WO2004010996A1 - Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose - Google Patents

Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose Download PDF

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Publication number
WO2004010996A1
WO2004010996A1 PCT/JP2002/007679 JP0207679W WO2004010996A1 WO 2004010996 A1 WO2004010996 A1 WO 2004010996A1 JP 0207679 W JP0207679 W JP 0207679W WO 2004010996 A1 WO2004010996 A1 WO 2004010996A1
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Prior art keywords
naphthalenyl
oxy
group
benzoxazolyl
acid
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PCT/JP2002/007679
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English (en)
Japanese (ja)
Inventor
Kiyoshi Nakatogawa
Masamichi Takagi
Makoto Akashima
Noriaki Ohishi
Akiko Ohshima
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Shizuoka Coffein Co Ltd
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Shizuoka Coffein Co Ltd
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Priority to AU2002368133A priority Critical patent/AU2002368133A1/en
Priority to JP2004524089A priority patent/JP4334476B2/ja
Priority to PCT/JP2002/007679 priority patent/WO2004010996A1/fr
Publication of WO2004010996A1 publication Critical patent/WO2004010996A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2

Definitions

  • the present invention has a plasminogen activator (PA) activity promoting effect and a plasminogen activator inhibitor (PAI-1) inhibitory activity, and is useful as a thrombolytic agent and an antithrombotic agent. , 3-azole derivatives.
  • thrombolytic therapy therapies to administer PAs, that is, thrombolytic therapy (fibrinolytic therapy)
  • thrombolytic therapy a precursor of the regulator of the blood fibrinolytic system, to plasmin, and the resulting plasmin exerts its enzymatic action to become a component of thrombus. Degradation of certain fibrins leads to thrombolysis.
  • thrombolytic agents used in this fibrinolytic therapy include in vivo substances such as perokinase (UK) and tissue plasminogen activator (t-PA), streptokinase (SK), and staphylokinase (SAK ) And their genetically modified products are known.
  • t-PA tissue plasminogen activator
  • SK streptokinase
  • SAK staphylokinase
  • An object of the present invention is to provide a pharmaceutical composition having a thrombolytic action and an antithrombotic action that does not have the above-mentioned disadvantages.
  • PAI-1 plasminogen activator inhibitor
  • the present invention has been made based on such findings, and has excellent PA activity promoting action and PAI-1P harmful activity, and can be orally administered, and has a fibrinolytic promoting action, a thrombolytic action and an antithrombotic action. And a pharmaceutical composition having the same.
  • the present invention relates to the following inventions.
  • R i is hydrogen or a lower alkyl group which may be substituted with a lower alkoxy group
  • R 2 and R 3 are each independently substituted with hydrogen or a lower alkoxy group, Kill group
  • R 4 is hydrogen, substituted with a lower alkoxy group, a lower alkyl group
  • R 5 and R 6 are independently hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, a benzyl group
  • R 7 is hydrogen, substituted with a lower alkoxy group, lower alkyl group, benzyl group
  • R 8 and R 9 are each independently hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, ben 5.
  • Arylene groups include 1,4- and 1,2-phenylene groups, [1,1, -biphenyl] -4,4'-diyl groups, 2,6-, 2,3- and 6,6,1-naphthalenediyl group of formula (6) with oxygen bonded to the 6-position)
  • R 0 is hydrogen, substituted with a lower alkoxy group, lower alkyl group, benzyl group
  • R 1] L and 2 are each independently hydrogen, a lower alkyl group which may be substituted by a lower alkoxy group, a benzyl group,
  • R 13 is hydrogen, lower alkyl group
  • R 14 and 5 are each independently substituted with hydrogen, lower alkoxy, good alkyl, lower alkyl, benzyl
  • R 6 may be substituted with hydrogen or lower alkoxy group
  • arylene group is a 14-phenylene group, [11, -biphenylinole]-
  • R i 7 is hydrogen, substituted with a lower oxy group, lower alkyl group, benzyl group
  • the amino group may be substituted with a lower alkyl group or a benzyl group.
  • R i 8 is hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group
  • treating thrombosis comprising administering to a subject an effective amount of the compound represented by the formula (1) in the above [1], or a pharmaceutically acceptable salt thereof or a solvate thereof. how to.
  • R 4 is hydrogen, lower alkyl or benzyl which may be substituted with lower acyloxy
  • R 5 and R 6 are independently hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, a benzyl group
  • R 7 is hydrogen, lower alkyl or benzyl which may be substituted with lower acyloxy
  • R 8 and R 9 are each independently hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group
  • Arylene groups include 1,4- and 1,2-phenylene groups, [1,1, -biphenyl] -4,4'-diyl groups, 2,6-, 2,3- and 6It means the 6,1-naphthalenediyl group of formula (6) with oxygen bonded to the 6-position.
  • Ariren group is 1, 4-phenylene group, if b 2, b 3 to below are both hydrogen except the methylene group as a lower alkylene group.
  • R 1 L and 2 are independently hydrogen, a lower alkyl group which may be substituted by a lower alkoxy group, a benzyl group,
  • R! 3 is hydrogen, lower alkyl group
  • R 14 and Ri 5 are each independently substituted with hydrogen, lower asinoleoxy, good alkyl, lower alkyl, benzyl
  • R 16 is hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, a benzyl group
  • Arylene group is [1, 1'-biphenyl] -4,4, -diyl group, 2,6-, 2,3- and a 2 is bonded to 6-position in formula (12). 6, trinaphthalenediyl group)
  • the amino group may be substituted with a lower alkyl group or a benzyl group.
  • R i 8 is hydrogen, substituted with a lower Ashiruokishi group a lower alkyl group, Baie
  • R 19 and R 20 are independently hydrogen, a lower alkyl group or a benzyl group which may be substituted with a lower alkoxy group))
  • R 4 is hydrogen, substituted with a lower alkoxy group, and is a lower alkyl group
  • R 5 and R 6 are independently of each other hydrogen, a lower alkyl group which may be substituted by a lower alkoxy group, a benzyl group
  • the 2> arylene group is a 1,4-phenylene group or a 2,6-naphthalenediyl group.
  • a is a carbonyl group, a lower alkoxycarbonyl group, a methylene group is a lower alkylene group, and when the following is hydrogen, excluding 1,4-phenylene group)
  • ⁇ l> a 2 is a hydroxyl group
  • the arylene group is a 1,4-phenylene group or a 2,6-naphthalenediyl group (however, at the same time, when a 2 is a hydroxyl group and the following is hydrogen, the 1,4-phenylene group is excluded) )
  • R i is hydrogen or a lower alkyl group which may be substituted with a lower alkoxy group
  • R 2 and R 3 are independently hydrogen or a lower alkyl group which may be substituted with a lower alkoxy group
  • R 4 is hydrogen, substituted by lower alkoxy group A good lower alkyl group
  • R 5 and R 6 are independently hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, a benzyl group
  • arylene group is 2,6-naphthalenediyl group) (ii) arylene group a 2... (12)
  • a 2 is a hydroxyl group
  • R 4 is hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, a benzyl group
  • arylene group is 2, 6-naphthalenediyl group
  • R 0 is hydrogen, a lower alkyl group which may be substituted with a lower alkoxy group, a benzyl group
  • arylene group is 2,6-naphthalenediinole group) (iii) —lower alkylene group COOR 17 ... (17)
  • lower alkyl group refers to a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group. Butyl group, isobutyl group, sec -butyl group and tert-butyl group.
  • “Lower alkylene group” means a linear or branched alkylene group having 1 to 7 carbon atoms, such as a methylene group, an ethanediyl group, a propanediyl group, a butanediyl group, a pentanedyl group, a hexanediyl group, a heptanediyl group Corresponds to these.
  • the “lower alkoxy group” means a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group.
  • the "lower alkoxycarbonyl group” is an alkoxycarbonyl group having a lower alkoxy group having 1 to 4 carbon atoms as described above, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group. Can be mentioned.
  • the “lower acyloxy group” is a linear or branched 1-oxoalkyloxy group having 1 to 7 carbon atoms, and is an acetyloxy group, a 1-oxopropoxy group, a 2,2-dimethyl-1-o group.
  • Examples include a oxopropoxy group, a 1-oxobutoxy group, a 1-oxopentyloxy group, a 1-oxohexyloxy group, and a 1-oxoheptyloxy group.
  • 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 acid or ester. Further, those compounds may be solvates. Salts include pharmacologically acceptable caro salts with acids, 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. Include alkali metal such as sodium salt and potassium salt, alkaline earth metal salt such as magnesium salt and calcium salt, aluminum salt and the like.Ammonium salt includes salt such as ammonium and organic amine addition. Examples of the salt include addition salts such as morpholine and piperidine, and examples of the amino acid addition salt include addition salts such as glycine and lysine. Examples of the solvates include hydrates. Esters include lower alkyl esters and the like.
  • X represents a halogen.
  • the carboxylic acid represented by the formula (A1) is reacted with a para-haloketone compound represented by the formula (A2) in an aqueous alcohol containing an alkali carbonate such as sodium carbonate, for example, under reflux, to obtain the obtained formula.
  • the oxazole represented by the formula (A4) can be obtained by heating the ester represented by the formula (A3) with a nitrogen source such as urea or ammonium acetate in acetic acid (Reference: Heterocyclic Compounds, Wiley & Sons, Inc., 5, 302-323).
  • the ester compound represented by the formula (A3) is obtained by converting the acid halide represented by the formula ( ⁇ 5) to a para-hydroxyketone derivative represented by the formula ( ⁇ 6) in the presence of a pyridine or a trialkylamine. It can also be obtained by reacting at room temperature to 100 ° C.
  • a hydroxyl group is present in the above-mentioned substituent P, it is protected by a benzyl group or the like in advance according to a conventional method, and oxazole itself represented by the formula (A4) itself or its substituents Tl, T2, etc.
  • the oxazole derivative after conversion to another group can be subjected to elimination of the protecting group.
  • C The above method is an example, and other similar known methods can also be used.
  • a carboxylic acid halide represented by 3) and a 2-aminophenol compound represented by formula (B1) are converted to benzene, toluene, xylene, dioxane, 13-dimethyl-2-imidazolidinone, etc. in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • This amide is converted to benzene, toluene, xylene, 13-dimethyl-2-imidazolidino
  • a solvent such as By heating with refluxing with enesulfonic acid monohydrate (PTS) to remove water generated or by heating with thionyl halide, benzoxazole represented by formula (B5) is obtained.
  • PTS enesulfonic acid monohydrate
  • benzoxazole represented by formula (B5)
  • benzoxazole represented by formula (B5) or a substituent tlt 2, t 3 etc. are each a different group, for example, benzoxoxa after converting a hydroxyl group to an acyloxy group etc. It is preferable to remove the protecting group in the sol form.
  • the didazole derivative is obtained according to Scheme C.
  • a hydroxyl group is present in the above-mentioned substitution group P, it is stored in advance according to a conventional method, for example, with a benzyl group. Can be protected.
  • the compound represented by the formula (C4) can be easily obtained by reacting an aldehyde represented by P-CHO and nitromethane with a catalytic amount of n-butylamine in acetic acid by heating under reflux (Reference: Organic Reactions, John Wiley & Sons, Inc., 15, Chapter 2).
  • an ester of a carboxylic acid represented by the formula (D2) is added and the mixture is subjected to a reflux reaction for several hours to obtain a benzothiazole represented by the formula (D3).
  • a hydroxyl group is present in the substituent P, it is protected in advance by a conventional method, for example, with a benzyl group or the like, and the benzothiazole itself represented by the formula (D3) or the substituent tl, t 2 , t 3 and the like may be converted to different groups, and the benzothiazole derivative may be subjected to elimination of the protecting group.
  • the above method is an example, and other similar known methods can be used.
  • the conversion of the ester group present in the compound represented by the general formula (1), that is, the lower alkoxycarbonyl group or the like, to a carboxylic acid is carried out according to a conventional method. After treating for several hours at room temperature or under reflux, acid precipitation is achieved.
  • the obtained free carboxylic acid can be obtained as an alkali metal salt such as sodium salt by dissolving with an equivalent amount of sodium hydroxide and freeze-drying.
  • a lower alkoxycarbonyl group is present in the compound represented by the general formula (1), the compound itself forms one form of the pharmaceutical composition of the present invention. It can be converted into the corresponding carboxyl group and its salt, which is another form of the present invention.
  • An acid addition salt of the compound represented by the general formula (1) with hydrochloric acid or the like is also one form constituting the pharmaceutical composition of the present invention, and these are formed according to a conventional method. Alternatively, it can be obtained by treating with an equivalent amount of hydrochloric acid in a solvent such as aqueous alcohol or aqueous acetone and, if necessary, concentrating under reduced pressure.
  • the above method is an example and not a limitation.
  • compositions containing the 1,3-azole derivative represented by the general formula (1) or a salt thereof or a solvate thereof as an active ingredient thus produced are usually used in mammals ( (Including human patients) can be administered as tablets, capsules, powders, fine granules, syrups, orally, rectally, or by injection. Further, the compound of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, ordinary oral excipients, lubricants, binders, disintegrants, wetting agents, coating agents and the like can be used for oral IJ.
  • Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or as a dry syrup prepared with water or other suitable solvent before use. Is also good. Said solutions may contain conventional additives such as suspending agents, flavors, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cocoa butter, lauric butter, macrogol, glycerinated gelatin, witetbsol, sodium stearate or a mixture thereof, and, if necessary, emulsifiers, suspending agents, preservatives, etc. Can be added.
  • Injectable is a dissolving or dissolving aid such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol, etc., which can constitute an aqueous or ready-to-use dosage form, pH adjuster, isotonic
  • Pharmaceutical ingredients such as a stabilizing agent and a stabilizing agent are used. Specific examples of 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, calcium hydrogen phosphate, light calcium anhydride, non-water cake Acid, Avicel, various starches, dextrin, carboxymethyl starch (CMS), lactose, etc.
  • Binder ethyl cellulose (EC), carboxymethylcellulose Na (CMC — Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches, dextrins, sodium alginate, gelatin , Polyvinylinolearkonore (PVA), polyvinylinolepyrrolidone (PVP) and so on.
  • Disintegrators synthetic aluminum silicate, magnesium aluminate metasilicate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS), etc.
  • Anti-solidification agents 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 cycle mouth dextrins, phospholipids etc.
  • Absorption promoters polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, medium-chain fatty acid triglycerides, and the like.
  • Solubilizing agents ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene propylene 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 anoregate, polyvinylacetate argyleaminoacetate, polyatarylate Na, copolymers of various acrylate methacrylate derivatives, polyglycolic acid Na, and the like.
  • CMEC carboxymethylethylcellulose
  • CAP cellulose acetate phthalate
  • HPMC hydroxypropylmethylcellulose phthalate
  • HPC sodium anoregate
  • polyvinylacetate argyleaminoacetate polyatarylate Na
  • 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, the dosage is about lmg to 100mg / person / day by oral or rectal administration. It is about 0.1 to 50 Omg / person Z days. However, these numerical values are merely examples, and the dosage may be appropriately adjusted according to various conditions such as the patient's symptoms.
  • 6-benzyloxy-2-naphthoic acid mouthride (2.Og) to 6-amino-m-cresol (l.Og), triethylamine (0.8 g) to 1,3-dimethyl-2-imidazolidinone (40 mL) )
  • the reaction solution was added to a saturated aqueous solution of potassium hydrogen carbonate (400 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain crude crystals.
  • the crude crystal was stirred and suspended under reflux with methanol, and the crystal was collected by filtration to obtain an intermediate amide compound (0.46 g).
  • a 10% aqueous solution of potassium hydroxide (10 mL) was added to Compound 90 (Wet 3.9 g) in methanol (40 mL), and the mixture was reacted at room temperature for 3 days and at 60 to 70 ° C for 4 hours.
  • 6- (1-Methylethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 112), 6- [6- (1-Methylethyl) -2-benzobenzoxazolyl] -2-naphtha Lenol (compound 113), 6-[[6- [6- (1-methylethyl) 2-benzoxazolyl] -2-naphthalenyl] oxy] hexyl hexate (compound 114), 6-[[6 -[6- (1-Methylethyl) -2-benzobenzozolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 115), 6-[[6- [6- (1-Methylethyl) -2-benzoxoxa] Preparation of zolyl] -2_naphthalenyl] oxy] hexanoic
  • 6-Benzyloxy-2-naphthoic acid cleft (2.5 g) to 2-amino-5-isopropylphenol hydrochloride (2.4 g) and triethylamine (2.4 g) to 1,3-dimethyl-2-imidazolidinone (50 mL), and reacted at room temperature for 5 hours.
  • 6-Ethoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (disulfide compound 143), 6- (6-ethoxy-2-benzoxazolyl) _2-naphthalenol (compound 144), 6 _ [[6- (6-ethoxy-2-benzoxazolyl) -2-naphthaleninole] oxy] hexyl oxalate (compound 145), 6-[[6- (6-ethoxy-2 -Benoxoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (compound 146), 6-[[6- (6-Ethoxy-2-benzoxazolyl) -2-naphthaleninole] oxy] hexanoate hexanoate Preparation of the salt (compound 147):
  • 1,4-Dioxane (5 mL) and methanol (45 mL) were added to and dissolved in compound 183 (500 mg), and a 15% aqueous sodium oxide solution (2 mL) was added, followed by reaction at room temperature overnight and at about 50 ° C for 7 hours. .
  • 1,4-Dioxane (20 mL;) and methanol (80 mL) were added to and dissolved in compound 189 (600 mg).
  • An aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 50 ° C for 2 hours.
  • the reaction solution was concentrated under reduced pressure, water (40 mL) was added to the residue to dissolve it, and then dilute hydrochloric acid was added to perform acid precipitation.
  • 6_ (cyclohexyloxy) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazonole (compound 199), 6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenol ( Compound 200), 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolinole] -2-naphthaleninole] oxy] hexinoate ethoxylate (compound 201), 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 202), 6-[[6- [6-(cyclohexyloxy) -2-] Preparation of Benzoxazolyl] -2-naphthaleninole] oxy] hexanoic acid potassium salt
  • 6-Benzyloxy-2-naphthoic acid mouthride (7.0 g) is converted to 2-amino-4 -tert-butylphenol (4.7 g) and triethylamine (2.9 g) to 1,3-dimethyl-2-imidazo.
  • the solution was added to a lydinone (80 mL) solution, and reacted at room temperature for 3.5 hours.

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Abstract

L'invention concerne un dérivé 1,3-azole représenté par la formule (1). Ce dérivé favorise l'accélération de l'activité d'agrégation plaquettaire et l'activité inhibitrice de PAI-1 et peut être utilisé en tant qu'agent antithrombotique ou thrombolytique, et administré par voie orale.
PCT/JP2002/007679 2002-07-29 2002-07-29 Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose Ceased WO2004010996A1 (fr)

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AU2002368133A AU2002368133A1 (en) 2002-07-29 2002-07-29 1,3-azole derivative and medicinal composition containing the derivative for treatment for thombosis
JP2004524089A JP4334476B2 (ja) 2002-07-29 2002-07-29 １，３アゾール誘導体及び同誘導体を含む血栓症治療のための医薬組成物
PCT/JP2002/007679 WO2004010996A1 (fr) 2002-07-29 2002-07-29 Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose

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WO2006023865A1 (fr) * 2004-08-23 2006-03-02 Wyeth Acides d'oxazolo-naphthyl utilises en tant modulateurs de l'inhibiteur de type-1 (pai-1) de l'activateur de plasminogene utiles dans le traitement de la thrombose et des maladies cardio-vasculaires
WO2007111136A1 (fr) * 2006-03-28 2007-10-04 Adeka Corporation Composition de resine epoxy durcissable
JP2007530459A (ja) * 2004-03-26 2007-11-01 メシルジーン、インコーポレイテッド ヒストンデアセチラーゼの阻害剤
WO2007138705A1 (fr) 2006-06-01 2007-12-06 Japan As Represented By Director General Of Agency Of National Cancer Center Suppresseur de tumeurs
JP2007537253A (ja) * 2004-05-12 2007-12-20 アボット・ラボラトリーズ ３環式および２環式ヘテロアリールヒスタミン３受容体リガンド
US8323805B2 (en) 2009-06-04 2012-12-04 Nitto Denko Corporation Emissive aryl-heteroaryl acetylenes
US8354668B2 (en) 2009-06-29 2013-01-15 Nitto Denko Corporation Emissive triaryls
US8426040B2 (en) 2010-12-22 2013-04-23 Nitto Denko Corporation Compounds for use in light-emitting devices
US8927121B2 (en) 2009-06-29 2015-01-06 Nitto Denko Corporation Emissive aryl-heteroaryl compounds
US8933243B2 (en) 2011-06-22 2015-01-13 Nitto Denko Corporation Polyphenylene host compounds
CN105392777A (zh) * 2013-06-27 2016-03-09 株式会社Lg生命科学 作为gpr120激动剂的联芳基衍生物
CN109456274A (zh) * 2018-12-07 2019-03-12 广东药科大学 苯并咪唑类衍生物、其制备方法及其作为药物的用途

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JP2007530459A (ja) * 2004-03-26 2007-11-01 メシルジーン、インコーポレイテッド ヒストンデアセチラーゼの阻害剤
JP2007537253A (ja) * 2004-05-12 2007-12-20 アボット・ラボラトリーズ ３環式および２環式ヘテロアリールヒスタミン３受容体リガンド
JP4881859B2 (ja) * 2004-05-12 2012-02-22 アボット・ラボラトリーズ ３環式および２環式ヘテロアリールヒスタミン３受容体リガンド
WO2006023865A1 (fr) * 2004-08-23 2006-03-02 Wyeth Acides d'oxazolo-naphthyl utilises en tant modulateurs de l'inhibiteur de type-1 (pai-1) de l'activateur de plasminogene utiles dans le traitement de la thrombose et des maladies cardio-vasculaires
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
WO2007111136A1 (fr) * 2006-03-28 2007-10-04 Adeka Corporation Composition de resine epoxy durcissable
JP2007262204A (ja) * 2006-03-28 2007-10-11 Adeka Corp エポキシ樹脂硬化性組成物
US7763700B2 (en) 2006-03-28 2010-07-27 Adeka Corporation Epoxy resin curing composition
CN101389684B (zh) * 2006-03-28 2012-05-30 株式会社艾迪科 环氧树脂固化性组合物
WO2007138705A1 (fr) 2006-06-01 2007-12-06 Japan As Represented By Director General Of Agency Of National Cancer Center Suppresseur de tumeurs
US8323805B2 (en) 2009-06-04 2012-12-04 Nitto Denko Corporation Emissive aryl-heteroaryl acetylenes
US8354668B2 (en) 2009-06-29 2013-01-15 Nitto Denko Corporation Emissive triaryls
US8927121B2 (en) 2009-06-29 2015-01-06 Nitto Denko Corporation Emissive aryl-heteroaryl compounds
US8426040B2 (en) 2010-12-22 2013-04-23 Nitto Denko Corporation Compounds for use in light-emitting devices
US9373797B2 (en) 2010-12-22 2016-06-21 Nitto Denko Corporation Compounds for use in light-emitting devices
US8933243B2 (en) 2011-06-22 2015-01-13 Nitto Denko Corporation Polyphenylene host compounds
US9548458B2 (en) 2011-06-22 2017-01-17 Nitto Denko Corporation Polyphenylene host compounds
CN105392777A (zh) * 2013-06-27 2016-03-09 株式会社Lg生命科学 作为gpr120激动剂的联芳基衍生物
US10221138B2 (en) 2013-06-27 2019-03-05 Lg Chem, Ltd. Biaryl derivatives as GPR120 agonists
CN109456274A (zh) * 2018-12-07 2019-03-12 广东药科大学 苯并咪唑类衍生物、其制备方法及其作为药物的用途
CN109456274B (zh) * 2018-12-07 2021-11-05 广东药科大学 苯并咪唑类衍生物、其制备方法及其作为药物的用途

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