WO2007083689A1 - Inhibiteur de type inhibiteur-1 des activateurs du plasminogène - Google Patents

Inhibiteur de type inhibiteur-1 des activateurs du plasminogène Download PDF

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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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English (en)
Japanese (ja)
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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/ja
Publication of WO2007083689A1 publication Critical patent/WO2007083689A1/fr

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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.

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Abstract

La présente invention concerne un inhibiteur PAI-1 et une préparation pharmaceutique contenant un composé de formule (1) ci-dessous ou un sel de ce composé au titre de principe actif. [Formule chimique 1] (1) [Dans la formule, R1 représente un atome d'hydrogène ou un groupement alkyle linéaire ou ramifié en C1-C4 ; R2 représente un groupement phényle ou thiényle éventuellement substitué, ou un groupement alkyle linéaire ou ramifié en C1-C6, R3 représente un atome d'hydrogène, ou, de façon alternative, R2 et R3 s'associent pour former un cycle à cinq ou six chaînons ; A représente un alkylène, un alcénylène ou un alcynylène linéaire ou ramifié en C1-C7, ou une liaison simple ; et R4 représente un atome d'hydrogène, un groupement phényle ou furyle éventuellement substitué, ou un groupement représenté par la formule (2) suivante : [Formule chimique 2] (2) (où R1’, R2’ et R3’ ont respectivement les mêmes valeurs que R1, R2 et R3).]
PCT/JP2007/050666 2006-01-19 2007-01-18 Inhibiteur de type inhibiteur-1 des activateurs du plasminogène WO2007083689A1 (fr)

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WO2009013915A1 (fr) * 2007-07-25 2009-01-29 Renascience Co., Ltd. Inhibiteur de l'inhibiteur de l'activateur du plasminogène de type 1
WO2009076454A2 (fr) * 2007-12-12 2009-06-18 Calcimedica, Inc. Compositions qui modulant le calcium intracellulaire
WO2009123241A1 (fr) * 2008-03-31 2009-10-08 株式会社レナサイエンス Inhibiteur de l'inhibiteur de l'activateur du plasminogène-1
WO2010025295A2 (fr) * 2008-08-27 2010-03-04 Calcimedica Inc. Composés modulant le calcium intracellulaire
WO2010113022A1 (fr) * 2009-03-31 2010-10-07 株式会社レナサイエンス Agent inhibiteur de l'inhibiteur de l'activateur du plasminogène 1
WO2010137160A1 (fr) * 2009-05-29 2010-12-02 株式会社 静岡カフェイン工業所 Agent prophylactique ou thérapeutique pour fibrose pulmonaire
US8263641B2 (en) 2007-09-10 2012-09-11 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US8524763B2 (en) 2008-09-22 2013-09-03 Calcimedica, Inc. Inhibitors of store operated calcium release
US8618307B2 (en) 2009-09-16 2013-12-31 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9079891B2 (en) 2010-08-27 2015-07-14 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10092537B2 (en) 2013-04-15 2018-10-09 Renascience Co., Ltd. Use for PAI-1 inhibitor
WO2022029210A1 (fr) * 2020-08-05 2022-02-10 Enyo Pharma Composés de thiophène destinés à être utilisés dans le traitement de la fibrose rénale

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