+

WO2006006644A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

Info

Publication number
WO2006006644A1
WO2006006644A1 PCT/JP2005/012996 JP2005012996W WO2006006644A1 WO 2006006644 A1 WO2006006644 A1 WO 2006006644A1 JP 2005012996 W JP2005012996 W JP 2005012996W WO 2006006644 A1 WO2006006644 A1 WO 2006006644A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
alkyl
defined above
Prior art date
Application number
PCT/JP2005/012996
Other languages
English (en)
Japanese (ja)
Inventor
Koji Yanagawa
Atsuko Sato
Kimihisa Ueno
Shinya Fujii
Akiko Watanabe
Ichiro Miki
Kaori Tozaki
Seiji Aratake
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to JP2006529110A priority Critical patent/JPWO2006006644A1/ja
Publication of WO2006006644A1 publication Critical patent/WO2006006644A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • 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
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a heterocyclic compound having elastase inhibitory action or the like, or a pharmaceutically acceptable salt thereof, and the like.
  • Serine protease is a general term for proteolytic enzymes (proteases) having a serine residue in an active site such as elastase, chymotrypsin, cathebucin G, trypsin, thrombin, and the like. There are three residues, histidine and aspartate, which are responsible for substrate degradation.
  • elastase is a general term for proteases having an activity of degrading elastin constituting the connective tissue. For example, neutrophil elastase, spleen elastase, meta-oral elastase, and the like are known.
  • HNE Human neutrophil elastase
  • ⁇ 1-PI 1 proteinase inhibitor
  • factor IX is known to be activated by erythrocytes.
  • the enzyme responsible for activating factor IX is elastase on the erythrocyte membrane [Biochemical and Biophysics Res. Commun. , 2004, 316, ⁇ .65-70, etc.], it is considered that venous thromboembolism can be prevented by inhibiting the activity of elastase.
  • R a represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic alkyl, etc.
  • R bl represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic alkyl, di-lower alkylamino, etc.
  • R b2 and R b3 represent same or different, each represent a hydrogen atom, methyl, isopropyl, etc.
  • R b5 represents a hydrogen atom, carbobenzyloxy O carboxymethyl etc. Represents
  • R d represents hydroxy, aminocarbol, hydroxymethyl, etc.
  • X f represents a hydrogen atom or a fluorine atom
  • i represents methyl, isopropyl, n-butyl.
  • R e represents a hydrogen atom or an amino.
  • the compound has a skeleton of 1- (aminocarbonylmethyl) pyridin-2-one, 1- (aminocarbonylmethyl) pyrimidine1-2-one or 1- (aminocarbomethyl) pyrazin-2-one in the structure. It is known to be useful as an anticoagulant (see Patent Document 5, Patent Document 6, and Patent Document 7).
  • Patent Document 1 Pamphlet of International Publication No. 96/16080
  • Patent Document 2 International Publication No. 98/24806 Pamphlet
  • Patent Document 3 International Publication No. 01/40263 Pamphlet
  • Patent Document 4 Japanese Patent Application Laid-Open No. 64-45395
  • Patent Document 5 Pamphlet of International Publication No. 00/69826
  • Patent Document 6 International Publication No. 00/69832 Pamphlet
  • Patent Document 7 International Publication No. 00/69834 Pamphlet
  • Non-Patent Document 1 "Journal 'Ob' Medicinal Chemistry” (J. Med. Chem.), 1995, No. 38, p.76-85
  • Non-Patent Document 2 “Journal 'Ob' Medicinal Chemistry” (2001), No. 44, p.1268-1285
  • An object of the present invention is to provide, for example, a heterocyclic compound having an elastase inhibitory action or the like or a pharmacologically acceptable salt thereof.
  • the present invention relates to the following (1) to (36).
  • R 2 and R 3 are the same or different and each represents a hydrogen atom, lower alkyl or alicyclic alkyl,
  • R 1 is the formula ( ⁇ )
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, lower alkyl or alicyclic alkyl,
  • R 6 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aromatic heterocyclic ring. Represents a group,
  • R 7 is a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or Unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyloxy, —NR 9 (wherein R 8 and R 9 are the same or different and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted Alicyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic Ring alkyl, substituted or unsub
  • X 1 and X 2 are the same or different and represent a nitrogen atom or CR 11 (wherein R 11 represents a hydrogen atom, lower alkyl or halogen), and two Rs when X 1 and X 2 are both CR 11 11 can be the same or different ⁇ ]
  • R 12 and R 13 are the same or different and each represents a hydrogen atom or lower alkyl
  • R 1 is the above formula ( ⁇ ) and
  • the cyclic A group has the formula (IVA)
  • T represents a nitrogen atom or CH
  • U represents an oxygen atom or a sulfur atom
  • R 22 is hydroxy, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted Substituted lower alkoxy, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic hetero Cyclic group, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted alicyclic heterocyclic alkyl, substituted Or an unsubstituted lower alkoxy carbo yl, a substituted or unsubstituted aryl chloride, a substituted or unsubstituted lower alkyl sul
  • R 27a and R 27b are the same or different and each represents a hydrogen atom, Cal Bokishi, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic Represents a heterocyclic group or a substituted or unsubstituted lower alkoxycarbonyl),
  • R 2 & and R 28d are the same or different and each represents a hydrogen atom, carboxy, lower alkyl, lower alkenyl, lower alkynyl, alicyclic alkyl, aryl, aralkyl, aromatic heterocyclic group, alicyclic heterocyclic group, aromatic heterocyclic Represents a cyclic alkyl or a lower alkoxy carbo)) or [Chemical 11]
  • R b are the same or different and each represents a hydrogen atom, hydroxy, carboxy, amino, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl; -, Substituted or unsubstituted lower alkynyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Represents an alicyclic heterocyclic group or a substituted or unsubstituted lower alkoxycarbonyl) ⁇ or
  • T is as defined above, and R 3 ° a , R 3Qb and R 3Qe are the same or different and each represents a hydrogen atom, a halogen, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl.
  • R 1 is the above formula ( ⁇ ), and In the formula ( ⁇ )!
  • X 1 is CR 11 (wherein R 11 is as defined above), X 2 is a nitrogen atom and R 7 is a hydrogen atom or NR (wherein R 8 and R 9 are each The cyclic A group has the formula (IVB)
  • R 19B is lower alkyl, substituted or unsubstituted lower alkoxyalkyl, substituted or unsubstituted alicyclic alkyloxyalkyl, substituted or unsubstituted Substituted alicyclic heterocyclic oxyalkyl, substituted or unsubstituted alicyclic alkyl alkyl, substituted or unsubstituted alicyclic alkyl alkyl, substituted or unsubstituted lower alkylsulfuralkyl, substituted or unsubstituted arylsulfur -Alkyl, substituted or unsubstituted lower alkylsulfonyl alkyl, substituted or unsubstituted arylsulfonyl alkyl, substituted or unsubstituted alicyclic alkylalkyl, substituted or unsubstituted alicyclic alkylalkyl.
  • the cyclic A group is of formula (IVC)
  • T and U are as defined above, and each represents a substituted or unsubstituted lower alkylsulfoalkyl) or a pharmacology thereof Acceptable salt.
  • Cyclic A A group is of formula (IVA)
  • Nitrogen atom or CR 11 (wherein, R 11 has the same meaning as defined above) X 1A and X 2A are the same or different and represent, two R 11 when X 1A and X 2A is CR 11 together are in the same It ’s okay to be different.
  • Cyclic A group A is formula (IVA)
  • R 7A (Wherein Q 1 and R 1 (> are as defined above), respectively, or a heterocyclic compound or a pharmaceutically acceptable salt thereof according to (8) or (9).
  • R 2 , R 3 , R 4 , R 5 , R 6 and RU are each as defined above,
  • R 7B represents a hydrogen atom or —NR (wherein R 8 and R 9 are the same as defined above),
  • Cyclic A B group is of formula (IVB-i)
  • the cyclic A B group is of formula (IVB-ii)
  • a medicament comprising, as an active ingredient, the heterocyclic compound according to any one of (1) to (23) or a pharmaceutically acceptable salt thereof.
  • An elastase inhibitor comprising, as an active ingredient, the heterocyclic compound according to any one of (1) to (23) or a pharmacologically acceptable salt thereof.
  • a neutrophil elastase inhibitor comprising the heterocyclic compound according to any one of (1) to (23) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a disease involving a neutrophil elastase comprising the heterocyclic compound according to any one of (1) to (23) or a pharmacologically acceptable salt thereof as an active ingredient Treatment and Z or preventive.
  • a neutrophil elastase characterized by administering an effective amount of the heterocyclic compound according to any one of (1) to (23) or a pharmacologically acceptable salt thereof. How to inhibit. (31) Elastase characterized by administering an effective amount of the heterocyclic compound according to any one of (1) to (23) above or a pharmacologically acceptable salt thereof is involved. Disease treatment and Z or prevention methods.
  • an effective amount of the heterocyclic compound according to any one of (1) to (23) or a pharmaceutically acceptable salt thereof is administered.
  • Treatment and Z or prevention methods for diseases involving neutrophil elastase are particularly preferred.
  • a heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (23) above for the treatment of a disease involving elastase and the manufacture of a Z or prophylactic agent. use.
  • lower alkyl and lower alkyl in lower alkoxy, lower alkoxyalkyl, lower alkylsulfur, lower alkylsulfuryl, lower alkylsulfuralkyl, lower alkylsulfuralkyl and lower alkoxycarbocycle include Examples thereof include linear or branched alkyl having 1 to 12 carbon atoms.
  • methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Examples include butyl, tert-butyl, pentinole, isopentyl, neopentyl, hexyl, heptinole, octyl, noel, decyl, undecyl, dodecyl and the like.
  • alkylene moiety of alkyl, lower alkylsulfanylalkyl, lower alkylsulfoalkyl, arylsulfuralkyl and arylarylalkyl include those obtained by removing one hydrogen atom from the lower alkyl.
  • Examples of the lower alkali include linear or branched alcohol having 2 to 12 carbon atoms. Specific examples include bulle, allyl, 1-probe, iso-probe, methacrylate, butur, crotyl, pentell, hexyl, heptul, decel, dodecyl, etc. Is done.
  • alkene moiety of the alicyclic alkyl alkaryl examples include those obtained by removing one hydrogen atom from the lower alkenyl.
  • Examples of the lower alkynyl include linear or branched alkyl having 2 to 12 carbon atoms. Specific examples include ethur, propargyl, butur, pentyl, hexul, heptul, decynyl, dodecynyl and the like.
  • alkylene moiety of the alicyclic alkyl alkyl include those obtained by removing one hydrogen atom from the lower alkyl.
  • Examples of the alicyclic alkyl moiety include monocyclic or polycyclic alkyl having 3 to 12 carbon atoms.
  • examples of the monocyclic cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, and the like.
  • examples of the polycyclic cyclic alkyl include pina- And adamantyl, bicyclo [3.3.1] noel, bicyclo [3.1.1] heptyl, bicyclo [2.1.1] hexyl and the like.
  • Examples of the alicyclic alkenyl moiety of the alicyclic alkylalkyl include, for example, 4 to 8 carbon atoms.
  • the following are examples of the circular balloon. Specifically, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptyl, cyclootatule and the like are exemplified.
  • aryls and aryl moieties of aryl reels, aryl reel alkyls, aryl reel alkyls and aryl reels include aryls having 6 to 14 carbon atoms. Specific examples include phenol, naphthyl, indul, anthryl, pyrenyl and the like.
  • Examples of the aralkyl portion of aralkyl and aralkyloxy include those exemplified in the above-mentioned examples of aralkyl, and examples of the alkylene portion of aralkyl and aralkyloxy include those obtained by removing one of the lower alkyl force hydrogen atoms. . Specific examples include propyl, phenylpropyl, phenylbutyl, benzhydryl, trityl, naphthylmethyl, naphthylethyl and the like.
  • Examples of the aromatic heterocyclic group part of the aromatic heterocyclic group and the aromatic heterocyclic alkyl include, for example, a nitrogen atom, an oxygen atom and sulfur atomic energy.
  • pyridyl pyrazinyl, pyrimidyl, pyridazyl, oxopyridazil, quinolyl, isoquinolyl, phthaladyl, quinazolyl, quinoxalinyl, naphthyridyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl, triazolyl, tetrazolyl, Chenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzochel, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, purinyl, dibenzofuranyl, etc. Illustrated.
  • the alicyclic heterocyclic group portion of the alicyclic heterocyclic group, alicyclic heterocyclic alkyl and alicyclic heterocyclic oxyalkyl is, for example, at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • 4- to 10-membered monocyclic alicyclic heterocyclic group containing atoms, bicyclic or tricyclic condensed 3- to 8-membered ring, nitrogen atom, oxygen atom and sulfur nuclear power are selected Examples thereof include a condensed alicyclic heterocyclic group containing at least one atom.
  • heterocyclic group formed together with the adjacent nitrogen atom examples include, for example, a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group). May contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed ring-containing heterocyclic group containing 3 to 8 membered rings and containing at least one nitrogen atom (The condensed polycyclic group may contain other nitrogen atom, oxygen atom or sulfur atom) and the like.
  • pyrrolidyl piperidyl-containing piperazil, morpholino, thiomorpholine-containing homopiverided homopiperadur, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl and the like.
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • Substituents in substituted lower alkoxy, substituted lower alkylsulfol, substituted lower alkylsulfanyl, substituted lower alkoxyalkyl, substituted lower alkylsulfuralkyl, substituted lower alkylsulfuralkyl, and substituted lower alkoxycarbonyl (A ) are the same or different and include, for example, a substituent having 1 to 3 substituents.
  • -tro sialylated hydroxy, formyl, carboxy, ureido, thioureido, nitrogen, substituted or unsubstituted Lower alkoxy, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxy carbocycle, alicyclic alkyl, alicyclic alkyl Kiroxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkyloxy, — NR 31 R 32 (wherein R 31 and R 32 are the same or different and represent a hydrogen atom, lower alkyl, alicyclic alkyl, aryl , Aralkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, aromatic heterocyclic alkyl, alicyclic heterocyclic alkyl, lower alkanoyl, alicyclic alkylcarbonyl,
  • Til lower alkenyl, lower alkynyl, lower alkoxy, alicyclic alkyl, alicyclic alkyloxy, aryl, aralkyl, aromatic heterocyclic group, alicyclic heterocyclic group, aromatic heterocyclic alkyl, alicyclic heterocyclic alkyl Or SR 34 (wherein R 34 represents a hydrogen atom, lower alkyl, trifluoromethyl, lower alkenyl, lower alkynyl, alicyclic alkyl, aryl, aralkyl, aromatic, or substituted or unsubstituted amino) An aromatic heterocyclic group or an alicyclic heterocyclic group).
  • substituent (b) in the substituted aryloxy and substituted aralkyloxy include the same or different, for example, a substituent having 1 to 3 substituents.
  • -Tro sia-containing hydroxy, formyl, carboxy, ami-in halogen, lower alkoxy, lower alkoxy carbo yl, etc.
  • substituent (c) in the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group are the same or different and include, for example, a substituent having 1 to 3 substituents, specifically, halogen, lower alkyl, lower alkoxy, amino-substituted lower amine. Kiruamino, di-lower ⁇ alkylamino, and the like.
  • substituent (d) in the substituted amino group exemplified in the substituent (A) is the same or different, and examples thereof include a substituent having 1 or 2 substituents, specifically, a lower alkyl, Examples thereof include alicyclic alkyl, aryl, aralkyl, aromatic heterocyclic group, alicyclic heterocyclic group, aromatic heterocyclic alkyl, alicyclic heterocyclic alkyl and the like.
  • Halo in the examples of the substituent (A), the substituent (a), the substituent (b), the substituent (c), and the substituent (d) Gen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkenyl, lower alkynyl, alicyclic alkyl, alicyclic alkyloxy, aryl, aralkyl, aralkyloxy, aromatic heterocyclic group, alicyclic heterocyclic group, aromatic heterocyclic Cyclic alkyl and alicyclic heterocyclic alkyl are as defined above, and the aryl moiety of allyloxy and alloy are as defined above, and lower alkylamino-containing dilower alkylamimed lower alkylaminocarbol, dialkyl.
  • the lower alkyl part of the lower alkylaminocarbol and lower alkanoyl has the same meaning as the aforementioned lower alkyl, and the two lower alkyl parts of the dilower alkylamino and dilower alkylaminocarbo may be the same or different.
  • a substituted or unsubstituted lower alkyl a substituted or unsubstituted aryl, substituted or substituted Non-replaceable aralkyl and the like.
  • the lower alkyl, aryl and aralkyl mentioned in the examples of the substituent (B) have the same meanings as described above, and the substituents in the substituted lower alkyl, substituted aryl and substituted aralkyl have 1 to 3 substituents. Examples thereof include the substituents, and specific examples thereof include the groups exemplified in the substituent (b).
  • substituent (C) in the substituted lower alkyl, the substituted lower alkyl and the substituted lower alkyl are the same or different and include, for example, a substituent having 1 to 3 substituents, specifically -tro, Sheared hydroxy, formyl, carboxy, ureido, thioureido, noble Logene, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted alicyclic alkenyl, substituted or unsubstituted alicyclic Alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted alicyclic heterocyclicoxy, —NR 31 R 32 (wherein R 31 and R 32 are as defined above) ), — S 0 R 33A
  • Examples of the substituent (e) in the substituted lower alkyl, substituted lower alkoxy and substituted aryl exemplified in the substituent (C) include substituents having 1 to 3 substituents.
  • Examples of the substituent (A) include the groups described above, and the substituents in the substituted alicyclic alkyl, substituted alicyclic alkyl, substituted alicyclic alkyloxy and substituted alicyclic heterocyclicoxy ( Examples of 1) include, for example, substituents having 1 to 3 substituents, and specific examples include the groups exemplified in the substituent (B), and examples of the substituents in the substituted lower alkoxy carbo Examples include substituents having 1 to 3 substituents, and specific examples include the groups exemplified in the substituent (a).
  • Examples of the substituents in substituted aryloxy and substituted aralkyloxy include, for example, the number of substituents. 1 to 3 substituents are mentioned, specifically, substituents (
  • a cyclic group, an alicyclic heterocyclic group, an aromatic heterocyclic alkyl, and an alicyclic heterocyclic alkyl have the same meanings as described above, and an alicyclic alkenyl has the same meaning as the alicyclic alkenyl part of the alicyclic alkenyl alkyl.
  • the alicyclic heterocyclic group portion of the alicyclic heterocyclic oxy is the alicyclic heterocyclic group.
  • the aryl group of the aryloxy is synonymous with the aryl.
  • Examples of the pharmacologically acceptable salt of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Examples of the pharmacologically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, tartrate, and queen.
  • Organic acid salts such as acid salts and methanesulfonates are exemplified, and examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metals such as magnesium salts and calcium salts Metal salts, aluminum salts, zinc salts, and the like are listed, and pharmacologically acceptable ammonium salts include, for example, salts such as ammonium and tetramethyl ammonium salts.
  • Examples of acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and examples of pharmacologically acceptable amino acid addition salts include addition salts such as lysine, dalysin, and ferrolanine. can give.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of diseases involving elastase such as neutrophil elastase.
  • Diseases involving elastase such as neutrophil elastase are diseases in which elastase is considered to be involved in the pathogenesis of the disease due to destruction of the control mechanism by elastase and endogenous protease inhibitor protein.
  • Diseases caused by abnormal increase in elastin degradation by elastase such as neutrophil elastase, collagen fiber degradation, proteodarican degradation, factor IX which is one of the blood coagulation factors in plasma by elastase on erythrocyte membrane Examples include diseases caused by child activity.
  • CO PD chronic obstructive pulmonary disease
  • emphysema chronic bronchitis
  • chronic and acute interstitial pneumonia idiopathic interstitial pneumonia
  • diffuse panbronchiolitis cystic fibrosis
  • ARDS adult breathing Compression syndrome
  • bronchiectasis asthma, knee inflammation, nephritis, rheumatoid arthritis, arthritis, psoriasis, periodontal disease, atherosclerosis, myocardial ischemia-reperfusion injury, septic shock, organ Examples include rejection reactions in transplantation, conjunctivitis, keratitis, corneal ulcers, diseases associated with increased airway mucus secretion, venous thromboembolism, and the like.
  • Compound (I) can be produced by the following steps.
  • Compound (I) can be obtained by reacting compound (VII) with compound (VI).
  • the example of the manufacturing method is shown below.
  • a salt thereof can also be used in the reaction.
  • the compound (VI) or a salt thereof can be obtained from, for example, WO00 / 69826, WO00 / 69832, Journal of Ob Medicinal Chemistry (J. Med. Chem.), 38th page, page 98 (1995), the method described in Reference Examples and the like described later, or a method analogous thereto.
  • a salt thereof can also be used in the reaction.
  • Compound (VII) or a salt thereof is, for example, a method described in WO00 / 55145, a reference example described later, examples and the like, or a method analogous thereto. Can be obtained.
  • the obtained acid or ride is obtained in an inert solvent in the presence of 1 to 5 equivalents, preferably 1 to 3 equivalents of base, 0.5 to 2 equivalents, preferably 1 to 1.2 equivalents of compound (VII) and 20 ° C.
  • the compound (I) is obtained by reacting at a temperature between the boiling points of the solvents, preferably at a temperature between 10 ° C and 30 ° C for 15 minutes to 48 hours, preferably 1 to 10 hours. be able to.
  • Examples of the inert solvent used in the reaction for obtaining an acid halide include chloroform, methylene chloride, pyridine, tetrahydrofuran (THF), 1,2-dimethoxyethane, toluene, DMF, dioxane, and ethyl acetate. These may be used alone or as a mixture. Of these, methylene chloride or toluene is preferred.
  • Examples of the acid halogenating agent include thionyl chloride and oxalyl chloride.
  • Examples of the inert solvent used in the reaction of the acid halide with the compound (VII) include chloroform, methylene chloride, pyridine, THF, 1,2-dimethoxyethane, toluene, DMF, dioxane, and ethyl acetate. These may be used alone or as a mixture. Of these, methylene chloride or DMF is preferred!
  • Examples of the base include pyridine, triethylamine, dimethylaminopyridine, ⁇ , ⁇ -diisopropylpropylamine, aqueous sodium hydrogen carbonate solution, aqueous sodium hydroxide solution, and the like. Of these, triethylamine is preferred.
  • Compound (VI) is reacted at a temperature between 30 ° C. and 40 ° C., preferably at a temperature between 30 ° C. and 0 ° C. for 5 minutes to 24 hours, preferably 10 minutes to 2 hours.
  • An acid anhydride is prepared.
  • the compound (I) can be obtained by reacting for 5 minutes to 24 hours, preferably 10 minutes to 2 hours.
  • Examples of the inert solvent include black mouthform, methylene chloride, pyridine, THF, 1,2-dimethone.
  • Examples include xetitan, toluene, DMF, dioxane, acetonitrile, and ethyl acetate. These may be used alone or as a mixture. Of these, THF, DMF, and acetonitrile are preferred.
  • Examples of the base include pyridine, triethylamine, dimethylaminopyridine, N-methylmorpholine, ⁇ , ⁇ -diisopropylethylamine and the like. Of these, ⁇ -methylmorpholine or triethylamine is preferred.
  • Examples of the mixed acid anhydride-forming reagent include isobutyl chloroformate, ethyl chloroformate, phosphoyl chloride, tosyl chloride, mesyl chloride and the like. Of these, isobutyl chloroformate or mesyl chloride lid is preferred! /.
  • 1 to 20 equivalents preferably 1 to 2 equivalents of condensing agent
  • 0.5 to 2 equivalents preferably 1 to 1.2 equivalents of compound (VII) and a temperature between 30 ° C. and 60 ° C., preferably between 30 ° C. and 40 ° C.
  • the compound (I) can be obtained by reacting for 30 minutes to 48 hours, preferably 1 to 18 hours.
  • 0.5 to 2 equivalents of, for example, 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine may be added.
  • inert solvent examples include black mouth form, methylene chloride, pyridine, THF, 1,2-dimethoxetane, toluene, DMF, dimethyl sulfoxide (DMSO), dioxane, acetonitryl, and ethyl acetate. These are used alone or as a mixture. Of these, DMF, THF or acetonitrile is preferred.
  • Examples of the base include pyridine, triethylamine, dimethylaminopyridine, N-methylmorpholine, ⁇ , ⁇ -diisopropylethylamine, etc. Among them, ⁇ -methylmorpholine or triethylamine is preferred.
  • Examples of the condensing agent include 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide or its hydrochloride, 1,1'-carbodiimidazole, 1 , 3-Diisopropylcarbodiimide, diphenylphosphoryl azide, iodinated 2-chloro- 1-methylpyridium, 1-benzotriazolyl mesylate, 1-benzotriazolyl tosylate, 1-benzotriazolyl sulfonate, etc.
  • 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide or its hydrochloride or 1-benzotriazolyl mesylate is preferable.
  • Compound (I) can also be produced by the following steps.
  • compound (IX) can be obtained from compound (VI) and compound (VIII).
  • respective salts can also be used in the reaction.
  • the compound (VIII) or a salt thereof can be obtained from, for example, the journal 'Ob' Medical 'chemistry (J. Med Chem.), Page 4, page 1268 (2001), the methods described in Reference Examples, Examples and the like described later, or a method analogous thereto.
  • Compound (IX) is added in an inert solvent in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents of Dess-Martin reagent (1,1,1,1-triacetoxy-1,1-dihydro-1,2-benzododecoxide.
  • Dess-Martin reagent 1,1,1,1-triacetoxy-1,1-dihydro-1,2-benzododecoxide.
  • Examples of the inert solvent include black mouth form, methylene chloride, pyridine, DMF, DMSO, Examples include acetonitrile, ethyl acetate, and the like, which are used alone or as a mixture. Of these, methylene chloride or DMF is preferred.
  • Examples of the salt of compound (VI), compound (VII) and compound (VIII) include salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, hydrochloric acid Examples thereof include acid addition salts such as salts, hydrobromides, sulfates, trifluoroacetates and methanesulfonates.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. be able to. Further, the intermediate can be subjected to the next reaction without any particular purification.
  • Some compounds (I) may have stereoisomers such as geometric isomers and optical isomers, but the present invention includes all possible isomers including these isomers and their isomers. Includes the mixture.
  • compound (I) When the salt of compound (I) is obtained, if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, compound (I) can be appropriately converted. It can be dissolved or suspended in a solvent and isolated or purified by adding an acid or base.
  • the compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents. These adducts are also included in the present invention. .
  • Test Example 1 Inhibitory activity against human neutrophil elastase
  • the enzyme reaction was started by adding human neutrophil elastase (final concentration: 0.1 U / mL, Elastin Products) to the resulting mixture. After performing the enzyme reaction at room temperature for 30 minutes, the enzyme reaction was stopped by adding isopropyl alcohol and acetic acid (respectively 4% and 0.4 mol / L, respectively) to the reaction mixture. After the reaction was stopped, the absorbance (405 nm) of the enzyme reaction solution was measured to quantify the amount of p-nitro-lide (pNA) produced as the enzyme reaction product.
  • pNA p-nitro-lide
  • Test The amount of pNA produced when the enzyme reaction was performed in the presence of the test compound.
  • Blank The amount of pNA produced when the enzyme reaction was performed without adding human neutrophil elastase in the presence of the test compound.
  • the inhibitory activity of a test compound on human neutrophil elastase is expressed as the concentration (IC value) of the compound that inhibits the enzyme reaction by human neutrophil elastase by 50%.
  • Test Example 2 Inhibitory action on neutrophil elastase activity in hamster peripheral blood
  • the administration solvent 0.5 weight Z volume% methylcellulose (Wako Pure Chemical Industries, Osaka) aqueous solution (hereinafter referred to as the administration solvent) or 2 mg / mL in the administration solvent
  • Test compounds suspended at concentrations were orally administered at 5 mL / kg body weight.
  • the group to which the administration solvent was orally administered was designated as the solvent group, and the group to which the test compound was orally administered was designated as the test compound group.
  • MeO-Suc-Ala-Ala-Pro-V a ⁇ MCA Metal-alanyl-alanyl-prolyl-noryl-l 4-methylcoumaryl-7-amide: Peptide Institute, Osaka, a substrate of neutrophil elastase in plasma ) was added to a final concentration of 0.5 mmol / L to initiate the reaction.
  • AMC 7-amino-4-methylcoumarin
  • ONO-6818 a selective inhibitor of neutrophil elastase [Journal 'Ob' Medicinal 'Chemistry (J. Med. Chem), No. 43, 4927-4929 (2000), final concentration:
  • AM C amount at).
  • the inhibition rate (%) of neutrophil elastase activity in peripheral blood by compound (I) was expressed by the following formula.
  • AMC amount in solvent group AMC amount in test compound group
  • Inhibition rate (%) X 1 O 0 AMC amount in solvent group — AMC amount in 0N0 group
  • Compound (I) or a pharmacologically acceptable salt thereof has an elastase inhibitory action such as neutrophil elastase and is useful for diseases involving elastase such as neutrophil elastase. It is believed that there is.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention contains Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. be able to. Moreover, those pharmaceutical preparations are pharmacologically acceptable for the active ingredient. It can be prepared by any method well known in the pharmaceutical arts, mixed with one or more carriers.
  • Examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a salt solution, a glucose solution, a mixed solution of a salt solution and a bud sugar solution, or the like.
  • the dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc.
  • parenteral administration such as intravenous administration
  • 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day.
  • these doses and number of doses vary depending on the various conditions described above.
  • Step 1 2-Amino-3-methyl-1- (thiazol-2-yl) butan-1-one (compound a-la) Chloride all compounds (116 mg, 0.365 mmol) obtained in Reference Example 1 It was dissolved in methylene (2.1 mL), trifluoromethanesulfonic acid (161 n 1.83 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. The resulting reaction solution was diluted with methylene chloride, water was added, and the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain the title compound (78 mg, 0.37 mmol, quantitative) as an amorphous substance.
  • Step 2 Compound a-1
  • the obtained reaction mixture was diluted with black mouth form, poured into ice water, and the organic layer was separated. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography to obtain the title compound (40 mg, 0.093 mmol, 70%) as a white solid.
  • Example 7 The title compound (65 mg, 76%) was obtained in the same manner as in Example 2 except that the compound a-7 obtained in Example 7 was used instead of the compound a-1.
  • Example 15 The title compound (315 mg, 75%) was obtained in the same manner as in Example 15 except that the compound b-6-l obtained in Reference Example 12 was used instead of the compound b-4-l.
  • the title compound (130 mg, 73%) was obtained in the same manner as in Example 42 by using the compound f-5 obtained in Example 53 instead of the compound d-10.
  • Example 66 The title compound (90 mg, 81%) was obtained in the same manner as in Example 66, using Compound i-3 obtained in Example 65 instead of Compound i-1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé hétérocyclique représenté par la formule (I) suivante (dans laquelle R2 et R3 sont identiques ou différents et représentent chacun un hydrogène, un alkyle inférieur, etc. ; R1 représente la formule (II) ou (III) suivante ; et un groupe cyclique A représente la formule (IVA) suivante, etc.) ; ou sel acceptable du point de vue pharmacologique du composé. Le composé ou sel a, par exemple, une activité d'inhibition de l'élastase.
PCT/JP2005/012996 2004-07-14 2005-07-14 Composé hétérocyclique WO2006006644A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006529110A JPWO2006006644A1 (ja) 2004-07-14 2005-07-14 複素環式化合物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2004-207079 2004-07-14
JP2004207079 2004-07-14
JP2004304181 2004-10-19
JP2004-304181 2004-10-19

Publications (1)

Publication Number Publication Date
WO2006006644A1 true WO2006006644A1 (fr) 2006-01-19

Family

ID=35783980

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/012996 WO2006006644A1 (fr) 2004-07-14 2005-07-14 Composé hétérocyclique

Country Status (2)

Country Link
JP (1) JPWO2006006644A1 (fr)
WO (1) WO2006006644A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2105477A1 (fr) 2008-03-24 2009-09-30 FUJIFILM Corporation Procédé de formation d'une image à jet d'encre
US7951823B2 (en) 2006-05-23 2011-05-31 Irm Llc Compounds and compositions as channel activating protease inhibitors
US8293915B2 (en) 2007-02-09 2012-10-23 Irm Llc Compounds and compositions as channel activating protease inhibitors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001040263A1 (fr) * 1999-12-03 2001-06-07 Ono Pharmaceutical Co., Ltd. Derives de 1,3,4-oxadiazoline-2-one et medicaments contenant ces derives utiles comme ingredient actif
WO2002026229A1 (fr) * 2000-09-29 2002-04-04 Ono Pharmaceutical Co., Ltd. Inhibiteurs de secretions de muqueuses des voies aeriennes
WO2002026230A1 (fr) * 2000-09-29 2002-04-04 Ono Pharmaceutical Co., Ltd. Remedes contre les troubles inflammatoires des intestins
WO2003006014A1 (fr) * 2001-07-10 2003-01-23 Ono Pharmaceutical Co., Ltd. Medicament contenant une combinaison d'un compose heterocyclique a cinq chainons avec un produit compensant ou renforcant l'activite dudit compose
JP2004189659A (ja) * 2002-12-10 2004-07-08 Ono Pharmaceut Co Ltd 好中球エラスターゼ阻害剤を有効成分とする吸入剤
JP2004256473A (ja) * 2003-02-27 2004-09-16 Ono Pharmaceut Co Ltd エラスターゼ阻害活性を有する１，３，４−オキサジアゾール誘導体
JP2005154430A (ja) * 2003-11-04 2005-06-16 Ajinomoto Co Inc ピリミジン誘導体の製造方法、および中間体とその製造方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001040263A1 (fr) * 1999-12-03 2001-06-07 Ono Pharmaceutical Co., Ltd. Derives de 1,3,4-oxadiazoline-2-one et medicaments contenant ces derives utiles comme ingredient actif
WO2002026229A1 (fr) * 2000-09-29 2002-04-04 Ono Pharmaceutical Co., Ltd. Inhibiteurs de secretions de muqueuses des voies aeriennes
WO2002026230A1 (fr) * 2000-09-29 2002-04-04 Ono Pharmaceutical Co., Ltd. Remedes contre les troubles inflammatoires des intestins
WO2003006014A1 (fr) * 2001-07-10 2003-01-23 Ono Pharmaceutical Co., Ltd. Medicament contenant une combinaison d'un compose heterocyclique a cinq chainons avec un produit compensant ou renforcant l'activite dudit compose
JP2004189659A (ja) * 2002-12-10 2004-07-08 Ono Pharmaceut Co Ltd 好中球エラスターゼ阻害剤を有効成分とする吸入剤
JP2004256473A (ja) * 2003-02-27 2004-09-16 Ono Pharmaceut Co Ltd エラスターゼ阻害活性を有する１，３，４−オキサジアゾール誘導体
JP2005154430A (ja) * 2003-11-04 2005-06-16 Ajinomoto Co Inc ピリミジン誘導体の製造方法、および中間体とその製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EDOWARDS P.D. ET AL: "Peptidyl a-Ketoheterocyclic Inhibitors of HUman Neutrophil Elastase. 2. Effect of Varying the Heterocyclic Ring on in Vitro Potency.", JOURNAL OF MEDICINAL CHEMISTRY., vol. 38, no. 1, 1995, pages 76 - 85, XP002991737 *
OHMOTO K. ET AL: "Development of Orally Active Nonpeptidic Inhibitors of Human Neutrophil Elastase.", JOURNAL OF MEDICINAL CHEMISTRY., vol. 44, no. 8, 2001, pages 1268 - 1285, XP002908876 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7951823B2 (en) 2006-05-23 2011-05-31 Irm Llc Compounds and compositions as channel activating protease inhibitors
US8338469B2 (en) 2006-05-23 2012-12-25 Irm Llc Compounds and compositions as channel activating protease inhibitors
US8293915B2 (en) 2007-02-09 2012-10-23 Irm Llc Compounds and compositions as channel activating protease inhibitors
EP2105477A1 (fr) 2008-03-24 2009-09-30 FUJIFILM Corporation Procédé de formation d'une image à jet d'encre

Also Published As

Publication number Publication date
JPWO2006006644A1 (ja) 2008-05-01

Similar Documents

Publication Publication Date Title
US6376484B1 (en) Tetrazole compounds and pharmaceutical agents containing such derivative as an active ingredient
EP3056485B1 (fr) Composés de modulation du récepteur d'androgènes
EP2598486B1 (fr) Inhibiteurs d'acétyl-coa-carboxylase bicycliques
KR102759231B1 (ko) 키나제 억제제로서의 아미노피롤로트리아진
JP3155536B2 (ja) アミノブタン酸誘導体
EP2518067B1 (fr) Dérives de n-[(1h-pyrazol-1-yl)aryl]-1h-indole ou 1h- indazole-3-carboxamide et leurs applications en thérapeutique comme antagonistes de p2y12.
US9062028B2 (en) Bicyclic nitrogen containing heteroaryl TGR5 receptor modulators
US8017612B2 (en) Piperazine compound and use thereof as a HCV polymerase inhibitor
BRPI0918174A2 (pt) composto que apresenta atividade contra o vírus da hepatite c (hcv), sua composição e seu uso
US20070004642A1 (en) Oxadiazole derivatives and drugs containing these derivatives as the active ingredient
IL271117A (en) Diazabicyclic substituted imidazopyrimidines and their use for the treatment of breathing disorders
KR20170096034A (ko) Cftr 활성을 증가시키는 화합물, 조성물 및 방법
JP2019533022A (ja) 化合物及びその使用
EP2017263A1 (fr) Derive acide carboxylique inferieur d'heteroarylamide
US6900207B2 (en) N-containing five-membered ring compounds and pharmaceutical agents comprising the same as active ingredient
JP4242274B2 (ja) 因子Ｘａ阻害剤としてのピロリジン誘導体
JP2004535422A (ja) カテプシン阻害剤としての新しい化合物および組成物
CA2979926A1 (fr) N-bicyclo-2-arylchinolino-4-carboxamides substitues et leur utilisation
CA3059954A1 (fr) N-arylethyl-2-aminoquinoleine-4-carboxamides substitues et leur utilisation
WO2006006644A1 (fr) Composé hétérocyclique
WO2019136112A1 (fr) Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation
WO2020221816A1 (fr) Nouvelles urées de phényle et de pyridyle actives contre le virus de l'hépatite b (vhb)
JP2006515840A (ja) トロンビンおよびｘａ因子の阻害剤としてのピロリジン−２−オン誘導体
EP4073073B1 (fr) Dérivés de thiénopyrimidine utilisés en tant qu'inhibiteurs du récepteur 2 de lpa
US8680090B2 (en) Sulfonyl containing benzothiazole inhibitors of endothelial lipase

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006529110

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载