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WO2000031036A1 - Nouveaux derives de naphtalene - Google Patents

Nouveaux derives de naphtalene Download PDF

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Publication number
WO2000031036A1
WO2000031036A1 PCT/JP1999/002939 JP9902939W WO0031036A1 WO 2000031036 A1 WO2000031036 A1 WO 2000031036A1 JP 9902939 W JP9902939 W JP 9902939W WO 0031036 A1 WO0031036 A1 WO 0031036A1
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WIPO (PCT)
Prior art keywords
acid
formula
compound
group
methyl
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PCT/JP1999/002939
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English (en)
Japanese (ja)
Inventor
Hiroshi Ashizawa
Yoshiharu Ito
Tatsuhiko Watanuki
Atsushi Midorikawa
Shigeru Ikeda
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Torii Pharmaceutical Co., Ltd.
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Application filed by Torii Pharmaceutical Co., Ltd. filed Critical Torii Pharmaceutical Co., Ltd.
Priority to AU40584/99A priority Critical patent/AU4058499A/en
Priority to PCT/JP2000/002279 priority patent/WO2001077076A1/fr
Publication of WO2000031036A1 publication Critical patent/WO2000031036A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/04—Five-membered rings
    • 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
    • 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

Definitions

  • the present invention relates to a naphthalene derivative having a fibrinolysis-promoting action and useful as a thrombolytic agent and an antithrombotic agent.
  • the blood coagulation system acts as a defense mechanism to prevent bleeding, and forms a hemostatic thrombus at the damaged site.
  • a fibrinolytic system that dissolves thrombus formed in the blood vessels and maintains blood flow.
  • t-PA Produce and secrete
  • t-PA converts the inactive form of plasminogen present in the blood to the active form of plasmin on the thrombus.
  • the resulting plasmin exerts an enzymatic action and degrades fibrin, a component of the thrombus, thereby promoting thrombolysis. This series of reactions is called fibrinolysis.
  • a plasminogen activator (PA) other than t-PA a perokinase-type plasminogen activator (u-PA) is known to be present in blood vessels. Dissolution of this thrombus must occur at the appropriate time.
  • the thrombus dissolves too early, it causes bleeding, and if it is too late, the thrombus increases, resulting in narrowing or occlusion of blood vessels.
  • the homeostasis of the living body is maintained by this delicate balance between the coagulation system and the fibrinolysis system. This subtle balance breaks down, and when leaning toward the coagulation system, it becomes thrombotic and produces thrombi.
  • a blood vessel becomes narrowed or obstructed by this thrombus, the tissue under the control of the blood vessel may become severely ischemic, such as myocardial infarction, stroke, angina, pulmonary embolism, disseminated intravascular coagulation (DIC) And so on.
  • DIC disseminated intravascular coagulation
  • thrombolytic therapy therapies to administer PAs to dissolve thrombus, namely thrombolytic therapy (fibrinolytic therapy) 1 are widely practiced.
  • the thrombolytic agents used in this fibrinolytic therapy include biological substances such as perokinase (UK) and t-PA, and bacterial cell producing substances such as streptokinase (SK) and staphylokinase (SAK). Genetically modified products and the like are known.
  • thrombolytic drugs are all protein preparations, they have a short half-life in blood, are rapidly metabolized in the liver, and have thrombi due to the presence of inhibitors in vivo. Large-dose administration is required to exert a thrombolytic effect locally. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate. However, such a transient large-volume administration of a thrombolytic agent significantly enhances the thrombolytic activity systemically, resulting in thromboembolic sites. Is expected to be opened, but serious side effects of bleeding are observed. Further, even if the embolization site is temporarily opened by administration of these thrombolytic agents, reocclusion tends to occur easily, which is a major problem.
  • the method of administration used for treatment is intravenous systemic administration or intracoronary administration, and since it is directly administered into blood vessels, there is a problem that long-term administration requires a large burden on patients. . Therefore, development of orally administrable thrombolytic agents based on a new mechanism of action is desired.
  • An object of the present invention is to provide an antithrombotic agent and a thrombolytic agent which have a fibrinolysis promoting action and can be orally administered.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the following novel naphthalene derivatives have excellent fibrinolysis-promoting activity and are extremely useful as antithrombotic agents and thrombolytic agents. That is, the present invention provides the following formula (1)
  • R 1 represents a hydrogen atom, R 2 -carbonyl lower alkyl group or R 3 -lower alkyl group
  • R 2 represents a hydroxyl group, a lower alkoxy group, a lower alkylamino group having a substituent, or a lower alkyl group
  • R 3 represents a phenyl group having a substituent, an amino group having a substituent or a hydroxyl group
  • R 4 represents a hydrogen atom or a lower acyl group
  • X represents an oxygen atom or a sulfur atom
  • R5 represents a halogen, a hydroxyl group, a mercapto group, one OR6 or one S R6, R6 represents a lower alkyl group or R7-carbonyl lower alkyl group, R7 represents a hydroxyl group or a lower alkoxy group,
  • R 8 represents a hydrogen atom or a lower alkyl group
  • the compound represented by is useful as a synthetic intermediate for the compound represented by the formula (1).
  • the lower alkyl group as a part of the lower alkyl group and the lower alkoxy group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methyl group, an ethyl group Propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and hexyl group.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the compound represented by the above formula (1) of the present invention can be converted into a pharmacologically acceptable salt as required, or the resulting salt can be converted into a free base or a free acid. Further, those compounds may be solvates.
  • Salts include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, and amino acid addition salts.
  • examples of the acid addition salts include inorganic acid salts such as hydrochloride, phosphate, and sulfate, and organic acid salts such as acetate, citrate, and methanesulfonate, and sodium as the metal salt.
  • Alkali metal salts such as salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts; etc.
  • Ammonium salts include salts such as ammonium, and organic amine salt addition salts Include addition salts such as morpholine and piperidine, and amino acid addition salts include addition salts such as glycine and lysine. Examples of the solvates include hydrates.
  • A is as defined above.
  • the compound represented by the formula (1) can be obtained by using the compound represented by the formula (3) and the compound represented by the formula (5) by the method of Somma i Pivsa-Art et al. [Bull. Chem. Soc. Jpn., 71, 467 (1998).].
  • the compound represented by the formula (3) is a 6-promo-2-naphthol derivative
  • the compound represented by the formula (5) is a heterocyclic compound.
  • a compound such as N-methylbenzimidazole, benzothiophene, benzoxazole or benzothiazole is used, the corresponding compound represented by the formula (1) is converted to the corresponding 6- (1-methylbenzimidazole).
  • the base refers to an inorganic base such as sodium, an alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, or sodium hydroxide, or an organic base such as triethylamine or pyridine.
  • inorganic base such as sodium, an alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, or sodium hydroxide
  • organic base such as triethylamine or pyridine.
  • the compound represented by the formula (1) can be obtained by using a compound represented by the formula (3) and a compound represented by the formula (6) by Sti 11 e et al. [TN Mitche 11, Synthesis, 803 (1) 9 9 2).] Can also be manufactured.
  • a compound represented by the formula (3) has a 6-bromo-2-naphthol derivative
  • a compound represented by the formula (6) has a triptylstannyl group.
  • the corresponding compound represented by the formula (1) is converted into the corresponding 6- (2-furyl) -12-naphthol A derivative or a 6-phenyl-1-naphthol derivative can be obtained.
  • the desired compound represented by the formula (1) can be produced by subjecting the shaku 1 to the same reaction as in the step 1 above. The above method is an example, and other known methods may be used.
  • the compound represented by the formula (4) can be produced by heating the compound represented by the formula (3) and bis (tributyltin) in a suitable solvent in the presence of tetrakis (triphenyl) phosphine palladium.
  • a suitable solvent for example, methyl (6-bromo-2-naphthyloxyacetate) is used as the compound represented by the formula (3), bis (tributyltin) is added to a dioxane solution of tetrakis (triphenyl) phosphinepalladium, and the mixture is heated under reflux.
  • R 1 can perform the same reaction as in Step 1.
  • the compound represented by the formula (1) can also be produced from the compound represented by the formula (4) and the compound represented by the formula (7) according to the method of Stille et al.
  • the compound represented by the formula (4) methyl 6-tributylstanyl-2-naphthyloxyacetate
  • various heterocyclic derivatives for example, 2-bromopyridine, 3-bromopyridine , 4-bromopyridine, 3-bromofuran, 3-bromothiophene, 5-bromopyrimidine, 2-bromo-1,3-thiazonoline, 3-bromoquinoline, 4-bromoisoquinoline, N-acetinolate 4-bromopyrazonole, 5 —Bromo-2—Metinorebenzo
  • thiazole or 4-bromoantipyrine etc. the corresponding methyl 6- (2-pyridyl) -12-naphthyloxyacetate, methyl 6- (3-pyr
  • the method of Paul C. Unangst et al. was carried out using the compound represented by the formula (8) and carbonyl sulferyl chloride. ],
  • the compound represented by the formula (9) can be produced.
  • 6-hydroxyxaphthalene-12-carboxamide is used as the compound represented by the formula (8)
  • 5- (6-hydroxy-2-naphthyl) 1-2-oxo-1 is used as the compound represented by the formula (9).
  • 1,3,4 Monooxathiazole is obtained.
  • the obtained compound represented by the formula (9) can be converted to a desired compound by converting a functional group according to the method described in Step 1 as necessary.
  • the above method is an example, and other known methods can be used.
  • the compound represented by the formula (11) can be produced in accordance with the method of Pau1C. Unangst et al. Described above. For example, when methyl 6-cyano 2-naphthyl oxyacetate is used as the compound represented by the formula (10), methyl 6-hydroxyamidino 2 is used as the compound represented by the formula (11). —Naphthyloxy acetate is obtained.
  • the compound represented by the formula (13) can be produced.
  • the compound represented by the formula (13) corresponds to 3- (2-Methoxy ethoxy methoxy-6-naphthyl) 1,1,2,4-oxaziazol-l 5-ol or methyl 6- (5-hydroxyl 1,2,4-l-oxaziazol-l 3-inole) 1 2—Naphthoxy acetate is obtained.
  • the resulting 3- (2-methoxyethoxyethoxy 6-naphthyl) -1-1,2,4-oxaziazol-1-yl 5-ol can be treated with an acid, for example, hydrochloric acid, or trifluoroacetic acid.
  • an acid for example, hydrochloric acid, or trifluoroacetic acid.
  • [2— (6—Hydroxynaphthyl)] 1,2,4-oxaziazol-l-5-ol is obtained, and methyl 6- (5-hydroxyl 1,2,4l-oxaziazol-13f) 1 2 —Naphthoxyacetate can be treated with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent to give 6- (5-hydroxy-1,1,2,4-oxaziazol-13-yl).
  • the compound represented by the formula (14) can be produced by using the compound represented by the formula (10), sodium azide and ammonium chloride.
  • methyl 6-cyano 2-naphthyl oxyacetate is used as the compound represented by the formula (10)
  • methyl 6- (5-tetrazolyl) 12-naphthyl oxyacetate is used as the compound represented by the formula (14). Is obtained.
  • the obtained compound represented by the formula (14) can be converted into a desired compound by converting a functional group according to the method described in Step 1 as necessary. The above method is an example, and other known methods can also be used.
  • the compound of formula (15) is produced by converting a rubamoyl group into an alkoxycarboximidyl group by the method of Te trahedron Lett., 61 (1968).] And then reacting with ammonia. or c can, using the compound represented by the formula (1 0), P inner et al [R.
  • the compound represented by the formula (16) can be produced by dissolving methylamine in dioxane and heating in the presence of a base using, for example, potassium t-butoxide.
  • a base for example, potassium t-butoxide.
  • 2-amidino-6-naphthol'methanesulfonate is used as the compound represented by the formula (15)
  • 6- (1,3,5-triazine) is obtained as the compound represented by the formula (16).
  • 1 2- ⁇ f) 1 2-naphthol is obtained.
  • the obtained compound represented by the formula (16) can be converted into a desired compound by converting a functional group according to the method described in Step 1 as necessary.
  • the above method is an example, and other known methods can be used.
  • the compound represented by (17) can be produced.
  • the compound represented by the formula (17) becomes ethyl-6- ⁇ midazolyl2- Naphthoxy acetate is obtained.
  • the obtained compound represented by the formula (17) can be converted into a functional group by the method described in Step 1 as necessary to obtain a target compound.
  • the above method is an example, and other known methods can be used.
  • the compound represented by (19) can be produced. For example, by performing a reaction using t-butyl 6-formyl-12-naphthyloxyacetate as a compound represented by the formula (18), t-butyl is converted to a compound represented by the formula (19). 6- (1,2,3-triazole-4-yl) 1-2-naphthyloxyacetate is obtained.
  • R 1 can perform the same reaction as in step 1.
  • R 1 can be converted to a functional compound by the method described in Step 1 to obtain a target compound.
  • the above method is an example, and other known methods can be used.
  • R 10 represents lower alkyl or arylalkyl; and in the formula (22), R 11 represents a substituted lower alkyl.
  • R 1 is as described above.
  • the compound represented by 1) can be produced.
  • chloroiodide is used as the lower alkyl halide and benzyl bromide is used as the arylalkyl halide
  • the corresponding compound represented by the formula (21) will be ethyl 6-hydroxy-12-naphthate.
  • Benzyl 6-hydroxy-2-naphthate is obtained.
  • a compound represented by the formula (21) in which both 11 and 1-10 are substituted by an alkyl group or an arylalkyl group can be produced.
  • the above method is an example, and other known methods can be used.
  • 6-hydroxy-1-N- (2-hydroxyxethyl) -1-2-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxypropyl) -1-2-naphthalene Carboxamide can be manufactured.
  • the compound represented by the formula (23) is obtained by the method of Guy D. Diana et al. [J. Med. Chem., 30, 383 (187)]. Can be produced.
  • the expression (2 As the compound represented by 2) 6-hydroxy N— (2.—hydroxyxetyl) obtained in step 11-1-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxypropyl)
  • 2-naphthalenecarboxamide the corresponding compound represented by the formula (23) is 6- (4,5-dihydro-1,3-oxazolyl-2-yl).
  • Naphthol or 6- (5,6-dihydro-4H-1,3-oxazine-12- ⁇ f) -12_naphthol can be produced.
  • R 1 can be converted into a functional group by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.
  • benzyl 6-benzyloxy-1-naphthate is used as the compound represented by the formula (21) and ethylenediamine or 2-aminoethanethiol is used as the lower alkylamine having a substituent
  • the compound is represented by the formula (24)
  • the corresponding compounds are 2-benzyloxy-6- (2-imidazolinyl) naphthalene or 2-benzyl / reoxy-1-6- (4,5-dihydro-1,1,3-thiazoline-12-yl) naphthalene, respectively.
  • 11 can be converted into a target compound by converting a functional group by the method described in step 1. The above method is an example, and other known methods can be used.
  • the compound represented by the formula (25) can be produced.
  • a compound represented by the formula (22) is a compound in which R 11 is a methyl group
  • the compound represented by the formula (25) can be produced.
  • R 1 can be converted to a functional compound by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.
  • compositions containing as an active ingredient are usually used in mammals (including human patients).
  • mammals including human patients
  • it can be administered as an oral preparation such as tablets, capsules, powders, fine granules and syrups, a rectal preparation or an injection.
  • the compound of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. Although they may be administered alone, they are generally administered in the form of a pharmaceutical composition.
  • These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives.
  • additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, and coating agents can be used for oral administration.
  • Oral liquids may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or provided as dry syrups in water or other suitable solvent before use. Is also good.
  • Said solutions may contain usual additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository.
  • Suppositories are based on suitable substances such as cocoa butter, lauric fat, macrogol, glycemic gelatin, witetbsol, sodium stearate or a mixture thereof, and are emulsifiers, suspending agents, and preservatives as necessary. Etc. can be added. Injectables are dissolving or dissolution aids such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol, etc., which can constitute aqueous or ready-to-use dosage forms, pH adjusters, isotonic Pharmaceutical ingredients such as a stabilizing agent and a stabilizing agent are used.
  • excipients and the like used in the above composition are shown below.
  • Excipients calcium hydrogen phosphate, synthetic aluminum silicate, magnesium aluminate metasilicate, aluminum hydroxide 'magnesium hydroxide, magnesium silicate, calcium carbonate, magnesium carbonate, light silicic anhydride, silicate anhydride, Avicel, various types Starch, dextrin, carboxymethyl starch (CMS), lactose, etc.
  • Binders Ethyl cellulose (EC), carboxymethyl cellulose Na (CMC) -Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches, dextrin, sodium alginate, Gelatin, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), etc.
  • Disintegrators synthetic aluminum silicate, magnesium aluminate metasilicate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (HPS), etc.
  • Anti-solidification agent Light caustic anhydride, synthetic aluminum silicate, etc.
  • Lubricants synthetic aluminum silicate, carboxylic anhydride, talc, Avicel, etc.
  • Flavoring agents mannitol, cunic acid, cunic acid Na, sugar, etc.
  • Emulsifiers gelatin, cunic acid, sodium citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, phospholipids, etc.
  • Stabilizers sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, phospholipids etc.
  • Absorption promoter polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, medium-chain fatty acid triglycerides, etc.
  • Dissolution aids ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, etc.
  • Suspending agent CMC_Na, HPMC, MC, HPC, sodium alginate, gelatin, propylene glycol, lauryl sulfate Na, etc.
  • Coating agent EC, magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), HPMC, hydroxypropylmethylcellulose phthalate ( HPMCP), MC, HPC, sodium alginate, polyvinylacetate rugethylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid methacrylic acid derivatives, polyglycolic acid Na, and the like.
  • Colorant titanium oxide, tar dye, caramel, etc.
  • the dose varies depending on the age, symptoms, etc. of the patient.In general, for adults, 1 mg to 100 mg / day for oral or rectal administration, about 100 mg / day, injection In 0.1 ⁇ 50 OmgZ people Z days is about. However, these numerical values are merely examples, and the dose may be appropriately adjusted according to various conditions such as the patient's symptoms.
  • Methyl 6_triptyl styrene 2-naphthyloxyacetate Methyl 6_bromo-2-naphthyloxyacetate (5.9 g) and tetrakis (triphenylphosphine) palladium (461 mg) Bis (tributyltin) (13.lml) was added to the dioxane (5Oml) solution, and the mixture was heated under reflux for 10 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by a silica gel column (hexane-ethyl acetate) to obtain methyl 6-tributylstannyl-2-naphthyloxy acetate. Reference Example 3, Production of methyl 6-cyano-1-naphthyloxyacetate
  • Example 3 using methyl 6-tributylstannyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), and 3-thiophenobromide (0.28 ml) The same operation as described above was performed to obtain methyl 6- (3-Chenyl) -12-naphthyloxyacetate. The resulting methyl 6- (3-Chenyl) -12-naphthyloxyacetate (150 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to obtain Compound 4.
  • the same operation as in 3 was performed to obtain methyl 6- (3-quinolyl) -12-naphthyloxyacetate.
  • the obtained methyl 6- (3-quinolyl) -12-naphthyloxyacetate (14 Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to give Compound 6. Obtained as a solid.
  • N-acetyl-4 monobromide pyrazo monophosphate 567 mg
  • methinole 6-tryptinoresta / 2 / le 2-naphthy / reoxyacetate 505 mg
  • tetrakis (triphenylphosphine) paradigm 58 mg.
  • the same operation as in Example 3 was performed to obtain methyl 6- (N-acetyl-4-pyrazolyl) _2-naphthyloxyacetate.
  • Methyl 6— (5-hydroxy-1,2-, 4-oxaziazol-3-yl) 12-Naphthoxyacetate 190 mg was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (1.6 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with citric acid, and the precipitated solid was collected by filtration to obtain Compound 12.
  • the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white solid.
  • the obtained white solid was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 13.
  • Acetamide (236 mg) and 1,1-dimethoxytrimethylamine (0.64 ml) were stirred at 80 ° C. for 1 hour, concentrated under reduced pressure, and dried to prepare a reaction reagent.
  • Dissolve 2-amidino 6-naphthyl methanesulfonate (282 mg) and potassium t-butoxide (112 mg) in dioxane (5 ml) add the reagent prepared above, and heat to reflux for 2 hours. did.
  • the reaction mixture was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (form-form-ethanol).
  • N-methyl-6- (t-butyldimethylsilyl) oxy-12-naphthoic acid amide The obtained N-methyl-6- (t-butyldimethylsilyl) oxy-1-naphthoic acid amide (145 mg) and sodium azide (90 mg) were dissolved in acetonitrile (5 ml), and trifluoromethanesulfonic anhydride was added. (0.23 ml) and Molecular Sieve 4A (20 Omg) were added, and the mixture was stirred at room temperature for 1 hour.
  • reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-form-ethanol).
  • 1-methyltetrazole-5-yl) -2-naphthol was obtained.
  • 6- (1-methyltetrazole-5-yl) -2-naphthol (25mg) and anhydrous potassium carbonate (46mg) were added to DMF.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified by a silica gel column (hexane monoethyl acetate) to obtain a white solid.
  • the obtained white solid was dissolved in 4N hydrochloric acid-dioxane solution (3.3 ml) and stirred at room temperature for 5 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 17.
  • 6- (5-Thioxo-1,2,4-oxaziazol-1-yl) _2-naphthol (10 Omg) and anhydrous potassium carbonate (141 mg) are suspended in DMF (3 ml), and the suspension is kept at room temperature. Then, t-butyl bromide acetate (0.12 ml) was added thereto, and the mixture was stirred with stirring. The reaction solution was partitioned between ethyl acetate and purified water.
  • the ethyl acetate layer was washed with purified water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-form-methanol) to obtain a colorless oil.
  • the obtained colorless oil was dissolved in methanol (1 ml), 4N aqueous sodium hydroxide solution (1.5 ml) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was neutralized with dilute hydrochloric acid, concentrated under reduced pressure, and then purified by a silica gel column (form-form-methanol-acetic acid) to obtain Compound 23 as a solid.
  • 6-Hydroxy-2-naphthamide (300 mg) is suspended in a mixed solvent (30 ml) of toluene-tetrahydrofuran (2: 1), and carbonyl sulfenyl chloride (0.27 ml) is added thereto. Heated to reflux for an hour. After the reaction solution was concentrated under reduced pressure, the residue was suspended in methanol (10 ml) and the insoluble matter was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by a silica gel column (chloroform-form-methanol) to obtain Compound 24 as a solid.
  • 2-Aminoethanethiol 'hydrochloride (168 mg) is dissolved in toluene (14 ml), and a 15% triisobutyl phenolic hexane solution (7.4 ml) is added dropwise under a nitrogen stream, and the solution is added for 30 minutes. After heating under reflux, a toluene (15 ml) solution of ethyl 6-benzyloxy12-naphthate (500 mg) obtained above was added dropwise. The reaction solution was heated under reflux for 2 hours, and partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution.
  • 6-Hydroxy-N- (3-hydroxypropyl) naphthoamide (300 mg) was dissolved in isopropyl acetate (10 ml), and thionyl chloride (0.34 ml) was added dropwise thereto. Stirred. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain Compound 28 as a solid.
  • 6- (4,5- Dihydro-1,3-oxazol-13 f) -12-naphthol was obtained as a white solid.
  • 6- (4,5-dihydro-1,3-oxazol-3-yl) -12-naphthol (45 mg) and anhydrous potassium carbonate (1 16 mg) were added to DMF (2 ml).
  • the suspension was suspended, and methyl bromide acetate (0.06 ml) was added at room temperature, followed by stirring at room temperature.
  • the reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was solidified from ethanol in the form of ethanol to form ethyl 6_ (N —Benzyloxycarboninolea midino)
  • ethyl 6_ N —Benzyloxycarboninolea midino
  • 6- (N-benzyloxycarbonylamidino) -12-naphthyloxyacetate 1.5 dissolved in ethanol (30 ml), and 10% palladium on activated carbon (300 mg) was dissolved.
  • Acetic acid (0.21 ml) was added, and the mixture was stirred for 2 hours under a hydrogen stream. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration to obtain ethyl 6-amidino 2-naphthyloxyacetate acetate.
  • the obtained ethyl 6-amidino 2-naphthyloxyacetate 'sulfate (40 Omg) was dissolved in dioxane (1 Oml), and acetoaldehyde getylacetal bromide (3.6 ml) and Triethylamine (0.33 ml) was added, and the mixture was heated under reflux for 1 hour.
  • t-butyl 6-formyl-12-naphthyloxyacetate (lO Omg) was dissolved in methanol (5 ml), and nitromethane (5 ml) and ammonium acetate (27 Omg) were added. And stirred at room temperature for 3 hours. After partitioning the reaction solution with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (ethyl hexane monoacetate).
  • the above is used as a suppository in a conventional manner.
  • the compound of the present invention has a fibrinolytic promoting action and exhibits an excellent thrombolytic action, it is effective for diseases caused by thrombus.
  • thrombosis including venous thrombosis, myocardial infarction, pulmonary embolism, cerebral infarction, atrial thrombus in atrial fibrillation, disseminated intravascular coagulation (DIC), diabetic complications, and slowly progressing cerebral thrombosis Treatment of thromboembolism associated with vascular surgery and extravasation and improvement of blood flow, prevention or treatment of restenosis or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), chronic arterial occlusion Treatment of thrombosis and embolism associated with ischemic cerebrovascular disease, as a therapeutic agent for thromboembolism in general, as a thrombolytic agent, antithrombotic agent alone, or as a thrombolytic agent It can be used in combination with a therapeutic agent for thrombosis
  • the present compound, 1 X 1 0- 2 was dissolved in dimethyl sulfoxide (DMS O) such that M, 2 Omm phosphate buffer solution containing the prepared solution 0. 1 5 M sodium chloride (p H 7. 1. 2 X 1 0 4) - diluted 3 M, to prepare the present compound solution.
  • DMS O dimethyl sulfoxide
  • M 2 Omm phosphate buffer solution containing the prepared solution 0. 1 5 M sodium chloride
  • p H 7. 1. 2 X 1 0 4 -diluted 3 M
  • Glutamate-type human plasminogen final concentration: 0.1 ⁇
  • human recombinant t-PA final concentration: 50 / M
  • the compound solution of the present invention final concentration: 300 ⁇
  • a synthetic substrate solution (S-2251, 2 mM), which is a plasmin substrate, is added to each well at a ratio of 50/1, and immediately after the addition, the absorbance (A1) at 405 nm is measured. Then, incubate again at 37 ° C for 15 minutes, and measure the absorbance (A 2) at 405 nm. The difference between the obtained absorbances (A1 and A2) and the ratio to the control (control) can be determined to determine the plasmin formation promoting activity. As a result, it was revealed that the compound of the present invention has an excellent plasmin formation promoting action. Table 2 shows the results.
  • mice were performed using 15 to 20 dd Y male mice, 6 weeks old, per group.
  • the compound of the present invention was suspended in distilled water to give lmgZkg (lOml) and orally administered to a mouse that had been fasted for 4 hours. Distilled water was orally administered to the disease control group.
  • thrombin (1 OUZm 1) was administered at a dose of 1 ml from the tail vein to induce thrombus. The next day, death and death were confirmed, and the survival rate was determined. Table 3 shows the results. Table 3
  • an antithrombotic agent and a thrombolytic agent which have a fibrinolysis promoting action and can be orally administered.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)

Abstract

L'invention se rapporte à de nouveaux dérivés de naphtalène représentés par la formule générale (1), qui sont dotés d'un excellent pouvoir d'accélération de la fibrinolyse et s'avèrent utiles en tant qu'agents antithrombotiques ou en tant qu'agents thrombolytiques.
PCT/JP1999/002939 1998-11-20 1999-06-02 Nouveaux derives de naphtalene WO2000031036A1 (fr)

Priority Applications (2)

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AU40584/99A AU4058499A (en) 1998-11-20 1999-06-02 Novel naphthalene derivatives
PCT/JP2000/002279 WO2001077076A1 (fr) 1999-06-02 2000-04-07 Nouveaux derives de naphtalene

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JP33174798A JP2002275157A (ja) 1998-11-20 1998-11-20 新規ナフタレン誘導体
JP10/331747 1998-11-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077076A1 (fr) * 1999-06-02 2001-10-18 Torii Pharmaceutical Co., Ltd. Nouveaux derives de naphtalene
EP1274424A1 (fr) * 2000-04-12 2003-01-15 Smithkline Beecham Corporation Composes et procedes
WO2006092430A1 (fr) * 2005-03-03 2006-09-08 Universität des Saarlandes Inhibiteurs selectifs de synthases de corticoides humaines
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003291329A1 (en) * 2002-11-12 2004-06-03 Abbott Laboratories Bicyclic-substituted amines as histamine-3 receptor ligands
JP4390460B2 (ja) * 2003-02-21 2009-12-24 株式会社静岡カフェイン工業所 オキサゾール誘導体
BRPI0514549A (pt) 2004-08-23 2008-06-17 Wyeth Corp ácidos de pirrol-naftila como inibidores de pai-1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020917A1 (fr) * 1995-01-05 1996-07-11 Torii Pharmaceutical Co., Ltd. Derives d'ester d'amidinonaphtyle substitues
JPH1017549A (ja) * 1996-07-02 1998-01-20 Banyu Pharmaceut Co Ltd 二環性芳香族アミジン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020917A1 (fr) * 1995-01-05 1996-07-11 Torii Pharmaceutical Co., Ltd. Derives d'ester d'amidinonaphtyle substitues
JPH1017549A (ja) * 1996-07-02 1998-01-20 Banyu Pharmaceut Co Ltd 二環性芳香族アミジン誘導体

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077076A1 (fr) * 1999-06-02 2001-10-18 Torii Pharmaceutical Co., Ltd. Nouveaux derives de naphtalene
EP1274424A1 (fr) * 2000-04-12 2003-01-15 Smithkline Beecham Corporation Composes et procedes
EP1274424A4 (fr) * 2000-04-12 2003-09-17 Smithkline Beecham Corp Composes et procedes
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
WO2006092430A1 (fr) * 2005-03-03 2006-09-08 Universität des Saarlandes Inhibiteurs selectifs de synthases de corticoides humaines
US9271963B2 (en) 2005-03-03 2016-03-01 Universitat Des Saarlandes Selective inhibitors of human corticosteroid synthases

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AU4058499A (en) 2000-06-13

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