WO2006028284A1 - モルホリン化合物 - Google Patents

モルホリン化合物 Download PDF

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Publication number
WO2006028284A1
WO2006028284A1 PCT/JP2005/017002 JP2005017002W WO2006028284A1 WO 2006028284 A1 WO2006028284 A1 WO 2006028284A1 JP 2005017002 W JP2005017002 W JP 2005017002W WO 2006028284 A1 WO2006028284 A1 WO 2006028284A1
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Prior art keywords
substituent
methyl
morpholine
acetamide
ylthio
Prior art date
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PCT/JP2005/017002
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English (en)
French (fr)
Japanese (ja)
Inventor
Yoshihito Tanaka
Shuzo Takeda
Hidemitsu Higashi
Mamoru Matsuura
Fujio Kobayashi
Maiko Hamada
Minoru Tanaka
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Mitsubishi Pharma Corporation
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Application filed by Mitsubishi Pharma Corporation filed Critical Mitsubishi Pharma Corporation
Priority to IN3493CHN2014 priority Critical patent/IN2014CN03493A/en
Priority to EP05783689.2A priority patent/EP1801108B9/en
Priority to ES05783689T priority patent/ES2396419T3/es
Priority to US11/662,228 priority patent/US7935700B2/en
Priority to PL05783689T priority patent/PL1801108T3/pl
Priority to JP2006535186A priority patent/JP4970946B2/ja
Priority to DK05783689.2T priority patent/DK1801108T3/da
Priority to CA2579207A priority patent/CA2579207C/en
Priority to CN2005800301370A priority patent/CN101014580B/zh
Publication of WO2006028284A1 publication Critical patent/WO2006028284A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61P37/08—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
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel morpholine compound having an affinity for CCR 3, the compound or a salt thereof is a disease in which cells having CCR 3 play an important role in the onset, progression, and maintenance of pathological conditions, For example, as a therapeutic and / or preventive for asthma, sinusitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease, rheumatoid arthritis, etc. Useful.
  • chemotactic substance that induces migration and local infiltration of leukocytes such as neutrophils and monocytes, arachidonic acid metabolism such as complement degradation products C 3 a and 5a, le uk otriene B 4 etc.
  • Classic chemotactic factors such as products, platelet-activating factor, and bacterially-formylated peptides. These are secondary products mainly associated with tissue injury.
  • chemokines a series of cytokines produced by new gene expression and responsible for the induction and activation of specific leukocytes, so-called chemokines, were purified in 1987 by Matsushima et al. (Interle uk in (IL))-8 (CXCL8) has been proven to exist (eg Proc. Natl. Acad. Sci. USA, 84, 9223-9237 (1987) and J ". Exp. Med. , 167, 1883-1893 (1988)).
  • chemokines have been identified, and chemokines are classified into four subgroups based on their amino acid sequence characteristics. That is, C chemokine, CC chemokine,. . It's a chemokine and 3 chemokines.
  • XC L 1 belonging to the C chemokine exhibits a migration activity against T cells and NK cells.
  • CC chemokines exhibit migratory activity against monocytes other than neutrophils, lymphocytes, Langerhans cells, dendritic cells, eosinophils, mast cells and basophils.
  • CXC chemokines as represented by CXCL 8, mainly affect neutrophils
  • CX 3 C chemokines mainly affect NK cell migration.
  • These chemokines exert their actions by binding to G protein-coupled receptors (chemokine receptors).
  • chemokine receptors G protein-coupled receptors
  • a substance that inhibits the binding between chemokine and its receptor suppresses the selective migration and activity of leukocytes, and prevents or treats acute and chronic inflammatory diseases including allergic diseases. It is considered useful as a pharmaceutical product.
  • Eosinophil infiltration into inflamed tissue is included. Therefore, eosinophils are thought to play an important role in the onset, progression and maintenance of these diseases. It is known that CCR 3, which is a receptor for CC chemokine, plays an important role in the activation of eosinophils in the local area of inflammation. As well as inflammatory cells such as mast cells, basophils, dendritic cells and Th 2 cells (J. Clin.
  • compounds having affinity for CCR 3 can be expected to be useful as pharmaceuticals for the prevention or treatment of immune and inflammatory diseases.
  • Heteroaromatic derivatives of the ring system, etc., W099 / 55324 and WO 99/55330 have affinity for chemokine receptors, such as phenylalanine derivatives WO00 no 58305 have affinity for chemokine receptors
  • Piperazine derivatives such as WO 00/31033, WO 00-53600, WO 01/143 33, WO02 / 66460, and WO 02/881 11 include piperidine derivatives having affinity for chemokine receptors. Etc. are disclosed.
  • WO02 / 1 8335 discloses a cyclic amine derivative having a CCR 3 antagonistic action.
  • WO 02/26722, WO 02/26723, WO 03/82292, WO 03/82294, WO 03/82861, WO 03/82862, WO 0-3 82295, WO 03/82863, WO 03/99287, and WO 03/99798 discloses morpholine derivatives having affinity for chemokine receptors and the like. However, these compounds do not have the structural features (that is, compounds having a sulfur atom at the tip of the alkylene chain from the morpholine ring via the methylene amide) as a preferred embodiment of the compound of the present invention described later.
  • CCR 3 antagonists with different structures are considered to be acute, including immune and allergic diseases. It is expected to be a drug for the treatment or prevention of chronic inflammatory diseases.
  • An object of the present invention is to provide a pharmaceutical product having affinity for CCR3 and for the treatment and / or prevention of immune and inflammatory diseases.
  • the present inventors have conducted extensive studies to find a non-peptide compound exhibiting a CCR3 antagonistic action. It has been found that the pharmaceutically acceptable salts of these compounds, or their hydrates or solvates inhibit the binding of CCR3 to its ligand and act as antagonists. Therefore, the present invention was completed by finding that the compound of the present invention can be a pharmaceutical for the treatment or prevention of acute and chronic inflammatory diseases including immunity and allergic diseases.
  • the gist of the present invention is as follows.
  • Ring A represents an aryl which may have a substituent, or a heteroaryl which may have a substituent,
  • Ring B may have a substituent group Ariren, 2 may have a substituent 3 ⁇ 4 valence of heterocyclic group, or an optionally C 3 _ 8 cycloalkylene which may have a substituent , M represents an integer from 0 to 2,
  • n an integer from 1 to 5
  • X is a bond, 1 NH—, 1 NR 1 — (wherein R 1 represents C 6 alkyl optionally having a substituent), —CO—, 1 CO 2 —, — OCO—, -CONR a-
  • R a represents a hydrogen atom or C 6 alkyl optionally having a substituent.
  • R 2 R 3 may be the same or different and each may have a hydrogen atom or a substituent, and represents 0 to 6 alkyl, or an atom to which R 2 and R 3 are bonded together And may form a ring which may have a substituent.
  • Y represents a bond, one NH—, —NR 4 — (wherein R 4 represents an optionally substituted C 6 alkyl. The same shall apply hereinafter.), One CO—, one C0 2 —, 1 OCO—, 1 CO N 3 ⁇ 4- (wherein R b represents a hydrogen atom or an alkyl which may have a substituent. The same shall apply hereinafter.), 1 NR b CO—, 1 NR 5 CONR 6 — (In the formula, R 5 and R 6 may be the same or different and each represents a hydrogen atom or C 6 alkyl optionally having a substituent. Alternatively, R 5 and R 6 are combined together.
  • Z represents a hydrogen atom, a halogen atom, which may have a substituent - 6 alkyl, which may have a location substituent 0 3 _ 8 cycloalkyl, optionally ⁇ Li may have a substituent Group, optionally substituted heterocyclic group, hydroxy, nitro, amino, cyano, optionally substituted alkoxy, optionally substituted mono or di . 6 Arukiruamino may have a substituent. 7 Asylua Mino, optionally substituted sulfonylamino, optionally substituted hydrazino, optionally substituted guanidino or optionally substituted amidino . ]
  • Ring B is an arylene which may have a substituent, or a divalent heterocyclic group which may have a substituent,
  • X is a bond, 1 NH—, 1 NR 1 — (wherein R 1 may have a substituent; 6 represents alkyl), — CO—, — C0 2 —, — OCO —, —CONR a — (In the formula, R a represents a hydrogen atom or a C 6 alkyl optionally having a substituent. The same shall apply hereinafter.), NR a CO—, —N 2 CONR 3 — (Wherein R 2 and R 3 may be the same or different and each represents a hydrogen atom or an alkyl which may have a substituent.
  • R 2 and R 3 together represent , Oxygen atom, sulfur atom, —SO—, one S0 2 —, one NR a S0 2 —, one S0 2 NR a -, alkylene 6 which may have a substituent, which may have a substituent C 2 - 6 Aruke - Ren, good C 2 _ 6 alkylene which may have a substituent - Ren, one O- X a (X a in the formula represents an alkylene optionally have a substituent or less the same..), One X a - O-, -CO- X a -, one X a - CO-, one CONR a - X a ⁇ , 1 X a — CONR a ⁇ , 1 NR a CO— X a ⁇ , 1 — NR a CO—, 1 S— X a —, 1 X a — S—, 1 SO— X a —, 1
  • X is a bond, one NH—, —NR 1 — (wherein R 1 represents an alkyl which may have a substituent), one CO—, 1 C0 2 —, — OCO—, 1 CONR a — (wherein R a represents a hydrogen atom or C 6 alkyl which may have a substituent.
  • 1 NR a CO— , -N 2 CONR 3 (wherein R 2 and R 3 may be the same or different and each represents a hydrogen atom or a Ci-e alkyl optionally having a substituent), oxygen Atom, Sulfur atom, One SO—, One S0 2 —, One NR a S0 2 —, One S0 2 NR a —, optionally substituted C 2 — 6 alkerene, One CO— X a — (In the formula, X a represents alkylene which may have a substituent.
  • Which may be C 3 - 8 cycloalkylidene a is the above-mentioned [1] to a compound or a pharmaceutically acceptable salt thereof of the mounting serial any one of [4] or their hydrate or solvate thereof.
  • X represents a bond, one CO—, —CONR a — (wherein R a represents a hydrogen atom or an optionally substituted alkyl. The same shall apply hereinafter. ), 1 NR a CO—, 1 CO— X a — (wherein X a represents C 6 alkylene which may have a substituent. The same shall apply hereinafter.), 1 X a — CO—,
  • Y is a bond, 1 NH—, 1 NR 4 — (wherein R 4 represents an optionally substituted C 6 alkyl), — CO—, —C0 2 —, 1 OCO—, 1 CONR b — (wherein R b represents a hydrogen atom or an optionally substituted C 6 alkyl; the same shall apply hereinafter), 1 NR b CO—, 1 NR 5 CONR 6 — (wherein R 5 and R 6 may be the same or different and each represents a hydrogen atom or The alkyl which may have a substituent is shown.
  • Y represents a bond, one CO—, —CONR b — (wherein R b represents a hydrogen atom or an alkyl which may have a substituent. The same shall apply hereinafter. .), one NR b CO-, one CO- X b -..
  • X b in the formula represents a C ⁇ one 6 alkylene which may have a substituent hereinafter the same), one X b - CO-,
  • Z is a hydrogen atom, a halogen atom, Ci-e alkyl optionally having substituent, which may have a substituent C 3 - 8 cycloalkyl, substituted An optionally substituted aryl, an optionally substituted heterocyclic group, a hydroxy, a nitro, an amino, a cyano, an optionally substituted — 6 alkoxy, a substituted group Mono- or di-alkylamino optionally having a substituent, C- 7 acylamino optionally having a substituent, sulfonylamino optionally having a substituent, hydrazino optionally having a substituent,
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (8), which is an optionally substituted guanidino, or an optionally substituted amidino, or Their hydrates or solvates.
  • Z may have a hydrogen atom, hydroxy, amino, an optionally substituted alkyl, or an optionally substituted group.
  • (6 ) The compound according to any one of (1) to (9) above, which is an alkoxy, an optionally substituted aryl, or an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. Or a hydrate or solvate thereof.
  • (la) The compound according to any one of (1) to (9) above, which is an alkoxy, an optionally substituted aryl, or an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. Or a hydrate or solvate thereof.
  • ring c represents aryl or heteroaryl which may have a substituent, and other symbols are as defined above in [1].
  • n is 1 to 3, the compound according to any one of the above [1] to [: 12], or a pharmaceutically acceptable salt thereof, or a hydrate thereof, Solvate.
  • the absolute configuration at the 2-position of morpholine is the S configuration, the compound according to any one of the above [1] to [13], or a pharmaceutically acceptable salt thereof, or water thereof Japanese solvate or solvate.
  • a CCR3 antagonist comprising the compound according to any one of [1] to [15] above or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [15] above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable carrier. .
  • [19] comprising administering an effective amount of the compound according to any one of [1] to [15] above or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to an animal
  • the disease involving CCR 3 is asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis
  • Ring B may ⁇ Li one Ren may have a substituent, 2 may have a substituent monovalent
  • n an integer from 1 to 5
  • X is a bond, 1 NH—, —NR 1 — (wherein R 1 represents an optionally substituted C 6 alkyl), —CO_, —C0 2 —, —OCO—, One CONR a —
  • R a represents a hydrogen atom or an alkyl which may have a substituent.
  • NR a CO—, —NR 2 CONR 3 — (where R 2 , R 3 Are the same or different and each represents a hydrogen atom or 6 alkyl optionally having a substituent, or R 2 and R 3 together and the atom to which they are bonded together ), Oxygen atom, sulfur atom, —SO—, — S0 2 —, one NR a S0 2 —, — S0 2 NR a —, a substituent alkylene which may have, which may have a substituent C 2 - 6 alkenylene, substituents which may have C 2 - 6 alkynylene one O- X a - (X a in the formula May have a substituent — 6 represents alkylene, the same shall apply hereinafter)), one X a — O—, one CO— X a —,
  • Y represents a bond, one NH—, —NR 4 — (wherein R 4 represents an optionally substituted C 6 alkyl. The same shall apply hereinafter.), One CO—, one co 2 —, One OCO—, —CO NR b — (wherein R b represents a hydrogen atom or an alkyl which may have a substituent. The same shall apply hereinafter.), One NR b CO—, —NR 5 CONR 6 — (In the formula, R 5 and 6 may be the same or different and each represents a hydrogen atom or a Ci_ 6 alkyl which may have a substituent. Alternatively, R 5 and R 6 are taken together.
  • Z represents a hydrogen atom, a halogen atom, which may have a substituent C 6 alkyl which may have a location substituent C 3 - 8 cycloalkyl, optionally ⁇ Li may have a substituent Group, optionally substituted heterocyclic group, hydroxy, nitro, amino, cyano, optionally substituted Ci-e alkoxy, optionally substituted mono- or di - C i-6 alkylamino, substituents one may have a 7 Ashirua amino, which may have a substituent sulfo - Ruamino, which may have a substituent hydrazino, substituted Guanidino which may have a group or amidino which may have a substituent. Or a salt thereof and a general formula (8)
  • ring A represents an aryl which may have a substituent, or an heteroaryl which may have a substituent.
  • diseases in which cells having CCR 3 play an important role in the onset, progression and maintenance of pathological conditions such as asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergy
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • aryl in “optionally substituted aryl” means a monocyclic to tricyclic ring.
  • 0 6 _ 1 4 means aryl, for example, phenyl, naphthyl, anthryl, indenyl, etc., preferred examples include phenyl, naphthyl, etc., more preferred examples include phenyl. .
  • aryls may be partially hydrogenated.
  • the position to be hydrogenated is not particularly limited. Examples of partially hydrogenated aryls include tetrahydronaphthyl and indanole.
  • aryl has “substituent”, the type and number thereof are not particularly limited, and “substituent” force defined below, one selected substituent at the substitutable position Have four.
  • substituents that the aryl may have include a halogen atom, cyano, nitro, Ci- 6 alkyl, C- 6 haloalkyl, 6 alkoxy, hydroxy, amino, mono- or di-acyl) amino, carboxy, - 6 alkoxy one carbo - le, Karupamoiru, hydroxyamidino and the like, more preferably a chlorine atom as an example, a fluorine atom, Shiano, nitro, methyl, tri Furuoromechiru, main butoxy, human Dorokishi, amino, Asechiruamino , Carboxy, methoxycarboel, carbamoyl, hydroxyamidino, more preferable examples include fluorine atom, chlorine atom, methyl or trifluoromethyl, and still
  • Heteroaryl in “optionally substituted heteroaryl” refers to 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring atom.
  • heteroaryl is a 5- to 7-membered member containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring atoms.
  • groups derived from aromatic heterocycles (bicyclic or higher) formed by condensation of aromatic heterocycles with benzene rings or the above aromatic heterocycle (monocyclic) groups for example, indolyl, isoindolyl Benzo [b] furyl, benzo [b] cenyl, benzoimidazolyl, benzoxazolinole, benzoisoxazoly / re, benzothiazoly / re, benzoisothiazolyl, quinolyl, isoquinolyl and the like.
  • heteroaryls may be partially hydrogenated.
  • the position to be hydrogenated is not particularly limited.
  • examples of the partially hydrogenated heteroaryl include tetrahydrobenzoimidazolyl, tetrahydroquinolyl, tetrahydroquinol isoquinolyl and the like.
  • heteroaryl examples include furyl, chael, thiazolyl, pyridinole, indolyl, benzo [b] furyl, benzo [b] chell, benzoxazolinole, benzothiazolyl, quinolyl, isoquinolyl, and more Preferable examples include furyl, chael, thiazolyl and pyridyl.
  • heteroaryl force S “substituent”
  • the type and number thereof are not particularly limited, and one substituent selected from “substituent” defined below can be substituted at one of the substitutable positions.
  • Preferable examples of the substituent which the heteroaryl may have include a halogen atom, cyano and nitro, and more preferable examples include a halogen atom.
  • arylene in the “arylene optionally having a substituent” means a divalent group further having a bond at an arbitrary position of the above “aryl”, for example, phenylene, And divalent groups such as naphthylene and indenylene.
  • arylenes may be partially hydrogenated. Position to be hydrogenated Is not particularly limited. Examples of the partially hydrogenated arylene include tetrahydronaphthylene and indanylene.
  • arylene examples include phenylene, naphthylene, indanylene and the like, and more preferable examples include phenylene and the like.
  • the “arylene” has a substituent
  • the kind and number thereof are not particularly limited, and 1 to 3 substituents selected from the “substituent” defined below are present at substitutable positions.
  • substituents that arylene may have include Ci-ealkyl, Ci-ealkoxy, hydroxy, oxo and the like, and more preferable examples include oxo. it can.
  • heterocyclic group in “an optionally substituted divalent heterocyclic group” in ring B and “an optionally substituted heterocyclic group” in Z is ring Atom containing 1 to 4 types of heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms 5- to 4-membered monocyclic to tricyclic heterocycles Means a group.
  • Heterocyclic group includes saturated rings, aromatic rings (including “heteroaryl” as defined above), and partially hydrogenated ring groups thereof.
  • Partially hydrogenated heteroaryls include, for example, dihydrofuryl, dihydrocenyl, pyrrolinyl, thiazolinyl, biazolinyl, oxazolinyl, isoxazolinyl, isothiazolinyl, imidazolinyl, 1, 2, 4-oxadiazolinyl, 1, 3, 4—oxadiazolinyl, 1, 2, 3—triazolinyl, 1, 2, 4—triazolinyl, 1, 2, 4—thiadiazolinyl, 1, 3, 4—thiadiazolinyl, dihydropyridazinyl, tetrahydro Examples include benzoimidazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl and the like.
  • heterocyclic group examples include pyrrolidyl, piperidyl, piperazinyl, tetrahydrofuranyl, monolepholinyl, thiazolidyl, thiomorpholinyl, homopiperagel and the like.
  • heterocyclic group includes “bridged hetero ring group” containing 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom as ring atom.
  • bridging ring group examples include 3-azabicyclo [3.2.2] nonane-1-yl, 8-azabicyclo [3.2. 1] One octane 8-yl.
  • heterocyclic group has a “substituent”, the kind and number thereof are not particularly limited, and one substituent selected from the “substituent” defined below is located at the substitutable position. ⁇ 4 have.
  • substituent that the heterocyclic group may have include C 6 alkyl, hydroxy, nitro, amino, cyano, carboxy, alkoxyl alkenyl, carbamoyl, oxo and the like. Ethoxycarbonyl, carbamoyl and oxo are more preferred.
  • heterocyclic group examples include pyridyl, bilazyl, jellimidyl, pyridazyl, imidazolyl, pyrrolyl, pyrrolidyl, morpholyl, chael, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl Quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinolizinyl, quinazolyl, quinoxalinyl, cinnolinole, phthalazine, 1,8-naphthyridinyl, attaridinyl, purinyl, pteridinyl, 1,2,4 Oxadiazolinyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 5-triazinyl, 1,
  • the “divalent heterocyclic group optionally having a substituent” means a divalent group having a bond at an arbitrary position of the “heterocyclic group”.
  • the position of the bond is not particularly limited, and can be appropriately selected depending on the type of group.
  • the “divalent heterocyclic group” include pyrrolyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxa'zolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl 1, 2, 4-triazolyl, 1, 2, 4 1 thiadiazolyl, 1, 3, 4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, partially hydrogenated pyridazinyl, partially hydrogenated Optionally indenothiazolyl, partially hydrogenated naphthothiazolyl, quinazolyl, chromenyl, partially hydrogenated thiazolopyridyl, benzozepiel, thienopyridyl, benzothiazolyl, imidazolyl, tetrazolyl More preferred examples include chenil, thia Examples include zolyl, 1,3,4-thiadiazoly
  • the type and number are particularly limited There is no particular definition, and it contains 1 to 3 substituents selected from the “substituent” forces defined below at substitutable positions.
  • the substituent that the divalent heterocyclic group may have include C alkyl, haloalkyl, —6 alkoxy, hydroxy, halogen atom, oxo, thixo and the like, and more preferable examples are Examples thereof include methyl and oxo, and oxo is more preferred.
  • C 3 _ 8 cycloalk Killen" of the "optionally substituted C 3 _ 8 cycloalkylene” is a monocyclic - tricyclic cycloalkylene ( "cross-linking of 3-8 carbon atoms Including, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, norporylene, bicyclo [2.2.1] heptylene or bicyclo [2 2.2] octylene and the like are preferable, and cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene are preferable.
  • C 3 8 cycloalkylene has “substituent” are not particularly limited to the type and number, a substituent selected from the “substituents” defined below at its substitutable position It has 1 to 4 pieces.
  • C 3 _ 8 C i- e alkyl Preferable examples of the cycloalkylene good location substituent optionally having, alkoxy, hydroxy, Amino, halogen atom, C - 6 haloalkyl, - be mentioned 6 haloalkoxy etc. In monkey.
  • dialkyl in “optionally substituted alkyl” means straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl , Isohexyl, 1-Methylpentyl, 2-Methylpentyl, 3-Methylpentyl, 1,1-Dimethylptyl, 1,2-Dimethylptyl, 2,2-Dimethyloleptyl Z-re, 1-Echi / Leptinore, 1, 1 , 2-trimethylenopropynole, 1,2,2-trimethyleno
  • C 6 -6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl and the like, and more preferable examples include methyl, ethyl and the like.
  • R 2 and R 3 may be the same or different and each represents a hydrogen atom or alkyl. Alternatively, R 2 and R 3 together.
  • the ring to which they are bonded may form a ring, and the ring which may have a substituent formed by R 2 and R 3 together with the atom to which they are bonded in “Ring” includes “nitrogen-containing saturated heterocycle” (for example, 1,3-imidazolidin-2-one, 3, 4,5,6-tetrahydro-2- ( 1 H) —pyrimidinone, etc.).
  • the type and number thereof are not particularly limited, and 1 to 3 substituents selected from the “substituent” defined below can be substituted at the substitutable position. contains.
  • substituents that the “ring” may have include 6 alkyl, alkoxy, hydroxy, halogen atom and the like.
  • “0 ⁇ 6 alkylene” in “C i—e alkylene which may have a substituent” means an alkylene chain having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, Examples include pentamethylene and hexamethylene.
  • Preferable examples of “C alkylene” include methylene, ethylene, and trimethylene, and more preferable examples include methylene and ethylene.
  • a branched alkylene chain eg, methylmethylene, dimethylmethylene, 1 monomethylethylene, 2-methylenoethylene, 1 , 1-Dimethylethylene, 2,2-Dimethylenoethylene, Ethenolemethylene, Getinolemethylene, 1-Ethenoreethylene, 2-Ethylethylene, 1-Methyltrimethylene, 1,1-dimethyltrimethylene, 2-Methyltrimethylene 2,2-dimethyltrimethylene, 3-methinotritrimethylene, 3,3-dimethylenotritrimethylene, 1-ethylene / retrimethylene, 2-ethinoretrimethylene, 3-ethyltrimethylene, etc.).
  • a branched alkylene chain eg, methylmethylene, dimethylmethylene, 1 monomethylethylene, 2-methylenoethylene, 1 , 1-Dimethylethylene, 2,2-Dimethylenoethylene, Ethenolemethylene, Getinolemethylene, 1-Ethenoreethylene, 2-Ethylethylene,
  • Optionally substituted C 2 - 6 alkenylene and “C 2 _ 6 7 Luque two Len” includes straight-chain or branched having a double bond at any position of the "CI_ 6 alkylene” It is an alkyrene with 2 to 6 carbon atoms in the branch. The position and number of double bonds are not particularly limited.
  • C 2 _ 6 alkylene has a “substituent” 5017002
  • Kinds and numbers are not particularly limited, and have 1 to 3 substituents selected from the “substituents” defined below at substitutable positions.
  • substituent which may be "C 2 - - 6 alkylene” optionally has can be mentioned alkyl, alkoxy, hydrate port alkoxy, a halogen atom.
  • 0 may have a substituent group 3 - 8 cycloalkylidene” is a "C 3 _ 8 Shikuroa Rukiriden” on, is a monocyclic - tricyclic cycloalkylidene ( "cross-linking of 3-8 carbon atoms
  • cyclopropylidene, cyclopropylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, cyclootatilidene, norbornylidene, bicyclo [2.2.1] heptylidene or Bicyclo [2.2.2] octylidene and the like are preferable, and cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene are preferable.
  • R 5 and R 6 may be the same or different and each represents a hydrogen atom or alkyl. Alternatively, R 5 and R 6 are the same. And the atoms to which they are bonded may form a ring.) "The ring that may have a substituent formed by R 5 and R 6 together with the atoms to which they are bonded”
  • the term “ring” includes “nitrogen-containing saturated heterocycle” (for example, 1,3-imidazolidin-2-one, 3, 4, 5, 6-tetrahydro-2 (1H ) —Pyrimidinone).
  • the type and number thereof are not particularly limited, and the “substituent” defined in the following is the power of the selected substituent. Contains. Preferable examples of the substituent that the “ring” may have — 6 alkyl, CI_ 6 alkoxy, human Dorokishi, and a halogen atom.
  • C 3 - 8 cycloalkyl and "Ji 3 _ 8 cycloalkyl,” on, it is a monocyclic - tricyclic cycloalkyl ( "cross-linking of 3-8 carbon atoms Including, for example, cyclopropyl, cyclobutyl, cyclopentyl / le, cyclohexenole, cycloheptinole, cyclootatinole, nonoleponorinole, bicyclo [2.2.1] heptyl or bicyclo [ 2.2.2] Octyl and the like are preferable, and cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl / le are preferable.
  • C 3 8 cycloalkyl When having - "C 3 8 cycloalkyl” force S "substituent", the kind ⁇ Pi number is not limited especially, the substitutable substituents selected from the “substituents" defined below 1 to 4 in effective positions.
  • C -e alkyl as preferred examples of the C 3 _ 8 cycloalkyl substituent which may have. 6 Alkoxy, hydroxy, halogen atom, etc. can be mentioned.
  • C _ 6 alkoxy in the "optionally C w alkoxy optionally having substituent” means alkoxy straight or branched chain containing from 1 to 6 carbon atoms, for example, main butoxy, ethoxy carboxylate, n-propoxy, isopropoxy, ⁇ -butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, 1-methylptoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1 1-Methylpropoxy, Hexinoreoxy, Isohexyloxy, 1-Methylenopentoxy, 2-Methylenopentoxy, 3-Methylenopentoxy, 1,1-Dimethylptoxy, 1,2-Dimethylptoxy, 2 , 2-dimethylbutoxy, 1-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylenopropoxy, 1 Examples include chilled
  • “6 alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like, and more preferable examples include methoxy, ethoxy and the like.
  • C ⁇ 6 alkoxy has a substituent
  • the type and number are not particularly limited.
  • one to four “substituents” defined below may be present at substitutable positions, and the type and number of substituents are not particularly limited.
  • Preferable examples of the substituent that “.-6 alkoxy” may have include C 6 alkyl, alkoxy, hydroxy, halogen atom and the like.
  • “Mono or di C w alkylamino” in “optionally substituted mono or di C w alkylamino” means a linear or branched alkyl having 1 to 6 carbon atoms and mono. Or a di-substituted alkylamino (total number of carbon atoms in dialkylamino is 2 to 12) and is methylamino, dimethylamino, ethylamino, jetamino, methylethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino Ptylamino, dibutylamino, isopeptylamino, secondary butylamino, tertiary ptylamino, pentylamino, hexylamino and the like.
  • Mechinoreamino Echireamino, Jechi / Reamino, Mechinoreechi ⁇
  • Amino, Puropinore Amino, Jipuropiruamino, isopropyl ⁇ amino, diisopropylamino and the like elevation Gerare more preferred examples Examples thereof include methylamino, dimethylamino, ethylamino, jetylamino, methylethylamino, propylamino and the like.
  • Ci acilamino in “optionally substituted Ci acilamino” means an alkanoyl having 1 to 7 carbon atoms in the acyl moiety (eg, formyl, acetyl, propiol, pentylyl, parrelyl).
  • An alkylamine having 3 to 7 carbon atoms for example, acryloyl, methacryloyl, crotonol
  • an alkynol having 3 to 7 carbon atoms for example, propioroyl
  • benzoyl etc. Acetylamino, propionylamino, petitrilamino, Parerylamino, bivalloamino, benzoylamino and the like are shown.
  • 0 ⁇ 7 acylamino include acetylamino, propionylamino, petitlylamino, pareillyamino, piperoylamino, benzoylamino and the like, and more preferable examples include acetylamino, propionylamino, benzoylamino and the like.
  • “Diacylamino” force S When having a “substituent”, the type and number thereof are not particularly limited, and one substituent selected from the “substituent” defined below can be substituted at one of the substitutable positions. Have four.
  • the ⁇ 7 Ashiruamino of the substituent which may have good case in point may be mentioned C 6 alkyl, alkoxy, hydroxy, halogen atom and the like.
  • sulfonylamino In the case of having an “optionally substituted sulfonylamino” force “substituent”, the type and number thereof are not particularly limited, and a substituent selected from the “substituent” defined below is used. It has an amino group. Preferable examples of the substituent that sulfonylamino may have include amino, C- 6 alkyl, aryl, heteroaryl and the like.
  • hydrazino When “optionally substituted hydrazino” has “substituent”, there is no particular limitation on the type and number of the substituent, and a substituent selected from the “substituent” defined below is used. There are 1 to 3 at the substitutable positions.
  • substituent that hydrazino may have include Ci 6 alkyl, aryl, heteroaryl and the like. Examples of aryl and hetero reels are as described above.
  • guanidino When “optionally substituted guanidino” has “substituent”, the type and number thereof are not particularly limited, and a substituent selected from “substituent” defined below is used. There are 1 to 3 at the substitutable positions. Preferable examples of the substituent that guanidino may have include hydroxy, nitro, and cyano.
  • “Amidino which may have a substituent” force When “substituent” is present, the type and number thereof are not particularly limited, and the substituent selected from the “substituent” defined below is substituted. 1 to 3 in possible positions. Substituent which amidino may have Preferred examples of are hydroxy, nitro, cyan and the like.
  • each group that may have a substituent is not particularly limited.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • C- 6 alkyl Formula example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentinole, neopentinole, tertiary pentyl, 1-methylbutyl, 2-methylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl,
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • C- 6 alkyl Formula example, methyl, ethyl, n-propyl, isopropyl, n-buty
  • heptyl or bicyclo [2.2. 2] Okuchiru etc. C 3 - 8 cycloalkyl O alkoxy (e.g., Shikuropu port Piruokishi, cycloalkyl Petit Ruo alkoxy, cyclopentyloxy Ruo alkoxy, Kishiruo carboxymethyl cyclohexane, consequent opening Ptyloxy, cyclooctyloxy, norbornyloxy, bicyclo [2.2.1] heptyloxy or bicyclo [2.2.2] octyloxy, etc.), haloalkyl (for example, the above halogen such as trifluoromethyl)
  • 6 alkoxy eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-ptoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, isopentoxy Neopentoxy
  • Aarukanoiru e.g., Akuriroiru, methacryloyl, Kurotonoiru etc.
  • C 3 _ 7 Arukinoiru e.g., propionate port I
  • C 7 — aroyl e.g, benzoyl, 1-naphthoyl, 2_naphthyl, etc.
  • mono or di (d-uT syl) amino eg, acetylylamino, benzoylamino, etc.) amino
  • mono- or di one (E _ 6 alkoxy one carbonyl) amino e.g., main Tokishikarubo - Ruamino, eth Kishikarubo - Ru
  • ring A represents an aryl which may have a substituent, or a heteroaryl which may have a substituent, and preferably a phenol which may have a substituent. It is.
  • substituent for ring A examples include a halogen atom (for example, a fluorine atom, a chlorine atom, etc., particularly a chlorine atom), and Ci- 6 alkyl which may have a substituent (for example, substituted with a halogen atom).
  • a halogen atom for example, a fluorine atom, a chlorine atom, etc., particularly a chlorine atom
  • Ci- 6 alkyl which may have a substituent (for example, substituted with a halogen atom).
  • which may be C i-6 alkyl, especially methyl, triflusulfuron Ruo b methyl) or optionally substituted C i _ 6 alkoxy (e.g., alkoxy substituted by halogen atoms, in particular methoxy) and the like Is preferred.
  • Ring A is particularly preferably phenyl substituted with 1 or 2 fluorine atoms or chlorine atoms, more preferably phenyl substituted at the 3-position and Z- or 4-position with fluorine atoms or chlorine atoms, more preferably 3,4-dichlorophenyl or 3,4-difunoleorofeni / re.
  • Ring B may have a substituent group Ariren may have a substituent divalent to heterocyclic group, an optionally C 3 _ 8 cycloalkylene which may have a substituent, Preferred is an arylene which may have a substituent, or a heteroarylene which may have a substituent.
  • Preferred examples of ring B include phenylene, chainylene, pyridylene, thiazolylene optionally substituted with methyl, 1,3,4-thiadiazolylene, optionally substituted with oxo, and partially hydrogenated.
  • An even more preferred embodiment is thiazolylene. Further, another preferred embodiment is 1,3,4-thiadiazolylene. Yet another more preferable embodiment is pyridazinylene which may be substituted with oxo and may be partially hydrogenated. In addition, as the substituent of ring B, alkyl or oxo is preferable, and methyl is more preferable.
  • n represents an integer of 0 to 2, preferably 0 or 2, and more preferably 0.
  • n an integer of 1 to 5, preferably 1 to 3, and more preferably 1.
  • R 2 and R 3 are And together with the atoms to which they are bonded, they may form a ring that may have a substituent, the same shall apply hereinafter.), Oxygen atoms, sulfur atoms, one SO—, —S0 2 —, one NR a S0 2 -, - S0 2 NR a - a 6 Aruke two lens, the substituent - may have a substituent CI- e alkylene, but it may also have a substituent group C 2 May C 2 - 6 Aruki two lens, one O- X a - (X a in the formula may have a substituent -.
  • a bond 1 NH—, 1 NR 1 —, 1 CO—, 1 C0 2 —, 1 OCO—, 1 CONR a —, 1 NR a CO—, — NR 2 CONR 3 —, an oxygen atom, a sulfur atom, ⁇ SO—, 1 S0 2 —, 1 NR a S0 2 —, 1 S0 2 NR a —, optionally substituted C 2 — 6- anolekenylene, 1 CO— X a —, 1 X a — CO— , 1 CONR a — X a —, -X a — CONR a —, 1 NR a CO— X a —, 1 X a — NR a CO— or optionally substituted c 3 — 8 cycloalkylidene
  • 1 CO— a CO—, 1 C0 2 —, 1 OCO— 1 CONR a —, 1 NR a CO—, —
  • a bond, —CO—, one CONR a— , one NR a CO—, one CO—X a , one X a — CO—, one CONR a — X a —, —X a — CONR a —, - NR a CO - X a - or one X a - is NR a CO-.
  • R 1 represents an alkyl which may have a substituent, and is preferably an alkyl;
  • R 2 and R 3 may be the same or different and each has a hydrogen atom or a substituent;
  • R a represents a hydrogen atom or an alkyl which may have a substituent, preferably a hydrogen atom or alkyl
  • X a may have a substituent — 6 represents alkylene, preferably alkylene.
  • Y represents a bond, 1 NH—, —NR 4 — (wherein R 4 represents 6 alkyl which may have a substituent. The same shall apply hereinafter.), 1 CO—, 1 CO 2 — , 1 OCO—, —C ONR b — (wherein Rb represents a hydrogen atom or d-6 alkyl optionally having a substituent. The same shall apply hereinafter.), 1 NR b CO—, 1 NR 5 CONR 6 — (wherein R 5 and R 6 may be the same or different and each has a hydrogen atom or a substituent. Also good Ci- 6 alkyl. Alternatively, R 5 and R 6 may be joined together to form an optionally substituted ring with the atoms to which they are attached.
  • Oxygen atom, sulfur atom, —SO—, — S0 2 —, — NR b S0 2 —, —S0 2 NR b —, may have a substituent, alkylene, may have a substituent have good C 2 - 6 Aruke two alkylene which may have a substituent C 2 - 6 alkylene - alkylene, single O- X b _ (3 ⁇ 4 wherein ⁇ may have a substituent Ci- e represents alkylene, and so on.), — X b — O—, —CO— X b —, One X b — CO—, One CONR b — X b —, — X b — CONR b —, One NR b CO— X b —, 1 X b — NR b CO—, 1 S— X b —, 1 X b — S—, 1 SO— X
  • a bond Preferably a bond, one NH—, — NR 4 —, one CO—, one C ⁇ 2 —, one OCO—, one CONR b —, one NR b CO—, — NR 5 CONR 6 —, an oxygen atom, a sulfur atom , 1 SO—, 1 S0 2 —, — NR b S0 2 —, 1 S0 2 NR b —, — CO— X b —, 1 X b — CO—, 1 CONR b — X b —, 1 X b— coNR b —, — NR b CO— X b — or — X b — NR b CO—;
  • R 4 represents an optionally substituted C- 6 alkyl, preferably Ci- 3 alkyl
  • R 5 and R 6 may be the same or different and each represents a hydrogen atom or 6- alkyl which may have a substituent, preferably a hydrogen atom
  • R b may have a hydrogen atom or a substituent It indicates Kill, preferably hydrogen atom or an 0 3 alkyl
  • x b is, C] optionally have a substituent - 6 an alkylene, preferably a C i-3 alkylene.
  • Z represents a hydrogen atom, a halogen atom, an alkyl which may have a substituent, which may have a substituent group c 3 _ 8 cycloalkyl, optionally ⁇ reel may have a substituent, the substituent Heterocyclic group optionally having hydroxy, nitro, amino, cyano, optionally having alkoxy, optionally having mono- or di-6-alkylamino, substituent C-7 acylamino, optionally substituted sulfonylamino, optionally substituted hydrazino, optionally substituted guanidino Or amidino optionally having substituents;
  • a hydrogen atom More preferably, a hydrogen atom, a hydroxy, an amino, an optionally substituted 6 alkyl, an optionally substituted — 6 alkoxy, an optionally substituted aryl or a substituted group It is a heterocyclic group which may have.
  • Even more preferred is a hydrogen atom, hydroxy or amino, and even more preferred is hydroxy or amino. An even more preferred embodiment is hydroxy. An even more preferred embodiment is amino.
  • Preferable examples of the group represented by Z—Y—X— include a hydrogen atom, carboxyl, carboxymethyl, amino, carbamoyl, carbamoylmethyl, (2-amino-2-oxoethyl) aminocarbonyl and the like.
  • the compound represented by the general formula (1) includes the general formula (la)
  • ring C represents aryl or heteroaryl which may have a substituent, and other symbols are as defined above.
  • ring C is preferably phenyl, pyridyl, partially hydrogenated 1, 2, 4-oxadiazolyl, 1, 2, 4_triazolyl, tetrazolyl, isoxazolyl, etc. is there.
  • Ci-e alkyl, —6 alkoxy, hydroxy, nitro, amino, cyan, forceful loxy, Ci- 6 alkoxy forceful lponyl, force lupamoyl, oxo and the like are preferable, and methoxy, Hydroxy, amino, carboxy, methyl, carbamoyl and oxo are more preferred.
  • the compound of the general formula (1) and pharmaceutically acceptable salts thereof may exist in the form of hydrates or solvates (for example, ethanol solvates). Therefore, these hydrates, solvates Also included in the present invention. Further, since the compound of the general formula (1) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention.
  • the compound of the general formula (1) is prepared by the following methods (1) to (11) and methods according to these methods, methods known to those skilled in the art of organic synthesis, and WO 97/24325, WO 98/25617. , WO 98/02151, WO 98/04554, WO 00 no 34278, WO 99 no 55324, WO 99/55330, WO 00/58 305, WO 00/31033, WO 00/53600, WO 01/14333, WO02 / 66460 , WO 02/881 1 1, WO 02/18335, WO 0 229 5, WO 03/82863, WO 03/99287, WO 03/99798 (these documents are incorporated herein by reference) and can be synthesized by a method according to the method described in, etc. .
  • heteroaryl (including heteroarylene) necessary substituents used in the description of the synthesis method below means an addition reaction or water, alcohol, acid in many cases by an acid or base catalyst, light, heat, etc. It means a substituent necessary for constructing a heteroaryl by a condensation reaction accompanied by elimination of hydrogen halide or the like.
  • Specific examples of the “substituents necessary for the construction of heteroaryl” include one of a combination of promoacetyl and thioamide in the construction of thiazole, and a combination of hydroxyamidine and carboxylic acid in the construction of 1, 2, 4-oxadiazole.
  • under ice cooling or at room temperature means 0 to 30 ° C.
  • an appropriate solvent that does not inhibit the reaction for example, tetrahydrofuran (hereinafter abbreviated as THF), dichloromethane, ⁇ , ⁇ -dimethylformamide (hereinafter abbreviated as DMF) or any mixed solvent thereof, etc., in the presence of a tertiary amine such as triethylamine, diisopropylethylamine, etc., in the presence of a condensing agent [e.g.
  • DCC ⁇ - (3-Dimethylaminopropyl)- ⁇
  • EDC monoethyl carpositimide
  • EDQ 2-ethoxy-1 1-ethoxycarboyl 1,2-Dihydroxyquinoline
  • CD I Carposiimidazole
  • PyBOP Jetyl phosphoryl cyanide Benzotriazole 1-yloxytrispyrrolidinophosphohexahexenoreophosphate
  • DPPA diphenylphosphoryl azide
  • isobutyl chloroformate jetylacetyl chloride, trimethyl chloride A cetyl etc.
  • the compound represented by the general formula (1) can be obtained by reacting the compound represented by the general formula (2) as a reactive derivative (for example, acid chloride, acylimidazole, etc.).
  • a reactive derivative for example, acid chloride, acylimidazole, etc.
  • this reaction is carried out in the presence of a tertiary amine such as triethylamine or pyridine in an appropriate solvent that does not inhibit the reaction (eg THF, dichloromethane, chloroform, benzene, or any mixed solvent thereof). Perform for 1 to 24 hours under ice cooling or at room temperature.
  • a tertiary amine such as triethylamine or pyridine
  • an appropriate solvent that does not inhibit the reaction
  • G 1 represents a protecting group (for example, tert-ptoxycarbonyl (B oc), benzyloxycarbol (Cb z))). Or a tertiary amine such as triethylamine or diisopropylethylamine in an appropriate solvent that does not inhibit the reaction (THF, dichloromethane, DMF, or any mixed solvent thereof).
  • a condensing agent synthetic with the condensing agent described in Method (1)
  • each symbol is the same as described above.
  • the protecting group is a Boc group in this compound, for example, hydrogen chloride or trifluoroacetic acid (hereinafter abbreviated as TFA) in an inert solvent such as acetonitrile, THF, 1,4-dioxane, ethyl acetate or the like. Deprotection is usually performed using acid at 30-60 ° C for 10 minutes-24 hours.
  • the protecting group is a Cb Z group, for example, in an inert solvent such as methanol, ethanol, ethyl acetate, etc.
  • a catalyst such as palladium on carbon, deprotection is carried out by reaction at ⁇ 30 to 60 ° C. for 10 minutes to 24 hours using an acid such as catalytic reduction with hydrogen or hydrogen bromide monoacetic acid.
  • This compound is represented by the general formula (7)
  • L 1 represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfuroxy, etc., and other symbols are the same as above.
  • a suitable solvent that does not inhibit the reaction THF, dichloromethane, DMF, or any mixed solvent thereof
  • X represents one CONH— (CH 2 ) q — (wherein q represents an integer from 0 to 6). Is obtained.
  • the compound represented by the general formula (1) can be obtained by reacting the compound of the general formula (9) as a reactive derivative (acid chloride, acyl imidazole, etc.) in the same manner.
  • X represents one NHCO— (CH 2 ) q ⁇ (wherein q represents an integer of 0 to 6). Is obtained.
  • the compound represented by the general formula (1) can be obtained by reacting the compound of the general formula (12) as a reactive derivative (acid chloride, acyl imidazole, etc.) in the same manner.
  • L 2 represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and other symbols are as defined above.
  • an acid addition salt thereof in the presence of a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium bicarbonate, sodium hydroxide, or the like, in an ice-cooled state or at room temperature for 1 to 24 hours.
  • a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium bicarbonate, sodium hydroxide, or the like
  • n 1, and is an optically active substance.
  • the compound represented by the above or an acid addition salt thereof is converted into an appropriate solvent that does not inhibit the reaction (eg, dichloromethane, chloroform, dichloroethane, acetic acid, or any of these). In a mixed solvent, etc.), it is produced by reacting with a halogenating agent such as chlorine, bromine, pyridine tribromide, trimethylphenylammonium tribromide, iodine, etc. at 0-100 ° C for 10 minutes to 24 hours. Can do.
  • the compound represented by the general formula (26) or an acid addition salt thereof is a novel compound and can be produced by converting the optically active form of the compound represented by the above general formula (3) into acetylene by a conventional method. it can.
  • L 3 represents a leaving group such as chlorine, bromine, iodine, methanesulfo-loxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and other symbols are as defined above.
  • an acid addition salt thereof in a suitable solvent that does not inhibit the reaction for example, dichloromethane, chloroform, dichloroethane, jetyl ether, dimethylformamide, water, or any mixed solvent thereof.
  • an appropriate solvent that does not inhibit the reaction for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, black mouth form, etc.
  • an oxidizing agent such as tachloroperbenzoic acid, or an oxidizing agent such as hydrogen peroxide in a carboxylic acid solvent such as acetic acid, trifluoroacetic acid, formic acid, etc.
  • the substituent when an amino group or the like that does not participate in the reaction is present in the reactant, the substituent is protected with an appropriate protecting group, and then the reaction is carried out, and the protecting group can be removed after the reaction.
  • Protecting groups for the amino group used in this case include tertiary butoxycarbonyl, carpamates such as benzyloxycarbonyl, amides such as formyl, acetyl, trifnoreoloacetylinole, benzoinole, benzinole, p- And arylalkyl such as methoxybenzyl and trityl.
  • These protecting groups can be removed by, for example, solvolysis using an acid such as hydrochloric acid, formic acid or trifluoroacetic acid, or a base such as sodium hydroxide or potassium hydroxide, or reduction using a metal hydride complex
  • the palladium-carbon catalyst can be obtained by catalytic reduction using Raney nickel or the like, or oxidation using 2,3-dichloro-1,5,6-dichloro-1, p-benzoquinone or the like.
  • ring B represents heteroarylene which may have a substituent, and other symbols are as defined above.
  • Z represents an optionally substituted heteroaryl, and the other symbols are the same as those described above. It is synonymous with. ) Is obtained.
  • X is —Qi— (CH 2 ) q — [wherein is one NH—, —NR 7 — (wherein R 7 may have a substituent — 6 alkyl ) Represents an oxygen atom or a sulfur atom, and q represents an integer of 0 to 6. ], It can also be synthesized by the following method.
  • G 6 represents one NH 2 , —NHR 7 (wherein R 7 represents an optionally substituted substituent_ 6 alkyl), one OH or one SH, The symbols are as defined above. ] Or a suitable solvent that does not inhibit the reaction.
  • L 4 represents a leaving group such as chlorine, bromine, iodine, methanesulfo-loxy, p-toluenesulfonyl / leoxy, trifluoromethanesulfo-oxy, and other symbols are as defined above.
  • X is — Q 2 — (CH 2 ) q — (wherein Q 2 is 1 NH—, 1 NR 7 — (wherein R 7 may have a substituent) — Represents 6 alkyl)) represents an oxygen atom or sulfur atom, and q represents an integer of 0 to 6. In the case of), it can also be synthesized by the following method.
  • L 5 represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, ⁇ -toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and other symbols are as defined above.
  • an acid addition salt thereof in an appropriate solvent that does not inhibit the reaction for example, dichloromethane, chloroform, dichloroethane, jetyl ether, water, or any mixed solvent thereof).
  • G 7 one NH 2, (In the formula, R 7 is a good 0 E _ 6 alkyl which may have a substituent.) -NHR 7, one OH or - indicates SH, the other The symbols are as defined above. Or the acid addition salt thereof in the presence of a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium bicarbonate, sodium hydroxide, or the like, in an ice bath or at room temperature for 1 to 24 hours.
  • a base such as triethylamine, pyridine, DMAP, potassium carbonate, sodium bicarbonate, sodium hydroxide, or the like
  • Examples of the pharmaceutically acceptable salt of the compound of the general formula (1) include acid addition salts with inorganic acids or organic acids, and the compound of the general formula (1) is treated with an inorganic acid or an organic acid by a conventional method. To obtain a salt. Further, hydrates and solvates of the compound of the general formula (1) are also included in the present invention and can be produced by a known method.
  • the compound of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization or column chromatography.
  • a conventional method such as recrystallization or column chromatography.
  • the resulting product is a racemate, it can be resolved into the desired optically active substance, for example, by fractional recrystallization of a salt with an optically active acid, or by passing through a power ram filled with an optically active carrier. Can do.
  • Individual diastereomers can be separated by means of fractional crystallization, column chromatography and the like. These can also be obtained by using optically active raw material compounds.
  • Stereoisomers can be isolated by recrystallization, column chromatography, or the like.
  • a carrier for example, an excipient, a binder
  • a disintegrant, etc. can be administered orally or parenterally in the form of a pharmaceutical composition obtained by mixing with a disintegrant, etc. or a preparation (eg, tablet, liquid, etc.).
  • the pharmaceutical composition can be formulated according to a usual method.
  • Dosage depends on age, weight, general health, sex, diet, time of administration, method of administration, excretion rate, combination of drugs, and the patient's current condition, or other factors Determined in consideration of
  • the daily dose of the compound of the present invention varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc. For example, orally, the dose is 0.01 to 100 mg / kg body weight per day. Yes, it is administered once to several times a day, and parenterally, about 0.0 1 to 10 O mg Z kg body weight is administered one to several times a day. preferable.
  • Diseases that can be treated or prevented include, for example, diseases in which cells with CCR 3 play an important role in the pathogenesis, progression, and maintenance of diseases, such as asthma, sinusitis, allergy Rhinitis, atopic dermatitis, allergic conjunctivitis, Examples include allergic myelitis, ulcerative colitis, Crohn's disease, and rheumatoid arthritis.
  • the treatment in the present invention is intended to cure a disease, reduce a disease, prevent a disease from worsening, or prevent a seizure in an individual who has already developed a disease (for example, a mammal including a human).
  • prevention means that the compound of the present invention is administered to a healthy individual who has not developed the disease (for example, mammals including humans) for the purpose of preventing the onset of the disease. Means.
  • the 1 H-NMR spectrum of the compound was measured at 30 OMHz or 40 OMHz.
  • TMS tetramethylsilane
  • ⁇ relative delta
  • Coupling constants indicate trivial multiplicity in hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet-of-doublets) , Brs (broad singlet), etc.
  • Column chromatography was performed using silica gel manufactured by Fuji Silicon Chemical Co., Ltd. Separation by HP LC was carried out using a column made by WATERS or Shiseido, using a mixed solvent of 0.05% TFA aqueous solution and 0.05% TFA-acetonitrile solution as the eluent.
  • room temperature used in the description of the following examples means 10 to 30 ° C.
  • the title compound 65 Omg was obtained as a slightly yellow amorphous solid from 422 mg of the product of (1-1) and 302 mg of the product of (5-1) by the same method as (1-4).
  • the obtained residue was purified by silica gel column chromatography using a mixed solvent of black mouth form and ethanol as an eluent. The solvent was distilled off from the eluate to give 202 mg of the title compound as a white amorphous solid.
  • the obtained residue was purified by silica gel column chromatography using a mixed solvent of black mouth form and methanol as an eluent.
  • the solvent was distilled off from the eluate to obtain 3.87 g of the title compound as a slightly yellow amorphous solid.
  • Example 9 To a solution of 262 mg of pyridine in 2 mL, 5 7 L of acetic anhydride was added dropwise. The reaction was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was removed from the eluate to obtain 279 tng of the title compound as a white amorphous solid.
  • the obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was distilled off from the eluate to obtain 44 lmg of the title compound free form as a slightly yellow amorphous solid. From the obtained residue, the title compound (357 mg) was obtained as slightly yellow crystals by the same method as in (1-2).
  • the product 490111 ⁇ of (22-2) was dissolved in xylene 61111 ⁇ and pyridine 1111. After 104 L of acetic anhydride was added dropwise, the mixture was heated to reflux for 2 hours. After allowing to cool, 28 L of acetic anhydride was added dropwise, and the mixture was further heated to reflux for 4 hours. Ethyl acetate was added to the reaction solution, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of black mouth form and methanol as an eluent. The solvent was removed from the eluate to give the title compound-free compound 45 7 mg as a pale yellow oil. From the obtained residue, 75 mg of the title compound 2 was obtained as white crystals by the same method as (1 1 2).
  • the title compound 5 2 Omg was obtained as a pale yellow powder from 500 mg of the product of (2 6-1) and 700 mg of the product of (1-1) by the same method as in (1 -4).
  • the title compound 5 7 Omg was obtained as a white amorphous solid from 60 mg of the product (28-2) by the same method as in Example 9.
  • Example 3 Product of 1 50 Omg and 4 monopyridylboronic acid 25 Omg were dissolved in a mixed solvent of ethylene glycol dimethyl ether 25 niL and water 5 ml, sodium hydrogen carbonate 500 mg and tetrakistriethanol ⁇ phosphine palladium 6 Omg was added and stirred at 100 ° C overnight.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using a mixed solvent of black mouth form and methanol as an eluent. The solvent was distilled off from the eluate, and the obtained residue was recrystallized with ethyl acetate to give the title compound 9 Omg as a pale brown powder.
  • Example 33 The product of Example 33 was obtained in the same manner as in Example 9 and 300 mg of the title compound as a white powder.
  • the title compound (592 mg) was obtained as a white amorphous solid by the same method as in Example 16 using 476 mg of the product of (1-5) and 20 lmg of glycine mono-tert-butyl ester hydrochloride.
  • the title compound trifluoroacetate was obtained as a colorless oil from 2 mg of the product (4 6-1) in the same manner as in (4 2-2). From the residue obtained (1 1 2) In the same manner, 531 mg of the title compound was obtained as a white powder.
  • the title compound trifluoroacetate was obtained as a colorless oil from 56 lmg of the product of Example 47 by a method similar to (42-2). From the obtained residue, 49 lmg of the title compound was obtained as a white powder by the same method as (1 1-2).
  • the title compound-free product was obtained as a colorless oil from 500 mg of the product (50-1) by the same method as (1-5). From the obtained residue, the title compound (470 mg) was obtained as a white powder in the same manner as in (1-2).
  • the title compound 6 7 7 mg was obtained as a pale yellow oil from 476 mg of the product of (1-5) and L-alanin benzyl ester tosylate 4 • 22 mg in the same manner as in Example 16.
  • the title compound-free product was obtained as a colorless oil from 6 7 7 mg of the product (5 1-1) in the same manner as in (1-5).
  • the title compound 4 8 Omg was obtained as a white powder from the obtained residue by the same method as in (1-2).
  • the reaction was performed from 975 mg of the product of (54-2) by the same method as in (1-5), and purification was performed by HP LC to obtain the trifluoroacetate salt of the title compound as a colorless oil.
  • the title compound 12 Omg was obtained as a white solid from the obtained residue by the same method as (1 1 2).
  • the title compound 1.31 g was obtained as a white amorphous solid from 1.34 g of the product of (55-3) by the same method as (1-5).
  • the title compound 1 8 3 mg was obtained as a white amorphous solid from the product 4 4 O mg of (6 8-2) by the same method as (1-5).
  • the title compound 3 6 lmg was obtained as a white amorphous solid from 45 Omg of the product (72-1) by the same method as (70-2).
  • the title compound 14 Omg was obtained as a pale yellow solid from 36 mg of the product 7-2) by the same method as (70-3).
  • the title compound 4.40 g was obtained as a white amorphous solid from 3.96 g of the product of (75-3) by the same method as (1-2).
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the resulting residue was purified by silica gel gel chromatography using a mixed solvent of black mouth form and acetone as an eluent. The solvent was distilled off from the eluate to obtain 830 mg of the title compound as a colorless oil.

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WO2008123582A1 (ja) 2007-04-04 2008-10-16 Kowa Company, Ltd. テトラヒドロイソキノリン化合物
JP2010504347A (ja) * 2006-09-19 2010-02-12 インサイト・コーポレイション インドールアミン２，３−ジオキシゲナーゼのモジュレーターとしてのｎ−ヒドロキシアミジノヘテロサイクル
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WO2020203822A1 (ja) * 2019-03-29 2020-10-08 千寿製薬株式会社 血管新生を伴う網膜疾患の治療又は予防のための併用医薬

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KR20070099528A (ko) 2007-10-09
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CN101014580B (zh) 2011-05-04
US20070265257A1 (en) 2007-11-15
CA2579207A1 (en) 2006-03-16
EP1801108A1 (en) 2007-06-27
CN101014580A (zh) 2007-08-08
JPWO2006028284A1 (ja) 2008-05-08
PT1801108E (pt) 2012-12-03
TWI367209B (US06903085-20050607-C00131.png) 2012-07-01
US7935700B2 (en) 2011-05-03
CA2579207C (en) 2011-10-18
JP4970946B2 (ja) 2012-07-11
EP1801108B9 (en) 2013-11-20
DK1801108T3 (da) 2013-02-18
PL1801108T3 (pl) 2013-04-30
EP1801108A4 (en) 2010-10-13
IN2014CN03493A (US06903085-20050607-C00131.png) 2015-07-03
KR101011848B1 (ko) 2011-02-01
EP1801108B1 (en) 2012-11-14

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