WO1996020920A1 - Derive d'ester d'amidinonaphtyle - Google Patents

Derive d'ester d'amidinonaphtyle Download PDF

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Publication number
WO1996020920A1
WO1996020920A1 PCT/JP1995/000002 JP9500002W WO9620920A1 WO 1996020920 A1 WO1996020920 A1 WO 1996020920A1 JP 9500002 W JP9500002 W JP 9500002W WO 9620920 A1 WO9620920 A1 WO 9620920A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
compound
thrombolytic
medicament
thrombosis
Prior art date
Application number
PCT/JP1995/000002
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyuki Uchiyama
Toyoo Nakayama
Hiroyuki Kawamura
Original Assignee
Torii Pharmaceutical Co., Ltd.
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 Torii Pharmaceutical Co., Ltd. filed Critical Torii Pharmaceutical Co., Ltd.
Priority to AU13917/95A priority Critical patent/AU1391795A/en
Priority to PCT/JP1995/000002 priority patent/WO1996020920A1/fr
Publication of WO1996020920A1 publication Critical patent/WO1996020920A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to a novel amidino naphthyl ester derivative and a medicament containing the same as an active ingredient.
  • thrombosis A clot formed by coagulation of blood in the heart or blood vessels is called a thrombus, and the pathological phenomenon associated with the formation of this thrombus is called thrombosis.
  • thrombosis There are various types of thrombosis, including cerebral infarction, myocardial infarction, and pulmonary infarction.
  • Treatment methods for thrombosis can be broadly classified into two types according to their mechanism of action. Antithrombotic therapy to prevent thrombus formation, and thrombolytic therapy to dissolve the formed thrombus.
  • thrombolytic therapy uses a thrombolytic agent to activate plasminogen, a precursor of the regulator of the blood fibrinolysis system, into plasma, which is then converted into blood vessels. It is thought that by breaking down the fibrin that forms the thrombus, the blood is lysed and the obstructed site is opened.
  • Drugs used in this thrombolytic therapy include tissue plasminogen activator, plasminogen activator that activates plasminogen to plasmin (t-PA) and perokinase (t-PA). (UK)), cell-producing substances such as staphylokinase, streptokinase, etc. And their recombinants are known.
  • t-PA and the like are generally considered to be effective when administered intravenously.
  • the half-life in blood is short, and it is quickly removed from the liver. Therefore, these thrombolytic actions in the local area where a thrombus has occurred require a large amount of administration due to the presence of an inhibitory factor in vivo.
  • the transient large dose administration of this thrombolytic agent markedly enhances the thrombolytic effect systemically and is expected to open the occluded site, while severe hemorrhagic symptoms are observed. Etc. have been reported.
  • animal experiments and clinical cases have shown that reocclusion is likely to occur even when the site of occlusion is temporarily opened by administration of a thrombolytic agent.
  • since it is an injection there is also a problem in the administration method that the burden on the patient is long when administered for a long time.
  • An object of the present invention is to provide an amidinonaphthyl ester derivative which can be orally administered, has a fibrinolytic promoting action, and exhibits a systemic thrombolytic action.
  • the compound represented by The compound of the present invention has a dilysis promoting action, exhibits a strong thrombolytic action, and is also effective for diseases caused by thrombus.
  • the compound of the present invention represented by the formula (I) is converted into a corresponding acid addition salt by a known method.
  • the acid that can be used is not particularly limited as long as it is a salt that can be used as a medicament.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid
  • drunk acid lactic acid, and quencher Acid
  • Organic acids such as leic acid are exemplified.
  • the compound of the present invention can be administered orally or rectally to mammals (including human patients).
  • the compound of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. Examples of such compositions include tablets, powders, capsules, syrups or aqueous solutions. Additives such as ordinary excipients, lubricants, disintegrants and wetting agents can be used in the oral composition. Oral fluids may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or the like, or be reconstituted with water or another suitable solvent before use. It may be served as a dry mouth. Said solutions may contain conventional additives such as suspending agents, flavors, diluents or emulsifiers.
  • suppositories are cocoa butter, laurin fat, macrogol, grise mouth gelatin, and wite.
  • An appropriate substance such as Tubul, sodium stearate or a mixture thereof may be used as a base, and an emulsifier, a suspending agent, a preservative and the like may be added as necessary.
  • Excipients calcium hydrogen phosphate, synthetic aluminum phosphate Aluminum, magnesium magnesium silicate, aluminum magnesium hydroxide, magnesium magnesium silicate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, light gay anhydride, gay anhydride , Avicel, various starch dextrin carboxymethyl starch (CMS), lactose. Binders: ethylcellulose (EC), carboxymethylcellulose Na (CMC—Na), low-substituted hydroquinone propylcellulose (L-HPC), hydroquinone methyl Le Loose
  • HPMC methylcellulose
  • HPC methylcellulose
  • HPC methylcellulose
  • HPC hydroxypropylcellulose
  • various starches dextrins, sodium alginate, gelatin, polyvinyl alcohol
  • PVA polyvinylpyrrolidone
  • PVP polyvinylpyrrolidone
  • disintegrants synthetic aluminum gaymate, metasilicate aluminum
  • Anti-solidification agent Polyamic anhydride, Synthetic aluminum manganese lubricant Lubricant: Synthetic aluminum manganate, Gay anhydride, talc Avicel.
  • Flavoring agents mannitol, cunic acid, cunic acid Na, sugar Emulsifiers: gelatin, cunic acid, cunic acid Na, polyoxy Silicone-hardened castor oil (HCO—40, 60), macrogol (PEG), propylene glycol fatty acid ester, polyethylene glycol polypropylene Glycol, propylene glycol, raurylsulfate Na, phospholipids.
  • HCO—40, 60 polyoxy Silicone-hardened castor oil
  • PEG macrogol
  • propylene glycol fatty acid ester polyethylene glycol polypropylene Glycol
  • propylene glycol raurylsulfate Na
  • phospholipids phospholipids.
  • Stabilizers sodium bisulfite, borosilicate
  • Hydrogenated castor oil (HCO—40, 60), PEG propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene propylene glycol.
  • Lenggol, rauryl sulfate Na various natural and synthetic cyclodextrins, phospholipids.
  • Absorption promoter Polyoxyethylene hardened castor oil (HCO)
  • Solubilizing agent ethanol, HCO—40, HC0-60
  • Polypropylene glycol fatty acid ester Polyoxyethylene Polyoxypropylene propylene glycol, propylene glycol, lauric sulfate Na, Various natural and synthetic cyclodextrins.
  • Suspending agent CMC-Na, HPMC :, MC ;, HPC sodium alginate, gelatin, propylene glycol, lauryl sulfate Na.
  • Coating agent EC, magnesium gayate, talc, titanium oxide, calcium carbonate, triacetin, carboxime methyl ethyl cellulose (CMEC), cellulose nitrate phthalate (CAP), HPMC, hydroxypropyl methylcellulose Free Rate
  • HPCP HPC
  • sodium alginate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • polyvinyl acetal getylamino acetoacetate sodium alginate
  • Colorant titanium oxide, tar dye, caramel.
  • the dose is 100 to 1 OOO mg / day, preferably 200 to 900 mg Z days, more preferably 400 to 8 mg / day. It can be administered at a dose of 0 O mgZ daily.
  • the dose when administered to humans for therapeutic purposes is appropriately adjusted according to the severity of the illness, age and weight.
  • Example 2 A mixed solution of 0.2 g of DMAP, 15 ml of pyridine and 55 ml of DMF was stirred under ice cooling. Then DCC 2.0 g was added and reacted. The same operation as in Example 2 was performed to obtain 2.3 g of the desired product.
  • Magnesium stearate 2 mg Fill the capsules with a total amount of 20 Omg or press them into tablets Formulation example 2
  • the compound of the present invention has a fibrinolytic accelerating action and exhibits an excellent thrombolytic action, and is therefore effective for various diseases caused by thrombus.
  • the obtained plasma was incubated with 0.1 M borate buffer (pH 8.5) and Boc-Va Leu-Lys-MCA at 37 ° C for 30 minutes, and the reaction was stopped by adding 15% acetic acid.
  • the fluorescence intensity was measured and the brassin-like activity was determined, the compound of the present invention showed a strong increase in the blood brassin-like activity.
  • Table 2 shows the results.
  • the PAI-11 antigen was measured using the plasma obtained in the above test (2).
  • the toxicity of the compound of the present invention was very low, and it was determined that there would be no problem in administering it to humans or mammals.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'ester d'amidinonaphthyle efficace dans le traitement de la thrombose.
PCT/JP1995/000002 1995-01-05 1995-01-05 Derive d'ester d'amidinonaphtyle WO1996020920A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU13917/95A AU1391795A (en) 1995-01-05 1995-01-05 Amidinonaphthyl ester derivative
PCT/JP1995/000002 WO1996020920A1 (fr) 1995-01-05 1995-01-05 Derive d'ester d'amidinonaphtyle

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1995/000002 WO1996020920A1 (fr) 1995-01-05 1995-01-05 Derive d'ester d'amidinonaphtyle

Publications (1)

Publication Number Publication Date
WO1996020920A1 true WO1996020920A1 (fr) 1996-07-11

Family

ID=14125558

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/000002 WO1996020920A1 (fr) 1995-01-05 1995-01-05 Derive d'ester d'amidinonaphtyle

Country Status (2)

Country Link
AU (1) AU1391795A (fr)
WO (1) WO1996020920A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5753454A (en) * 1980-09-16 1982-03-30 Torii Yakuhin Kk Guanidinobenzoate and anticomplementary agent
JPS57179146A (en) * 1981-04-28 1982-11-04 Torii Yakuhin Kk Amidine compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5753454A (en) * 1980-09-16 1982-03-30 Torii Yakuhin Kk Guanidinobenzoate and anticomplementary agent
JPS57179146A (en) * 1981-04-28 1982-11-04 Torii Yakuhin Kk Amidine compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEM. PHARM. BULL., Vol. 33, No. 4, (1985), AOYAMA TAKUO et al., "Synthesis and Structure-Activity Study of Protease Inhibitors. IV. Admidinonaphthols and Related Acyl Derivatives", p. 1458-1471. *

Also Published As

Publication number Publication date
AU1391795A (en) 1996-07-24

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