WO1999011617A1 - Nouveaux derives de naphtamide et sels de ces derives - Google Patents

Nouveaux derives de naphtamide et sels de ces derives Download PDF

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Publication number
WO1999011617A1
WO1999011617A1 PCT/JP1998/003847 JP9803847W WO9911617A1 WO 1999011617 A1 WO1999011617 A1 WO 1999011617A1 JP 9803847 W JP9803847 W JP 9803847W WO 9911617 A1 WO9911617 A1 WO 9911617A1
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Prior art keywords
lower alkyl
conh
compound
acid
phenyl
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PCT/JP1998/003847
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English (en)
Japanese (ja)
Inventor
Fukushi Hirayama
Hiroyuki Koshio
Tsukasa Ishihara
Hiroyuki Kaizawa
Tomihisa Kawasaki
Yuzo Matsumoto
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU88866/98A priority Critical patent/AU8886698A/en
Publication of WO1999011617A1 publication Critical patent/WO1999011617A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4

Definitions

  • the present invention is useful as a medicament, particularly an activated suspected factor X inhibitor! Regarding naphthamide derivatives or their salts.
  • thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis are increasing year by year, and the importance of their treatment is increasing. I am waiting.
  • Injunctive therapy together with fibrinolytic therapy and iJtifii platelet therapy, plays a part in medical treatment in the treatment and prevention of thrombosis (General Clinical 41: 2141-2145, 1989).
  • Perfaline potassium is widely used worldwide as the only oral antimicrobial agent, but is based on its mechanism of action.
  • Thrombin is not only involved in the conversion of fibrinogen to fibrin, which is the final stage of coagulation, but also plays a significant role in platelet activation and fiber (Osamu Matsuo, edited by T-PA and Pro-UK, interdisciplinary project) Pp. 5-40 Hematology, 1986), and its inhibitors have long been at the center of drug discovery research as a target for drug discovery.
  • oral administration of bi oa vai I abi Iity has a problem in terms of safety (Bioome d. Bioc him. Acta 44, 1201 -1210, 1985).
  • no orally administrable thrombin inhibitor has been reported.
  • Utagukata factor X is K ey E n Z yme located at the confluence of the extrinsic and intrinsic coagulation cascade one de reaction, inhibition of this factor to located upstream from thrombin It may be more efficient than thrombin inhibition and may specifically inhibit the coagulation system (THROMBOS IS RESEARCH (19), 339-349, 1980).
  • Activation Amidinonaphthylalkylbenzene derivative or a salt thereof is known as a compound exhibiting a suspected factor X inhibitory action (Japanese Patent Application Laid-Open No. 5-208946, Thrombos is Haemos tasis 71 (3) , 314-319, 1994, and Thrombosis Haemos tasis 72 (3), 393-396, 1994).
  • WO 96Z16940 discloses an amidinonaphthyl derivative represented by the following general formula or a salt thereof.
  • R 1 hydrogen atom or a group represented by the formula —A—W—R 4
  • A a group represented by the formula —CX—, a group represented by the formula —CO—CO—, wherein one S0 2 - group represented by, X: ⁇ child or a sulfur atom, W: a single bond or a formula one NR 5 - group represented by, R 2: lower alkyl
  • R 3 a hydrogen atom, a halogen atom
  • R 4 : — OH, _0—lower alkyl, etc.
  • R 5 hydrogen atom, — CONH 2, etc., n: 0 or 1)
  • the present inventors have characterized in that amidinonaphthyl and a substituted phenyl are bonded via an amide, and that the amide has a lower alkyl as a substituent.
  • the present inventors have found that the naphthamide derivative or a salt thereof represented by (I) has an excellent inhibitory action on activated blood and blood factor X, and completed the present invention.
  • the present invention relates to a naphthamide derivative represented by the following general formula (I) or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient, in particular, an activated blood factor X inhibitor.
  • R 1 is lower alkyl, wherein the lower alkyl is a halogen atom, one COOH, one COO—lower alkyl, one NH 2 , one CN, one N ⁇ 2 , —OH, —O, one lower alkyl, one CONH 2 , -CONH- (lower alkyl), -CON- (lower alkyl) 2, -CONH- optionally be (S 0 2 _ lower alkyl) and substituted is selected from good Ariru, 1 or the same - or different two was May be substituted with a substituent of
  • R 2 is a hydrogen atom or a group represented by the formula:
  • R 3 a hydrogen atom, a halogen atom, One COOH, one COO- lower alkyl, One NH 2, One CN, one N0 2, one OH, one O- lower alkyl, lower alkyl, One CONH 2, -CONH- (lower alkyl), -CON- (lower alkyl) 2 or one CON H- (S0 2 - lower ⁇ alkyl), n: 0 or 1)
  • the compound of the present invention differs in structure from the compound mentioned in WO 96/16940 in that R 1 is lower alkyl in the above general formula.
  • an activated blood suspected factor X inhibitor can be expected to be more efficient and specific inhibition of the coagulation system than a thrombin inhibitor in a suspected therapy.
  • lower alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butylyl, isoptyl, sec-butylyl, tert-butylyl, pentizole, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-methylbutyl , 2-dimethylpentyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methyl Pentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,
  • those having 1 to 3 carbon atoms are preferred, and methyl and ethyl are particularly preferred.
  • aryl that constitutes “optionally substituted aryl” means both a carbon ring aryl and a heterocyclic aryl, unless otherwise specified. Phenyl, naphthyl, anthryl, phenanthryl and the like.
  • Heterocyclic aryls include, but are not limited to, furyl, chenyl, pyrrolyl, imidazolyl, virazolyl, isothiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, indolizinyl, quinolyl, quinolyl, quinolyl Quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, dihydrobenzofuranyl, naphthyridinyl, 1,2-benzoisoxazolyl, benzoyloxazolyl, benzothiazolyl, oxazolic pyridyl, isothiazolopyridyl, benzochenyl, etc. Can be
  • bicyclic heteroaryl examples include benzofuran, indole, benzothiophene, benzimidazole, benzoxazole, benzthiazole, quinoline, and quinazoline, and preferably benzofuran or indole.
  • Halogen atom includes a fluorine atom, a chlorine atom, an iodine atom and a bromine atom.
  • n means 0 or 1, but when it is 0, it means pyrrolidinyl, and when it is 1, it means piperidyl. Of these, particularly preferred Are compounds having piperidyl where n is 1.
  • the compound having pyrrolidinyl necessarily has an asymmetric carbon, and other compounds may include an asymmetric carbon atom depending on the type of the substituent. Therefore, the compound of the present invention includes a mixture of various isomers such as geometric isomers, tautomers, and optically active substances, and isolated compounds.
  • the compound (I) of the present invention may form an acid addition salt. Further, depending on the type of the substituent, a salt with a base may be formed.
  • salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, m-acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid.
  • examples thereof include inorganic bases, organic bases such as methylamine, ethylamine, and ethanolamine; and ammonium salt with a basic amino acid such as lysine and ornithine.
  • the present invention also includes hydrates of compound (I), various pharmaceutically acceptable solvates and polymorphs thereof. It is to be understood that the present invention is not limited to the compounds described in the Examples below, but may be a naphthamide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. It is all inclusive.
  • an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride, or ammonium acetate is reacted.
  • the solvent methanol, ethanol, acetone, tetrahydrofuran or the like is used.
  • Hydrogen sulfide is allowed to act on these two (II) under an organic base such as methylamine, triethylamine, pyridine or picoline to obtain a thioamide.
  • This thioamide can also be obtained by reacting the nitrile (II) with o, o-diethyl dithiophosphate under hydrogen chloride.
  • the above thioamide is reacted with a lower alkyl halide such as methyl iodide or acetyl iodide to obtain a thioimidate, and then reacted with an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride, or ammonium acetate.
  • a lower alkyl halide such as methyl iodide or acetyl iodide
  • an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride, or ammonium acetate.
  • a reagent such as 2 NM g B r.
  • the solvent include chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, and dimethylformamide.
  • a base such as sodium hydride or an acid such as aluminum chloride or P-toluenesulfonic acid as a catalyst may significantly accelerate the reaction. The reaction can be carried out under cooling or heating.
  • the amino protecting group exemplified by P may not be cleaved.
  • the compound (Ia) of the present invention can be obtained by further cleaving the protecting group P by a method suitable for cleaving.
  • amino-protecting group exemplified by P is not particularly limited as long as it is a group used for protecting amino, and examples thereof include lower alkoxycarbonyl, aralkyloxycarbonyl, acyl, lower alkyl, Aralkyl and sulfonyl.
  • Aralkyl J means a group in which a hydrogen atom of the above alkyl is substituted by aryl. Specifically, benzyl, phenyl Chill and the like.
  • racyl include formyl, acetyl, propionyl, and butyrino.
  • the compound (Ia) having a secondary amino and subjected to NH it can be obtained by reacting the imidate compound with a suitable solvent, usually in the presence of a base, under cooling or heating.
  • Solvents to be used are water, alcohols having 1 to 4 carbon atoms such as ethanol and propanol, aliphatic ethers such as getyl ether, halogenated hydrocarbons such as chloroform, N, N-dimethylformamide And a solvent such as dimethyl sulfoxide and a mixed solvent thereof.
  • Examples of the base include N-methylmorpholine, triethylamine, trimethylamine, sodium hydroxide, potassium hydroxide and the like.
  • the usual hydrolysis can be carried out under acidic conditions or neutral conditions under the condition of 1 ton of the base according to the formula.
  • examples of the base to be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, and the like.
  • the acid to be used includes hydrochloric acid, sulfuric acid, boron trichloride, and the like. Examples include Lewis acids, trifluoroacetic acid, and P-toluenesulfonic acid.
  • halogen ions such as lithium iodide and lithium bromide, thiol, and Metal salts, eodotrimethylsilane, and esterases.
  • Solvents used in the reaction include water, alcohols (eg, methanol, ethanol), acetone, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, ketone, pyridine acetate, lutidine, collidine and the like. Used.
  • the above-mentioned conventional solvent may be a mixture with water.
  • the reaction usually proceeds at M ⁇ , but there are some that need to be performed under ice-cooling or some that require heating.
  • the compound represented by the general formula (I) can be produced by arbitrarily combining other commonly known steps such as alkylation, acylation, oxidation, reduction, hydrolysis and the like.
  • This reaction is a reaction in which an amide of the compound (II) is reacted with a carboxylic acid of the compound (IV), preferably in the presence of a condensing agent, to synthesize an amide of the compound (V).
  • This reaction may be performed according to a conventional acylation reaction.
  • N, N-dicyclohexylcarposimide (DCC), 1-ethyl-3 1- (3- (N, N-dimethylamino) propyl) carbodiimide, casoleponyldiimidazole, diphenylphosphoryl azide (DPPA) ⁇ ethylphosphoryl cyanide and the like can be preferably used.
  • Examples of the active derivative of the carboxylic acid to be used include active esters obtained by reacting with phenolic compounds such as P-nitrophenol, N-hydroxyamine compounds such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole, Monoalkyl carbonate or mixed acid anhydride obtained by reacting with an organic acid, diphenylphosphoryl chloride, phosphoric acid-based mixed acid anhydride obtained by reacting with N-methylmorpholine, and hydrazine, Acid halides such as acid azide, acid chloride and acid bromide obtained by reacting with alkyl nitrate, symmetric acid anhydrides and the like can be mentioned. Usually, the reaction is carried out in a solvent under cooling or under cooling, but depending on the type of acylation reaction, it may be necessary to carry out the reaction under anhydrous conditions.
  • an organic solvent such as dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, Dimethyl sulfoxide and the like, a mixed solvent thereof and the like can be used, but it is preferably selected according to the method to be applied.
  • an organic solvent such as dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, Dimethyl sulfoxide and the like, a mixed solvent thereof and the like can be used, but it is preferably selected according to the method to be applied.
  • the reaction may be carried out under a base such as N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, potassium mono-t-butoxide, butyllithium, or sodium diamide, or using these bases as a solvent. In some cases, the reaction proceeds smoothly.
  • a base such as N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, potassium mono-t-butoxide, butyllithium, or sodium diamide, or using these bases as a solvent.
  • This reaction is a reaction in which the amide of compound (V) is reacted with the alkyl halide and alkyl sulfonate of compound (VI) to synthesize the starting compound (II).
  • This reaction may be carried out according to a conventional N-alkylation reaction of an amide.
  • the amide of the compound (V) is reacted with a corresponding amount of the compound (VI) in a base, in an organic solvent which does not participate in the reaction, under cooling to a It is performed while stirring under heat.
  • the base used is sodium hydride, lithium hydride, potassium hydride, butyllithium, potassium tert-butoxide, sodium amide, potassium carbonate, sodium carbonate, Sodium hydroxide, potassium hydroxide, N-methylmorpholine, trietholeamine, pyridine and the like are used.
  • This reaction is a reaction of reacting the amine compound of the compound (III) with the alkyl halide, alkylsulfonate or aldehyde of the compound (VI) to synthesize the compound (VII).
  • This reaction does not involve the compound (VI) with the compound (VI) in the reaction described in Chapter 5 and is carried out in an organic solvent with stirring under cooling or heating.
  • a base for example, an inorganic base such as potassium carbonate or thorium carbonate, or an organic base such as triethylamine.
  • This reaction is a reductive amination reaction in which a compound (III), a corresponding aldehyde (VI), and a reducing agent are reacted.
  • this reducing agent for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like are used.
  • This reaction does not participate in the alcohol or tin reaction, and is carried out in an organic solvent with stirring under cooling or heating.
  • catalytic hydrogenation may be performed under normal pressure or under pressure in the presence of a catalyst such as palladium-carbon or platinum oxide.
  • the compound (V I) is an ⁇ , unsaturated carbonyl compound such as acrylic acid
  • the compound (V I) can be synthesized using a Michael condensation reaction. This reaction does not involve the compound (III) and the compound (VI) in the self-organization reaction, and is carried out in an organic solvent with stirring under cooling or heating.
  • an acid for example, hydrochloric acid, hydrochloric acid, p-toluenesulfonic acid, etc.
  • a base for example, potassium carbonate, charcoal thorium, triethylamine, etc.
  • a solvent is used. Preferably, it is used.
  • This reaction is a reaction of reacting the compound (VII) with the carboxylic acid of the compound (IV) to synthesize the starting compound (II).
  • the compound of the present invention thus produced can be isolated and purified by a known method, for example, extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like.
  • the salt of the compound of the present invention can be converted to a desired salt by subjecting the salt to a usual salt formation reaction.
  • ⁇ isomers can be subdivided by a conventional method such as fractional crystallization, which recrystallizes with an appropriate salt, or column chromatography.
  • the compound of the present invention specifically inhibits the activation factor; suspected factor X, and has a strong suspecting action. Therefore, it is useful as a quasi-inhibitory agent or a prophylactic / therapeutic agent for diseases caused by bowel thrombus or embolism.
  • Suitable diseases include cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA), subarachnoid hemorrhage (vascular spasm) and other cerebrovascular disorders, acute and chronic myocardial infarction, unstable angina, Diseases in ischemic heart disease such as coronary thrombolysis, diseases in pulmonary vasculopathy such as pulmonary infarction, pulmonary embolism, peripheral arterial occlusion, deep thromboembolism, generalized 14 ⁇ intravascular coagulation syndrome, after artificial vascular surgery and Thrombosis after human valve replacement, reocclusion and stenosis after coronary artery vinostomy, reocclusion and stenosis after PTCA (Pecutaneoustranslum inalcoronaryangiop I asty) or PTCR (Percutaneoustranslum inalcoronary recanalization) And diseases in each 3 ⁇ 41 & tract disorders such as thrombosis during extracorporeal circulation.
  • the inhibitory effect of the compound of the present invention on activated blood; suspected factor X suggests its potential as a prophylactic / therapeutic agent for influenza virus infection based on the activity of inhibiting influenza virus growth (Japanese Patent Application Laid-Open No. 6-227971). No.)
  • the excellent activated blood pseudo-factor X inhibitory activity of the compound of the present invention was confirmed by the following fiber method.
  • the mixture was heated at 7 ° C for 3 minutes, and 100 I of a 20 mM CaCl solution was added to measure the coagulation time.
  • AmeIng KC4A was used for the measurement of the coagulation time.
  • the clotting time 2-fold extension dose (abbreviated as CT2) was calculated based on the clotting time when 1 ⁇ I of physiological saline was added instead of the drug.
  • CT2 The clotting time 2-fold extension dose
  • AmeIng KC4A was used for the measurement of the coagulation time.
  • the clotting time 2-fold extension dose (abbreviated as CT2) was calculated based on the clotting time when 100 I of physiological saline was added. As a result, the compound of the present invention showed strong activity.
  • Tissue thromboplastin 54 mg Zvia I, lyophilized formulation, Ortho
  • the above-mentioned thrompoplastin solution (50 I) was added and the setting time was measured.
  • AmeIng KC4A was used for the measurement of the coagulation time.
  • the coagulation time when physiological saline was administered instead of the drug was taken as the control, and the activity of the drug was shown as a relative value when this control was regarded as ⁇ .
  • the compound of the present invention showed strong activity.
  • the compounds of Examples 8 and 9 were 3.7 times and 2.9 times stronger than the control, respectively, and showed a coagulation time extending effect.
  • Activated thrombofax (Ortho) 50 I, 50 I of the above plasma were heated at 37 ° C for 3 minutes, and 50 ⁇ I of 2 OmM CaC I solution pre-warmed at 37 ° C was added and coagulation time Was measured.
  • Ame Iung KC4A was used for the measurement of the coagulation time.
  • the clotting time when saline was administered instead of the drug was used as a control, and the activity of the drug was shown as a relative value when this control was set to 1.
  • the dose-dependency and time-course of the suspected action were also examined in the same manner by changing the administered dose or time.
  • the compound of the present invention was found to have an effect of prolonging the coagulation time upon intravenous administration.
  • compositions containing one or more of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a carrier for commonly used pharmaceutical preparations. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., using tablets and powders, and other It is administered orally.
  • the clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the patient's symptoms, weight, age, age, etc., and is usually 0.1 to 500 mg orally per adult per day, parenteral OOmg, which is administered once or in several divided doses.
  • the dose varies under various conditions, so a dose smaller than the above dose range may be sufficient. is there.
  • the one or more active substances comprise at least one inert diluent, such as 3 ⁇ 4 ⁇ , mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with metasilicic acid and magnesium aluminate.
  • the composition may contain additives other than the inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid or azono.
  • a solubilizing or solubilizing agent such as laginic acid may be included. If necessary, tablets or pills may be provided with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate.
  • a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water Includes ethyl alcohol.
  • the composition may contain, in addition to the inert diluent, a solubilizing or solubilizing agent, a humectant, an auxiliary agent such as a syrup, a sweetening agent, a flavoring agent, a fragrance, and a preservative.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and diluents for foaming agents include, for example, distilled water for size and physiological saline.
  • water-insoluble solution agents and diluents for ⁇ agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (trade name).
  • compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, lactating agents, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. May be. These are sterilized by, for example, thighs passed through a nocteria retaining filter, blending of a fungicide or irradiation. They can also be used to produce a sterile solid composition which is dissolved in sterile water or a sterile injectable solvent before use.
  • additives such as tonicity agents, preservatives, wetting agents, lactating agents, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. May be. These are sterilized by, for example, thighs passed through a nocteria retaining filter, blending of a fungicide or irradiation. They can also be used to produce a sterile solid composition which is dissolved in sterile water or a ster
  • a solubilization treatment may be performed.
  • known methods applicable to pharmaceutical preparations for example, surfactants (polyoxyethylene hydrogenated castor oil, A method of adding polyoxetylene sorbitan high-class fatty acid esters, polyoxetylenepolyoxypropylene glycols, sucrose fatty acid esters, etc.), a drug and a solubilizer such as a polymer (hydroxypropyl methylcellulose) (HPMC), polyvinylpyrrolidone (PV
  • water-soluble polymers such as polyethylene glycol (PEG), carboxymethylethyl cellulose (CMEC), hydroxypropyl methylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer (Eudragit, S, trade name: ROHM-AND /, an enteric polymer such as Issu Corporation).
  • PEG polyethylene glycol
  • CMEC carboxymethylethyl cellulose
  • HPMCP hydroxypropyl methylcellulose phthalate
  • methyl methacrylate-methacrylic acid copolymer Eudragit, S, trade name: ROHM-AND /, an enteric polymer such as Issu Corporation.
  • a method of forming a soluble salt, a method of forming an inclusion compound by using cyclodextrin or the like can be adopted.
  • the means of solubilization can be changed as appropriate according to the target drug [ ⁇ Recent formulation technologies and their applications], Isamu Utsumi, Pharmaceutical
  • the production method of the compound of the present invention will be specifically described with reference to Production Examples of the compound of the present invention.
  • the starting compounds of the compounds of the present invention also include novel compounds, and the production methods of these compounds will be described as reference examples.
  • Example 3 The compound of Example 2 (Table 3) was obtained in the same manner as in Example 1.
  • a small amount of 1N hydrochloric acid was added, followed by freeze-drying and drying of ethyl N— [ 4-[((4-Piperidyl) oxy] phenyl] —N— (5-amidino-1-benzobenzoyl) glycinate dihydrochloride 95 mg was obtained.
  • Example 13 was synthesized in the same manner as Example 3 (Table 9).
  • Example 14 was synthesized in the same manner as in Example 9 (Table 9).
  • Example 15 was synthesized in the same manner as in Example 1 (Table 10).
  • Example 16 was synthesized in the same manner as in Example 3 (Table 11). The structural formulas and physicochemical properties of the compounds of Reference Examples and Examples are shown in the attached table. The symbols in the table have the following meaning.
  • R f. Reference example number
  • Ex . Example number
  • NMR Nuclear magnetic resonance spectrum (unless otherwise specified, in TMS, MS: mass spectrometry (m / z), Me: methyl, Et: ethyl, Bo c: t-butoxycarbonyl

Abstract

Cette invention se rapporte à des dérivés de naphtamide, représentés par la formule générale (I), ou à des sels de ces dérivés. Dans cette formule, le cycle (a) représente naphtalène ou hétéroaryle dicyclique; R1 représente alkyle inférieur éventuellement substitué par un ou deux substituants identiques ou différents, choisis parmi des atomes d'halogène, -COOH, -COO-(alkyle inférieur), -NH¿2?, -CN, NO2, -OH, -O-(alkyle inférieur), -CONH2, -CONH-(alkyle inférieur), -CON-(alkyle inférieur)2, -CONH-(SO2-(alkyle inférieur)) et aryle éventuellement substitué; R?2¿ représente hydrogène ou un groupe représenté par (b); R3 représente hydrogène, halogéno, -COOH, -COO-(alkyle inférieur), -NH¿2?, -CN, NO2, -OH, -O-(alkyle inférieur), alkyle inférieur, -CONH2, CONH-(alkyle inférieur), -CON-(alkyle inférieur)2, ou -CONH-(SO2-(alkyle inférieur)); et n est égal à 0 ou à 1. Ces composés ont une action anticoagulante grâce à l'inhibition du facteur de coagulation sanguine X activé et ils sont par conséquent utiles comme inhibiteur de la coagulation sanguine ou comme prophylactique/remède contre les maladies provoquées par des thrombus ou des emboles.
PCT/JP1998/003847 1997-09-01 1998-08-28 Nouveaux derives de naphtamide et sels de ces derives WO1999011617A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002356A1 (fr) * 1999-07-01 2001-01-11 Sankyo Company, Limited Dérivés d'indoline ou tétrahydroquinoline
WO2001056989A2 (fr) * 2000-02-01 2001-08-09 Cor Therapeutics, Inc. INHIBITEURS DU FACTEUR Xa CONTENANT DU PHENYLENE BIVALENT
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

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JPH05208946A (ja) * 1991-10-31 1993-08-20 Dai Ichi Seiyaku Co Ltd 芳香族アミジン誘導体及びその塩
JPH07179407A (ja) * 1993-11-12 1995-07-18 Green Cross Corp:The 新規縮合環系化合物またはその塩、およびその医薬用途
JPH0853398A (ja) * 1994-06-06 1996-02-27 Green Cross Corp:The 新規縮合環カルボン酸誘導体またはその塩、およびその医薬用途
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JPH08231548A (ja) * 1995-02-28 1996-09-10 Green Cross Corp:The 新規双環カルボン酸誘導体またはその塩、およびその医薬用途

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WO2001002356A1 (fr) * 1999-07-01 2001-01-11 Sankyo Company, Limited Dérivés d'indoline ou tétrahydroquinoline
WO2001056989A2 (fr) * 2000-02-01 2001-08-09 Cor Therapeutics, Inc. INHIBITEURS DU FACTEUR Xa CONTENANT DU PHENYLENE BIVALENT
WO2001056989A3 (fr) * 2000-02-01 2002-02-28 Cor Therapeutics Inc Inhibiteurs du facteur xa contenant du phenylene bivalent
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

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