得られた化合物を必要により加水分解し、 Rが  And then hydrolyzing the resulting compound as necessary, so that R is
1 水素原子で示される化合物 (IX特に化合物（17))を製造する。  1 A compound represented by a hydrogen atom (IX, particularly compound (17)) is produced.
[0158] また Rとして水素原子、または置換基を有して 、てもよ 、フエニル基またはフリル基 [0158] R may have a hydrogen atom or a substituent, and may be a phenyl group or a furyl group.
4  Four
を有する化合物は下記 (B)の製法 2またはこれに準じた方法で製造することができる  Can be produced by the production method 2 of (B) below or a method analogous thereto
[0159] [0159]
式（20)：  Formula (20):
[0160] [化 53]  [0160] [Chemical 53]
Figure imgf000028_0002
Figure imgf000028_0002
[0161] (式中、 Aは上記で定義した通りであり、 Xは脱離基、 R は水素原子、置換基を有し [In the formula, A is as defined above, X is a leaving group, R is a hydrogen atom, and has a substituent.
4  Four
ていてもよいフ -ル基またはフリル基を示す。 )  A fur group or a furyl group which may be present. )
で示される化合物を、式（18)  A compound represented by formula (18)
[0162] [化 54] [0162] [Chemical 54]
Figure imgf000028_0003
Figure imgf000028_0003
(式中、 R 、 Rおよび Rは、上記で定義した通りである。 )  (Wherein R 1, R and R are as defined above.)
1 2 3  one two Three
で示される化合物と反応させ、次いで得られた化合物を必要により加水分解し、 Rが 水素原子、 Rが水素原子、または置換基を有していてもよいフエ-ル基またはフリル 基で示される化合物（1)を製造する。 Then, the resulting compound is hydrolyzed if necessary, and R is a hydrogen atom, R is a hydrogen atom, or a phenyl group or furyl optionally having a substituent. The compound (1) represented by the group is produced.
[0164] ここで、式（19)および式 (20)中、 Xで示される脱離基としては、例えばハロゲン原子 を挙げることができる。ハロゲン原子として、具体的には、フッ素原子、塩素原子、臭 素原子およびヨウ素原子を挙げることができる。好ましくは塩素である。  Here, in the formula (19) and the formula (20), examples of the leaving group represented by X include a halogen atom. Specific examples of the halogen atom include a fluorine atom, a chlorine atom, an fluorine atom, and an iodine atom. Preferably it is chlorine.
[0165] 化合物（18)と化合物（19)または化合物（18)と化合物 (20)との反応は当業者には 公知の、通常のァシル化反応に準じて行われ、適宜な溶媒中、適宜な塩基の存在 下で行うことができる。塩基としてはトリエチルァミン、ピリジンなどの有機塩基を好適 に用いることができる。このようにして得られるアミド一エステル体を、必要によりアル カリ加水分解反応に供することにより、 Rが水素である目的化合物（1) (アミドーカル ボン酸体)を製造することができる。本アルカリ加水分解反応は当業者には公知の、 通常の方法で行うことができ、使用するアルカリとしては水酸ィ匕カリウム、水酸化ナトリ ゥム、水酸化バリウムなどが用いられる。  [0165] The reaction of the compound (18) and the compound (19) or the compound (18) and the compound (20) is carried out according to a conventional acylation reaction known to those skilled in the art, and is appropriately performed in an appropriate solvent. In the presence of a simple base. As the base, an organic base such as triethylamine or pyridine can be suitably used. By subjecting the amide monoester thus obtained to an alkali hydrolysis reaction as necessary, the target compound (1) (amide-carboxylic acid body) in which R is hydrogen can be produced. This alkaline hydrolysis reaction can be carried out by an ordinary method known to those skilled in the art. Examples of the alkali used include potassium hydroxide, sodium hydroxide, barium hydroxide and the like.
[0166] 化合物（1)の PAI— 1阻害活性は、インビトロアッセィ系で評価することができる。か 力るインビトロアッセィ系としては、たとえば、化合物（1)の存在下で、組織プラスミノ 一ゲンァクチべ一ター (t PA)に対する PAI— 1の活性変動を測定する方法を挙げ ることができる。なお、力かる PAI—1の活性変動は、基質に対する t—PAの作用に よって生じる反応生成物を指標とすることによって測定することができる。例えば、後 述する実験例 1では、発色性基質 (S-2288)に対する t PAの作用によって生じる p 一二トロアニリド (反応生成物）の量を指標として、 PAI— 1の活性変動を測定するイン ビトロアツセィ系を例示している。反応生成物の生成量が少ないほど、 PAI—1阻害 活性が高いと判断できる。  [0166] The PAI-1 inhibitory activity of the compound (1) can be evaluated by an in vitro assay system. As such an in vitro assay system, for example, a method for measuring a change in the activity of PAI-1 with respect to tissue plasminogen activator (tPA) in the presence of compound (1) can be mentioned. In addition, the active fluctuation of PAI-1 can be measured by using the reaction product generated by the action of t-PA on the substrate as an index. For example, in Experimental Example 1 described later, the activity variation of PAI-1 is measured using the amount of p-12 troanilide (reaction product) generated by the action of tPA on the chromogenic substrate (S-2288) as an index. The Vitro Atssey system is illustrated. It can be judged that the smaller the amount of reaction product produced, the higher the PAI-1 inhibitory activity.
[0167] またィ匕合物（1)の PAI— 1阻害活性は、化合物（1)の存在下で、 PAI— 1と t PA との複合体 (ΡΑΙ-1/t-PA複合体)の形成変動を、例えばウェスタンブロッテイング法 などで測定することによつても評価することができる（例えば、実験例 2参照)。ここで P ΑΙ-1/t-PA複合体の形成量が少な ヽほど (ΡΑΙ-1/t-PA複合体形成阻害）、 PAI— 1 阻害活性が高いと判断できる。  [0167] In addition, the PAI-1 inhibitory activity of the compound (1) is in the presence of the compound (1) in the complex of PAI-1 and tPA (t-1 / t-PA complex). Variation in formation can also be evaluated by measuring, for example, by Western blotting (see, for example, Experimental Example 2). Here, it can be judged that the smaller the amount of P ΑΙ-1 / t-PA complex formed (ΡΑΙ-1 / t-PA complex formation inhibition), the higher the PAI-1 inhibitory activity.
[0168] 化合物（1)は、 PAI— 1の活性を阻害する作用を有する。中でも化合物 a〜l、好ま しくは化合物 a、 b、 d、 eおよび h、特に好ましくは化合物 a、 b、 dおよび hは、後述する 実験例で示すように優れた PAI— 1活性阻害作用を有している。当該作用により、プ ラスミンによるフイブリンの分解およびフイブリノ一ゲンの分解を高めることができ、生 体の線溶系を促進すること、また生体の線溶系低下を改善することが可能である。 [0168] Compound (1) has an action of inhibiting the activity of PAI-1. Among them, compounds a to l, preferably compounds a, b, d, e and h, particularly preferably compounds a, b, d and h are described later. As shown in the experimental examples, it has an excellent PAI-1 activity inhibitory action. This action can enhance fibrin degradation and fibrinogen degradation by plasmin, promote the biological fibrinolytic system, and improve the degradation of the biological fibrinolytic system.
[0169] また、今回、糸且織線維化の原因の一つが PAI— 1であることが判明した。従って、化 合物（1)によれば、その PAI— 1の活性を阻害する作用に基づいて、組織線維化な らびに組織線維化に関係する疾患を予防または改善することが可能である。  [0169] In addition, it has now been found that one of the causes of yarn and woven fibrosis is PAI-1. Therefore, compound (1) can prevent or ameliorate tissue fibrosis and diseases related to tissue fibrosis based on the action of inhibiting the activity of PAI-1.
[0170] 本発明の PAI— 1阻害剤は、かかる化合物（1)を有効成分とするものである。本発 明の PAI— 1阻害剤は、化合物（1) 100%力もなるものであってもよいし、またそうで なくても PAI— 1阻害作用を発揮する有効量の化合物（1)を含有するものであればよ い。制限されないが、 PAI— 1阻害剤には、通常、化合物（1)が 0. 1〜99重量％、好 ましくは 1〜80重量0 /0の範囲で含まれる。 [0170] The PAI-1 inhibitor of the present invention comprises such a compound (1) as an active ingredient. The PAI-1 inhibitor of the present invention may be compound (1) 100% potent, or otherwise contains an effective amount of compound (1) that exhibits PAI-1 inhibitory action. It only has to do. But are not limited to, the PAI 1 inhibitor, usually the compound (1) is 0.1 to 99 wt%, good Mashiku comprises in the range of 1 to 80 weight 0/0.
[0171] (in Mt  [0171] (in Mt
本発明は、前述する PAI— 1阻害剤を有効成分として含有する医薬組成物を提供 する。言い換えれば、本発明の医薬組成物は、前述する化合物（1)を有効成分とし て含有するものである。本発明の医薬組成物は、化合物（1)を有効量含むことによつ て、 PAI—1阻害作用を有しており、その結果、プラスミンによるフイブリンの分解およ びフイブリノ一ゲンの分解を高めて、生体の線溶系を促進する作用、または生体の低 下した線溶系を改善する作用を有する。  The present invention provides a pharmaceutical composition containing the aforementioned PAI-1 inhibitor as an active ingredient. In other words, the pharmaceutical composition of the present invention contains the compound (1) described above as an active ingredient. The pharmaceutical composition of the present invention has a PAI-1 inhibitory action by containing an effective amount of the compound (1). As a result, fibrin is degraded by plasmin and fibrinogen is degraded. It enhances and promotes the fibrinolytic system of the living body, or improves the lowered fibrinolytic system of the living body.
[0172] このため、本発明の医薬組成物は線溶系の促進薬として用いることができる。具体 的には、本発明の医薬組成物は、 PAI—1活性が発症に関わっている血栓性の疾患 や病態、または線溶系低下を原因とする疾患や病態の予防または治療剤として有用 である。力かる疾患または病態として、例えば、狭心症、心筋梗塞、心房細動におけ る心房内血栓、心不全等の虚血性心疾患、脳塞栓症、脳梗塞、一過性脳虚血発作 等の虚血性脳血管障害、動脈硬化症、肺塞栓症、外科手術時の深部静脈血栓症（ [0172] Therefore, the pharmaceutical composition of the present invention can be used as a fibrinolytic promoter. Specifically, the pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for thrombotic diseases and conditions in which PAI-1 activity is involved in the onset, or diseases and conditions caused by a decrease in fibrinolytic system. . Possible diseases or conditions include, for example, angina pectoris, myocardial infarction, intra-atrial thrombus in atrial fibrillation, ischemic heart disease such as heart failure, cerebral embolism, cerebral infarction, transient ischemic attack, etc. Ischemic cerebrovascular disease, arteriosclerosis, pulmonary embolism, deep vein thrombosis during surgery (
DVT)、播種性血管内凝固症候群 (DIC)、糖尿病合併症 (血管障害、神経障害、網 膜症、腎症など)、経皮的冠動脈形成術 (PTCA)後の再狭窄等の血栓形成が関与 する種々の疾患または病態を挙げることができる。 DVT), disseminated intravascular coagulation syndrome (DIC), diabetic complications (angiopathy, neuropathy, retinopathies, nephropathy, etc.), thrombus formation such as restenosis after percutaneous coronary angioplasty (PTCA) Mention may be made of the various diseases or conditions involved.
[0173] また本発明の医薬組成物は、化合物（1)を有効量含むことによって PAI— 1阻害作 用を有しており、その結果、組織や器官の線維化を予防または改善する作用を有す る。このため、本発明の医薬組成物は、 PAI—1活性に関連して生じる組織または器 官の線維化に関係する疾患や病態の予防または治療剤として有用である。かかる疾 患または病態として、例えば、肺線維症、心筋梗塞に伴う組織の線維化、腎症に伴う 組織の線維化等を挙げることができる。 [0173] Furthermore, the pharmaceutical composition of the present invention comprises a PAI-1 inhibitory action by containing an effective amount of compound (1). As a result, it has the effect of preventing or improving fibrosis of tissues and organs. Therefore, the pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for diseases and pathologies related to tissue or organ fibrosis caused by PAI-1 activity. Examples of such diseases or conditions include pulmonary fibrosis, tissue fibrosis associated with myocardial infarction, tissue fibrosis associated with nephropathy, and the like.
[0174] 本発明の医薬組成物は、通常、線溶系の促進 (若しくは改善)または抗線維化に有 効量の化合物（1)に加えて、薬学的に許容される担体または添加剤を配合して調製 される。医薬組成物中の化合物（1)の配合量は、対象とする疾患や病態の種類ゃ投 与形態に応じて適宜選択されるが、通常、全身投与製剤の場合には、医薬組成物の 全体重量（100重量％)の 0.001〜50重量％、特に 0.01〜10重量％とすることがで きる。 [0174] The pharmaceutical composition of the present invention usually contains a pharmaceutically acceptable carrier or additive in addition to an effective amount of the compound (1) for promoting (or improving) the fibrinolytic system or antifibrosis. It is prepared as follows. The compounding amount of the compound (1) in the pharmaceutical composition is appropriately selected according to the type of disease or pathology to be administered and the administration form. Usually, in the case of a systemic preparation, the entire pharmaceutical composition It can be 0.001 to 50% by weight, particularly 0.01 to 10% by weight of the weight (100% by weight).
[0175] 本発明の医薬組成物の投与方法として、経口投与、ならびに静脈内投与、筋肉内 投与、皮下投与、経粘膜投与、経皮投与、および直腸内投与等の非経口投与を挙 げることができる。好ましくは経口投与および静脈内投与であり、より好ましくは経口 投与である。本発明の医薬組成物は、力かる投与方法に応じて、種々の形態の製剤 (剤型）に調製することができる。以下に、各製剤 (剤型）について説明するが、本発 明において用いられる剤型はこれらに限定されるものではなぐ医薬製剤分野にお V、て通常用いられる各種剤型を用いることができる。  [0175] The administration method of the pharmaceutical composition of the present invention includes oral administration and parenteral administration such as intravenous administration, intramuscular administration, subcutaneous administration, transmucosal administration, transdermal administration, and rectal administration. be able to. Oral administration and intravenous administration are preferred, and oral administration is more preferred. The pharmaceutical composition of the present invention can be prepared into various forms of preparations (dosage forms) according to the powerful administration method. In the following, each formulation (drug form) will be described, but the dosage form used in the present invention is not limited to these, and various dosage forms commonly used in the pharmaceutical formulation field can be used. .
[0176] 経口投与を行う場合の剤型として、散剤、顆粒剤、カプセル剤、丸剤、錠剤、エリキ シル剤、懸濁剤、乳剤およびシロップ剤を挙げることができ、これらの中から適宜選択 することができる。また、それらの製剤について徐放化、安定化、易崩壊化、難崩壊 ィ匕、腸溶性化、易吸収化等の修飾を施すことができる。  [0176] Examples of dosage forms for oral administration include powders, granules, capsules, pills, tablets, elixirs, suspensions, emulsions, and syrups. can do. In addition, these formulations can be modified such as sustained release, stabilization, easy disintegration, hard disintegration, entericity, easy absorption, and the like.
[0177] また、静脈内投与、筋肉内投与、または皮下投与を行う場合の剤型として、注射剤 または点滴剤 (用時調製の乾燥品を含む)等があり、適宜選択することができる。  [0177] In addition, dosage forms for intravenous administration, intramuscular administration, or subcutaneous administration include injections and infusions (including dry products prepared at the time of use), and can be appropriately selected.
[0178] また、経粘膜投与、経皮投与、または直腸内投与を行う場合の剤型として、咀嚼剤 、舌下剤、パッカル剤、トローチ剤、軟膏剤、貼布剤、液剤等があり、適応場所に応じ て適宜選択するここができる。また、それらの製剤についても徐放化、安定化、易崩 壊化、難崩壊化、易吸収化等の修飾を施すことができる。 [0179] 本発明の医薬組成物にはその剤形 (経口投与または各種の非経口投与の剤形）に 応じて、薬学的に許容される担体および添加剤を配合することができる。薬学的に許 容される担体及び添加剤としては、溶剤、賦形剤、コーティング剤、基剤、結合剤、 滑沢剤、崩壊剤、溶解補助剤、懸濁化剤、粘稠剤、乳化剤、安定剤、緩衝剤、等張 ィ匕剤、無痛化剤、保存剤、矯味剤、芳香剤、着色剤が挙げられる。以下に、医薬上 許容される担体および添加剤の具体例を列挙するが、本発明はこれらに制限される ものではない。 [0178] In addition, dosage forms for transmucosal administration, transdermal administration, or rectal administration include mastication agents, sublingual agents, buccal agents, troches, ointments, patches, liquids, etc. You can choose here depending on the location. These formulations can also be modified such as sustained release, stabilization, easy disintegration, difficulty disintegration, and easy absorption. [0179] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable carriers and additives depending on the dosage form (oral administration or various parenteral administration dosage forms). Pharmaceutically acceptable carriers and additives include solvents, excipients, coating agents, bases, binders, lubricants, disintegrants, solubilizers, suspending agents, thickeners, emulsifiers. , Stabilizers, buffers, isotonic agents, soothing agents, preservatives, flavoring agents, fragrances, and coloring agents. Specific examples of pharmaceutically acceptable carriers and additives are listed below, but the present invention is not limited thereto.
[0180] 溶剤としては、精製水、滅菌精製水、注射用水、生理食塩液、ラッカセィ油、ェタノ ール、グリセリン等を挙げることができる。賦形剤としては、デンプン類 (例えばバレイ ショデンプン、コムギデンプン、トウモロコシデンプン）、乳糖、ブドウ糖、白糖、結晶セ ルロース、硫酸カルシウム、炭酸カルシウム、炭酸水素ナトリウム、塩ィ匕ナトリウム、タ ルク、酸化チタン、トレハロース、キシリトール等を挙げることができる。  [0180] Examples of the solvent include purified water, sterilized purified water, water for injection, physiological saline, laccase oil, ethanol, glycerin and the like. Excipients include starches (eg, potato starch, wheat starch, corn starch), lactose, glucose, sucrose, crystalline cellulose, calcium sulfate, calcium carbonate, sodium bicarbonate, sodium chloride salt, tark, oxidized Titanium, trehalose, xylitol and the like can be mentioned.
[0181] 結合剤としては、デンプンおよびその誘導体、セルロースおよびその誘導体 (たとえ ばメチノレセノレロース、ェチノレセノレロース、ヒドロキシプロピノレセノレロース、カノレボキシメ チルセルロース）、ゼラチン、アルギン酸ナトリウム、トラガント、アラビアゴム等の天然 高分子化合物、ポリビニルピロリドン、ポリビュルアルコール等の合成高分子化合物、 デキストリン、ヒドロキシプロピルスターチ等を挙げることができる。  [0181] As binders, starch and derivatives thereof, cellulose and derivatives thereof (for example, methinoresenorelose, ethinoresenorelose, hydroxypropinoresenorelose, canoleboxymethylcellulose), gelatin, sodium alginate, tragacanth, arabian Examples thereof include natural polymer compounds such as rubber, synthetic polymer compounds such as polyvinyl pyrrolidone and polybutyl alcohol, dextrin and hydroxypropyl starch.
[0182] 滑沢剤としては、軽質無水ケィ酸、ステアリン酸およびその塩類 (たとえばステアリン 酸マグネシウム）、タルク、ワックス類、コムギデンプン、マクロゴール、水素添加植物 油、ショ糖脂肪酸エステル、ポリエチレングリコール、シリコン油等を挙げることができ る。  [0182] Lubricants include light anhydrous carboxylic acid, stearic acid and its salts (eg, magnesium stearate), talc, waxes, wheat starch, macrogol, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol, Examples include silicone oil.
[0183] 崩壊剤としては、デンプンおよびその誘導体、寒天、ゼラチン末、炭酸水素ナトリウ ム、炭酸カルシウム、セルロースおよびその誘導体、ヒドロキシプロピルスターチ、力 ルボキシメチルセルロースおよびその塩類ならびにその架橋体、低置換型ヒドロキシ プロピルセルロース等を挙げることができる。  [0183] Disintegrants include starch and derivatives thereof, agar, gelatin powder, sodium hydrogen carbonate, calcium carbonate, cellulose and derivatives thereof, hydroxypropyl starch, strength ruboxymethyl cellulose and salts thereof, and cross-linked products thereof, low substitution And hydroxypropylcellulose.
[0184] 溶解補助剤としては、シクロデキストリン、エタノール、プロピレングリコール、ポリエ チレングリコール等を挙げることができる。懸濁化剤としては、カルボキシメチルセル ロースナトリウム、ポリピ-ルピロリドン、アラビアゴム、トラガント、アルギン酸ナトリウム 、モノステアリン酸アルミニウム、クェン酸、各種界面活性剤等を挙げることができる。 [0184] Examples of the solubilizer include cyclodextrin, ethanol, propylene glycol, and polyethylene glycol. Suspending agents include sodium carboxymethyl cellulose, polypyrrole pyrrolidone, gum arabic, tragacanth, sodium alginate , Aluminum monostearate, citrate, various surfactants and the like.
[0185] 粘稠剤としては、カルボキシメチルセルロースナトリウム、ポリピ-ルピロリドン、メチ ルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、トラガント [0185] Examples of thickeners include sodium carboxymethylcellulose, polypyrrole pyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, tragacanth.
、アラビアゴム、アルギン酸ナトリウム等を挙げることができる。 Arabic gum, sodium alginate and the like.
[0186] 乳化剤は、アラビアゴム、コレステロール、トラガント、メチルセルロース、レシチン、 各種界面活性剤（たとえば、ステアリン酸ポリオキシル 40、セスキォレイン酸ソルビタ ン、ポリソルベート 80、ラウリル硫酸ナトリウム）等を挙げることができる。 [0186] Examples of the emulsifier include gum arabic, cholesterol, tragacanth, methylcellulose, lecithin, various surfactants (for example, polyoxyl 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate).
[0187] 安定剤としては、トコフエロール、キレート剤（たとえば EDTA、チォグリコール酸）、 不活性ガス (たとえば窒素、二酸ィ匕炭素）、還元性物質 (たとえば亜硫酸水素ナトリウ ム、チォ硫酸ナトリウム、ァスコルビン酸、ロンガリット）等を挙げることができる。 [0187] Stabilizers include tocopherols, chelating agents (eg EDTA, thioglycolic acid), inert gases (eg nitrogen, diacid-carbon), reducing substances (eg sodium hydrogen sulfite, sodium thiosulfate, ascorbine) Acid, longalite) and the like.
[0188] 緩衝剤としては、リン酸水素ナトリウム、酢酸ナトリウム、クェン酸ナトリウム、ホウ酸等 を挙げることができる。 [0188] Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium citrate, boric acid and the like.
[0189] 等張化剤としては、塩ィ匕ナトリウム、ブドウ糖等を挙げることができる。無痛化剤こし ては、局所麻酔剤（塩酸プロ力イン、リドカイン）、ペンジルアルコール、ブドウ糖、ソル ビトール、アミノ酸等を挙げることができる。  [0189] Examples of isotonic agents include sodium chloride salt and glucose. Examples of soothing agents include local anesthetics (pro-in hydrochloride, lidocaine), pendyl alcohol, glucose, sorbitol, amino acids and the like.
[0190] 矯味剤としては、白糖、サッカリン、カンゾゥエキス、ソルビトール、キシリトール、ダリ セリン等を挙げることができる。芳香剤としては、トウヒチンキ、ローズ油等を挙げること ができる。着色剤としては、水溶性食用色素、レーキ色素等を挙げることができる。  [0190] Examples of the corrigent include sucrose, saccharin, licorice extract, sorbitol, xylitol, dariserine and the like. Examples of the fragrances include spruce tincture and rose oil. Examples of the colorant include water-soluble food dyes and lake dyes.
[0191] 保存剤としては、安息香酸およびその塩類、パラォキシ安息香酸エステル類、クロ ロブタノール、逆性石けん、ベンジルアルコール、フエノール、チロメサール、デヒドロ 酢酸、ホウ酸、等を挙げることができる。  [0191] Examples of the preservative include benzoic acid and its salts, para-benzoic acid esters, chlorobutanol, reverse soap, benzyl alcohol, phenol, tiromesal, dehydroacetic acid, boric acid and the like.
[0192] コーティング剤としては、白糖、ヒドロキシプロピルセルロース（HPC)、セラック、ゼ ラチン、グリセリン、ソルビトール、ヒドロキシプロピルメチルセルロース（HPMC)、ェ チルセルロース、ポリビュルピロリドン（PVP)、ヒドロキシプロピルメチルセルロースフ タレート（HPMCP)、セルロースアセテートフタレート（CAP)、メチルメタアタリレート メタアクリル酸共重合体および上記記載した高分子等を挙げることができる。  [0192] Coating agents include sucrose, hydroxypropylcellulose (HPC), shellac, gelatin, glycerin, sorbitol, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polybutylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate ( HPMCP), cellulose acetate phthalate (CAP), methyl methacrylate, methacrylic acid copolymer, and the polymers described above.
[0193] 基剤としては、ワセリン、流動パラフィン、カルナウパロウ、牛脂、硬化油、ノ ラフィン 、ミツロウ、植物油、マクロゴール、マクロゴール脂肪酸エステル、ステアリン酸、カル ボキシメチルセルロースナトリウム、ベントナイト、カカオ脂、ウイテツブゾール、ゼラチ ン、ステアリルアルコール、加水ラノリン、セタノール、軽質流動パラフィン、親水ヮセリ ン、単軟膏、白色軟膏、親水軟膏、マクロゴール軟膏、ハードフアット、水中油型乳剤 性基剤、油中水型乳剤性碁剤等を挙げることができる。 [0193] Bases include petrolatum, liquid paraffin, carnauba wax, beef tallow, hydrogenated oil, beef wax, beeswax, vegetable oil, macrogol, macrogol fatty acid ester, stearic acid, cal Sodium boxymethylcellulose, bentonite, cacao butter, wittebuzole, gelatin, stearyl alcohol, hydrolanolin, cetanol, light liquid paraffin, hydrophilic salmon, single ointment, white ointment, hydrophilic ointment, macrogol ointment, hard fat, oil-in-water Type emulsion base and water-in-oil type emulsion glaze.
[0194] なお、上記の各剤型について、公知のドラッグデリバリーシステム（DDS)の技術を 採用することができる。本明細書にいう DDS製剤とは、徐放化製剤、局所適用製剤（ トローチ、バッカル錠、舌下錠等)、薬物放出制御製剤、腸溶性製剤および胃溶性製 剤等、投与経路、バイオアベイラビリティ一、副作用等を勘案した上で、最適の製剤 形態にした製剤である。  [0194] For each of the above dosage forms, a known drug delivery system (DDS) technique can be employed. The DDS preparations referred to in this specification include sustained release preparations, topical preparations (troches, buccal tablets, sublingual tablets, etc.), drug release control preparations, enteric preparations and gastric preparations, etc., administration routes, bioavailability First, it is a drug product in the optimal drug product form taking into account side effects.
[0195] 本発明の医薬組成物を、線溶系の低下 (血栓形成）に関連する病態に対する予防 薬または治療薬として用いる場合、その経口投与量として、化合物（1)の量に換算し て 0. 03〜300mgZkg体重の範囲力 子ましく、より好ましくは 0.1〜50mgZkg体重 である。静脈内投与をする場合、化合物（1)の有効血中濃度が 0. 2〜50 gZmL 、より好ましくは 0. 5〜20/ζ 8ΖπΛの範囲となるような投与量を挙げることができる。 [0195] When the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic agent for a disease state associated with a decrease in fibrinolytic system (thrombosis), its oral dose is converted to the amount of compound (1). 03-300 mgZkg body weight range force, more preferably 0.1-50 mgZkg body weight. In the case of intravenous administration, a dose such that the effective blood concentration of compound (1) is in the range of 0.2 to 50 gZmL, more preferably 0.5 to 20 / ζ 8 ΖπΛ can be mentioned.
[0196] また本発明の医薬組成物を、組織線維化に関連する病態に対する予防薬または 治療薬として用いる場合、その経口投与量として、化合物（1)の量に換算して 0. 03 〜300mgZkg体重の範囲力 子ましく、より好ましくは 0.1〜50mgZkg体重である。 静脈内投与をする場合、化合物（1)の有効血中濃度が 0. 2〜50;^ΖπΛ、より好 ましくは 0. 5〜20 /ζ 8Ζιϋの範囲となるような投与量を挙げることができる。なお、こ れらの投与量は、年齢、性別、体型等により変動し得る。 [0196] When the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic agent for a disease state associated with tissue fibrosis, the oral dose is 0.03 to 300 mgZkg in terms of the amount of compound (1). Range of body weight More preferably, it is 0.1 to 50 mgZkg body weight. When administered intravenously, the dosage should be such that the effective blood concentration of compound (1) is in the range of 0.2-50; ^ ΖπΛ, more preferably 0.5-20 / ζ 8 8ιϋ. be able to. These dosages may vary depending on age, sex, body type, and the like.
[0197] (III)新親.化合物およびその用涂  [III] New parent. Compound and its use
前述するように、一般式（1)で示される化合物の中で、下式（3)で示される化合物 およびその塩は、文献未収載の新規化合物である。  As described above, among the compounds represented by the general formula (1), the compound represented by the following formula (3) and a salt thereof are novel compounds not yet described in literatures.
[0198] [化 55]  [0198] [Chemical 55]
Figure imgf000034_0001
[0199] 〔式中、 と 'は、同一または異なって、水素原子または炭素数 1〜4の直鎖または 分枝鎖状のアルキル基; Rと R 'は、同一または異なって、水素原子、置換基を有し
Figure imgf000034_0001
[Wherein and are the same or different, a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; and R and R ′ are the same or different, a hydrogen atom, Has a substituent
2 2  twenty two
ていてもよいフエニル基、または炭素数 1〜6の直鎖または分枝鎖状のアルキル基; R と R 'は、同一または異なって、水素原子、置換基を有していてもよいフエニル基、 An optionally substituted phenyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R and R ′ may be the same or different and each may have a hydrogen atom or a substituent. ,
3 3 3 3
炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロゲン原子; Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、または炭素数 3〜8のシクロアルキレンを 示す。但し、 Rおよび R，が置換基を有さないフエ-ル基であり且つ Rおよび R 'が  A linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom; A represents a linear or branched alkylene having 1 to 7 carbon atoms or a cycloalkylene having 3 to 8 carbon atoms . Provided that R and R are phenyl groups having no substituent and R and R ′ are
2 2 3 3 水素原子であるとき、 Aはブチレンおよび CH -C (CH ) -CH一のいずれでも  When 2 2 3 3 is a hydrogen atom, A is either butylene or CH 2 -C (CH 2) 2 -CH 1
2 3 2 2  2 3 2 2
なぐまた Rおよび R，がイソブチル基であり且つ Rおよび R，が水素原子であるとき  When R and R are isobutyl groups and R and R are hydrogen atoms
2 2 3 3  2 2 3 3
、 Aはブチレンではない。〕  A is not butylene. ]
で示される化合物またはその塩。  Or a salt thereof.
[0200] 本発明は、力かる新規ィ匕合物を提供するものである。  [0200] The present invention provides a powerful new compound.
[0201] ここで上記式（3)中、 R 、 R 、 R 、 R，、： R，、： R，および Aのおのおのの具体的な  [0201] Here, in the above formula (3), each of R 1, R 2, R 3, R 5, R 5 6
1 2 3 1 2 3  1 2 3 1 2 3
定義は、前述する化合物（1)に関して説明した通りである。  The definition is as described for the compound (1) described above.
[0202] 本発明が対象とする新規化合物（3)として、 Rおよび R ' 1S 同一または異なって、 水素原子、または ter-ブチル基であるものを挙げることができる。好ましくは Rおよび R 'が水素原子であるものである。また、新規ィ匕合物（3)として、 Rおよび R 'が、同[0202] Examples of the novel compound (3) targeted by the present invention include those in which R and R'1S are the same or different and are a hydrogen atom or a ter-butyl group. Preferably, R and R ′ are hydrogen atoms. Also, as new compound (3), R and R '
1 2 2 一または異なって、水素原子、置換基としてハロゲン原子を有する力または置換を有 しないフエ-ル基、メチル基、イソプロピル基、イソブチル基〔一 CH CH (CH ) 〕で 1 2 2 One or different, a hydrogen atom, a force having a halogen atom as a substituent, or a non-substituted phenyl group, methyl group, isopropyl group, isobutyl group [one CH CH (CH)]
2 3 2 あるものを挙げることができる。さらに、新規ィ匕合物（3)として、 Rおよび R 'が、同一  2 3 2 There are some. Furthermore, as new compound (3), R and R ′ are the same
3 3 または異なって、水素原子、メチル基、イソプロピル基、フエ-ル基、ハロゲン原子で あるものを挙げることができる。また、 Aとしては、プロピレン、ブチレン、ペンチレン、 -CH -C (CH ) -CH 一、またはシクロへキシレンを挙げることができる。  3 3 or different may be a hydrogen atom, a methyl group, an isopropyl group, a phenol group, or a halogen atom. Examples of A include propylene, butylene, pentylene, -CH 2 -C (CH 2) 2 -CH 1, and cyclohexylene.
2 3 2 2  2 3 2 2
[0203] 新規化合物（3)として、具体的には下記の化合物 o〜zzを挙げることができる。かか る化合物の製造方法は、製造例 5〜17にて詳述する。  [0203] Specific examples of the novel compound (3) include the following compounds o to zz. The production method of such a compound will be described in detail in Production Examples 5-17.
[0204] 化合物 o [0204] Compound o
2-[5-(3， -カルボキシ- 4， -(P-クロ口フエ-ル)チォフェン- 2， -ィルカルバモイル)-ペン タノィルァミノ] -4-(p-クロ口フエ-ル)チォフェン- 3-カルボン酸 [0205] [化 56] 2- [5- (3, -Carboxy-4,-(P-Black mouth phenyl) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (p-Black mouth felt) thiophene-3 -carboxylic acid [0205] [Chem 56]
Figure imgf000036_0001
Figure imgf000036_0001
(o) ， -ィルカルバモイル)-ブチリルアミ  (o), -ylcarbamoyl) -butyrylami
Figure imgf000036_0002
Figure imgf000036_0002
( P ) (P)
[0208] [0208]
2-[4-(3， -カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバモイル)- 3,3-ジメチル ブチリルァミノ] -4-イソブチルチオフェン- 3 -力ルボン酸  2- [4- (3, -Carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino] -4-isobutylthiophene-3 -power rubonic acid
[0209] [化 58]  [0209] [Chemical 58]
Figure imgf000036_0003
Figure imgf000036_0003
( q )  (q)
[0210]  [0210]
2-[6-(3' -カルボキシ -4' -フエ-ルチオフェン- 2， -ィルカルバモイル) - 、キサノィルァ ミノ] -4 -フエ-ルチオフェン- 3-カルボン酸  2- [6- (3'-Carboxy-4'-phenylthiophene-2, -ylcarbamoyl)-, xanoylamino] -4-phenylthiophene-3-carboxylic acid
[0211] [化 59]
Figure imgf000037_0001
[0211] [Chemical 59]
Figure imgf000037_0001
( r ) (r)
[0212] 化合物 s [0212] Compound s
2-[5-(3， -カルボキシ -5， -メチル- 4， -フエ-ルチオフェン- 2， -ィルカルバモイル) - ンタノィルァミノ] -5 -メチル -4-フエ-ルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -methyl-4, -phenylthiophene-2, -ylcarbamoyl) -tertanoylamino] -5-methyl-4-phenylthiophene-3-carboxylic acid
[0213] [化 60] [0213] [Chemical 60]
Figure imgf000037_0002
Figure imgf000037_0002
( s )  (s)
[0214] 化合物 t [0214] Compound t
2-[5-(3， -カルボキシ -5， -フエ-ルチオフェン- 2， -ィルカルバモイル)-ペンタノィルァ ミノ] -5-フエ二ルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -phenylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-phenylthiophene-3-carboxylic acid
[0215] [化 61] [0215] [Chemical 61]
Figure imgf000037_0003
Figure imgf000037_0003
( t ) (t)
[0216] 化合物 u [0216] Compound u
2-[5-(3， -カルボキシ- 5， -クロロチォフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ ]-5-クロロチォフェン- 3-カルボン酸 [0217] [化 62] 2- [5- (3, -Carboxy-5, -chlorothiophene-2, -ylcarbamoyl) -pentanoylamino] -5-chlorothiophene-3-carboxylic acid [0217] [Chemical 62]
Figure imgf000038_0001
Figure imgf000038_0001
( u )  (u)
[0218] 化合物 v [0218] Compound v
2-[4-(3， -カルボキシ -4， -フエ二ルチオフェン- 2 ' -ィルカルバモイル)-シクロへキシル カルボ-ルァミノ] -4-フエ二ルチオフェン- 3-カルボン酸  2- [4- (3, -Carboxy-4, -phenylthiophene-2'-ylcarbamoyl) -cyclohexylcarbolamino] -4-phenylthiophene-3-carboxylic acid
[0219] [化 63] [0219] [Chemical 63]
Figure imgf000038_0002
Figure imgf000038_0002
( v)  (v)
[0220] 化,合物 w  [0220] Chemical compound w
2-[5-(3， -カルボキシ- 5， -イソプロピル- 4， -メチルチオフェン - 2 ' -ィルカルバモイル) - ペンタノィルァミノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -isopropyl-4, -methylthiophene-2'-ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0221] [化 64] [0221] [Chemical 64]
Figure imgf000038_0003
Figure imgf000038_0003
[0222] 化合物 X  [0222] Compound X
2-[3-(3， -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバモイル)-プロパノィル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [3- (3, -Carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -propanoylamino] -4-isobutylthiophene-3-carboxylic acid
[0223] [化 65]
Figure imgf000039_0001
[0223] [Chemical 65]
Figure imgf000039_0001
( x )  (x)
[0224] ィ [0224]
2-[5-(3， -カルボキシ- 4， -イソプロピルチオフェン- 2， -ィルカルバモイル)一 ンタノィ ルァミノ] -4-イソプロピルォフェン- 3-カルボン酸  2- [5- (3, -Carboxy-4, -isopropylthiophene-2, -ylcarbamoyl) tertanoylamino] -4-isopropylophene-3-carboxylic acid
[0225] [化 66]  [0225] [Chemical 66]
Figure imgf000039_0002
Figure imgf000039_0002
( y)  (y)
[0226] ィ  [0226]
2-[5-(3， -カルボキシ -5， -メチルチオフェン- 2 ' -ィルカルバモイル)-ペンタノィルアミ ノ] -5-メチルチオフェン- 3-カルボン酸  2- [5- (3, -Carboxy-5, -methylthiophene-2'-ylcarbamoyl) -pentanoylamino] -5-methylthiophene-3-carboxylic acid
[0227] [化 67]  [0227] [Chemical 67]
Figure imgf000039_0003
Figure imgf000039_0003
( z )  (z)
[0228] ィ ·ζζ [0228] i ζζ
2-[5-(3， -tert-ブトキシカルボニル -5， -メチルチオフェン- 2 ' -ィルカルバモイル) - ンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸  2- [5- (3, -tert-Butoxycarbonyl-5, -methylthiophene-2'-ylcarbamoyl) -tertanoylamino] -5-methylthiophene-3-carboxylic acid
[0229] [化 68] [0229] [Chemical 68]
Figure imgf000040_0001
Figure imgf000040_0001
[0230] これらの化合物は、前述するように PAI— 1阻害作用を有しており、 PAI— 1が発症 に関係している疾患や病態、例えば線溶系の低下 (血栓形成）に関連する病態また は組織線維化に関連する病態に対する予防薬または治療薬 (医薬組成物)の有効 成分として有用である。これらの化合物 (ィ匕合物 o〜zz)の中でも好ましくは化合物 o 〜xであり、より好ましくは化合物 s、 t、 r、 qおよび wであり、さらに好ましくは化合物 s、 tおよび rである。 [0230] These compounds have PAI-1 inhibitory action as described above, and diseases and pathologies related to the onset of PAI-1 such as pathological conditions related to decreased fibrinolytic system (thrombosis). It is also useful as an active ingredient in prophylactic or therapeutic agents (pharmaceutical compositions) for pathological conditions related to tissue fibrosis. Among these compounds (compounds o to zz), compounds o to x are preferable, compounds s, t, r, q, and w are more preferable, and compounds s, t, and r are more preferable. .
[0231] ゆえに、本発明は、上記化合物（3)、特に化合物 o〜zz (好ましくは化合物 o〜x)若 しくはその薬学的に許容される塩、またはその溶媒和物を有効成分とする医薬組成 物を提供する。当該医薬組成物は、（II)の記載に従って、定法により投与形態に応じ て適切な製剤形態に調製することができる。  [0231] Therefore, the present invention comprises the above compound (3), particularly the compounds o to zz (preferably compounds o to x) or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. A pharmaceutical composition is provided. The pharmaceutical composition can be prepared in an appropriate formulation form according to the dosage form by a conventional method according to the description in (II).
実験例  Experimental example
[0232] 以下、本発明を製造例および実験例によりさらに具体的に説明する力 本発明はこ れらの例に制限されるものではない。  [0232] Hereinafter, the present invention will be described more specifically with reference to production examples and experimental examples. The present invention is not limited to these examples.
[0233] 製造例 1 [0233] Production Example 1
図 1に示すスキーム（Step 1、 Step2、 Step3)に従って、下式（21)：  According to the scheme shown in Figure 1 (Step 1, Step 2, Step 3), the following formula (21):
[0234] [化 69] [0234] [Chem 69]
Figure imgf000040_0002
Figure imgf000040_0002
[0235] (式中、 Rはフエ-ル基または 2—チェ-ル基である。 ) に示される化合物を合成した。 [In the formula, R is a phenyl group or a 2-chael group.) The compound shown in was synthesized.
[0236] 式中、 Rがフエ-ル基である化合物は、 2- [3- (3'-カルボキシ- 4'-フエ-ルチオフエ ン- 2 '-ィルカルバモイル)-ペンタノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸 であり、以下「化合物 a」ともいう。一方、 Rおよび R 'が 2—チェニル基である化合物  [0236] In the formula, the compound in which R is a phenol group is 2- [3- (3'-carboxy-4'-phenylthiophene-2'-ylcarbamoyl) -pentanoylamino] -4 -Phenolthiophene-3-carboxylic acid, hereinafter also referred to as “compound a”. On the other hand, compounds in which R and R ′ are 2-chenyl groups
2 2  twenty two
は、 2- [3- (3 '-カルボキシ- 4'-チェ-ルチオフェン- 2しィルカルバモイル)-ペンタノィ ルァミノ] -4-チェ-ルチオフェン- 3-カルボン酸であり、以下「化合物 b」とも!/、う。  Is 2- [3- (3′-carboxy-4′-cherthiophene-2-silylcarbamoyl) -pentanoylamino] -4-chelthiophene-3-carboxylic acid, hereinafter “compound b” Tomo!
[0237] (1) Step 1：アミド エステル (3)の合成  [0237] (1) Step 1: Synthesis of amide ester (3)
10g (54.6mmol)のアジピン酸クロリド無水物（1) 114mmolのァミノエステル化合物 (2) ( R=フエ-ル基、または 2 チェ-ル基）、および 11ml (114mmol)のピリジンの混合物 を、乾燥ジォキサン 70ml中で 2.5時間加熱した。反応混合液を暖カ 、うちに冷水の中 に注入し、次いで炭酸カリウム 15gを添加してアルカリ化した。沈殿物を濾別し、水で 洗浄した。沈殿物を乾燥させた後、 MeOH/THF (50:50, 400ml)の混合液を用い て再結晶し、 16〜21gのアミド—エステル (3)〔R=フエ-ル基： 2- [3- (3'-カルボキシ- 4' -フエ二ルチオフェン- 2しィルカルバモイル)-ペンタノィルァミノ] -4-フエ二ルチオフエ ン- 3-カルボン酸ジェチルエステル、 R = 2 チェ-ル基： 2- [3- (3 '-カルボキシ- 4'- ( 2 チェ-ル）チォフェン- 2しィルカルバモイル)-ペンタノィルァミノ] -4- (2 チェ- ル）チォフェン- 3-カルボン酸ジェチルエステル〕を得た（収率 70%)。  10 g (54.6 mmol) of adipic acid chloride anhydride (1) 114 mmol of the amino ester compound (2) (R = phenol group or 2 chael group) and 11 ml (114 mmol) of pyridine were mixed with dry dioxane. Heated in 70 ml for 2.5 hours. The reaction mixture was warmed and poured into cold water, and then alkalinized by adding 15 g of potassium carbonate. The precipitate was filtered off and washed with water. The precipitate was dried and recrystallized using a mixture of MeOH / THF (50:50, 400 ml) to give 16-21 g of amide-ester (3) [R = phenol group: 2- [3 -(3'-carboxy-4'-phenylthiophene-2-silylcarbamoyl) -pentanoylamino] -4-phenylthiophene-3-carboxylic acid jetyl ester, R = 2 chalcyl group: 2- [3- (3'-Carboxy-4 '-(2Che) thiophene-2-silcarbamoyl) -pentanoylamino] -4- (2Che) thiophene-3-carboxylic acid jetyl Ester] (yield 70%).
[0238] (2) Step 2：アミド—エステル (3)の加水分解  [0238] (2) Step 2: Hydrolysis of amide-ester (3)
42.3mmolのアミドーエステル（3)を 870mLの THFに溶解し、これに 115mlの水に溶 解した 0.91mmol水酸ィ匕ナトリウム水溶液 (4)を添加した。攪拌しながら 3.5時間加熱し 、次いで終夜室温に放置した。非溶解性の不純物を濾別除去し、次いで混合物を、 容量が約 250mlになるまでエバポレートした (T =40°C)。残渣の塩 (5)〔R=フエ- bath  42.3 mmol of amide ester (3) was dissolved in 870 mL of THF, and 0.91 mmol of sodium hydroxide aqueous solution (4) dissolved in 115 ml of water was added thereto. Heated with stirring for 3.5 hours and then left at room temperature overnight. Insoluble impurities were filtered off and the mixture was then evaporated to a volume of about 250 ml (T = 40 ° C.). Residual salt (5) [R = Hue-bath
ル基： 2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモイル)-ペンタノ ィルァミノ] -4-フ -ルチオフェン- 3-カルボン酸ジナトリウム塩、 R= 2—チェ-ル基： 2- [3- (3'-カルボキシ- 4'- (2 チェ-ル）チォフェン- 2しィルカルバモイル)-ペンタノ ィルァミノ] -4- (2—チェ-ル）チォフェン- 3-カルボン酸ジナトリウム塩〕を濾取し、塩 ィ匕メチレンとメタノールで洗浄した（収率 30%)。  2- [3- (3'-Carboxy-4'-phenylthiophene-2-silylcarbamoyl) -pentanoylamino] -4-furthiophene-3-carboxylic acid disodium salt, R = 2 —Chayl group: 2- [3- (3'-Carboxy-4 '-(2Che) thiophene-2sylcarbamoyl) -pentanoylamino] -4- (2-Che)) thiophene-3 -Carboxylic acid disodium salt] was collected by filtration and washed with sodium chloride and methanol (yield 30%).
[0239] (3) Step 3 :アミド—カルボン酸（6) (化合物 a、 b)の合成 上記で得られた塩 (5)を、 THFZH O (150mlZ200ml)の混合液に溶解し、 20%酢 [0239] (3) Step 3: Synthesis of amide-carboxylic acid (6) (compounds a and b) Dissolve the salt (5) obtained above in a mixture of THFZH 2 O (150 ml Z 200 ml) and add 20% vinegar.
2  2
酸水溶液により酸性ィ匕した。沈殿物を濾取し、水で洗浄した。次いで、得られた酸 (6 )〔R=フエ-ル基： 2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモイ ル)-ペンタノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸（分子量： 552.67) (ィ匕 合物 a)、 R = 2 チェ-ル基： 2- [3- (3'-カルボキシ- 4'- (2 チェ-ル）チォフェン- 2' -ィルカルバモイル)-ペンタノィルァミノ] -4- (2 チェ-ル）チォフェン- 3-カルボン酸 (分子量: 560.69) (化合物 b)〕を室温下、真空して乾燥した。全収率は、約 15%であ つた。化合物 aおよび bの NMRのデータをそれぞれ図 2および 3に示す。  Acidified with aqueous acid solution. The precipitate was collected by filtration and washed with water. Next, the obtained acid (6) [R = phenol group: 2- [3- (3'-carboxy-4'-phenolthiophene-2-silylcarbamoyl) -pentanoylamino] -4- Phenolthiophene-3-carboxylic acid (molecular weight: 552.67) (compound a), R = 2 chael group: 2- [3- (3'-carboxy-4'- (2 chael) Thiophene-2′-ylcarbamoyl) -pentanoylamino] -4- (2 che) thiophene-3-carboxylic acid (molecular weight: 560.69) (compound b)] was dried under vacuum at room temperature. The overall yield was about 15%. The NMR data for compounds a and b are shown in FIGS. 2 and 3, respectively.
[0240] 製造例 2  [0240] Production Example 2
2-「5-(3 ' -カルボキシ- 4' -(2-チェニル)チォフェン- 2 ' -ィルカルバモイル)-ペンタノィ ルァミノ 1-4-(2-チェニル)チオフ ン- 3-カルボン酸 (化合物 b)のジナトリウム塩の製 造  2-``5- (3'-carboxy-4 '-(2-cenyl) thiophene-2'-ylcarbamoyl) -pentanoylamino 1-4- (2-cenyl) thiophene-3-carboxylic acid (compound b) Of disodium salt
[0241] [化 70]  [0241] [Chemical 70]
Figure imgf000042_0001
Figure imgf000042_0001
[0242] 製造例 1で合成したィ匕合物 bを、 THF中 NaOH水溶液を用いてジナトリウム塩に変換 して掲題の化合物を調製した。 [0242] The compound b synthesized in Production Example 1 was converted to a disodium salt using an aqueous NaOH solution in THF to prepare the title compound.
m.p.： 258-260°C  m.p .: 258-260 ° C
'H-NMR (DMSO-d6) δ： 1.60— 1.80(4Η, m), 2.35- 2.60(4Η, m), 6.76(2Η, s), 6.95(1 Η, dd, J=3.4,3.4Hz), 7.30(1H, dd, J=1.2, 3.4Hz), 7.35(1H, dd, J=1.2, 3.4Hz), 14.1(2 H, s)。  'H-NMR (DMSO-d6) δ: 1.60— 1.80 (4 Η, m), 2.35- 2.60 (4 Η, m), 6.76 (2 Η, s), 6.95 (1 Η, dd, J = 3.4, 3.4 Hz) 7.30 (1H, dd, J = 1.2, 3.4 Hz), 7.35 (1H, dd, J = 1.2, 3.4 Hz), 14.1 (2 H, s).
[0243] 製诰例 3 [0243] Ironmaking example 3
2-Γ5-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2 ' -ィルカルバモイル)-ペンタノィル アミノ 1-4-イソプチルチオフェン- 3-カルボン酸 (化合物 d)のジナトリウム の觀告  Notice of disodium 2-Γ5- (3'-carboxy-4'-isobutylthiophene-2'-ylcarbamoyl) -pentanoylamino 1-4-isoptylthiophene-3-carboxylic acid (compound d)
[0244] [化 71]
Figure imgf000043_0001
[0244] [Chemical 71]
Figure imgf000043_0001
[0245] 化合物 d (Specs社、オランダ）を、 THF中 NaOH水溶液を用いてジナトリウム塩に変換 して掲題の化合物を調製した。 [0245] The title compound was prepared by converting compound d (Specs, The Netherlands) to the disodium salt using aqueous NaOH in THF.
m.p.： 248-25 l°C(dec.)  m.p .: 248-25 l ° C (dec.)
JH-NMR (DMSO-d6) δ 0.81(12Η, d, J=6.8Hz), 1.55— 1.70(4H, m), 1.90(2H, septet , J=6.8Hz), 2.24-2.43(4H, m), 2.72(2H, d, J=6.8Hz), 6.26(2H, s)。 J H-NMR (DMSO-d6) δ 0.81 (12Η, d, J = 6.8Hz), 1.55— 1.70 (4H, m), 1.90 (2H, septet, J = 6.8Hz), 2.24-2.43 (4H, m ), 2.72 (2H, d, J = 6.8 Hz), 6.26 (2H, s).
[0246] 製诰例 4 [0246] Example 4
2-「4-(3'-カルボキシ -4'-(2-チェニル)チォフェン- 2'-ィルカルバモイル)- 3.3-ジメチ ルブチリルァミノ 1-4-(2-チェニル)チオフ ン- 3-カルボン酸（化合物 h)のジナトリウム 塩の觀告  2- "4- (3'-Carboxy-4 '-(2-Cenyl) thiophene-2'-ylcarbamoyl)-3.3-dimethylbutyrylamino 1-4- (2-Cenyl) thiophene-3-carboxylic acid (compound h) Notification of disodium salt
[0247] [化 72] [0247] [Chemical 72]
Figure imgf000043_0002
Figure imgf000043_0002
[0248] 化合物 h (Specs社、オランダ）を、 THF中 NaOH水溶液を用いてジナトリウム塩に変 換して掲題の化合物を調製した。  [0248] The title compound was prepared by converting Compound h (Specs, The Netherlands) to the disodium salt using aqueous NaOH in THF.
m.p.： 245-248°C(dec.)  m.p .: 245-248 ° C (dec.)
1H-NMR (DMSO-d6) δ： 1.14(6H, s), 2.48(4H, s), 6.76(2H, s), 6.95(1H, dd, J=3.4, 5.2Hz), 7.29(1H, dd, J=1.2, 3.4Hz), 7.35(1H, dd, J=1.2, 5.2Hz), 14.1(2H, s)。  1H-NMR (DMSO-d6) δ: 1.14 (6H, s), 2.48 (4H, s), 6.76 (2H, s), 6.95 (1H, dd, J = 3.4, 5.2Hz), 7.29 (1H, dd , J = 1.2, 3.4Hz), 7.35 (1H, dd, J = 1.2, 5.2Hz), 14.1 (2H, s).
[0249] 製造例 5 [0249] Production Example 5
2-「5- (3 ' -カルボキシ- 4， -(D-クロ口フエニル)チォフェン- 2 ' -ィルカルバモイル)-ペン タノィルァミノ 1-4-(D-クロ口フエニル)チォフェン- 3-カルボン酸（化合物 o)の製造  2- "5- (3'-Carboxy-4,-(D-Chroostylphenyl) thiophene-2'-ylcarbamoyl) -pentanoylamino 1-4- (D-Chroostylphenyl) thiophene-3-carboxylic acid ( Preparation of compound o)
後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0250] [化 73]
Figure imgf000044_0001
[0250] [Chemical 73]
Figure imgf000044_0001
[0251] (l)Step 1 [0251] (l) Step 1
7.73g (50mmol)の p-クロロアセトフエノン、 4.96g (50mmol)のシァノ酢酸メチル、 0.4 5g (7.5mmol)の酢酸及び 0.19g (2.5mmol)の酢酸アンモ-ゥムを 30mlのトノレェン中 で 3時間脱水加熱還流した。冷却した後、反応混合液を酢酸ェチルで希釈して水で 洗浄した。得られた有機層を硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。 得られた残渣に 60mlのメタノール、 1.6 g (50mmol)の硫黄及び 4.4g (50mmol)のモル ホリンを加えて 4時間加熱還流した。その後反応液を冷却後、濾過し濾過液を濃縮し た。得られた残渣を酢酸ェチルで希釈して水で洗浄し、硫酸マグネシウムで乾燥後 溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで分離 精製して l.lgの 2-ァミノ- 4-(p-クロ口フエ-ル)チォフェン- 3-カルボン酸メチルエステ ルを得た（収率 7%)。  7.73 g (50 mmol) of p-chloroacetophenone, 4.96 g (50 mmol) of methyl cyanoacetate, 0.45 g (7.5 mmol) of acetic acid and 0.19 g (2.5 mmol) of ammonium acetate in 30 ml of toluene. The mixture was dehydrated and heated to reflux for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The obtained organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue, 60 ml of methanol, 1.6 g (50 mmol) of sulfur and 4.4 g (50 mmol) of morpholine were added and heated under reflux for 4 hours. Thereafter, the reaction solution was cooled and then filtered to concentrate the filtrate. The obtained residue was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain l.lg of 2-amino-4- (p-chlorophenol) thiophene-3-carboxylic acid methyl ester (yield). 7%).
[0252] (2)Step 2 [0252] (2) Step 2
0.16ml (l.lmmol)のアジピン酸クロリドおよび 0.64g (2.3mmol)の 2-ァミノ- 4- (4，-クロ 口フエ-ル)- 3-チォフェンカルボン酸メチルエステルの混合物を 5mlの DMF中室温で 一晩攪拌した。反応混合液を氷水に注入した。沈殿物を濾別し、水およびジェチル エーテルで洗浄し、乾燥することにより 0.66gの 2- [5- (3，-カルボキシ- 4，- (p-クロロフ ェ -ル)チォフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ]- 4- (p-クロ口フエ-ル） チォフェン- 3-カルボン酸ジメチルエステルを得た（収率 92%)。  Mix 5 ml of DMF with a mixture of 0.16 ml (l.lmmol) adipic acid chloride and 0.64 g (2.3 mmol) 2-amino-4- (4, -chlorophenol) -3-thiophenecarboxylic acid methyl ester. Stir at room temperature overnight. The reaction mixture was poured into ice water. The precipitate was filtered off, washed with water and jetyl ether, and dried to give 0.66 g of 2- [5- (3, -carboxy-4,-(p-chlorophenyl) thiophene-2, Rucarbamoyl) -pentanoylamino] -4- (p-chlorophenol) thiophene-3-carboxylic acid dimethyl ester was obtained (yield 92%).
[0253] (3)Step 3 [0253] (3) Step 3
0.61g (0.9mmol)の 2- [5- (3， -カルボキシ- 4， -(p-クロ口フエ-ル)チォフェン- 2， -ィル 力ルバモイル)-ペンタノィルァミノ] -4-(p-クロ口フエ-ル)チォフェン- 3-カルボン酸ジ メチルエステルを 10mlの THF溶液に溶解し、次いで 2.2mlの 1N水酸化ナトリウム水溶 液を加えて 50〜60°Cで 2.5時間攪拌し、更に室温で 15時間攪拌した。反応混合物を 濃縮し、残渣を濾取し水で洗浄した。得られた残渣に THF-酢酸ェチル -水を加えた 後、 IN塩酸を加えて酸性化した有機層を分離した後濃縮し得られた残渣を水、酢酸 ェチルで洗浄し、次いで乾燥することにより、掲題の 2- [5- (3，-カルボキシ- 4，- (p-クロ 口フエ-ル)チォフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ]- 4- (p-クロ口フエ- ル)チォフェン- 3-カルボン酸 (化合物 o)を得た（収率 45%)。 0.61 g (0.9 mmol) of 2- [5- (3, -Carboxy-4,-(p-crophine pheyl) thiophene-2, -yl rubamoyl) -pentanoylamino] -4- ( p-chlorophenol) thiophene-3-carboxylic acid dimethyl ester was dissolved in 10 ml of THF solution, then 2.2 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50-60 ° C for 2.5 hours. The mixture was further stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was collected by filtration and washed with water. To the resulting residue was added THF-ethyl acetate-water. Then, the residue obtained by separating and concentrating the acidified organic layer by adding IN hydrochloric acid was washed with water and ethyl acetate, and then dried to give the title 2- [5- (3, -carboxy- 4,-(p-chlorophine) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (p-chlorophenol) thiophene-3-carboxylic acid (compound o) was obtained. (Yield 45%).
m.p.： 271-273°C (dec.)  m.p .: 271-273 ° C (dec.)
1H-NMR (DMSO-d6) δ： 1.60— 1.80(4Η, m), 2.50- 2.65(4Η, m), 6.89(2Η, s), 7.29-7. 41(8Η, m), 11.2(2Η, s)。  1H-NMR (DMSO-d6) δ: 1.60— 1.80 (4Η, m), 2.50-2.65 (4Η, m), 6.89 (2Η, s), 7.29-7.41 (8Η, m), 11.2 (2Η, s).
[0254] 製造例 6 [0254] Production Example 6
2-Γ4-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2 ' -ィルカルバモイル)-ブチリルアミ ノ 1-4-イソプチルチオフェン- 3-カルボン酸 (化合物 Ό)の製诰  Preparation of 2-Γ4- (3'-carboxy-4'-isobutylthiophene-2'-ylcarbamoyl) -butyrylamino 1-4-isoptylthiophene-3-carboxylic acid (compound Ό)
後述する Step 1〜2に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 and 2 described later, the title compound represented by the following formula was synthesized.
[0255] [化 74] [0255] [Chemical 74]
Figure imgf000045_0001
Figure imgf000045_0001
[0256] (l)Step 1 [0256] (l) Step 1
0.2ml(1.5mmol)のグルタル酸クロリドおよび 0.64g (3mol)の 2-ァミノ- 4-イソブチルチ ォフェン- 3-カルボン酸メチルエステルの混合物を 6mlの DMA中室温でー晚攪拌した 。反応混合液に酢酸ェチルを加えて抽出後硫酸マグネシウムで乾燥、濃縮して 0.73 gの 2-[4- (3， -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバモイル)-ブチリル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸ジメチルエステルを得た（収率 93%)。  A mixture of 0.2 ml (1.5 mmol) glutaric chloride and 0.64 g (3 mol) 2-amino-4-isobutylthiophene-3-carboxylic acid methyl ester was stirred in 6 ml DMA at room temperature. Ethyl acetate was added to the reaction mixture and the mixture was extracted, dried over magnesium sulfate and concentrated to 0.73 g of 2- [4- (3, -carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -butyrylamino]- 4-Isobutylthiophene-3-carboxylic acid dimethyl ester was obtained (yield 93%).
[0257] (2)Step 2 [0257] (2) Step 2
730mg (1.4mmol)の 2- [4- (3， -カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバ モイル)-ブチリルァミノ] -4-イソブチルチオフェン- 3-カルボン酸ジメチルエステルを T HFに溶解し、次いで、 1N水酸ィ匕ナトリウム水溶液をカ卩えて 50〜60°Cで 16時間攪拌し た。冷却後 THFを減圧留去した。残渣を濾取して水及び酢酸ェチルで洗浄した。得 られた残渣を水に懸濁して 1N塩酸をカ卩えて酢酸ェチルで抽出し、有機層を水で洗 浄した。有機層を無水硫酸マグネシウムで乾燥、濃縮した。得られた残渣を濾取しジ ェチルエーテルで洗浄した後乾燥することにより、掲題の 2-[4-(3，-カルボキシ -4，- イソブチルチオフェン- 2 ' -ィルカルバモイル)-ブチリルァミノ] -4-イソブチルチオフエ ン- 3-カルボン酸 (化合物 p)を得た（収率 17%)。 Dissolve 730 mg (1.4 mmol) of 2- [4- (3, -carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -butyrylamino] -4-isobutylthiophene-3-carboxylic acid dimethyl ester in THF. Then, 1N sodium hydroxide aqueous solution was added and stirred at 50-60 ° C for 16 hours. After cooling, THF was distilled off under reduced pressure. The residue was collected by filtration and washed with water and ethyl acetate. The obtained residue was suspended in water, 1N hydrochloric acid was added and extracted with ethyl acetate, and the organic layer was washed with water. Purified. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was dried after washing with filtration and di Echirueteru a 2 The title - [4 - (3 - carboxy - 4 - isobutyl thiophene - 2 '- I-carbamoyl) - Buchiriruamino] -4- Isobutylthiophene-3-carboxylic acid (compound p) was obtained (yield 17%).
m.p.： 217-218°C(dec.)  m.p .: 217-218 ° C (dec.)
1H-NMR (DMSO-d6) δ： 0.84(12H, d, J=7.4Hz), 1.60— 2.10(4H, m), 2.40-2.74(4H, m), 2.60(4H, d, J=7.4Hz), 6.60(2H, s), 11.3(2H, s)。  1H-NMR (DMSO-d6) δ: 0.84 (12H, d, J = 7.4Hz), 1.60— 2.10 (4H, m), 2.40-2.74 (4H, m), 2.60 (4H, d, J = 7.4Hz ), 6.60 (2H, s), 11.3 (2H, s).
[0258] 製造例 7 [0258] Production Example 7
2-Γ4-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2 ' -ィルカルバモイル) -3,3-ジメチル プチリルアミノ 1-4-イソプチルチオフェン- 3-カルボン酸 (化合物 α)の觀告  2-Γ4- (3'-Carboxy-4'-isobutylthiophene-2'-ylcarbamoyl) -3,3-dimethyl-butyrylamino 1-4-isoptylthiophene-3-carboxylic acid (compound α)
後述する Step 1〜2に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 and 2 described later, the title compound represented by the following formula was synthesized.
[0259] [化 75] [0259] [Chemical 75]
Figure imgf000046_0001
Figure imgf000046_0001
[0260] (l)Step 1 [0260] (l) Step 1
0.46g
Figure imgf000046_0002
ジクロリド l.Og (4.69mol)および 2 -ァミノ- 4-イソブチルチオフェン- 3-カルボン酸メチルエステルの混合物を DMA溶液 中室温で一晩攪拌した。反応混合液を氷水に注入し、炭酸水素ナトリウムを添加して アルカリィ匕した。次いで酢酸ェチルで抽出し硫酸マグネシウムで乾燥、濃縮した。得 られた粗生成物をシリカゲルカラムクロマトグラフィーで分離精製することにより 1.29g の 2-[4- (3， -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバモイル) -3,3-ジメチ ルブチリルァミノ] -4-イソブチルチオフェン- 3-カルボン酸ジメチルエステルを得た（収 率 92%)。 0.46g
Figure imgf000046_0002
A mixture of dichloride l.Og (4.69 mol) and 2-amino-4-isobutylthiophene-3-carboxylic acid methyl ester was stirred in DMA solution at room temperature overnight. The reaction mixture was poured into ice water and alkalized by adding sodium bicarbonate. Next, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The crude product obtained was separated and purified by silica gel column chromatography to obtain 1.29 g of 2- [4- (3, -carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino. ] -4-Isobutylthiophene-3-carboxylic acid dimethyl ester was obtained (yield 92%).
[0261] (2)Step 2 [0261] (2) Step 2
1.19g (2.17mmol)の 2- [4- (3， -カルボキシ- 4， -イソブチルチオフェン- 2， -ィルカルバ モイル)- 3,3-ジメチルブチリルァミノ] -4-イソブチルチオフェン- 3-カルボン酸ジメチル エステルを THFに溶解して、次いで 1N水酸化ナトリウムを添カ卩し 50〜60°Cで 4時間 攪拌した。次いで室温で一晩攪拌し、反応混合液を減圧留去して得られた残渣に 1N 塩酸を加えて酸性ィ匕し攪拌した。これを濾過し、母液を濃縮した。析出した結晶を濾 過し乾燥することにより、掲題の 2-[4-(3， -カルボキシ- 4' -イソブチルチオフェン- 2， - ィルカルバモイル) -3, 3-ジメチルブチリルァミノ] -4-イソブチルチオフェン- 3-カルボン 酸 (化合物 q)を得た (収率 22%)。 1.19 g (2.17 mmol) of 2- [4- (3, -carboxy-4, -isobutylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino] -4-isobutylthiophene-3-carboxylic acid Dissolve dimethyl ester in THF, then add 1N sodium hydroxide and add at 50-60 ° C for 4 hours. Stir. Next, the mixture was stirred overnight at room temperature, and the reaction mixture was evaporated under reduced pressure, and 1N hydrochloric acid was added to the resulting residue, followed by stirring. This was filtered and the mother liquor was concentrated. The precipitated crystals were filtered and dried to give the title 2- [4- (3, -carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino] -4- Isobutylthiophene-3-carboxylic acid (compound q) was obtained (yield 22%).
m.p.： 198-201°C(dec.)  m.p .: 198-201 ° C (dec.)
'H-NMR (DMSO-d6) δ： 0.84(12Η, d, J=6.6Hz), 1.12(6H, s), 1.70— 1.95(2H, m), 2.5 3-2.64(8H, m), 6.60(1H, s), 11.4(1H, s)。  'H-NMR (DMSO-d6) δ: 0.84 (12Η, d, J = 6.6Hz), 1.12 (6H, s), 1.70— 1.95 (2H, m), 2.5 3-2.64 (8H, m), 6.60 (1H, s), 11.4 (1H, s).
[0262] 製造例 8 [0262] Production Example 8
2-Γ6-(3 ' -カルボキシ -4 ' -フエ-ルチオフェン- 2 ' -ィルカルバモイル)-へキサノィルァ ミノ 1-4-フ 二ルチオフ ン- 3-カルボン酸（化合物）の合成  Synthesis of 2-Γ6- (3'-carboxy-4'-phenylthiophene-2'-ylcarbamoyl) -hexanoylamino 1-4-furthiophene-3-carboxylic acid (compound)
後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0263] [化 76]  [0263] [Chem 76]
Figure imgf000047_0001
Figure imgf000047_0001
[0264] (l)Step 1 [0264] (l) Step 1
10.6g (88.2mmol)のべンゾフエノン、 20g (141.6mmol)のシァノ酢酸 tert-ブチルエス テル、 5.3g (88.2mmol)の酢酸及び 6.2g (70.8mmol)のモルホリンを 50mlのトルエン中 で 12.5時間脱水加熱還流した。冷却した後、反応液を水で洗浄した。得られた有機 層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。得られた残渣に 100ml の DMF、 2.8g (88.2mmol)の硫黄及び 7.7g (88.2mmol)のモルホリンをカ卩えてー晚攪 拌した。その後、反応液に酢酸ェチルを加えた後、水で洗浄した。得られた有機層を 無水硫酸ナトリウムで乾燥後溶媒を減圧留去した。得られた粗生成物をシリカゲル力 ラムクロマトグラフィーで分離精製し、次いでへキサンで再結晶して、 14.7gの 2-ァミノ -4-フエ-ルチオフェン- 3-カルボン酸 tert-ブチルエステルを得た（収率 60.5%)。 [0265] (2)Step 2 10.6 g (88.2 mmol) benzophenone, 20 g (141.6 mmol) tert-butyl ester cyanoacetate, 5.3 g (88.2 mmol) acetic acid and 6.2 g (70.8 mmol) morpholine in 50 ml toluene for 12.5 hours Refluxed. After cooling, the reaction solution was washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the resulting residue, 100 ml of DMF, 2.8 g (88.2 mmol) of sulfur and 7.7 g (88.2 mmol) of morpholine were added and stirred. Thereafter, ethyl acetate was added to the reaction solution, followed by washing with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel chromatography and then recrystallized from hexane to obtain 14.7 g of 2-amino-4-phenolthiophene-3-carboxylic acid tert-butyl ester. (Yield 60.5%). [0265] (2) Step 2
0.36g, (1.82mmol)のピメロイルクロリドおよび l.Og (3.63mmol)の 2—ァミノ— 4—フエ-ル チォフェン- 3-カルボン酸 tert-ブチルエステルの混合物を DMF溶液中室温でー晚 攪拌した。反応液を氷水中に注入し、炭酸水素ナトリウムを添加してアルカリ化した。 沈殿物を濾別し、水、酢酸ェチル -IPE混合液で洗浄し、乾燥して、 0.68gの 2-[6-(3，- カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-へキサノィルァミノ]- 4-フ ェ-ルチオフェン- 3-カルボン酸ジ -tert-ブチルエステルを得た（収率 55%)。  A mixture of 0.36 g, (1.82 mmol) pimeloyl chloride and l.Og (3.63 mmol) 2-amino-4-phenolthiophene-3-carboxylic acid tert-butyl ester in DMF solution at room temperature. Stir. The reaction solution was poured into ice water and alkalized by adding sodium hydrogen carbonate. The precipitate was filtered off, washed with water, ethyl acetate-IPE mixture, dried and 0.68 g of 2- [6- (3, -carboxy-4, -phenolthiophene-2, -ylcarbamoyl] ) -Hexanoylamino] -4-phenylthiophene-3-carboxylic acid di-tert-butyl ester was obtained (yield 55%).
[0266] (3)Step 3 [0266] (3) Step 3
0.66g (0.98mmol)の 2-[6-(3， -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモ ィル) -へキサノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸ジ -tert-ブチルエス テルおよび TFAを塩化メチレン溶媒中室温で一晩攪拌した。反応溶液を濃縮した後 、残渣を濾取し、酢酸ェチル -IPEで洗浄、乾燥することにより、掲題の 2-[6-(3' -カル ボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-へキサノィルァミノ] -4-フエ- ルチオフェン- 3_カルボン酸（ィヒ合物 r)を得た（収率 85%)。  0.66 g (0.98 mmol) 2- [6- (3, -carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -hexanoylamino] -4-phenolthiophene-3-carboxylic acid di -tert-Butyl ester and TFA were stirred overnight in a methylene chloride solvent at room temperature. After concentrating the reaction solution, the residue was collected by filtration, washed with ethyl acetate-IPE and dried to give the title 2- [6- (3'-carboxy-4, -phenolthiophene-2,- Ylcarbamoyl) -hexanoylamino] -4-phenylthiophene-3-carboxylic acid (Dych compound r) was obtained (yield 85%).
m.p.： 204-206°C(dec.)  m.p .: 204-206 ° C (dec.)
JH-NMR (DMSO-d6) δ 1.24— 1.46(2Η, m), 1.68(4Η, q, J=7.6Hz), 2.75(4H, t, J=7.6 Hz), 6.84(1H, s), 7.23-7.40(10H, m), 11.3(2H,s), 12.9(2H, br)。 J H-NMR (DMSO-d6) δ 1.24— 1.46 (2Η, m), 1.68 (4Η, q, J = 7.6Hz), 2.75 (4H, t, J = 7.6 Hz), 6.84 (1H, s), 7.23-7.40 (10H, m), 11.3 (2H, s), 12.9 (2H, br).
[0267] 製诰例 9 [0267] Example 9
2-Γ5-(3， -カルボキシ -5， -メチル -4' -フエ-ルチオフェン- 2， -ィルカルバモイル)-ぺ ンタノィルァミノ 1-5-メチル -4-フエ二ルチオフェン- 3-カルボン酸（化合物 s)の製造 後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  2-Γ5- (3, -carboxy-5, -methyl-4'-phenylthiophene-2, -ylcarbamoyl) -pentanoylamino 1-5-methyl-4-phenylthiophene-3-carboxylic acid ( Production of Compound s) According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0268] [化 77] [0268] [Chemical 77]
Figure imgf000048_0001
Figure imgf000048_0001
[0269] (l)Step 1 [0269] (l) Step 1
10g (74.5mmol)のプロピオフエノン、 14.9g (105.5mmol)のシァノ酢酸 tert-ブチルェ ステル、 4.51g (74.5mmol)の酢酸及び 5.19g (59.5mmol)のモルホリンを 100mlのトルェ ン中で 3.5時間脱水加熱還流した。冷却した後、反応液を水で洗浄した。得られた有 機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。得られた残渣に 100 mlの DMF、 2.4g (74.5mmol)の硫黄及び 6.5g (74.5mmol)のモルホリンをカ卩えてー晚 攪拌した後、反応液に酢酸ェチルを加えて水で洗浄した。得られた有機層を無水硫 酸ナトリウムで乾燥後溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロ マトグラフィ一で分離精製することにより 8.38gの 2-ァミノ- 5-メチル -4-フエ二ルチオフ ェン- 3-カルボン酸 tert-ブチルエステルを得た（収率 39%)。 10 g (74.5 mmol) propiophenone, 14.9 g (105.5 mmol) cyanoacetic acid tert-butyl ester Steal, 4.51 g (74.5 mmol) acetic acid and 5.19 g (59.5 mmol) morpholine were dehydrated and heated to reflux in 100 ml toluene for 3.5 hours. After cooling, the reaction solution was washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue, 100 ml of DMF, 2.4 g (74.5 mmol) of sulfur and 6.5 g (74.5 mmol) of morpholine were added and stirred. Ethyl acetate was added to the reaction solution and washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain 8.38 g of 2-amino-5-methyl-4-phenyl-thiophene-3-carboxylic acid tert-butyl ester. Rate 39%).
[0270] (2)Step 2 [0270] (2) Step 2
0.32g (1.7mmol)のアジピン酸クロリドおよび l.Og (3.6mmol)の2-ァミノ-5-メチル-4- フエ-ルチオフェン- 3-カルボン酸 tert-ブチルエステルの混合物を 5mlの DMA中室 温で 2時間攪拌した。反応混合液を氷水中に注入し、次いで炭酸水素ナトリウムを添 カロしてアルカリィ匕した。沈殿物を濾別し、水及び IPEで洗浄し乾燥して 1.2gの 2-[5- (3' -カルボキシ -5，メチル -4， -フエ二ルチオフェン- 2， -ィルカルバモイル) -ペンタノィル ァミノ] -5-メチル -4-フエ-ルチオフェン- 3-カルボン酸ジ -tert-ブチルエステルを得 た（収率 87%)  A mixture of 0.32 g (1.7 mmol) adipic acid chloride and l.Og (3.6 mmol) 2-amino-5-methyl-4-phenylthiophene-3-carboxylic acid tert-butyl ester was added to 5 ml of DMA chamber. Stir at warm for 2 hours. The reaction mixture was poured into ice water and then alkalinized with sodium bicarbonate. The precipitate was filtered off, washed with water and IPE and dried to give 1.2 g of 2- [5- (3'-carboxy-5, methyl-4, -phenylthiophene-2, -ylcarbamoyl) -pentanoyl Amino] -5-methyl-4-phenylthiophene-3-carboxylic acid di-tert-butyl ester was obtained (yield 87%).
(3)Step 3  (3) Step 3
0.97g (1.4mmol)の 2- [5- (3，-カルボキシ- 5，メチル -4，-フエ-ルチオフェン- 2，-ィ ルカルバモイル)-ペンタノィルァミノ] -5-メチル -4-フエ-ルチオフェン- 3-カルボン酸 ジ -tert-ブチルエステルおよび 2mlの TFAを 3mlの塩化メチレン中室温でー晚攪拌し た。反応混合液を濃縮した後、残渣を濾取し、酢酸ェチル -IPEで洗浄し乾燥すること により、掲題の 2- [5- (3， -カルボキシ- 5，メチル -4， -フエ-ルチオフェン- 2， -ィルカル バモイル)-ペンタノィルァミノ] -5-メチル -4-フエ-ルチオフェン- 3-カルボン酸（ィ匕合 物 s)を得た (収率 98%)。  0.97 g (1.4 mmol) of 2- [5- (3, -carboxy-5, methyl-4, -phenylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-methyl-4-phenol -Luthiophene-3-carboxylic acid di-tert-butyl ester and 2 ml TFA were stirred in 3 ml methylene chloride at room temperature. After concentrating the reaction mixture, the residue was collected by filtration, washed with ethyl acetate-IPE and dried to give the title 2- [5- (3, -carboxy-5, methyl-4, -phenylthiophene]. -2, -ilcarbamoyl) -pentanoylamino] -5-methyl-4-phenylthiophene-3-carboxylic acid (compound s) was obtained (yield 98%).
m.p.： 250-252°C(dec.)  m.p .: 250-252 ° C (dec.)
1H-NMR (DMSO-d6) δ 1.59- 1.80(4H, m), 2.07(3H, s), 2.55- 2.63(4H, m), 7.14-7. 40(10H, m), 11.3(2H, s), 12.6(2H, br)。  1H-NMR (DMSO-d6) δ 1.59- 1.80 (4H, m), 2.07 (3H, s), 2.55- 2.63 (4H, m), 7.14-7. 40 (10H, m), 11.3 (2H, s ), 12.6 (2H, br).
[0271] 製造例 10 2-「5-(3 ' -カルボキシ -5 ' -フエ二ルチオフェン- 2 ' -ィルカルバモイル)-ペンタノィルァ ミノ 1-5-フ 二ルチオフェン- 3-カルボン酸 (化合物 t)の製造 [0271] Production Example 10 Preparation of 2- "5- (3'-carboxy-5'-phenylthiophene-2'-ylcarbamoyl) -pentanoylamino 1-5-furthiothio-3-carboxylic acid (compound t)
後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0272] [化 78]  [0272] [Chemical 78]
Figure imgf000050_0001
Figure imgf000050_0001
[0273] (l)Step 1 [0273] (l) Step 1
10.6.g (88.2mmol)のフエ-ルアルデヒド、 20g (Hl.lmmol)のシァノ酢酸 tert-ブチ ルエステル、 5.3g (88.2mmol)の酢酸及び 6.2g (70.6mmol)のモルホリンを 50mlのトル ェン中で 6.5時間脱水加熱還流した。冷却した後、反応液を水で洗浄した。得られた 有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去した。得られた残渣を 10 0mlの DMF、 2.83g (88.2mmol)の硫黄及び 7.68g (88.2mmol)のモルホリンをカ卩えて一 晚攪拌した。その後、反応液に酢酸ェチルを加えた後、水で洗浄した。得られた有 機層を無水硫酸ナトリウムで乾燥後溶媒を減圧留去した。得られた粗生成物をシリカ ゲルカラムクロマトグラフィーで分離精製することにより 2.69gの 2-ァミノ- 5-フエ-ルチ ォフェン- 3-カルボン酸 tert-ブチルエステルを得た（収率 11.1%)。  10.6.g (88.2 mmol) phenol aldehyde, 20 g (Hl.l mmol) cyanoacetic acid tert-butyl ester, 5.3 g (88.2 mmol) acetic acid and 6.2 g (70.6 mmol) morpholine in 50 ml toluene The mixture was dehydrated and heated to reflux for 6.5 hours. After cooling, the reaction solution was washed with water. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was stirred while adding 100 ml of DMF, 2.83 g (88.2 mmol) of sulfur and 7.68 g (88.2 mmol) of morpholine. Thereafter, ethyl acetate was added to the reaction solution, followed by washing with water. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain 2.69 g of 2-amino-5-phenolphen-3-carboxylic acid tert-butyl ester (yield 11.1%).
[0274] (2)Step 2 [0274] (2) Step 2
0.42g (2.3mmol)のアジピン酸クロリドおよび l.Og (3.6mmol)の 2-ァミノ- 5-フエ-ル チォフェン- 3-カルボン酸 tert-ブチルエステルの混合物を 10mlの DMA中室温で一 晚攪拌した。反応混合液を酢酸ェチルで希釈して炭酸水素ナトリウム水溶液、食塩 水および水で洗浄し、有機層を無水硫酸ナトリウムで乾燥後溶媒を減圧留去した。 得られた粗生成物をシリカゲルカラムクロマトグラフィーで分離精製することにより 0.37 gの 2-[5-(3， -カルボキシ -5， -フエ-ルチオフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -5-フエ-ルチオフェン- 3-カルボン酸ジ -tert-ブチルエステルを得た（収率 31%)。 [0275] (3)Step 3 Stir a mixture of 0.42 g (2.3 mmol) adipic acid chloride and l.Og (3.6 mmol) 2-amino-5-phenol thiophene-3-carboxylic acid tert-butyl ester in 10 ml DMA at room temperature. did. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution, brine and water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain 0.37 g of 2- [5- (3, -carboxy-5, -phenylthiophene-2, -ylcarbamoyl) -pentanoylamino]- 5-Phenolthiophene-3-carboxylic acid di-tert-butyl ester was obtained (yield 31%). [0275] (3) Step 3
0.37g (0.56mmol)の2-[5-(3，-カルボキシ-5，-フェ-ルチォフェン-2，-ィルカルバ モイル)-ペンタノィルァミノ] -5-フエ-ルチオフェン- 3-カルボン酸ジ -tert-ブチルェ ステルおよび 2mlの TFAを 3mlの塩化メチレン中氷冷下で 2時間、次!、で室温で 1時間 攪拌した。反応混合液を濃縮した後、残渣を濾取し、酢酸ェチルで洗浄し、乾燥した 。次いで THF/へキサンの混合液を用いて再結晶することにより、掲題の 2-[5-(3' -力 ルボキシ -5， -フエ-ルチオフェン- 2， -ィルカルバモイル) -ペンタノィルァミノ] -5-フエ 二ルチオフェン- 3-カルボン酸 (ィ匕合物 t)を得た（収率 52%)。  0.37 g (0.56 mmol) 2- [5- (3, -Carboxy-5, -ferrothiophene-2, -ylcarbamoyl) -pentanoylamino] -5-phenolthiophene-3-carboxylic acid di -Tert-butyl ester and 2 ml of TFA were stirred in 3 ml of methylene chloride for 2 hours under ice-cooling, then for 1 hour at room temperature. After concentration of the reaction mixture, the residue was collected by filtration, washed with ethyl acetate and dried. Next, recrystallization using a THF / hexane mixture gave the title 2- [5- (3'-force ruboxy-5, -phenylthiophene-2, -ylcarbamoyl) -pentanoylamino. ] -5-phenyldithiophene-3-carboxylic acid (compound t) was obtained (yield 52%).
m.p.： 289-291°C(dec.)  m.p .: 289-291 ° C (dec.)
'H-NMR (DMSO-d6) δ： 1.61- 1.80(4Η, m), 2.57-2.71(4Η, m), 7.20- 7.69(10Η, m), 7.51(2Η, s), 11.K2H, s), 13.3(2H, br)。  'H-NMR (DMSO-d6) δ: 1.61- 1.80 (4Η, m), 2.57-2.71 (4Η, m), 7.20-7.69 (10Η, m), 7.51 (2Η, s), 11.K2H, s ), 13.3 (2H, br).
[0276] 製诰例 11 [0276] Ironmaking Example 11
2-Γ5-(3 ' -カルボキシ -5 ' -クロロチォフェン- 2 ' -ィルカルバモイル)-ペンタノィルアミノ ]-5-クロロチオフ ン- 3-カルボン酸（化合物 u)の製诰  2-Γ5- (3'-Carboxy-5'-chlorothiophene-2'-ylcarbamoyl) -pentanoylamino] -5-chlorothiophene-3-carboxylic acid (compound u)
後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0277] [化 79]  [0277] [Chemical 79]
Figure imgf000051_0001
Figure imgf000051_0001
[0278] (l)Step 1 [0278] (l) Step 1
2.2ml (15.4mmol)のアジピン酸クロリドおよび 5.3g (33.9mmol)の 2-アミノチォフェン- 3-カルボン酸メチルエステルの混合物を 30mlの DMA中室温で 1.5時間攪拌し、次!ヽ で 50〜60°Cで 1時間攪拌した。反応混合液を氷水中に加えた後、炭酸水素ナトリウム 水溶液を加えてアルカリ性とした。析出した沈殿物を濾取して水及び酢酸ェチルで 洗浄、乾燥することにより 6.5gの 2-[5-(3， -カルボキシチォフェン- 2， -ィルカルバモイ ル)-ペンタノィルァミノ] -チォフェン- 3-カルボン酸ジメチルエステルを得た (収率 99%)  Stir a mixture of 2.2 ml (15.4 mmol) adipic acid chloride and 5.3 g (33.9 mmol) 2-aminothiophene-3-carboxylic acid methyl ester in 30 ml DMA at room temperature for 1.5 hours, then The mixture was stirred at 60 ° C for 1 hour. The reaction mixture was added to ice water and then made alkaline with an aqueous sodium hydrogen carbonate solution. The precipitated precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give 6.5 g of 2- [5- (3, -carboxythiophene-2, -ylcarbamoyl) -pentanoylamino] -thiophene. -Obtained 3-carboxylic acid dimethyl ester (99% yield)
[0279] (2)Step 2 0.85g (2mmol)の 2-[5-(3， -カルボキシチォフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -チォフェン- 3-カルボン酸ジメチルエステルのエタノール溶液に 1N水酸化 ナトリウム水溶液をカ卩えて室温で 0.5時間攪拌の後、 50〜60°Cで 3時間攪拌した。冷 却後エタノールを減圧留去した。得られた残渣に水を加えて酢酸ェチルで洗浄後、 水層に 1N塩酸水溶液を加えると沈殿物を得た。得られた沈殿物を濾取して水で洗 浄後乾燥し 0.73gの 2-[5-(3， -カルボキシチォフェン- 2， -ィルカルバモイル)-ペンタノ ィルァミノ] -チォフェン- 3-カルボン酸を得た（収率 91%)。 [0279] (2) Step 2 0.85 g (2 mmol) 2- [5- (3, -Carboxythiophene-2, -ylcarbamoyl) -pentanoylamino] -thiophene-3-carboxylic acid dimethyl ester in ethanol solution was diluted with 1N sodium hydroxide aqueous solution. After stirring at room temperature for 0.5 hour, the mixture was stirred at 50-60 ° C for 3 hours. After cooling, ethanol was distilled off under reduced pressure. Water was added to the resulting residue, washed with ethyl acetate, and a 1N hydrochloric acid aqueous solution was added to the aqueous layer to obtain a precipitate. The resulting precipitate was collected by filtration, washed with water, and dried. 0.73 g of 2- [5- (3, -carboxythiophene-2, -ylcarbamoyl) -pentanoylamino] -thiophene-3-carboxylic acid (91% yield).
[0280] (3)Step 3 [0280] (3) Step 3
0.5g (1.26mmol)の 2-[5-(3， -カルボキシチォフェン- 2， -ィルカルバモイル)-ペンタノ ィルァミノ]-チォフェン- 3-カルボン酸及び 0.34g (2.52mmol)の NCSを THF/DMFの混 合液中室温で一晩攪拌した。反応混合液を氷水に注入した後沈殿物を濾取し、メタ ノール及び酢酸ェチルで洗浄、乾燥した後 THF/へキサンの混合液で再結晶し、 2-[ 5-(3， -カルボキシ -5， -クロロチォフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ] -5 -クロロチォフェン- 3-カルボン酸を得た（収率 53%)。  0.5 g (1.26 mmol) 2- [5- (3, -Carboxythiophene-2, -ylcarbamoyl) -pentanoylamino] -thiophene-3-carboxylic acid and 0.34 g (2.52 mmol) NCS in THF / DMF The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, and the precipitate was collected by filtration, washed with methanol and ethyl acetate, dried, recrystallized with a mixture of THF / hexane, and 2- [5- (3, -carboxy- 5, -Chlorothiophene-2, -ylcarbamoyl) -pentanoylamino] -5-chlorothiophene-3-carboxylic acid was obtained (yield 53%).
m.p.： 282-284°C(dec.)  m.p .: 282-284 ° C (dec.)
'H-NMR (DMSO-d6) δ： 1.46- 1.78(4Η, m), 2.50-2.72(4Η, m), 7.12(2Η, s), 11.0(2 Η, s), 11.3(2Η, br)。  'H-NMR (DMSO-d6) δ: 1.46- 1.78 (4 Η, m), 2.50-2.72 (4 Η, m), 7.12 (2 Η, s), 11.0 (2 Η, s), 11.3 (2 Η, br) .
[0281] 製诰例 12 [0281] Example of iron making 12
2-Γ4-(3 ' -カルボキシ -4' -フエ-ルチオフェン- 2 ' -ィルカルバモイル)-シクロへキシル カルボニルァミノ 1-4-フ 二ルチオフェン- 3-カルボン酸（化合物 V)の製造  Preparation of 2-Γ4- (3'-carboxy-4'-phenylthiophene-2'-ylcarbamoyl) -cyclohexyl carbonylamino-1-4-dithiophene-3-carboxylic acid (compound V)
後述する Step 1〜2に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 and 2 described later, the title compound represented by the following formula was synthesized.
[0282] [化 80] [0282] [Chemical 80]
Figure imgf000052_0001
Figure imgf000052_0001
[0283] (l)Step 1 [0283] (l) Step 1
0.52g(3.0mmol)の 1,4-シクロへキサンジカルボン酸（cis, trans混合物）および 2.2ml( 30mmol)の塩ィ匕チォニルの混合液を室温で一晩攪拌した後、濃縮した。得られた残 渣と 1.49g(5.4mmol)の 2-ァミノ- 5-フエ-ルチオフェン- 3-カルボン酸 tert-ブチルエス テルを DMA中室温で 4時間攪拌した。反応混合液を氷水中に注入し、炭酸水素ナト リウムを添加してアルカリ化した。沈殿物を濾取し、水、ジェチルエーテルで洗浄、乾 燥し、 0.97gの 2-[4- (3， -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル) - シクロへキシルカルボ-ルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸ジ -tert-ブチ ルエステルを得た（収率 52%)。 0.52 g (3.0 mmol) 1,4-cyclohexanedicarboxylic acid (cis, trans mixture) and 2.2 ml ( 30 mmol) of chlorothionyl was stirred at room temperature overnight and then concentrated. The obtained residue and 1.49 g (5.4 mmol) of 2-amino-5-phenylthiophene-3-carboxylic acid tert-butyl ester were stirred in DMA at room temperature for 4 hours. The reaction mixture was poured into ice water and alkalized by adding sodium hydrogen carbonate. The precipitate was collected by filtration, washed with water and jetyl ether, dried, and 0.97 g of 2- [4- (3, -carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -cyclohex [Xylcarbo-lamino] -4-phenylthiophene-3-carboxylic acid di-tert-butyl ester was obtained (yield 52%).
[0284] (2)Step 2 [0284] (2) Step 2
0.41g (0.6mmol)の 2- [4- (3， -カルボキシ- 4， -フエ-ルチオフェン- 2， -ィルカルバモ ィル) -シクロへキシルカルボ-ルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸ジ -tert -ブチルエステルおよび lmlの TFAを 3mlの塩化メチレン中室温で 5時間攪拌した。反 応混合液を濃縮し、得られた残渣を濾取し、 IPEで洗浄し、乾燥した。次いで THF/へ キサンの混合液を用いて再結晶し、 2-[4-(3， -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-シクロへキシルカルボ-ルァミノ] -4-フエ-ルチオフェン- 3-カル ボン酸を得た（収率 73%)。  0.41 g (0.6 mmol) of 2- [4- (3, -carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -cyclohexylcarbolamino] -4-phenolthiophene-3- Carboxylic acid di-tert-butyl ester and 1 ml of TFA were stirred in 3 ml of methylene chloride at room temperature for 5 hours. The reaction mixture was concentrated and the resulting residue was collected by filtration, washed with IPE and dried. Next, recrystallization was performed using a mixture of THF / hexane and 2- [4- (3, -carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -cyclohexylcarbo-lamino] -4- Phenolthiophene-3-carboxylic acid was obtained (yield 73%).
m.p.： >290°C  m.p .:> 290 ° C
'H-NMR (DMSO-d6) δ： 1.34-2.10(8Η, m), 2.51— 2.68(2Η, m), 6.69(2Η, s), 7.22-7. 40(10Η, m), 13.3(2Η, br)。  'H-NMR (DMSO-d6) δ: 1.34-2.10 (8Η, m), 2.51— 2.68 (2Η, m), 6.69 (2Η, s), 7.22-7. 40 (10Η, m), 13.3 (2Η , br).
[0285] 製诰例 13 [0285] Example of iron making 13
2-「5-(3 ' -カルボキシ -5 ' -イソプロピル- 4， -メチルチオフェン- 2 ' -ィルカルバモイル) - ペンタノィルァミノ 1-4-イソブチルチオフェン- 3-カルボン酸（化合物 w)の製造  Preparation of 2- "5- (3'-carboxy-5'-isopropyl-4, -methylthiophene-2'-ylcarbamoyl) -pentanoylamino 1-4-isobutylthiophene-3-carboxylic acid (compound w)
後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0286] [化 81] [0286] [Chemical 81]
Figure imgf000053_0001
Figure imgf000053_0001
[0287] (l)Step 1 54ml (430mmol) の 4-メチル -2-ペンタノン、 25ml (285mol)のシァノ酢酸メチルエス テル、 3.5ml (61mmol)の酢酸及び 1.5g (19mmol)の酢酸アンモ-ゥムを 90mlのトルェ ン中で 2.5時間脱水加熱還流した。冷却後、反応混合液を酢酸ェチルで希釈し、炭 酸水素ナトリウム水溶液、 NaCl水溶液で洗浄した。得られた有機層を硫酸マグネシゥ ムで乾燥後、溶媒を減圧留去した。得られた残渣に、 80mlのメタノール、 8.8g (276mm ol)の硫黄及び 7.4ml (85mmol)モルホリンをカ卩えて 6時間加熱還流した。反応液を冷 却後、濾過し濾液を濃縮した。得られた残渣を酢酸ェチルで希釈して水及び NaCl水 溶液で洗浄し、硫酸マグネシウムで乾燥後溶媒を減圧留去し、シリカゲルカラムクロ マトグラフィ一で分離精製し、 2-ァミノ- 5-イソプロピル- 4-メチルチオフェン- 3-カルボ ン酸メチルエステル及び 2-ァミノ- 4-イソブチルチオフェン- 3-カルボン酸メチルエス テルの混合物を得た。 [0287] (l) Step 1 54 ml (430 mmol) 4-methyl-2-pentanone, 25 ml (285 mol) methyl cyanoacetate, 3.5 ml (61 mmol) acetic acid and 1.5 g (19 mmol) ammonium acetate in 90 ml toluene. The mixture was dehydrated and refluxed for an hour. After cooling, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and aqueous NaCl. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 80 ml of methanol, 8.8 g (276 mmol) of sulfur and 7.4 ml (85 mmol) of morpholine were added and heated to reflux for 6 hours. The reaction solution was cooled and then filtered, and the filtrate was concentrated. The obtained residue is diluted with ethyl acetate, washed with water and aqueous NaCl solution, dried over magnesium sulfate, evaporated under reduced pressure, separated and purified by silica gel column chromatography, 2-amino-5-isopropyl- A mixture of methyl methyl 4-methylthiophene-3-carboxylate and methyl 2-amino-4-isobutylthiophene-3-carboxylate was obtained.
[0288] (2)Step 2 [0288] (2) Step 2
4.27gの上記混合物と 0.7ml (5mmol)のアジピン酸クロリドを 20mlの DMA中室温で 15 時間攪拌した。反応混合液を氷水に注入し、次いで炭酸水素ナトリウムを添加して中 和した。得られた混合液に酢酸ェチルを加えて抽出した後、硫酸マグネシウムで乾 燥、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで分離精製し、 ジェチルエーテル Iへキサンで結晶を析出させ濾別した。得られた濾液を濃縮し、 ジェチルエーテルで結晶化することで 0.81gの 2-[5-(3， -カルボキシ -5， -イソプロピル - 4' -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ] -4-イソブチルチオ フェン- 3-カルボン酸ジメチルエステルを得た。  4.27 g of the above mixture and 0.7 ml (5 mmol) of adipic acid chloride were stirred in 20 ml of DMA at room temperature for 15 hours. The reaction mixture was poured into ice water and then neutralized by adding sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The obtained crude product was separated and purified by silica gel column chromatography, crystals were precipitated with jetyl ether I hexane and separated by filtration. The obtained filtrate was concentrated and crystallized with jetyl ether to give 0.81 g of 2- [5- (3, -carboxy-5, -isopropyl-4'-methylthiophene-2, -ylcarbamoyl) -penta Nylamino] -4-isobutylthiophene-3-carboxylic acid dimethyl ester was obtained.
[0289] (3)Step 3 [0289] (3) Step 3
0.3g (0.56mmol)の 2- [5- (3， -カルボキシ- 5， -イソプロピル- 4， -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ] -4-イソブチルチオフェン- 3-カルボン酸ジメ チルエステルをエタノールに溶解し、次いで 2mlの 1N水酸化ナトリウムをカ卩えて 60〜 65°Cで 3時間加熱した。反応混合物を濃縮した後、残渣に氷水を加えて酢酸ェチル で洗浄した。次いで、水層に氷冷下で 1N塩酸を加えて減圧濃縮後，残渣に Et 0を  0.3 g (0.56 mmol) of 2- [5- (3, -carboxy-5, -isopropyl-4, -methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carbon The acid dimethyl ester was dissolved in ethanol, then 2 ml of 1N sodium hydroxide was added and heated at 60-65 ° C. for 3 hours. The reaction mixture was concentrated, ice water was added to the residue, and the mixture was washed with ethyl acetate. Next, 1N hydrochloric acid was added to the aqueous layer under ice-cooling, concentrated under reduced pressure, and Et 0 was added to the residue.
2 加えて析出した結晶を濾取し、 Et 0および水で洗浄することにより、掲題の 2-[5-(3' - 2 The precipitated crystals were collected by filtration and washed with Et 0 and water to give the title 2- [5- (3 '-
2 2
カルボキシ -5， -イソプロピル- 4， -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -4-イソブチルチオフェン- 3-カルボン酸（ィ匕合物 w)を得た（収率 47%)。 m.p.： 190-192°C(dec.) Carboxy-5, -isopropyl-4, -methylthiophene-2, -ylcarbamoyl) -pentanoy Lumino] -4-isobutylthiophene-3-carboxylic acid (compound w) was obtained (yield 47%). mp: 190-192 ° C (dec.)
1H-NMR (DMSO-d6) δ 0.84(6H, d, J=6.6Hz), 1.20(6H, d, J=6.8Hz), 1.15- 1.70(1H , m), 1.70-1.90(1H, m), 2.22(3H, s), 2.40-2.60(6H, m), 3.25(1H, septet, J=6.6Hz), 6.59(1H, s), 11.2(lH,s), 11.3(1H, s)。  1H-NMR (DMSO-d6) δ 0.84 (6H, d, J = 6.6Hz), 1.20 (6H, d, J = 6.8Hz), 1.15- 1.70 (1H, m), 1.70-1.90 (1H, m) , 2.22 (3H, s), 2.40-2.60 (6H, m), 3.25 (1H, septet, J = 6.6Hz), 6.59 (1H, s), 11.2 (lH, s), 11.3 (1H, s).
[0290] 製造例 14  [0290] Production Example 14
2-Γ3-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2 ' -ィルカルバモイル)-プロパノィル ァミノ 1-4-イソブチルチオフェン- 3-カルボン酸 (化合物 X)の製造  Preparation of 2-Γ3- (3'-carboxy-4'-isobutylthiophene-2'-ylcarbamoyl) -propanoylamino 1-4-isobutylthiophene-3-carboxylic acid (compound X)
後述する Step 1〜2に従って、下式に示す、掲題の化合物 Xを合成した。  According to Steps 1 and 2 described later, the title compound X shown in the following formula was synthesized.
[0291] [化 82] [0291] [Chemical 82]
Figure imgf000055_0001
Figure imgf000055_0001
[0292] (l)Step 1 [0292] (l) Step 1
0.17ml(1.5mmol)のこはく酸クロリドおよび 640mg (3mol)の 2-ァミノ- 4-イソブチルチオ フェン- 3-カルボン酸メチルエステルの混合物を 6mlの DMA中室温で 18時間攪拌した 。反応混合液を氷水に注入し、炭酸水素ナトリウムを添加してアルカリィ匕した。沈殿 物を濾別し、水、 IPEで洗浄した後乾燥して、 646mgの 2-[3-(3' -カルボキシ- 4' -イソ ブチルチオフェン- 2 ' -ィルカルバモイル) -プロパノィルァミノ] -4-イソブチルチオフエ ン- 3-カルボン酸ジメチルエステルを得た（収率 84%)。  A mixture of 0.17 ml (1.5 mmol) succinic chloride and 640 mg (3 mol) 2-amino-4-isobutylthiophene-3-carboxylic acid methyl ester was stirred in 6 ml DMA at room temperature for 18 hours. The reaction mixture was poured into ice water and alkalized by adding sodium bicarbonate. The precipitate was filtered off, washed with water, IPE and dried to give 646 mg of 2- [3- (3'-carboxy-4'-isobutylthiophene-2'-ylcarbamoyl) -propanoylamino] -4-Isobutylthiophene-3-carboxylic acid dimethyl ester was obtained (yield 84%).
[0293] (2)Step 2 [0293] (2) Step 2
610mg (1.2mmol)の 2-[3-(3， -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバ モイル)-プロパノィルァミノ] -4-イソブチルチオフェン- 3-カルボン酸ジメチルエステ ルを THFに溶解し、次いで、 1N水酸ィ匕ナトリウム水溶液をカ卩えて 50〜60°Cで 6時間 攪拌した。冷却後 THFを減圧留去した。残渣を濾取して水及び酢酸ェチルで洗浄し た。得られた残渣を水に懸濁して 1N塩酸をカ卩えて酢酸ェチル -THFで抽出し、有機 層を NaCl水溶液で洗浄後、有機層を無水硫酸マグネシウムで乾燥、濃縮した。得ら れた残渣を濾取しエタノールで再結晶することにより、掲題の 2-[3-(3' -カルボキシ -4 ' -イソプチルチオフェン- 2 ' -ィルカルバモイル)-プロパノィルァミノ] -4-イソブチルチ オフヱン- 3-カルボン酸を得た（収率 26%)。 610 mg (1.2 mmol) of 2- [3- (3, -carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -propanoylamino] -4-isobutylthiophene-3-carboxylic acid dimethyl ester in THF Then, 1N sodium hydroxide aqueous solution was added and stirred at 50 to 60 ° C. for 6 hours. After cooling, THF was distilled off under reduced pressure. The residue was collected by filtration and washed with water and ethyl acetate. The obtained residue was suspended in water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate-THF. The layer was washed with an aqueous NaCl solution, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was filtered and recrystallized from ethanol to give the title 2- [3- (3'-carboxy-4'-isoptylthiophene-2'-ylcarbamoyl) -propanoylamino]- 4-Isobutylthiophene-3-carboxylic acid was obtained (yield 26%).
m.p.： 278-280 °C(dec.)  m.p .: 278-280 ° C (dec.)
1H-NMR (DMSO-d6) δ 0.84(12H, d, J=6.6Hz), 1.81(2H, septet, J=6.8Hz), 2.61(4 H, d, J=6.8Hz), 2.86(4H, s), 6.60(2H, s), 11.3(2H,br)。  1H-NMR (DMSO-d6) δ 0.84 (12H, d, J = 6.6Hz), 1.81 (2H, septet, J = 6.8Hz), 2.61 (4 H, d, J = 6.8Hz), 2.86 (4H, s), 6.60 (2H, s), 11.3 (2H, br).
[0294] 製造例 15 [0294] Production Example 15
2-「5-(3 ' -カルボキシ- 4' -イソプロピルチオフェン- 2 ' -ィルカルバモイル)-ペンタノィ ルァミノ 1-4-イソプロピルオフ ン- 3-カルボン酸（化合物 V)の製诰  Preparation of 2- “5- (3′-carboxy-4′-isopropylthiophene-2′-ylcarbamoyl) -pentanoylamino 1-4-isopropylone-3-carboxylic acid (compound V)
後述する Step 1〜3に従って、下式に示す、掲題の化合物を合成した。  According to Steps 1 to 3 described later, the title compound represented by the following formula was synthesized.
[0295] [化 83]  [0295] [Chemical 83]
Figure imgf000056_0001
Figure imgf000056_0001
[0296] (l)Step 1 [0296] (l) Step 1
15.2g (176mmol) の 3-メチル -2-ブタノン、 24.9g (176mmol)のシァノ酢酸 tert-ブチ ルエステル、 5.7g (176mmol)の硫黄及び 15.4g(176mmol)モルホリンの混合物を 75ml の DMFに加えてアルゴン雰囲気下室温で 15時間攪拌した。その後反応液を 70〜80 °Cで 8時間攪拌した.反応混合液を NaCl水溶液中に注入し，酢酸ェチルで抽出した .次いで有機層を水で洗浄し，溶媒を減圧留去した.得られた粗生成物をシリカゲル カラムクロマトグラフィーで分離精製し 18.3gの 2-ァミノ- 4-イソプロピルチオフェン- 3- カルボン酸 tert-ブチルエステルを得た（収率 43%)。  A mixture of 15.2 g (176 mmol) 3-methyl-2-butanone, 24.9 g (176 mmol) cyanoacetic acid tert-butyl ester, 5.7 g (176 mmol) sulfur and 15.4 g (176 mmol) morpholine is added to 75 ml DMF. The mixture was stirred at room temperature for 15 hours under an argon atmosphere. The reaction mixture was then stirred at 70-80 ° C for 8 hours. The reaction mixture was poured into aqueous NaCl solution and extracted with ethyl acetate. The organic layer was washed with water and the solvent was distilled off under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 18.3 g of 2-amino-4-isopropylthiophene-3-carboxylic acid tert-butyl ester (43% yield).
[0297] (2)Step 2 [0297] (2) Step 2
1.1ml (7.5mmol)のアジピン酸クロリドおよび 3.63g (15mmol)の 2-ァミノ- 4-イソプロピ ルチオフェン- 3-カルボン酸 tert-ブチルエステルの混合物を 20mlの DMA中室温で 1 5時間攪拌した。反応混合液を氷水に注入した。得られた沈殿物を濾取し、水、へキ サンで洗浄して 4.19gの 2-[5-(3， -カルボキシ- 4， -イソプロピルチオフェン- 2， -ィルカ ルバモイル)-ペンタノィルァミノ] -4-イソプロピルォフェン- 3-カルボン酸ジ -tert-ブチ ルエステルを得た (収率 93%)。 A mixture of 1.1 ml (7.5 mmol) adipic acid chloride and 3.63 g (15 mmol) 2-amino-4-isopropylthiophene-3-carboxylic acid tert-butyl ester was stirred in 20 ml DMA at room temperature for 15 hours. The reaction mixture was poured into ice water. The resulting precipitate is collected by filtration, water, 4.19 g of 2- [5- (3, -carboxy-4, -isopropylthiophene-2, -ilcarbamoyl) -pentanoylamino] -4-isopropylophene-3-carboxylic acid di- The tert-butyl ester was obtained (93% yield).
[0298] (3)Step 3 [0298] (3) Step 3
1.2g (2mmol)の 2-[5-(3， -カルボキシ- 4， -イソプロピルチオフェン- 2， -ィルカルバモ ィル) -ペンタノィルァミノ] -4-イソプロピルォフェン- 3-カルボン酸ジ -tert-ブチルエス テルをクロ口ホルムに溶解し、次いで 2mlの TFAをカ卩えて室温で 16時間攪拌した。反 応混合物を濃縮した後、残渣に水を加えて沈殿物を濾取し、水および Et 0で洗浄す  1.2 g (2 mmol) of 2- [5- (3, -carboxy-4, -isopropylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isopropylophene-3-carboxylic acid di-tert -Butyl ester was dissolved in black mouth form, then 2 ml of TFA was added and stirred at room temperature for 16 hours. After concentrating the reaction mixture, water is added to the residue, and the precipitate is collected by filtration and washed with water and Et 0.
2 ることにより、掲題の 2-[5-(3， -カルボキシ- 4' -イソプロピルチオフェン- 2， -ィルカル バモイル)-ペンタノィルァミノ] -4-イソプロピルオフェン- 3-カルボン酸（化合物 X)を得 た（収率 75%)。  2 to the title 2- [5- (3, -carboxy-4'-isopropylthiophene-2, -ilcarbamoyl) -pentanoylamino] -4-isopropylofen-3-carboxylic acid (compound X) (Yield 75%).
m.p.： 247-249°C(dec.)  m.p .: 247-249 ° C (dec.)
JH-NMR (DMSO-d6) δ 1.17(12Η, d, J=6.8Hz), 1.66(4H, m), 2.50-2.60(4H, m), 3. J H-NMR (DMSO-d6) δ 1.17 (12Η, d, J = 6.8Hz), 1.66 (4H, m), 2.50-2.60 (4H, m), 3.
50(2H, septet, J=6.8Hz), 6.68(2H, s), 11.4(2H, s)。 50 (2H, septet, J = 6.8Hz), 6.68 (2H, s), 11.4 (2H, s).
[0299] 製诰例 16および 17 [0299] Ironmaking examples 16 and 17
2-Γ5-(3 ' -カルボキシ -5 ' -メチルチオフェン- 2 ' -ィルカルバモイル)-ペンタノィルアミ ノ 1-5-メチルチオフェン- 3-カルボン酸（化合物 ζ)、および 2-「5-(3， -tert-ブトキシカ ルボニル -5 ' -メチルチオフェン- 2 ' -ィルカルバモイル)-ペンタノィルァミノ] -5-メチル チオフ ン- 3-カルボン酸 (化合物 zz)の製诰  2-Γ5- (3'-carboxy-5'-methylthiophene-2'-ylcarbamoyl) -pentanoylamino 1-5-methylthiophene-3-carboxylic acid (compound ζ), and 2- "5- (3, -tert-butoxycarbonyl-5'-methylthiophene-2'-ylcarbamoyl) -pentanoylamino] -5-methylthiophene-3-carboxylic acid (compound zz)
後述する Step 1〜3に従って、下式に示す、掲題の化合物 zを合成し、次いで Step 4 により、掲題の化合物 zzを合成した。  The title compound z shown in the following formula was synthesized according to Steps 1 to 3 described later, and then the title compound zz was synthesized according to Step 4.
[0300] [化 84] [0300] [Chemical 84]
Figure imgf000058_0001
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0002
[0301] (l)Step 1 [0301] (l) Step 1
5.8g (99.9mmol) のプロピオンアルデヒド、 14. lg (176mmol)のシァノ酢酸 tert-ブチ ルエステル、 59mg(0.68mmol)のモルホリン、 41mg (0.68mmol)の酢酸およびモレキュ ラシーブ 4Aの混合溶液をトルエン中で 3日間攪拌した。その後、反応溶液をろ過し、 水で洗浄後に硫酸マグネシウムで乾燥後溶媒を減圧濃縮した。得られた残渣と 3.2g (99.9mmol)の硫黄及び 8.7g (99.9mmol)モルホリンの混合物を 100mlの DMFに加えて 一晩攪拌した。反応混合液を水に注入し，酢酸ェチルで抽出した.次いで有機層を 硫酸マグネシウムで乾燥し，溶媒を減圧留去した.得られた粗生成物をシリカゲル力 ラムクロマトグラフィーで分離精製して 4.93gの 2-ァミノ- 4-メチルチオフェン- 3-カル ボン酸 tert-ブチルエステルを得た（収率 23%)。  A mixed solution of 5.8 g (99.9 mmol) propionaldehyde, 14. lg (176 mmol) cyanoacetic acid tert-butyl ester, 59 mg (0.68 mmol) morpholine, 41 mg (0.68 mmol) acetic acid and molecular sieve 4A in toluene. Stir for 3 days. Thereafter, the reaction solution was filtered, washed with water, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. A mixture of the obtained residue, 3.2 g (99.9 mmol) of sulfur and 8.7 g (99.9 mmol) of morpholine was added to 100 ml of DMF and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified by silica gel chromatography. g of 2-amino-4-methylthiophene-3-carboxylic acid tert-butyl ester was obtained (yield 23%).
[0302] (2)Step 2 [0302] (2) Step 2
0.47g (2.58mmol)のアジピン酸クロリドおよび l.Og (4.69mmol)の 2-ァミノ- 4-メチル チォフェン- 3-カルボン酸ジ -tert-ブチルエステルの混合物を 10mlの DMA中室温で 3時間攪拌した。反応混合液を氷水に注入し、次いで炭酸水素ナトリウムを加えてァ ルカリ化した。得られた沈殿物を濾取し、酢酸ェチル /THF/へキサンで再結晶して 0. 96gの 2-[5-(3， -カルボキシ -5， -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -5-メチルチオフェン- 3-カルボン酸ジ -tert-ブチルエステルを得た (収率 77 %)。  Stir a mixture of 0.47 g (2.58 mmol) adipic acid chloride and l.Og (4.69 mmol) 2-amino-4-methylthiophene-3-carboxylic acid di-tert-butyl ester in 10 ml DMA at room temperature for 3 hours did. The reaction mixture was poured into ice water and then alkalized with sodium bicarbonate. The resulting precipitate was collected by filtration and recrystallized with ethyl acetate / THF / hexane to give 0.96 g of 2- [5- (3, -carboxy-5, -methylthiophene-2, -ylcarbamoyl)- Pentanoylamino] -5-methylthiophene-3-carboxylic acid di-tert-butyl ester was obtained (yield 77%).
[0303] (3)Step 3  [0303] (3) Step 3
0.96g (1.8mmol)の 2- [5- (3， -カルボキシ- 5， -メチルチオフェン- 2， -ィルカルバモイ ル)-ペンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸ジ -tert-ブチルエステル の塩化メチレンに溶解し、次いで 2mlの TFAをカ卩えて室温で 3時間攪拌した。反応混 合物を濃縮した後、残渣にへキサンを加えて濾過し、 IPE、酢酸ェチルで洗浄した。 次 、で THF/へキサンで再結晶し、掲題の 2-[5-(3， -カルボキシ -5， -メチルチオフエ ン -2， -ィルカルバモイル)-ペンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸（ィ匕 合物 z)を得た (収率 75%)。 0.96 g (1.8 mmol) of 2- [5- (3, -carboxy-5, -methylthiophene-2, -ylcarbamoy (L) -pentanoylamino] -5-methylthiophene-3-carboxylic acid di-tert-butyl ester was dissolved in methylene chloride, and 2 ml of TFA was added thereto and stirred at room temperature for 3 hours. After the reaction mixture was concentrated, hexane was added to the residue and filtered, and washed with IPE and ethyl acetate. Next, recrystallized with THF / hexane, and the title 2- [5- (3, -carboxy-5, -methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-methylthiophene- 3-carboxylic acid (compound z) was obtained (yield 75%).
m.p.： 260-262°C(dec.)  m.p .: 260-262 ° C (dec.)
JH-NMR (DMSO-d6) δ 1.59-1.75(4Η, m), 2.32(6Η, d, J=1.2Hz), 2.50- 2.61(4H, m ), 6.82(2H, d, J=1.2Hz), 10.9(2H, s), 13.0(2H, br)。 J H-NMR (DMSO-d6) δ 1.59-1.75 (4Η, m), 2.32 (6Η, d, J = 1.2Hz), 2.50- 2.61 (4H, m), 6.82 (2H, d, J = 1.2Hz ), 10.9 (2H, s), 13.0 (2H, br).
[0304] (4)Step 4 [0304] (4) Step 4
次いで、上記濾液および洗浄液を全て合わせて減圧濃縮し、得られた粗生成物を シリカゲルカラムクロマトグラフィーで分離精製することにより、掲題の 2-[5-(3，-tert- ブトキシカルボ-ル -5， -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸（化合物 zz)を得た（収率 16%)。  Next, all of the filtrate and washing solution were combined and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to give the title 2- [5- (3, -tert-butoxycarbol- 5,5-Methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-methylthiophene-3-carboxylic acid (compound zz) was obtained (yield 16%).
m.p.： 175-177 °C  m.p .: 175-177 ° C
'H-NMR (DMSO-d6) δ： 1.54(9Η, s), 1.60— 1.71(4Η, m), 2.30- 2.33(6Η, m), 2.49-2. 63(4Η, m), 6.78(1Η, d, J=1.3Hz), 6.82(1H, d, J=1.3Hz), 10.7(1H, s), 11.4(1H, br)。  'H-NMR (DMSO-d6) δ: 1.54 (9Η, s), 1.60—1.71 (4Η, m), 2.30- 2.33 (6Η, m), 2.49-2. 63 (4Η, m), 6.78 (1Η , d, J = 1.3Hz), 6.82 (1H, d, J = 1.3Hz), 10.7 (1H, s), 11.4 (1H, br).
[0305] 実験例 1 化合物 aおよび bの PAI— 1阻害活性の測定 [0305] Experimental Example 1 Measurement of PAI-1 inhibitory activity of compounds a and b
ヒト PAI— 1 (Molecular Innovations Inc.製（米国)、以下同じ）に対する化合物 aおよ び b (被験化合物)の阻害作用を評価した。具体的には、上記各被験化合物を各種 の濃度（20、 35、 50および 100 M)で含む、 0.1% Tween80含有 lOOmM Tris- HC1 ( pH8)溶液にヒト由来の PAI— 1を入れて、 37°Cで 15分間インキュベートした。次いで これに 0.53 pmol/ Lに調整したヒト由来糸且織プラスミノーゲンァクチべ一ター（t—P A) (American Diagnostica, Inc.製 (米国)、以下同じ）を入れて、引き続き 37°Cで 15分 間インキュベートした。続いて、これに発色性基質である 1.25mMの S-2288合成基質（ Chromogenix社製 (イタリア）、以下同じ）を添カ卩した。最終混合液は、 lOOmM Tris- H Cl (pH8)、 30mM NaCl、 1% DMSO、 0.1% Tween80、 67nM PAト 1、 9.8nM t— PAゝ lm M S-2288および各被験化合物 aまたは b (20、 35、 50または 100 M)を含んでいる。 [0306] t PAの作用によって発色性基質 (S-2288)から切断されて遊離した P 二トロア二 リドを、分光光度計を用いて吸光度 405nmで 5分毎、 30分間測定した。被験化合物を 配合しな 、系につ ヽても同様に試験し、この系（コントロール系）の 30分後の PAI— 1 活性を 100%として、各被験化合物を添加した場合の PAI— 1活性を評価した。 The inhibitory action of compounds a and b (test compound) on human PAI-1 (Molecular Innovations Inc. (USA), the same applies hereinafter) was evaluated. Specifically, human-derived PAI-1 was added to a lOOmM Tris-HC1 (pH8) solution containing 0.1% Tween80 containing each of the above test compounds at various concentrations (20, 35, 50 and 100 M). Incubated for 15 minutes at ° C. Next, human-derived yarn and weave plasminogen activator (t—PA) (American Diagnostica, Inc. (USA), the same applies hereinafter) adjusted to 0.53 pmol / L was added and continued at 37 ° C. Incubated for 15 min. Subsequently, a 1.25 mM S-2288 synthetic substrate (Chromogenix (Italy), the same applies hereinafter) as a chromogenic substrate was added thereto. The final mixture was lOOmM Tris-HCl (pH 8), 30 mM NaCl, 1% DMSO, 0.1% Tween 80, 67 nM PA to 1, 9.8 nM t—PA ゝ lm M S-2288 and each test compound a or b (20 35, 50 or 100 M). [0306] P 2 troanilide cleaved from the chromogenic substrate (S-2288) by the action of tPA was measured at an absorbance of 405 nm every 5 minutes for 30 minutes using a spectrophotometer. The same test was conducted for the system without the test compound, and the PAI-1 activity after 30 minutes of this system (control system) was taken as 100%, and the PAI-1 activity when each test compound was added. Evaluated.
[0307] 比較試験として、上記被験化合物に代えて抗血栓薬として米国で臨床試験に導入 されている下式の化合物（tiplaxtinin) (但し、濃度 20、 35、 50 M)についても同様に 試験を行った。  [0307] As a comparative test, a similar test was conducted for the compound of the following formula (tiplaxtinin) (concentrations of 20, 35, and 50 M) introduced in clinical trials in the United States as an antithrombotic agent instead of the above-mentioned test compound. went.
[0308] [化 85]  [0308] [Chemical 85]
Figure imgf000060_0001
Figure imgf000060_0001
[0309] 結果を図 4 (A)〜（C)に示す。図 4 (A)、（B)および (C)は、それぞれ化合物 a〔2-[ 3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモイル)-ペンタノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸〕（濃度 20、 35、 50、 100 μ Μ)、化合物 b〔2- [3-( 3'-カルボキシ- 4'-チェ-ルチオフェン- 2しィルカルバモイル)-ペンタノィルァミノ]- 4 -チェ-ルチオフェン- 3-カルボン酸〕（濃度 20、 35、 50、 100 M)、および tiplaxtinin ( 比較化合物）（濃度 20、 35、 M)を添加した場合の PAI—1活性（％)を示す。こ の結果、 35 μ Μおよび 50 μ Μの濃度において、化合物 aおよび bのほうが、 tiplaxtinin (比較ィ匕合物)よりも強ぐ PAI— 1活性を抑制することがゎカゝつた (PAI— 1阻害活性The results are shown in FIGS. 4 (A) to (C). Fig. 4 (A), (B) and (C) are the compounds a [2- [3- (3'-carboxy-4'-phenolthiophene-2-silylcarbamoyl) -pentanoylamino]- 4-phenylthiophene-3-carboxylic acid] (concentration 20, 35, 50, 100 μΜ), compound b [2- [3- (3'-carboxy-4'-cherthiophene-2 Rucarbamoyl) -pentanoylamino] -4-chelthiophene-3-carboxylic acid] (concentration 20, 35, 50, 100 M), and tiplaxtinin (comparative compound) (concentration 20, 35, M) were added. Shows PAI-1 activity (%). As a result, at concentrations of 35 μ を and 50 μΜ, compounds a and b were found to inhibit PAI-1 activity, which was stronger than tiplaxtinin (comparative compound) (PAI— 1 Inhibitory activity
) o ) o
[0310] 実験例 2 PAI— 1と t PAとの複合体形成阻害作用  [0310] Experimental Example 2 Inhibition of complex formation between PAI-1 and tPA
各被験化合物（化合物 aおよび b)について、 PAI—1と t— PAとの複合体 (ΡΑΙ-1/t -PA複合体)形成阻害活性をウェスタンブロッテイング法により試験した。  Each test compound (compounds a and b) was tested for the inhibitory activity of PAI-1 and t-PA complex formation (—-1 / t-PA complex) by Western blotting.
[0311] 具体的には、 6.7pmol/ μ Lに調整した PAI— 1溶液と、各被験化合物をモル比で 1 500倍となるように、 0.1% Tween80を含む 20mM Tris-HCl (pH7.8)中で混合して 37 °Cで 15分間インキュベーションした。反応液を 10000カットフィルター（ミリポア）を用い て被験化合物を除去した後、 1.4pmolZ w Lに調整した t PAを添加して 37°Cで 15分 間反応させた。 [0311] Specifically, a PAI-1 solution adjusted to 6.7 pmol / μL and 20 mM Tris-HCl (pH 7.8) containing 0.1% Tween 80 so that each test compound is 1500 times in molar ratio. ) And incubated at 37 ° C for 15 minutes. Use 10000 cut filter (Millipore) for the reaction solution After removing the test compound, tPA adjusted to 1.4 pmolZ w L was added and reacted at 37 ° C for 15 minutes.
[0312] これを SDS ポリアクリルアミド電気泳動にかけ、ウェスタンブロッテイングを行った 。具体的には、反応溶液を PBSでタンパク量が 0.3 g/レーンとなるように調製し、 lo ading buffer (第一化学薬品製）と混合し、 100°Cで 5分間加熱したものをサンプル溶液 とした。当該サンプル溶液を電気泳動装置 (第一化学薬品製)およびトリスーグリシン 緩衝液 (第一化学薬品製)を用いて 4〜20%ポリアクリルアミドゲル (第一化学薬品製 )で電気泳動を行った。電気泳動終了後、ウェスタンブロッテイングを行った。具体的 には、電気泳動したタンパク質をポリビ-リデンジフルオライド膜 (PVDF膜、 Biorad製 )に転写（100Vで 1時間）し、その後、 PVDF膜をブロックエース（雪印乳業)で室温 2 時間振とうしてブロッキングした。その後、 1000倍希釈した t— PA抗体（Cedarlane La boratories Ltd.製（カナダ)）と 4°Cでー晚反応させた。その後、アルカリフォスファタ一 ゼ標識ヒッジ IgG抗体を加え、室温で 1時間反応後、 NBT— BCIP溶液で発色させ た。  [0312] This was subjected to SDS polyacrylamide electrophoresis, and Western blotting was performed. Specifically, the reaction solution was prepared with PBS so that the protein amount was 0.3 g / lane, mixed with loding buffer (Daiichi Chemical), and heated at 100 ° C for 5 minutes. It was. The sample solution was electrophoresed on a 4-20% polyacrylamide gel (Daiichi Chemical) using an electrophoresis apparatus (Daiichi Chemical) and tris-glycine buffer (Daiichi Chemical). . After the completion of electrophoresis, Western blotting was performed. Specifically, the electrophoresed protein is transferred to a polyvinylidene difluoride membrane (PVDF membrane, manufactured by Biorad) (100V for 1 hour), and then the PVDF membrane is shaken with Block Ace (Snow Brand Milk Products) for 2 hours at room temperature. Finally, it blocked. Thereafter, the mixture was reacted with a 1000-fold diluted t-PA antibody (Cedarlane Laboratories Ltd. (Canada)) at 4 ° C. Thereafter, alkaline phosphatase labeled Hedge IgG antibody was added, reacted for 1 hour at room temperature, and then developed with NBT-BCIP solution.
[0313] 結果を図 5に示す。図 5中、レーン 1は t—PAの電気泳動像、レーン 2および 3は被 験化合物としてそれぞれィ匕合物 aおよび bを用いた場合のサンプル溶液の電気泳動 像、レーン 4は被験化合物 (ィ匕合物 a、 b)を使用しないで PAI 1と t PAを反応させ たサンプル溶液の電気泳動像をそれぞれ示す。  [0313] The results are shown in FIG. In Fig. 5, lane 1 is an electrophoretic image of t-PA, lanes 2 and 3 are electrophoretic images of sample solutions when compounds a and b are used as test compounds, respectively, and lane 4 is a test compound ( Electrophoretic images of sample solutions obtained by reacting PAI 1 and tPA without using compounds a and b) are shown.
[0314] この結果からわかるように、化合物 a〔2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2'-ィルカルバモイル)-ペンタノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸〕お よび化合物 b〔2-[3-(3，-カルボキシ -4し (2-チェ-ル)チォフェン- 2しィルカルバモイ ル)-ペンタノィルァミノ] -4-(2 チェ-ル)チォフェン- 3-カルボン酸〕は、ともに PAI 1と t PAとの複合体の形成を阻害した。  [0314] As can be seen from the results, the compound a [2- [3- (3'-carboxy-4'-phenylthiophene-2'-ylcarbamoyl) -pentanoylamino] -4-phenol Thiophene-3-carboxylic acid] and compound b [2- [3- (3, -carboxy -4 (2-cell) thiophene-2 ylcarbamoyl) -pentanoylamino] -4- (2 (Chel) thiophene-3-carboxylic acid] both inhibited the formation of a complex of PAI 1 and tPA.
[0315] 実験例 3 線維素溶解作用の評価  [0315] Experimental Example 3 Evaluation of fibrinolytic activity
各被験化合物 (化合物 aおよび b)の線維素溶解作用を、松尾らの文献 (Matsuo, 0. et al.， Haemostasis 16, 43-50 (1986))に従って評価した。  The fibrinolytic activity of each test compound (compounds a and b) was evaluated according to Matsuo et al. (Matsuo, 0. et al., Haemostasis 16, 43-50 (1986)).
[0316] 具体的には、 0.2mlの生理食塩水に溶解したトロンビン（10NIH U/ml:持田製薬製） を、 9cmプレート上で、 1.5 mgZmlの割合でフイブリノ一ゲン（Organon Teknica社製） を含む水溶液（25mM バルピタールナトリウム、 50 mM NaCl、および 25 mM CaCl [0316] Specifically, thrombin (10NIH U / ml: manufactured by Mochida Pharmaceutical) dissolved in 0.2 ml of physiological saline was used for fibrinogen (produced by Organon Teknica) at a rate of 1.5 mgZml on a 9 cm plate. Aqueous solution (25 mM sodium valpital, 50 mM NaCl, and 25 mM CaCl
2 含有)を加え、室温で 2時間放置した。これを用いて、線維素溶解アツセィを行った。  2 contained) and left at room temperature for 2 hours. A fibrinolysis assay was performed using this.
[0317] すなわち、上記プレートの上に、 PAI— 1、 t PAおよび各被験化合物の混合物を 滴下し、室温で 18時間インキュベートし、プラスミノーゲン活性ィ匕による線維素溶解を 、プレート上の溶解面積で測定した。なお、 PAI— 1、 t PAおよび各被験化合物の 混合物として、実施例 2と同様に反応させた後、 tPAが 50 NIHZmLになるように調整 したものを用いた。結果を図 6に示す。 [0317] That is, a mixture of PAI-1, tPA and each test compound is dropped on the above plate, incubated at room temperature for 18 hours, and fibrinolysis by plasminogen activity is dissolved on the plate. Measured by area. As a mixture of PAI-1, tPA and each test compound, a mixture prepared by reacting in the same manner as in Example 2 and adjusting tPA to 50 NIHZmL was used. The result is shown in FIG.
[0318] その結果、化合物 a〔2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモ ィル)-ペンタノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸〕および化合物 b [2-[ 3- (3'-カルボキシ- 4'- (2 チェ-ル)チォフェン- 2しィルカルバモイル)-ペンタノィル ァミノ] -4-(2 チェ-ル)チォフェン- 3-カルボン酸〕は、ともに、 PAI— 1による線維素 溶解の抑制を阻害することがわ力つた。 [0318] As a result, compound a [2- [3- (3'-carboxy-4'-phenylthiophene-2-silcarbamoyl) -pentanoylamino] -4-phenolthiophene-3- Carboxylic acid] and Compound b [2- [3- (3'-Carboxy-4 '-(2 chayl) thiophene-2 sylcarbamoyl) -pentanoylamino] -4- (2 chalc) thiophene-3 -Carboxylic acid] both inhibited the inhibition of fibrinolysis by PAI-1.
[0319] 実験例 4 アンチプラスミン (AP)活性に対する被験化合物の阻害作用の検討 アンチプラスミン (AP)活性に対する各被験化合物の阻害作用を評価した。  Experimental Example 4 Examination of inhibitory action of test compound on antiplasmin (AP) activity The inhibitory action of each test compound on antiplasmin (AP) activity was evaluated.
[0320] 具体的には、 0.2 pmolZ μ Lに調整した AP (Sigma-Aldrich Co.製）に各被験化合 物をモル比で 6000〜60000倍に相当する過剰量添加し、 0.1% Tween80を含む 20 m M Tris-HCl (pH7.8)中で 37°C、 15分間インキュベーションした。その後、 0.2 pmol/ μ Lに調整したプラスミンと 37°Cで 15分間反応させた。つづいて、 1.25 mMプラスミン 合成基質 (ペプチド研究所、 日本)を添加し、プラスミンの切断作用によって上記基 質から遊離する AMC (7-ァミノ 4 メチルクマリン）を蛍光波長 380nm、励起波長 460應で 5分毎、 30分間測定した。対照試験として、上記被験化合物を配合しない系 についても同様に試験を行い、この反応 30分後の AP活性を 100%として、各被験化 合物の AP阻害作用を評価した。  [0320] Specifically, each test compound was added in an excess amount corresponding to 6000 to 60000 times in molar ratio to AP (Sigma-Aldrich Co.) adjusted to 0.2 pmolZ μL, and 0.1% Tween80 was included. Incubation was carried out in 20 mM Tris-HCl (pH 7.8) at 37 ° C for 15 minutes. Thereafter, the mixture was reacted with plasmin adjusted to 0.2 pmol / μL at 37 ° C for 15 minutes. Subsequently, 1.25 mM plasmin synthetic substrate (Peptide Laboratories, Japan) was added, and AMC (7-amino-4-methylcoumarin) released from the above substrate by plasmin cleaving action was detected at a fluorescence wavelength of 380 nm and an excitation wavelength of 460. Measured every minute for 30 minutes. As a control test, the same test was performed on a system not containing the test compound, and the AP inhibitory effect of each test compound was evaluated with the AP activity 30 minutes after the reaction as 100%.
[0321] 化合物 a〔2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモイル)-ぺ ンタノィルァミノ] -4-フエ二ルチオフェン- 3-カルボン酸〕に関する結果を図 7 (A)に、 化合物 b〔2- [3- (3 '-カルボキシ- 4'- (2 チェ-ル)チォフェン- 2しィルカルバモイル) - ペンタノィルァミノ] -4-(2 チェニル)チォフェン- 3-カルボン酸〕に関する結果を図 7 ( B)に示す。この結果、化合物 aおよび bは、いずれも AP活性を阻害しなカゝつた。この 結果から、化合物 aおよび bは、 PAI— 1活性とは異なるセリンプロテーゼには作用せ ず、 PAI— 1活性に対して特異的に作用することが確認できた。 [0321] Results for Compound a [2- [3- (3'-Carboxy-4'-phenylthiophene-2-silylcarbamoyl) -pentanoylamino] -4-phenylthiophene-3-carboxylic acid] Fig. 7 (A) shows compound b [2- [3- (3'-carboxy-4 '-(2 cheyl) thiophene-2sylcarbamoyl) -pentanoylamino] -4- (2 chenyl) The results for [thiophene-3-carboxylic acid] are shown in FIG. 7 (B). As a result, both compounds a and b did not inhibit AP activity. this From the results, it was confirmed that compounds a and b did not act on a serine prosthesis different from PAI-1 activity but acted specifically on PAI-1 activity.
[0322] 実験例 5 プラスミンとアンチプラスミンの複合体形成阻害の検討  [0322] Experimental Example 5 Inhibition of plasmin and antiplasmin complex formation
アンチプラスミン (AP)活性に対する化合物 bの阻害作用を評価した。  The inhibitory effect of compound b on antiplasmin (AP) activity was evaluated.
[0323] 具体的には、 7.5 pmolZ μ Lに調整した AP溶液と 1 mMの〔2- [3- (3'-カルボキシ- 4' -(2 チェ-ル)チォフェン- 2しィルカルバモイル)-ペンタノィルァミノ] -4-(2 チェ- ル)チォフェン- 3_カルボン酸（化合物 b)をモル比で 3,000倍または 15,000倍となるよう に添加し、 0.1% Tween80を含む 20 mM Tris— HCl (pH7.8)中で 37°C、 15分間インキ ュベーシヨンした。同様に 6.7 pmolZ Uこ調整した PAI—1溶液と ImMの化合物 bを モル比で 3,000倍または 15,000倍になるように混合した。反応液から 10,000カットフィ ルター（ミリポア）を用いて化合物 bを除去した後、 12.6pmolZ Uこ調整したプラスミ ンを添加して 37°Cで 15分間反応させた。  [0323] Specifically, an AP solution adjusted to 7.5 pmolZ μL and 1 mM [2- [3- (3'-carboxy-4 '-(2 cheyl) thiophene-2-silcarbamoyl)- [Pentanoylamino] -4- (2 cell) thiophene-3_carboxylic acid (compound b) is added at a molar ratio of 3,000-fold or 15,000-fold, and 20 mM Tris—HCl containing 0.1% Tween80 Incubation was carried out at 37 ° C for 15 minutes in (pH 7.8). Similarly, 6.7 pmolZ U of the adjusted PAI-1 solution and ImM compound b were mixed at a molar ratio of 3,000 times or 15,000 times. Compound b was removed from the reaction solution using a 10,000 cut filter (Millipore), 12.6 pmolZU of plasmin was added, and the mixture was reacted at 37 ° C for 15 minutes.
[0324] 反応溶液を loading buffer (第一化学薬品製）と混合し、 100°Cで 5分間加熱したもの をサンプル溶液とした。当該サンプル溶液を電気泳動装置 (第一化学薬品製)およ びトリス—グリシン緩衝液 (第一化学薬品製)を用いて 4〜20%ポリアクリルアミドゲル ( 第一化学薬品製)で電気泳動した。電気泳動終了後、通常の染色法 (クーマシー 'ブ リリアント 'ブルー）でバンドを検出した。結果を図 8に示す。図 8中、レーン 1〜3はそ れぞれプラスミン（Plasmin)、アンチプラスミン (AP)、および PAI— 1の電気泳動像、 レーン 4は化合物 bを使用しないでプラスミンとアンチプラスミンを反応させたサンプ ル溶液の電気泳動像、レーン 5および 6は化合物 bをそれぞれ 3,000倍および 15,000 倍のモル比で使用してプラスミンとアンチプラスミンを反応させたサンプル溶液の電 気泳動像、レーン 7は化合物 bを使用しないでプラスミンと PAI— 1を反応させたサン プル溶液の電気泳動像、レーン 8および 9は化合物 bをそれぞれ 3,000倍および 15,00 0倍のモル比で使用してプラスミンと PAI— 1を反応させたサンプル溶液の電気泳動 像を、それぞれ示す。  [0324] The reaction solution was mixed with loading buffer (Daiichi Kagaku) and heated at 100 ° C for 5 minutes to obtain a sample solution. The sample solution was electrophoresed on a 4-20% polyacrylamide gel (Daiichi Chemical) using an electrophoresis apparatus (Daiichi Chemical) and Tris-Glycine buffer (Daiichi Chemical). . After the electrophoresis, the band was detected by the usual staining method (Coomassie 'Brilliant' Blue). The results are shown in FIG. In Fig. 8, lanes 1 to 3 are electrophoresis images of plasmin, antiplasmin (AP), and PAI-1, respectively, and lane 4 is a reaction of plasmin and antiplasmin without using compound b. Electrophoresis image of sample solution, lanes 5 and 6 are electrophoretic images of sample solution obtained by reacting plasmin and antiplasmin using compound b in molar ratios of 3,000 and 15,000 times, respectively, and lane 7 is compound b. Electrophorograms of sample solutions of plasmin and PAI-1 reaction without using lanes, lanes 8 and 9 are plasmin and PAI-1 using compound b in molar ratios of 3,000 and 15,00 0 respectively. Electrophoresis images of the sample solutions reacted with are shown respectively.
[0325] 図 8に示すように、 2- [3- (3'-カルボキシ- 4'- (2 チェ-ル)チォフェン- 2しィルカル バモイル)-ペンタノィルァミノ] -4-(2 チェ-ル)チォフェン- 3-カルボン酸（化合物 b) は、モル比 3,000倍でプラスミンと PAI— 1との複合体形成を阻害した。一方、プラスミ ンと APとの複合体形成に対してはモル比 3,000倍および 15,000倍では阻害しなかつ た。 [0325] As shown in Fig. 8, 2- [3- (3'-Carboxy-4 '-(2 cell) thiophene-2 silylcarbamoyl) -pentanoylamino] -4- (2 cell- Lu) thiophene-3-carboxylic acid (compound b) inhibited the complex formation of plasmin and PAI-1 at a molar ratio of 3,000 times. On the other hand, It did not inhibit the complex formation between AP and AP at molar ratios of 3,000 and 15,000.
[0326] 実験例 6  [0326] Experimental Example 6
(1)上記化合物 a〔2- [3- (3'-カルボキシ- 4'-フエ-ルチオフェン- 2しィルカルバモイ ル)-ペンタノィルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸〕および化合物 b [2-[3 -(3'-カルボキシ- 4'- (2—チェ-ル)チォフェン- 2しィルカルバモイル)-ペンタノィル ァミノ] -4-(2—チェニル)チォフェン- 3-カルボン酸〕、ならび表 1に示すィ匕合物 c〜lに ついて、実験例 1に記載する方法に従って、ヒト PAI— 1に対する阻害活性を調べた 。被験化合物を配合しない系についても同様に試験し、この系の 30分後の PAI—1 活性を 100%として、各被験化合物 (化合物 c〜l、濃度 20、 35、および 50 M)を添加 した場合の PAI— 1活性を評価した。  (1) The above compound a [2- [3- (3′-carboxy-4′-phenylthiophene-2-silcarbamoyl) -pentanoylamino] -4-phenolthiophene-3-carboxylic acid] And compound b [2- [3- (3′-carboxy-4 ′-(2-Chel) thiophene-2-silylcarbamoyl) -pentanoylamino] -4- (2-Cenyl) thiophene-3-carboxylic acid Then, for the compounds c to l shown in Table 1, the inhibitory activity against human PAI-1 was examined according to the method described in Experimental Example 1. The same test was performed on the system not containing the test compound, and each test compound (compound c to l, concentrations 20, 35, and 50 M) was added with the PAI-1 activity 30 minutes after this system as 100%. Cases were evaluated for PAI-1 activity.
[0327] なお、これらの化合物 a〜lは、 Ambinter社 (46 quai Louis Bleriot Paris, F- 75016 [0327] These compounds a to l are manufactured by Ambinter (46 quai Louis Bleriot Paris, F- 75016
France： http://www.ambinter.com.)
Figure imgf000064_0001
(213 Avenue Kennedy BP 1140 M ontlucon, Cedex, 03103 France: http://WWW.interchim.com.)、 Enamine社 (I.Kudri str.41 Apt. 29 Kiev 042, 01042 Ukraine: http://www.enamie.relc.com)ゝ SPEC and BioSPECS社（Fleminglaan 16 CP Rijswijk, 2289 Netherlands: http://www.specs.net) の化合物ライブラリ一力 入手した。 (France: http://www.ambinter.com.)
Figure imgf000064_0001
(213 Avenue Kennedy BP 1140 Montlucon, Cedex, 03103 France: http://WWW.interchim.com.), Enamine (I.Kudri str. 41 Apt. 29 Kiev 042, 01042 Ukraine: http: // www. enamie.relc.com) ゝ SPEC and BioSPECS (Fleminglaan 16 CP Rijswijk, 2289 Netherlands: http://www.specs.net).
[0328] 結果を表 1に合わせて示す。  [0328] The results are shown in Table 1.
[0329] [表 1] [0329] [Table 1]
Figure imgf000065_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000066_0001
〔s033 [0331] この結果から、化合物 a〜lはいずれも PAI— 1活性に対して阻害作用を有しているこ とがわかる。中でも化合物 a、 b、 dおよび e、特に化合物 dは優れた阻害活性を有して いる。 [S033 [0331] From these results, it can be seen that all of the compounds a to l have an inhibitory effect on the PAI-1 activity. Of these, compounds a, b, d and e, particularly compound d, have excellent inhibitory activity.
(2)調製例 5〜 14で調製したィ匕合物。〜 Xにつ 、ても、実験例 1に記載する方法に従 つて、ヒト PAI— 1に対する阻害活性を調べた。上記と同様に、被験化合物を配合し ない系の 30分後の PAI— 1活性を 100%として、各化合物 o〜x (濃度 40、 50および 10 0 M)を添カ卩した場合の PAI— 1活性を評価した。  (2) Compound prepared in Preparation Examples 5-14. For X, the inhibitory activity against human PAI-1 was examined according to the method described in Experimental Example 1. In the same manner as above, PAI after 30 minutes of the system not containing the test compound—when the activity of each compound o to x (concentrations of 40, 50 and 100 M) is taken as 100% and PAI— 1 activity was evaluated.
[0332] 結果を表 2に示す。  [0332] The results are shown in Table 2.
[0333] [表 2] [0333] [Table 2]
Figure imgf000068_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000069_0001
[0335] この結果から、化合物 o xはいずれも PAI— 1活性に対して阻害作用を有している ことがわかる。中でも化合物 s t v r qおよび w、特に化合物 s t vおよび rは高い 阻害活性を有している。 [0335] From these results, it can be seen that all of the compounds ox have an inhibitory action on PAI-1 activity. Among them, the compounds stv r q and w, especially the compounds st v r and r have high inhibitory activity.
[0336] 験例 7 ブレオマイシン誘導肺線維症に対する効果の評価 本発明の化合物（1)の、生体内での抗線維作用を評価するため、ブレオマイシン で人為的に肺線維症を誘導したモデル動物（マウス）を用いて以下の実験を行った。 [0336] Example 7: Evaluation of effects on bleomycin-induced pulmonary fibrosis In order to evaluate the anti-fibrotic effect of the compound (1) of the present invention in vivo, the following experiment was conducted using a model animal (mouse) in which pulmonary fibrosis was artificially induced with bleomycin.
[0337] まず、 C57BL/6マウス（雄、体重 19-21g)にペントバルビタールを腹腔内投与して麻 酔をかけ、頸部の器官を切開した。コントロールに 10匹のマウスを使用した。コント口 ール用のマウス（n=10)には、 14日間に亘つて、 1日〖こ 2回、生理食塩水に溶解したブ レオマイシン（日本ィ匕薬製）（1.5U/kg)を気管内投与した。一方、被験対象マウスに は、 14日間に亘つて、 1日に 2回、上記の気管内投与に加えて、 0.5%のカルボキシメ チルセルロース水溶液に懸濁させた化合物 b (2- [3- (3'-カルボキシ- 4'-チェ-ルチ ォフェン- 2しィルカルバモイル)-ペンタノィルァミノ] -4-チェ二ルチオフェン- 3-カル ボン酸）（200 mg/kg)を強制経口投与した。次いで、これらのコントロールマウスおよ び被験マウスの肺組織を組織分析にかけ、またヒドロキシプロリン量を測定した。なお 、肺組織のヒドロキシプロリン量は、 Kivirikkoらの方法（Anal. Biochem.19,249-255 (1 967))に従って、肺組織の加水分解物中の量として測定した。肺線維症のレベル (重 篤度）は、 Ashcortらの方法 (J.Clin.Pathol.41,467- 470、（1988))を用いて 0〜8にスコ ァした。また、これらのコントロールマウスと被験対象マウスについて、血漿の PAI—1 活性 (ng/ml)を測定した。肺組織の組織分析の結果を図 9 (aは線維症スコア、 bは組 織染色画像）に、肺組織中のヒドロキシプロリン量および血漿 PAI—1活性を表 3に示 す。  [0337] First, pentobarbital was intraperitoneally administered to C57BL / 6 mice (male, body weight: 21-21 g) to cause intoxication, and the cervical organ was dissected. Ten mice were used for control. Mice for control mouth (n = 10) were treated with bleomycin (Nihon Shakuyaku) (1.5 U / kg) dissolved in physiological saline twice a day for 14 days. Intratracheal administration. On the other hand, in addition to the above-mentioned intratracheal administration twice a day for 14 days, the test subject mice received Compound b (2- [3- (3'-carboxy-4'-cherthiophene-2-sylcarbamoyl) -pentanoylamino] -4-chelylthiophene-3-carboxylic acid (200 mg / kg) was forcibly administered orally . Subsequently, lung tissues of these control mice and test mice were subjected to histological analysis, and the amount of hydroxyproline was measured. The amount of hydroxyproline in the lung tissue was measured as the amount in the hydrolyzate of lung tissue according to the method of Kivirikko et al. (Anal. Biochem. 19, 249-255 (1967)). The level (severity) of pulmonary fibrosis was scored from 0 to 8 using the method of Ashcort et al. (J. Clin. Pathol. 41,467-470, (1988)). In addition, plasma PAI-1 activity (ng / ml) was measured for these control mice and test mice. The results of histological analysis of lung tissue are shown in Fig. 9 (a is the fibrosis score, b is the tissue-stained image), and the amount of hydroxyproline in the lung tissue and plasma PAI-1 activity are shown in Table 3.
[0338] [表 3] [0338] [Table 3]
処 理 中のヒドロキシプロリン量 （ g/肺) 雌 PAI-1¾1生 (ngml) Hydroxyproline content during treatment (g / lung) Female PAI-1¾1 raw (ngml)
n=10 n=10 コントロール 理) 140.2 ±4.8 0.8 ±0.1 ブレ才マイシン +ベヒクノ 0.5°/oCMC) 232.9 ± 8.5 a 1.7 ±0.2 ブレオマイシン +化合物 b n = 10 n = 10 Control) 140.2 ± 4.8 0.8 ± 0.1 Bremymycin + Behycno 0.5 ° / oCMC) 232.9 ± 8.5 a 1.7 ± 0.2 Bleomycin + Compound b
204.2 ± 9.5 b 1.2 ±0.1 b 204.2 ± 9.5 b 1.2 ± 0.1 b
(200mgkg,p.o.,2[i]/日） (200mgkg, p.o., 2 [i] / day)
Data are expressed as mean土 SE. Data are expressed as mean Sat SE.
aP< 0.001 vs control by Mann Whitney© U test. bP< 0.05 vs vehicle by Mann Whitney© U test. aP <0.001 vs control by Mann Whitney © U test. b P <0.05 vs vehicle by Mann Whitney © U test.
[0339] この結果から、ブレオマイシン投与によって著しく増加した肺組織中のヒドロキシプ 口リンの量力 化合物 bの投与によって有意に減少することがわかる。また、ブレオマ イシン投与によって血漿 PAI— 1活性が顕著に増加すること、そしてこの血漿 PAI— 1活性の増カロも化合物 bの投与によって有意に減少することがわ力つた。 [0339] From these results, it can be seen that the amount of hydroxyproline in the lung tissue, which was significantly increased by the administration of bleomycin, was significantly decreased by the administration of compound b. It was also found that administration of bleomycin significantly increases plasma PAI-1 activity, and that this increase in plasma PAI-1 activity is also significantly reduced by administration of compound b.
[0340] また図 9からわ力るように、ブレオマイシン投与によって誘導された肺線維症 (線維 症スコア： 4.7±0.17、コントロール群： 0.5±0.17、 P〈0.001)は、化合物 bの投与によつ て有意に改善され (線維症スコア： 2.9±0.42、 Pく 0.01)、上記 PAI— 1活性の結果と 一致した。  [0340] Also, as can be seen from FIG. 9, pulmonary fibrosis induced by bleomycin administration (fibrosis score: 4.7 ± 0.17, control group: 0.5 ± 0.17, P <0.001) is caused by administration of compound b. Significantly improved (fibrosis score: 2.9 ± 0.42, P 0.01), consistent with the above PAI-1 activity results.
[0341] これらの結果は、化合物 bを始めとする PAI— 1阻害作用を有する本発明の化合物  [0341] These results show that the compound of the present invention having PAI-1 inhibitory action including compound b
(1)が、線溶系促進作用に加えて、肺線維化のプロセスを防止する作用を有すること を示している。既に、 Eitzmanらによって、 PAI— 1遺伝子を過剰発現するか、または 欠損させたマウスの肺組織では、 PAI— 1発現とコラーゲン蓄積との間に強い関係が 認められることが報告されて!、る (j.Chin.Invest.97,232-237 (1996) )。強!、PAI— 1阻 害活性を有する化合物 bが、肺線維症を改善することを示す上記の結果は、 PAI- 1 が肺線維症の単なる指標ではなぐその主な要因であることを示唆している。線維化 は、肺だけでなぐ心臓、血管、肝臓、および腎臓を含む多くの組織や器官で生じる ため、この知見は極めて重要である。すなわち、 PAI— 1活性を阻害することによって 、繊維症に関連した各種の疾患 (心疾患、肝硬変、腎臓病または放射線障害)を予 防または治療することが可能と考えられる。  (1) shows that in addition to the fibrinolytic system promoting action, it has the action of preventing the pulmonary fibrosis process. Already, Eitzman et al. Have reported a strong relationship between PAI-1 expression and collagen accumulation in the lung tissue of mice overexpressing or deficient in the PAI-1 gene! (j.Chin.Invest.97,232-237 (1996)). Strong !, PAI-1 inhibitory compound b improves pulmonary fibrosis The above results suggest that PAI-1 is not the only indicator of pulmonary fibrosis is doing. This finding is extremely important because fibrosis occurs in many tissues and organs, including the heart, blood vessels, liver, and kidneys, not just the lungs. That is, by inhibiting PAI-1 activity, various diseases related to fibrosis (heart disease, cirrhosis, kidney disease or radiation injury) can be prevented or treated.
[0342] 実験例 8  [0342] Experimental Example 8
血栓モデル動物に対する 2 -「3- (3' -カルボキシ -4' -チェ二ルチオフェン- 2' -ィルカ ルバモイル) -ペンタノィルァミノ 4-チェ二ルチオフェン- 3-カルボン酸（化合物 a)の 木全ィ乍  2- (3- (3'-carboxy-4'-cenylthiophene-2'-ilcarbamoyl) -pentanoylamino 4-cenylthiophene-3-carboxylic acid (compound a) Kizen
本発明の化合物の抗血栓に対する有効性を確認するため、血栓モデル動物であ るラット AVシャントモデルを用いて、 2-[3-(3' -カルボキシ -4' -チェ-ルチオフェン- 2 ，-ィルカルバモイル) -ペンタノィルァミノ] -4-チェ-ルチオフェン- 3-カルボン酸（ィ匕 合物 a)の抗血栓作用を調べた。また、これに加えて血液凝固検査も並行して行った [0343] なお、ここで AVシャントモデル試験は、公知文献（R.F.Peters,et al.Thromb Haem ost 1991;65, 268-274 :Yoshiyuki Morishima, et al, Thromb Haemost 1997;78, 1366 -1371 :Atsuhiro Sugidachi, et al., British Journal of Phermacology 2000;129, 1349—1 446)に従って行った。 In order to confirm the effectiveness of the compound of the present invention against antithrombosis, a rat AV shunt model, which is a thrombus model animal, was used to produce 2- [3- (3′-carboxy-4′-chelthiophene-2, -Ylcarbamoyl) -pentanoylamino] -4-Chelthiophene-3-carboxylic acid (a compound a) was examined for antithrombotic activity. In addition to this, a blood coagulation test was also performed in parallel. [0343] It should be noted that the AV shunt model test here is a well-known literature (RFPeters, et al. Thromb Haem ost 1991; 65, 268-274: Yoshiyuki Morishima, et al, Thromb Haemost 1997; 78, 1366-1371: Atsuhiro Sugidachi , et al., British Journal of Phermacology 2000; 129, 1349-1 446).
[0344] (1)試験化合物および投与液の調製  [0344] (1) Preparation of test compound and administration solution
試験化合物として、本発明の化合物 aに加えて、比較化合物（陽性対照化合物）と して、ヮーフアリン (和光純薬工業 (株)製）とチクロビジン塩酸塩 (Sigma- Aldrich Co. 製)を用いた。  As a test compound, in addition to the compound a of the present invention, フ farin (manufactured by Wako Pure Chemical Industries, Ltd.) and ticlovidin hydrochloride (manufactured by Sigma-Aldrich Co.) were used as comparative compounds (positive control compounds). .
[0345] これらの試験化合物は、カルボキシメチルセルロース (ナカライテスタ株式会社製） ( 以下、 rCMC-Naj t 、う） 0.5gを注射用水 (大塚製薬 (株)製) lOOmLに溶解した溶媒（ 0.5% CMC-Na溶液）に懸濁して、投与液とした。具体的には、化合物 aは、 0.5% C MC-Na溶液に 75mg/mL濃度となるように懸濁させ、チクロビジン塩酸塩は 0.5% CM C- Na溶液に 142.3mg/mL濃度となるように懸濁させ、また、ヮーフアリンは 0.5% CMC -Na溶液に 0.3mg/mL濃度となるように懸濁させて、投与液を調製した。  [0345] These test compounds consist of carboxymethyl cellulose (manufactured by Nacalai Testa Co., Ltd.) (hereinafter, rCMC-Naj t), 0.5 g CMC, dissolved in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) in lOOmL. -The solution was suspended in Na solution. Specifically, Compound a is suspended in a 0.5% CMC-Na solution at a concentration of 75 mg / mL, and ticlovidin hydrochloride is suspended in a 0.5% CMC-Na solution at a concentration of 142.3 mg / mL. The dosing solution was prepared by suspending it, and suspending fufarin in a 0.5% CMC-Na solution to a concentration of 0.3 mg / mL.
[0346] (2)試験動物  [0346] (2) Test animals
AVシャントモデル試験に使用する動物としては、馴化飼育にぉ 、て体重増加量が 平均値 ± 3SDの正常範囲内にある 8週令の体重 270〜300gの CD(SD)系ラット（日 本チヤ一ルス'リバ一株式会社製)を用いた。これらのラット (合計 28匹）は、溶媒投与 群（ 1群: n = 7)、化合物 a投与群の（2群: n = 7)、チクロビジン塩酸塩投与群（3群: n = 7)、及びヮーフアリン投与群 (4群： n= 7)の 4つの群に群分けした。  As an animal used for the AV shunt model test, CD (SD) rats (8-week-old body weight 270-300 g) with a body weight gain within the normal range of mean value ± 3SD (Japan Illus' manufactured by Ribaichi Co., Ltd.). These rats (28 animals in total) were divided into the vehicle administration group (1 group: n = 7), the compound a administration group (2 groups: n = 7), the ticlobidine hydrochloride administration group (3 groups: n = 7), And the group was divided into 4 groups, 4 groups: 4 groups: n = 7.
[0347] (3)試験方法  [0347] (3) Test method
(3-1) AVシャントモデル試験  (3-1) AV shunt model test
各試験化合物は、試験動物における各化合物の体内動態を考慮し、 AVシャント手 術を実施する時間に最大血中濃度に達するように、試験動物に投与した。具体的に は、試験化合物 aは麻酔'シャント手術の 17.5時間前に 300mg/kg、ヮーフアリンは 23.5 時間前に 1.2mg/kg、チクロビジン塩酸塩は 1.5時間前に 500mg/kgの割合でそれぞれ 投与した。 AVシャントモデルの施術は、各試験化合物の体内動態を考慮し、最大血 中濃度に達する時点で行った。 [0348] AVシャントモデルの作成手術は下記の方法に従って行った。 Considering the pharmacokinetics of each compound in the test animal, each test compound was administered to the test animal so that the maximum blood concentration was reached at the time of performing the AV shunt procedure. Specifically, test compound a was administered at a rate of 300 mg / kg 17.5 hours before anesthesia and shunt surgery, ヮ farin at a rate of 1.2 mg / kg 23.5 hours before, and ticlovidin hydrochloride at a rate of 500 mg / kg 1.5 hours before. . The AV shunt model was performed when the maximum blood concentration was reached, considering the pharmacokinetics of each test compound. [0348] The operation for creating the AV shunt model was performed according to the following method.
[0349] まず、 8cmの 7号ポリエチレン製チューブ（ヒビキネ土製）内に 6.5cm絹糸（松田医科 1-0 号）を通し、その両端に 5号チューブ（1.5cm)を介して 3号チューブ（12.5cm)を接続し[0349] First, a 6.5cm silk thread (Matsuda Medical 1-0) was passed through an 8cm No. 7 polyethylene tube (made of hibikine earth), and No. 3 tube (12.5) via No. 5 tube (1.5cm) at both ends. cm)
、シャント用カテーテルを作成した。絹糸を通した接続部には、血液が漏れないようパ ラフイルムを巻いた。 A shunt catheter was created. A film was wrapped around the connection through the silk thread to prevent blood from leaking.
[0350] ラットを、ペントバルビタール (大日本住友製薬 (株)製)を 50mg/kgの割合で腹腔内 に投与して麻酔し、上記カテーテル内に生理食塩液を満たし、カテーテルの両端を 各々右頸動脈及び左頸静脈に挿入して、血液を灌流した。灌流開始から 30分後に カテーテルを鉗子ではさんで血流を止め、絹糸を通したチューブ部分を切り出した。 次いで、血液灌流により形成された血栓の重量を測定した。具体的には、切り出した チューブ力も絹糸を慎重に取り出し、液相を濾紙で除いて残った湿重量を測定し、さ らにこれから 6.5cmの絹糸の重量を引 、て、これを血栓重量とした。  [0350] Rats were anesthetized with pentobarbital (manufactured by Dainippon Sumitomo Pharma Co., Ltd.) intraperitoneally at a rate of 50 mg / kg, filled with physiological saline in the catheter, and both ends of the catheter on the right Blood was perfused by insertion into the carotid artery and left jugular vein. Thirty minutes after the start of perfusion, the catheter was clamped with forceps to stop blood flow, and the tube part through which silk thread was passed was cut out. Subsequently, the weight of the thrombus formed by blood perfusion was measured. Specifically, the cut tube force was also carefully taken out of the silk thread, the liquid phase was removed with filter paper, the remaining wet weight was measured, and the weight of the silk thread of 6.5 cm was further subtracted from this to determine the thrombus weight. did.
[0351] (3-2)血液凝固検査  [0351] (3-2) Blood coagulation test
上記血栓重量を測定する際にチューブを切り出すと同時に、腹部大動脈力 凝固 検査用に血液を採取した。全血 1.8mLを 3.13%クェン酸入り真空採血管に添加して、 遠心して血漿を得た。また、全血 0.5mLを血清分離剤と凝固促進剤が入った微量採 血管に添加し、血清を得た。全自動血液凝固測定装置を用い、血漿について活性 ィ匕部分トロンボプラスチン時間（activated partial thromboplastin time:APTT)及びプ ロトロンビン時間（prothrombin time： PT)を測定した。  At the time of measuring the thrombus weight, the tube was cut out, and blood was collected for abdominal aortic force coagulation test. 1.8 mL of whole blood was added to a vacuum blood collection tube containing 3.13% citrate and centrifuged to obtain plasma. In addition, 0.5 mL of whole blood was added to a micro blood collection tube containing a serum separating agent and a coagulation promoter to obtain serum. Using a fully automatic blood coagulation analyzer, the activated partial thromboplastin time (APTT) and prothrombin time (PT) of plasma were measured.
[0352] (4)結果  [0352] (4) Results
媒体投与群および各試験化合物投与群（1〜4群）について得られた血栓重量を 表 4に示す。  Table 4 shows the thrombus weight obtained for the vehicle administration group and each test compound administration group (Groups 1 to 4).
[0353] [表 4] [0353] [Table 4]
Figure imgf000074_0001
Figure imgf000074_0001
a ： Pく 0. 01 [0354] この結果力もわ力るように、上記ラット AVシャントモデルにおいて、本発明の化合物 a投与群の血栓重量は、陽性対照化合物 (ヮーフアリン、チクロビジン塩酸塩)投与群 と同様に、媒体投与群と比較して有意に減少した。なお、プロトロンビン時間 (PT)、 活性ィ匕部分トロンボプラスチン時間 (ΑΡΤΤ)について、媒体投与群と比較して、本発 明の化合物 a投与群に有意な変化は認められな力つた。 a ： P ku 0.01 [0354] As a result, in the rat AV shunt model, the thrombus weight of the compound a administration group of the present invention is the same as that of the positive control compound (ヮ -farin, ticlobidine hydrochloride) administration group, in the vehicle administration group. Compared with significantly decreased. The prothrombin time (PT) and the active 活性 partial thromboplastin time (ΑΡΤΤ) did not significantly change in the compound a administration group of the present invention compared to the vehicle administration group.
[0355] 一方、ヮーフアリン投与群は、血栓重量を減少させ、 PT及び APTTを延長した。チ クロビジン塩酸塩投与群は、血栓重量を減少させたが、本発明の化合物 aと同様に P T及び APTTに対して影響を示さなカゝつた。なお、ここで PTと APTTはいずれも凝固 系を判断する指標である。すなわち、この試験で、本発明の化合物 aは PTと APTT のいずれにも影響を与えな力 たという結果は、当該化合物 aが抗凝固剤と異なる性 質の化合物であることを意味して 、る。  [0355] On the other hand, the hufarin administration group decreased the thrombus weight and prolonged PT and APTT. The ticlovidin hydrochloride administration group reduced the thrombus weight, but did not show any effect on PT and APTT in the same manner as the compound a of the present invention. Here, PT and APTT are both indicators for determining the coagulation system. That is, in this test, the result that the compound a of the present invention did not affect both PT and APTT means that the compound a is a compound having a property different from that of the anticoagulant. The
[0356] 以上のラット AVシャントモデルを用いた試験結果から、 2-[3-(3' -カルボキシ -4， - チェ二ルチオフェン- 2， -ィルカルバモイル) -ペンタノィルァミノ] - 4 -チェ二ルチオフエ ン -3-カルボン酸 (ィ匕合物 a)は抗凝固剤とは異なる作用機序で抗血栓作用を示すこ とが明らかになった。  [0356] From the test results using the rat AV shunt model above, 2- [3- (3'-carboxy-4, -cenylthiophene-2, -ylcarbamoyl) -pentanoylamino]-4- It has been clarified that cherylthiophene-3-carboxylic acid (compound a) exhibits an antithrombotic action with a mechanism of action different from that of anticoagulants.
[0357] 実験例 9 細胞障害試験  [0357] Experimental Example 9 Cytotoxicity test
一般に、細胞質局在酵素である乳酸デヒドロゲナーゼ (LDH)は、障害により溶解 した細胞力も放出されることが知られている。該 LDHは比較的安定であるため、 LD Hを定量することにより、間接的に薬物の細胞障害を調べることができる。  In general, it is known that lactate dehydrogenase (LDH), which is a cytoplasmic local enzyme, also releases lysed cell force due to injury. Since LDH is relatively stable, the cytotoxicity of the drug can be indirectly examined by quantifying LDH.
[0358] 本発明の化合物 a及び bを、 250 μ Μ、 125 μ Μ、または 50 μ Μの割合で、 HeLa細 胞 (子宮頸がん由来上皮様細胞株）に添加し、細胞力も溶出した LDHを、 INT (テト ラゾリウム塩）と 30分間酵素反応を行い、 INTから変換された赤色ホルマザンを 490η mで定量することにより、化合物 aおよび bの細胞障害性を試験した。また、対照試験 として、化合物 aおよび bに代えて、 0.5%の DMSOを用いて同様に試験を行った。本 発明の化合物 aおよび bは、いずれも 250 Mまで細胞障害性が認められな力つた。  [0358] Compounds a and b of the present invention were added to HeLa cells (cervical cancer-derived epithelial cell line) at a rate of 250 μ μ, 125 μΜ, or 50 μΜ, and the cell force was also eluted. The cytotoxicity of compounds a and b was tested by subjecting LDH to an enzyme reaction with INT (tetrazolium salt) for 30 minutes and quantifying red formazan converted from INT at 490 ηm. As a control test, a similar test was performed using 0.5% DMSO instead of compounds a and b. The compounds a and b of the present invention were both strong enough to show no cytotoxicity up to 250 M.
[0359] 実験例 10 急性毒性試験  [0359] Experimental Example 10 Acute toxicity test
ICRマウス（日本クレア株式会社から入手、雄、 19〜21g) (n=5)に化合物 a及び b を、それぞれ単回経口投与で lgZkg投与し、 2週間経過観察を行った。両化合物と も死亡個体は認められな力つた。 ICR mice (obtained from CLEA Japan, male, 19-21 g) (n = 5) were each given a single oral administration of lgZkg of compounds a and b, followed by follow-up for 2 weeks. With both compounds Even the dead individuals were unacceptable.
[0360] 実験例 11 吸収性試験  [0360] Experimental example 11 Absorbency test
Wisterラット（日本クレア株式会社力も入手、雄、 160〜180g) (n=5)に化合物 a及 び bを、それぞれ 50 mg/kgで経口投与し、 1、 2, 6、 18、 24時間後および 7日後に静脈 力 採血して、血液中の化合物量を測定し、最高血中濃度 (Cmax)、および半減期（ T1/2)を調べた。比較対照試験として、化合物 a及び bに代えて tiplaxtininを用いて同 様にして試験を行った。化合物 aと bおよび tiplaxtininの半減期 (T1/2)を表 5に示す。  Wister rats (obtained by CLEA Japan, male, 160-180g) (n = 5) were orally administered compounds a and b at 50 mg / kg, respectively 1, 2, 6, 18, 24 hours later And 7 days later, venous force was collected, the amount of the compound in the blood was measured, and the maximum blood concentration (Cmax) and half-life (T1 / 2) were examined. As a comparative control test, the same test was performed using tiplaxtinin instead of compounds a and b. Table 5 shows the half-lives (T1 / 2) of compounds a and b and tiplaxtinin.
[0361] [表 5]  [0361] [Table 5]
Tipl axt inin 2. 4時間 Tipl axt inin 2. 4 hours
化合物 a 54. 0 時間  Compound a 54. 0 hours
化合物 124. 0 時間  Compound 124. 0 hours
[0362] この結果力 わ力るように、化合物 a及び bは、 tiplaxtininよりも顕著に長い血中持続 性を示した。 [0362] As a result, compounds a and b showed significantly longer blood persistence than tiplaxtinin.
図面の簡単な説明  Brief Description of Drawings
[0363] [図 1]本発明の化合物（1) (特に化合物 aと b)の合成スキームを示す図である。 FIG. 1 is a diagram showing a synthesis scheme of compound (1) of the present invention (particularly compounds a and b).
[図 2]本発明の化合物 a (Ν,Ν' -ビス [3,3，—カルボキシ— 4,4，—フエ-ル— 2,2，—チ ェニル]へキサンジカルボキシアミド）の NMRデータを示す。  [FIG. 2] NMR data of compound a of the present invention (Ν, Ν′-bis [3,3, -carboxy-4,4, -phenol-2,2-phenyl] hexanedicarboxamide) Indicates.
[図 3]本発明の化合物 b (Ν,Ν，-ビス [3,3，—カルボキシ— 4,4， - (2,2，-チェ-ル）—2 ,2'—チェ-ル]へキサンジカルボキシアミド）の NMRデータを示す。  [Fig. 3] Compound b of the present invention (b, Ν, -bis [3,3, -carboxy-4,4,-(2,2, -chael) -2,2'-chael] The NMR data of xanthodicarboxamide) are shown.
[図 4] (Α) Ν,Ν，-ビス [3,3，—カルボキシ— 4,4，—フエ-ル— 2,2，—チェ-ル]へキサ ンジカルボキシアミド（ィ匕合物 a)、 (B) N,N' -t^[3,3'—カルボキシ一 4,4， - (2,2，- チェ-ル） -2,2'—チェ-ル]へキサンジカルボキシアミド（ィ匕合物 b)および（C)tipla xtininの PAI— 1阻害活性を示す図である。縦軸は、 PAI— 1活性 (%)を示す (実験 例 1)。  [Fig. 4] (Α) Ν, Ν, -bis [3,3, -carboxy-4,4, -phenol-2,2, chael] hexanedicarboxamide (compound a ), (B) N, N'-t ^ [3,3'-carboxy 1,4,4,-(2,2, -chael) -2,2'-chael] hexanedicarboxamide It is a figure which shows the PAI-1 inhibitory activity of (i compound b) and (C) tipla xtinin. The vertical axis shows PAI-1 activity (%) (Experimental Example 1).
[図 5]ウェスタンブロッテイング法による、各化合物の組織プラスミノーゲンァクチべ一 タ (t PA)と PAI— 1の複合体形成阻害効果を示す電気泳動像である（実験例 2)。  FIG. 5 is an electrophoretic image showing the inhibitory effect on complex formation between tissue plasminogen activator (tPA) and PAI-1 of each compound by Western blotting (Experimental Example 2).
[図 6]フイブリンプレート法 (天然基質法）による、各化合物の PAI— 1阻害効果を示す 図である (実験例 3)。 [図 7]N,N，-ビス [3,3，一カルボキシ一4,4，一フエ-ルー 2,2，一チェ-ル]へキサンジ カルボキシアミド（ィ匕合物 a) (図（A) )、および Ν,Ν，-ビス [3,3，一カルボキシ一 4,4， -FIG. 6 shows the PAI-1 inhibitory effect of each compound by the fibrin plate method (natural substrate method) (Experimental Example 3). [Fig. 7] N, N, -Bis [3,3, 1-carboxy-1,4,4, 1-Fel 2,2,1 chael] hexanedicarboxamide (compound a) (Fig. (A )), And Ν,-, -bis [3,3, one carboxy, one 4,
(2,2，-チェ-ル）—2,2，一チェ-ル]へキサンジカルボキシアミド（ィ匕合物 b) (図（B) ) のアンチプラスミン (AP)活性に対する効果を示す図である（実験例 4)。 (2,2, -Chael) -2,2, Che] Hexanedicarboxamide (Compound b) (Figure (B)) shows the effect on antiplasmin (AP) activity (Experimental example 4).
[図 8]ウェスタンブロッテイング法による、 Ν,Ν，-ビス [3,3，一カルボキシ一 4,4， - (2,2， [Fig. 8] ブ ロ ッ, Ν, -bis [3,3, 1-carboxyl 4,4,-(2,2,
-チェ-ル） -2,2' チェ-ル]へキサンジカルボキシアミド（ィ匕合物 b)のプラスミンと アンチプラスミンの複合体形成阻害効果を示す電気泳動像である。 -Cher) -2,2'Chair] Hexanedicarboxamide (Compound b) is an electrophoretic image showing the inhibitory effect of plasmin and antiplasmin complex formation.
[図 9]ブレオマイシン誘導肺線維症に対する Ν,Ν' -ビス [3,3，—カルボキシ— 4,4， - ( [Fig. 9] Ν, Ν'-bis [3,3, -carboxy- 4,4,-(for bleomycin-induced pulmonary fibrosis
2,2，-チェ-ル） 2,2，一チェ-ル]へキサンジカルボキシアミド（ィ匕合物 b)の抗線維 効果を示す、 aは線維症スコア、 bは組織染色画像である（実験例 7)。 2,2, -ch) 2,2,1]] hexanedicarboxamide (compound b) showing anti-fibrotic effect, a is fibrosis score, b is tissue staining image (Experimental example 7).

Claims

請求の範囲 下式 (1) : Claims The following formula (1):
[化 1]  [Chemical 1]
Figure imgf000078_0001
Figure imgf000078_0001
〔式中、 Rは水素原子または炭素数 1〜4の直鎖または分枝鎖状のアルキル基; R  [Wherein, R is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R
1 2 は水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル基、または炭素 数 1〜6の直鎖または分枝鎖状のアルキル基; Rは水素原子、置換基を有していても  1 2 is a hydrogen atom, an optionally substituted phenyl group or a chaer group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R is a hydrogen atom or a substituent. Even if
3  Three
よいフエニル基、炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロゲン 原子を示す。また Rおよび Rは互いに結合して 5〜6員の環を形成していてもよい； A good phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a halogen atom. R and R may be bonded to each other to form a 5- to 6-membered ring;
2 3  twenty three
Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、ァルケ-レン若しくはアルキ 二レン、炭素数 3〜8のシクロアルキレン、またはシングルボンド; Rは水素原子、置  A is a straight-chain or branched alkylene having 1 to 7 carbon atoms, alkene or alkylene, cycloalkylene having 3 to 8 carbon atoms, or a single bond; R is a hydrogen atom,
4  Four
換基を有していてもよいフエ-ル基またはフリル基、または、下式（2)； A phenyl group or a furyl group which may have a substituent, or the following formula (2);
[化 2]  [Chemical 2]
Figure imgf000078_0002
Figure imgf000078_0002
(式中、 R，は水素原子または炭素数 1〜4の直鎖または分枝鎖状のアルキル基; R  (In the formula, R, is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R
1 2 1 2
'は水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル基、または炭 素数 1〜6の直鎖または分枝鎖状のアルキル基; R，は水素原子、置換基を有してい 'Represents a hydrogen atom, an optionally substituted phenyl group or a chaer group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R, represents a hydrogen atom or a substituent. Have
3  Three
てもよいフエニル基、炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロ ゲン原子を示す。また R，および R，は互いに結合して 5〜6員の環を形成していても An optionally substituted phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a halogen atom; R and R may be bonded to each other to form a 5- to 6-membered ring.
2 3  twenty three
よい。）を示す。〕 Good. ). ]
で示される化合物若しくはその塩、またはこれらの溶媒和物を有効成分とする、ブラ スミノーゲンァクチべ一ターインヒビタ一一 1阻害剤。 Or a salt thereof, or a solvate thereof. Suminogen inhibitor inhibitor.
一般式（1)中、 Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、または炭素 数 3〜8のシクロアルキレン; Rは、下式（2)；  In the general formula (1), A is a linear or branched alkylene having 1 to 7 carbon atoms, or a cycloalkylene having 3 to 8 carbon atoms; R is the following formula (2);
4  Four
[化 3]  [Chemical 3]
Figure imgf000079_0001
Figure imgf000079_0001
(式中、 R，は水素原子または炭素数 1 (In the formula, R, is a hydrogen atom or carbon number 1
1 〜4の直鎖または分枝鎖状のアルキル基; R  1-4 straight or branched alkyl groups; R
2 2
'は水素原子、置換基を有していてもよいフエニル基若しくはチェ-ル基、または炭 素数 1〜6の直鎖または分枝鎖状のアルキル基; R，は水素原子、置換基を有してい 'Represents a hydrogen atom, an optionally substituted phenyl group or a chaer group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R, represents a hydrogen atom or a substituent. Have
3  Three
てもよいフエニル基、炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロ ゲン原子を示す。また R，および R，は互いに結合して 5〜6員の環を形成していても  An optionally substituted phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a halogen atom; R and R may be bonded to each other to form a 5- to 6-membered ring.
2 3  twenty three
よい。 )  Good. )
で示される化合物若しくはその塩、またはこれらの溶媒和物を有効成分とする、請求 項 1記載のプラスミノーゲンァクチべ一ターインヒビタ一一 1阻害剤。  The inhibitor of plasminogen activator inhibitor according to claim 1, which comprises a compound represented by the formula (1) or a salt thereof, or a solvate thereof as an active ingredient.
[3] Rおよび R，力 同一または異なって、置換基を有していてもよいフエ-ル基、 2— [3] R and R, force The same or different, a phenyl group which may have a substituent, 2—
2 2  twenty two
チェニル基、 CH CH (CH ) である力、または同一または異なって、 Rと Rもしく  A Cenyl group, a CH CH (CH) force, or the same or different, R and R or
2 3 2 2 3 は R，と R，がそれぞれ結合して、縮合 6員環を形成している、請求項 1に記載するプ 2. The composition according to claim 1, wherein R 3 and R 2 are bonded to each other to form a condensed 6-membered ring.
2 3 twenty three
ラスミノーゲンァクチべ一ターインヒビタ一一 1阻害剤。  Rasminogen activator inhibitor.
[4] Rおよび R ' 1S 同一または異なって、水素原子、炭素数 1〜3の直鎖または分枝 [4] R and R ′ 1S the same or different, hydrogen atom, straight or branched chain having 1 to 3 carbon atoms
3 3  3 3
鎖状のアルキル基、フエ-ル基、またはハロゲン原子である、請求項 1に記載するプ ラスミノーゲンァクチべ一ターインヒビタ一一 1阻害剤。  The plasminogen inhibitor inhibitor according to claim 1, which is a chain alkyl group, a phenyl group, or a halogen atom.
[5] A力 炭素数 3〜5の直鎖状のアルキレン、—CH—C (CH ) —CH—、またはシ [5] A force Linear alkylene having 3 to 5 carbon atoms, —CH—C (CH) —CH—, or
2 3 2 2  2 3 2 2
クロへキシレンである、請求項 1に記載するプラスミノーゲンァクチべ一ターインヒビタ —— 1阻害剤。  The plasminogen activator inhibitor according to claim 1, which is chlorohexylene.
[6] Rが水素原子であり、 Rおよび R 'がフエ-ル基または 2 チェ-ル基であり、 Aが  [6] R is a hydrogen atom, R and R ′ are a phenol group or a 2-chael group, and A is
1 2 2  1 2 2
ブチレンである、請求項 1に記載するプラスミノーゲンァクチべ一ターインヒビタ一一 1 阻害剤。 The plasminogen inhibitor according to claim 1, which is butylene 1 Inhibitor.
[7] 請求項 1乃至 6のいずれかに記載するプラスミノーゲンァクチべ一ターインヒビター — 1阻害剤、および薬学的に許容される担体または添加剤を含む、医薬組成物。  [7] A pharmaceutical composition comprising the plasminogen activator inhibitor-1 inhibitor according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier or additive.
[8] プラスミノーゲンァクチべ一ターインヒビタ一一 1活性が発症に関わっている疾患の 予防または治療薬である請求項 7記載の医薬組成物。  [8] The pharmaceutical composition according to claim 7, which is a prophylactic or therapeutic agent for a disease whose plasminogen activator inhibitor activity is involved in the onset.
[9] 線溶系促進薬である請求項 8に記載する医薬組成物。  [9] The pharmaceutical composition according to claim 8, which is a fibrinolytic promoter.
[10] プラスミノーゲンァクチべ一ターインヒビタ一一 1活性が発症に関わっている疾患が 、狭心症、心筋梗塞もしくは心房細動における心房内血栓、虚血性心疾患、虚血性 脳血管障害、動脈硬化症、肺塞栓症、外科手術時の深部静脈血栓症 (DVT)、播種 性血管内凝固症候群 (DIC)、糖尿病合併症としての血管障害、神経障害、網膜症 もしくは腎症、または経皮的冠動脈形成術 (PTCA)後の再狭窄である、請求項 8〖こ 記載する医薬組成物。  [10] Plasminogen activity inhibitors 1 The disease involved in the onset of activity is angina, myocardial infarction or atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder , Arteriosclerosis, pulmonary embolism, deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or The pharmaceutical composition according to claim 8, which is restenosis after percutaneous coronary angioplasty (PTCA).
[11] プラスミノーゲンァクチべ一ターインヒビタ一一 1活性が発症に関わっている疾患が 組織線維化を伴う疾患である、請求項 8に記載する医薬組成物。  [11] The pharmaceutical composition according to claim 8, wherein the disease whose plasminogen activator inhibitor activity is involved in onset is a disease associated with tissue fibrosis.
[12] 組織線維化を伴う疾患が肺線維症である、請求項 11に記載する医薬組成物。  [12] The pharmaceutical composition according to claim 11, wherein the disease associated with tissue fibrosis is pulmonary fibrosis.
[13] 経口投与形態を有する請求項 7に記載する医薬組成物。  [13] The pharmaceutical composition according to claim 7, which has an oral dosage form.
[14] 下式 (3) :  [14] Formula (3):
[化 4]  [Chemical 4]
Figure imgf000080_0001
Figure imgf000080_0001
〔式中、 Rと R 'は、同一または異なって、水素原子または炭素数 1〜4の直鎖または 分枝鎖状のアルキル基; Rと R 'は、同一または異なって、水素原子、置換基を有し  [Wherein, R and R ′ are the same or different, a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms; R and R ′ are the same or different, a hydrogen atom, Have a group
2 2  twenty two
ていてもよいフエニル基、または炭素数 1〜6の直鎖または分枝鎖状のアルキル基; R と R 'は、同一または異なって、水素原子、置換基を有していてもよいフエニル基、 An optionally substituted phenyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms; R and R ′ may be the same or different and each may have a hydrogen atom or a substituent. ,
3 3 3 3
炭素数 1〜6の直鎖または分枝鎖状のアルキル基、またはハロゲン原子; Aは炭素数 1〜7の直鎖または分枝鎖状のアルキレン、または炭素数 3〜8のシクロアルキレンを 示す。但し、 Rおよび R，が置換基を有さないフエ-ル基であり且つ Rおよび R，がA linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom; A is a linear or branched alkylene having 1 to 7 carbon atoms, or a cycloalkylene having 3 to 8 carbon atoms Show. Provided that R and R are phenyl groups having no substituent, and R and R are
2 2 3 3 水素原子であるとき、 Aはブチレンおよび CH -C (CH ) -CH一のいずれでも When 2 2 3 3 is a hydrogen atom, A is either butylene or CH 2 -C (CH 2) 2 -CH 1
2 3 2 2  2 3 2 2
なぐまた Rおよび R，がイソブチル基であり且つ Rおよび R，が水素原子であるとき When R and R are isobutyl groups and R and R are hydrogen atoms
2 2 3 3  2 2 3 3
、 Aはブチレンではない。〕  A is not butylene. ]
で示される化合物またはその塩。 Or a salt thereof.
下式 (4)〜（ 15)に示される化合物またはその塩：  A compound represented by the following formulas (4) to (15) or a salt thereof:
2-[5-(3， -カルボキシ- 4， -(P-クロ口フエ-ル)チォフェン- 2， -ィルカルバモイル)-ペン タノィルァミノ] -4-(p-クロ口フエ-ル)チォフェン- 3-カルボン酸 2- [5- (3, -Carboxy-4,-(P-Black mouth phenyl) thiophene-2, -ylcarbamoyl) -pentanoylamino] -4- (p-Black mouth felt) thiophene-3 -carboxylic acid
[化 5] [Chemical 5]
Figure imgf000081_0001
Figure imgf000081_0001
2-[4-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2 ' -ィルカルバモイル)-ブチリルアミ ノ] -4-イソブチルチオフェン- 3-カルボン酸 2- [4- (3'-carboxy-4'-isobutylthiophene-2'-ylcarbamoyl) -butyrylamino] -4-isobutylthiophene-3-carboxylic acid
[化 6] [Chemical 6]
Figure imgf000081_0002
Figure imgf000081_0002
2-[4-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバモイル) -3,3-ジメチル ブチリルァミノ] -4-イソブチルチオフェン- 3-カルボン酸  2- [4- (3'-Carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -3,3-dimethylbutyrylamino] -4-isobutylthiophene-3-carboxylic acid
[化 7] [Chemical 7]
Figure imgf000081_0003
Figure imgf000081_0003
2-[6-(3 ' -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-へキサノィルァ ミノ] -4-フエ-ルチオフェン- 3-カルボン酸 [化 8] 2- [6- (3'-carboxy-4, -phenolthiophene-2, -ylcarbamoyl) -hexanoylamino] -4-phenolthiophene-3-carboxylic acid [Chemical 8]
Figure imgf000082_0001
Figure imgf000082_0001
2-[5-(3 -カルポキシ -5 -メチル -4 -フエ-ルチオフェン- 2 -ィルカルバモイル) - ンタノィルァミノ] -5-メチル -4-フエ-ルチオフェン- 3-カルボン酸 2- [5- (3-Caloxy-5-methyl-4-phenylthiophene-2-ylcarbamoyl) -tertanoylamino] -5-methyl-4-phenylthiophene-3-carboxylic acid
[化 9] [Chemical 9]
Figure imgf000082_0002
Figure imgf000082_0002
2-[5-(3， -カルボキシ -5， -フエ-ルチオフェン- 2， -ィルカルバモイル)-ペンタノィルァ ミノ] -5-フエ-ルチオフェン- 3-カルボン酸 2- [5- (3, -Carboxy-5, -phenylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-phenolthiophene-3-carboxylic acid
[化 10] [Chemical 10]
Figure imgf000082_0003
Figure imgf000082_0003
2- [5- (3， -カルボキシ- 5， -クロロチォフェン- 2， -ィルカルバモイル) - ンタノィルァミノ ]-5-クロロチォフェン- 3-カルボン酸 2- [5- (3, -Carboxy-5, -chlorothiophene-2, -ylcarbamoyl) -tanoylamino] -5-chlorothiophene-3-carboxylic acid
[化 11] [Chemical 11]
Figure imgf000082_0004
Figure imgf000082_0004
2-[4-(3 ' -カルボキシ -4， -フエ-ルチオフェン- 2， -ィルカルバモイル)-シクロへキシル ルァミノ] -4-フエ-ルチオフェン- 3-カルボン酸 2- [4- (3'-carboxy-4, -phenylthiophene-2, -ylcarbamoyl) -cyclohexyl Luamino] -4-phenylthiophene-3-carboxylic acid
Figure imgf000083_0001
Figure imgf000083_0001
2-[5-(3， -カルボキシ- 5， -イソプロピル- 4， -メチルチオフェン- 2， -ィルカルバモイル) - ペンタノィルァミノ] -4-イソブチルチオフェン- 3-カルボン酸 2- [5- (3, -Carboxy-5, -isopropyl-4, -methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isobutylthiophene-3-carboxylic acid
[化 13] [Chemical 13]
Figure imgf000083_0002
Figure imgf000083_0002
2-[3-(3 ' -カルボキシ- 4' -イソブチルチオフェン- 2， -ィルカルバモイル)-プロパノィル ァミノ] -4-イソブチルチオフェン- 3-カルボン酸 2- [3- (3'-carboxy-4'-isobutylthiophene-2, -ylcarbamoyl) -propanoylamino] -4-isobutylthiophene-3-carboxylic acid
[化 14] [Chemical 14]
Figure imgf000083_0003
Figure imgf000083_0003
2-[5-(3 ' -カルボキシ- 4' -イソプロピルチオフェン- 2， -ィルカルバモイル)-ペンタノィ ルァミノ] -4-イソプロピルォフェン- 3-カルボン酸 2- [5- (3'-Carboxy-4'-isopropylthiophene-2, -ylcarbamoyl) -pentanoylamino] -4-isopropylophen-3-carboxylic acid
[化 15] [Chemical 15]
Figure imgf000083_0004
2-[5-(3， -カルボキシ -5， -メチルチオフェン- 2， -ィルカルバモイル)-ペンタノィルアミ ノ] -5-メチルチオフェン- 3-カルボン酸
Figure imgf000083_0004
2- [5- (3, -Carboxy-5, -methylthiophene-2, -ylcarbamoyl) -pentanoylamino] -5-methylthiophene-3-carboxylic acid
[化 16] [Chemical 16]
Figure imgf000084_0001
Figure imgf000084_0001
2-[5-(3 ' -tert-ブトキシカルボ-ル -5， -メチルチオフェン- 2 ' -ィルカルバモイル)-ぺ ンタノィルァミノ] -5-メチルチオフェン- 3-カルボン酸 2- [5- (3'-tert-Butoxycarbol-5, -methylthiophene-2'-ylcarbamoyl) -pentanoylamino] -5-methylthiophene-3-carboxylic acid
[化 17] [Chemical 17]
Figure imgf000084_0002
請求項 14または 15に記載する化合物若しくはその薬学的に許容される塩、または これらの溶媒和物からなる群から選択される少なくとも 1つを有効成分とする医薬組 成物。
Figure imgf000084_0002
16. A pharmaceutical composition comprising as an active ingredient at least one selected from the group consisting of the compound according to claim 14 or 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof.
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