WO2013018372A1 - Dérivé d'amide et médicament le contenant - Google Patents

Dérivé d'amide et médicament le contenant Download PDF

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WO2013018372A1
WO2013018372A1 PCT/JP2012/004934 JP2012004934W WO2013018372A1 WO 2013018372 A1 WO2013018372 A1 WO 2013018372A1 JP 2012004934 W JP2012004934 W JP 2012004934W WO 2013018372 A1 WO2013018372 A1 WO 2013018372A1
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general formula
compound represented
group
compound
reaction
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靖志 河野
貢司 落合
森生 樋口
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杏林製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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]

Definitions

  • the present invention relates to an amide derivative useful as, for example, a phosphodiesterase 4 (PDE4) inhibitor.
  • PDE4 phosphodiesterase 4
  • Phosphodiesterase 4 is an enzyme that degrades cyclic AMP (cAMP) and cyclic GMP (cGMP), which are second messengers in vivo.
  • cAMP cyclic AMP
  • cGMP cyclic GMP
  • 11 types of PDEs 1 to 11 have been found, and each type determines whether cAMP is specifically decomposed, cGMP is specifically decomposed, or both cAMP and cGMP are decomposed. ing.
  • There is a difference in the distribution of each type of PDE and it is considered that the cell reaction is controlled by various types of PDEs depending on the type of organ.
  • PDE3 inhibitors are therapeutic agents for angina pectoris, heart failure, hypertension, etc., platelet aggregation inhibitors or anti-asthma drugs, and PDE5 inhibitors are male. Already used clinically as a dysfunction drug.
  • minocycline was effective as a PDE10A modulator by using it for a Huntington's disease patient (Patent Document 1). It is also disclosed that PDE10 inhibitors are effective as therapeutic agents for various psychiatric disorders such as Huntington's disease, Alzheimer's disease, dementia, Parkinson's disease, and schizophrenia (Patent Document 2).
  • a pyrazolopyridine-carboxamide derivative has been reported as a compound having a PDE inhibitory action (Patent Document 7). Further, pyrazolopyridine derivatives (Patent Documents 3 to 6) and carboxamide derivatives (Patent Documents 8 to 32 and Non-Patent Documents 3 to 9) have been reported as compounds having a PDE inhibitory action.
  • PDE4 inhibitors are therapeutic agents for bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia, Parkinson's disease, etc. As expected.
  • Non-Patent Document 1 Non-Patent Document 1
  • Non-patent Document 2 anti-inflammatory steroids developed for the purpose of reducing systemic side effects have recently been reported.
  • the anti-inflammatory steroid has an activity locally, and when it enters the body, it is rapidly metabolized and inactivated, or exhibits a kinetics such that the activity becomes low.
  • An object of the present invention is to provide a novel amide derivative that has an excellent phosphodiesterase 4 inhibitory action and is rapidly metabolized in vivo to enhance its safety by reducing its activity.
  • the inventors of the present invention have made extensive studies with the aim of creating a compound having an excellent PDE4 inhibitory action and being rapidly metabolized in vivo and having reduced activity. As a result, it was found that a novel amide derivative has a strong PDE4 inhibitory activity and is rapidly metabolized in vivo to reduce the activity, thereby completing the present invention.
  • the first invention relates to an amide derivative represented by the general formula (1), a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • A represents a condensed aromatic heterocyclic group represented by the following formula a) or formula b).
  • R 1 represents a C 1-6 alkyl group or a C 7-10 aralkyl group
  • R 2 is C 1-6 alkoxy groups, one or two C 1-6 alkyl amino group which may be substituted with a group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group or a C 1-
  • R 3 represents a hydrogen atom or a halogen atom
  • R 4 and R 5 represent a hydrogen atom or a halogen atom.
  • R 4 and R 5 may be the same atom, or R 4 and R 5 may be different from each other.
  • the second invention is an amide derivative according to the first invention, wherein the compound represented by the general formula (1) is a compound represented by the following formula (1a) or a compound represented by the following formula (1b): It relates to a pharmacologically acceptable salt thereof or a hydrate thereof.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as described in the first invention.
  • the third invention is an amide derivative according to the first invention, wherein the compound represented by the general formula (1) is a compound represented by the following formula (1aa) or a compound represented by the following formula (1bb): It relates to a pharmacologically acceptable salt thereof or a hydrate thereof.
  • R 1a represents a C 1-6 alkyl group
  • R 4a and R 5a represent a halogen atom
  • R 2 and R 3 are as described in the first invention.
  • 4th invention is a compound represented by General formula (1) in 1st invention, 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methoxypyrazolo [1,5-a] pyridine-2-carboxylate, 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylaminopyrazolo [1,5-a] pyridine-2-carboxylate, Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methoxyimidazo [1,2-a] pyridine-2-carboxylate, Ethyl 3-chloro-5- (3,5-dichloropyridin-4-yl) carbamoyl-8-methylaminoimidazo [1,2-a] pyridine-2-carboxylate, 4- (3,5-dichloropyridin-4-yl) carbamoyl-7-methylthiopyrazolo [
  • the fifth invention also relates to a medicament comprising the amide derivative according to any one of the first to fourth inventions, a pharmacologically acceptable salt thereof or a hydrate thereof.
  • the sixth invention relates to an external preparation containing the amide derivative according to any one of the first invention to the fourth invention, a pharmacologically acceptable salt thereof or a hydrate thereof.
  • the seventh invention provides bronchial asthma and chronic obstructive lung containing the amide derivative according to any one of the first invention to the fourth invention, a pharmacologically acceptable salt thereof or a hydrate thereof.
  • the present invention relates to a therapeutic or preventive drug for disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia or Parkinson's disease.
  • COPD therapeutic or preventive drug for disease
  • an eighth invention provides bronchial asthma and chronic obstructive lung containing the amide derivative according to any one of the first invention to the fourth invention, a pharmacologically acceptable salt thereof or a hydrate thereof.
  • the present invention relates to an external preparation for treatment or prevention of disease (COPD), atopic dermatitis or psoriasis.
  • novel amide derivatives, addition salts and hydrates thereof according to the present invention have excellent PDE4 inhibitory activity and are rapidly metabolized in vivo to reduce the activity. Therefore, the novel amide derivatives (including addition salts and hydrates) according to the present invention are suitable for topical administration, for example. In particular, it is useful as a preventive or therapeutic agent for bronchial asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, psoriasis and the like.
  • COPD chronic obstructive pulmonary disease
  • the compound according to this embodiment is an amide derivative represented by the general formula (1). Further, the compound according to this embodiment may be a pharmacologically acceptable salt of the amide derivative, or may be a hydrate of the amide derivative or a hydrate of the salt of the amide derivative. .
  • A represents a condensed aromatic heterocyclic group represented by the following formula a) or formula b).
  • R 1 represents a C 1-6 alkyl group or a C 7-10 aralkyl group
  • R 2 is C 1-6 alkoxy groups, one or two C 1-6 alkyl amino group which may be substituted with a group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group or a C 1-
  • R 3 represents a hydrogen atom or a halogen atom
  • R 4 and R 5 represent a hydrogen atom or a halogen atom.
  • R 4 and R 5 may be the same atom, or R 4 and R 5 may be different from each other.
  • the “C 1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like.
  • the “C 7-10 aralkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a phenyl group.
  • Examples of the C 7-10 aralkyl group include a benzyl group, a phenethyl group, a 3-phenylpropyl group, and a 4-phenylbutyl group.
  • the “C 1-6 alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the C 1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. It is done.
  • amino group optionally substituted with 1 or 2 C 1-6 alkyl groups means an amino group in which the hydrogen atom contained is unsubstituted, or 1 or 2 hydrogen atoms contained in the group is C 1-1.
  • An amino group substituted with a 6 alkyl group examples include, for example, an amino group, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, and an isobutylamino group.
  • the C 1-6 alkylamino group is an amino group substituted with one C 1-6 alkyl group.
  • Examples of the C 1-6 alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, and a tert-butylamino group. It is done.
  • the “C 1-6 alkylsulfanyl group” is a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkylsulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a tert-butylsulfanyl group, and a pentylsulfanyl group. Group, hexylsulfanyl group and the like.
  • the “C 1-6 alkylsulfinyl group” is a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkylsulfinyl group include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, an isobutylsulfinyl group, a sec-butylsulfinyl group, a tert-butylsulfinyl group, and a pentylsulfinyl group.
  • the “C 1-6 alkylsulfonyl group” is a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, and a pentylsulfonyl group.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an
  • Examples of the pharmacologically acceptable salt of the compound according to this embodiment include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, citrate, and tartrate. There may be mentioned acid addition salts.
  • R 1 is preferably a C 1-6 alkyl group, and more preferably an ethyl group.
  • R 2 is preferably a C 1-6 alkoxy group, a C 1-6 alkylamino group, a C 1-6 alkylsulfanyl group, a C 1-6 alkylsulfinyl group or a C 1-6 alkylsulfonyl group, and a C 1-6 alkoxy group Group or a C 1-6 alkylamino group is more preferable, and a methoxy group or a methylamino group is particularly preferable.
  • R 4 is preferably a halogen atom, particularly preferably a chlorine atom.
  • R 5 is preferably a halogen atom, particularly preferably a chlorine atom.
  • Examples of the compound represented by the general formula (1) include a compound represented by the following formula (1a) or a compound represented by the following formula (1b).
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • R 3 is preferably a hydrogen atom.
  • R 3 is preferably a halogen atom, and more preferably a chlorine atom.
  • examples of the compound represented by the general formula (1) include a compound represented by the following formula (1aa) or a compound represented by the following formula (1bb).
  • R 1a represents a C 1-6 alkyl group
  • R 4a and R 5a represent a halogen atom
  • R 2 and R 3 have the same meanings as described above.
  • R 3 is preferably a hydrogen atom.
  • R 3 is preferably a halogen atom, and more preferably a chlorine atom.
  • the compound represented by the general formula (1) according to this embodiment can be produced by various synthesis methods. Next, a typical production method of the compound represented by the general formula (1) according to this embodiment will be described.
  • a compound in which R 3 is a hydrogen atom that is, a compound represented by the general formula (1c) can be produced, for example, by the synthesis route A shown below.
  • R 1a , R 2 , R 4a and R 5a are as defined above.
  • R 2 has the same meaning as described above.
  • R 2 has the same meaning as described above.
  • R 6 represents a C 1-6 alkyl group or a benzyl group
  • Pro represents a paramethoxybenzyl group, a tetrahydropyranyl group, a methoxymethyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group.
  • R 2 and Pro are as defined above.
  • R 2 and Pro have the same meanings as described above.
  • R 2 and Pro have the same meanings as described above.
  • R 2 and Pro have the same meanings as described above.
  • R 2 and Pro are as defined above.
  • R 2 , R 4a , R 5a and Pro are as defined above.
  • R 10a R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • the mixture (3a) in the synthesis route A can be produced by reacting the compound represented by the general formula (2a) with O-mesitylenesulfonylhydroxylamine (MSH) (step A-1).
  • MSH O-mesitylenesulfonylhydroxylamine
  • a compound represented by the general formula (2a) is dissolved in dichloromethane to prepare a dichloromethane solution of the compound represented by the general formula (2a).
  • MSH acts on the compound represented by the general formula (2a) by mixing the obtained dichloromethane solution of the compound represented by the general formula (2a) with a dichloromethane solution of MSH at 0 ° C. to room temperature.
  • normal temperature means 15 to 25 ° C. as defined in the Japanese Pharmacopoeia.
  • the compound represented by the general formula (4a) can be produced by reacting the mixture (3a) and the compound represented by the general formula (13) in the presence of a base (step A- 2).
  • R 6 and Pro have the same meaning as described above.
  • the mixture (3a) is reacted with the compound represented by the general formula (13) in a solvent in the presence of a base.
  • the solvent include methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), toluene, benzene, cyclohexane, Cyclopentane, dichloromethane, chloroform, acetonitrile and the like can be used.
  • an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, or an organic base such as triethylamine
  • the reaction temperature can be, for example, 0 ° C. to room temperature.
  • the compound represented by the general formula (5a) can be produced by hydrolyzing the compound represented by the general formula (4a) (step A-3). Specifically, an aqueous solution of a base is added to a solution of the compound represented by the general formula (4a), and the base is allowed to act on the compound represented by the general formula (4a) at a temperature from room temperature to heating reflux.
  • the solvent for preparing the solution of the compound represented by the general formula (4a) include methanol, ethanol, THF, CPME, DMSO, DMF, 1,4-dioxane and the like.
  • the aqueous solution of the base to be added include an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous lithium hydroxide solution, preferably an aqueous sodium hydroxide solution.
  • the compound represented by the general formula (6a) can be produced by decarboxylating the compound represented by the general formula (5a) (step A-4). Specifically, first, a solution of the compound represented by the general formula (5a) is prepared using an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, and xylene. Next, the prepared compound solution represented by the general formula (5a) is heated to 100 ° C. to 160 ° C. to decarboxylate the compound represented by the general formula (5a).
  • an organic solvent such as benzene, chlorobenzene, dichlorobenzene, bromobenzene, toluene, and xylene.
  • the compound represented by the general formula (7a) can be produced by oxidizing the compound represented by the general formula (6a) (step A-5). This reaction can be performed using a technique generally used for converting alcohols to aldehydes or ketones by oxidation.
  • oxidation using chromium oxide-pyridine complexes such as pyridinium chlorochromate and pyridinium dichromate
  • metal oxidants such as chromium oxide and manganese dioxide
  • sulfur trioxide-pyridine complex sulfur trioxide-pyridine complex
  • oxalyl chloride anhydrous tri
  • oxidation using a hypervalent iodine oxidant such as DMSO oxidation or Dess-Martin oxidation using a DMSO activator such as fluoroacetic acid, acetic anhydride, N, N-dicyclohexylcarbodiimide (DCC).
  • the reaction temperature can be, for example, ⁇ 78 ° C. to 100 ° C.
  • a compound represented by the general formula (6a) using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or 1-methylazaadamantane N-oxyl (1-Me-AZADO) By oxidation, the compound represented by the general formula (7a) can also be obtained.
  • TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl
  • 1-methylazaadamantane N-oxyl (1-Me-AZADO) 1-methylazaadamantane N-oxyl
  • the reaction temperature can be, for example, 0 ° C. to room temperature.
  • the compound represented by the general formula (8a) can be produced by oxidizing the compound represented by the general formula (7a) (step A-6).
  • the reaction can be carried out using sodium chlorite in the presence of 2-methyl-2-butene and sodium dihydrogen phosphate in a mixed solvent of t-butanol, THF or DMSO and water.
  • the compound represented by the general formula (9a) can be produced by reacting the compound represented by the general formula (8a) with the compound represented by the general formula (14) (process) A-7).
  • R 4a and R 5a have the same meanings as described above.
  • This reaction can be performed based on a synthesis reaction of amides by a condensation reaction of carboxylic acids and amines that are generally used.
  • the compound represented by the general formula (8a) is converted to acid chloride using thionyl chloride, oxalyl chloride or the like.
  • the compound represented by the general formula (8a) is converted into a mixed acid anhydride using ethyl chloroformate, isopropyl chloroformate, pivaloyl chloride, or the like.
  • the resulting acid chloride or mixed acid anhydride of the compound represented by the general formula (8a) is treated with a base such as sodium hydride or n-butyl lithium. Reaction with the resulting compound.
  • a base such as sodium hydride or n-butyl lithium.
  • the compound represented by the general formula (8a) is converted to a so-called active ester such as 4-nitrophenyl ester or 1-hydroxybenzotriazole ester, and then represented by the general formula (14).
  • the compound obtained by treating the resulting compound with a base such as sodium hydride or n-butyllithium is reacted with the resulting active ester.
  • a mixture of the compound represented by the general formula (8a) and the compound represented by the general formula (14) is added to N, N-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl).
  • DCC N-dicyclohexylcarbodiimide
  • the reaction can also be carried out by the action of a dehydration condensing agent such as —N′-ethylcarbodiimide (EDC).
  • EDC —N′-ethylcarbodiimide
  • the reaction temperature can be, for example, 0 ° C. to 100 ° C.
  • the compound represented by the general formula (10a) can be produced by deprotecting the compound represented by the general formula (9a) (step A-8).
  • the reaction can be performed, for example, as follows when the protecting group represented as Pro is a paramethoxybenzyl group.
  • the deprotection is carried out by treating the compound represented by the general formula (9a) with an acid such as trifluoroacetic acid, preferably in the presence of anisole in a solvent such as dichloromethane or chloroform at 0 ° C. to room temperature.
  • an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ceric ammonium nitrate (CAN) is used, and a solvent such as dichloromethane is used in the presence of water.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • CAN ceric ammonium nitrate
  • the protecting group represented by Pro is a methoxymethyl group or a tetrahydropyranyl group, for example, methanol, ethanol, ethyl acetate or diethyl ether containing trifluoroacetic acid or hydrogen chloride is used at a general formula (0 Deprotection is carried out by treating the compound represented by 9a).
  • the protecting group represented by Pro is a silyl group such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, for example, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, fluorine Deprotection is carried out by treating the compound represented by the general formula (9a) with hydrofluoric acid in a solvent such as acetonitrile or THF at 0 ° C. to room temperature.
  • a solvent such as acetonitrile or THF
  • the compound represented by the general formula (11a) can be produced by oxidizing the compound represented by the general formula (10a) (step A-9). This reaction can be carried out by the same method as in Step A-5.
  • the compound represented by the general formula (12a) in the synthesis route A can be produced by oxidizing the compound represented by the general formula (11a) (step A-10). This reaction can be carried out by the same method as in Step A-6.
  • the compound represented by the general formula (1c) is produced by reacting the compound represented by the general formula (12a) with the compound represented by the general formula (15) in the presence of a base. (Step A-11).
  • X represents a chlorine atom, a bromine atom or an iodine atom
  • R 1a has the same meaning as described above.
  • an inorganic base such as potassium carbonate or sodium carbonate or an organic base such as triethylamine or diisopropylethylamine in a solvent such as DMF or THF
  • an organic base such as triethylamine or diisopropylethylamine in a solvent such as DMF or THF
  • R 1a of the compound represented by the general formula (1c) is a methyl group
  • the compound represented by the general formula (12a) may be reacted with diazomethane or trimethylsilyldiazomethane in the general formula (1c).
  • the compounds represented can be produced.
  • diazomethane for example, the compound represented by the general formula (12a) is reacted with diazomethane in a solvent such as diethyl ether at 0 ° C. to room temperature.
  • trimethylsilyldiazomethane When trimethylsilyldiazomethane is used, for example, it is carried out by reacting the compound represented by the general formula (12a) with trimethylsilyldiazomethane in the presence of methanol in a solvent such as diethyl ether, toluene, benzene or chloroform at 0 ° C. to room temperature. be able to.
  • a solvent such as diethyl ether, toluene, benzene or chloroform
  • the compound represented by the general formula (11a) in the synthesis route A can also be produced by the following synthesis route B. ⁇ Synthetic route B>
  • R 2 has the same meaning as described above.
  • the mixture (3b) is the same as the mixture (3a) and can be prepared by the same method as the mixture (3a).
  • R 2 , R 6 and R 7 are as defined above.
  • R 7 represents a C 1-6 alkyl group, and R 2 has the same meaning as described above.
  • R 2 and R 7 are as defined above.
  • R 2 and R 7 are as defined above.
  • R 2 and R 7 are as defined above.
  • R 2 and R 7 are as defined above.
  • R 2 and R 7 are as defined above.
  • R 2 , R 4a , R 5a and R 7 are as defined above.
  • the compound represented by the general formula (4b) can be produced by reacting the mixture (3b) and the compound represented by the general formula (16) in the presence of a base (Step B- 1).
  • R 2 , R 6 and R 7 are as defined above.
  • R 6 and R 7 are as defined above. This reaction can be carried out by the same method as in step A-2.
  • the compound is produced by a process B-1 of the formula the two R 7 being represented in (4b) is formed by connecting, C 1-6 alkyl optionally substituted by a group C 2 It may be a compound having a -4 methylene chain.
  • the compound represented by the general formula (5b) can be produced by hydrolyzing the compound represented by the general formula (4b) (step B-2). This reaction can be carried out by the same method as in step A-3.
  • the compound represented by the general formula (6b) can be produced by decarboxylating the compound represented by the general formula (5b) (step B-3). This reaction can be carried out by the same method as in Step A-4.
  • the compound represented by the general formula (7b) can be produced by oxidizing the compound represented by the general formula (6b) (step B-4). This reaction can be carried out by the same method as in Step A-5.
  • the compound represented by the general formula (8b) can be produced by oxidizing the compound represented by the general formula (7b) (step B-5). This reaction can be carried out by the same method as in Step A-6.
  • the compound represented by the general formula (9b) can be produced by reacting the compound represented by the general formula (8b) with the compound represented by the general formula (14) (process) B-6). This reaction can be carried out by the same method as in Step A-7.
  • the compound represented by the general formula (11a) can be produced by deprotecting the compound represented by the general formula (9b) (step B-7).
  • an acid catalyst such as paratoluenesulfonic acid monohydrate or pyridinium paratoluenesulfonate (PPTS) is used in acetone, and the compound represented by the general formula (9b) is treated at a temperature ranging from room temperature to heating reflux. Can be done.
  • the reaction can also be carried out by treating the compound represented by the general formula (9b) with methanol, ethanol, ethyl acetate or diethyl ether containing hydrogen chloride at 0 ° C. to room temperature.
  • R 2 is an amino group optionally substituted with a C 1-6 alkoxy group, 1 or 2 C 1-6 alkyl groups, or C 2
  • a compound having a 1-6 alkylsulfanyl group, that is, a compound represented by the general formula (7c) can also be produced by the synthesis route C shown below.
  • R 2a is C 1-6 alkoxy groups, one or two C 1-6 alkyl amino group which may be substituted with a group, represents a C 1-6 alkylsulfanyl group, R 7 is Same meaning as above.
  • R 6 and R 7 are as defined above.
  • R 7 has the same meaning as described above.
  • R 7 has the same meaning as described above.
  • Pro ′ represents an alcohol protecting group such as a paramethoxybenzyl group, a tetrahydropyranyl group, a methoxymethyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triisopropylsilyl group, R 7 has the same meaning as described above.
  • Xa represents a halogen atom
  • R 7 and Pro ′ are as defined above.
  • Xa and R 7 are as defined above.
  • Xa and R 7 are as defined above.
  • a mixture of compounds represented as (3c) in the synthetic pathway C (hereinafter abbreviated as mixture (3c)) is obtained by reacting the compound represented by formula (2c) with O-mesitylenesulfonylhydroxylamine (MSH). It can be manufactured (Step C-1). This reaction can be carried out by the same method as in step A-1.
  • the compound represented by the general formula (4c) can be produced by reacting the mixture (3c) and the compound represented by the general formula (16) in the presence of a base (Step C- 2). This reaction can be carried out by the same method as in step A-2.
  • the compound represented by the general formula (5c) can be produced by hydrolyzing the compound represented by the general formula (4c) (step C-3).
  • the reaction can be carried out by the same method as in step A-3.
  • the compound represented by the general formula (6c) can be produced by decarboxylation of the compound represented by the general formula (5c) (step C-4). This reaction can be carried out by the same method as in Step A-4.
  • the compound represented by the general formula (17) can be produced by subjecting the compound represented by the general formula (6c) to various alcohol protection reactions (step C-5).
  • paramethoxybenzyl chloride or paramethoxybenzyl bromide is represented by the general formula (6c) at 0 ° C. to room temperature in the presence of a base in a solvent. It acts on the compound.
  • a base for example, sodium hydride, potassium hydride, lithium hydride and the like can be used.
  • solvent for example, DMF, THF, diethyl ether and the like can be used.
  • dihydropyran is a compound represented by the general formula (6c) in the presence of an acid catalyst such as p-toluenesulfonic acid in a solvent such as dichloromethane at 0 ° C. to room temperature. It is preferable to act on.
  • an acid catalyst such as p-toluenesulfonic acid
  • a solvent such as dichloromethane
  • Pro ′ is a methoxymethyl group
  • chloromethyl methyl ether or bromomethyl methyl ether is allowed to act on the compound represented by the general formula (6c) at 0 ° C. to room temperature in the presence of a base in a solvent. .
  • the base for example, sodium hydride, diisopropylethylamine, triethylamine and the like can be used.
  • the solvent for example, DMF, THF, diethyl ether, dichloromethane or the like can be used.
  • Pro ′ is a silyl protecting group such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, etc.
  • an alkyl corresponding to the protecting group to be introduced in a solvent in the presence of a base Silyl chloride, alkylsilyl bromide, or alkylsilyl trifluoromethanesulfonate is allowed to act on the compound represented by the general formula (6c) at 0 ° C. to room temperature.
  • the base imidazole, triethylamine or the like can be used.
  • solvent DMF, THF, diethyl ether, dichloromethane, or the like can be used.
  • the compound represented by the general formula (18) can be produced by halogenating the compound represented by the general formula (17) (step C-6).
  • the compound represented by the general formula (17) is first treated with a base in a solvent such as THF or CPME at ⁇ 78 ° C. to 0 ° C.
  • a base such as THF or CPME
  • LDA lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazane
  • NaHMDS sodium hexamethyldisilazane
  • Halogenating agents include N-fluorobenzenesulfonimide, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 1,2-dibromoethane, bromine, N-iodosuccinimide (NIS), iodine, 1,2 -Diiodoethane or the like can be used.
  • the compound represented by the general formula (19) can be produced by deprotecting the compound represented by the general formula (18) (step C-7). This reaction can be carried out by the same method as in Step A-8.
  • the compound represented by the general formula (20) can be produced by oxidizing the compound represented by the general formula (19) (step C-8). This reaction can be carried out by the same method as in Step A-5.
  • the compound represented by the general formula (7c) can be produced by alkoxylation, amination, or sulfanylation of the compound represented by the general formula (20) (step C-9).
  • R 2a is a C 1-6 alkoxy group
  • the reaction can be performed, for example, as follows. Specifically, a sodium salt, a potassium salt, or a lithium salt of an alcohol (compound represented by R 2a —H) corresponding to the introduced C 1-6 alkoxy group is represented by the general formula in a solvent at room temperature to 80 ° C. It is made to act on the compound represented by (20).
  • an alcohol corresponding to the C 1-6 alkoxy group As the solvent, an alcohol corresponding to the C 1-6 alkoxy group, DMF, DMSO, THF and the like can be used, and an alcohol corresponding to the C 1-6 alkoxy group is preferable.
  • R 2a is an amino group which may be substituted with 1 or 2 C 1-6 alkyl groups, that is, when amination is performed, the reaction can be performed, for example, as follows. Specifically, an amine (compound represented by R 2a -H) corresponding to an amino group which may be substituted with 1 or 2 C 1-6 alkyl groups to be introduced is allowed to react at room temperature in a solvent. The compound represented by the general formula (20) is allowed to act at 80 ° C.
  • R 2a is a C 1-6 alkylsulfanyl group
  • the reaction can be performed, for example, as follows. Specifically, sodium salt, potassium salt and lithium salt of thiol (compound represented by R 2a -H) corresponding to the introduced C 1-6 alkylsulfanyl group are generally used in a solvent at ordinary temperature to 80 ° C. It is made to act on the compound represented by Formula (20).
  • DMF, DMSO, THF, or the like can be used as the solvent.
  • R 2 is an amino group optionally substituted with a C 1-6 alkoxy group, 1 or 2 C 1-6 alkyl groups, or C 2
  • a compound having a 1-6 alkylsulfanyl group, that is, a compound represented by the general formula (7d) can also be produced by the synthesis route D shown below.
  • R 6 and Pro are as defined above.
  • Pro has the same meaning as described above.
  • Pro has the same meaning as described above.
  • Pro and Pro ′ are as defined above.
  • Xa, Pro, and Pro ′ are as defined above.
  • Xa and Pro are as defined above.
  • Xa and Pro are as defined above.
  • the compound represented by the general formula (4d) can be produced by reacting the mixture (3c) and the compound represented by the general formula (13) in the presence of a base (step D-1). ). This reaction can be carried out by the same method as in step A-2.
  • the compound represented by the general formula (5d) can be produced by hydrolyzing the compound represented by the general formula (4d) (step D-2). This reaction can be carried out by the same method as in step A-3.
  • the compound represented by the general formula (6d) can be produced by decarboxylating the compound represented by the general formula (5d) (Step D-3). This reaction can be carried out by the same method as in Step A-4.
  • the compound represented by the general formula (17d) can be produced by subjecting the compound represented by the general formula (6d) to various alcohol protection reactions (step D-4). This reaction can be carried out by the same method as in Step C-5.
  • the compound represented by the general formula (18d) can be produced by halogenating the compound represented by the general formula (17d) (step D-5). This reaction can be carried out by the same method as in Step C-6.
  • the compound represented by the general formula (19d) can be produced by deprotecting the compound represented by the general formula (18d) (step D-6). This reaction can be carried out by the same method as in Step C-7.
  • the compound represented by the general formula (20d) can be produced by oxidizing the compound represented by the general formula (19d) (step D-7). This reaction can be carried out by the same method as in Step A-5.
  • the compound represented by the general formula (7d) can be produced by alkoxylation, amination, or sulfanylation of the compound represented by the general formula (20d) (step D-8). .
  • This reaction can be carried out by the same method as in Step C-9.
  • a compound in which R 3 is a chlorine atom that is, a compound represented by the general formula (1e) can be produced by the synthesis route E shown below.
  • R 2 has the same meaning as described above.
  • R 2 and R 6 have the same meanings as described above.
  • R 2 and R 6 are as defined above.
  • R 2 and R 6 have the same meanings as described above.
  • R 2 has the same meaning as described above.
  • R 2 and Pro have the same meanings as described above.
  • R 2 and Pro have the same meanings as described above.
  • R 2 , R 4a , R 5a and Pro are as defined above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • R 2 , R 4a and R 5a have the same meanings as described above.
  • the compound represented by the general formula (22) can be produced by reacting the compound represented by the general formula (21) with the compound represented by the general formula (32) (process) E-1).
  • R 6 and X are as defined above.
  • the compound represented by the general formula (21) is reacted with the compound represented by the general formula (32) at a temperature ranging from room temperature to heating reflux using methanol, ethanol, isopropanol or the like as a solvent.
  • the compound represented by the general formula (23) can be produced by chlorinating the compound represented by the general formula (22) (step E-2). Specifically, a chlorinating agent such as NCS is allowed to act on the compound represented by the general formula (22) at room temperature to 100 ° C. in a solvent such as DMF or acetonitrile.
  • a chlorinating agent such as NCS is allowed to act on the compound represented by the general formula (22) at room temperature to 100 ° C. in a solvent such as DMF or acetonitrile.
  • the compound represented by the general formula (24) can be produced by brominating the compound represented by the general formula (23) (step E-3). Specifically, a brominating agent such as NBS is allowed to act on the compound represented by the general formula (23) at room temperature to 100 ° C. in a solvent such as DMF or acetonitrile.
  • a brominating agent such as NBS is allowed to act on the compound represented by the general formula (23) at room temperature to 100 ° C. in a solvent such as DMF or acetonitrile.
  • the compound represented by the general formula (25) can be produced by reducing the compound represented by the general formula (24) (step E-4). Specifically, a metal hydride such as diisobutylaluminum hydride, lithium borohydride, lithium aluminum hydride or the like is used in a solvent to reduce the compound represented by the general formula (24) at ⁇ 78 ° C. to room temperature. As the solvent, THF, diethyl ether, 1,4-dioxane and the like can be used. Further, the compound represented by the general formula (25) can also be produced by reducing the mixed acid anhydride obtained after derivatizing the compound represented by the general formula (24) into the mixed acid anhydride. .
  • a metal hydride such as diisobutylaluminum hydride, lithium borohydride, lithium aluminum hydride or the like is used in a solvent to reduce the compound represented by the general formula (24) at ⁇ 78 ° C. to room temperature.
  • the solvent THF, diethyl ether
  • a solution of the compound represented by the general formula (24) is prepared using a solvent such as methanol, ethanol, THF, CPME, DMSO, DMF, and 1,4-dioxane.
  • a solvent such as methanol, ethanol, THF, CPME, DMSO, DMF, and 1,4-dioxane.
  • an aqueous solution of a base such as an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution, or an aqueous lithium hydroxide solution is added to the resulting solution of the compound represented by the general formula (24), and the solution is generally treated at a temperature of 0 ° C to heating reflux.
  • a base is allowed to act on the compound represented by the formula (24) to obtain a carboxylic acid form.
  • the resulting carboxylic acid compound is mixed with ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, etc. at 0 ° C to Let it react at room temperature to make a mixed acid anhydride. Then, the obtained solution containing the mixed acid anhydride is added to an aqueous sodium borohydride solution, and sodium borohydride is allowed to act on the mixed acid anhydride obtained at 0 ° C. to room temperature.
  • a base such as triethylamine, diisopropylethylamine, or N-methylmorpholine
  • a solvent such as THF or dichloromethane
  • the compound represented by the general formula (26) can be produced by introducing a protecting group into the compound represented by the general formula (25) (step E-5).
  • This reaction can be carried out by the same method as in Step C-5. It can also be produced by subjecting the compound represented by the general formula (22) to the reaction in the order of reduction, introduction of a protecting group, chlorination, and bromination (step E-13).
  • the reduction can be performed by the same method as in Step E-4.
  • the introduction of the protecting group can be performed by the same method as in Step E-5.
  • Chlorination can be performed by the same method as in Step E-2.
  • Bromination can be performed by the same method as in Step E-3.
  • the compound represented by the general formula (27) can be produced by carboxylating the compound represented by the general formula (26) (step E-6). Specifically, first, n-butyllithium, sec-butyllithium, tert-butyllithium or the like is used in a solvent such as THF or diethyl ether, and is represented by the general formula (26) at ⁇ 78 ° C. to 0 ° C. A halogen-lithium exchange reaction is performed on the compound. Next, carbon dioxide gas is allowed to act on the obtained compound at ⁇ 78 ° C. to room temperature.
  • the compound represented by the general formula (28) can be produced by reacting the compound represented by the general formula (27) with the compound represented by the general formula (14) (step E). -7). This reaction can be carried out by the same method as in Step A-7.
  • the compound represented by the general formula (29) can be produced by deprotecting the compound represented by the general formula (28) (step E-8). This reaction can be carried out by the same method as in Step A-8.
  • the compound represented by the general formula (30) can be produced by oxidizing the compound represented by the general formula (29) (step E-9). This reaction can be carried out by the same method as in Step A-5.
  • the compound represented by the general formula (31) can be produced by oxidizing the compound represented by the general formula (30) (step E-10). This reaction can be carried out by the same method as in Step A-6.
  • the compound represented by the general formula (1e) can be produced by reacting the compound represented by the general formula (31) with the compound represented by the general formula (15) in the presence of a base. Yes (step E-11). This reaction can be carried out by the same method as in Step A-11.
  • R 8 represents a C 1-6 alkyl group
  • R 1a , R 4a and R 5a have the same meanings as described above.
  • R 6 has the same meaning as described above.
  • R 9 represents t- butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz) group, a methoxycarbonyl group, a protecting group of a general amino group such as an ethoxycarbonyl group, R 6 is Same meaning as above.
  • R 6 , R 8 and R 9 are as defined above.
  • R 6 , R 8 and R 9 are as defined above.
  • R 6 , R 8 and R 9 have the same meanings as described above.
  • R 8 and R 9 are as defined above.
  • R 8 , R 9 and Pro are as defined above.
  • R 8 , R 9 and Pro have the same meanings as described above.
  • R 4a , R 5a , R 8 , R 9 and Pro have the same meanings as described above.
  • R 4a , R 5a and R 8 have the same meanings as described above.
  • R 4a , R 5a, and R 8 are as defined above.
  • R 4a , R 5a and R 8 have the same meanings as described above.
  • the compound represented by the general formula (33) can be produced by reacting the compound represented by the general formula (21f) with the compound represented by the general formula (32) (process) F-1). This reaction can be carried out by the same method as in Step E-1.
  • the compound represented by the general formula (34) can be produced by introducing a protecting group for the compound represented by the general formula (33) (step F-2).
  • R 6 and R 9 are as defined above.
  • R 9 is a Boc group
  • di-t-butyl dicarbonate is allowed to act on the compound represented by the general formula (33) at a temperature of 0 ° C. to heating under reflux in a solvent such as dichloromethane, acetonitrile, or THF.
  • a base such as triethylamine, diisopropylamine or diisopropylethylamine may be used as necessary.
  • DMAP 4-dimethylaminopyridine
  • LHMDS or NaHMDS is added as a base to a mixture of the compound represented by the general formula (33) and di-t-butyl dicarbonate in a solvent such as THF and diethyl ether, and the general formula (33
  • the compound represented by the general formula (34) can also be produced by reacting the compound represented by) with di-t-butyl dicarbonate.
  • R 9 is a Cbz group, for example, in a solvent such as 1,4-dioxane to which an aqueous sodium hydroxide solution or an aqueous sodium carbonate solution is added, benzyloxycarbonyl chloride is represented by the general formula (33) at 0 ° C. to room temperature.
  • the compound represented by the general formula (34) By reacting with the compound to be produced, the compound represented by the general formula (34) can be produced.
  • R 9 is a methoxycarbonyl group or an ethoxycarbonyl group, methoxycarbonyl chloride or ethoxycarbonyl chloride and a compound represented by the general formula (33) at a temperature of 0 ° C. to heating under reflux in a solvent containing a base such as THF, dichloromethane, and acetone.
  • the compound represented by General formula (34) can be manufactured by making the compound represented by these react.
  • the base for example, an inorganic base such as potassium carbonate, or an organic base such as triethylamine, diisopropylethylamine, or pyridine can be used.
  • the compound represented by the general formula (35) can be produced by reacting the compound represented by the general formula (34) with the compound represented by the general formula (36) (process) F-3).
  • R 8 and X are as defined above. Specifically, a compound represented by the general formula (34) in a solvent such as DMF, THF, or diethyl ether in the presence of a base such as sodium hydride, lithium hydride, or potassium hydride at 0 ° C. to room temperature. And a compound represented by the general formula (36) are reacted.
  • the compound represented by the general formula (23f) can be produced by chlorinating the compound represented by the general formula (35) (step F-4). This reaction can be carried out by the same method as in Step E-2.
  • the compound represented by the general formula (24f) can be produced by brominating the compound represented by the general formula (23f) (step F-5). This reaction can be carried out by the same method as in Step E-3.
  • the compound represented by the general formula (25f) in the synthesis route F can be produced by reducing the compound represented by the general formula (24f) (step F-6). This reaction can be carried out by the same method as in Step E-4.
  • the compound represented by the general formula (26f) can be produced by introducing a protecting group into the compound represented by the general formula (25f) (step F-7). This reaction can be carried out by the same method as in Step C-5.
  • the compound represented by the general formula (26f) can also be produced by subjecting the compound represented by the general formula (35) to the reaction in the order of reduction, introduction of a protecting group, chlorination, and bromination. (Step F-15).
  • the reduction can be performed by the same method as in Step E-4.
  • the introduction of the protecting group can be performed by the same method as in Step E-5.
  • Chlorination can be performed by the same method as in Step E-2.
  • Bromination can be performed by the same method as in Step E-3.
  • the compound represented by the general formula (27f) can be produced by carboxylating the compound represented by the general formula (26f) (Step F-8). This reaction can be carried out by the same method as in Step E-6.
  • the compound represented by the general formula (28f) can be produced by reacting the compound represented by the general formula (27f) with the compound represented by the general formula (14) (Step F). -9). This reaction can be carried out by the same method as in Step A-7.
  • the compound represented by the general formula (29f) in the synthesis route F can be produced by deprotecting the compound represented by the general formula (28f) (step F-10). Removal of R 9, when R 9 is a Boc group, methanol containing trifluoroacetic acid or hydrogen chloride, ethanol, with ethyl acetate or diethyl ether, compounds represented by the general formula (28f) at 0 ° C. ⁇ room temperature This can be done by processing. When R 9 is a Cbz group, palladium-activated carbon, palladium hydroxide-activated carbon, etc. are used as a catalyst in a solvent such as ethanol, methanol, THF, ethyl acetate, etc.
  • R 9 can be removed.
  • R 9 is a methoxycarbonyl group or an ethoxycarbonyl group
  • R 9 can be removed by treating the compound represented by the general formula (28f) with hydrobromic acid-acetic acid or trimethylsilyl iodide. it can.
  • R 9 is a methoxycarbonyl group or an ethoxycarbonyl group
  • R 9 can also be removed by applying alkaline hydrolysis conditions to the compound represented by the general formula (28f).
  • Pro can be removed by the same method as in Step A-8. Pro and R 9 can be removed stepwise and in some cases simultaneously.
  • the compound represented by the general formula (30f) can be produced by oxidizing the compound represented by the general formula (29f) (Step F-11). This reaction can be carried out by the same method as in Step A-5.
  • the compound represented by the general formula (31f) can be produced by oxidizing the compound represented by the general formula (30f) (step F-12). This reaction can be carried out by the same method as in Step A-6.
  • the compound represented by the general formula (1f) can be produced by reacting the compound represented by the general formula (31f) with the compound represented by the general formula (15) in the presence of a base. Yes (step F-13). This reaction can be carried out by the same method as in Step A-11.
  • a compound in which R 2 is a C 1-6 alkylsulfinyl group or a C 1-6 alkylsulfonyl group and R 3 is a hydrogen atom that is, a compound represented by the general formula (1g) Can also be produced by the synthetic route G shown below.
  • the compound represented by the general formula (1g) can be produced by oxidizing the compound represented by the general formula (1g ′) (step G-1).
  • R 1a , R 4a , R 5a and R 8 have the same meanings as described above.
  • the compound represented by the general formula (1g) can be produced by oxidizing the compound represented by the general formula (1g ′) at 0 ° C. to room temperature using oxone in a THF-water mixed solvent.
  • the compound represented by general formula (1g ') can be manufactured by the synthetic pathway A.
  • R 1a , R 4a , R 5a , R 8 and l are as defined above. ⁇ Synthetic route H>
  • the compound represented by the general formula (1h) can be produced by oxidizing the compound represented by the general formula (1h ′) (step H-1).
  • R 1a , R 4a , R 5a and R 8 have the same meanings as described above. This reaction can be carried out by the same method as in Step G-1.
  • the compound represented by general formula (1h ') can be manufactured by the synthetic pathway E.
  • R 2 is an amino group optionally substituted with 1 or 2 C 1-6 alkyl groups
  • R 3 is a hydrogen atom, that is, the compound represented by the general formula (1)
  • the compound represented by 1i) can also be produced by the synthetic route I shown below.
  • R 8 ′ and R 10 represent a hydrogen atom or a C 1-6 alkyl group, and R 1a , R 4a and R 5a have the same meanings as described above. ⁇ Synthetic route I>
  • the compound represented by the general formula (1i) can be produced by amination of the compound represented by the general formula (1i ′) (Step I-1).
  • R 11 represents a C 1-6 alkyl group
  • R 1a , R 4a and R 5a are as defined above.
  • an amine compound represented by R 8 ′ —NH—R 10
  • the compound represented by the general formula (1i ′) is aminated in a solvent such as DMF, DMSO, and THF at room temperature to 80 ° C.
  • the compound represented by general formula (1i ') can be manufactured by the synthetic pathway A.
  • the compound of the present embodiment shows excellent PDE4 inhibitory activity.
  • the compound of this embodiment is a disease in which a PDE4 inhibitor is effective as a preventive or therapeutic agent, such as bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis Can be used to treat or prevent psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia, or Parkinson's disease.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • interstitial pneumonia allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, dementia, or Parkinson's disease It can also be used to manufacture a medicament for prevention.
  • COPD chronic obstructive pulmonary disease
  • the medicament containing the compound of this embodiment as an active ingredient is, for example, bronchial asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, allergic rhinitis, atopic dermatitis, psoriasis, rheumatoid arthritis, multiple It can be used as a preventive or therapeutic agent for systemic sclerosis, Alzheimer's disease, dementia and Parkinson's disease.
  • COPD chronic obstructive pulmonary disease
  • interstitial pneumonia allergic rhinitis
  • atopic dermatitis psoriasis
  • rheumatoid arthritis multiple It can be used as a preventive or therapeutic agent for systemic sclerosis, Alzheimer's disease, dementia and Parkinson's disease.
  • the compound of the present embodiment has an excellent PDE4 inhibitory action, but is rapidly metabolized in vivo to reduce its activity.
  • the compound of this embodiment shows an excellent PDE4 inhibitory action when taken into a living body.
  • the compound of this embodiment is rapidly metabolized, for example, after being absorbed into the living body, and as a result of the ester moiety of the amide derivative represented by formula (1) being changed to a carboxyl group, the PDE4 inhibitory activity is attenuated. Therefore, the occurrence of systemic side effects such as vomiting and vasculitis can be suppressed as compared with conventional PDE4 inhibitors. Therefore, the compound of this embodiment is suitably used when performing local administration such as transdermal administration or inhalation administration.
  • the medicine containing the compound of the present embodiment can be in the form of a pharmaceutical composition, for example.
  • the pharmaceutical composition containing the compound of the present embodiment may be in any form of a solid composition, a liquid composition, and other compositions, and the optimal one is selected as necessary.
  • a pharmaceutical composition containing the compound of this embodiment can be produced by blending the compound of this embodiment with a pharmacologically acceptable carrier.
  • a pharmacologically acceptable carrier Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers, aqueous or non-aqueous solvents, etc. are added, and by conventional formulation techniques, It can be prepared into powders, granules, tablets, capsules, liquids and the like.
  • External preparations refer to all drugs used directly on the living body, excluding internal preparations and injections.
  • external preparations include coating agents, eye drops, nasal drops, ear drops, inhalants, sprays, suppositories and the like.
  • an inhalant and a spray are suitable
  • an external preparation for treatment or prevention of atopic dermatitis and psoriasis is used. Is suitable.
  • the compound of this embodiment is particularly suitable for local administration such as transdermal administration and inhalation administration for the reasons described above, the compound of this embodiment is suitable for bronchial asthma and chronic obstructive lung among the above-mentioned diseases. Particularly suitable for use in treating or preventing disease (COPD), atopic dermatitis or psoriasis.
  • COPD chronic obstructive lung
  • the dose of the compound of the present embodiment is not particularly limited and varies depending on the disease, symptoms, body weight, age, sex, administration route and the like.
  • it is preferably about 0.01 to about 1000 mg / kg body weight / day, more preferably about 0.5 to about 200 mg / kg body weight / day, It can be administered once or divided into several times.
  • those skilled in the art can appropriately determine the disease, symptom, body weight, age, sex, administration route and the like.
  • the medicament according to this embodiment includes, for example, about 0 of the compound of this embodiment. About 0.01% to about 95% by weight is contained.
  • a topical application for example, an ointment for the treatment of atopic dermatitis or psoriasis contains the compound of the present embodiment at a concentration of 0.01 to 95%, for example.
  • the dose of the compound of the present embodiment by inhalation is 0.5 to 200 mg per day.
  • N-Butyllithium (1.65 mol / L hexane solution, 8.5 mL) was added dropwise to the reaction solution at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 30 minutes.
  • ethyl chloroformate (3.6 mL) was added to the reaction solution all at once, and the mixture was stirred as it was for 1 hour.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • the compound of Reference Example 2 (1.74 g) was dissolved in ethanol (44 mL) to obtain a reaction solution.
  • a 1 mol / L aqueous sodium hydroxide solution (13 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours under heating to reflux. After evaporating the solvent under reduced pressure, the residue was dissolved in water, and acidified (pH 3-4) by adding 1 mol / L hydrochloric acid under ice cooling. The resulting solid was collected by filtration, washed with water, and dried at 60 ° C. under reduced pressure to obtain a carboxylic acid compound (1.57 g) as a light aqua solid.
  • the compound of Reference Example 3 (1.36 g) was dissolved in chloroform (20 mL) to prepare a reaction solution.
  • Manganese dioxide (75%, 2.4 g) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 7 hours.
  • the insoluble material was filtered off using celite, and the filtrate was evaporated under reduced pressure to give the title compound (1.35 g) as a yellow oil.
  • the compound of Reference Example 5 (1.15 g) was dissolved in dichloromethane (34 mL) to give a reaction solution.
  • dichloromethane 34 mL
  • 4-nitrophenol 514 mg
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 837 mg
  • 4-dimethylaminopyridine 41.1 mg
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the compound of Reference Example 6 (694 mg) was dissolved in dichloromethane (35 mL) to obtain a reaction solution.
  • Anisole (4.6 mL) and trifluoroacetic acid (4.2 mL) were added to the reaction solution under ice cooling.
  • the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, sodium chloride was further added, and the mixture was extracted with tetrahydrofuran.
  • the organic layer was dried using anhydrous magnesium sulfate and anhydrous sodium sulfate was removed by filtration, and then the solvent was distilled off under reduced pressure.
  • the compound of Reference Example 7 (488 mg) was dissolved in N, N-dimethylformamide (13 mL) to prepare a reaction solution.
  • Manganese dioxide (75%, 771 mg) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 7 hr.
  • Manganese dioxide (75%, 771 mg) was added to the reaction solution, and the mixture was further stirred for 21 hours.
  • the insoluble material was removed by filtration using celite and silica gel, and the filtrate was evaporated under reduced pressure.
  • the resulting solid was suspended in a mixed solution of ethyl acetate-diisopropyl ether and collected by filtration to give the title compound (261 mg) as a green solid.
  • the compound of Reference Example 8 (260 mg) was dissolved in dimethyl sulfoxide (6 mL) to prepare a reaction solution. After adding 2-methyl-2-butene (0.76 mL) to the reaction mixture, a mixed aqueous solution of sodium chlorite (80%, 242 mg) and sodium dihydrogen phosphate dihydrate (555 mg) at room temperature ( 1 mL) was added dropwise to the reaction solution and stirred at room temperature for 1.5 hours. A 1 mol / L aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and the mixture was stirred for 15 minutes, and then the aqueous layer was separated.
  • the compound of Reference Example 9 (200 mg) was dissolved in N, N-dimethylformamide (10 mL) to obtain a reaction solution. To the reaction solution were added iodoethane (50 mL) and potassium carbonate (94.5 mg), and the mixture was stirred at room temperature for 15 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate) to give the title compound (158 mg) as a pale yellow solid.
  • Example 1 The compound of Example 1 (83 mg) was dissolved in N, N-dimethylformamide (2 ml) to give a reaction solution. Methylamine (2 mol / L tetrahydrofuran solution, 1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Methylamine (2 mol / L tetrahydrofuran solution, 1 mL) was added to the reaction solution, and the mixture was further stirred at 60 ° C. for 7 hours. Ice water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the compound (5.00 g) of Reference Example 10 was added little by little to a tetrahydrofuran suspension (98.7 mL) of lithium aluminum hydride (1.03 g) under ice cooling to prepare a reaction solution.
  • the reaction solution was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes.
  • a saturated Rochelle salt aqueous solution was added to the reaction solution under ice-cooling, ethyl acetate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the compound of Reference Example 12 (5.05 g) was dissolved in N, N-dimethylformamide (18 mL) to obtain a reaction solution.
  • N-chlorosuccinimide (2.54 g) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction solution, and the resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in ethyl acetate and dried using anhydrous magnesium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure.
  • the compound of Reference Example 13 (4.62 g) was dissolved in N, N-dimethylformamide (14 mL) to obtain a reaction solution.
  • N-bromosuccinimide (2.76 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hours. Ice water was added to the reaction solution, and the resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in ethyl acetate and dried using anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • the separated aqueous layer was adjusted to pH 3-4 by adding 1 mol / L hydrochloric acid under ice cooling.
  • the resulting solid was collected by filtration, washed with water, and dried at room temperature under reduced pressure.
  • the obtained solid was dissolved in chloroform and dried using anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (990 mg) as a colorless solid.
  • the compound of Reference Example 16 (140 mg) was dissolved in tetrahydrofuran (3 mL) to give a reaction solution.
  • Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.33 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Ice water was added to the reaction solution, and the resulting solid was collected by filtration, washed with water, and dried at room temperature under reduced pressure. The obtained solid was dissolved in a chloroform-methanol mixed solvent and dried using anhydrous sodium sulfate.
  • the compound of Reference Example 17 (109 mg) was dissolved in dimethyl sulfoxide (2.7 mL) to obtain a reaction solution. Triethylamine (0.38 mL) and sulfur trioxide-pyridine complex (216 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Ice water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give the titled compound (77 mg) as a colorless solid.
  • the compound of Reference Example 19 (130 mg) was dissolved in N, N-dimethylformamide (6 mL) to give a reaction solution. To the reaction solution were added iodoethane (27.5 ⁇ L) and diisopropylethylamine (60 ⁇ L), and the mixture was stirred at room temperature for 21 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • 2,3-Diaminopyridine (18.4 g) and ethyl bromopyruvate (36.1 g,) were suspended in ethanol (330 mL) to prepare a reaction solution.
  • the reaction solution was stirred for 14 hours under heating to reflux.
  • the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the solvent was distilled off under reduced pressure.
  • the solid was filtered off using celite and the filtrate was extracted with ethyl acetate.
  • the organic layer was dried using anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution under ice cooling, water and ethyl acetate were added, and the mixture was separated into an aqueous layer and an organic layer.
  • the compound of Reference Example 20 (7.79 g) was dissolved in N, N-dimethylformamide (100 mL) to obtain a reaction solution.
  • To the reaction solution was added 60% sodium hydride (1.22 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
  • iodomethane (1.90 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was poured into ice water, and the precipitated solid was collected by filtration to give the title compound (6.91 g) as a pale yellow solid.
  • the compound of Reference Example 21 (3.90 g) was dissolved in N, N-dimethylformamide (61 mL) to obtain a reaction solution.
  • N-chlorosuccinimide (1.71 g) was added to the reaction solution, and the mixture was stirred at 70 ° C. for 2 hours, cooled to room temperature, and saturated aqueous sodium carbonate solution was added. Subsequently, water and ethyl acetate were added to the reaction solution, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • the compound of Reference Example 22 (3.31 g) was dissolved in N, N-dimethylformamide (47 mL) to obtain a reaction solution.
  • N-bromosuccinimide (1.83 g) was added to the reaction mixture, and the mixture was stirred at 70 ° C. for 1.5 hr. After cooling the reaction solution to room temperature, a saturated aqueous sodium carbonate solution was added. Next, water and ethyl acetate were added, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • N-methylmorpholine (0.38 mL) and isobutyl chloroformate (0.45 mL) were added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 30 min.
  • the combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain a brown oil.
  • the brown oil solution (14.6 mL) of the brown oil obtained above was slowly added dropwise to an aqueous solution (7.3 mL) of sodium borohydride (481 mg) under ice cooling to prepare a reaction solution.
  • diisopropylethylamine (0.53 mL) and chloromethyl methyl ether (0.24 mL) were added dropwise to a dichloromethane solution (13 mL) of the compound of Reference Example 24 (1.01 g) under ice cooling to prepare a reaction solution. .
  • the reaction was stirred at ambient temperature for 19 hours.
  • diisopropylethylamine (0.44 mL) and chloromethyl methyl ether (0.20 mL) were added dropwise to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • the compound of Reference Example 27 (353 mg) was dissolved in 4 mol / L hydrochloric acid-ethyl acetate solution (6.5 mL) to give a reaction solution.
  • the reaction solution was stirred at room temperature for 3 hours and at 50 ° C. for 1 hour.
  • water was added to the residue, and the mixture was further neutralized by adding a 1 mol / L aqueous sodium hydroxide solution under ice cooling. Further, sodium chloride was added to the resulting mixture and extracted with tetrahydrofuran. The organic layer was dried using anhydrous magnesium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • Potassium carbonate (16.7 g) was added to an ethanol solution (200 mL) of the compound of Reference Example 1 (10.0 g) and the compound of Example 3 of International Publication No. 2008/029829 (24.7 g) to prepare a reaction solution.
  • the reaction was stirred at ambient temperature for 17 hours.
  • the insoluble material was filtered off using celite, and the filtrate was evaporated under reduced pressure.
  • the residue was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate.
  • the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • the compound of Reference Example 32 (3.59 g) was dissolved in N, N-dimethylformamide (80 mL) to obtain a reaction solution.
  • To the reaction solution were added imidazole (2.45 g) and t-butyldimethylsilyl chloride (2.17 g), and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • n-butyllithium (1.65 mol / L hexane solution, 9.45 mL) was slowly added dropwise to a tetrahydrofuran solution (35 mL) of the compound of Reference Example 33 (4.95 g) at -78 ° C to prepare a reaction solution. .
  • the reaction was stirred at the same temperature for 30 minutes.
  • a tetrahydrofuran solution (35 mL) of 1,2-diiodoethane (4.06 g) was slowly added dropwise to the reaction solution at ⁇ 78 ° C., and the reaction solution was stirred at the same temperature for 1 hour.
  • the compound of Reference Example 34 (6.33 g) was dissolved in tetrahydrofuran (60 mL) to give a reaction solution.
  • Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 14.2 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure.
  • Example 5 The compound of Example 5 (171 mg) was dissolved in tetrahydrofuran (8 mL) and water (2 mL) to give a reaction solution. To the reaction solution was added an aqueous solution (2 mL) of oxone (185 mg), and the mixture was stirred at room temperature for 5 hours. Oxone (25 mg) was added to the reaction solution, and the mixture was further stirred for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 1 PDE4 Inhibitory Activity
  • the compounds of Examples 1 and 2 were each dissolved in dimethyl sulfoxide (hereinafter abbreviated as DMSO) to prepare a 10 mmol / L test compound solution.
  • DMSO dimethyl sulfoxide
  • the obtained 10 mmol / L test compound solution was serially diluted with DMSO to prepare a test compound solution having a concentration of 0.5 nmol / L to 50 ⁇ mol / L.
  • test compound solution 2 ⁇ L of test compound solution, substrate solution [100 nmol / LcAMP, 16 nmol / L [ 3 H] cAMP, 40 mmol / L Tris-HCl (pH 7.4), 10 mmol / L MgCl] 50 ⁇ L and enzyme solution [0.05 unit amount 48 ⁇ L of human-derived recombinant PDE4 catalytic region (hereinafter abbreviated as PDE4cat; manufactured by Scottish Biomedicals), 20 mmol / L Tris-HCl (pH 7.4)] was added to a 1.5 mL tube and reacted at 30 ° C. for 40 minutes. Then, after standing at 70 ° C.
  • PDE4cat human-derived recombinant PDE4 catalytic region
  • the concentration of each component in the substrate solution represents the concentration in the substrate solution.
  • 1 unit represents the amount of PDE that decomposes 1 pmol of cAMP in 1 minute under the conditions of pH 7.4 and 30 ° C.
  • the concentration of Tris-HCl represents the concentration in the enzyme solution.
  • AG1-X8 Resin represents the concentration in the AG1-X8 Resin solution.
  • 300 ⁇ L of the supernatant is taken and added to 5 mL of ACS IIScintillation Cocktail (Amersham).
  • Radiation dose was measured using Tri-Carb 2910 TR (manufactured by PerkinElmer).
  • the residual PDE4 activity was calculated from the measured radiation dose.
  • IC 50 value was calculated by the following formula.
  • A Minimum compound concentration at which PDE4 activity is less than 50%
  • B Maximum compound concentration at which PDE4 activity is greater than 50%
  • C PDE4 activity remaining rate at the minimum compound concentration at which PDE4 activity is less than 50%
  • D PDE4 activity remaining rate at the maximum compound concentration at which PDE4 activity is greater than 50%
  • the compounds according to the present embodiment is an ester body is rapidly metabolized when absorbed into the body, in the compounds of ester moiety becomes a carboxyl group (formula (1), R 1 is represented by H Compound, hereinafter referred to as carboxylic acid form). Since the carboxylic acid form has weaker PDE4 inhibitory activity than the ester form, the risk of developing systemic side effects derived from the PDE4 inhibitory action is low. Therefore, it can be said that a compound having a larger PDE4 inhibitory activity ratio between the ester form and the carboxylic acid form is preferable as a topical administration agent. Therefore, IC 50 values were similarly calculated for the carboxylic acid compounds of the compounds of Examples 1 and 2.
  • the compounds of Examples 1 and 2 is an ester body and PDE4 inhibitory activity ratio of their carboxylic acid form for (carboxylic acid form IC 50 / ester IC 50), 1 ⁇ activity ratio ⁇ 10 (-), 10 ⁇ Activity ratio ⁇ 100 is represented in Table 1 as (+), and 100 ⁇ Activity ratio ⁇ 1000 is represented as (++).
  • the compound of this embodiment has potent PDE4 inhibitory activity.
  • 5v / v% tolylene 2,4-diisocyanate dissolved in acetone containing 20% olive oil 10 ⁇ L of the solution was applied to each mouse left and right hind limbs.
  • a compound solution containing the compound of Example 2 at a concentration of 0.03 w / v% dissolved in 10% DMSO-containing acetone was added to the left and right pinna. 20 ⁇ L each was applied.
  • the compound of Example 2 showed an inhibitory action of 50% or more. As described above, the effectiveness of the compound of this embodiment was also confirmed in animal experimental models.
  • Whole blood was collected from the abdominal aorta under ether anesthesia and collected in a vacuum blood collection tube containing ethylenediaminotetraacetate dipotassium (EDTA-2K).
  • EDTA-2K ethylenediaminotetraacetate dipotassium
  • the collected blood was centrifuged (2,000 ⁇ g, 10 minutes, 4 ° C.), and the supernatant was used as plasma.
  • Reaction Rat blank plasma was mixed with an additive solution to a final concentration of 10 ⁇ M, and incubated at 37 ° C. Take 20 ⁇ L after 0.5 min, 1 min, 2 min, 5 min (5 min, 10 min, 30 min, 60 min for non-ester compounds), and then add 20 ⁇ L of acetonitrile and internal standard. The reaction was stopped by adding 20 ⁇ L of the solution and stirring.
  • purified water 1: 1.
  • MS / MS Micromass Quattro Ultima HPLC: Agilent 1100 (Agilent)
  • Mobile phase A, 0.05% formic acid aqueous solution, B, 0.05% formic acid acetonitrile solution
  • the drug concentration was calculated by the internal standard method using the peak area ratio between the test drug and the internal standard substance. Further, the calibration curve measurement value was obtained by using the peak area of the calibration curve sample measured before and after the sample measurement, and the drug concentration in the sample was calculated from the standard calibration curve obtained by the weighted least square method (weight: 1 / Conc.). LC-MS / MS operation software Masslynx was used for peak identification, area ratio calculation, calibration curve creation and sample concentration calculation.
  • the half-life (t 1/2 ) was calculated.
  • the compound of Example 1 has a half-life of 1.1 minutes
  • the compound of Example 78 (non-ester compound) of WO2008026687 has a half-life of 120 minutes. From the above results, it can be seen that the compound of this embodiment is rapidly metabolized in vivo and the activity is attenuated.
  • novel amide derivatives, their addition salts, and their hydrates according to this embodiment have excellent PDE4 inhibitory activity and are rapidly metabolized in vivo to reduce the activity. I found.
  • Such a compound is useful as a preventive or therapeutic agent for bronchial asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, psoriasis and the like.
  • COPD chronic obstructive pulmonary disease

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Abstract

L'invention a pour objet un nouveau dérivé d'amide ayant une plus grande innocuité et ayant une activité d'inhibition de la phosphodiestérase 4 supérieure. Le nouveau dérivé d'amide, qui est représenté par la formule générale (1), a une puissante activité d'inhibition de la PDE 4 et il est rapidement métabolisé dans le corps, ce qui fait qu'il a une activité qui s'atténue, et donc il est possible de supprimer la survenue d'effets indésirables systémiques. Du fait desdites caractéristiques, le composé de la présente invention convient particulièrement bien à une administration localisée. Dans la formule (1), A représente un groupe hétérocyclique aromatique condensé représenté par la formule (a) ou la formule (b).
PCT/JP2012/004934 2011-08-03 2012-08-02 Dérivé d'amide et médicament le contenant WO2013018372A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008026687A1 (fr) * 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé
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

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008026687A1 (fr) * 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé
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

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Title
DATABASE CAPLUS 24 September 2012 (2012-09-24), accession no. 009:984298 *
GRACIA, J: "Antedrug PDE4 inhibitors for the topical treatment of psoriasis, Abstracts of Papers", 238TH ACS NATIONAL MEETING, 16 August 2009 (2009-08-16), WASHINGTON, DC, UNITED STATES *
ISAO KITAGAWA ET AL., MEDICINAL CHEMISTRY, 31 March 2003 (2003-03-31), pages 229 - 230 *
NICHOLAS, B. ET AL.: "Drug targeting via retrometabolic approaches", PHARMACOLOGY & THERAPEUTICS, vol. 76, no. 1-3, 1997, pages 1 - 27 *
ZHANG, Y. ET AL.: "Design and synthesis of boron-containing PDE4 inhibitors using soft- drug strategy for potential dermatologic anti-inflammatory application", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 7, 2010, pages 2270 - 2274 *

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