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WO2006123639A1 - Dérivé de pyrimidine - Google Patents

Dérivé de pyrimidine Download PDF

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Publication number
WO2006123639A1
WO2006123639A1 PCT/JP2006/309713 JP2006309713W WO2006123639A1 WO 2006123639 A1 WO2006123639 A1 WO 2006123639A1 JP 2006309713 W JP2006309713 W JP 2006309713W WO 2006123639 A1 WO2006123639 A1 WO 2006123639A1
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Prior art keywords
group
substituted
optionally substituted
compound
general formula
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PCT/JP2006/309713
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English (en)
Japanese (ja)
Inventor
Kenji Naganuma
Hirotsugu Yokoi
Original Assignee
Asahi Kasei Pharma Corporation
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Publication of WO2006123639A1 publication Critical patent/WO2006123639A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P17/04—Antipruritics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel pyrimidine derivative having an anti-inflammatory action and useful as an active ingredient of a medicine.
  • Stimulation from the outside is transmitted into cells via receptors on the cell membrane.
  • This biological signal is generated by enzymes such as adenylate cyclase or dallate cyclase, and the intracellular second messengers cyclic adenosine 3 ', 5,-phosphate (cAMP) and cyclic guanosine.
  • cAMP cyclic adenosine
  • cyclic guanosine 3 , 5,-It is known that its action is manifested by increasing the concentration of phosphoric acid (cGMP).
  • cGMP phosphoric acid
  • PDE nucleotide phosphodiesterase
  • PDE4 type 4PDE selectively degrades cAMP and decreases intracellular cAMP concentration.
  • PDE4 has been found in many tissues and cells including blood vessels, heart, intestine, brain, spleen, bronchial smooth muscle, leukocytes, and lymphocytes. It is known that cAMP increased by inhibiting PDE4 at these sites exerts an effect of preventing or ameliorating many diseases.
  • Non-Patent Documents 3 to 5 PDE4 inhibitor suppresses inflammatory cell activity, suppresses tumor necrosis factor a (TNF- ⁇ ) release, suppresses degranulation, suppresses release of inflammatory site force-in, It has effects such as suppression (Non-Patent Documents 3 to 5) and is considered to be effective for many inflammatory, allergic, and immune related diseases. For example, in respiratory diseases, it is effective for asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, inflammatory airway disease, emphysema, adult respiratory distress syndrome (ARDS), etc.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • acute bronchitis acute bronchitis
  • chronic bronchitis chronic bronchitis
  • inflammatory airway disease emphysema
  • ARDS adult respiratory distress syndrome
  • Non-patent Document 6 Joint-related diseases are related to skin diseases such as rheumatism, osteoarthritis, acute arthritis, and chronic arthritis.
  • Diseases related to the gastrointestinal tract such as atopic dermatitis, psoriasis, seborrheic eczema, allergic contact eczema, etc.
  • Allergic rhinitis, chronic rhinitis, allergic conjunctivitis etc. are reported as diseases, and immune system related diseases are reported to be effective for transplant rejection, multiple sclerosis, AIDS, etc.
  • Non-patent Document 7 ⁇ 12).
  • PDE4 inhibition in bronchial smooth muscle relaxes smooth muscle, and this is also considered to be effective for respiratory diseases such as asthma and COPD.
  • PDE4 inhibitors may cause side effects such as vomiting as an undesirable effect.
  • Side effects such as nausea and nausea have been reported in clinical trials such as rolipram and silomilast.
  • One of the causes of these side effects is the selectivity between PDE4 isoforms.
  • Four isoforms (A, B, C, D) have been reported in PDE4, and lysoform B is involved in pharmacological actions such as anti-inflammatory effects, while lyoform D is associated with side effects such as vomiting and nausea. (Non-patent Document 13).
  • PDE4 inhibitors have been reported because they are expected to be effective against many diseases (Patent Documents 1 to 3), but currently reported PDE4 inhibitors are effective and have side effects. Satisfied in terms, not a spider! /.
  • Patent Document 1 W098Z45268 Publication
  • Patent Document 2 WO95Z01338
  • Patent Document 3 W099Z55696
  • Non-Patent Literature l Soderling, S. H. and Beavo, J. A., Curr. Opin. Cell. Biol, 12, pl74— 1 79, 2000
  • Non-Patent Document 2 Hetman, J. M., et al, Proc. Natl. Acad. Sci. U S A., 97, pl2891- 128 95, 2000
  • Non-patent document 3 Teixeira, MM, et al., Trends Pharmacol. Sci., 18, pl64-170, 1997
  • Non-patent document 4 Beavo, JA, et al., Trends Pharmacol. Sci., 11, pl50-155 , 1990
  • Non-patent literature 5 Nicholson, C. D "et al” Trends Pharmacol. Sci., 12, pl9-27, 1991
  • Non-patent literature 6 Lipworth, BJ, Lancet, 365, pl67-175, 2005
  • Non-Patent Document 7 Dyke, HJ and Montana, JG, Expert Opin.Investig. Drugs, 11, pi -13, 2002
  • Non-patent literature 8 Burnouf, C, et al., Curr. Pharm. Des., 8, pl255-1296, 2002
  • Non-patent literature 9 Banner, K. H. and Trevethick, M. A., Trends Pharmacol. Sci., 25, p4
  • Non-Patent Document 10 Rickards, K. J., et al "Vet. Immunol. ImmunopathoL, 98, pl53-165, 2004
  • Non-patent literature ll Sun, Y., et al "J. Immunol, 165, pl755-1761, 2000
  • Non-Patent Document 12 Dousa, M. K., et al., Clin. Nephrol, 47, pl87-189, 1997
  • Non-Patent Document 13 Lipworth, B. J., Lancet, 365, pl67-175, 2005
  • An object of the present invention is to provide a novel substance having a PDE4 activity inhibitory action. More specifically, it is an object of the present invention to provide a novel substance having excellent PDE4 activity inhibitory action and few side effects.
  • Ar 1 is a furyl group, Choi - group, Toriazoriru group, a thiazolyl group, Okisazo Lil group, or base indicates Nzochiazoriru group; Ar 1 may be substituted;
  • Ar 2 is - E—Ar GQ (Ar represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group or an alkylene group; Q represents a carboxy group, —CON (R 41 ) (R 42 ) (R 41 and R 42 may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aryl group.
  • R 41 and R 42 together form a 3- to 7-membered ring to represent a cyclic amine as N (R 41 ) (R 42 ), provided that when R 41 is a hydroxyl group, R 42 is A group other than a hydroxyl group), or —COOR 43 (R 43 represents an optionally substituted alkyl group or an optionally substituted aryl group)), E—Ar 21 —G 2 — GQ (E, Ar 21 , G, Q are as defined above; G 2 is one O, one S, one SO, one SO—, or one NR G21
  • R G21 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted acyl group, or an optionally substituted sulfonyl group).
  • Ar 2 may be substituted; R 1 and R 2 may be the same or different and each independently , A hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted group A good alkylthio group, substituted, may be an alkylsulfier group, or substituted !, may!
  • R 3 may be a hydrogen atom or substituted An alkyl group is shown. Or a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;
  • Ar 1 may be substituted, but the compound described in [A1] above, which is a [furyl group or a chael group], possible stereoisomers or racemates thereof, or pharmacological thereof Acceptable salts, hydrates, solvates, or prodrugs thereof;
  • Ar 1 is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, and a substituted
  • the compound according to the above [A1] or [A2] which may be substituted by one or a plurality of groups each independently selected from the group consisting of an acyl group] force, possible stereoisomers thereof, or Racemates, or pharmaceutically acceptable salts, hydrates, solvates thereof, or prodrugs thereof
  • [A ⁇ Ar 1 is independently selected from the group consisting of [halogen atom, optionally substituted alkyl group, optionally substituted V, alkoxy group, and optionally substituted, amino group].
  • the compound described in the above [A1] or [A2] its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof, water, Solvates, solvates, or prodrugs thereof;
  • [ASjAr 1 is [halogen atom, lower alkyl group, trifluoromethyl group, hydroxymethyl group, hydroxyethyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, —NH group, lower alkylamino group] Group, lower dialkylamino group, acylamino group,
  • Ar 1 may be substituted with one or more halogen atoms, but the compound according to the above [A1] or [A2], its possible stereoisomer or racemate, or its pharmacology Acceptable salts, hydrates, solvates, or prodrugs thereof;
  • Ar 1 is substituted by one or more halogen atoms, the compound according to the above [A1] or [A2], its possible stereoisomer or racemate, or pharmacologically acceptable Salts, hydrates, solvates, or prodrugs thereof;
  • AR 1 is a lower alkyl group, a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt or hydrate thereof , Solvates, or prodrugs thereof;
  • Ar 2 is substituted with one or more groups each independently selected from the group consisting of [hydroxyl group, halogen atom, optionally substituted alkyl group, and optionally substituted alkoxy group].
  • groups each independently selected from the group consisting of [hydroxyl group, halogen atom, optionally substituted alkyl group, and optionally substituted alkoxy group.
  • Ar 2 is [hydroxyl group, halogen atom, lower alkyl group, trifluoromethyl group, lower group
  • [ASSjAr 1 is a chael group
  • Ar 1 is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, I also, Amino groups and substituted, by also, Yogu Ar 2 optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar 2 GQ
  • Ar 21 is a benzene ring or a benzene ring substituted with one or more halogen atoms
  • E is a single bond
  • Q is a carboxy group, on Ar 2
  • Ar 1 is a chael group
  • Ar 1 is [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted alkylthio group, substituted Ar 2 which may be substituted by one or a plurality of groups each independently selected from the group consisting of an amino group and a substituted acyl group].
  • Ar 2 GQ Ar 21 is a benzene ring, E is a single bond, G is a methylene group, Q is a carboxy group, Ar 2 has no further substituents, and R 1 is a methyl group Or a ethyl group, R 2 is an aryl group, an ethyl group, or a hydroxymethyl group, and R 3 is a hydrogen atom, the possible stereoisomer or racemate thereof, or A pharmacologically acceptable salt, hydrate, solvate, or prodrug thereof; [ASSjAr 1 is a chael group, Ar 1 is a [halogen atom, optionally substituted alkyl, Group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted, optionally, amino group, and a substituted, optionally substituted, acyl group] each independently from the group May be substituted by one or more groups selected by Ar 2 is —E—Ar 2 GQ, Ar 21
  • R 1 is methyl group or Echiru group
  • R 2 is Ariru group
  • R 3 is a hydrogen atom, possible stereoisomers or racemates of that, Or a pharmacologically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;
  • [ASejAr 1 is a chael group
  • Ar 1 is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, I also, Amino groups and substituted, by also, Yogu Ar 2 optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar 2 GQ
  • Ar 21 is a benzene ring
  • E is a single bond
  • G is a methylene group
  • Q is a carboxy group
  • Ar 2 has no further substituents
  • R 1 is a methyl group Or an ethyl group
  • R 2 is an ethyl group
  • R 3 is a hydrogen atom, the compound according to [A1], its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof. Salts, hydrates, solvates, or prodrugs thereof;
  • [ASYjAr 1 is a chael group
  • Ar 1 is [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted alkylthio group, substituted, I also, Amino groups and substituted, by also, Yogu Ar 2 optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar 2 GQ, Ar 21 substituted with a benzene ring or one or more halogen atoms A benzene ring, E is a single bond, G force methylene group, Q is a carboxy group, no further substituent on Ar 2 , R 1 is a methyl group or an ethyl group, R A compound of the above-mentioned [A1], which is a 2- force S-hydroxymethyl group, and R 3 is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt, hydrate thereof, Solvates, or prodrugs
  • [ASSjAr 1 is a chael group
  • Ar 1 is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, I also, Amino groups and substituted, by also, Yogu Ar 2 optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar 2 GQ
  • Ar 21 is a benzene ring
  • E is a single bond
  • G is a methylene group
  • Q is a carboxy group
  • Ar 2 has no further substituents
  • R 1 is a methyl group Or an ethyl group
  • R 2 is a hydroxymethyl group
  • R 3 is a hydrogen atom, the compound according to [A1], a possible stereoisomer or racemate thereof, or a pharmacologically acceptable salt thereof.
  • [AS Ar 1 is a chael group
  • Ar 1 is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, , I even, Amino groups and substituted, by also, Yogu Ar 2 optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar 2 GQ
  • Ar 21 is a benzene ring substituted with one or more halogen atoms
  • E is a single bond
  • G is a methylene group
  • Q is a carboxy group, and is further placed on Ar 2
  • [ASC ⁇ Ar 1 is independently selected from the group consisting of [halogen atom, optionally substituted alkyl group, optionally substituted V, alkoxy group, and optionally substituted, amino group].
  • the compounds described in any one of the above [A1] to [A29], possible stereoisomers or racemates thereof, or pharmacologically thereof may be substituted with one or more groups selected from Acceptable salts, hydrates, solvates, or prodrugs thereof;
  • [A3 Ar 1 is [halogen atom, lower alkyl group, trifluoromethyl group, hydroxymethyl group, hydroxyethyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, —NH group, lower An alkylamino group, a lower dialkylamino group, an acylamino group,
  • [ASSjAr 1 is [halogen atom, lower alkyl group, trifluoromethyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, NH group, lower alkylamino group]
  • [A36] The compound according to any one of [A1] to [A35], a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof Or a medicament containing these prodrugs as active ingredients; [A37] The medicament according to [A36], which is a preventive and Z or therapeutic agent for inflammation;
  • [A42] A method for the prevention and Z or treatment of inflammation, the compound according to any one of the above [A1] to [A35], a possible stereoisomer or racemate thereof, or a pharmacologically acceptable method thereof.
  • a method for inhibiting PDE4 activity in vivo in mammals including humans comprising the compound according to any one of the above [A1] to [A35], its possible stereoisomer or racemate Administering an effective amount of the body, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof to a mammal, including a human;
  • Ar 1 is a furyl group, Choi - group, Toriazoriru group, a thiazolyl group, Okisazo Lil group, or base indicates Nzochiazoriru group; Ar 1 may be substituted;
  • Ar 2 is - E—Ar GQ (Ar 21 represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group, or an alkylene group; Q represents a carboxy group; , -CON (R 41 ) (R 42 ) (R 41 and R 42 may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or a substituted group.
  • R 41 and R 42 together form a 3- to 7-membered ring to represent a cyclic amine as N (R 41 ) (R 42 ), provided that R 41 And R 42 is a group other than a hydroxyl group), or —COOR 43 (R 43 represents an optionally substituted alkyl group or an optionally substituted aryl group).
  • Ar 2 may be substituted;
  • R 1 and R 2 may be the same or different and each independently represents hydrogen;
  • R 3 represents a hydrogen atom or an optionally substituted alkyl group; Indicates. Or a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;
  • Ar 1 may be substituted, and the compound according to [B1] above, which is a [furyl group or a phenyl group], a possible stereoisomer or racemate thereof, or a pharmacologically acceptable salt thereof. Salts, hydrates, solvates, or prodrugs thereof;
  • R 2 is a lower alkyl group [B1] - [B5], the compound according to any displacement, its Possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;
  • Ar 2 is substituted with one or more groups each independently selected from the group consisting of [hydroxyl group, halogen atom, optionally substituted alkyl group, and optionally substituted alkoxy group].
  • groups each independently selected from the group consisting of [hydroxyl group, halogen atom, optionally substituted alkyl group, and optionally substituted alkoxy group.
  • [BlSjAr 1 is a chael group
  • Ar 1 is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, and a substituted Ar 2 is —E—Ar 21 —G—Q
  • Ar 21 is a ben, which may be substituted by one or more groups each independently selected from the group that also has an acyl group] force.
  • Zen ring E is a single bond
  • G is a methylene group
  • Q is a carboxy group
  • R 1 is a methyl group or an ethyl group
  • R 3 is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt or hydrate thereof , Solvates, or prodrugs thereof;
  • [B21] A method for the prevention and Z or treatment of inflammation, the compound according to any one of the above [B1] to [B15], its possible stereoisomer or racemate, or a pharmacologically acceptable method thereof Administering a prophylactic and Z or therapeutically effective amount of a salt, hydrate, solvate, or prodrug thereof to a mammal, including a human;
  • a method for inhibiting PDE4 activity in vivo in mammals including humans comprising the compound according to any one of the above [B1] to [B15], its possible stereoisomer or Administering a racemate, or a pharmacologically acceptable salt, hydrate, solvate thereof, or an effective amount of a prodrug thereof to a mammal including a human;
  • Ar 1 represents a furyl group, a chael group, a triazolyl group, a thiazolyl group, an oxazolyl group, or a benzothiazolyl group; Ar 1 may be substituted; Ar 2 represents a carboxy group; Represents a thiophene group, a carboxyalkylphenol group, a carboxynaphthyl group, a carboxyalkylnaphthyl group, or a monocyclic aromatic heterocycle other than a virazolyl group; Ar 2 may be substituted; R 1 R 2 may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or a substituted group.
  • R 3 represents a hydrogen atom or an alkyl group. Or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;
  • Ar 2 is carboxyalkylnaphthyl A compound, a possible stereoisomer or racemate thereof, or a group, a carboxyphenol group, a carboxyalkyl group, or a [monocyclic aromatic heterocycle other than a virazolyl group], Pharmacologically acceptable salts, hydrates, solvates, or prodrugs thereof;
  • Ar 1 is substituted !, may be! /, Substituted with an alkoxy group !, the compounds according to the above [C1] to [C3], possible stereoisomers or racemates thereof, or Pharmacologically acceptable salts, hydrates, solvates, or prodrugs thereof; 5] The compound according to any one of the above [C1] to [C4], wherein 1 ⁇ is lower alkyl, its possible stereoisomer or racemate, or a pharmacologically acceptable salt or hydrate thereof Solvates, or prodrugs thereof;
  • R 2 is a lower alkyl group [C1] - [C6], compounds according to any displacement, possible stereoisomers or racemates of that or a pharmaceutically acceptable salt thereof, Hydrates, solvates, or prodrugs thereof;
  • [C15] A method for preventing and / or treating inflammation, comprising the above [C1] to [C9] A prophylactic and Z or therapeutically effective amount of the described compound, possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof; Comprising the step of administering to a mammal comprising: and
  • [C16] A method for inhibiting PDE4 activity in vivo in mammals including humans, the compound according to any one of the above [C1] to [C9], possible stereoisomers or racemates thereof, or A method comprising administering an effective amount of a pharmacologically acceptable salt, hydrate, solvate, or prodrug thereof to a mammal, including a human.
  • the compound of the present invention or a salt thereof exhibits a strong PDE4 inhibitory action in the living body of mammals including humans, and thus, for example, a medicament for prevention and Z or treatment of various diseases caused by inflammation. It is useful as an active ingredient.
  • the compound of the present invention or a salt thereof can be used as an active ingredient of a safe pharmaceutical with extremely low toxicity.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “lower” substituent means a substituent having up to 10 carbon atoms constituting the substituent, for example, a substituent having 1 to 6 carbon atoms. Preferred examples include substituents having 1 to 3 numbers.
  • Examples of the alkyl group include a saturated hydrocarbon group which is linear, branched, cyclic, or a combination thereof, and a lower alkyl group is preferable.
  • the lower alkyl group refers to an alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably an alkyl group having 1 to 3 carbon atoms.
  • Preferred examples of the alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group, and further includes 4 to 6 carbon atoms.
  • alkyl group n-butyl group, isobutyl group, s-butyl group, t-butyl group, Cyclobutyl, cyclopropylmethyl, n-pentyl, cyclopentyl, cyclopropylethyl, cyclobutylmethyl, n-hexyl, cyclohexyl, cyclopropylpropyl, cyclobutylethyl, or cyclopentylmethyl Groups and the like can be mentioned as suitable examples.
  • a methyl group, an ethyl group, an n-propyl group, or an isopropyl group is particularly preferable. Most preferably, the alkyl group includes a methyl group.
  • an ethyl group is mentioned as the most preferred alkyl group.
  • Examples of the alkenyl group include a lower alkenyl group containing one or more double bonds, and a lower alkenyl group containing one double bond is preferable.
  • the lower alkenyl group refers to an alkenyl group having 2 to 10 carbon atoms, and an alkenyl group having 2 to 4 carbon atoms is preferable, and an alkenyl group having 2 to 4 carbon atoms is particularly preferable.
  • Examples of the alkenyl group having 2 to 4 carbon atoms include a bur group, a allyl group, a propenyl group, a butylidene group, a but-1-enyl group, a but-2-enyl group, and a but-3-yl group.
  • alkyl group examples include pentylidene group, bent-1-ethyl group, pent-2-ethyl group, bent-3- Preferred examples include an enyl group or a bent-4-enyl group.
  • the alkenyl group is particularly preferably a vinyl group, more preferably a buyl group, a allyl group, or a probe group, or a allyl group, more preferably a allyl group.
  • Examples of the alkynyl group include a lower alkynyl group containing one or more triple bonds, and a lower alkyn group containing one triple bond is preferable.
  • the lower alkynyl group is preferably an alkynyl group having 2 to 5 carbon atoms.
  • ethynyl group, prop-1-yl group, prop-2-yl group, but-1-yl group, but-2-ynyl group, but-3-yl group Vent-1-yl group, bent-2-yl group, bent-3-yl group, or bent-4-yl group are preferable examples.
  • a -2-ynyl group or a -2-ynyl group is more preferred, and a propyl-2-ynyl group is more preferred, which is more preferably a prop-2-ynyl group.
  • the alkylene group can be exemplified by a divalent residue obtained by removing any one hydrogen atom from the alkyl group described above, and is linear, branched, cyclic, or those And a saturated hydrocarbon divalent group, and a lower alkylene group is preferred.
  • a lower alkylene group is an alkylene group having 1 to 10 carbon atoms, An alkylene group having 1 to 6 carbon atoms is preferred, and an alkylene group having 1 to 3 carbon atoms is more preferred, and an alkylene group having 1 carbon atom is more preferred.
  • Examples of the alkylene group having 1 carbon atom include a methylene group, and preferable examples of the alkylene group having 2 to 3 carbon atoms include an ethylene group, an n-propylene group, an isopropylene group, and a cyclopropylene group.
  • suitable alkylene groups having 4 to 6 carbon atoms any one hydrogen atom may be removed from the groups listed in the above examples of suitable alkyl groups having 4 to 6 carbon atoms. Bivalent residues that can be produced.
  • a methylene group, an ethylene group, an n-propylene group, or an isopropylene group is particularly preferable.
  • the most preferred alkylene group is a methylene group. There is another embodiment in which an ethylene group is mentioned as the most preferable alkylene group.
  • Examples of the alkellene group include divalent residues formed by removing any one hydrogen atom from the alkenyl group described above, and include one or two or more double groups. And a lower alkylene group containing a bond, and a lower alkylene group containing one double bond is preferred.
  • the lower alkylene group refers to an alkylene group having 2 to 10 carbon atoms, and an alkylene group having 2 to 4 carbon atoms is preferable to an alkylene group having 2 to 5 carbon atoms. Is particularly preferred.
  • Examples of the alkylene group having 2 to 4 carbon atoms include a beylene group, a pavemental group, a but-1-erene group, a but-2-erene group, and a but-3-ene group. -Len group and the like are listed as preferred examples. Furthermore, as the alkylene group having 5 carbon atoms, any one hydrogen atom from the groups listed in the examples of the preferred alkenyl groups having 5 carbon atoms is used. Examples of divalent residues that can be formed by removing.
  • the alkylene group is particularly preferably a vinylene group or a vinylene group, more preferably a propylene group.
  • Examples of the alkoxy group include a saturated alkyl ether group which is linear, branched, cyclic, or a combination thereof, and a lower alkoxy group is preferable.
  • a lower alkoxy group an alkoxy group having 1 to 6 carbon atoms is exemplified.
  • An alkoxy group having 1 to 4 carbon atoms is preferable.
  • Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, n_propoxy group, isopropoxy group, cyclopropoxy group, n-butoxy group, isobutoxy group, s -butoxy group, and t -butoxy group.
  • Cyclobutoxy group, cyclopropyl methoxy group and the like are preferable examples.
  • alkoxy group having 5 or 6 carbon atoms n- Pentyloxy, cyclopentyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, n-hexyloxy, cyclohexyloxy, cyclopropylpropyloxy, cyclobutylethyloxy, or cyclopentylmethyl
  • a suitable example is a silicon group.
  • the alkylthio group includes a saturated alkylthioether group which is linear, branched, cyclic, or a combination thereof, and a lower alkylthio group is preferred.
  • a lower alkylthio group an alkylthio group having 1 to 4 carbon atoms is preferable.
  • Examples of the alkoxycarbo yl group include groups having a carbonyl group at the end of the above alkoxy group, and a lower alkoxy carbo yl group is preferable.
  • the lower alkoxy carbo group includes a group having a carbo group attached to the end of an alkoxy group having 1 to 6 carbon atoms.
  • a carbo yl group is attached to the end of an alkoxy group having 1 to 4 carbon atoms. The group attached is preferred.
  • Specific examples include a methoxycarbon group, an ethoxycarbon group, an n-propoxy carbonyl carbonyl group, an isopropoxy carbonyl carbonyl group, a cyclopropoxy carbonyl group, an n-butoxy carbonyl group, and an isobutoxy carbonyl group.
  • Preferred examples include a s-butoxycarbonyl group, a t-butoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopropylmethoxycarbonyl group, and the like.
  • alkoxy group examples include an alkenyl ether group having an oxygen atom at the end of the alkenyl group, and a lower alkenyl oxy group containing one or more double bonds is preferred. A lower alkenyloxy group containing one double bond is more preferred.
  • the lower alkoxy group an alkoxy group having 2 to 4 carbon atoms is preferred. Specifically, a vinyloxy group, an aryloxy group, or a propenyloxy group is preferable, and an aryloxy group is particularly preferable.
  • Examples of the alkarylthio group include an alkenyl thioether group having a sulfur atom attached to the terminal of the alkenyl group, and the like, and a lower alkenyl group containing one or more double bonds.
  • a dialkylthio group is preferred
  • a lower alkylthio group containing one double bond is more preferred.
  • the lower alkthio group is preferably an alkthio group having 2 to 4 carbon atoms.
  • a arylthio group, in which a berylthio group, a arylthio group, or a propenylthio group is preferable, is particularly preferable.
  • the acyl group is preferably, for example, an alkanoyl group or an aryl carbonate group, and is exemplified as an example.
  • a lower alkanoyl group in which an alkanoyl group is preferred is more preferred.
  • the alkanol group includes a saturated alkylcarbonyl group that is linear, branched, cyclic, or a combination thereof.
  • the alkyl moiety may contain one or more unsaturated bonds. Good.
  • an acyl group having 2 to 5 carbon atoms is preferred.
  • acetyl group, propanol group, butanol group, 2_methyl propanol group, cyclopropyl carbonyl group, pentanoyl group, 3-methyl butanol group, 2,2-dimethyl propanol group, or cyclobutyl carbonyl group, etc. Is a suitable example.
  • acyloxy group for example, an alkanoyloxy group (alkylcarboxyloxy group) or an allylcarbonyloxy group can be mentioned as a preferred example, and a lower alkanoyloxy group preferred by an alkanoyloxy group is further exemplified. preferable.
  • the alkyl part of the alkanoyloxy group may contain one or more unsaturated bonds.
  • an acyloxy group having 2 to 5 carbon atoms is preferable.
  • a suitable example is a propanoyloxy group or a cyclobutylcarboxoxy group.
  • Preferred examples of the alkyl sulfier group include lower alkyl sulfier groups.
  • the lower alkylsulfur group an alkylsulfur group having 1 to 4 carbon atoms is preferable. Specifically, methylsulfyl group, ethylsulfuryl group, n-propylsulfuryl group, isopropylsulfuryl group, cyclopropylsulfuryl group, n-butylsulfuryl group, isobutylsulfuryl group, s-butyl Sulfiel group, t-butylsulfier group, cycloptylsulfier group, or cyclopropylmethyls
  • a suitable example is a luffyl group.
  • alkylsulfol group examples include lower alkylsulfol groups.
  • the lower alkyl sulfo group an alkyl sulfo group having 1 to 4 carbon atoms is preferable.
  • Preferred examples of the alkyl-strength rubamoyl group include lower alkyl-strength rubamoyl groups.
  • As the lower alkyl strength rubamoyl group an alkyl strength rubamoyl group having 1 to 4 carbon atoms is preferable.
  • a suitable example is a rucarbamoyl group, a cycloptylcarbamoyl group, or a cyclopropylmethylcarbamoyl group.
  • amino groups include NH groups.
  • aryl rings include monocyclic aromatic rings and condensed polycyclic aromatic rings.
  • the aryl ring may be a hydrocarbon ring, but as a ring constituent atom other than a carbon atom, for example, a nitrogen atom, a sulfur atom, and one or more heteroatoms selected from the group power of oxygen nuclear power are selected.
  • One or more, for example, 1 to 3 may be included.
  • Examples of the monocyclic aromatic ring include a monocyclic aromatic hydrocarbon or a monocyclic aromatic heterocycle containing one or more heteroatoms.
  • a monocyclic aromatic hydrocarbon includes a benzene ring.
  • Monocyclic aromatic heterocycles include 5- or 6-membered aromatic heterocycles containing one or more heteroatoms.
  • 5- or 6-membered aromatic heterocycle examples include thiophene, pyridine, furan, thiazole, oxazole, azole, pyrazine, pyrimidine, pyrrole, imidazole, pyridazine, isothiazole, isoxazole, 1, Suitable examples include 2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and furazane.
  • Examples of the condensed polycyclic aromatic ring include condensed polycyclic aromatic hydrocarbons, condensed polycyclic aromatic heterocycles containing one or more heteroatoms, and the like.
  • condensed polycyclic aromatic hydrocarbon examples include, for example, a condensed polycyclic having 9 to 14 carbon atoms, that is, a bicyclic or tricyclic aromatic hydrocarbon. Specific examples include naphthalene, indene, Fluorene, anthracene or the like is a suitable example.
  • the condensed polycyclic aromatic heterocycle includes, for example, a 9 to 14-membered, preferably 9- or 10-membered condensed polycyclic aromatic heterocycle containing 1 or more heteroatoms, for example 1 to 4 heteroatoms.
  • Benzfuran benzothiophene, benzimidazole, benzoxazole, benzothiazonole, benzisothiazole, naphtho [2,3-b] thiophene
  • quinoline isoquinoline, indole, quinoxaline, phenanthridine
  • phenothiazine phenoxazine, phthalazine, naphthyridine, quinazoline, cinnoline, carbazole, 13 carboline, atalidine, phenazine, phthalimide, and thixanthene.
  • the aryl group includes, for example, a monocyclic aromatic group or a condensed polycyclic aromatic group, and is a monovalent aromatic group formed by removing any one hydrogen atom from the aryl ring described above. Residues can be exemplified.
  • Examples of the monocyclic aromatic group include monovalent residues formed by removing any one hydrogen atom from a monocyclic aromatic ring.
  • Specific examples of the monocyclic aromatic group include a phenyl group, a phenyl group (2- or 3-phenyl group), a pyridyl group (2-, 3- or 4-pyridyl group), and a furyl group (2- or 3-furyl group), thiazolyl group (2-, 4- or 5-thiazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group), pyrazolyl group (1-, 3- or 4-pyrazolyl group) 2-birazinyl group, pyrimidyl group (2-, 4- or 5-pyrimidyl group), pyrrolyl group (1-, 2- or 3-pyrrolyl group), imidazolyl group (1-, 2- or 4) -Imidazolyl group), pyridazil group (3- or 4-pyridazyl group), 3-isothi
  • the condensed polycyclic aromatic group is a monovalent group formed by removing any one hydrogen atom from a condensed polycyclic aromatic ring having 2 to 4, preferably 2 or 3 ring forces. Of the residues
  • condensed polycyclic aromatic group examples include 1-naphthyl group, 2-naphthyl group, 2-indene Group, 2-anthryl group, quinolyl group (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-, 4-, 5 -, 6-, 7- or 8-isoquinolyl group), indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group), isoindolyl group (1-, 2-, 4- or 5-isoindolyl group), phthaladyl group (1-, 5- or 6-phthaladyl group), quinoxalinyl group (2-, 3- or 5-quinoxalyl group), benzofuryl group (2-, 3-, 4-, 5- or 6-benzofulleryl group), benzothiazolyl group (2-, 4-, 5- or 6-benzothiazolyl group), benzimidazolyl group (1-
  • substituents in the alkyl group examples include a hydroxyl group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, and an alkoxy group optionally substituted with one or more halogen atoms.
  • the number of substituents in an optionally substituted group is not particularly limited, but is usually 1 to several. 1 is preferable. In another embodiment, when the substituent in the optionally substituted group is a halogen atom, the number of the substituent is preferably 1 to 3.
  • the alkyl group which may be substituted preferred examples of the alkyl group described above are preferable.
  • the optionally substituted alkyl group includes the above-mentioned substituents.
  • Preferred is an alkyl group substituted by a suitable substituent in the alkyl group.
  • Examples of the alkyl group which may be substituted include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, and cyclobutyl.
  • Preferred examples include cyclopentylmethyl group, trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group, methoxymethyl group, or 2-methoxyethyl group, and more preferable examples include methyl group and ethyl group.
  • Substituted in the alkenyl group, substituted !, or the substituent in the alkyl group may be substituted as described above! /, Same as the substituent in the alkyl group.
  • alkenyl group may be substituted, the preferred examples of the alkenyl group described above are preferably substituted.
  • the alkynyl group which may be substituted is preferably the above-described alkenyl group. A preferred example is preferred.
  • the substituent in the alkoxy group may be the same as the substituent in the alkyl group, which may be substituted.
  • the alkoxy group may be substituted, but preferred examples of the alkoxy group described above are preferred.
  • the alkoxy group is preferably a suitable alkoxy group substituted by a suitable substituent in the alkoxy group as described above. Better ,.
  • methoxy group, ethoxy group, trifluoromethoxy group, or 2-methoxyethoxy group is mentioned as a preferred example, more preferred examples include methoxy group, ethoxy group, trifluoromethoxy group, or 2-methoxyethoxy group, and particularly preferred examples include methoxy group or ethoxy group, A most preferred example is a methoxy group.
  • the substituent in the optionally substituted alkylthio group is the same as the above-described substituent in the substituted V or alkyl group.
  • the alkylthio group is preferably the above-mentioned preferred example of the alkylthio group. Specifically, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, isobutylthio group, s-butylthio group, t-butylthio group, cycloptylthio group, cyclopropyl
  • a methylthio group, a 2-methoxyethylthio group or the like is a preferred example, and a more preferred example is a methylthio group, an ethylthio group, or a 2-methoxyethylthio group, and a particularly preferred example is methylthio group.
  • Group, or an ethylthio group isopropylthio group.
  • the above-described substituted V may be one having a carbonyl group attached to the terminal of the alkoxy group. It is done. Specifically, methoxycarbon group, ethoxycarbon group, n-propoxycarbol group, isopropoxycanenoboninole group, cyclopropoxynoleboninore group, n-butoxycanonolonol group, iso A butoxycarbol group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopropylmethoxycarbonyl group, and the like are given as preferred examples. Group, an ethoxycarbo ol group, or a t-butoxy carbo ol group, and particularly preferred examples include a methoxy carbo ol group or an ethoxy carbo ol group.
  • amino group which may be substituted includes NH group, alkylamino group, dialkyla
  • acylamino group acyl (alkyl) amino group, alkylsulfolumino group, alkylsulfo (alkyl) amino group, alkylamino group optionally substituted with one or more halogen atoms, one or more halogens
  • alkylsulfoamino group optionally substituted with an atom
  • alkylsulfoamino group optionally substituted with one or more halogen atoms.
  • the optionally substituted amino group includes 1 or 2 substituted !, may!
  • arylmolybamino group may be substituted Varylthiolamino group, substituted !, may be alkyloxycarbolamino group, or may be substituted A xylcarbolumino group may also be mentioned.
  • the alkylamino group is preferably a lower alkylamino group, and examples thereof include.
  • the lower alkylamino group is preferably an alkylamino group having 1 to 4 carbon atoms. Specifically, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, n -butylamino group, isobutylamino group, s-butylamino group, t-butylamino group, cyclobutylamino group Group, cyclopropylmethylamino group and the like are preferable examples, and more preferable examples include methylamino group, ethylamino group, and isopropylamino group, and particularly preferable examples include methylamino group and ethylamino group. It is done.
  • dialkylamino group examples include an amino group substituted with the same or different alkyl group, and a lower dialkylamino group is usually preferred.
  • a lower dialkylamino group an amino group substituted with an alkyl having 1 to 4 carbon atoms is preferable.
  • Preferred examples include amino group, isobutyl (methyl) amino group, s-butyl (methyl) amino group, t-butyl (methyl) amino group, cyclobutyl (methyl) amino group, and cyclopropylmethyl (methyl) amino group. More preferred examples include a dimethylamino group, a dimethylamino group, or an ethyl (methyl) amino group, and particularly preferred examples include a dimethylamino group or a jetylamino group.
  • Examples of the isylamino group include an amino group substituted with the above-mentioned acyl group, and preferred examples of the acyl group are the same as those described above. Specific examples include an acetylamino group, a propanoylamino group, a butanoylamino group, a 2-methylpropanoylamino group, a cyclopropylcarbono group. Preferred examples include a boramino group, a pentanolumino group, a 3-methylbutanoylamino group, a 2,2-dimethylpropanolumino group, and a cyclobutylcarbolamino group.
  • An acetylamino group, a propanoylamino group, or a 2,2-dimethylpropanoylamino group and particularly preferred examples include an acetylamino group or a propanoylamino group.
  • Examples of the acyl (alkyl) amino group include one asil group and an amino group substituted with one alkyl group at the same time.
  • Preferred examples of the acyl group and the alkyl group include: It is the same.
  • Preferred examples include methyl (pentanoyl) amino group, methyl (3-methylbutanol) amino group, 2,2-dimethylpropanol (methyl) amino group, and cycloptylcarbonyl (methyl) amino group, and more preferred.
  • Examples include a acetyl (methyl) amino group or a methyl (propanol) amino group, and particularly preferably a acetyl (methyl) amino group.
  • alkylsulfoamino group examples include an amino group substituted with the alkylsulfo group.
  • Preferred examples of the alkylsulfo group are the same as those described above. Specifically, methyl sulfo-lamino group, ethyl sulfo-lamino group, n-propyl sulforamino group, isopropyl sulfo-lamino group, cyclopropyl sulfo-lamino group, n-butyl sulfo-lamino group, isobutyl sulfo-lamino group, Suitable examples include s-butylsulfo-amino group, t-butylsulfo-lumino group, cyclobutylsulfo-lumino group, and cyclopropylmethylsulfo-lumino group, and more preferably methylsulfo-lumino group,
  • the alkylsulfo (alkyl) amino group includes one alkylsulfo group and an amino group substituted simultaneously with one alkyl group. Preferred examples are the same as described above. Specifically, methyl (methylsulfol) amino group, ethylsulfol (methyl) amino group, methyl (n-propylsulfurate) Hol) amino group, isopropylsulfol (methyl) amino group, cyclopropylsulfol
  • alkylamino group optionally substituted with one or more halogen atoms examples include alkylamino groups in which one or more hydrogen atoms of the above alkylamino groups are substituted with any kind of halogen atoms.
  • An alkylamino group having 1 to 4 carbon atoms optionally substituted with one or more halogen atoms is preferred.
  • the halogen atoms may be the same or different.
  • Specific examples include a chloromethylamino group, a dichloromethylamino group, a trichloromethylamino group, a fluoromethylamino group, a difluoromethylamino group, a trifluoromethylamino group, and a fluorethylamino group.
  • a 2,2,2-trifluoroethylamino group and the like are preferable examples, more preferably a trifluoromethylamino group, or a 2,2,2-trifluoroethylamino group, Particularly preferred is a trifluoromethylamino group.
  • the alkylsulfo-lumino group optionally substituted with one or more halogen atoms includes an alkylsulfonyl in which one or more hydrogen atoms of the alkylsulfo-lumino group are substituted with any kind of halogen atom
  • the amino group include an alkylsulfonylamino group having 1 to 4 carbon atoms optionally substituted with one or more halogen atoms.
  • the halogen atoms may be the same or different. Specific examples include a trifluoromethylsulfo-lumino group.
  • alkylsulfol (alkyl) amino group optionally substituted with one or more halogen atoms one or more hydrogen atoms of the aforementioned alkylsulfol (alkyl) amino group may be of any kind.
  • alkylsulfol (alkyl) amino groups substituted with halogen atoms usually an alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms.
  • Killsulfol (alkyl) amino groups are preferred.
  • the halogen atoms may be the same or different. Specific examples include a methyl (trifluoromethylsulfo) amino group.
  • a preferred example is preferred.
  • the amino group substituted with one or two optionally substituted alkyl groups may be substituted as described above, or may be substituted with a suitable substituent in the alkyl group. Or, an amino group substituted with two alkyl groups is preferred.
  • the amino group substituted with one or two optionally substituted alkyl groups may be substituted with a suitable substituent in the alkyl group as described above. Preferred is an amino group substituted with one alkyl group. In still another embodiment, the amino group substituted with one or two optionally substituted alkyl groups may be substituted as described above, or may be substituted with a suitable substituent in the alkyl group. U, preferably an amino group substituted with one alkyl group and one lower alkyl group.
  • a dimethylamino group, a jetylamino group, an ethylmethylamino group, a methoxyethylamino group, a methyl (methoxyethyl) amino group, a hydroxyethylamino group, or a hydroxyethyl (methyl) amino group is preferred.
  • Particularly preferred examples include dimethylamino group, methoxyethylamino group, and hydroxyethylamino group.
  • 1 or 2 substituted may be substituted in an amino group substituted with an aryl group !, or may be an aryl group, which will be described later, may be substituted as an aryl group. Preferred examples are preferred.
  • an amino group substituted with one or two optionally substituted aryl groups an amino group substituted with one preferred example of the aforementioned aryl group is preferred! /.
  • a phenylamino group As an example, mention may be made of a phenylamino group.
  • Substituted, aryl, and substituted ! may! /, Amino groups substituted with alkyl groups, substituted, and preferred aryl groups, for example Similarly, the substituent in the alkyl group which may be substituted is the above-described substituted group. ! However, preferred examples of alkyl groups are preferred. Substituted !, may, or aryl groups and may be substituted, alkylamino groups substituted with alkyl groups include substituted! Alkylamino groups substituted with aryl groups. Is preferred. Particular preference is given to the methyl (phenyl) amino group as an example.
  • amino group substituted with an acyl group include an acetylylamino group, a propanoylamino group, a butanoylamino group, and a phenylacetylamino group.
  • Substituted may be an amino group substituted with an alkylsulfol group, and substituted
  • the substituent of the alkyl sulfo group in the alkyl amino group substituted with the alkyl sulfo group may be substituted as described later !, may! /, The substitution in the alkyl sulfo group.
  • Preferred examples of groups are preferred.
  • Particularly preferable examples of the amino group substituted and substituted with an alkylsulfol group include a methanesulfonylamino group, a trifluoromethanesulfo-lumino group, a methyl (methanesulfol) amino group, or Mention may be made of methyl (trifluoromethanesulfol) amino group.
  • the substituent in the alkyl strength ruberamoylamino group may be substituted when the substitution position of the substituent is on the alkyl group, the substituent may be substituted as described above. Preferred examples of the substituent are preferred, or when the substitution position of the substituent is on the nitrogen atom of the alkyl strength ruberamoylamino group, the substituent is a preferred example of the alkyl group which may be substituted as described above. Or a hydrogen atom is preferred. Replaced! However, there may be one or more substituents in the alkyl strength ruberamoylamino group, and each may be independently the same or different.
  • alkylcarbamoylamino group a group in which one substituent exists and the substitution position is on the alkyl group is preferable. Particularly preferred examples include ethylcarbamoylamino group and methylcarbamoylamino group.
  • the alkylthio group may be a ruberamoylamino group! It is the same as the respective cases corresponding to the examples of the alkyl power ruberamoylamino group.
  • Particularly preferred examples include an ethylthio-powered ruberamoylamino group or a methylthio-powered ruberamoylamino group.
  • the alkyloxycarbolamino group is preferably preferred! /, And examples thereof are the same as in the respective cases corresponding to the examples of the alkyl power ruberamoylamino group.
  • Particularly preferred examples include an ethoxycarbo-amino group or a methoxycarbo-amino group.
  • the optionally substituted allyl force ruberamoylamino group is preferably a group that is present as a substituent on the allyl force ruberamoylamino group and the substitution position is on the allyl group.
  • a particularly preferred example is an optionally substituted phenylcarbamoylamino group.
  • the arylo-powered ruberamoylamino group Even if it is substituted, it is preferable to use the arylo-powered ruberamoylamino group, and examples thereof are the same as those in the respective examples corresponding to the above-mentioned examples of the arylo-powered ruberamoylamino group.
  • the aryloxycarbo-lamino groups are preferred! /, And examples thereof are the same as those in the respective cases corresponding to the above-described examples of the aryl force ruberamoylamino groups.
  • Particular preference is given to mention, as an example, a substituted thiol-molybamoylamino group.
  • the substituent in the acyl group may be the same force as the substituent in the alkyl group that may be substituted, in particular, one or more halogen atoms are preferred. Yes.
  • the optionally substituted acyl group is preferably an acyl group optionally substituted with one or more halogen atoms. From 2 carbon atoms optionally substituted with one or more halogen atoms. An acyl group of 5 is preferred. When substituted with two or more halogen atoms, the halogen atoms may be the same or different. A suitable example is a trifluoroacetyl group.
  • the acyl group includes an acetyl group, a propanol group, a butanol group, a 2-methyl propanol group, a cyclopropyl carbonyl group, a pentanoyl group, and a 3-methyl butanol group.
  • Group, 2,2-dimethylpropanol group, cyclobutylcarbol group, etc. are preferred, more preferably acetyl group, propanol group, or 2,2-dimethylpropanol group, particularly preferably acetyl group.
  • Group or a propanol group is preferred, more preferably acetyl group, propanol group, or 2,2-dimethylpropanol group.
  • the above-mentioned substituted! Is preferably one having an oxygen atom attached to the terminal of the acyl group.
  • a suitable example is a trifluoroacetoxy group.
  • substituted! May be used.
  • the acyloxy group include acetoxy group, propanoyloxy group, butanoyloxy group, 2-methylpropanoyloxy group, cyclopropyl group sulfonyloxy group, and pentanoyloxy group.
  • 3-methylbutanoyloxy group, 2,2-dimethylpropanoyloxy group, cyclobutylcarboxoxy group, etc. are more preferable, acetooxy group, propanoloxy group, or 2 1,2-dimethylpropanoyloxy group, particularly preferably acetooxy group or propanoyloxy group.
  • the substituent in the optionally substituted alkylsulfier group is the same force as the substituent in the above optionally substituted alkyl group, and particularly preferably one or more halogen atoms.
  • the optionally substituted alkylsulfiel group is preferably an alkylsulfinyl group optionally substituted with one or more halogen atoms.
  • the number of carbon atoms arbitrarily substituted with one or more halogen atoms is preferred. 1 to 4 alkylsulfier groups are preferred!
  • the halogen atoms may be the same or different.
  • a preferred example is a trifluoromethanesulfinyl group.
  • alkylsulfur group examples include methylsulfyl group, ethylsulfuryl group, n-propylsulfuryl group, isopropylsulfuryl group.
  • cyclopropylsulfuryl group n-butylsulfuryl group, isobutylsulfuryl group, s-butylsulfuryl group, t-butylsulfuryl group, cycloptylsulfuryl group, or cyclopropylmethylsulfuryl group More preferred examples of which are preferred include methylsulfyl group or ethylsulfuryl group, and particularly preferred is methylsulfuryl group.
  • the substituent in the optionally substituted alkylsulfonyl group is the same force as the substituent in the above optionally substituted alkyl group, and particularly preferably one or more halogen atoms.
  • the substituted alkylsulfonyl group is preferably an alkylsulfonyl group optionally substituted with one or more halogen atoms.
  • the number of carbon atoms optionally substituted with one or more halogen atoms is 1-4.
  • the alkylsulfol group is preferred! When two or more halogen atoms are substituted, the halogen atoms may be the same or different.
  • a suitable example is a trifluoromethanesulfonyl group.
  • the alkylsulfol group may be substituted !, methylsulfol group, ethylsulfol group, n-propylsulfol group, isopropylsulfol group, cyclopropyl group.
  • a sulfo group, an n-butyl sulfo group, an isobutyl sulfo group, an s-butyl sulfonyl group, a t-butyl sulfo group, a cyclobutyl sulfo group, or a cyclopropyl methyl sulfonyl group is preferred. More preferable examples include a methylsulfol group or an ethylsulfol group, and a methylsulfol group is particularly preferable.
  • Substituted in the aryl ring may be substituted, and the substituent in the aryl group may be a hydroxyl group, an alkyl group optionally substituted with one or more hydroxyl groups, Halogen atom, alkyl group optionally substituted with one or more halogen atoms, alkoxy group, alkylthio group, alkoxy group optionally substituted with one or more halogen atoms
  • Substituted alkylamino groups, acylamino groups, acyl (alkyl) amino groups, alkylsulfo-amino groups, alkyls Preferred are a sulfonyl (alkyl) amino group, an alkyl sulfo-lamino group optionally substituted with one or more halogen atoms, or an alkyl sulfonyl (alkyl) amino group optionally substituted with one or more halogen atoms. Take as an example.
  • Substituted ! may be an aryl ring, may be substituted !, or an aryl group may be the aforementioned aryl group or aryl group having the above-mentioned substituents.
  • Preferred examples include a reel ring and an aryl group.
  • Ar 1 represents a furyl group, a phenyl group, a triazolyl group, a thiazolyl group, an oxazolyl group, or a benzothiazolyl group, and Ar 1 may be substituted.
  • Ar 1 is substituted, even I, being a tooth replacement, Nakutemoyo, but, Ar 1 is substituted!, Rukoto is good Masui.
  • Ar 1 is particularly preferably a furyl group, a chenyl group, or a thiazolyl group, more preferably a furyl group or a chenyl group, and even more preferably a chenyl group.
  • Ar1 -9 A -10 Ar1 -11 Ar1 -12 A -13 A -14 is preferred
  • Ar1-4 Ar1-5 Ar1-8 is particularly preferred.
  • Ar1-23 Ar1-24 AM -25 A -26 Ar1-27 A -28 is preferred,
  • Arl-19 Is particularly preferred.
  • Ar1-31 Ar 32 Ar1-38 Ar1-39 Ar 40 A ⁇ 1 is more preferred
  • AM-47 Ar1-48 Ar1, 49 A -51 are particularly preferred.
  • Ar 68 A -70 AM -71 is particularly preferred.
  • the substituent is preferably a halogen atom, a hydroxyl group, Group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group.
  • An optionally substituted alkylsulfol group, an optionally substituted aryl group, —CON (RU) (R 12 ) (R 11 and R 12 may be the same or different, and each independently.
  • a hydrogen atom, an optionally substituted alkyl group, or a substituted may represent an aryl group, or R 11 and R 12 together form a 3- to 7-membered ring to form an NR 11 ) (R 12 ) represents a cyclic amine.
  • R 14 may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, or R 13 and R 14 Together form a 3- to 7-membered ring, and N (R 13 ) (R 14 ) represents a cyclic amine. ) Is any one or more groups selected from the group consisting of 1) or 2 groups, more preferably 1 group. In another embodiment, two groups are more preferable. When Ar 1 is substituted, the substituent is more preferably a halogen atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkoxy group, or optionally substituted.
  • the substituent When Ar 1 is substituted, the substituent includes: a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted Preferred is an amino group which may be substituted, and any group selected from the group which may be substituted or may also be an acyl group. There are also embodiments.
  • the substituent is a group consisting of [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted amino group]. There is another embodiment in which any group selected is more preferable.
  • Ar 1 when Ar 1 is substituted, as the substituent, [halogen atom, optionally substituted alkyl group, substituted or optionally alkoxy group] any group selected from the group consisting of There are other preferred embodiments.
  • the substituent is particularly preferably an optionally substituted alkoxy group.
  • Ar 1 when Ar 1 is substituted, there is another embodiment in which an amino group which may be substituted is particularly preferable as the substituent.
  • the substituent in Ar 1 is substituted or an amino group, it is not particularly limited as long as it is an amino group as described above, but it is not particularly limited, but —NH group, alkylamino group, dialkylamino group
  • an acylamino group an acyl (alkyl) amino group, an alkylsulfolumino group, an alkylsulfo (alkyl) amino group, an alkylamino group optionally substituted with one or more halogen atoms, and one or more halogens
  • An alkylsulfo-amino group optionally substituted with an atom or an alkylsulfo (alkyl) amino group optionally substituted with one or more halogen atoms is preferred and Ar 1 is substituted
  • CON (R 11 ) (R 12 ) R 11 and R 12 are as defined above) is particularly preferable as the substituent.
  • a halogen atom is particularly preferable as the substituent.
  • the halogen atom is particularly preferably bromine, preferably fluorine, chlorine or bromine.
  • chlorine or fluorine is preferred as the halogen atom.
  • chlorine is preferred as the halogen atom, and there is another embodiment in which fluorine is further preferred.
  • the substituents may be the same or different.
  • a particularly preferred combination of the above is a case where Ar 1 is a chaer group and is substituted with one halogen atom, and has the above-mentioned Arl-19 bonding mode.
  • Ar 2 represents E—Ar 21 —GQ (Ar 21 represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group, or an alkene group; and Q represents a carboxy group.
  • Group, CON (R 41 ) (R 42 ) (R 41 and R 42 may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or a substituted group; However, it may be an aryl group, or R 41 and R 42 together form a 3- to 7-membered ring to represent a cyclic amine as N (R 41 ) (R 42 ).
  • R 41 is a hydroxyl group
  • R 42 is a group other than a hydroxyl group.
  • Or —COOR 43 R 43 represents an optionally substituted alkyl group or an optionally substituted aryl group).
  • -E-Ar 21 -G 2 -G- Q E, Ar 21 , G, Q are as defined above, G 2 is —O, S—, SO—, —SO—,
  • R 21 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted acyl group, or an optionally substituted sulfol group).
  • Ar 2 may be substituted.
  • Ar 2 one as E-Ar 21 - GQ, one E-Ar 21 - G 2 -GQ , or [monocyclic aromatic heterocyclic ring other than Birazorinore radical can be mentioned, E- Ar 21 - GQ or one E —Ar 21 —G 2 —G —Q is preferred, and E—Ar 21 —GQ is more preferred. Further, E—Ar 21 —G 2 -G—Q is more preferred, and there is another embodiment.
  • Ar 2 is substituted !, may! /, And is substituted !, and may not be !, but Ar 2 is preferably substituted! There is also another embodiment in which substitution is preferred.
  • the substituent is preferably a halogen atom, a hydroxyl group, a cyan group, a nitro group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, An optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, and an optionally substituted alkoxy carbo group.
  • An optionally substituted acyl group, a substituted may be an alkylsulfier group, a substituted !, may!
  • R 13 and R 14 may be the same or different, and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group. Or R 13 and R 14 together form a 3- to 7-membered ring, and N (R 13 ) (R 14 ) represents a cyclic amine.) Any one or more selected from the group consisting of Group, more preferably halogen An atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, an optionally substituted Alkoxycarbonyl group, optionally substituted acyl group, optionally substituted alkylsulfonyl group, optionally substituted aryl group, —CO
  • R 14 is as defined above), more preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group.
  • the amino group may be any one or more groups selected from the group consisting of When Ar 2 is substituted, the substituent is particularly preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group. .
  • Ar 2 is one or more groups selected from the group consisting of [hydroxyl group, halogen atom, substituted, alkyl group, and substituted !, may! /, Alkoxy group]. There is another embodiment in which it is particularly preferably substituted by.
  • the halogen atom is particularly preferably bromine, preferably fluorine, chlorine or bromine.
  • chlorine or fluorine is preferred as the halogen atom.
  • chlorine is preferable as the halogen atom
  • fluorine is more preferable.
  • Ar 2 is substituted with a plurality of substituents, the substituents may be the same or different.
  • Ar 2 is substituted, it is preferred that it is substituted with one or two groups. It is more preferred that it is substituted with one group. There is also another embodiment in which substitution with two groups is more preferred.
  • Replacement which may also be a substituent on Ar 2 is to connexion bond such together with a portion of another Ar 2 on optionally substituted substituent or Ar 2,, or connexion same such together It may be combined with an oxygen atom, sulfur atom, or nitrogen atom to form a ring.
  • Substituents on Ar 2 is connexion bond such together with a portion of the Ar 2, or together such connexion same oxygen atom, a sulfur atom, or as an example of joined to form a ring with nitrogen atom is A case where Ar 2 is a phthalimido-5-yl group or a 1,4-dioxo 1,2,3,4-tetrahydrophthalazine-6-yl group can be exemplified.
  • the alkyl groups may be joined together to form a ring.
  • examples of the substitution position of the substituent include substitutable positions on Ar 2 .
  • the substitution position of the substituent is preferably E, Ar 21 , or G.
  • Ar 21 Or, it is more preferable to be on Ar 21 which is more preferable on G.
  • Ar 2 is —E—Ar 21 —G—Q, Ar 2 is substituted, the substitution position of the substituent is on G, and G is an alkylene group
  • a preferred example is the same force as that exemplified in the substituent of Ar 2 above.
  • two bonds formed by removing two hydrogen atoms on the same carbon on the alkylene group are joined together. An example in which they are bonded to the same oxygen atom and substituted as an oxo isomer can also be mentioned as a preferred example.
  • Ar 21 examples include a benzene ring or a naphthalene ring, and a benzene ring is preferred.
  • E include a single bond or a lower alkylene group, and a single bond, a methylene group, a single bond in which an ethylene group is preferable, or a single bond in which an ethylene group is more preferable is more preferable.
  • G include a single bond, a lower alkylene group, and a lower alkylene group, and a single bond, a methylene group, an ethylene group, or a beylene group are preferred, a single bond, a methylene group, Or, a single bond in which a beylene group is more preferable or a methylene group in which a methylene group is more preferable is particularly preferable.
  • G is more preferably a lower alkylene group, preferably a single bond or a lower alkylene group.
  • E is a single bond and [G is a single bond or a lower alkylene group].
  • E is a single bond and G is a lower alkylene group. It is more preferable that
  • ⁇ 21-13 is preferred
  • AT21-1 ⁇ 21-15 is even more preferred
  • Ar21-1 Is particularly preferred.
  • Q include a carboxy group, CON (R 41 ) (R 42 ), or —COOR 43 , and a carboxy group or a carboxy group that is preferred to —CON (R 41 ) (R 42 ) is more preferred. I like it.
  • R 41 and R 42 may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, a substituted, an alkyl group, or a substituted !, may! /, Aryl R 41 and R 42 together form a 3- to 7-membered ring, and N (R 41 ) (R 42 ) represents a cyclic amine. However, when R 41 is a hydroxyl group, R 42 is a group other than a hydroxyl group. R 41 is most preferably a hydrogen atom, preferably a hydrogen atom or an optionally substituted alkyl group, or a hydrogen atom more preferably a methyl group. R 42 is a hydrogen atom, hydroxyl group or substituted!
  • an aryl group that may be substituted with an aryl group, or an alkyl group or an alkoxy group is preferably a hydrogen atom, a hydroxyl group, or an alkyl group. More preferred are an atom, a hydroxyl group, or a methyl group.
  • R 43 substituted !, may be an alkyl group, or may be substituted, an aryl group may be mentioned as a specific example, and an optionally substituted alkyl group is preferred.
  • G 2 is one O, one S, one SO—, one SO—, or NR G21 — (R G21 is a hydrogen atom, substituted Optionally substituted alkyl group, substituted
  • an optionally substituted acyl group or an optionally substituted sulfol group. There is no particular limitation, but O—, —S—, or —NH is particularly preferred. Further, R G21 in —NR G21 — is more preferably a hydrogen atom. Preferred examples of E, Ar 21 , G, and Q when Ar 2 is one E—Ar 21 —G 2 —GQ are the same as described above.
  • Ar 2 represents a carboxyphenyl group, a carboxyalkyl phenyl group, a carboxy naphthyl group, a carboxyalkyl naphthyl group, or [monocyclic aromatic heterocycle other than virazolyl group], Ar 2 is substituted, Moyo ⁇ .
  • Ar 2 is preferably a carboxyphenyl group, a carboxyalkylphenyl group, or a carboxycinnaftyl group.
  • Ar 2 may be a carboxyphenol group or a carboxyalkyl group.
  • a phenyl group or [monocyclic aromatic heterocycle other than virazolyl group] is preferred.
  • a carboxyphenol group is particularly preferred.
  • a carboxyalkylphenyl group is particularly preferable as Ar 2 .
  • a carboxynaphthyl group is particularly preferred as Ar 2 , and there is another embodiment.
  • Ar 2 is a carboxyalkyl furol group or a carboxyalkyl naphthyl group
  • the “alkyl” in these groups preferably has 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. More preferably, one or two is even more preferable, and one is particularly preferable.
  • Ar 2 is a carboxyalkyl phenyl group
  • Ar2-23 Ar2-24 Ar2-25 Ar2-26 is preferred
  • Ar 2 is a carboxynaphthyl group
  • Ar2-30 is particularly preferred.
  • the substituent is preferably a halogen atom, a hydroxyl group, a cyan group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, or a substituted group.
  • R 11 and R 12 may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or a substituted or unsubstituted aryl group, Alternatively R 11 and R 12 Forming a connexion 3-7 membered ring such the cord shows a cyclic amine as NR 11) (R 12). ), And -SO N (R 13 ) (R 14 ) (R 13
  • R 14 may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, or R 13 and R 14 Together form a 3- to 7-membered ring, and N (R 13 ) (R 14 ) represents a cyclic amine. Any one or more groups selected from the group consisting of: a halogen atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group.
  • the substituent is particularly preferably a halogen atom, an optionally substituted alkyl group, or an optionally substituted alkoxy group.
  • Ar 2 with multiple substituents When substituted, the substituents may be the same or different.
  • the combination is that Ar 2 is a carboxyalkyl phenyl group and is an alkyl group-powered methylene group, and is substituted with one halogen atom on the phenyl group.
  • R 1 and R 2 may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted alkenyl.
  • a group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted, optionally, alkylsulfier group, or a substituted !, may! /, Alkylsulfol Indicates a group.
  • R 1 and R 2 are preferably an alkyl group which may be substituted, or V which is substituted, or a alkenyl group! R 1 is substituted !, may!
  • R 2 is an optionally substituted alkyl group, or an optionally substituted alkyl group, more preferably a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group having 2 to 4 carbon atoms.
  • An alkenyl group is more preferably a methyl group, an ethyl group, a propyl group, or an aryl group, and an ethyl group or an aryl group is particularly preferable.
  • the aryl group is most preferred.
  • an ethyl group is most preferred.
  • a methyl group substituted with a hydroxyl group is most preferred.
  • R 3 is a hydrogen atom or a substituted or unsubstituted alkyl group.
  • R 3 is particularly preferably a hydrogen atom or a hydrogen atom, preferably a lower alkyl group, or more preferably a methyl group.
  • Ar 1 is substituted with —CON (RU) (R 12 ) (R 11 and R 12 are as defined above);
  • ⁇ 19> 1 ⁇ is a lower alkyl group having 1 to 3 carbon atoms
  • ⁇ 20> a compound in which R 2 is a lower alkyl group having 1 to 4 carbon atoms;
  • R 2 is a lower alkenyl group having 2 to 4 carbon atoms
  • ⁇ 24> a compound which is ⁇ 1> and ⁇ 8> above;
  • ⁇ 32> a compound which is ⁇ 2> and ⁇ 7> above;
  • ⁇ 33> a compound which is ⁇ 2> and ⁇ 8> above;
  • ⁇ 34> a compound which is ⁇ 2> and ⁇ 9> above;
  • ⁇ 41> a compound which is ⁇ 4> and ⁇ 7> above;
  • Ar 2 is a compound that is —E—Ar 21 —G—Q;
  • Ar 21 is a naphthalene ring
  • Ar 2 is substituted with a hydroxyl group
  • ⁇ 74> 1 ⁇ is a lower alkyl group
  • ⁇ 78> A compound according to any one of ⁇ 9> and ⁇ 54> to ⁇ 61>, and ⁇ 8>;
  • ⁇ 95> A compound that is ⁇ 94> in any one of ⁇ 15> to ⁇ 18>, ⁇ 71> to ⁇ 73>, and ⁇ 86> to ⁇ 90>;
  • R 2 is a compound which is a hydroxymethyl group or an ethoxymethyl group
  • ⁇ 104> a compound in which R 2 is a methyl group substituted with a lower alkylsulfier group
  • ⁇ 105> a compound in which R 2 is a methyl group substituted by a lower alkylsulfol group; ⁇ 106> a compound in which R 2 is an ethyl group;
  • ⁇ 107> A compound which is ⁇ 96> in any of the above ⁇ 100> to ⁇ 106>; ⁇ 108> A compound which is ⁇ 97> in any of the above ⁇ 100> to ⁇ 106>; ⁇ 109> In any of ⁇ 107> and ⁇ 108>, a compound wherein ⁇ 22>.
  • the compound of the present invention is a novel compound not described in the literature.
  • the compound of the present invention represented by the general formula (1) can be produced, for example, by the following method, but the production method of the compound of the present invention is not particularly limited.
  • reaction time is not particularly limited. However, since the progress of the reaction can be easily traced by a known analysis means, it may be terminated when the yield of the target product is maximized.
  • the compound of the present invention represented by the general formula (1) can be produced, for example, according to the reverse synthesis route of the following reaction route.
  • the general formula (2) [—in the general formula (2), R 3 is as defined above, and Ar la , Ar 2a , R la , and R 2a are Each of them is synonymous with Ar 1 Ar 2 , R 1 , and R 2 , or one or more groups thereof may be protected.
  • the compound represented by the general formula (1) can be produced by simultaneously or sequentially deprotecting all protecting groups. The deprotection reaction may be carried out according to a known method such as the method described in Protective Groups organic synthesis, John Wiley and 3 ⁇ 4ons fll (1999).
  • the general formula (3) [in the general formula (3), Ar la , R la , and R 2a are as defined above.
  • the amount of the compound represented by the general formula (4) is used in the compound represented by the general formula (3).
  • the power of 1Z10 to 10 equivalents, preferably 1Z5 equivalents to 5 equivalents, more preferably 1 equivalents to 3 equivalents. Purity, yield, purification efficiency, etc. of the compound represented by the general formula (2) May be designed as appropriate.
  • an acid addition salt such as hydrochloric acid
  • the acid include mineral acids such as hydrochloric acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and P-toluenesulfonic acid.
  • Acetic acid or trifluoroacetic acid is a preferred example. It is done.
  • the acid dose is preferably an equivalent amount or an excess amount relative to the compound represented by the general formula (3), for example, 1 to 10 equivalents, more preferably 1 to 20 equivalents. Preferably as an excess, for example a solvent Can be used in quantities.
  • Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butyl acetate, and acetonitrile.
  • Preferred examples include black mouth form, toluene, and tetrahydrofuran.
  • reaction conditions include conditions where acetic acid is used in a solvent amount.
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C.
  • reaction time is not particularly limited, it is usually 1 to 96 hours, preferably 3 to 60 hours, and examples thereof.
  • the compound shown can be produced by reacting the compound represented by the general formula (3) and the compound represented by the general formula (4) in the presence of a base.
  • the amount of the compound represented by the general formula (4) is used with respect to the compound represented by the general formula (3).
  • 10 to 10 equivalents of 1Z can be used, preferably 1 to 5 equivalents of 1Z, more preferably 1 to 3 equivalents
  • Bases include triethylamine, diisopropylethylamine, or 1,8 diazabicyclo [5.4.0.
  • Undekar 7 Organic bases such as Undekar 7 are listed, and 1,8 diazabicyclo [5. 4. 0] Unde force 7-Yen is preferred U, for example.
  • the dose of the base is preferably equivalent or excessive to the compound represented by the general formula (3), for example, 1 to 10 equivalents, more preferably 1 to 20 equivalents.
  • reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C.
  • reaction time is not particularly limited, it is usually 0.1 to 96 hours, preferably 1 to 60 hours, and is exemplified.
  • Q in Ar 2 in general formula (1) corresponding to the Ar 2a moiety in general formula (2) It is synonymous.
  • the compound is represented by Q in Ar 2 in the general formula (1) corresponding to the Ar 2a moiety in the general formula (2) [Q is as defined above].
  • DCC dicyclohexylcarbodiimide
  • Q Q in Ar 2 in the general formula (1) corresponding to the Ar 2a moiety in the general formula (2) is as defined above.
  • the compound has the same meaning as defined above for Q [Q in Ar 2 in general formula (1) corresponding to the Ar 2a moiety in general formula (2). ] Can be used in an equivalent amount to an excess amount relative to the compound showing a carboxy group, and examples thereof include 1 to 10 equivalents, preferably 1 to 5 equivalents. It is also desirable to add an auxiliary agent to the condensation reaction. Hydroxybenzotriazole (HO BT).
  • the base include trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. Preferred is triethylamine, diisopropylethylamine, N-methylmorpholine, or pyridine.
  • Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, pyridine, and dimethylformamide. It is also suitable to use a mixture of two or more of these solvents. Preferred is dimethylformamide or tetrahydrofuran.
  • the reaction temperature is usually from ⁇ 80 ° C to 100 ° C. Although reaction time is not specifically limited, Usually, 1 to 96 hours are illustrated, and 2 to 48 hours are preferable examples. Ammonia, primary amine, secondary amine, or hydroxyamine in the reaction may be protected.
  • protected hydroxylated amine may be O- (2-methoxypropane-2-yl. ) Hydroxyamine, and the protecting group can be deprotected according to a known method (Mori, K., Tetrahedron, 44, 6013 (1988)).
  • Ar 1 in the formula (1) corresponding to Ar la moiety in the general formula (2) is, be also good Ariru or substituted optionally be substituted
  • Ar 1 in general formula (1) corresponding to the Ar la moiety in general formula (2) is substituted with bromine or iodine. It can also be produced from a compound. The production can be carried out under the known Suzuki reaction conditions or under the Heck reaction conditions. The reaction conditions are described in known literature (RFHeck, Organic Reactions, 27, 345 (1 982)., RFHeck, Palladium Reagents in urganic Synthesis). , Academic Press, 1985., N. Miyaura et.al, J. Am. Chem. Soc., 107, 972 (1985)., N. Miyaya, A. Suzuki, Chem. R ev. 95, 2457 (1995) ) Etc.
  • a compound in which Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with an optionally substituted alkyl group in this case, in the compound, Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) may be substituted, an alkenyl group or a substituted group. Substituted by an alkyl group! It can also be produced from these compounds.
  • the production method include a method using catalytic hydrogen reduction.
  • the catalytic hydrogen reduction can be carried out using a catalyst in a solvent under a hydrogen atmosphere.
  • the catalyst include palladium-carbon, acid platinum, platinum-carbon, palladium hydroxide and the like.
  • the solvent used for the reaction examples include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, and ethanol. Tetrahydrofuran or methanol is preferred. It is also preferable to use a mixture of two or more of these solvents.
  • the reaction temperature is usually from –80 ° C to 100 ° C. The temperature is preferably 0 ° C to 50 ° C.
  • the reaction time is not particularly limited, it is usually 1 to 96 hours, preferably 3 hours and 48 hours, and examples are given.
  • the compound can also be produced from the compound in which Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with bromine or iodine.
  • the production can be carried out via a known Buchwald-Hart wig reaction, and the reaction conditions are known (AR Mud, S ⁇ . Buchwald, Top. Curr. Chem., 219, 131 (2002). JF Hartwig, Angew. Chem., Int. Ed., 37, 2046 (1998)., D. Baranano, G.
  • the product may be obtained in a state where the amino group is protected.
  • a derivative having an amino group can be produced by appropriately performing a deprotection reaction.
  • a compound in which Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with an electrophile is reacted with an electrophile. It can also be manufactured.
  • electrophiles include acyl chloride, acyl bromide, acid anhydride, alkylsulfonyl chloride, alkyl sulfonic acid anhydride, aryl chloride sulfone, aryl sulfonic acid anhydride, isocyanate, isothiocyanate, and power rubamoyl chloride. Or black formate.
  • the electrophile is used in an equivalent or excess amount relative to the compound in which Ar 1 in general formula (1) corresponding to the Ar la moiety in general formula (2) is substituted with an amino group.
  • 1 to 10 equivalents are preferred, and preferably 1 to 3 equivalents.
  • a base can be used, and the base may be either an organic or inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, Examples thereof include trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine.
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is an equivalent amount or an excess amount relative to the compound substituted with the amino group. More preferably, 1 to 100 equivalents, particularly preferably 1 to 10 equivalents are exemplified.
  • An inert solvent can be used as a solvent used in the reaction. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, and butyl acetate.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably from ⁇ 10 ° C. to 50 ° C.
  • the reaction time is not particularly limited, it is usually exemplified by 0.2 to 24 hours, and preferably 1 to 5 hours.
  • the general formula (2) General formula corresponding to Ar 2a moiety in (1) of Ar 2 guard E-Ar 21 - G- is Q, and G is A compound which is an alkylene group and has two bonds formed by removing two hydrogen atoms on the same carbon on the alkylene group, bonded together to the same oxygen atom and substituted as an oxo isomer for, among the compounds represented by the general formula (2), the general formula (2) Ar 2 in the general formula (1) corresponds to Ar 2a moiety in guard E-Ar 21 - G- is Q, And G is an alkylene group, and is produced by subjecting a compound substituted on the alkylene group by a hydroxyl group to an oxidation reaction. Can do. Examples of the oxidation reaction include a method using a Dess-Martin reagent, a Swern acid method, or an acid method using chromic acid. These acid methods can be easily carried out by those skilled in the art.
  • Ar 1 in the formula (1) corresponding to Ar la moiety in the general formula (2) is a compound substituted by an alkyl group substituted by a hydroxyl group
  • a compound in which Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with an acyl group is subjected to a reduction reaction. It can be manufactured by providing.
  • the reducing conditions include hydride reduction.
  • the hydride reduction condition include a condition in which a metal hydride is reacted in the presence of an acid if necessary.
  • Examples of the metal hydride include hydrosilane such as triethylsilane, sodium borohydride, sodium tellurium hydride and the like.
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) among the compounds represented by the general formula (2) is substituted with an acyl group.
  • the compound can be used in an equivalent amount to an excess amount with respect to the compound, and examples thereof include 1 equivalent to 20 equivalents, preferably 1 equivalent to 10 equivalents.
  • the reaction can be carried out in the presence of an acid, which may be either an organic or inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid, Or, boron trifluoride 'diethyl ether complex may be mentioned, and trifluoroacetic acid is preferred.
  • an acid which may be either an organic or inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid, Or, boron trifluoride 'diethyl ether complex may be mentioned, and trifluoroacetic acid is preferred.
  • the amount of acid, among the compounds represented by the general formula (2), Ar 1 in the formula (1) that corresponds to Ar la moiety in the general formula (2) is substituted by Ashiru group It can be used in an equivalent amount to an excess amount with respect to the compound, and is preferably 1 equivalent to 20 equivalents, more preferably 1 equivalent to 10 equivalent
  • Examples of the solvent used for the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxetane, methanol, and ethanol. Tetrahydrofuran or dichloromethane is preferred. It is also suitable to use a mixture of two or more of these solvents.
  • the reaction temperature is usually from ⁇ 80 ° C to 100 ° C. Preferably, it is 0 ° C to 50 ° C.
  • the reaction time is not particularly limited, but usually 1 to 48 hours is exemplified, and 3 hours A preferred example is 24 hours in between.
  • Ar 1 in the formula (1) corresponding to Ar la portion of the general formula (2) in is replaced by an alkyl group substituted by a hydroxyl group
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with an alkenyl group. It can be produced by subjecting the compound to a hydroxylation reaction by a hydroboration reaction. The hydroxylation reaction by hydroboration reaction can be easily performed by those skilled in the art.
  • the general formula (2) compound represented by Amino groups Ar 1 in the general formula (1) corresponding to Ar la portion of the general formula (2) it is substituted with alkyl group which may be substituted for compounds that have been substituted in, the compounds of the general formula (2) a r 1 of the general formula (1) corresponding to Ar la moiety is substituted with Amino group Ru compound in an alkylating agent If necessary, it can be produced by reacting in the presence of a base.
  • the alkylating agent for example, a corresponding alkyl halide can be used, and examples thereof include alkyl iodide, alkyl bromide, alkyl chloride, 2-bromoethyl methyl ether and the like.
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) in the compound represented by the general formula (2) is substituted with an amino group. It is preferable to use an equivalent amount or an excess amount with respect to the compound in question, for example, 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents.
  • a base can be used, and the base may be either an organic or inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, Examples thereof include trimethylamine, triethylamine, disopropylethylamine, N-methylmorpholine, pyridine, and 2,6-lutidine.
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is an equivalent amount or an excess amount relative to the compound substituted with an amino group. More preferably, it is 1 equivalent to 100 equivalents. More preferably, it is 1 equivalent to 10 equivalents.
  • An inert solvent can be used as a solvent used in the reaction. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, and butyl acetate.
  • reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably from ⁇ 10 ° C. to 50 ° C.
  • reaction time is not particularly limited, it is usually from 0.2 hours to 24 hours, and preferably from 1 hour to 5 hours.
  • a compound in which Ar 1 in general formula (1) corresponding to the Ar la moiety in general formula (2) is substituted with an amino group substituted with an optionally substituted alkyl group is generally
  • a compound in which Ar 1 in formula (1) corresponding to the Ar la moiety in formula (2) is substituted with an amino group is added to a solvent in the presence of an aldehyde or ketone, and optionally in the presence of an acid. It can also be produced by reductive amination reaction conditions in which a reducing agent acts. Examples of the solvent used in the reaction include jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, and acetonitrile.
  • Methanol or acetonitrile is preferred. It is also suitable to use a mixture of two or more of these solvents.
  • aldehyde or ketone include formaldehyde, acetoaldehyde, and acetone.
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with an amino group. It is preferable to use an equivalent amount or an excess amount with respect to the compound, more preferably 1 equivalent to 10 equivalents.
  • Acetic acid or an acidic buffer solution is preferred as the acid to be used as necessary.
  • Sodium cyanobium hydride is preferred as a reducing agent.
  • reaction temperature is usually from -20 ° C to 100 ° C, preferably from -10 ° C to 50 ° C. Although reaction time is not specifically limited, Usually, 0.2 to 36 hours are illustrated, and 1 to 24 hours are preferable examples.
  • Ammin and Examples thereof include N, N, monodimethyl-1,2-diaminocyclohexane and the like, and a catalytic amount is preferably used.
  • An inert solvent such as dioxane or tetrahydrofuran can be used as the solvent.
  • the reaction temperature is preferably from room temperature to 150 ° C.
  • the reaction time is exemplified by 1 to 50 hours, preferably 3 to 30 hours.
  • the compounds represented by the general formula (2) when Ar 1 in the general formula (1) corresponding to Ar la moiety in the general formula (2) is a compound which is substituted by chlorine, the compounds have the general formula It can be produced by reacting a compound in which Ar 1 in the general formula (1) corresponding to the Ar la part in (2) is substituted with bromine and copper chloride.
  • An example of a preferable copper salt is copper (I) chloride, and it is preferable to use an equivalent amount or an excess amount.
  • an inert solvent such as N, N-dimethylformamide, dioxane or tetrahydrofuran can be used.
  • the reaction temperature is preferably from room temperature to 150 ° C.
  • the reaction time is exemplified from 1 to 50 hours, preferably 3 to 30 hours U.
  • Ar 1 in the general formula (2) is optionally substituted alkyl - substituted with Le group
  • the compound can also be produced from the compound in which Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) is substituted with bromine or iodine.
  • the production can be carried out under the known Sonogashira reaction conditions.
  • the reaction conditions the known literature (K. Sonogashira, et al. Tetrahedron lett., 50, 4467 (1975)., J. Organomet Chem., 653, 46 (2002).).
  • Ar 1 in the formula (1) corresponding to Ar la moiety in the general formula (2) is optionally substituted alkylsulfonyl - is substituted by Le group
  • Ar 1 in the general formula (1) corresponding to the Ar la moiety in the general formula (2) may be substituted or substituted with an alkylthio group. It can also be produced by reacting a compound with an oxidizing agent in a solvent. Examples of the solvent used in the reaction include dichloromethane, chloroform, tetrasalt-carbon, and the like. Preferred is dichloromethane. It is also suitable to use a mixture of two or more of these solvents.
  • the reaction temperature is usually from ⁇ 80 ° C. to 100 ° C. The temperature is preferably 0 ° C to 50 ° C.
  • the reaction time is not particularly limited, but usually 0.1 hour force is also exemplified by 48 hours, and 0.3 to 24 hours is preferable. A good example.
  • the general formula (5) [In the general formula (5), Ar la , R la , and R 2a are as defined above. Can be produced by reacting in the presence of a cross-linking agent.
  • a cross-linking agent there may be mentioned acid salts such as phosphorus oxychloride, sodium chloride, or oxalyl chloride.
  • the acid salt is preferably phosphorus oxychloride.
  • the amount of the cross-linking agent used can be 1 to 10 equivalents, preferably 1 to 5 equivalents, more preferably 1 to 3 equivalents, relative to the compound represented by the general formula (5). is there.
  • the reaction is also preferably carried out in the presence of an amine such as triethylamine or ⁇ , ⁇ -dimethylamine, and the equivalent of amine at this time is preferably, for example, 0.5 to 10 equivalents. More preferably, it is 1 to 3 equivalents.
  • an amine such as triethylamine or ⁇ , ⁇ -dimethylamine
  • Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butylacetate, and acetonitrile. In another embodiment, it is also preferable to use the cross-linking agent as a solvent.
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 0.1 hours to 100 hours, and preferred examples are 0.5 hours to 10 hours.
  • the compound can be produced from a compound in which Ar 1 corresponding to the Ar la moiety in the general formula (3) is substituted with a hydroxyl group.
  • the production can be carried out under known Mitsunobu reaction conditions, and the reaction conditions are known (Mitsunobu, 0., Synthesis, 1981, 1 "Hughes, DL, Org. React., 42, 335 (1992). ) Etc.
  • the compound represented by the general formula (3) when Ar 1 corresponding to the Ar la moiety in the general formula (3) is substituted with a hydroxyl group, the compound is represented by the general formula (3). It can be produced from a compound in which Ar 1 corresponding to the Ar la moiety of is substituted with a methoxy group.
  • the production method is a demethylation reaction as a deprotection method. For example, Protective Groups in Or ganic Synthesis, John Wiley and Sons flj (1999).
  • Ar 1 corresponding to the Ar la moiety in the general formula (3) may be substituted with an alkyl group, or may be substituted with an aminomethyl group
  • the compound is a compound in which Ar 1 corresponding to the Ar la moiety in the general formula (3) is substituted with a chloromethyl group, in the presence of a base in a solvent, if necessary, in the presence of primary or 2 It can be produced by reacting a grade amine.
  • the base used as necessary include triethylamine.
  • the primary or secondary amine can be used in an amount equivalent to 1 equivalent or excess of the compound in which Ar 1 corresponding to the Ar la moiety in the general formula (3) is substituted with a chloromethyl group.
  • reaction temperature can usually be 0 ° C to 200 ° C, preferably 20 ° C to 100 ° C.
  • the reaction time is not particularly limited, but usually 0.1 to 100 hours is exemplified, and 1 to 30 hours are preferred examples.
  • the compound represented by the general formula (3) when Ar 1 corresponding to the Ar la moiety in the general formula (3) is substituted with a chloromethyl group, the compound is represented by the general formula (3). It can be produced by reacting a compound obtained by substituting Ar 1 corresponding to the Ar la moiety with a hydroxymethyl group in the presence of a cross-linking agent.
  • the cross-linking agent include acid salts such as phosphorus oxychloride, thionyl chloride, and salt oxalyl.
  • the acid chloride is preferably phosphorus oxychloride.
  • the amount of the cross-linking agent used can be from 1Z10 to 10 equivalents, preferably 1Z5 based on the compound in which Ar 1 corresponding to the Ar la part in the general formula (3) is substituted with a hydroxymethyl group Equivalent to 5 equivalents, more preferably 1 equivalent to 3 equivalents.
  • the amount of the cross-linking agent used is excessive with respect to the compound in which Ar 1 corresponding to the Ar la moiety in the general formula (3) is substituted with a hydroxymethyl group. It is also preferable to use an amount, for example, as a solvent.
  • the reaction is also preferably carried out in the presence of an amine such as triethylamine or ⁇ , ⁇ -dimethylamine, and the equivalent of the amine at this time is preferably, for example, 0.5 to 10 equivalents. More preferably, it is ⁇ 3 equivalents.
  • the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butyl acetate, and acetonitrile.
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C.
  • the reaction time is not particularly limited, but usually 0.1 to 100 hours is exemplified, and 0.5 hour force is also a preferred example of 10 hours.
  • the compound represented by the general formula (3) can be used with a protective group introduced or deprotected as necessary.
  • the introduction of the protecting group and the deprotection reaction may be carried out according to a known method, for example, the method described in Protective Groups Organic Synthesis ⁇ John Wiley anaions (1999).
  • Examples of the compound represented by the general formula (4) include commercially available 4-aminobenzoic acid (manufactured by Aldrich), 6 amino-2-naphthalene carboxylic acid (manufactured by Oakwood), 4 aminophenylacetic acid (manufactured by Aldrich), 4- Amino-1-methoxybenzoic acid (manufactured by Aldrich) and the like can be used.
  • the compound represented by the general formula (4) can also be produced by subjecting the corresponding nitro compound to a reduction reaction.
  • the reduction reaction include a method using catalytic hydrogen reduction or a method using a metal-hydrogen complex compound.
  • the catalytic hydrogen reduction can be carried out using a catalyst in a solvent in a hydrogen atmosphere.
  • the catalyst include palladium-carbon, acid platinum, platinum carbon, palladium hydroxide and the like.
  • the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetinoreethenole, tetrahydrofuran, dixanthane, dimethoxyethane, methanol, and ethanol.
  • the reaction temperature is usually from 80 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • Reaction time is Although not particularly limited, usually 1 to 96 hours are exemplified, and 3 to 48 hours are preferable examples.
  • the reduction reaction with the metal hydride complex can be carried out in a solvent by adding additives as necessary.
  • Preferred examples of the metal hydride complex include sodium borohydride.
  • the metal hydride complex can be used in an equivalent amount or an excess amount relative to the nitro compound, preferably 1 to 10 equivalents.
  • Examples of the solvent used in the reaction include jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, or ethanol. Tetrahydrofuran or methanol is preferred. It is also suitable to use a mixture of two or more of these solvents. It is preferable to use Lewis acid or metal salt as an additive, and preferable examples include nickel salt.
  • the additive may be used in an excess amount of a catalytic amount relative to the -tro compound, and is preferably 0.01 to 1 equivalent.
  • the reaction temperature is usually from ⁇ 80 ° C. to 100 ° C., preferably from ⁇ 20 ° C. to 50 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 96 hours, and preferred examples are 0.5 to 24 hours.
  • the -tro compound in the reaction include commercially available compounds such as Ethyl 4-nitrophenyl glyoxylate (Lancaster).
  • Corresponding -tro compounds can also be prepared by the -troation reaction of aromatic compounds.
  • the nitration reaction can be carried out by reacting nitric acid or nitrate in sulfuric acid, and can be carried out based on known reaction conditions.
  • the intermediate body which has a carboxymethyl group among this nitro compound can be manufactured with the following method. First, for the corresponding bromo compound, trimethylsilylacetonitrile, metal complexes such as Pd (dba), complex such as Xantphos, etc.
  • a cyanomethyl compound is produced by using a body ligand and a metal salt such as zinc fluoride.
  • the production can be carried out by a known method (Wu, Shi et al., J. Am. Chem. Soc, 127, 15824- (2005).).
  • a carboxymethyl compound can be produced by carrying out a hydrolysis reaction on the cyanomethyl compound.
  • the hydrolysis reaction can be carried out by allowing water and an acid to act in a solvent.
  • As the amount of water it is more preferable to use an excess amount as a preferred solvent or solvent.
  • the solvent to be used water, THF, 1,4 dioxane, methanol, ethanol and the like are preferable.
  • the acid to be used hydrochloric acid, sulfuric acid and the like are preferable, and sulfuric acid is more preferable.
  • the amount of acid used is the cyanome It is preferable to use an excess amount relative to the chill form. Specifically, a method in which an aqueous solution obtained by diluting concentrated sulfuric acid with water twice is used as a solvent.
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C.
  • the reaction time is not particularly limited, it is usually 0.1 to 96 hours, and preferred examples are 1 to 10 hours.
  • the compound represented by the general formula (4) can also be produced by a commercially available halogen compound via the known Buchwald Hartwig reaction, and the reaction conditions are known (AR Muci, S ⁇ . Buchwald, Top. Curr. Chem., 219, 131 (2002)., JFHartwig, Angew. Chem., Int. Ed., 37, 2046 (1998)., D. Baranano, G. Mann, Hartwig, JF Curr. Org. Chem. 1, 287 (1997)., CGFrost, P. Mendonca, J. Chem. Soc. Perkin Trans. 1, 1998, 2615.) and the like.
  • the product may be obtained in a state where the amino group is protected.
  • a derivative having an amino group can be produced by appropriately performing a deprotection reaction.
  • halogenated compounds include Methyl 2- (4-bromophenyl) -2,2-dimethylacetate (Tronto).
  • the compound represented by the general formula (4) can be used after introducing a protecting group if necessary, and certain! / ⁇ can be deprotected.
  • the introduction of the protecting group and the deprotection reaction may be carried out in accordance with a known method, for example, the method described in Protective Groups Organic Synthesis ⁇ John Wiley anaions (1999).
  • R la and R 2a are as defined above, and R 4 represents a lower alkyl group.
  • a compound represented by the general formula (7) [-In the general formula (7), Ar la has the same meaning as described above. Can be produced by reacting in the presence of a base.
  • the amount of the compound represented by the general formula (7) is used with respect to the compound represented by the general formula (6).
  • 10 to 10 equivalents can be used, preferably from 1 to 5 equivalents, more preferably from 0.5 to 2 equivalents, but the purity, yield and purification of the compound represented by the general formula (5) What is necessary is just to design suitably considering efficiency etc.
  • an acid addition salt such as hydrochloric acid.
  • the base used in the reaction is sodium methoxide or sodium ethoxide.
  • examples thereof include metal alkoxides, carbonates such as sodium carbonate, potassium carbonate, or cesium carbonate, metal hydrides such as sodium hydride, sodium hydroxide, potassium hydroxide, and the like.
  • Sodium ethoxide, sodium methoxide, or sodium hydride is preferred.
  • Examples of the dose of the base to be used include 1Z5 equivalents to 10 equivalents, preferably 1Z2 equivalents to 3 equivalents, relative to the compound represented by the formula (7).
  • Solvents used in the reaction include, for example, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol nomonomethylenoateol, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene.
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C.
  • the reaction time is not particularly limited, it is typically 1 to 96 hours, preferably 3 to 36 hours, and is exemplified.
  • R 2 corresponding to R 2a moiety in the general formula (5) [ ⁇ alkoxy group, Ashiruokishi group or have the Amin may be substituted with an alkyl group
  • the compound is obtained by adding an alcohol, a carboxylic acid, or an amine to a compound in which R 2a in general formula (5) is substituted with a bromomethyl group. It can manufacture by making it act as.
  • the alcohol include methanol and ethanol
  • examples of the carboxylic acid include acetic acid
  • examples of the amine include dimethylamine.
  • the nucleophile is an alcohol or a carboxylic acid
  • an amine is used as the nucleophile
  • an alcohol such as methanol or ethanol is used. It is preferable to use an organic solvent Good.
  • the nucleophile used is an alcohol or carboxylic acid, it is desirable to add an acid such as hydrochloric acid as necessary.
  • the equivalent of the nucleophile used is equivalent or excess, preferably 1 to 100 equivalents.
  • the reaction temperature is usually 0 ° C to 200 ° C, preferably 10 ° C to 50 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 96 hours, and preferred examples are 0.5 to 36 hours.
  • the compound in which R 2a in the general formula (5) is substituted with a bromomethyl group is different from the compound having the R 2a force S methyl group in the general formula (5) in the presence of a radical initiator in a solvent. It can be produced by reacting N-prosuccinimide (NBS).
  • NBS N-prosuccinimide
  • the solvent include dichloromethane, black mouth form, carbon tetrachloride, benzene, toluene, xylene, and the like.
  • the radical initiator it is preferable to use a catalytic amount with respect to the compound in which R 2a in the general formula (5) in which 2-2′-azobis (isoptyl-tolyl) is preferred is a methyl group.
  • NBS can be used in an excess amount of 1 equivalent, and preferably 1 equivalent to 10 equivalents.
  • the reaction temperature can usually be carried out at 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 0.1 to 96 hours, and preferred examples are 0.5 to 36 hours.
  • the compound represented by the general formula (5) can be used after introducing or deprotecting a protecting group, if necessary.
  • the introduction of the protecting group and the deprotection reaction may be carried out according to a known method, for example, the method described in Protective Groups in Organic Synthesis ⁇ John Wiley and Sons (1999).
  • the compound represented by the general formula (6) includes, for example, commercially available acetyl acetoacetate (manufactured by Aldrich), benzoyl cetyl acetate (manufactured by Aldrich), 2-benzylacetoacetate ethyl (manufactured by Aldrich), 4,4, 4-Ethylfluoroacetoacetate (Aldrich), Propioleethyl acetate (Aldric h), 2-Cyanacetoacetate (Alfa Aesar), 2-Ethylacetoacetate (Aldrich), etc. And 2-allylacetoacetate acetate obtained by a known method (J. Org.
  • the compound represented by the general formula (7) is, for example, commercially available 2-thiophene carboxymidamide hydrochloride (Maybridge), 3-thiophene carboxymidamide hydrochloride (Maybridge), 3- Furancarboxymidamide hydrochloride (manufactured by Maybridge) can be used, and a commercially available aromatic derivative can be amidinized by a known method (4th edition, Experimental Chemistry Course, 20th and 21st, Maruzen). May be used.
  • a known method (4th edition, Experimental Chemistry Course, 20th and 21st, Maruzen). May be used.
  • 5-methoxythiophene-2-carboxymidamide hydrochloride can be produced from 2-methoxythiophene (Aldrich).
  • a commercially available aromatic derivative is subjected to a formylation reaction to produce an aromatic aldehyde intermediate.
  • the formylation reaction can be carried out under known Vilsmeier reaction conditions.
  • an aromatic-tolyl intermediate is produced by oximation of the aromatic aldehyde intermediate followed by a dehydration reaction.
  • the oximation and dehydration reaction can be produced by reacting hydroxylamine or a salt thereof with an aromatic aldehyde intermediate.
  • a base such as sodium acetate or triethylamine may be used as a reaction accelerator.
  • the compound represented by the general formula (7) can be produced by subjecting the obtained aromatic-tolyl intermediate to an amidinolysis reaction.
  • an amidination reaction a method in which lithium bis (trimethylsilyl) amide is used, a method in which an aluminum amide compound is allowed to act, or a method in which a metal alkoxide is first acted and then a salt or ammonium is allowed to act. Etc. can be mentioned.
  • the aromatic aldehyde intermediates in the production method in the case where the corresponding Ar 1 is substituted with a bromine atom, the compound is produced by carrying out a bromination reaction on the corresponding aromatic aldehyde compound. can do.
  • the bromination reaction can be carried out by using a brominating agent in a solvent.
  • a preferred example of the brominating agent is bromine. It is preferable to use an acidic solvent as the solvent. Specifically, acetic acid can be mentioned as a more preferable example.
  • the reaction temperature is usually from 20 ° C to 100 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 96 hours, and preferred examples are 0.5 to 36 hours.
  • the 2-alkylthiothiazole derivative has an alkylthiolate metal salt in the solvent acting on the corresponding 2 bromothiazole derivative. Can be manufactured.
  • alkyl thiolate metal salt examples include sodium methanolate.
  • the dose of the alkylthiolate metal salt is 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to the 2-bromothiazole derivative.
  • the solvent used in the reaction include ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol monomethyl ether, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, Examples include jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, ethyl acetate, butyl acetate, acetonitrile, N, N-dimethylformamide, or dimethyl sulfoxide, and ethanol, methanol, or N, N— Dimethylformamide is a preferred example.
  • reaction temperature is usually from ⁇ 50 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • Reaction time is not particularly limited. Generally, 0.1 to 96 hours are exemplified, and 1 to 36 hours are preferable examples.
  • the compound represented by the general formula (6) and the compound represented by the general formula (7) can be used after introducing or deprotecting a protecting group, if necessary.
  • the introduction of the protecting group and the deprotection reaction may be carried out according to a publicly known force method, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1999).
  • the compound of the present invention and the respective starting materials, compounds, and intermediates thus obtained can be isolated and purified according to conventional methods such as extraction, distillation, and chromatography.
  • a salt thereof can be produced from the compound represented by the general formula (1).
  • the method for producing the salt is not particularly limited, and as a method for producing the acid addition salt, for example, the compound of the general formula (1) is dissolved in alcohols such as methanol and ethanol, and an equivalent or several times the amount of the acid component is obtained. These acid addition salts can be obtained by adding.
  • the acid component used may be any acid component corresponding to the acid addition salt described below. Hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen sulfate, dihydrogen phosphate, citrate, maleic acid, tartaric acid, fumaric acid Suitable examples include pharmacologically acceptable mineral acids or organic acids such as darconic acid or methanesulfonic acid.
  • the acid addition salt in the same manner as in the method for producing the compound, it can be carried out using a base component instead of the acid component.
  • the base component used include sodium hydroxide, potassium hydroxide, N-methyl-D-glucamine, N, N, -dibenzylethylenediamine as long as the base component corresponds to the base addition salt described below.
  • Preferable examples include pharmacologically acceptable bases such as min, 2-aminoethanol, tris (hydroxymethyl) aminomethane, arginine, or lysine.
  • the type of the salt of the compound of the general formula (1) in the present invention is not particularly limited, and may be any of an acid addition salt or a base addition salt, and takes the form of an intramolecular counter ion.
  • the acid addition salt include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, kenate, maleate, tartrate, fumarate, dulconate, or Methane sulfonates or addition salts with optically active acids such as camphor sulfonic acid, mandelic acid, or substituted mandelic acids are included.
  • the base addition salt examples include metal salts such as sodium salt and potassium salt, N-methyl-D-dalkamine, N, N, -dibenzylethylenediamine, 2-aminoethanol, tris (hydroxymethyl) aminomethane, Examples thereof include addition salts with organic bases such as arginine or lysine.
  • the types of salts are not limited to these and can be selected as appropriate by those skilled in the art. Of these, pharmacologically acceptable salts are preferred.
  • the compound of the present invention may exist as a hydrate or a solvate, and these substances are also included in the scope of the present invention.
  • the compound force represented by the general formula (1) is also used as the prodrug, for example, by using a prodrug reagent such as a corresponding halogen compound, the hydroxyl group and the compound in the compound represented by the general formula (1) Amino group strength It can be produced by appropriately introducing a group constituting a prodrug into one or more selected groups according to a conventional method and then isolating and purifying it according to a conventional method as needed.
  • a group constituting a prodrug can be appropriately introduced into the carboxyl group in the compound represented by the general formula (1) using a prodrug reagent such as a corresponding alcohol or amine according to a conventional method.
  • a prodrug reagent such as a corresponding alcohol or amine according to a conventional method.
  • it may be produced using a protecting group present in the compound represented by the general formula (2).
  • the prodrug of the compound of the general formula (1) in the present invention is not particularly limited, Examples thereof include compounds in which a group constituting a prodrug is introduced into one or more arbitrary groups selected from a hydroxyl group, an amino group, and a carboxyl group of the compound represented by the general formula (1).
  • Examples of the group constituting a prodrug with respect to a hydroxyl group and an amino group include an acyl group and an alkoxycarbonyl group.
  • Preferable examples include a acetyl group, a pionyl group, a methoxycarbonyl group, or an ethoxycarbonyl group, and an ethoxycarbonyl group is particularly preferable.
  • a acetyl group is preferred, in some embodiments a propiol group is preferred, and in other embodiments a methoxycarbonyl group is preferred.
  • groups constituting prodrugs with respect to force lpoxyl groups include, for example, methyl group, ethyl group, n_propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, amino group. Examples are a group, a methylamino group, an ethylamino group, a dimethylamino group, or a jetylamino group.
  • Preferable examples include ethyl group, n-propyl group, isopropyl group and the like, and ethyl group is particularly preferable. There is also another embodiment in which an n-propyl group is particularly preferred. There is also another embodiment in which an isopropyl group is preferred.
  • the compound represented by the general formula (1) may have an asymmetric carbon.
  • the stereochemistry of these asymmetric carbons is not particularly limited, and may be either S configuration or R configuration, or a mixture of both! /.
  • Stereoisomers such as optically active forms or diastereoisomers in pure form based on these asymmetric carbons, any mixture of stereoisomers, racemates, etc. are all included in the scope of the present invention.
  • the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof has a strong PDE4 activity inhibitory action as shown in Test Example 1 described later, and has a high activity. Because it has metabolic stability, it is useful as an active ingredient in medicine. Inhibition of PDE4 activity is known to elevate intracellular cAMP concentration and to elicit effects that prevent, treat and Z or ameliorate many diseases. For example, it suppresses the activity of inflammatory cells (eosinophils, neutrophils, monocytes, macrophages, mast cells, CD4 + T lymphocytes, CD8 + T lymphocytes).
  • inflammatory cells eosinophils, neutrophils, monocytes, macrophages, mast cells, CD4 + T lymphocytes, CD8 + T lymphocytes.
  • TNF-a tumor necrosis factor a
  • the compound of the present invention is considered to be effective for the prevention and alleviation of many inflammatory, allergic or immune system related diseases.
  • TNF-a is known as a causative agent for many inflammatory diseases.
  • LPS polysaccharide
  • Specific uses of the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof include asthma, chronic obstructive disease (COPD), pneumoconiosis as a respiratory related disease.
  • COPD chronic obstructive disease
  • Examples include prevention and Z or treatment of bronchial asthma, acute bronchitis, chronic bronchitis, inflammatory airway disease, emphysema, eosinophilic granulomas, adult respiratory distress syndrome (ARDS), pulmonary fibrosis, etc.
  • the Examples of joint-related diseases include rheumatism, osteoarthritis, acute arthritis, chronic arthritic gouty arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, spondyloarthritis and the like.
  • diseases related to skin diseases include atopic dermatitis, psoriasis, seborrheic eczema, allergic contact eczema, and all types of urticaria.
  • diseases related to the gastrointestinal region include irritable colitis, ulcerative colitis, Crohn's disease, collagenous colitis, polypic colitis and the like.
  • diseases related to the eye-nose region include allergic rhinitis, chronic rhinitis, allergic conjunctivitis, irradiation conjunctivitis, catarrhal conjunctivitis, infectious conjunctivitis, and allergic pharyngitis.
  • diseases related to the immune system include transplant rejection, multiple sclerosis, AIDS and the like.
  • Inflammation in each tissue is accompanied by pain, which is considered to be effective in relieving pain associated with inflammation.
  • Symptoms of the above diseases include pain, fever and gout.
  • PDE4 inhibitors have been shown to be effective in animal models of depression (such as forced swimming tests) or animal models of memory (maze tests) (Saccomano, NA, et al., J. Med. Chem., 34 , p291-298, 1991; O 'Donnell, JM and Zhang, HT, Trends Pharmacol.Sci., 25, pl58-163, 2004; Zhang, HT and O' Donnell, JM, Psychopharmacology.
  • the compound of the present invention, its salt, or its prodrug is affected by central nervous system activity. It is expected to be effective for diseases that can be improved. For example, learning 'memory loss, Alzheimer's disease, arteriosclerotic dementia, depression, par Examples include Kinson's disease, Huntington's disease, and delayed movement disorder.
  • the compounds of the present invention, salts thereof, or prodrugs are expected to be effective against infectious diseases.
  • viral infections whose symptoms worsen by increasing or decreasing the production of TNF-a in the host body, such as HIV, cytomegalovirus (CMV), influenza virus, herpes virus (such as herpes zoster virus or simple herpes virus) Etc. are exemplified.
  • Inhibition of PDE4 activity can prevent proliferative cell chemotaxis or invasion, and therefore the compounds of the present invention, their salts, or prodrugs can be used to prevent tumor growth and entry into normal tissues. can do.
  • the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for the prevention and Z or treatment of asthma, for example, bronchial asthma
  • bronchial asthma For example, suppression of contraction of isolated bronchi, asthma model of bronchial asthma, inhibition of migration of human peripheral blood leukocytes (Kunihiko Iizuka: Allergy, 47, p.943, 1998, Kunihiko Iizuka, Akihiro Yoshii: Japanese Journal of Respirology, 37: pl96 , 1999).
  • Administration of the compound of the present invention, a salt thereof, or a prodrug thereof at 0.1 to 1000 mgZkg, preferably 0.1 to 100 mgZkg As a therapeutic agent for bronchial asthma by measuring the increase in bronchial resistance due to acetylcholine inhalation and histological analysis by oral administration, intravenous administration, or intraperitoneal administration to model animals. Usefulness can be confirmed.
  • the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicine for prevention, Z or treatment of chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • suppression of contraction of isolated bronchi, asthma model animal of bronchial asthma, exposure model of tobacco smoke exposure in guinea pigs (Keiichi Sugami et al., 73rd Annual Meeting of the Pharmacological Society of Japan, 2000), inhibition of migration of human peripheral blood leukocytes, etc. Can be confirmed.
  • a compound of the present invention, a salt thereof, or a prodrug thereof is administered orally, intravenously, or intraperitoneally to a guinea pig exposed to tobacco smoke at a dose of 0.1-lOOOOmgZkg, preferably 0.1-lOOmgZkg.
  • the usefulness of COPD as a therapeutic drug can be confirmed by measuring the number of migrating leukocytes in bronchoalveolar lavage fluid and histological analysis.
  • the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for the prevention and Z or treatment of pulmonary fibrosis. , Bleomycin-induced pulmonary fibrosis animal model, etc., for example, according to the method described in Am. J. Respir. Crit. Care Med., 163, p210-217, 2001.
  • the compound of the present invention, a salt thereof, or a prodrug thereof is orally administered intravenously to a pulmonary fibrosis mouse model at a dose of 0.1 to 1000 mg / kg, preferably 0.1 to 100 mg Zkg. Or by intraperitoneal injection and measuring respiratory function and the amount of hydroxyproline in lung tissue, its usefulness as a therapeutic agent for pulmonary fibrosis can be confirmed.
  • the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for the prevention and Z or treatment of rheumatoid arthritis. Or confirmed using a mouse collagen-induced arthritis model (Griffith, MM, et al, Arthritis Rheumatism, 24, p781, 1981; Wooley, PH, et al, J. Exp. Med., 154, p688, 1981.) it can.
  • the compound of the present invention, a salt thereof, or a prodrug thereof is administered orally, intravenously to a model mouse or model rat at a dose of 0.1-100 mg / kg, preferably 0.1-100 mg / kg, or Intraperitoneally administered, measuring footpad volume, and measuring bone destruction progress, confirmed its usefulness as a therapeutic agent for rheumatoid arthritis. It can be recognized.
  • a stress load model that the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for prevention and Z or treatment of irritable bowel syndrome.
  • stress model animals include restraint stress model rats (Miyata, K., et al, J. Pharmacol. Exp. Ther., 259, p8 15-819, 1991) and CRH-administered rat models (Miyata, K., et al. al, Am. J. Physiol., 274 (1998) G827-831) and the like.
  • the compound of the present invention, a salt thereof, or a prodrug thereof is administered orally, intravenously or intraperitoneally to a stress model animal at a dose of 0.1-1000 mg / kg, preferably 0.1-lOOmgZkg. Measure the number of defecations. The usefulness as a remedy for irritable bowel syndrome can be confirmed by the effect of reducing the number of defecations.
  • the compound of the present invention, a salt thereof, or a prodrug thereof is 0.1-lOOOOmgZkg, preferably 0 1—lOOmgZkg can be administered orally, intravenously or intraperitoneally, and its usefulness as an allergy drug can be confirmed by measuring plasma IgE level and eosinophil count.
  • the usefulness of the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof as an active ingredient of a medicine for prevention and Z or treatment of bone disease is, for example, removal of the ovary (Golub, LM, et al, Ann. NY Acad. Sci "878, p290-310, 1999)
  • the compound of the present invention and its salt , Or a prodrug thereof is administered orally, intravenously, or intraperitoneally to OVX mice at a dose of 0.1-lOOOmgZkg, preferably 0.1-lOOmgZkg, and the root loss and skeletal bone weight are measured. It can be confirmed to be useful as a remedy for dysplasia and osteoporosis due to the inhibitory effect on root loss and the decrease in skeletal bone weight.
  • the side effect of vomiting as a side effect is small! /,
  • ferrets Robotichaud, A "et al, Neuropharmacology, 38, p289-297, 1999; Endo, T. , et al "Biogenic. Amines., 9, pl63-175, 1992).
  • the compound should be administered orally, intravenously, or intraperitoneally to the ferret at a dose of 0.1-lOOOmg Zkg, preferably 0.1-lOOmgZkg, and then observe the frequency of vomiting and vomiting behavior. This makes it possible to confirm the presence or absence of side effects.
  • the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof has a less adverse effect on gastrointestinal disorders, which is an undesirable side effect. It can be confirmed by measuring gastric acid secretion enhancing activity (BergLindh et.al, Act a Physiol.Scand, 97: 401-414,1976 and Sack et.al, Am J.Physiol.243: G313-G319,198 2) .
  • in vitro inhibitory activity of PDE4B and 4D may be measured as a method for examining the selectivity of PDE4B and 4D. That is, the test compound was added to 40 mM Tris—HCl (pH 7 4), 5 mM MgCl, 4 mM 2-Mercaptoethanol, 3 M cAMP, 0.83 ⁇ Ci [
  • reaction mixture 100 1 containing the catalytic site of cAMP and human-type PDE4B and incubate at room temperature for 10 minutes. After stopping the enzymatic reaction by adding 25 1 of trichloroacetic acid to the reaction mixture, 0.1M 2 — [[Tris (hydroxylmethyl) methyl] amino] — 1 ethanesulfonic acid (TES) buffer (pH 8.0) Mix with neutral alumina equilibrated with). The supernatant is removed and neutral alumina is washed with a sufficient amount of 0.1M TES buffer and then eluted with 2N NaO 2 H.
  • TES ethanesulfonic acid
  • [ 3 H] Evaluation the in vitro inhibitory activity of the test compound against PDE4B by placing 500 1 of the eluate containing 5 'AMP product into a scintillation vial containing 3 ml of a scintillation cocktail and measuring the radioactivity. (Catherine Bar delle et.al, Analytical Biochemistry, 275, 148-155, 1999). The inhibitory activity of PDE4D can be measured in the same manner.
  • PDE4B and 4D it is also possible to examine the selectivity of PDE4B and 4D by using crude enzymes PDE4B and 4D obtained by culturing and purifying cells derived from a specific cancer cell line or tissue under certain conditions. It seems possible (International Immunopharmacology, 2, 1647-1656, 200 2). In other words, use HL60 cell line in RPMI1640 medium containing 10% non-immobilized fetal bovine serum and 1.3% DMSO for 10 days at 37 ° C, 95% air / 5% CO.
  • the PDE4D enzyme can be measured for in vitro inhibitory activity against PDE4D by using a partially purified PDE4D preparation obtained from U937 cultured in the usual manner (C. Shepherd et al. al., British Journal Of Pharmacology, 142, 339-351, 200 4).
  • the usefulness of the compound of the present invention represented by the general formula (1), a salt thereof, or a prodrug thereof is also confirmed by the value of the PDE4B inhibitory activity, which is an index of drug efficacy as an anti-inflammatory treatment. It seems possible to do.
  • the medicament of the present invention includes a compound represented by the general formula (1) or a salt thereof as an active ingredient.
  • a compound or a salt thereof administered as a prodrug is metabolized in vivo to give a compound represented by the general formula (1) or a pharmacologically acceptable product thereof.
  • a compound represented by the general formula (1) or a pharmacologically acceptable product thereof is metabolized in vivo to give a compound represented by the general formula (1) or a pharmacologically acceptable product thereof.
  • a pharmaceutical composition is prepared by adding one or more pharmacologically acceptable carriers to one or a mixture of two or more of the compounds represented by 1) or a pharmacologically acceptable salt thereof. It is preferable to prepare and administer.
  • permitted pharmacologically is not specifically limited, For example, an excipient
  • Examples of the disintegrant include corn starch.
  • Examples of the lubricant include glycerin.
  • Examples of the additive include paraoxybenzoic acid esters.
  • examples of additives include surfactants such as polyoxyethylenesorbitan monooleate (tween 80) and HC60.
  • the medicament of the present invention when administered to humans, it can be orally administered in the form of tablets, powders, granules, capsules, dragees, liquids, syrups, etc., or injections, drops, suppositories. It can also be administered parenterally in the form of transdermal or absorbent. Inhalation in the form of sprays such as aerosols and dry powders is also preferred and can be mentioned as dosage forms.
  • the administration period of the medicament of the present invention is not particularly limited, but when it is administered for therapeutic purposes, the period during which clinical symptoms of each disease are determined to be expressed is selected as the administration period in principle. Can do. In general, administration is usually continued for several weeks to 1 year, but it can be further continued depending on the disease state, or it can be continued after recovery from clinical symptoms. . Furthermore, even if clinical symptoms do not appear, it can be administered prophylactically at the discretion of the clinician.
  • the dosage of the medicament of the present invention is not particularly limited. 1S For example, generally 0.01 to 2000 mg of an active ingredient per day for an adult can be divided into several doses.
  • the frequency of dosing can be administered once a month, daily, preferably once to Z weeks to 3 times Z weeks, or 5 times Z weeks, or daily.
  • Daily dose The administration period and administration frequency may be increased or decreased as appropriate depending on the patient's age, weight, physical health, disease to be treated and its severity.
  • the drug of the present invention and a drug that does not adversely affect the action of the drug of the present invention can be used in combination.
  • examples of such drugs for combined use include the combination of the medicament of the present invention and the following A) -TT).
  • Iprato mouth bromide anticholinergic agents tioto mouth bromide, oxytropium bromide, etc.
  • LTB4, LTC4, LTD4 and LTE4 receptor antagonists Plan norecast, Zafinole norecast, Montenorecast, etc.
  • Thromboxane A2 synthase inhibitor Ozadarel hydrochloride and the like.
  • Chemical mediator release inhibitor sodium cromoglycate, tralast, amlexanox, levirinast, ibudilast, tazanolast, pemirolast, etc.
  • H) Histamine HI receptor antagonists ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, terfenadine, emedastine fumarate, epinastine hydrochloride, istemizole, ebastine, fuexofenadine hydrochloride, olopatadine hydrochloride, bepotastiti besylate And cetirizine hydrochloride.
  • Th2 site force-in inhibitor suplatast tosylate and the like.
  • MMP Matrix 'meta-oral protease
  • Immunosuppressive drugs cyclosporine, mizoribine, methotrexate, etc.
  • Anti-gout agents Cortisine etc.
  • V) Xanthine oxidase inhibitor alopurinol and the like.
  • TGF ⁇ Transforming growth factor
  • TGF ⁇ Transforming growth factor
  • Adhesion molecule inhibitors VLA-4 antagonists etc.
  • Bradykinin I B1 Receptor Antagonist
  • Bradykinin I B2 Receptor Antagonist
  • IGF— 1 Insulin-like growth factor type 1
  • PDGF Platelet-derived growth factor
  • PP Fibroblast growth factor: bFGF etc.
  • GM-CSF Granulocyte-macrophage mouth-priming factor
  • the administration time of the aforementioned concomitant drug is not limited, and the drug of the present invention and the concomitant drug may be administered to the administration subject at the same time or with a time difference.
  • the dose of the concomitant drug may be appropriately selected according to the administration subject, administration route, disease, combination of the drug of the present invention and the concomitant drug, etc., according to the clinically used dose. it can.
  • the administration mode of the concomitant drug is not particularly limited, as long as the drug of the present invention and the concomitant drug are combined in administration.
  • dosage forms include: 1) A single preparation obtained by simultaneously formulating the compound of the present invention, its salt, or its prodrug, which is an active ingredient of the medicament of the present invention, and a concomitant drug.
  • the mixing ratio of the medicament of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the usefulness of the medicament of the present invention is that mammals including humans (for example, mice, rats, hamsters, frets, inu, monkeys, etc.) and cells of mammals including humans (immune cells, inflammation, etc.) (E.g., cells, cancer progenitor cells, primary cells, living cells, etc.), effects on the compound of the present invention, salts thereof, or prodrugs thereof, and changes in Z or blood concentration (e.g., maximum blood concentration). Effective blood concentration duration, blood half-life, AUC, etc.) Further, by examining the low toxicity of the compound of the present invention, a salt thereof, or a prodrug thereof, it can be confirmed that the usefulness as a medicament is higher. Furthermore, the usefulness can be confirmed by the blood concentration transition in humans or animals, enzyme induction, enzyme inhibition, and stability to microsomes.
  • LC-MS HPLC was performed using a column (Develosil C30-UG-54.6X50mm) manufactured by Japan Nomura Chemical Co., using water-acetonitrile (containing 0.1% ( ⁇ / ⁇ ) acetic acid) gradient elution. The target product was eluted by. The detailed elution conditions are shown below.
  • Reference Example 6 5-Methoxythiophene-2-carboxamidine Dissolve the compound of Reference Example 5 (281 mg) in jetyl ether (12 mL), add lithium bis (trimethylsilyl) amide in 2M hexane (4 mL) at 0 ° C under a nitrogen atmosphere, and stir at room temperature for 1 hour. did. After that, 2M hydrochloric acid (6mL) and water (10mL) were added at 0 ° C, and 2M sodium hydroxide aqueous solution (9mL) was added to the separated aqueous layer, extracted with chloroform, and the organic layer was extracted with magnesium sulfate. Concentration was performed after drying with a solution to obtain 267 mg of the title compound.
  • Example 2 to 27 The compounds of Examples 2 to 27 were synthesized according to the method of Example 1. Details of Examples 2 to 27 are shown in Table 1. The meanings of the symbols in Table 1 are as shown below. “Exp.”: Example number, “Str.”; Example compound, “RT”: LCMS retention time (minutes), “MS”; LCMS mass spectral data, “Ref.” Correspondence A method for producing an intermediate. The symbols in the Ref. Column indicate the method for producing the intermediate as follows. “A”: production method shown in Reference Example 1, “B”: production method shown in Reference Example 2, “C”: production method shown in Reference Example 3, “D”: production shown in Reference Example 4 “E”: production method shown in Reference Example 5, “F”: production method shown in Reference Example 6.
  • 5-formylthiophene-2-carboxylic acid (3.13 g, manufactured by Tokyo Chemical Industry Co., Ltd.) is dissolved in ⁇ , ⁇ -dimethylformamide (lOOmL), sodium carbonate (8.64 g, manufactured by Wako Pure Chemical Industries, Ltd.), and odomethane (2.49 mL) , Manufactured by Tokyo Chemical Industry Co., Ltd.) at room temperature and stirred for 11 hours. Not from reaction mixture The solute was filtered off, water (200 mL) was extracted with sodium ketyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated to give 3.26 g of the title compound.
  • reaction mixture was allowed to cool to room temperature, then transferred to a mixture of silica gel 60 (14 g, Merck) and black mouth form (20 ml, Wako Pure Chemical Industries), stirred for 5 minutes, and filtered through a glass filter. The filtrate was concentrated and dried to obtain 458 mg of the title compound.
  • 5-bromothiophene-2-carbo-tolyl (333 ⁇ 1, Aldrich) was added to anhydrous methanol (7 ml, dissolved in Wako Pure Chemical Industries, Ltd.), sodium methoxide (28% methanol solution, 288 1) was added dropwise at room temperature and stirred for 1 hour. Thereafter, sodium chloride sodium (321 mg, manufactured by Aldrich) and anhydrous ethanol (7 ml, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was stirred at 90 ° C. for 14 hours. The residue obtained by concentrating the filtrate was washed several times with jetyl ether and filtered to obtain 660 mg of the title compound.
  • Nitrogen atmosphere 2- (4-Nitrofuryl) -2-oxoacetate (0.99 g) was dissolved in methanol (40 ml), and 10% Pd / C (0.48 g) was added. The nitrogen atmosphere was replaced with a hydrogen atmosphere under reduced pressure, and the mixture was stirred at room temperature for 3 hours. The mixture obtained by filtering the reaction solution was concentrated and then applied to a silica gel column (hexane / ethyl acetate 1/1) to obtain 837.2 mg of the title compound.
  • the compound of Reference Example 23 (90 mg) was dissolved in tetrahydrofuran (10 mL), sodium borohydride (53 mg, manufactured by Wako Pure Chemical Industries, Ltd.) was added at room temperature, and the mixture was stirred as it was for 4 hours. Water (30 mL) was extracted from the reaction mixture with sodium ketyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated to obtain 83 mg of the title compound.
  • Example 29 The compound of Example 29 (60.3 mg) was dissolved in toluene (0.338 ml) and methanol (0.135 ml), and 2M aqueous sodium carbonate solution (122 ⁇ 1), tetrakistriphenylphosphine palladium (15.6 mg, manufactured by Aldrich) ) And 4-ethylphenylboronic acid (30.5 mg, manufactured by Aldrich) were added and stirred at 85 ° C. for 13 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, washed several times with methanol, and the mother liquor was concentrated. Water was added to the resulting residue, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated.
  • LC-MS HPLC retention time 5.18 min (LC condition 1), m / z 458 (M + H).
  • L C-MS HPLC retention time 3.58 min (LC condition 1), m / z 439 (M + H).
  • Example 29 The compound of Example 29 (23 mg) was dissolved in dimethylformamide (0.5 ml). 12.6 mg (manufactured by Kokusan Chemical Co., Ltd.) and tetraptylammonium chloride (13.9 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) were added, and the mixture was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was filtered through celite, washed with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated.
  • Example 29 The compound of Example 29 (45.9 mg) was dissolved in toluene (0.5 ml), and cyclopropylboronic acid (11 • 2 mg, manufactured by Aldrich), potassium phosphate (74.3 mg, manufactured by Aldrich), tricyclohexylphosphine (2.8 mg, manufactured by Aldrich), palladium acetate (0.5 mg, manufactured by Wako Pure Chemical Industries) and water (251) were added, followed by stirring at 100 ° C. for 19 hours in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through celite, washed with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate.
  • Example 29 The compound of Example 29 (91.8 mg) was dissolved in 1-propanol (2 ml), and potassium butyl trifluoroborane (32.2 mg, manufactured by LANCASTER), (1,1, -bis (diphenylphosphino) phenolate) dichloro Palladium 'dichloromethane complex (3.26 mg, manufactured by Aldrich) and triethylamine (27.91, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was stirred at 105 ° C for 4.5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated.
  • Example 44 The compound of Example 44 (23.4 mg) was dissolved in tetrahydrofuran (0.4 ml), and a solution of borane / tetrahydrofuran complex in tetrahydrofuran (66.2 1, manufactured by Kanto Sugaku Co., Ltd.) was stirred and stirred for 5 minutes. Thereafter, the mixture was stirred at room temperature for 22 hours. Cool the reaction mixture to -15 ° C, add 30% hydrogen peroxide solution (391, manufactured by Pure Chemicals), stir for 30 minutes, and then add 2N sodium hydroxide aqueous solution (921, Wako Pure Chemical). The mixture was stirred for 1 hour and then further stirred at room temperature for 2 hours.
  • Example 29 The compound of Example 29 (45.9 mg) was dissolved in 1,4-dioxane (0.5 ml), and copper iodide (1 mg, manufactured by Wako Pure Chemical Industries, Ltd.), sodium iodide (30 mg, manufactured by Wako Pure Chemical Industries, Ltd.) and ( 1S, 2S)-(+)- ⁇ , ⁇ , -dimethylcyclohexane 1,2-diamin (1.421, manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred at 110 ° C for 23 hours.
  • LC-MS HPLC retention time 5.56 min (LC condition 1), m / z 450 (M + H).
  • Example 47 The compound of Example 47 (7.9 mg) was dissolved in methanol (0.5 ml), and sodium hydroxide palladium (2 mg, Pd type, manufactured by EN Chemcat) was added and stirred for 13 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with ethyl acetate and chloroform, and concentrated to give 8. lmg of the title compound.
  • LC-MS HPLC retention time 4.47 minutes (LC condition 1), m / z 454 (M + H).
  • Examples 50 to 267 The production of the compounds of Examples 50 to 267 is shown below. Details of Examples 50 to 267 are shown in Table 3. The meanings of the symbols in Table 3 are as shown below. “E xp.”; Example number, “Str.”; Example compound, “RT”; Retention time of liquid chromatography in LCMS (minutes), “LC”; “MS”: LCMS mass spectral data, “Ref.” Corresponding intermediate production method, “Ex.” Corresponding example compound production method. The symbols in the Ref. Column and Ex. Column indicate the manufacturing method as follows.
  • the compound of Reference Example 22 (61 mg) was dissolved in phosphorus oxychloride (4 mL) and stirred at 100 ° C. for 2.5 hours under a nitrogen atmosphere. Concentrate the reaction mixture, add saturated aqueous sodium hydrogen carbonate solution (5 mL) and water (25 mL) to the residue, extract with ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and concentrate to give 62 mg of the title compound. Got.
  • Methyl 2- (3-fluorophenyl) acetate (10.76 g) was dissolved in concentrated sulfuric acid (16.5 ml), cooled to 0 ° C., concentrated nitric acid (2.99 ml) was added, and the mixture was stirred for 4 hours.
  • the reaction mixture was poured into ice water and extracted with ethyl acetate.
  • the obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated.
  • Example 273 to 389 The production of the compounds of Examples 273 to 389 is shown below. Details of Examples 273 to 389 are shown in Table 5. The meanings of the symbols in Table 5 are as shown below. “Exp.”; Example number, “Str.”; Example compound, “RT”; Retention time of liquid chromatography in LCMS (min), “LC”; Solvent conditions for liquid chromatography in LCMS, “ MS ”; mass spectral data in LCMS,“ Ref. ”Corresponding intermediate production method, ⁇ .” Corresponding example compound production method. The symbols in the Ref. Column and Ex. Column indicate the manufacturing method as follows.
  • Example 390 2- (4- (2- (5- (Difluoromethoxy) thiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) ethyl acetate 2- (4- (2- (5-hydroxythiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenyl) ethyl acetate (61 mg) was added to ⁇ , ⁇ -dimethyl Dissolve in formamide (4 mL), add lithium carbonate (34 mg, manufactured by Kanto Chemical Co., Inc.) and t-butyl chlorodifluoroacetate (86 mg, manufactured by Apollo) sequentially, and stir at 90 ° C for 1 hour in a nitrogen atmosphere.
  • lithium carbonate 34 mg, manufactured by Kanto Chemical Co., Inc.
  • t-butyl chlorodifluoroacetate 86 mg, manufactured by Apollo
  • PDE4 enzyme protein was also purified from U937 cells, which are cells derived from lymphoma. Buffer U937 cells with protease inhibitor cocktail (Sigma) (20 mM Tris HCl (pH 6.5), ImM MgCl, 0. ImM EGTA, 3 mM 2-mercaptoethanol
  • the cells were disrupted by sonication, disrupted by sonication, and ultracentrifuged (100,000G, 30 minutes, 4 ° C) to obtain a soluble fraction.
  • a 1.6 ⁇ 25 cm Q Sepharose column equilibrated with Buffer A was packed with the resulting soluble fraction.
  • the packed soluble fraction was eluted with buffer A containing a linear gradient of 0-1M sodium acetate.
  • the elution rate was 1.33 ml Z and 11 ml fractions were collected.
  • Each fraction was examined for cAMP metabolizing PDE activity and the fraction containing PDE4 enzyme protein was determined. It was also confirmed that this PDE4 fraction did not degrade cGMP.
  • Test compounds at desired concentrations of 40 mM Tris-HCl (pH 7.4), 5 mM MgCl, 4 mM
  • reaction was carried out at 30 ° C. for 10 minutes in a reaction mixture (100 1) containing M 2 -mercaptoethanol, 3 cAMP, 0.83 ⁇ Ci [ 3 H] —cAMP and PD E4 fractions.
  • the enzyme reaction was stopped by adding triclonal acetic acid 25 1 to the reaction mixture.
  • the reaction solution was packed in a neutral alumina column equilibrated with 0.1M 2-[[Tris (hydroxylmethyl) methyl] amino]-1-ethanesulfonic acid (TES) buffer (pH 8.0) After washing with an amount of 0.1M TES buffer, it was eluted with 2N NaOH.
  • TES Tris (hydroxylmethyl) methyl] amino]-1-ethanesulfonic acid
  • Examples of compounds that showed PDE4 inhibitory activity of 50% or more at a compound concentration of 20 / M are shown below.
  • ⁇ Test Example 2 Inhibition of TNF-a production using mouse mononuclear cells (in-vitro system) Mouse mononuclear cells were isolated from peripheral blood of C3HZHe mice (Japan SLC, male) and 10% bovine serum Suspended in a culture solution (RPMI1640; GIBCO). Cells to 96-well plate The test compound was added to a desired concentration and left in a 37 ° C, 5% CO incubator for 15 minutes. Then LPS at a final concentration of 5 gZml
  • the culture medium containing the produced TNF-a was collected and measured with a mouse TNF-a measurement ELISA kit (R & D System) according to the attached protocol.
  • a mouse TNF-a measurement ELISA kit R & D System
  • the inhibitory effect on TNF- ⁇ production was expressed as an IC50 value (nM).
  • IC50 value nM
  • gastric glands were collected by collagenase enzyme treatment using male rabbits (Japanese white species, oriental yeast).
  • Test compound 14 C-Aminopyrine (1.0 nmol / ml; 0.1 ⁇ Ci / nmol), and histamine (0.3-1.0
  • Deviation A Gastric acid secretion capacity EC50 value ZTNFa production inhibition IC50 value [0161] [Table 10]

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Abstract

Composé représenté par la formule générale (1) lequel a un effet inhibiteur sur l'activité de la phosphodiestérase 4 (PDE4) et produit peu d'effets secondaires négatifs : (1) dans laquelle Ar1 représente un groupe furyle, thiényle, triazolyle, thiazolyle, oxazolyle ou benzothiazolyle ; Ar2 représente -E-AR21-G-Q (où Ar21 représente un noyau benzénique ou naphtalénique ; E représente une simple liaison ou un groupe alkylène ; G représente une simple liaison, un groupe alkylène ou un groupe alcénylène ; et Q représente un groupe carboxyle, -CON(R41)(R42) ou -COOR43), -E-Ar21-G2-G-Q (où E, Ar21, G et Q sont tels que définis ci-dessus ; et G2 représente -O-, -S-, -SO-, -SO2- ou -NRG21-) ou un hétérocycle aromatique monocyclique autre qu'un groupe pyrazolyle ; R1 et R2 sont identiques ou différents l'un de l'autre et représentent indépendamment un atome d'hydrogène, un groupe alkyle qui peut être substitué ou similaire ; et R3 représente un atome d'hydrogène ou un groupe alkyle qui peut être substitué.
PCT/JP2006/309713 2005-05-18 2006-05-16 Dérivé de pyrimidine WO2006123639A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865723B2 (en) 2012-10-25 2014-10-21 Tetra Discovery Partners Llc Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury
JP2016505512A (ja) * 2012-10-25 2016-02-25 テトラ ディスカバリー パートナーズ エルエルシー Ｐｄｅ４のヘテロアリール阻害剤

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JPH0789958A (ja) * 1993-08-26 1995-04-04 Ono Pharmaceut Co Ltd ４−アミノピリミジン誘導体、その製造方法およびそれを含有する医薬品
WO2001083460A1 (fr) * 2000-04-28 2001-11-08 Tanabe Seiyaku Co., Ltd. Composes cycliques
WO2004014913A2 (fr) * 2002-08-08 2004-02-19 Memory Pharmaceuticals Corporation Inhibiteurs de la phosphodiesterase 4
WO2006004776A1 (fr) * 2004-06-29 2006-01-12 Rigel Pharmaceuticals, Inc. Composés de 4-pyrimidineamine et leurs utilisations en tant qu’agent anti-prolifération
WO2006037117A1 (fr) * 2004-09-27 2006-04-06 Amgen Inc. Composes heterocycliques substitues et procedes d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0789958A (ja) * 1993-08-26 1995-04-04 Ono Pharmaceut Co Ltd ４−アミノピリミジン誘導体、その製造方法およびそれを含有する医薬品
WO2001083460A1 (fr) * 2000-04-28 2001-11-08 Tanabe Seiyaku Co., Ltd. Composes cycliques
WO2004014913A2 (fr) * 2002-08-08 2004-02-19 Memory Pharmaceuticals Corporation Inhibiteurs de la phosphodiesterase 4
WO2006004776A1 (fr) * 2004-06-29 2006-01-12 Rigel Pharmaceuticals, Inc. Composés de 4-pyrimidineamine et leurs utilisations en tant qu’agent anti-prolifération
WO2006037117A1 (fr) * 2004-09-27 2006-04-06 Amgen Inc. Composes heterocycliques substitues et procedes d'utilisation

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865723B2 (en) 2012-10-25 2014-10-21 Tetra Discovery Partners Llc Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury
JP2016505512A (ja) * 2012-10-25 2016-02-25 テトラ ディスカバリー パートナーズ エルエルシー Ｐｄｅ４のヘテロアリール阻害剤
US11401286B2 (en) 2012-10-25 2022-08-02 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US11767334B2 (en) 2012-10-25 2023-09-26 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US12264169B2 (en) 2012-10-25 2025-04-01 Tetra Discovery Partners Heteroaryl inhibitors of PDE4

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