WO2006088011A1

WO2006088011A1 - Inhibitor of plasminogen activator inhibitor-1

Info

Publication number: WO2006088011A1
Application number: PCT/JP2006/302509
Authority: WO
Inventors: Toshio Miyata; Noriaki Hirayama
Original assignee: Tokai University Educational System
Priority date: 2005-02-15
Filing date: 2006-02-14
Publication date: 2006-08-24
Also published as: JPWO2006088011A1

Abstract

It is intended to provide an inhibitor of plasminogen activator inhibitor-1 (PAI-1) whose active ingredient is a compound represented by the formula (I): [Chemical formula 1] (I) in a free or salt form. The inhibitor of PAI-1 of the invention is a fibrinolytic system-promoting agent derived from a small molecule compound with high safety and can be synthesized in a large amount in the category of fibrinolytic system-promoting agent and is effective particularly in the prevention or treatment of angina pectoris, atrial thrombus in cardiac infarction or atrial fibrillation, ischemic heart diseases, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary thromboembolism, deep vein thrombosis (DVT) in surgery, disseminated intravascular coagulation (DIC), angiopathy, neuropathy, retinopathy or nephropathy as a diabetic complication, or restenosis after percutaneous transluminal coronary angioplasty (PTCA).

Description

Specification

Plasminogen activator inhibitor 1 inhibitor

Technical field

The present invention relates to a plasminogen activator inhibitor 1 (PAI-1) inhibitor. More specifically, the present invention has an excellent plasminogen activator inhibitor 1 activity inhibitory action, etc., and ischemic heart such as angina pectoris, myocardial infarction, atrial thrombus in atrial fibrillation, heart failure, etc. Disease, cerebral embolism, cerebral infarction, ischemic cerebrovascular disorder such as transient cerebral ischemic attack, arteriosclerosis, pulmonary embolism, deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), diabetic complications (angiopathy, neuropathy, retinopathy, nephropathy, etc.), drugs for preventing or treating restenosis after percutaneous coronary angioplasty (PTCA).

Background art

[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] The fibrinolysis (fibrinolysis) system plays an important role in thrombolysis, tissue destruction and repair, cell migration, and the like. The fibrinolytic system is activated by the plasminogen activator (hereinafter referred to as “PA”) by converting plasminogen to plasmin. On the other hand, plasminogen inhibitor inhibitor 1 (hereinafter referred to as “PAI-1”) inhibits PA.

[0004] Tissue plasminogen activator (t-PA) converts plasminogen, a precursor of plasmin, to plasmin. Plasmin breaks down fibrin into a fibrin degradation product.

[0005] PAI-1 is tPA and urokinase-type plasminogen activator (u-PA) Is a serine protease inhibitor that specifically inhibits plasmin, suppresses the production of plasmin, and thus inhibits the degradation of fibrin.

[0006] PAI-1 is classified into an active form showing PA inhibitory activity and a latent form not showing depending on the three-dimensional structure. Normally, 20 ngZmL of PAI-1 is present in plasma, and it is also known to be produced in hepatocytes, megakaryocytes, and fat cells in addition to vascular endothelial cells, which are the main production cells.

[0007] PAI-1 is an acute phase protein, and its production is enhanced by various site force-in and growth factors. As a cause of ischemic organ damage in sepsis and disseminated intravascular coagulation syndrome (DIC) It is considered. In addition, genetic polymorphism due to single nucleotide substitution of the PAI-1 gene promoter is known, and an increase in plasma PAI-1 concentration has been clarified.

[0008] Further, in diabetes, it is considered that the promotion of arteriosclerosis and microvascular complications cause ischemic heart disease, diabetic retinopathy and kidney damage, which are important complications of diabetes. It has been. For example, diabetic nephropathy is characterized by increased glomerular extracellular matrix and interstitial fibrosis, which enhances the expression of PAI-1 in the glomeruli and tubules. Proximal tubule cultures show increased PAI-1 production under hyperglycemic conditions. In experiments using renal stromal fibrosis model mice, the correlation between the expression of PAI-1 in the renal tissue and macrophage infiltration has been confirmed (see Non-Patent Document 1).

[0009] Daily animal urine from a patient with nephrotic syndrome was concentrated, and the amount of PAI-1 in the urine was measured using a sandwich ELISA measurement kit (Biopool) using anti-PAI-1 monoclonal antibody polyclonal antibody. It has been reported that urinary PAI-1 concentration in patients with nephrotic syndrome showed a high value (see Non-Patent Document 2).

[0010] When an inactive PAI-1 mutant (Non-Patent Document 3) or tPA (Non-Patent Document 4) is administered as a PAI-1 antagonist to a Thy-1 nephritis model, inflammation (cell infiltration) is reduced. A decrease in TGF β and a decrease in mesangial substrate were confirmed, and an improvement in Thy-1 nephritis was observed.

[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! /, Some other thrombogenic abnormalities are also Have contributed to the formation of microthrombi and play an important role in the progression of diabetic microangiopathy and diabetic macroangiopathy.

[0012] Thus, PAI-1 is considered to be involved in the formation and development of various thrombosis, cancer, diabetes, arteriosclerosis and other pathological conditions. Therefore, compounds that inhibit the activity of PAI-1 are useful as preventive and therapeutic agents for thrombosis, cancer, diabetic complications, arteriosclerosis, etc. (Non-patent Document 5).

Non-Patent Document 1: 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. (Kiichi Niichi '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

Disclosure of the invention

Problems to be solved by the invention

[0013] Until now, urokinase (u-PA) has been known as a fibrinolytic promoter. It has been purified from human urine, and its production efficiency and safety are never high. Furthermore, the molecular weight of urokinase is about 54000, which is a so-called polymer. In addition, tisokinase, alteplase (genetical recombination), nasarplase (cell culture), nateplase (genetic recombination), monteplase (genetical recombination), nomitepase (genetic recombination) and batroxobin are known. Is also a polymer. Therefore, in the category of fibrinolytic promoters, there has been a demand for fibrinolytic promoters derived from low molecular weight compounds that can be synthesized in large quantities and are highly safe.

Means for solving the problem

[0014] As a result of diligent research to solve the above problems, the present inventors have found that free form or Salt form formula (I)

[Chemical 1]

The compound represented by the following formula (hereinafter referred to as the compound of the present invention), ie, 3,3′-bis-diphenyl-rucetylamino-biphenyl-4,4-dicarboxylic acid is a plasminogen activator. 1 (PAI-1) found to have inhibitory activity, and completed the present invention.

[0015] According to the present invention, a fibrinolytic promoter derived from a low molecular weight compound that can be synthesized in large quantities and has high safety is provided.

Brief Description of Drawings

FIG. 1 shows that the compound of the present invention has PAI-1 inhibitory activity.

FIG. 2 shows that the compound of the present invention does not have antiplasmin inhibitory activity. BEST MODE FOR CARRYING OUT THE INVENTION

[0017] In a first embodiment of the present invention, there is provided a PAI-1 inhibitor, wherein the active ingredient is the compound of the present invention.

[0018] In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier.

[0019] In still another embodiment of the present invention, intra-atrial thrombus in angina pectoris, myocardial infarction or atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary embolism, surgical hand Postoperative deep vein thrombosis (DVT), disseminated intravascular coagulation syndrome (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or percutaneous coronary angioplasty (P TCA) There is provided a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier for preventing or treating restenosis.

[0020] In still yet another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier for oral administration.

[0021] The compound of the present invention is commercially available, for example, from ASINEX (URL; http://www.asinex.com) as a product having the code number BAS00132591.

[0022] In the present specification, PAI-1 is a single-chain glycoprotein (molecular weight of about 50000) consisting of 379 amino acid residues and a sugar, and is a plasminogen activator such as urokinase in human urine. It forms a complex, or it exists in its free form. PAI-1 in the present specification may be either a complex or a free form. PAI-1 is described in detail, for example, in Biol. Chem. Hoppe-Seyler, vol. 377: 1-17, 1996.

[0023] The compound of the present invention has an excellent PAI-1 activity inhibitory action and the like. As a result, fibrin degradation action and fibrinogen degradation action by plasmin are enhanced. Therefore, the compound of the present invention is an ischemic brain such as 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. Vascular disorders, arteriosclerosis, pulmonary embolism, deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), diabetic complications (vascular disorder, neuropathy, retinopathy, nephropathy, etc.) ), Restenosis after percutaneous coronary angioplasty (PTCA), and is useful as a prophylactic or therapeutic agent for various pathological conditions involving thrombus formation.

[0024] When used as a prophylactic or therapeutic agent, the compound of the present invention can be used as it is or after being subjected to various treatments such as diluting in water, and is used in combination with pharmaceuticals, quasi drugs and the like. be able to. The compounding amount in this case is appropriately selected according to the disease state and the product. In the case of a 1S systemic system preparation, it can be 0.001 to 50% by weight, particularly 0.01 to L0% by weight based on the total weight of the preparation. If the amount is less than 0.001% by weight, a satisfactory preventive or therapeutic effect may not be observed. If the amount exceeds 50% by weight, the product itself may not be obtained. It is not preferable because the properties such as stability and flavor may be impaired.

[0025] The compounds of the present invention may be included in the formulation in free or salt form. Examples of the salt form generally include pharmaceutically acceptable salts such as salts with inorganic bases or organic bases, or acid addition salts such as inorganic acids, organic acids, basic or acidic 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 ammonium. Examples of the organic salt include primary amines such as ethanolamine; secondary amines such as jetylamine, diethanolamine, dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine; trimethylamine, And tertiary amines such as triethylamine, pyridine, picoline, triethanolamine and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of organic acids include formic acid, acetic acid, lactic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, succinic acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfone. Examples thereof include acid and ρ-toluenesulfonic acid. Examples of basic amino acids include arginine, lysine, ornithine and the like. Examples of acidic amino acids include aspartic acid and glutamic acid.

[0026] As a method for administering the pharmaceutical composition of the present invention, in addition to oral administration and intravenous administration, transmucosal administration, transdermal administration, intramuscular administration, subcutaneous administration, intrarectal administration and the like can be appropriately selected. It can be used as various preparations depending on the method. Each formulation is described below, but the dosage form used in the present invention is not limited to these and can be used as various formulations usually used in the field of pharmaceutical formulation. Further details about techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Macack Publishing Co, Easton PA).

[0027] When used as a prophylactic or therapeutic agent for a disease state involving thrombus formation, the oral dose of the compound of the present invention is preferably in the range of 0.03 mgZkg to 30 mgZkg, more preferably 0.1 mgZkg to 10 mgZkg. . For systemic administration, especially for intravenous administration, it may vary depending on age, sex, body type, etc., but effective blood concentration is 0.2 / z gZmL to 20 μg / mL, more preferably 0.5 μg / mL Administered to be in the range of ~ 10 μgZmL Should.

[0028] The dosage forms for oral administration include powders, granules, capsules, pills, tablets, elixirs, suspensions, emulsions and syrups, which can be selected as appropriate. In addition, these preparations can be modified such as sustained release, stabilization, easy disintegration, hardly disintegrating, enteric, and easy absorption. In addition, dosage forms for topical administration in the oral cavity include chewing agents, sublingual agents, buccal agents, troches, ointments, patches, liquids, etc., and can be selected as appropriate. In addition, these preparations can be modified such as sustained release, stabilization, easy disintegration, hardly disintegrating, enteric properties, and easy absorption.

[0029] 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 refers to a drug product in an optimal drug product form taking into account side effects.

[0030] The components of DDS basically consist of drugs, drug release modules, encapsulations, and therapeutic program powers, and each component reduces by half the blood concentration quickly, especially when release is stopped. Encapsulants that do not react with the biological tissue at the administration site where preferred drugs are preferred are preferred. In addition, it is preferable to have a treatment program that maintains the best drug concentration over a set period of time. The drug release module is basically a drug reservoir

, Having a release control, an energy source and a release hole or release surface. It is not necessary to have all of these basic components, and the best mode can be selected by adding or deleting as appropriate.

[0031] Materials that can be used in the DDS preparation include polymers, cyclodextrin derivatives, lecithin and the like. For polymers, insoluble polymers (silicon, ethylene 'butyl acetate copolymer, ethylene' butyl alcohol copolymer, ethyl cellulose, cellulose acetate, etc.), water-soluble polymers and hydroxyl gel-forming polymers (polyacrylamide) , Cross-linked polyhydroxyethyl methacrylate, polyacrylic cross-linked product, polybutyl alcohol, polyethylene oxide, water-soluble cellulose derivative, cross-linked poloxamer, chitin, chitosan, etc.), slowly soluble polymer (ethyl cellulose, methylbi- Luether 'maleic anhydride copolymer part Gastric soluble polymers (hydroxypropylmethylcellulose, hydroxypropylcellulose, carmellose sodium, macrogol, polybutylpyrrolidone, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, etc.), enteric polymers ( Hydroxypropylmethylcellulose phthalate, phthalcellulose acetate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, acrylate polymer, etc.), biodegradable polymers (thermally coagulated or crosslinked albumin, crosslinked gelatin, collagen, Fibrin, polycianoacrylate, polydalicolic acid, polylactic acid, poly 13 hydroxyacetic acid, poly force prolatatone, etc.) and can be appropriately selected depending on the dosage form

[0032] In particular, partial esters of silicon, ethylene 'acetic acid butyl copolymer, ethylene butyl alcohol copolymer, methyl butyl ether / maleic anhydride copolymer can be used for drug release control, and cellulose acetate is osmotic pressure. It can be used as a pump material. Ethenoresenorelose, hydroxypropinoremethinoresenorelose, hydroxypropinoresenorelose, and methylcellulose can be used as membrane materials for sustained-release preparations, and polyacrylic crosslinked products can be used for oral mucosa or ocular Can be used as a mucoadhesive agent.

[0033] In addition, the pharmaceutical preparation may contain a pharmaceutically acceptable carrier depending on its dosage form (known dosage forms such as oral administration agents, injections, and suppositories). Pharmaceutically acceptable carriers include solvents, excipients, coating agents, bases, binders, lubricants, disintegrants, solubilizers, suspending agents, thickeners, emulsifiers, stabilizers, buffers. Agents, tonicity agents, soothing agents, preservatives, flavoring agents, fragrances, colorants. Specific examples of the pharmaceutically acceptable carrier are listed below, but the carrier that can be used in the present invention is not limited thereto.

[0034] 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, talc, titanium oxide, Examples include trehalose and xylitol.

[0035] Coating agents include sucrose, hydroxypropyl cellulose (HPC), shellac, Latin, glycerin, sorbitol, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polybutylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), methylmethacrylate methacrylic acid copolymer And the above-described polymers.

[0036] Bases include petrolatum, liquid paraffin, carnauba wax, beef tallow, hydrogenated oil, norafin, beeswax, vegetable oil, macrogol, macrogol fatty acid ester, stearic acid, sodium carboxymethylcellulose, bentonite, cacao butter, witetbuzol , Gelatin, stearyl alcohol, hydrolanolin, cetanol, light liquid paraffin, hydrophilic salmon, single ointment, white ointment, hydrophilic ointment, macrogol ointment, hard fat, oil-in-water emulsion base, water-in-oil emulsion Can be mentioned.

[0037] Examples of binders include starch and its derivatives, cellulose and its derivatives (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.

[0038] 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.

[0039] Disintegrants include starch and derivatives thereof, agar, gelatin powder, sodium hydrogen carbonate, calcium carbonate, cellulose and derivatives thereof, hydroxypropyl starch, strength ruboxymethylcellulose and salts thereof, and cross-linked products thereof, low substitution type And hydroxypropylcellulose.

[0040] Examples of the solubilizer include cyclodextrin, ethanol, propylene glycol, and polyethylene glycol.

Examples of the suspending agent include sodium carboxymethylcellulose, polybutylpyrrolidone, arabic gum, tragacanth, sodium alginate, aluminum monostearate, citrate, and various surfactants. [0041] Examples of the thickening agent include sodium carboxymethylcellulose, polybutylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, tragacanth.

Arabic gum, sodium alginate and the like.

[0042] 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).

[0043] Stabilizers include tocopherols, chelating agents (eg EDTA, thioglycolic acid), inert gases (eg nitrogen, diacid-carbon), reducing substances (eg sodium bisulfite, sodium thiosulfate, ascorbine). Acid, longalite) and the like.

Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium citrate, boric acid and the like.

[0044] Examples of the isotonic agent include sodium chloride salt and glucose.

Examples of soothing agents include local anesthetics (pro-in hydrochloride, lidocaine), benzyl alcohol, glucose, sorbitol, amino acids and the like.

[0045] Examples of the preservative include benzoic acid and salts thereof, paraoxybenzoic acid esters, chlorobutanol, reverse soap, benzyl alcohol, phenol, thimerosal, dehydroacetic acid, boric acid, and the like.

Examples of the corrigent include sucrose, saccharin, licorice extract, sorbitol, xylitol, dariserine and the like.

[0046] Examples of the fragrances include spruce tincture and rose oil.

Examples of the colorant include water-soluble food dyes and lake dyes.

[0047] As described above, by making a pharmaceutical product into a DDS formulation such as a sustained release formulation, an enteric formulation or a controlled drug release formulation, the effective blood concentration of the drug can be maintained and the availability of the drug can be improved. The effect can be expected. However, the compounds of the present invention may be inactivated or degraded in vivo, resulting in a reduction or disappearance of the desired effect. Therefore, by using a substance that inhibits a substance that inactivates or degrades the compound of the present invention in combination with the preventive or therapeutic composition for the pathological condition involved in the thrombus formation of the present invention, the effects of the components can be further sustained. . These may be included in the formulation or administered separately. This A person skilled in the art can appropriately identify a substance that inactivates or decomposes the compound of the present invention, selects a substance that inhibits the substance, and mixes or uses it together.

[0048] In the preparation, components other than those described above that are used in ordinary compositions can be used, and the amount of these components added is a normal amount within a range that does not interfere with the effects of the present invention. It can be done.

[0049] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

[0050] All reagents used in the following examples are commercially available. An example is shown in Table 1 below.

[table 1]

table 1

Example 1

Chromogenic Atsey (Synthetic Substrate Method)

In order to evaluate the inhibitory effect of the compound of the present invention on the PAI-1 activity, 20 mM so that the PAI-1 solution adjusted to 6.7 pmol / μL and the compound of the present invention have a molar ratio of 750-7500 times. 37 in Tris-HCl (pH 7.8), 0.1% Tween80. C, incubated for 15 minutes, and then reacted with yarn and weave plasminogen activator (tPA) adjusted to 2.45 pmolZ L for 15 minutes at 37 ° C. Subsequently, 1. 25 mM S-2288 synthetic substrate (Daiichi Chemical Co., Ltd., Tokyo, Japan) was added, and P-trotro-rin released from the substrate peptide by tPA cleavage was absorbed every 5 minutes at an absorbance of 405 nm, 30 Measured for minutes. As a control, a buffer solution was added instead of the compound, and the PAI-1 inhibitory action of the compound was evaluated with the PAI-1 activity 30 minutes after this as 100%. As a result, the compound of the present invention showed almost no inhibition of PAI-1 activity at a final concentration of 20 M, and inhibited it to 85% and 60% at 100 / ζ / and 200 / ζ それ, respectively. (refer graph1).

Example 2 [0052] Examination of the inhibitory effect of P AI-1 low molecular weight compounds on antiplasmin (AP) activity by chromodientic assay (synthetic substrate method)

In order to evaluate the inhibitory effect of the compound of the present invention on antiplasmin (AP) activity, plasmin activity measurement using a synthetic substrate was examined. 3. Add AP adjusted to 2pmolZ L and the compound of the present invention in an excess amount equivalent to 15000 times in molar ratio, and add 20 mM Tris-HCl (pH 7.8), 0.1% Tween80 at 37 ° C. Incubated for 15 minutes. Then, it was reacted with plasmin adjusted to 0.5 pmolZ L at 37 ° C for 15 minutes. Subsequently, 1.25 mM plasmin synthetic substrate (Peptide Laboratories, Osaka, Japan) was added, and the substrate peptide force released by plasmin cleavage was measured at a fluorescence wavelength of 380 nm and an excitation wavelength of 460 nm every 5 minutes for 30 minutes. As a control, a buffer solution is added instead of the compound of the present invention, and AP activity is measured 30 minutes later. The AP inhibitory action of the compound of the present invention was evaluated with the AP activity of this control as 100%. As a result, it can be seen that the compound of the present invention does not inhibit AP activity even when an excessive amount of the compound of the present invention is added to AP, and has high PAI-1 specificity (see FIG. 2).

[0053] Production Example 1: Production of granules

Granules having the following composition (Table 2) are produced according to conventional methods. That is, the compound of the present invention is passed through a No. 30 sieve, and then the compound of the present invention, ratatose, Avicel PH102 and Polyplasdone XL are mixed in a mixer for 15 minutes. Granulate the mixture with a sufficient amount of water (approx. 500 mL), dry in an oven at 35 ° C overnight, and strain No. 20 sieve. The magnesium stearate is passed through a No. 20 sieve to make the granulation mixture, and the mixture is mixed in a mixer for 5 minutes to obtain granules.

[Table 2]

Table 2

Industrial applicability The compound of the present invention has an excellent PAI-1 activity inhibitory action and the like. As a result, fibrin degradation action and fibrinogen degradation action by plasmin are enhanced. Therefore, the compound of the present invention is an ischemic brain such as 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. Vascular disorders, arteriosclerosis, pulmonary embolism, deep vein thrombosis (DVT) during surgery, disseminated intravascular coagulation syndrome (DIC), diabetic complications (vascular disorder, neuropathy, retinopathy, nephropathy, etc.) ), Restenosis after percutaneous coronary angioplasty (PTCA), and is useful as a prophylactic or therapeutic agent for various pathological conditions involving thrombus formation. In addition, the PAI-1 inhibitor of the present invention provides a highly safe fibrinolytic promoter derived from a low molecular weight compound that can be synthesized in a large amount in the strength category of the fibrinolytic promoter.

Claims

Claims [1] The active ingredient is in the free or salt form of formula (I):

[Chemical 1]

A plasminogen inhibitor inhibitor, which is a compound represented by

[2] A pharmaceutical composition comprising the plasminogen inhibitor inhibitor according to claim 1 and at least one pharmaceutically acceptable carrier.

[3] Angina pectoris, intra-atrial thrombus in myocardial infarction or atrial fibrillation, ischemic heart disease, ischemic cerebrovascular disorder, arteriosclerosis, pulmonary embolism, deep vein thrombosis (DVT) during surgery, dissemination Claim 2 for preventing or treating restenosis after diabetic intravascular coagulation (DIC), vascular disorders as diabetic complications, neuropathy, retinopathy or nephropathy, or percutaneous coronary angioplasty (PTCA) A pharmaceutical composition according to 1.

[4] The pharmaceutical composition according to claim 2 or 3, for oral administration.