WO2003089426A1 - Medicament prophylactique ou therapeutique contre le syndrome de coagulation intravasculaire disseminee - Google Patents

Medicament prophylactique ou therapeutique contre le syndrome de coagulation intravasculaire disseminee Download PDF

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Publication number
WO2003089426A1
WO2003089426A1 PCT/JP2003/004985 JP0304985W WO03089426A1 WO 2003089426 A1 WO2003089426 A1 WO 2003089426A1 JP 0304985 W JP0304985 W JP 0304985W WO 03089426 A1 WO03089426 A1 WO 03089426A1
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WO
WIPO (PCT)
Prior art keywords
prevention
group
general formula
heparin
intravascular coagulation
Prior art date
Application number
PCT/JP2003/004985
Other languages
English (en)
Japanese (ja)
Inventor
Asako Hitomi
Yoshinori Toshima
Original Assignee
Asahi Kasei Pharma Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asahi Kasei Pharma Corporation filed Critical Asahi Kasei Pharma Corporation
Priority to AU2003231369A priority Critical patent/AU2003231369A1/en
Publication of WO2003089426A1 publication Critical patent/WO2003089426A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to an agent for preventing and treating disseminated intravascular coagulation.
  • DIC ART-Disseminated intravascular coagulation syndrome
  • jf Disseminated intravascular coagulation
  • secondary fibrinolysis is also added, resulting in a marked tendency to bleeding.
  • the principle of DIC treatment is to correct the hypercoagulable state together with the treatment of the underlying disease, and to treat heparin, low molecular weight heparin, gabexate mesylate.
  • Anticoagulant therapies such as nafamostat mesilate and dry concentrated human antithrombin III are being used, but anticoagulants are also subject to side effects such as bleeding. There is an eager need for superior DIC treatments.
  • Tissue factor (hereinafter abbreviated as “TF” in the present specification (Tissue Factor)) is expressed on the surface of vascular endothelial cells by stimulation of endotoxin and cytokin, and is said to be involved in the development of intravascular coagulation. ing.
  • tissue Factor Tissue Factor
  • the extrinsic coagulation cascade is deeply involved in the formation of the initial disease state.However, since TF is the starting point of this extrinsic coagulation cascade, inhibiting TF production requires early treatment of DIC. It is thought to be possible.
  • TF production inhibitors have no bleeding side effects compared to anticoagulants that act directly on clotting factors such as thrombin and plasmin in the treatment of DIC in which the coagulation and fibrinolytic system is compromised due to differences in the underlying disease It is expected as a new therapeutic agent [clinical blood, 35 (5), 461 (1994), History of medicine, 198 (1), 88 (2001)].
  • an anticoagulant such as heparin, low molecular weight heparin, gabexate mesylate, nafamostat mesilate, and dry concentrated human antithrombin III preparation have the mechanism of action. Are different, and additive or synergistic effects can be expected.
  • the compounds represented by the general formula (I) have kinase inhibitory activities such as rho kinase, myosin light chain phosphatase, and protein kinase C, and have a vascular smooth muscle relaxing action, a blood flow increasing action, a blood pressure lowering action, It is already known that it has a brain and cardioprotective effect, and is an effective substance in vasodilators (especially therapeutic agents for angina pectoris), brain and cardioprotectors, and the like. No. 152658, JP-A-61-22
  • the compound represented by the general formula (I) is a compound represented by the formula:
  • An object of the present invention is to provide a medicament for preventing or treating DIC.
  • the present inventors have conducted intensive studies on the compound represented by the general formula (I), and as a result, it has been found that the compound has the above-mentioned vascular smooth muscle relaxing action, blood flow increasing action, blood pressure lowering action, brain and heart protecting action. For example, the prevention and prevention of DIC, which is completely unexpected from And Z or have a therapeutic effect.
  • composition containing at least one or more drugs selected from the group consisting of the above can exert extremely high effects on the prevention and / or treatment of DIC as compared with the use alone. And completed the present invention.
  • R 1 represents a hydrogen atom or a hydroxyl group
  • a pharmaceutically acceptable salt thereof and a substance selected from the group consisting of hydrates and solvates thereof.
  • a pharmaceutical composition for preventing and / or treating DIC comprising at least one selected drug is provided.
  • a compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof for the production of the above-mentioned medicament or for the production of the above-mentioned pharmaceutical composition;
  • a method comprising the step of administering at least one therapeutic drug selected from the group consisting of gabexate acid, nafamostat mesilate, dry concentrated human antithrombin III, and thrombomodulin preparations simultaneously or at different times. Is done. BEST MODE FOR CARRYING OUT THE INVENTION
  • the compound represented by the general formula (I) can be prepared by a known method, for example, Chem. Pharam. Bull., 40, (3) 770-773 (1992), and JP-A-61-152658 Can be synthesized according to the method described in, for example.
  • an acid addition salt can be used, and for example, a pharmaceutically acceptable non-toxic salt is preferable.
  • examples include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and salts of organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, and methanesulfonic acid. Can be.
  • a hydrate or solvate of the compound represented by the above general formula (I) or a salt thereof may be used.
  • examples of the hydrate include / hydrate and the like (see US Pat. No. 5,924,505).
  • the medicament of the present invention can be administered orally or parenterally and can be prepared as a pharmaceutical composition in a form suitable for the administration route.
  • an effective compound selected from the group consisting of the compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof, and a hydrate and a solvate thereof is provided. What is necessary is just to mix the substance which is a component and a well-known pharmaceutically acceptable carrier.
  • the carrier examples include gelatin; sugars such as lactose and glucose; starches such as wheat, rice, and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; Alcohols such as stearin alcohol and benzyl alcohol; gums; polyalkylenedaricols and the like.
  • the liquid carrier examples include water, physiological saline, dextrose or a similar saccharide solution, and Darcols such as ethylene daricol, propylene glycolone, polyethylene glycolone, and polypropylene glycolone.
  • the pharmaceutical composition of the present invention can contain the above-mentioned substance which is an active ingredient in an amount of usually 0.01% by weight or more and 80% by weight or less, preferably 60% by weight or less.
  • Pharmaceutical compositions suitable for oral administration include tablets, capsules, powders, granules, liquids, elixirs and the like, and pharmaceutical compositions suitable for parenteral administration include liquids. When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, it is administered as a sterile solution containing other solutes such as salt or glucose to make the above active substance isotonic. You can also.
  • lidocaine hydrochloride solution for intramuscular injection
  • physiological saline for intramuscular injection
  • dextrose for intravenous injection
  • electrolyte solution for intravenous injection
  • it can be prepared so as to contain usually 0.01 to 20% by weight, preferably 0.1 to 10% by weight of the active ingredient.
  • liquid for oral administration In the case of liquid for oral administration,
  • the carrier includes aqueous excipients such as flavors, syrups, and pharmaceutical micelles.
  • the dosage of the medicament of the present invention may be, for example, the age, health condition, body weight, degree of symptoms, type of concurrent treatment, if any, treatment frequency, nature of desired effect, or administration route or administration schedule, etc.
  • parenteral administration is 0.01 to 20 mg / kgday
  • oral administration is 0.02 to 4 mg / kgday.
  • the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof The daily dose varies depending on the administration route and administration schedule, but generally, may be smaller than the single dose. For example, the parenteral dose is 0.005 to 2 OmgZkg 'day, and the oral dose is 0.01 to 40 mg / kg'day.
  • Drugs that should be used in combination include, for example, heparin, low molecular weight heparin, Examples include at least one drug selected from the group consisting of bexate, nafamostat mesilate, dry concentrated human antithrombin III, and oral tonbomodulin preparations. These drugs can be administered primarily by intravenous or intravenous infusion. Other administration methods may be used as long as the effective concentration can be reached in the blood, specifically, intramuscular injection, subcutaneous administration, oral, nasal, lung, enteral And transmucosal administration methods as described above.
  • Administration * 1 to 100,000 units / day for heparin, 1 to 10,000 units / day for low molecular weight heparin, 1-10000 units for anticiprombin III, Z day, 1 to 10 Omg / day for gabexate mesylate For acid nafamostat, 0.01 to 10 mg Z days is exemplified.
  • the dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like of the administration subject.
  • at least one therapeutic agent selected from the group consisting of gabexate mesilate, nafamostat mesilate, dry concentrated human antithrombin III, and thrombomodulin the order of administration of these active ingredients is restricted. There is no limitation, and they may be administered at the same time or individually at different times, but it is also possible to prepare a composition (a so-called combination drug) containing two or more active ingredients in combination and administer them simultaneously.
  • Example 1 Example 1
  • HUVEC human umbilical vein vascular endothelial cells
  • a medicament for Dc prevention and Z or treatment there is provided a medicament for Dc prevention and Z or treatment.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un médicament prophylactique ou thérapeutique contre le syndrome de coagulation intravasculaire disséminée. Son principe actif est une substance prise dans le groupe constitué par un composé représenté par la formule générale (I), l'un de ses sels pharmaceutiquement admis, l'un de ses hydrates et l'un de ses solvatés. Dans cette formule, R1 est atome d'hydrogène ou groupe hydroxyle.
PCT/JP2003/004985 2002-04-19 2003-04-18 Medicament prophylactique ou therapeutique contre le syndrome de coagulation intravasculaire disseminee WO2003089426A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003231369A AU2003231369A1 (en) 2002-04-19 2003-04-18 Medicine for prevention and/or therapy of disseminated intravascular coagulation syndrome

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002117356A JP2005320247A (ja) 2002-04-19 2002-04-19 播種性血管内凝固症候群予防、治療剤
JP2002-117356 2002-04-19

Publications (1)

Publication Number Publication Date
WO2003089426A1 true WO2003089426A1 (fr) 2003-10-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/004985 WO2003089426A1 (fr) 2002-04-19 2003-04-18 Medicament prophylactique ou therapeutique contre le syndrome de coagulation intravasculaire disseminee

Country Status (3)

Country Link
JP (1) JP2005320247A (fr)
AU (1) AU2003231369A1 (fr)
WO (1) WO2003089426A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005290A1 (fr) * 1992-09-03 1994-03-17 Asahi Kasei Kogyo Kabushiki Kaisha Inhibiteur d'agregation plaquettaire
JPH07277979A (ja) * 1994-04-12 1995-10-24 Asahi Chem Ind Co Ltd 過粘性症候群治療または予防剤
JP2002060345A (ja) * 2000-08-21 2002-02-26 Mochida Pharmaceut Co Ltd 血液凝固能異常に係わる疾患の予防・治療剤
EP1188770A1 (fr) * 1999-06-14 2002-03-20 Fujimori Kogyo Co., Ltd. Substance se liant au substrat du facteur de coagulation sanguine active en competition avec ce facteur pour reguler la reaction entre un tel facteur et le substrat, et procede de production de la substance et de l'adsorbant du facteur au moyen de la substance

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005290A1 (fr) * 1992-09-03 1994-03-17 Asahi Kasei Kogyo Kabushiki Kaisha Inhibiteur d'agregation plaquettaire
JPH07277979A (ja) * 1994-04-12 1995-10-24 Asahi Chem Ind Co Ltd 過粘性症候群治療または予防剤
EP1188770A1 (fr) * 1999-06-14 2002-03-20 Fujimori Kogyo Co., Ltd. Substance se liant au substrat du facteur de coagulation sanguine active en competition avec ce facteur pour reguler la reaction entre un tel facteur et le substrat, et procede de production de la substance et de l'adsorbant du facteur au moyen de la substance
JP2002060345A (ja) * 2000-08-21 2002-02-26 Mochida Pharmaceut Co Ltd 血液凝固能異常に係わる疾患の予防・治療剤

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Publication number Publication date
JP2005320247A (ja) 2005-11-17
AU2003231369A1 (en) 2003-11-03

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