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WO2001077076A1 - Nouveaux derives de naphtalene - Google Patents

Nouveaux derives de naphtalene Download PDF

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Publication number
WO2001077076A1
WO2001077076A1 PCT/JP2000/002279 JP0002279W WO0177076A1 WO 2001077076 A1 WO2001077076 A1 WO 2001077076A1 JP 0002279 W JP0002279 W JP 0002279W WO 0177076 A1 WO0177076 A1 WO 0177076A1
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WIPO (PCT)
Prior art keywords
group
formula
acid
naphthyloxyacetic acid
methyl
Prior art date
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PCT/JP2000/002279
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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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Torii Pharmaceutical Co Ltd
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Priority claimed from PCT/JP1999/002939 external-priority patent/WO2000031036A1/fr
Application filed by Torii Pharmaceutical Co Ltd filed Critical Torii Pharmaceutical Co Ltd
Priority to AU36738/00A priority Critical patent/AU3673800A/en
Publication of WO2001077076A1 publication Critical patent/WO2001077076A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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.
  • fibrinolytic system that dissolves thrombus formed in blood vessels and keeps blood flow.
  • vascular endothelial cells produce and secrete tissue plasminogen activator (t-PA) due to the stimulation of ischemia.
  • t_PA tissue plasminogen activator
  • t_PA converts inactive plasmaminogen present in the blood to active plasmin on the thrombus.
  • the resulting plasmin exerts an enzymatic action and degrades fibrin, a component of the thrombus, thereby promoting thrombolysis.
  • thrombolytic therapy therapies to administer PAs to dissolve thrombus, that is, 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 thrombus in the body due to the presence of inhibitors in the body.
  • large dose administration is required. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate.
  • 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.
  • 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 an excellent fibrinolysis-promoting action and are extremely useful as antithrombotic agents and thrombolytic agents. That is, the present invention relates to a naphthalene compound as described in detail below, and a pharmaceutical composition containing the compound as an active ingredient.
  • R21 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms
  • Substituted with Amino substituted C 1 _ 6 alkyl group or a carboxy group means also good I ⁇ reel alkyl group.
  • R23 means a straight or branched having 1 to 6 carbons ( ⁇ _ 6 alkyl group.)
  • Ci means a 6- acyl group
  • Ci— 6 means Ak_C0-R7, (Here, R7 represents a hydroxyl group or a -6 alkoxy group.)
  • P represents an oxygen atom, a sulfur atom or a nitrogen atom.
  • R1 is a hydrogen atom
  • A is
  • Y is-(CH 2 ) 2- and P is an oxygen atom or -NH-.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [2] as an active ingredient.
  • a thrombolytic agent comprising the compound according to any one of [1] to [2] as an active ingredient.
  • a fibrinolysis accelerator comprising the compound according to any one of [1] to [2] as an active ingredient.
  • An antithrombotic agent comprising the compound according to any one of [1] to [2] as an active ingredient.
  • the “alkylene group of 6” include a methylene group, an ethylene group, a propylene group, an isopropylene group, a butylene group, an isobutylene group, a sec-butylene group, a tert-butylene group, a pentylene group, and a hexylene group.
  • it is a linear or branched alkylene group having 1 to 4 carbon atoms.
  • C i- 6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group. Group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, and hexoxy group. Preferred is an alkoxy group having 1 to 4 carbon atoms which may be linear or branched.
  • linear or branched alkyl group having 1 to 6 carbon atoms specifically means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group Group, pentyl group, and hexyl group.
  • it is an alkyl group having 1 to 4 carbon atoms which may be linear or branched.
  • Note - 6 alkyl group also refers to similar straight chain or branched alkyl group having 1 to 6 carbon atoms.
  • Amino-substituted C-6 alkyl group means a Ci-6 alkyl group substituted with one to three, preferably one, amino group. The amino group may be substituted at any position.
  • Two C ⁇ _ 6 alkyl group preferably may be substituted with a methyl group or Echiru group.
  • a methyl group or Echiru group examples thereof include an aminomethyl group, a 2-aminoethyl group, a 3-aminopropyl group, a methylaminomethyl group, and a dimethylaminomethyl group.
  • they are an aminomethyl group and a dimethylamino group.
  • the ⁇ j which may be substituted with a carboxyl group '' in the ⁇ arylalkyl group which may be substituted with a carboxy group '' means that it may be substituted with one or two, preferably one, carboxy group .
  • the position of the substituent is not particularly limited and an arbitrary addition, " ⁇ reel alkyl group", ⁇ Flip mentioned above - in 6 Al kill group, phenyl group, a naphthyl group Aryl group is substituted, and specific examples include a benzyl group, a phenylethyl group, a phenylpropy / yl group, and a naphthylmethyl group.
  • a benzyl group substituted with a carboxy group It is.
  • the - "C i 6 Ashiru group” means a Ashiru group of 1 to 6 carbon atoms, specifically a formyl group, Asechiru group, a propionyl group, Puchiriru group, Isopuchiriru group, valeryl group, isovaleryl group, pivaloyl Group, hexanoyl group, acryloyl group, propylioroyl group, methacryloyl group, and crotonyl group.
  • it is an acetyl group having 1 to 4 carbon atoms, and particularly preferably, an acetyl group.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or 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.
  • the salt include a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine salt, and amino acid addition salt.
  • the acid addition salt include inorganic acid salts such as hydrochloride, phosphate, sulfate, etc., and organic acid salts such as lanthanate, citrate, methanesulfonate, and sodium salt 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; and the like; ammonium salts include salts such as ammonium; and organic amine salts and addition salts such as morpholine And addition salts such as piperidine, and the like.
  • Amino acid addition salts include addition salts such as glycine and lysine. Examples of the solvates include hydrates.
  • R 9 represents a halogen atom or a trifluoromethanesulfonyloxy group
  • Bu represents a butyl group.
  • R1 is as described above
  • the ring A is as described above.
  • the compound represented by the formula (1) can be prepared using the compound represented by the formula (3) and the compound represented by the formula (5) according to the method of Somma i Pivsa-Art et al. [Bull. Chem. Soc. Jpn., 71, 467 (1998).].
  • the compound represented by the formula (3) a 6-promo-2-naphthol derivative, and as the compound represented by the formula (5), various heterocyclic compounds, for example, N-methinolebenzoimidazoline, benzothiophene, benzoxazole, or When benzothiazole or the like is used, the compound represented by the formula (1) And the corresponding 6- (1-methylbenzimidazole_2-2-yl) -12-naphthol derivative, 6- (benzothiophene-2-yl) 1-2-naphthol derivative, 6- (benzoxoxazole — 2-—Tol) 12-naphthol derivative or 6- (benzothiazole-2-yl) 1-2-naphthol derivative can be obtained.
  • 6- (1-methylbenzimidazole_2-2-yl) -12-naphthol derivative 6- (benzothiophene-2-yl) 1-2-naphthol derivative
  • the base refers to an inorganic base such as sodium, alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, sodium hydroxide and the like, or an organic base such as triethylamine and pyridine.
  • Methods for introducing and removing protecting groups commonly used in organic synthetic chemistry include, for example, TW Green, "Protective Grupsin Organic Synthesis, 2nd Ed.”, John Wiley & Sons, 1 991.
  • the conversion reaction to the target functional group is, for example, in the case of a hydroxyl group, by reacting with a substituted or unsubstituted lower alkyl halide in the presence of a base in an appropriate solvent to obtain a substituted or unsubstituted lower alkoxy group.
  • a reaction for example, RC Larock,
  • 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) 992).] Can also be produced.
  • a compound represented by the formula (3) is a 6-promo2_naphthol derivative
  • a compound represented by the formula (6) is a heterocyclic derivative having a triptylstannyl group, for example, 2-triptylstanylfuran.
  • the compound represented by the formula (1) As a result, a corresponding 6- (2-furyl) 1-2-naphthol derivative or a 6-Chenyl-2-naphthol derivative can be obtained.
  • the desired compound represented by the formula (1) can be produced.
  • 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 (triptyltin) in an appropriate solvent in the presence of tetrakis (triphenyl) phosphine palladium.
  • a compound represented by the formula (3) methyl 6-bromo-2-naphthyloxyacetate is used, bis (triptyltin) is added to a dioxane solution of tetrakis (triphenyl) phosphinepalladium, and the mixture is heated under reflux.
  • reaction solution is concentrated under reduced pressure, and purified by a silica gel column (ethyl hexane monoacetate) to obtain methyl 6-tributylstannyl-2-naphthyloxy, a compound represented by the formula (4). You can get an acetate.
  • R1 can perform the same reaction as in step 1.
  • the compound represented by the formula (1) can also be produced by using 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_tributylstannyl-2-naphthyloxyacetate
  • various heterocyclic derivatives for example, 2-bromopyridine, 3-bromo Pyridine, 4-bromopyridine, 3-bromofuran, 3-bromothiophene, 5-bromopyrimidine, 2-bromo-1,3-thiazonole, 3-bromoquinoline, 4-bromoisoquinoline, N-acetinol 4-
  • bromopyrazolone, 5-bromo-2-methinobenzobenzothiazole or 4-bromoantipyrine the corresponding methyl 6- (2-pyridyl) -12-naphthyloxyacetate and methyl 6 — (3-pyr
  • a compound represented by the formula (9) can be produced.
  • 6-hydroxynaphthalene_2-carboxamide is used as the compound represented by the formula (8)
  • 5- (6-hydroxy-12-naphthyl) _2-oxo1-1 is used as the compound represented by the formula (9).
  • 3 and 4 are 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 (10) in the formula (11) can be obtained by treating the compound represented by the formula (8) with thionyl chloride or the like. .
  • it can be derived from 2_cyano-6_naphthol by the functional group conversion reaction described in Step 1.
  • 2-cyano-6-naphthol is reacted with methyl bromide acetate in a suitable solvent in the presence of a base such as potassium carbonate or sodium carbonate
  • methyl 6-cyano is obtained as a compound represented by the formula (10).
  • One-two-naphthoxy acetate is obtained.
  • the compound represented by the formula (11) can be produced by using the compound represented by the formula (10) and hydroxylamine according to the method of Pauul C. Unangst et al. For example, when methyl 6-cyano 12-naphthyloxyacetate is used as the compound represented by the formula (10), methyl 6-hydroxyamidino 1 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 methoxy 6-Naphthyl) 1, 1, 2, 4-oxaziazol-5-yl or methyl 6 _ (5-Hydroxy-1, 2, 2, 4-oxaziazol 3) —Ill)
  • 3 _ (2-Methoxy methoxy 6-Naphthyl) 1, 1, 2, 4-oxaziazol-5-yl or methyl 6 _
  • 6 _ (5-Hydroxy-1, 2, 2, 4-oxaziazol 3) —Ill
  • the resulting 3- (2-methoxethoxy methoxy-1-6-naphthyl) _ 1,2,4-oxaziazol-1-ol 5-ol can be treated with an acid such as hydrochloric acid or trifluoroacetic acid to give 3- [2- (6—Hydroxynaphthyl)] — 1,2,4-Oxaziazol-1-ol 5-ol is obtained, and methyl 6 _ (5-hydroxy-1,2,4_oxaziazol-1-yl 3-yl) 1 2—
  • Naphthoxyacetate can be treated with a base, for example, sodium hydroxide or potassium hydroxide, in an appropriate solvent to give 6- (5-hydroxy-1,2,4-oxoxadiazo-3-yl).
  • R1 and R5 can be converted into a desired functional group by the method described in step 1 and the method of Pau 1 C. Unangst described above.
  • the obtained 6_ (5-mercapto-1,2,4-oxadizazole-3 fle) —2-naphthol derivative is 6— (5-thioxo-4H-1, 2,4, oxaziazol-l- 3— Tyr) It is in a tautomeric relationship with a 12-naphthol derivative, and both compounds are equivalent.
  • the 5-mercapto-1,1,2,4-oxadiazole derivative described in the present invention shows both tautomeric isomers unless otherwise specified, and both isomers are included in the scope of the present invention. .
  • the above method is an example, and other known methods can be used.
  • the compound represented by the formula (14) can be produced.
  • methyl 6-cyano 2_naphthyl oxyacetate is used as the compound represented by the formula (10)
  • methyl 6- (5-tetrazolyl) _2-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.
  • P inner et al. P inner et al. [R.
  • the compound represented by the formula (15), acetoamide and 1,1-dimethoxytrimethylamine are dissolved in dioxane, and heated by using, for example, potassium t-butoxide in the presence of a base. ) Can be produced.
  • 2-amidino-16-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).
  • One 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 method of formula (1) was carried out according to the method of NS Zefirov et al. [Chem. Commun., 1001 (1971).
  • the compound represented by 9) can be produced.
  • R1 can perform the same reaction as in step 1.
  • R1 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.
  • 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.
  • 6-hydroxy-2-naphthoic acid as the compound represented by the formula (20), dissolve in a suitable solvent, and react with a substituted or unsubstituted lower alkyl halide or arylalkyl halide in the presence of a suitable base.
  • a compound represented by the formula (21) can be produced.
  • halogenated lower al When benzyl iodide is used as the kill and benzyl bromide is used as the arylogenyl arylalkyl, the corresponding compound represented by the formula (21) is ethyl 6-hydroxy-1-naphthate and benzyl 6-hydroxyl, respectively.
  • One 2-naphthate is obtained.
  • the formula (23) is obtained by the method of Guy D. Diana et al. [J. Med. Chem., 30, 383 (187)]. Can be produced.
  • a compound represented by the formula (22) 6-hydroxy-1-N_ (2-hydroxyethyl) -12-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxy) obtained in step 11
  • the corresponding compound represented by the formula (23) is 6- (4,5-dihydro-1,1,3-oxazo-1-yl-2-yl) -12-naphthol, respectively.
  • R1 is a functional group converted by the method described in Step 1; Can also be used.
  • 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). On the other hand, it can be administered as an oral preparation such as tablets, capsules, powders, fine granules and syrups, a rectal preparation or an injection. Ma Further, 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 preparations.
  • 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, glycerated gelatin, witepsol, sodium stearate or a mixture thereof, and, if necessary, emulsifiers, suspending agents, Preservatives and the like can be added.
  • injectables are soluble 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, etc.
  • Formulation components such as tonicity agents and stabilizers are used.
  • excipients and the like used in the above composition are shown below.
  • Excipients calcium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate aluminate, aluminum magnesium hydroxide / magnesium silicate, magnesium silicate, calcium carbonate, magnesium carbonate, light silicic anhydride, silicic anhydride, Avicel, various types Starch, dextrin, carboxymethyl starch (CMS), lactose etc.
  • Binders ethyl cellulose (EC), carboxymethylcellulose Na (CMC-Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxy Propyl cellulose (HPC), various starches, dextrin, sodium alginate, gelatin, polyvinyl alcohol (PVA), polybutylpyrrolidone (PVP), etc.
  • Disintegrators synthetic aluminum silicate, magnesium metasilicate aluminate, CMC—Ca, CMC, Avicel, L—HPC, HPMC, MC, various starches, CM S, 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, citrate, sodium citrate, 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.
  • CMEC carboxymethylethylcellulose
  • CAP cellulose acetate phthalate
  • HPMC hydroxypropylmethylcellulose phthalate
  • HPC 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 dosage of the compound of the present invention when administered to humans varies depending on the age, symptoms, etc. of the patient.In general, in the case of adults, 1 mg to 100 mg of oral or rectal administration is used. The injection is about 0.1-50 OmgZ per person. However, these figures are merely examples, and the dose may be appropriately adjusted according to various conditions such as the patient's symptoms.
  • Example 5 Production of 6- (5-pyrimidinyl) -1-naphthyloxyacetic acid (compound 5) Methyl 6_triptylstanyl-12-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), The same operation as in Example 3 was performed using 5- and pyrimidine bromide (0.48 ml) to obtain methyl 6- (5-pyrimidinyl) -12-naphthyl oxyacetate.
  • Example 9 Preparation of 6- (4-pyrazolyl) _2-naphthyloxyacetic acid (compound 9) 4-Pyrazole bromide (1.5 g) was dissolved in pyridine (20 ml), and anhydrous anhydride (4.7 ml) was added. And stirred at room temperature for 30 minutes. After the reaction mixture was partitioned with a solution of formaldehyde monosaturated aqueous sodium hydrogen carbonate, the form layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexane to obtain N-acetyl-14-pyrazole bromide.
  • the same operation as in 3 was performed to obtain methyl 6_ (N-acetyl-1-4-pyrazolyl) _2-naphthyloxyacetate.
  • methinole 6- N-acetyl-14-pyrazolyl -12-naphthinoleoxyacetate (ll Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3, Compound 9 was obtained as a solid.
  • the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate 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.
  • 2-Amidino 6-naphthol 'methanesulfonate (282 mg) and potassium t-butoxide (112 mg) were dissolved in dioxane (5 ml), and the reagent prepared above was added thereto, followed by heating under reflux for 2 hours.
  • the reaction solution was distributed 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). 3,5-Triazine-2- ⁇ )-l-Naphthol was obtained.
  • the obtained 6- (1,3,5-triazine_2fle) -2-naphthol (25mg) and anhydrous potassium carbonate (46mg) were suspended in DMF (2ml), and methyl bromide acetate (0. OlmI) was added and stirred for 1 hour.
  • 6-acetoxy 2_naphthoic acid (2.3 g) was dissolved in DMF (20 ml), and methylamine hydrochloride (743 mg), 1- (3-dimethylaminopropyl) -131ethylcarbodiimide ⁇ Hydrochloride (2.1 g), N-hydroxybenzotriazole-hydrate (1.5 g), and triethylamine (1.5 ml) were added, and the mixture was stirred at room temperature overnight.
  • the reaction solution was distributed between ethyl acetate and a saturated aqueous solution of ammonium chloride, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • N-methyl-6- (t-butyldimethylsilyl) oxy-12-naphthoic acid amide was obtained.
  • the obtained N-methyl-6- (t-butyldimethylsilyl) oxy_2-naphthoic acid amide (145 mg) and sodium azide (9 Omg) 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.
  • the reaction solution was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried. After drying over magnesium sulfate and concentrating under reduced pressure, the residue was purified on a silica gel column (chloroform-form-ethanol) to obtain 6- (1-methyltetrazol-1-yl) -2-naphthol.
  • the resulting 6- (1-methyltetrazole-5-yl) -2-naphthol (25 mg) and anhydrous potassium carbonate (46 mg) were suspended in DMF (2 ml), and methyl bromide acetate (0.02 ml) was suspended. Was added and stirred for 1 hour.
  • the reaction solution 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 washed with hexane and ethanol, and methyl 6- (1- Methyltetrazole-5-yl) 1-2-naphthyloxyacetate was obtained.
  • the obtained methyl 6- (1-methyltetrazole-5-yl) _2-naphthyloxyacetate was suspended in ethanol (5 ml), and a 2N aqueous sodium hydroxide solution (0. 2 ml) was added and stirred for 20 minutes.
  • the reaction solution was neutralized with dilute hydrochloric acid, concentrated under reduced pressure, purified water was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 16.
  • 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-Cyanol 2- (2-Methoxyethoxymethyl) naphthol (3.5 g) was dissolved in ethanol (120 ml), and hydroxylamine hydrochloride (2.8 g) and sodium carbonate (4. A solution of 3 g) in water (80 ml) was added, and the mixture was heated under reflux for 5 hours. After the reaction solution was concentrated under reduced pressure, the solution was extracted with chloroform. After drying the extract from the mouth with anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified on a silica gel column (ethyl hexane monoacetate) to give 6_ (2-methoxyethoxymethoxy) naphthalene-1-carboxy. Amidoxime was obtained.
  • 4_Oxaziazol-1--3-inole-2-naphthinoleoxyacetate was obtained as a yellow oily substance.
  • the obtained tert-butyl 6- (5-t-butoxycarboninolemethinolethiol 1,2 , 4_Oxazidazo-1-ol-3-inole) 1-2-naphthinoleoxyacetate (14 Omg) was dissolved in 4N hydrochloric acid-dioxane solution (3.9 ml), and the mixture was stirred at room temperature for 4 hours. A mixed solution (200 ml) of xane (1: 1) was added, and the precipitated solid was collected by filtration to obtain Compound 21.
  • the reaction solution was concentrated under reduced pressure, and then purified by reversed-phase column chromatography (C-18, water-methanol).
  • the obtained product was dissolved in a small amount of methanol, acidified with dilute hydrochloric acid, and ether was added. The precipitated brown solid was collected by filtration to obtain Compound 22.
  • 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-1-naphthamide (300 mg) was suspended in a mixed solvent of toluene and tetrahydrofuran (2: 1) (30 ml), and carbonyl sulfeyl chloride (0.27 ml) was 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.
  • 6-Hydroxy-1-naphthoic acid (1.9 g) is dissolved in ethanol (20 ml), a solution of cesium carbonate (2.4 g) in water (5 ml) is added, and the mixture is stirred at room temperature for 30 minutes. did. After the reaction solution was concentrated under reduced pressure and dried, the residue was suspended in DMF (30 ml) and iodinated chill (1. Oml) was added thereto. The mixture was stirred at C for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by a silica gel column (black-mouthed form) to obtain ethyl 6-hydroxy-12-naphthate.
  • 6- (4,5-Dihydro_1,3-thiazol-1-yl) _2_Naphthonolle (12 Omg) and anhydrous potassium carbonate (199 mg) are suspended in DMF (4 ml), and the mixture is stirred at room temperature. Then, methyl bromide acetate (0.09 ml) was added thereto, followed by stirring at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% aqueous solution of citric acid.
  • 3-Amino-11-propanol (695 mg) was added to ethyl 6-hydroxy-12-naphthate (1.Og) synthesized in Example 26, and the mixture was stirred at 120 ° C for 6 hours.
  • the reaction solution was purified by a silica gel column (form-form methanol) to obtain 6-hydroxy-1N- (3-hydroxypropyl) naphthamide as a pale red solid.
  • the obtained 6-hydroxy N- (3-hydroxypropyl) naphthoamide (30 Omg) was dissolved in isopropyl acetate (10 ml), and thiol chloride (0. 34 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain Compound 28 as a solid.
  • Example 29 was repeated using ethyl 6-hydroxynaphthoate (216 mg), 2_aminoethanol (122 mg), and thionyl chloride (0.19 ml).
  • 6- (4,5-dihydro_1,3-oxazolyl-13-yl) -12-naphthol was obtained as a white solid.
  • the obtained 6- (4,5-dihydro_1,3-oxoxazole_3-yl) -2-naphthol (45 mg) and anhydrous potassium carbonate (116 mg) were suspended in DMF (2 ml). At room temperature, methyl bromide acetate (0.06 ml) was added and the mixture was stirred overnight.
  • 6-Hydroxy-1-2-naphthaldehyde (172 mg) and anhydrous carbon dioxide (415 mg) are suspended in DMF (10 ml), and t-butyl bromide acetate (0.19 ml) is added to the suspension. For 2 hours. After the reaction solution was concentrated under reduced pressure, it was partitioned with ethyl acetate-purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane monoacetate) to obtain t-butyl 6-formyl-12-naphthyloxyacetate.
  • t-butyl 6-formyl-12-naphthyloxyacetate (lOOmg) was dissolved in methanol (5 ml), and nitromethane (5 ml) and ammonium acetate (27 Omg) were added. In addition, the mixture was 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 (hexane-ethyl acetate).
  • Table 1 shows the compounds obtained in the above Examples. ⁇ — ⁇
  • thrombosis associated with extravascular circulation and improvement of impaired blood flow prevention or treatment of restenosis or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), treatment of various symptoms associated with chronic arterial occlusion
  • PTCA percutaneous transluminal coronary angioplasty
  • a therapeutic agent for thromboembolism in general, such as treatment for thrombosis and embolism associated with ischemic cerebrovascular disease, as a thrombolytic agent, an antithrombotic agent alone, or as a therapeutic agent for other thrombolytic agents Can be used together.
  • the present compound 1 X 1 0- 2 so that M was dissolved in dimethyl sulfoxide (DMS O), the preparation of 0. 2 Omm phosphate buffer solution containing 1 5M sodium chloride (p H 7. 4 )
  • DMS O dimethyl sulfoxide
  • the experiments 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 so as to be lmgZkg (10 ml) and orally administered to a mouse fasted for 4 hours. Distilled water was orally administered to the disease control group.
  • 6 hours after the administration 1 ml of thrombin (1 OU / ml) was administered from the tail vein to induce thrombosis, and the following death was confirmed.
  • 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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Abstract

La présente invention concerne de nouveaux dérivés de naphtalène représentés par la formule (1) qui exercent un puissant effet favorisant la fibrinolyse et qui, par conséquent, sont utiles en tant qu'agents antithrombotiques et thrombolytiques destinés à être administrés par voie orale.
PCT/JP2000/002279 1999-06-02 2000-04-07 Nouveaux derives de naphtalene Ceased WO2001077076A1 (fr)

Priority Applications (1)

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AU36738/00A AU3673800A (en) 2000-04-07 2000-04-07 Novel naphthalene derivatives

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PCT/JP1999/002939 WO2000031036A1 (fr) 1998-11-20 1999-06-02 Nouveaux derives de naphtalene

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WO2001077076A1 true WO2001077076A1 (fr) 2001-10-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2146329A (en) * 1983-09-08 1985-04-17 Lilly Co Eli Naphthalenylimidazopyridine and derivatives and their preparation
JPS63139172A (ja) * 1986-12-02 1988-06-10 Morishita Seiyaku Kk ４，５−ジヒドロ−６−（６−置換−２−ナフチル）−３（２ｈ）−ピリダジノン誘導体
US4897405A (en) * 1989-04-21 1990-01-30 American Home Products Corporation Novel naphthalenylalkyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents
AU4765297A (en) * 1996-12-04 1998-06-11 Les Laboratoires Servier New imidazoline compounds, process for preparing them and pharmaceutical compositions containing them
AU2300699A (en) * 1998-02-17 1999-08-30 Ono Pharmaceutical Co. Ltd. Amidino derivatives and drugs containing the same as the active ingredient
WO2000031036A1 (fr) * 1998-11-20 2000-06-02 Torii Pharmaceutical Co., Ltd. Nouveaux derives de naphtalene
WO2000031045A1 (fr) * 1998-11-20 2000-06-02 Torii Pharmaceutical Co., Ltd. Derives de naphtalene

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2146329A (en) * 1983-09-08 1985-04-17 Lilly Co Eli Naphthalenylimidazopyridine and derivatives and their preparation
JPS63139172A (ja) * 1986-12-02 1988-06-10 Morishita Seiyaku Kk ４，５−ジヒドロ−６−（６−置換−２−ナフチル）−３（２ｈ）−ピリダジノン誘導体
US4897405A (en) * 1989-04-21 1990-01-30 American Home Products Corporation Novel naphthalenylalkyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents
AU4765297A (en) * 1996-12-04 1998-06-11 Les Laboratoires Servier New imidazoline compounds, process for preparing them and pharmaceutical compositions containing them
AU2300699A (en) * 1998-02-17 1999-08-30 Ono Pharmaceutical Co. Ltd. Amidino derivatives and drugs containing the same as the active ingredient
WO2000031036A1 (fr) * 1998-11-20 2000-06-02 Torii Pharmaceutical Co., Ltd. Nouveaux derives de naphtalene
WO2000031045A1 (fr) * 1998-11-20 2000-06-02 Torii Pharmaceutical Co., Ltd. Derives de naphtalene

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids

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