WO2008029882A1 - Dérivé de 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone, sel d'addition de celui-ci et inhibiteur de la pde comprenant le dérivé ou le sel en tant que matière active - Google Patents

Dérivé de 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone, sel d'addition de celui-ci et inhibiteur de la pde comprenant le dérivé ou le sel en tant que matière active Download PDF

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WO2008029882A1
WO2008029882A1 PCT/JP2007/067420 JP2007067420W WO2008029882A1 WO 2008029882 A1 WO2008029882 A1 WO 2008029882A1 JP 2007067420 W JP2007067420 W JP 2007067420W WO 2008029882 A1 WO2008029882 A1 WO 2008029882A1
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added
chemical
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carbon atoms
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Yasushi Kohno
Koji Ochiai
Satoshi Takita
Akihiko Kojima
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Kyorin Pharmaceutical Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a 2-alkyl 6- (pyrazophylpyridine-4-yl) pyridazinone derivative useful as a phosphodiesterase (PDE) inhibitor, its addition salt and hydrate.
  • PDE phosphodiesterase
  • Phosphodiesterase is an enzyme that degrades cyclic AMP (cAMP) and cyclic GMP (cGMP), which are second messengers in vivo.
  • cAMP cyclic AMP
  • cGMP cyclic GMP
  • PDEs have the power to see;! ⁇ 1 1 types, the ability to specifically degrade cAMP for each type, whether to specifically degrade cGMP or both It has been decided.
  • PDE3 inhibitors are used as therapeutic agents for angina pectoris, heart failure, hypertension, platelet aggregation inhibitors or anti-asthma drugs, and PDE4 inhibitors.
  • PDE5 inhibitors have already been used clinically for the treatment of male sexual dysfunction!
  • Patent Document 1 More recently, there was a report that minocycline was effective as a PDE10A modulator in patients with Huntington's disease (Patent Document 1), and PDE10 inhibitors were Huntington's disease, Alzheimer, dementia, Parkinson's disease, schizophrenia, etc.
  • An open patent gazette that has been shown to be effective as a therapeutic agent for various mental disorders has also been disclosed (Patent Document 2).
  • Patent Document 3 An international pamphlet showing that it is also effective against obesity and metabolic syndrome has been disclosed recently.
  • Patent Document 2 Japanese Patent Laid-Open No. 2002-363103
  • Patent Document 3 WO05120514 pamphlet
  • Patent Document 4 Republished W098 / 14448
  • Patent Document 6 Japanese Unexamined Patent Publication No. 2006-1 17647
  • Patent Document 8 WO200 plate 9818 non-fret
  • Patent Document 9 WO9947505 Nonfret
  • the present invention has excellent phosphodiesterase inhibitory action and reduced side effects.
  • the present inventors have conducted intensive research to create a compound having phosphodiesterase inhibitory activity and high safety, and as a result, a novel structure having a structure different from that of a known PDE inhibitor has been developed. 2
  • the present invention was completed by finding that —alkyl-6- (virazolopyridine-4-yl) pyridazinone derivatives have PDE inhibitory action.
  • the present invention provides
  • R 1 is a hydrogen atom, a halogen atom, a carbon number;! To 6 alkyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, a cyclopropylmethyloxy group, Carbon number;! To 6-alkylolsulfanyl group, 1 to 6 alkylsulfifer group, 1 to 6 alkylsulfonyl group, optionally substituted alkyl having 1 to 6 carbon atoms Amino group, phenyl amino group;!
  • Aromatic heterocycle or saturated heterocycle which may contain 2 heteroatoms, alkanoyl group having 1-6 carbon atoms, acylamino group having 1-6 carbon atoms, phenyl group , A rubamoyl group, a cyano group, an alkoxycarbonyl group having 1 to 6 carbon atoms or a carboxyl group, R 2 is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, 3 to 3 carbon atoms 8 cycloalkyl groups, 2-4 carbon alkenyl groups, 1-6 carbon atoms An alkanoyl group or an alkylsulfanyl group having 1 to 6 carbon atoms,
  • R 3 represents a hydrogen atom, a halogen atom, a carboxyl group, an alkoxycarbon group having 1 to 6 carbon atoms or a hydroxy group,
  • R 4 and R 5 are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
  • A represents a methylene chain having 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms or a cycloalkane having 3 to 8 carbon atoms,
  • B represents a single bond or an oxygen atom
  • C may be substituted with 1 or 2 or more substituents selected from an alkoxy group having 1 to 6 carbon atoms and a norogen atom! /, A benzene ring; or ! containing 2 heteroatoms! /, Tomoeray ⁇ aromatic heterocycle,
  • [0013] represents a single bond or a double bond], or a substituent represented by the following general formula
  • [0017] represents a single bond or a double bond.
  • a novel 2-alkyl-6- (bisazolopyridine-4-yl) pyridazinone derivative has an excellent PDE inhibitory action.
  • Compounds with such PDE inhibitory action include drugs for treating angina pectoris, heart failure, hypertension, platelet aggregation inhibitors or bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis , Atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease, various mental disorders such as Huntington's disease, Alzheimer's, dementia, Parkinson's disease, depression, schizophrenia, obesity, metabolic syndrome, etc. It is useful as a prophylactic or therapeutic drug for men, and as a therapeutic drug for male sexual dysfunction.
  • COPD chronic obstructive pulmonary disease
  • an alkyl group having 1 to 6 carbon atoms means a straight or branched hydrocarbon;! ⁇ 6 hydrocarbon, preferably an alkyl group having 1 to 4 carbon atoms.
  • a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a t-butyl group can be used.
  • the "C1-C6 alkoxy group” is a C1-C6 linear or branched alkoxy group, preferably a C1-C4 alkoxy group.
  • Alkoxy group having 1 to 6 carbon atoms which may have a substituent “C carbon number which may have a substituent;! -6 alkyl group”, “Although having a substituent” “A good alkylamino group having 1 to 6 carbon atoms” means a halogen atom, hydroxy group, carbon number;! To 6 alkylamino group or alkoxy group having 1 to 6 carbon atoms on a branched or straight chain carbon chain. You can list what you have
  • C3-C8 cycloalkyl group refers to cyclic hydrocarbons having 3 to 8 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group. .
  • the "C1-C6 alkanoyl group” is a linear or branched C1-C6 alkanoyl group, preferably a C1-C4 alkanoyl group.
  • a formyl group, a acetyl group, a propionyl group, a butyryl group or an isobutyryl group can be exemplified.
  • the “C1-C6 alkoxycarbonyl group” is a C1-C6 linear or branched alkoxycarbonyl group, preferably a C1-C4 alkoxycarbonyl group.
  • methoxycarbodi group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, t-butoxycarbonyl group and the like can be mentioned.
  • the "C1-C6 acylamino group” is a straight chain or branched C1-C6 acylamino group, preferably a C1-C4 acylamino group.
  • a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group or an isobutyrylamino group can be mentioned.
  • the “methylene chain substituted with a cycloalkane” means that the carbon atoms constituting the methylene group simultaneously constitute a cycloalkane, and the methylene group and the cycloalkane are bonded at one point of the carbon atom.
  • a 1-methylcyclopropylmethyl group, a 1-methylcyclobutylmethyl group, a 1-methylcyclopentylmethyl group, a 1-methylcyclohexylmethyl group, and the like can be cited.
  • the "aromatic heterocycle optionally containing 1 to 2 heteroatoms” means, for example, fragrances such as pyrrole, furan, thiophene, pyrazonole, isoxazomonore, isothiazonole, imidazolone, oxazol, thiazole, etc.
  • fragrances such as pyrrole, furan, thiophene, pyrazonole, isoxazomonore, isothiazonole, imidazolone, oxazol, thiazole, etc.
  • An aromatic 6-membered ring monocyclic compound or an aromatic 6-membered ring monocyclic compound such as pyridine, pyridazine, pyrimidin, and pyrazine.
  • the "saturated heterocyclic ring optionally containing 1 to 2 heteroatoms” includes, for example, 5- or 6-membered monocyclic compounds such as pyrrolidine, piperidine, piperazine, morpholine, etc. be able to.
  • Examples of the pharmacologically acceptable salt in the present invention include acid addition salts such as hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, kenate, and tartrate. The ability to raise S.
  • V is V ⁇ V 1 is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, or a paratoluene sulfonoxy group.
  • v 2 is a substituent that can be converted into a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonoxyloxy group, or a paratoluenesulfonyloxy group.
  • U represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifnoreo It represents a lomethanesulfonyloxy group, a benzenesulfonyloxy group, or a paratoluenesulfonyloxy group, and A and V are as described above]
  • reaction is carried out using n-butyllithium, sodium hydride, lithium alkoxide, sodium alkoxide, potassium alkoxide or the like as a base, tetrahydrofuran (THF) or N, N dimethylformamide (DMF) or the like as a reaction solvent at 0 ° C. Can be performed at ⁇ 100 ° C.
  • the substituent V 2 that can be converted into a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group or a paratoluenesulfonyloxy group is: for example t heptyl dimethylsilyl O carboxymethyl group, t chromatography butyl diphenyl silyl O alkoxy group, triisopropoxide building silyl O alkoxy group, tetrahydrofuryl Vila Niruokishi group, methoxymethyl O alkoxy group can be exemplified, and V 2 to V 1
  • Examples of the conversion method include a method in which V 2 is subjected to a general conversion reaction to alcohols, and then the resulting hydroxyl group is converted to V 1 by a general method.
  • V 1 is a chlorine atom, a bromine atom or an iodine atom
  • a general method for converting the resulting hydroxyl group to V 1 is chlorine, tetrachloride in the presence of tributylphosphine, triphenylphosphine, or triphenoxyphosphine.
  • Chlorinating agents such as carbon and N chlorosuccinimide, bromide, carbon tetrabromide, odorizing agents such as N-prosuccinimide, or iodinating agents such as iodine and N-hydrosuccinimide, and toluene, methyl chloride.
  • the compound represented by the general formula (1) is synthesized with the compound represented by the general formula (6) in the presence of a base in the compound represented by the general formula (2).
  • the reaction is carried out at 0 ° C to 100 ° C using n-butyllithium, sodium hydride, lithium alkoxide, sodium alkoxide, potassium alkoxide or the like as a base and THF or DMF as a reaction solvent. Can do.
  • R 3 is a hydrogen atom
  • [0063] is a compound having a single bond, that is, the general formula (2b) [0064] [Chemical 17]
  • the compound represented by can be produced, for example, by the synthesis route B or C shown below.
  • MSH 0-mesitylenesulfonylhydroxyamine
  • G represents an alkoxy group having 1 to 6 carbon atoms, a benzyloxy group, or an alkyl group having 1 to 6 carbon atoms, and R 1 and R 2 are as described above.
  • Reaction is methanol, ethanol, 1,4 dioxane, dimethyl sulfoxide (DMSG), DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride
  • the reaction temperature is from o ° c to room temperature in the presence of a base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or triethylamine.
  • the compound represented by general formula (9) can be produced by demethylating, hydrolyzing and decarboxylating the compound represented by general formula (9), or by demethylating and decarbonylating (step B— 3).
  • hydrobromic acid or acetic acid containing hydrogen bromide is used, and the reaction is performed under heating and refluxing.
  • the method is preferred.
  • the demethylation reaction is carried out using a Lewis acid such as aluminum chloride, boron trichloride or boron tribromide, preferably boron tribromide, and 0 ° C. using chloroform or methylene chloride, preferably methylene chloride as a solvent.
  • ⁇ Can be performed at room temperature.
  • ⁇ Forced rubonic acid can be produced by heating under reflux.
  • the carboxylic acid obtained by the hydrolysis reaction is heated to 140 ° C to 160 ° C using an organic solvent such as benzene, black benzene, dichlorobenzene, bromobenzene, tolylene, or xylene.
  • the compound represented by general formula (10) is a compound represented by general formula (14) after trifluoromethanesulfonylation of the hydroxyl group of the compound represented by general formula (10).
  • R represents an alkyl group having 1 to 6 carbon atoms or a benzyl group, and R 4 is as described above] and a Heck reaction (Step B). - Four).
  • the reaction is carried out first in a solvent such as THF, chloroform, methylene chloride or carbon tetrachloride, preferably in anhydrous methylene chloride in the presence of an organic salt such as diisopropylethylamine or triethylamine in methylene chloride.
  • a solvent such as THF, chloroform, methylene chloride or carbon tetrachloride
  • an organic salt such as diisopropylethylamine or triethylamine in methylene chloride.
  • Sulfonic acid is allowed to act at 0 ° C to room temperature to obtain trifluoromethanesulfonate, and the resulting trifluoromethanesulfonate and the compound represented by the general formula (14) are subjected to Heck reaction, followed by acid hydrolysis.
  • the solvent is not particularly limited, but in general, DMF is used, and palladium acetate and 1,3-bis (diphenylphosphino) propane are added as catalysts, and in the presence of triethylamine, room temperature to 150 ° C. Can be done in C.
  • the acid hydrolysis reaction of the compound obtained by the Heck reaction can be carried out at room temperature to 80 ° C by adding dilute hydrochloric acid in a solvent such as 1,4 dioxane, DMF or THF.
  • reaction was performed using sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, lithium diisopropylamide (LDA), lithium 2, 2, 6, 6 tetramethylpiperimbistrimethylsilylamide, etc. as a base.
  • LDA lithium diisopropylamide
  • THF 1,4-dioxane or 1,2-dimethoxyethane can be used as a reaction solvent at 78 ° C. to room temperature.
  • reaction passes through a carboxylic acid, ethanol, methanol, THF, 1,4-dioxane, or the like is used as a solvent, and a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, a lithium hydroxide aqueous solution, or the like is used as a base. It may be allowed to act at 0 ° C to room temperature, or when R is t-butyl group, it may be carried out at 0 ° C to room temperature using an acid such as trifluoroacetic acid with no solvent or methylene chloride as a solvent. it can.
  • R ′ represents an alkyl group having 1 to 6 carbon atoms, and R 1, R and R are as described above]
  • reaction is preferably carried out under reflux with heating using a compound of the general formula (19) in the presence of sodium alkoxide, potassium alkoxide, potassium hydride or sodium hydride in an amount of a solvent.
  • reaction is sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide: LD
  • THF 1,4 dioxane, 1,2-dimethoxyethane or the like
  • reaction solvent 78 ° C. to room temperature
  • the compound represented by general formula (17) can be produced by hydrolysis and decarboxylation (step C3).
  • the reaction can be carried out in hydrochloric acid or hydrobromic acid at 80 ° C to 100 ° C in the case of acidic conditions, and in the case of alkaline conditions, an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution is used.
  • Methanol, ethanol, THF, DMF, DMSO, etc. can be decarboxylated by hydrolyzing from 0 ° C to room temperature and then acidifying
  • the compound represented by the general formula (2b) in the synthetic route C can be produced by reacting the compound represented by the general formula (18) with hydrazine (step C-4).
  • the reaction is carried out by using hydrazine monohydrate or hydrazine acetate with benzene, toluene, ethanol or acetic acid, preferably ethanol as a reaction solvent, and at room temperature to heating under reflux.
  • the compound represented by the general formula (18), which is a synthetic intermediate of the compound (2b) in the synthetic route C, can also be produced by the following synthetic route D.
  • the compound represented by general formula (11) can be produced by halogenating the compound represented by general formula (11) (step D-1).
  • the reaction may be sulfuryl chloride, bromine, iodine, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), cupric chloride, cupric bromide or Using a halogenating agent such as cupric iodide, THF, 1, 4 dioxane, methyl chloride Can be carried out under reflux with heating using chlorobenzene, chloroform, or ethyl acetate as a solvent.
  • a halogenating agent such as cupric iodide, THF, 1, 4 dioxane, methyl chloride
  • the reaction is carried out using a base such as sodium alkoxide, potassium alkoxide, LDA, lithium 2, 2, 6, 6-noramide, potassium bistrimethylsilylamide, sodium hydride or potassium hydride, preferably sodium hydride as the reaction solvent.
  • a base such as sodium alkoxide, potassium alkoxide, LDA, lithium 2, 2, 6, 6-noramide, potassium bistrimethylsilylamide, sodium hydride or potassium hydride, preferably sodium hydride as the reaction solvent.
  • a base such as sodium alkoxide, potassium alkoxide, LDA, lithium 2, 2, 6, 6-noramide, potassium bistrimethylsilylamide, sodium hydride or potassium hydride, preferably sodium hydride as the reaction solvent.
  • THF THF, DMF, 1,4-dioxane, DMSO or the like, the reaction can be performed at room temperature to heating under reflux.
  • the compound represented by the general formula (18) in the synthesis route D can be produced by hydrolysis and decarboxylation of the compound represented by the general formula (21) (step D-3).
  • the reaction is carried out using a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution, using a reaction solvent such as methanol, ethanol, THF, DMF or DMSO, hydrolyzing at room temperature, and then acidifying. Can be decarboxylated.
  • the dicarboxylic acid obtained by hydrolysis is dissolved in methanol or ethanol and heated to reflux. You can be fi even if you do.
  • the synthetic intermediate represented by the general formula (11) in the synthetic pathways B and C refers to the ability to produce by the synthetic pathway E below.
  • R 6 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a acetyl group, a tetrahydrobiranyl group, or a triisopropylsilyl group, and R 1 and R 4 are as described above]
  • the compound represented by general formula (24) can be produced by reacting the compound represented by general formula (24) and the compound represented by general formula (13) in the presence of a base (step E-2).
  • reaction solvent methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, formaldehyde, etc.
  • reaction temperature can be 0 ° C to room temperature.
  • the compound represented by general formula (25) is produced by removing R 6 and hydrolyzing and decarboxylating the ester part or removing R 6 and decarbonylating the compound represented by the general formula (25). (Step E-3). [0147] In the reaction, when R 6 is an alkyl group having 1 to 6 carbon atoms or a tetrahydrobiranyl group, hydrobromic acid or acetic acid containing hydrogen bromide is allowed to act under heating under reflux to remove R 6 . In addition, it is possible to perform hydrolysis and decarboxylation of the ester part or removal of R 6 and decarboxylation at once.
  • R 6 is a acetyl group
  • the removal reaction of R 6 is carried out by heating a potassium hydroxide aqueous solution, a lithium hydroxide aqueous solution or a sodium hydroxide aqueous solution in a methanol, ethanol, THF, DMSO, DMF or dioxane solvent at room temperature to heating reflux.
  • R 6 is t-butyldimethylsilyl group, t-butyldiphenylsilyl group or triisopropylsilyl group
  • the reaction is carried out by allowing tetraptyl ammonium fluoride to act in THF solvent. That power S.
  • G is an alkoxy group having 1 to 4 carbon atoms or a benzyloxy group
  • hydrobromic acid or acetic acid containing hydrogen bromide is allowed to act under heating or reflux, or methanol, ethanol, THF, DMSO, DMF or
  • a potassium hydroxide aqueous solution a lithium hydroxide aqueous solution or a sodium hydroxide aqueous solution is allowed to act in a dioxane solvent under normal temperature to heating under reflux to convert it to the corresponding carboxylic acid, and then the carboxylic acid is converted into benzene, black mouth.
  • an organic solvent such as benzene, dichlorobenzene, bromobenzene, tolylene or xylene
  • a solvent such as ethanol or dioxane containing 2-10% aqueous sulfuric acid or 50% sulfuric acid
  • G is an alkyl group having 1 to 4 carbon atoms
  • the decarbonylation reaction is preferably carried out under heating and refluxing in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid.
  • the compound represented by the general formula (11) in the synthesis route E can be produced by oxidizing the compound represented by the general formula (26) (step E-4).
  • the reaction can be performed using a commonly used oxidative method of alcohol to aldehydes and ketones.
  • chromium oxide pyridine complex such as pyridinium chromate or pyridinium dichromate, chromium oxide, silver carbonate or
  • DMSO oxidation using various metal oxides such as manganese dioxide and various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, and DCC or oxidation reaction using sulfur trioxide pyridine complex.
  • the compound represented by general formula (25) can be produced by removing R 6 from the compound represented by general formula (25) and then oxidizing the resulting hydroxyl group (step E-5).
  • R 6 when R 6 is an alkyl group having 1 to 6 carbon atoms, in methylene chloride, it is preferable to effect boron trichloride or boron tribromide at 0 ° Celsius to room temperature .
  • R 6 when R 6 is a tetrahydrobiranyl group, it can be carried out by reacting an acid such as hydrochloric acid, sulfuric acid or paratoluenesulfonic acid at room temperature in a solvent such as methanol, ethanol or THF at room temperature. .
  • R 6 When R 6 is a acetyl group, it can be carried out by allowing a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide to act at room temperature in a solvent such as methanol or ethanol.
  • a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide
  • R 6 When R 6 is a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, or a triisopropylpropylsilyl group, it is preferable that tetraptylammonium fluoride is allowed to act at 0 ° C. to room temperature in a solvent such as THF.
  • the oxidation reaction can be carried out using a commonly used oxidative method of alcohol to aldehydes and ketones.
  • the compound represented by the general formula (11) is obtained by subjecting the compound represented by the general formula (27) to hydrolysis and decarboxylation or decarbonylation of the ester moiety. Therefore, it can be manufactured (Process E-6).
  • the force norevonic acid is dissolved in an organic solvent such as benzene, black benzene, dichlorobenzene, bromobenzene, toluene or xylene.
  • an organic solvent such as benzene, black benzene, dichlorobenzene, bromobenzene, toluene or xylene.
  • Decarboxylation by heating to 100 ° C in a heating force of 140 ° C to 160 ° C, or in a solvent such as ethanol or dioxane containing 2-10% sulfuric acid aqueous solution or 50% sulfuric acid Can do.
  • G is an alkyl group having 1 to 6 carbon atoms
  • the decarbonylation reaction is preferably carried out under heating and reflux in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid.
  • the reaction is performed by dissolving the compound represented by the general formula (28) in methylene chloride at 0 ° C to room temperature.
  • Step F-2 Can be produced by reacting the compound represented by the general formula (29) and the compound represented by the general formula (13) in the presence of a base (step F-2).
  • reaction solvent methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, or acetonitrile, etc.
  • a base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or triethylamine
  • the reaction temperature can be 0 ° C to room temperature.
  • the compound represented by the general formula (11) in the synthetic pathway F is converted from the compound represented by the general formula (30) to the carbonyl group of the acetal, and the hydrolysis and decarburization acid reaction of the ester moiety. Or by converting the acetal to a carbonyl group and decarbonylation (step F-3).
  • the reaction can be performed at once by hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing.
  • the conversion reaction of acetal to carbonyl group It can be carried out by reacting an acid such as hydrochloric acid, sulfuric acid or paratoluenesulfonic acid at room temperature in a solvent such as ethanol, ethanol or THF at room temperature.
  • G is an alkoxy group having 1 to 6 carbon atoms or a benzyloxy group
  • hydrobromic acid or acetic acid containing hydrogen bromide is allowed to act under heating or reflux, or methanol, ethanol, THF, DMSO, DMF, or dioxane.
  • the carboxylic acid After converting an aqueous solution of lithium hydroxide, aqueous lithium hydroxide, or aqueous sodium hydroxide in a solvent to normal carboxylic acid by acting under normal temperature to heating under reflux, the carboxylic acid is converted to benzene, black benzene.
  • organic solvents such as dichlorobenzene, bromobenzene, toluene or xylene, or heating to 140 ° C to 160 ° C, or in a solvent such as ethanol or dioxane containing 2-10% aqueous sulfuric acid, or in 50% sulfuric acid
  • the decarboxylation reaction can be carried out by heating to 100 ° C.
  • G is an alkyl group having a carbon number of ! to 4
  • the decarbonylation reaction is preferably performed in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid with heating under reflux.
  • the synthetic intermediate represented by the general formula (26) in the synthesis route E can be synthesized from the compound represented by the general formula (31) or the general formula (36) as shown in the following synthesis route G. it can.
  • Step G-1 Can be produced by reacting MSH with a compound represented by formula (Step G-1).
  • the reaction is performed by dissolving the compound represented by the general formula (31) in methylene chloride at 0 ° C to room temperature.
  • the compound represented by general formula (32) can be produced by reacting the compound represented by general formula (32) and the compound represented by general formula (13) in the presence of a base (step G-2).
  • the reaction can be performed at once by hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing.
  • G is an alkoxy group having 1 to 6 carbon atoms or a benzylinooxy group
  • hydrobromic acid or hydrogen bromide-containing acetic acid is allowed to act under heating reflux, or methanol, ethanol, THF, DMSO
  • the aqueous solution of potassium hydroxide, lithium hydroxide or sodium hydroxide in a DMF or dioxane solvent is allowed to act at room temperature to reflux under heating to convert it to the corresponding carboxylic acid.
  • Decarboxylation can be performed by heating to 100 ° C in% sulfuric acid.
  • G is an alkyl group having 1 to 6 carbon atoms
  • the decarbonylation reaction is desirably carried out under heating and refluxing in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid.
  • the reaction can be carried out using a commonly used oxidative method of alcohol to an aldehyde.
  • chromium oxide pyridine complexes such as pyridinium black chromate or pyridinium nichromate, chrome oxide, silver carbonate, manganese dioxide, etc.
  • DMSO oxidation using metal oxidizers, various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, or sulfur trioxide pyridine complex can be given.
  • a compound represented by the general formula (36) is dissolved in methylene chloride, and the reaction is carried out at 0 ° C to room temperature.
  • the compound represented by general formula (37) can be produced by reacting the compound represented by general formula (37) and the compound represented by general formula (13) in the presence of a base (step G-6).
  • Reaction is methanol, ethanol, 1,4 dioxane, DMSO, DMF, THF, toluene, benzene, cyclohexane, cyclopentane, methylene chloride, chloroform, formaldehyde or acetate.
  • Nitrile or the like can be used as a reaction solvent in the presence of a base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate or potassium carbonate, or triethylamine, and the reaction temperature can be carried out at a temperature of o ° c to room temperature.
  • the compound represented by the formula (34), (35) or (38) is produced from the compound represented by the force S.
  • the production force S can be obtained by subjecting it to an oxidation reaction (Step G-7).
  • the reaction can be carried out using a commonly used oxidative method of alcohol to an aldehyde.
  • DMSO oxidation using various DMSO activators such as metal oxidizers, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, and DCC, and pyridine complexes with sulfur trioxide.
  • the reaction can be carried out at once by hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing.
  • G is an alkoxy group having 1 to 6 carbon atoms or a benzylinooxy group
  • hydrobromic acid or hydrogen bromide-containing acetic acid is allowed to act under heating reflux, or methanol, ethanol, THF, DMSO .
  • a potassium hydroxide aqueous solution a lithium hydroxide aqueous solution or a sodium hydroxide aqueous solution into a corresponding carboxylic acid by reacting with an aqueous solution of potassium hydroxide, lithium hydroxide or sodium hydroxide in a DMF or dioxane solvent.
  • the decarboxylation reaction can be carried out by heating to 100 ° C in a solvent such as ethanol or dioxane or 50% sulfuric acid.
  • G is an alkyl group having 1 to 6 carbon atoms
  • the decarbonylation reaction is desirably carried out under heating and refluxing in hydrobromic acid, hydrobromic acid containing acetic acid or 50% sulfuric acid.
  • the conversion of the acetal into a carbonyl group and the hydrolysis and decarboxylation of the ester part are carried out, or the carbonyl group of the acetal is It can be produced by conversion to decarbonylation and decarbonylation (Step G-9).
  • the reaction can be performed at once by hydrobromic acid or acetic acid containing hydrogen bromide under heating and refluxing.
  • the conversion reaction of acetal to a carbonyl group should be carried out in a solvent such as methanol, ethanol or THF by reacting an acid such as hydrochloric acid, sulfuric acid, paratoluenesulfonic acid at 0 ° C to room temperature.
  • G is an alkoxy group having 1 to 6 carbon atoms or a benzyloxy group
  • hydrobromic acid or acetic acid containing hydrogen bromide is allowed to act under heating or reflux, or methanol, ethanol, THF, DMSO, DMF, or dioxane.
  • the carboxylic acid After converting an aqueous solution of lithium hydroxide, aqueous lithium hydroxide, or aqueous sodium hydroxide in a solvent to normal carboxylic acid by acting under normal temperature to heating under reflux, the carboxylic acid is converted to benzene, black benzene.
  • organic solvents such as dichlorobenzene, bromobenzene, toluene or xylene, or heating to 140 ° C to 160 ° C, or in a solvent such as ethanol or dioxane containing 2-10% aqueous sulfuric acid, or in 50% sulfuric acid
  • the decarboxylation reaction can be carried out by heating to 100 ° C.
  • G is an alkyl group having from 6 to 6 carbon atoms
  • the decarbonylation reaction is preferably performed in hydrobromic acid, acetic acid containing hydrogen bromide or 50% sulfuric acid with heating under reflux.
  • the compound represented by the general formula (26) is composed of the compound represented by the general formula (39) and the general formula (40).
  • the reaction can be carried out using THF, ether or 1,4 dioxane as a reaction solvent at a reaction temperature of 78 ° C to room temperature.
  • R 7 represents an alkyl group having 1 to 6 carbon atoms, and R 1 and R 2 are as described above]
  • the compound represented by the formula is a compound represented by the general formula (11), wherein R 4 is a hydrogen atom, that is, the general formula (l ib)
  • reaction was carried out using sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide.
  • the compound represented by general formula (17) is a compound in which R 4 is a hydrogen atom, that is, general formula (17b)
  • Pro represents a protecting group for an alcohol such as a methoxymethyl group, a t-butyldimethylsilyl group, a t-lyl group, a triisopropylpropylsilyl group, a tetrahydrobiranyl group, or a acetyl group; 2 and R 8 are as described above]
  • the compound represented by the formula is a compound represented by the general formula (26), wherein R 1 is a hydrogen atom, that is, the general formula (26a)
  • the reaction may be butyllithium, LDA or lithium bistrimethylsilylamide, preferably L
  • the compound represented by the general formula (42) can be produced by removing Pro of the compound represented by the general formula (44) and oxidizing the resulting hydroxyl group ( Step H 3).
  • Pro When Pro is a methoxymethyl group or a tetrahydrobiranyl group, the reaction is carried out using hydrogen chloride-containing methanol, ethanol, ethyl acetate or jetyl ether at 0 ° C to room temperature. Is preferred.
  • Pro When Pro is t-butyldimethylsilyl group, t-butyldiphenylsilyl group, or triisoprovirsilyl group, use potassium fluoride, cesium fluoride, or tetraptylammonium fluoride, and solvent such as acetonitrile or THF. It is preferably carried out at a temperature between 0 ° C and room temperature.
  • Pro When Pro is a acetyl group, use sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or lithium hydroxide aqueous solution, and use THF, methanol, ethanol or 1,4 dioxane as a solvent at 0 ° C to room temperature. Can be done.
  • the oxidation reaction of the hydroxyl group can be carried out by a general oxidation reaction of alcohol to ketone.
  • chromium oxide pyridine complex such as pyridinium chromate or pyridinium dichromate, chromium oxide, silver carbonate or dioxide.
  • DMSO oxidation using a metal oxidizer such as manganese and various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, and DCC, or a reaction using a sulfur trioxide pyridine complex.
  • a metal oxidizer such as manganese
  • various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, and DCC, or a reaction using a sulfur trioxide pyridine complex.
  • the compound represented by the formula is a compound represented by the general formula (11), wherein R 1 is a hydrogen atom, that is, the general formula (11c)
  • the compound represented by general formula (45) can be produced by halogenating the compound represented by the general formula (45) (step I2).
  • the reaction may be butyllithium, LDA or lithium bistrimethylsilylamide, preferably L
  • the compound represented by the general formula (42) in the synthetic route I can be produced by converting the acetal of the compound represented by the general formula (46) into a carbonyl group (step I 3). .
  • reaction is carried out using a force that allows paratoluenesulfonic acid to act under normal temperature to heating under reflux in an acetone solvent, or methanol, ethanol, ethyl acetate, or jetyl ether containing hydrogen chloride at 0 ° C to normal temperature. Can be reacted.
  • R 1 is substituted at the 7-position of the pyrazoguchi pyridine ring and may have a substituent.
  • ⁇ may have an optionally substituted alkoxy group having 1 to 6 carbon atoms, a cyclopropylmethyloxy group, an alkylsulfanyl group having 1 to 6 carbon atoms, and a substituent. Carbon number;! To 6 anolequinolamino group, phenylamino group, an aromatic or saturated heterocyclic ring which may contain 1 to 2 heteroatoms, an optionally substituted phenyl group, A C 1-6 acylamino group or cyano group, R 2 and R 8 are as described above]
  • the compound represented by general formula (42) can be produced by deriving the compound represented by general formula (42) into the corresponding compound.
  • Y may have a substituent, including an alkylamino group having 1 to 6 carbon atoms, a phenylamino group, or 1 to 2 heteroatoms! /, May! /, An aromatic heterocycle or In the case of saturated heterocycles, it is preferred to react the corresponding amine in methanol, THF, DMF, preferably DMF solvent, at 60-70 ° C.
  • Y is an optionally substituted phenyl group
  • the corresponding phenylboric acid derivative is used in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, sodium carbonate or cesium carbonate as a base, and THF.
  • a palladium catalyst such as tetrakistriphenylphosphine palladium, sodium carbonate or cesium carbonate as a base
  • THF tetrakistriphenylphosphine palladium, sodium carbonate or cesium carbonate
  • the reaction is preferably performed at 80 ° C. to heating under reflux.
  • Y is an acylamine group having 1 to 6 carbon atoms
  • the corresponding acylamine is preferably carried out at 80 ° C to 100 ° C in cesium carbonate and 1,4-dioxane.
  • Y is a cyano group
  • sodium cyanide, potassium cyanide or copper cyanide is used
  • DMSO, 1,4 dioxane, DMF or the like is preferably used as a solvent at 80 ° C. to 160 ° C.
  • R 3 is a halogen atom
  • the compound represented by general formula (11) is a compound obtained by halogenating the compound represented by general formula (11), that is, general formula (lid).
  • R 3 is an alkoxycarbonyl group having 1 to 6 carbon atoms
  • [0288] is a compound having a single bond, that is, the compound represented by the general formula (2d)
  • the compound represented by general formula (27a) is a compound in which G is an alkoxy group having 1 to 6 carbon atoms.
  • R 3 is a hydrogen atom
  • step J1 In the presence of a palladium catalyst (step J1).
  • the reaction is performed by adding a palladium catalyst such as tetrakistriphenylphosphine palladium or bistriphenylphosphine palladium dichloride, and an organic base such as triethylamine, jetylamine or dibutylamine in the presence of copper bromide or copper iodide.
  • a bacterial head reaction in which reaction is carried out at room temperature to 80 ° C. in an organic solvent such as acetonitrile, THF, DMF or benzene can be used.
  • the compound represented by general formula (49) can be produced by reacting the compound represented by the general formula (49) with MSH (see Example 12).
  • reaction is carried out using sodium carbonate or cesium carbonate as a base in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, and in a solvent such as THF, benzene, toluene, xylene, or 1,4-dioxane, from 80 ° C to It is preferable to carry out with heating under reflux.
  • a palladium catalyst such as tetrakistriphenylphosphine palladium
  • solvent such as THF, benzene, toluene, xylene, or 1,4-dioxane
  • the reaction is preferably carried out by heating to 80 to 90 ° C in acetic acid.
  • the reaction is carried out in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium using sodium carbonate or cesium carbonate as a base in a solvent such as THF, benzene, toluene, xylene, or 1,4 dioxane at 80 ° C to After reacting under heating and reflux, it can be heated by applying aqueous ammonia in a solvent such as methanol, ethanol or THF at 0 ° C to room temperature.
  • a palladium catalyst such as tetrakistriphenylphosphine palladium using sodium carbonate or cesium carbonate as a base
  • a solvent such as THF, benzene, toluene, xylene, or 1,4 dioxane
  • R 3 is a hydrogen atom, a halogen atom or an alkoxycarbonyl group having 1 to 4 carbon atoms, [0331] [Chemical 95]
  • [0332] is a compound having a double bond, that is, the compound represented by the general formula (2f)
  • the compound represented by general formula (2b), (2c) or (2d) can be produced by oxidizing the compound represented by general formula (2b), (2c) or (2d).
  • the reaction can be carried out by reacting bromine in an acetic acid solvent at 50 ° C to 60 ° C, or by reacting copper chloride ( ⁇ ) in acetonitrinore at room temperature to under heating. In addition, it can be treated by allowing sodium m-ditrobenzenesulfonate to act at room temperature to under reflux in a sodium hydroxide aqueous solution.
  • R 3 is a hydrogen atom, a halogen atom or a carbon number of 1 to
  • the compound represented by general formula (2f) can also be produced by reducing the compound represented by the general formula (2f) with a force S.
  • the reaction is preferably carried out at 80 ° C to 90 ° C by adding zinc in an acetic acid solvent.
  • the compound represented by general formula (2) is a compound represented by general formula (2), wherein R 3 is a hydrogen atom, that is, general formula (2i)
  • the reaction is preferably carried out at room temperature in a DMF solvent using NCS, NBS or NIS as a halogenating agent.
  • a fluorinating agent such as Selectfluor TM in acetonitrile at room temperature.
  • the compound represented by general formula (2d) or the compound represented by general formula (2f) is a compound in which Z is an alkoxycarbonyl group having 1 to 6 carbon atoms. It can be manufactured by decomposing.
  • R 1 is substituted at the 7-position of the pyrazomouth pyridine ring and may have a substituent; an alkoxy group having! To 6 Compound, ie, general formula (21) [0357] [Chemical Formula 103]
  • the compound represented by the general formula (57) is used in an amount of solvent, or THF or DMF is used as a solvent, and sodium metal, potassium hydride, or sodium hydride is added, and the temperature is from room temperature to 80 ° C. It can be carried out.
  • R 3 is a hydrogen atom
  • the reaction uses sodium carbonate or cesium carbonate as a base in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, and in a solvent such as THF, benzene, toluene, xylene, or 1,4-dioxane, 80 ° C to It is preferable to carry out with heating under reflux.
  • a palladium catalyst such as tetrakistriphenylphosphine palladium
  • a solvent such as THF, benzene, toluene, xylene, or 1,4-dioxane
  • Example 3 The compound of Example 3 (6.22 g) was dissolved in ethanol (150 mL), 10% aqueous potassium hydroxide solution (37 mL) was added, and the mixture was heated to reflux for 2 hr. After the solvent was distilled off under reduced pressure, the residue was dissolved in water and washed with ether. Concentrated hydrochloric acid was added to the aqueous layer to acidify the solution, and the mixture was extracted with ethyl acetate. The extract layer was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (4.58 g) as a gray solid.
  • Example 4 The compound of Example 4 (4.10 g) was suspended in bromobenzene (150 mL) and heated under reflux for 5 hours. After the solvent was distilled off under reduced pressure,
  • Example 5 The compound of Example 5 (2.50 g) was dissolved in dichloromethane (60 mL), activated manganese dioxide (1 0.5 g) was added, and the mixture was stirred at room temperature for 24 hours. Insoluble material was removed by filtration through Celite, and the solvent of the filtrate was evaporated under reduced pressure to obtain the target compound (2.28 g) as a gray solid.
  • Example 6 The compound of Example 6 (2.40 g) was dissolved in THF (100 mL) under an argon gas atmosphere. Ethylmagnesium bromide (0.97 mol / L, THF solution, 14.5 mU was added at 78 ° C, and The mixture was stirred for 3.5 hours at room temperature from 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, and the combined extracted layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (2.76 g) as a brown oily substance.
  • Example 7 Under an argon atmosphere, the compound of Example 7 (1.97 g) was dissolved in dichloromethane (45 mL), Dess-Martin reagent (4.99 g) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined extracted layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • Example 8 In an argon atmosphere, the compound of Example 8 (1.45 g) was dissolved in THF (40 mL), and lithium hexamethyldisilazane (1.0 mol / L, THF solution, 6.87 mU was added at 78 ° C. The mixture was stirred for 5 minutes while raising the temperature to around 20 ° C. To the reaction solution was added t-butyl bromoacetate (1.20 mL), stirred at room temperature for 1.5 hours, and then added with saturated aqueous ammonium chloride solution.
  • Example 10 In an argon gas atmosphere, the compound of Example 10 (4.00 g) was dissolved in dichloromethane (50 mL), and boron tribromide (1 mol / L dichloromethane solution, 27.5 mL) was added with stirring under ice cooling. At the same temperature And stirred for 30 minutes. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 11 The compound of Example 11 (1.85 g) was suspended in 50% sulfuric acid (70 mL) and stirred at 150 ° C for 10 hours. The reaction solution was allowed to cool, diluted with water, neutralized with potassium carbonate, and extracted with ethyl acetate. The extract layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the desired product (1.42 g) as a brown powder.
  • Ethylene glycol (8.00 mL) and paratoluenesulfonic acid monohydrate (170 mg) were added to a solution of the compound of Example 14 (3.35 g) in benzene (150 mL) under an argon gas atmosphere. -Heated to reflux for 6 hours with a Stark device. Triethylamine (4.00 mL) was added to the reaction solution, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • the target product (4.16 g) was obtained as a pale yellow oil.
  • n-Butyllithium (1.58 mol / L, hexane solution, 14.5 mL) was added dropwise to a THF (80 mL) solution of the compound of Example 15 (4.16 g) at 78 ° C under an argon gas atmosphere. The mixture was stirred at the same temperature for 30 minutes. To this was added a solution of 1,2 jodoethane (7.70 g) in THF (80 mL) at 78 ° C., and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Lithium bis (trimethylsilyl) amide (1.0 mol / L, THF solution, 0.962 mL) was added to a THF (10 mL) solution of the compound of Example 18 (200 mg) in an argon gas atmosphere at 78 ° C. Dripping The temperature was raised slowly to _50 ° C. After cooling to ⁇ 78 ° C. again, a THF (0.5 mL) solution of t-butyl bromoacetate (197 mg) was added dropwise, and the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate.
  • Example 20 The compound of Example 20 (60.0 mg) and sodium metanitrobenzenesulfonate (49.5 mg) were suspended in a 0.5 mol / L aqueous sodium hydroxide solution (4 mL) and heated to reflux for 8 hours.
  • the reaction solution was acidified with dilute hydrochloric acid and extracted with chloroform.
  • the target compound (yield 30%) was obtained as a yellow powder from the compound of Example 2 and 4, 4, 4 trifluoro-2-butyric acid ethyl ester in the same manner as in Example 3.
  • Example 24 In the same manner as in Example 7, the compound of Example 24 was reacted with ethylmagnesium promide to obtain the desired product as a pale yellow oil.
  • Example 25 Using the compound of Example 25, the target product was obtained as a colorless powder in the same manner as in Example 8.
  • Example 26 Using the compound of Example 26, the target product was obtained as a colorless powder in the same manner as in Example 9.
  • Example 28 The compound of Example 28 (1.64 g) was dissolved in dichloromethane (30.0 mL), and activated manganese dioxide (5.48 g) was added. The mixture was stirred at room temperature for 16 hours, and then activated manganese dioxide (5 48 g) was added and stirred at room temperature for 10 hours. Thereafter, active manganese dioxide (5.48 g) was further added, and the mixture was stirred at room temperature for 10.5 hours. Then, active manganese dioxide (2.74 g) was added again, and the mixture was stirred for 13.5 hours. The insoluble material of the reaction solution was filtered off using Celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain the desired product (1.08 g) as a pale yellow powder.
  • Example 29 Using the compound of Example 29, the target product was obtained as a yellow powder by the same method as in Example 19 and Example 20. Elemental analysis: as C H F N 0-1/5 H 0
  • Example 30 The compound of Example 30 (79.8 mg) and sodium metanitrosulfonate (57.6 mg) were suspended in 0.5 mol / L aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred with heating under reflux for 8 hours.
  • the reaction mixture was acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate.
  • the extract layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by NH-type silica gel column chromatography (ethyl acetate), and the desired product (23.1 mg) was yellow. Obtained as a powder.
  • Example 2 The compound of Example 2 (44.9 g) was dissolved in DMF (500 mL), and 4 (tetrahydropyran 2-yloxy) 2-butynoic acid ethyl ester (17.8 g) and potassium carbonate (34.8 g) were added. For 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract layer was washed with saturated Japanese brine and dried over anhydrous sodium sulfate.
  • Example 32 The compound of Example 32 (4.64 g) was dissolved in ethanol (60 mL), hydroxylated lithium (2.51 g) and water (19.2 mL) were added at room temperature, and the mixture was heated under reflux for 1.5 hours. Stir. The solvent of the reaction solution was distilled off under reduced pressure, diluted with water (70 mL), and diluted hydrochloric acid (35 mL) was added. The precipitated solid was collected by filtration to obtain the desired product (3.60 g) as a white solid.
  • Example 34 The compound of Example 34 (1.02 g) was dissolved in black mouth form (35 mL), and activated manganese dioxide (1.51 g) was added at room temperature, followed by stirring at 50 ° C for 4.5 hours. Insoluble material was removed by filtration through Celite, and the solvent of the filtrate was evaporated under reduced pressure to give the object compound (876 mg) as a yellow solid.
  • Example 35 Using the compound of Example 35, the target product was obtained as a pale yellow powder by the same method as in Example 7 and Example 8.
  • the target compound was obtained as a colorless powder in the same manner as in Example 9, using the compound of Example 36.
  • Methyl magnesium bromide (0.90 mol / L, THF solution, 0.878 mU) was added dropwise to a solution of the compound of Example 38 (90.6 mg) in THF (15 mL) at 78 ° C under an argon atmosphere, and gradually brought to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with THF (100 mL) The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the extract under reduced pressure. After concentration, the residue was purified by recrystallization (methanol acetate ethyl hexane) to obtain the desired product (38.0 mg) as a pale yellow powder.
  • the extract layer was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate.
  • the brown oil obtained by distilling off the solvent under reduced pressure was dissolved in acetonitrile (250 mL), montmorillonite KSF (30.0 g) was added, and the mixture was stirred for 7 hours under heating to reflux. Insoluble matter was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain a brown oily substance. This was dissolved in ethanol (300 mL), hydrazine monohydrate (22.0 mL) was added, and the mixture was stirred for 2.5 hours under heating under reflux.
  • Example 48 The compound of Example 48 (26.3 g) was dissolved in dichloromethane (500 mL), and added with ammonium chloride (323 g) under ice-cooling, and stirred at room temperature for 40 hours. The reaction solution was poured into ice water, extracted with THF, and the extracted layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting solid was suspended in diisopropyl ether and collected by filtration to obtain the desired product (20.9 g) as a pale yellow powder.
  • Example 49 The compound of Example 49 (6.50 g) was dissolved in 0.5 mol / L aqueous sodium hydroxide solution (350 mL), sodium paranitrobenzenesulfonate (6.70 g) was added, and the mixture was stirred under heating under reflux for 4 hr. The reaction mixture was neutralized with 6 mol / L hydrochloric acid, and the precipitated solid was collected by filtration to obtain the desired product (3.90 g) as a white solid.
  • Example 50 The compound of Example 50 (3.90 g) was dissolved in dichloromethane (180 mL), and aluminum chloride (24.
  • Example 53 In an argon atmosphere, the compound of Example 53 (159 mg) was dissolved in THF (4.0 mL), and tetraptyl ammonium fluoride (1.0 mol / L THF solution, 0.763 mL) was added at 0 ° C. In addition, the mixture was stirred at room temperature for 40 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate, 2-1 ⁇ 1_1) to obtain the desired product (32.2 mg) as a white solid.
  • Example 55 The compound of Example 55 (27.4 g) was dissolved in dichloromethane (100 mL), trifluoroacetic acid (30 mL) was added, and the mixture was allowed to stand for 16 hours, and then the solvent was evaporated under reduced pressure. The obtained oil was dissolved in ethanol (200 mL), hydrazine monohydrate (14.5 mL) was added, and the mixture was stirred under heating under reflux for 2.5 hr. After evaporating the solvent under reduced pressure, the residue was washed with jetyl ether, and the solid was collected by filtration to obtain the desired product (18.9 g) as a yellow solid.
  • Example 56 The compound of Example 56 (6.00 g) was dissolved in dichloromethane (300 mL), and aluminum chloride (78.

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Abstract

La présente invention concerne la préparation d'un dérivé de 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone utilisable en tant qu'agent pharmaceutique ayant une activité inhibitrice de la phosphodiestérase (PDE). Ledit dérivé de 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone est représenté par la formule générale (1) (exemple spécifique : 6-(7-méthoxy-2-trifluorométhylpyrazolo[1,5-a]pyridin-4-yl)-5-méthyl-2-[3-[4-(4-méthyl-6-oxo-1,4,5,6-tétrahydropyridazin-3- yl)phénoxy]propyl]-4,5-dihydro-2H-pyridazin-3-one).
PCT/JP2007/067420 2006-09-07 2007-09-06 Dérivé de 2-alkyl-6-(pyrazolopyridin-4-yl)pyridazinone, sel d'addition de celui-ci et inhibiteur de la pde comprenant le dérivé ou le sel en tant que matière active WO2008029882A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2008156094A1 (fr) * 2007-06-19 2008-12-24 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyridazinone et inhibiteur de la pde le contenant comme ingrédient actif
WO2010035745A1 (fr) 2008-09-25 2010-04-01 杏林製薬株式会社 Dérivé biarylique hétérocyclique et inhibiteur de pde le renfermant en tant qu'ingrédient actif
WO2010041711A1 (fr) 2008-10-09 2010-04-15 杏林製薬株式会社 Dérivé d'isoquinoléine et inhibiteur de la pde le comportant en tant qu’ingrédient actif
US8207168B2 (en) 2006-07-25 2012-06-26 Cephalon, Inc. Pyridazinone derivatives
CN104530113A (zh) * 2014-12-22 2015-04-22 上海树农化工有限公司 邻氟苯甲酸类化合物及其制备方法

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BRPI0809498A2 (pt) * 2007-04-02 2014-09-23 Inst Oneworld Health Compostos inibidores de cftr e seus usos
WO2014164704A2 (fr) * 2013-03-11 2014-10-09 The Broad Institute, Inc. Composés et compositions utilisables en vue du traitement du cancer

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WO1998014448A1 (fr) * 1996-10-04 1998-04-09 Kyorin Pharmaceutical Co., Ltd. Derives de pyrazolopyridylpyridazinone et procede de preparation des ces derniers
JP2006117647A (ja) * 2004-09-22 2006-05-11 Kyorin Pharmaceut Co Ltd ハロゲノピラゾロピリジンピリダジノン誘導体とその付加塩及びそれを有効成分とするｐｄｅ阻害剤
JP2006169138A (ja) * 2004-12-14 2006-06-29 Kyorin Pharmaceut Co Ltd ピラゾロピリジンピラゾロン誘導体とその付加塩及びｐｄｅ阻害剤

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Publication number Priority date Publication date Assignee Title
WO1998014448A1 (fr) * 1996-10-04 1998-04-09 Kyorin Pharmaceutical Co., Ltd. Derives de pyrazolopyridylpyridazinone et procede de preparation des ces derniers
JP2006117647A (ja) * 2004-09-22 2006-05-11 Kyorin Pharmaceut Co Ltd ハロゲノピラゾロピリジンピリダジノン誘導体とその付加塩及びそれを有効成分とするｐｄｅ阻害剤
JP2006169138A (ja) * 2004-12-14 2006-06-29 Kyorin Pharmaceut Co Ltd ピラゾロピリジンピラゾロン誘導体とその付加塩及びｐｄｅ阻害剤

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8207168B2 (en) 2006-07-25 2012-06-26 Cephalon, Inc. Pyridazinone derivatives
US8247414B2 (en) 2006-07-25 2012-08-21 Cephalon, Inc. Pyridizinone derivatives and the use thereof as H3 inhibitors
US8586588B2 (en) 2006-07-25 2013-11-19 Cephalon, Inc. Aryl pyridazinone derivatives and their use as H3 receptor ligands
US8673916B2 (en) 2006-07-25 2014-03-18 Cephalon, Inc. Methods of treating disorders mediated by histamine H3 receptors using pyridazinone derivatives
WO2008156094A1 (fr) * 2007-06-19 2008-12-24 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyridazinone et inhibiteur de la pde le contenant comme ingrédient actif
WO2010035745A1 (fr) 2008-09-25 2010-04-01 杏林製薬株式会社 Dérivé biarylique hétérocyclique et inhibiteur de pde le renfermant en tant qu'ingrédient actif
WO2010041711A1 (fr) 2008-10-09 2010-04-15 杏林製薬株式会社 Dérivé d'isoquinoléine et inhibiteur de la pde le comportant en tant qu’ingrédient actif
CN104530113A (zh) * 2014-12-22 2015-04-22 上海树农化工有限公司 邻氟苯甲酸类化合物及其制备方法

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