WO2004037817A1 - Composes de n-oxyde - Google Patents

Composes de n-oxyde Download PDF

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Publication number
WO2004037817A1
WO2004037817A1 PCT/JP2003/013591 JP0313591W WO2004037817A1 WO 2004037817 A1 WO2004037817 A1 WO 2004037817A1 JP 0313591 W JP0313591 W JP 0313591W WO 2004037817 A1 WO2004037817 A1 WO 2004037817A1
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Prior art keywords
substituent
alkyl
ylthio
oxopiperidine
dichlorobenzyl
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PCT/JP2003/013591
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English (en)
Japanese (ja)
Inventor
Yoshihito Tanaka
Shuzo Takeda
Hidemitsu Azuma
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Mitsubishi Pharma Corporation
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Priority to AU2003275632A priority Critical patent/AU2003275632A1/en
Publication of WO2004037817A1 publication Critical patent/WO2004037817A1/fr

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    • 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
    • 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
    • A61P11/06—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
    • 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
    • A61P37/02—Immunomodulators
    • 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

Definitions

  • the present invention relates to a novel N-oxide compound having affinity for a chemokine receptor, wherein the compound or a salt thereof plays an important role in the onset, progress, and maintenance of a disease state by a cell having a chemokine receptor.
  • ulcerative colitis such as atherosclerosis, rheumatoid arthritis, chronic osteoarthritis, psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergies, ulcers It is useful as a therapeutic and / or prophylactic agent for ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis, rejection response during organ transplant surgery, human immunodeficiency syndrome, and the like.
  • chemotactic substances that induce infiltration of migration and local leukocytes such as neutrophils and monocytes, degradation product C 3 a or C5a of complement, l eukot riene B Arakidon acid metabolites such as 4, platelet activity
  • chemotactic factors such as chemotactic factors and bacterially-formylated peptides. These are mainly secondary products associated with tissue damage.
  • chemokines a series of cytokins (chemokines), which are produced by new gene expression and are responsible for inducing and activating specific leukocytes, were purified by Matsushima et al. In 1987. erl euk in (IL) 18 (CXCL 8) proved its existence (for example, see Non-Patent Documents 1 and 2).
  • chemokines have been identified, and chemokines have been classified into four subgroups based on their amino acid sequence characteristics. C chemokines, CC chemokines, CXC chemokines and CX 3 C chemokines.
  • XCL1 which belongs to the C chemokine, has a chemotactic activity on T cells and NK cells.
  • CC chemokines exhibit chemotactic activity on monocytes other than neutrophils, lymphocytes, Langerhans cells, dendritic cells, eosinophils, mast cells, and basophils.
  • CXC chemokines Mainly to neutrophils as CXC chemokines are represented by CXCL8 is, CX 3
  • C chemokines mainly affect NK cell migration. These chemokines exert their effects by binding to G protein-coupled receptors (chemokine receptors). However, to date, 18 types of chemokine receptors have been identified (for example, see Non-Patent Documents 3 and 4).
  • substances that inhibit the binding of chemokines to their receptors inhibit the selective migration and activation of leukocytes, and acute and chronic inflammatory diseases, including allergic diseases, and human immunodeficiency syndrome, etc. It is considered to be useful as a medicament for the prevention or treatment of the disease.
  • compounds having affinity for chemokine receptors can be expected to be useful as pharmaceuticals for preventing or treating immune and inflammatory diseases.
  • Patent Document 1 discloses diphenylmethane derivatives
  • Patent Document 2 discloses arylpyrazine derivatives, and other compounds having affinity for chemokine receptors.
  • Patent Documents 3, 4, and 5 disclose compounds having affinity for chemokine receptors.
  • Patent Literatures 6 and 7 disclose a phenylalanine derivative having an affinity for a chemokine receptor
  • Patent Literature 8 disclose a pyrazine having an affinity for a chemokine receptor.
  • Patent Documents 9, 10, 11, and 12 disclose piperidine derivatives having affinity for chemokine receptors.
  • Patent Documents 13 and 14 disclose morpholine derivatives having affinity for chemokine receptors.
  • Patent Document 15 discloses a cyclic amine derivative having a CCR3 antagonistic action.
  • An object of the present invention is to provide a medicament having an affinity for a chemokine receptor and for treating and / or preventing an immune and inflammatory disease.
  • the present inventors have conducted intensive studies to find a non-peptidic compound exhibiting chemokine receptor antagonism.
  • an N-oxide compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is obtained.
  • the N-oxidized compounds of the present invention include conventional non-oxidized compounds, their optical isomers or their pharmaceutically acceptable salts [see, for example, Patent Documents 1 to 15 described above. Compounds shown above] have higher affinity for chemokine receptors and are found to be pharmacokinetically improved. Therefore, the compound of the present invention suppresses the selective migration and activation of leukocytes, and can be a medicament for treating or preventing acute and chronic inflammatory diseases including allergic diseases, and human immunodeficiency syndrome. This led to the completion of the present invention.
  • the present invention relates to the following compounds [1] to [8], optical isomers thereof, or pharmaceutically acceptable salts thereof.
  • Ring A represents an aryl which may have a substituent, a heterocyclic group which may have a substituent, or a cycloalkyl which may have a substituent,
  • R a and R b are the same or different from each other, a hydrogen atom, an alkyl, halogen atom, hydroxy, alkoxy, Shiano, Aminokaruponiru, carboxy or alkoxycarbonyl; or, taken R a and R b gar ⁇ R a and R b may form a ring together with the atom to which they are bonded,
  • p represents an integer from 0 to 2
  • n an integer from 0 to 5
  • n an integer from 0 to 5
  • V represents a bond, an optionally substituted Ci-e alkylene, one CO— or —S 0 2— ,
  • W represents — CH, _CH 2 —, — N, one NH—, an oxygen atom or a sulfur atom,
  • X is a bond, —NH—, —NR 1 — (wherein R 1 represents alkyl),
  • One CO—, one CONRc— or one NR c CO— (where R c represents a hydrogen atom or alkyl), -NR 2 CONR 3- (wherein R 2 is the same or different Each represents a hydrogen atom or an alkyl, or H 2 and R 3 may be taken together to form a ring together with the atom to which they are bonded)), an oxygen atom, a sulfur atom, —SO— , — S0 2 —, one NR c S0 2 — or
  • R c represents a hydrogen atom or alkyl.
  • One S0 2 - may have a substituent May have one or more mono- or mono-alkylene substituents — 6 alkylenes S
  • Y is a bond, one NH—, —NR 4 — (wherein, R 4 represents alkyl),
  • R d represents a hydrogen atom or alkyl.
  • C i-6 alkylene C 2 - - S0 2 NR d 6 alkenylene, C 2 - 6 alkynylene, -0- may have an optionally substituted C i_ 6 alkylene mono- or monosubstituted group C 6 alkylene - 0, which may have an S- substituent C 1- 6 alkylene mono- or mono-substituted C 6 alkylene mono-S-,
  • Ci- e alkylene one or - alkylene one may have a substituent group NR d - (wherein, R d represents a hydrogen atom or alkyl.)
  • Z is a bond, optionally C 6 alkylene which may have a substituent, C 2 one 6 alkenylene, C 2 _ 6 alkynylene, oxygen atom, sulfur atom, -SO-, one S0 2 -,
  • R 7 represents an alkyl.
  • R 7 represents an alkyl.
  • R 8 Represents a hydrogen atom or an alkyl.
  • One NR 8 CONR 9 — (wherein R 8 and R 9 may be the same or different and each represents a hydrogen atom or an alkyl. 8 And R 9 may be linked to form a ring together with the atoms to which they are attached.
  • - NR 8 S0 2 - or - S0 2 NR 8 - wherein, R 8 represents a hydrogen atom or alkyl Le
  • R 8 represents a hydrogen atom or alkyl Le
  • a NH 8 - CO- 0- (wherein, R 8 is. represents a hydrogen atom or an alkyl), one Q ⁇ one substituted optionally also have a good C 6 ⁇ alkylene mono- or monosubstituted group C i_ 6 alkylene one Qi- [wherein represents an oxygen atom, a sulfur atom, - SO-, one S0 2 -, one NH-, -NR 7 - (. wherein, R 7 is showing a alkyl), one CO-, one OCO-, one C0 2 -,
  • R 8 represents a hydrogen atom or an alkyl.
  • -NR 8 -CO-NR 9 - wherein, R 8, R 9 are the same or different Each represents a hydrogen atom or an alkyl, or R 8 and R 9 may be linked together to form a ring together with the atom to which they are attached.
  • A is a group selected from a bond, a divalent hydrocarbon ring group which may have a substituent and a divalent heterocyclic group which may have a substituent, or> CH—R 10 Or> N—R 1Q (wherein, R 1Q is selected from a hydrocarbon ring group which may have a substituent and a heterocyclic group which may have a substituent Base),
  • B represents a hydrogen atom, an aryl which may have a substituent, a heterocyclic group which may have a substituent, or a cycloalkyl which may have a substituent.
  • Ar represents an aryl which may have a substituent
  • ⁇ represents an integer from 1 to 5
  • r 0 or 1
  • X is a bond, — ⁇ —, -NR 1 — (wherein, R 1 represents alkyl),
  • R 3 may be the same or different and each represents a hydrogen atom or an alkyl.
  • An oxygen atom, a sulfur atom, -SO-, - S0 2 -, - NHS0 2 - or - S0 2 NH- indicates,
  • Y is a bond, one NH—, —NR 4 — (wherein R 4 represents alkyl),
  • R 6 may be the same or different and each represents a hydrogen atom or an alkyl.
  • An oxygen atom, a sulfur atom, One SO-, - S0 2 -, - NHS0 2 - or - S0 2 NH- indicates,
  • Z is a bond, which may have a substituent — 4 alkylene, an oxygen atom, a sulfur atom, one SO—, —SO 2 —, —NH—, one NR 7 — (R 7 represents alkyl. ),
  • A represents a bond, arylene which may have a substituent, heteroarylene which may have a substituent, or cycloalkylene which may have a substituent
  • B represents an aryl which may have a substituent, a heteroaryl which may have a substituent, or a cycloalkyl which may have a substituent.
  • n is an integer from 1 to 4,
  • n is an integer from 1 to 4,
  • X is —CO—, —CONH—, —NHCO—, —NR 2 CONR 3 — (wherein RR 3 may be the same or different and each represents a hydrogen atom or an alkyl).
  • SO-, one S0 2 -, one NHS0 2 - or a single S0 2 NH-, a is a bond, Teroari one Ren to may have an optionally substituted Ariren or substituent And
  • n is an integer from 1 to 4,
  • X is one CO—, one CONH—, one NHCO—, —NR 2 CONR 3 — (wherein, R 2 and R 3 may be the same or different and each represent a hydrogen atom or an alkyl.)
  • Y is a bond, an oxygen atom or a sulfur atom
  • A is a bond, arylene which may have a substituent or heteroarylene which may have a substituent,
  • the present invention also relates to the following pharmaceutical composition [9] or [10].
  • a pharmaceutical composition comprising the compound according to any one of [1] to [8] above, an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to the following.
  • a chronic rheumatoid arthritis, asthma, allergic rhinitis comprising the compound according to any one of the above [1] to [8], an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  • hydrocarbon group of the “hydrocarbon ring group optionally having substituent (s)” means a monocyclic to tricyclic hydrocarbon ring group having 3 to 20 carbon atoms.
  • the “hydrocarbon ring group” includes a saturated ring, an aromatic ring and a partially hydrogenated ring group.
  • hydrocarbon ring group examples include “aryl” (including partially hydrogenated aryl) as defined below, and “cycloalkyl”.
  • the “hydrocarbon ring group” has a “substituent”, the type and number of the substituent are not particularly limited, and the substituent selected from the “substituents” defined below is Have one to three in possible positions.
  • the c 6 _ 14 Ariru may be condensed with c 3 _ 8 cycloalkyl, the C 6 14 Ariru condensed with C 3 _ 8 cycloalkyl, for example, indanyl and tetrahydronaphthyl and the like.
  • the above “aryl” may be partially hydrogenated.
  • the site to be hydrogenated is not particularly limited. Partially hydrogenated aryls include, for example, dihydronaphthyl and the like.
  • aryl has a “substituent”, its type and number are not particularly limited, and a substituent selected from the “substituents” defined below is placed at a substitutable position.
  • Cycloalkyl in “cycloalkyl optionally having substituent (s)” includes C 3 to C 10 monocyclic to tricyclic cycloalkyl (including “bridged cycloalkyl”). '.), For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl Etc. ⁇
  • the type and number thereof are not particularly limited, and one or more substituents selected from the “substituents” defined below may be substituted at the substitutable position. Have three.
  • hydrocarbon ring group preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2. 2] octyl, phenyl, naphthyl, anthryl, indanyl, tetrahydronaphthyl, etc. o
  • heterocyclic group of the “heterocyclic group optionally having substituent (s)” refers to one to three heterocyclic groups selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring atom. 5- to 7-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 atoms You. “Heterocyclic group” includes a saturated ring and an aromatic ring (including “heteroaryl” as defined below. Also, includes a partially hydrogenated ring group).
  • Heterocyclic group includes “saturated heterocyclic group” containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring atoms.
  • Examples of the “heterocyclic group” include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, thiazolidinyl, homopiperazinyl and the like.
  • a “heterocyclic group” is a “cross-linked heterocyclic group” containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring atoms.
  • the cross-linked ring group includes, for example, 3-azabicyclo [3.2.2] nonane-3-yl, 8-azabicyclo [3.2.1] octane-18-yl and the like.
  • the “heterocyclic group” contains at least one nitrogen atom other than a carbon atom as a ⁇ atom, and may further contain a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Nitrogen-containing saturated heterocyclic group ".
  • nitrogen-containing saturated heterocyclic group examples include, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, homopiperazinyl and the like.
  • the “hetero group” has a “substituent”, the type and number thereof are not particularly limited, and one or more substituents selected from the “substituents” defined below may be substituted at the substitutable position. Have three.
  • heteroaryl of the “heteroaryl optionally having substituent (s)" is selected from the above-mentioned "heterocyclic group" as a ring atom selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom.
  • a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing 1 to 4 heteroatoms for example, furyl, chenyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, Isooxazolyl, isothiazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4 monooxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,5-triazinyl, 1, 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azepinyl, diazepinyl and the like.
  • Heteroaryl also includes a 5- to 7-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring atoms. Also included are groups derived from an aromatic heterocyclic ring (bicyclic or higher) formed by condensing a ring with a benzene ring or the above aromatic heterocyclic group, for example, indolyl, isoindolyl, benzo [b] furyl, Benzo [b] phenyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzo'isothiazolyl, quinolyl, isoquinolyl and the like.
  • heteroaryl may be partially hydrogenated.
  • the position to be hydrogenated is not particularly limited.
  • Partially hydrogenated heteroaryls include, for example, indolinyl, tetrahydrobenzoimidazolyl, chromanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrofuranyl, and the like.
  • heteroaryl has a “substituent”
  • the type and number thereof are not particularly limited, and one to three substituents selected from the “substituents” defined below may be substituted at the substitutable positions. Contained.
  • heterocyclic group preferably, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, tetraquinolyl, isoquinolyl Quinolyl, 1,2,4-oxadiazolyl, 1,3,4—oxadiazolyl, 1,2,3—triazolyl, 1,2,4-triazolyl, 1,3,5—triazinyl, 1,2,4-thiadiazolyl , 1,3,4-thiadiazolyl, piperidinyl, piperazinyl, azepinyl, azepanyl, diazepanyl, diazepinyl, tetrahydrofuranyl, morpholinyl, in
  • the divalent hydrocarbon ring group which may have a substituent” and “the divalent hetero ring group which may have a substituent” are the above “hydrocarbon ring group” and “heterocyclic group”.
  • Ring group '' Means a divalent group having a bond at any position. The position of the bonding hand is not particularly limited, and can be appropriately selected depending on the type of the group.
  • the type and number thereof are not particularly limited, and the “substituent” defined below It contains one to three selected substituents at substitutable positions.
  • the “arylene” of the “arylene which may have a substituent” means a divalent group having a bond at any position of the “aryl” included in the above “hydrocarbon ring group”. Examples thereof include divalent groups such as phenylene and naphthylene.
  • arylene has a substituent
  • the type and number thereof are not particularly limited, and a substituent selected from the “substituents” defined below may be replaced by one to three at the substitutable position.
  • Cycloalkylene in “cycloalkylene optionally having substituent (s)” refers to a divalent group having a bond at any position of “cycloalkyl” included in the above “hydrocarbon ring group”. Means a group, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene and the like.
  • the type and number thereof are not particularly limited, and one to three substituents selected from the “substituents” defined below may be substituted at the substitutable position.
  • heteroarylene of the “heteroarylene optionally having substituent (s)” is a divalent group having a bond at any position of the “heteroaryl” included in the “heterocyclic group”. And includes, for example, furylene, cherenylene, pyrrolylene, thiazolylen, pyrazolylen, oxazolylen, isosoxazolenylene, isotizazo'rylene, imidazolylene, 1,2,4-oxoxadiazolylene, 1,3, 4-oxosadiazolylene, 1,2,3-triazolylene, 1,2,4-triazolylene,
  • heteroarylene has a “substituent”
  • the type and number thereof are not particularly limited, and one or more substituents selected from “substituents” defined below can be substituted. Have three.
  • Alkyl means straight or branched chain —6 alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • Alkyl may have 1 to 3 “substituents” defined below at substitutable positions, and the type and number of the substituents are not particularly limited.
  • C alkyl are preferred in R 1
  • the R 2 C i _ 6 alkyl rather preferable
  • C WINCH 6 alkyl are preferred in R 3
  • the C i _ 6 alkyl in R 7 preferably, C iota _ 6 alkyl is preferable in R 8, and, in R 9 C 6 alkyl is preferred in addition, R a preferably d-6 alkyl Te odor, preferably C i-6 alkyl in R b, C WINCH 6 alkyl is preferable to have you to Rc, and, C alkyl is not preferable in R d.
  • ( ⁇ Alkylene) in “C i -e alkylene optionally having substituent (s)” means an alkylene chain having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, Pentamethylene, hexamethylene, etc.
  • ( ⁇ -4 alkylene) in “alkylene optionally having substituent (s)” means an alkylene chain having 1 to 4 carbon atoms in the above “( ⁇ -6 alkylene)”.
  • ( ⁇ _ 4 alkylene” has a “substituent”, its type and number are not particularly limited, and a substituent selected from the “substituents” defined below can be substituted at the substitutable position. Has one to three.
  • C 2 _ 6 alkenylene "above” (6 alkylene “,” C 2 - 6 alkylene down "any Aruke carbon number 2-6 straight or branched chain having a double bond in the position of The position and number of the double bond are not particularly limited.
  • R a and R b are the same or different from each other and represent a hydrogen atom, an alkyl, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a hydroxy (-OH), an alkoxy (—0— Alkyl (alkyl is as defined above), cyano (one CN :), aminocarbonyl (one CONH 2 ), carboxy (one COQ
  • R a and R b gar cord may form a Okiso group, or R a and R b becomes ⁇ together with the atoms to which they are attached It may form a ring.
  • R a and R b are linked together to form a ring together with the atom to which they are bonded
  • R 2 and R 3 may be the same or different and each represent a hydrogen atom or an alkyl; or R 2 and R 3 May form a ring together with the atom to which they are bonded.)
  • R 2 and R 3 may be the same or different and each represent a hydrogen atom or an alkyl; or R 2 and R 3 May form a ring together with the atom to which they are bonded.
  • cyclic group includes “nitrogen-containing saturated heterocycle”.
  • R 5 and R 6 may be the same or different and each represent a hydrogen atom or an alkyl; or R 5 and R 6 is and may form a ring together with the atoms to which they are attached.
  • Contact Keru to) "becomes R 5 and R 6 gar cord ring formed together with the atoms to which they are attached” includes the above defined “heteroaryl
  • cyclic group includes “nitrogen-containing saturated heterocycle”.
  • Z Represented by Z, mono-Q — optionally substituted C 6 -alkylene or mono-substituted — 6 alkylene — — wherein, is an oxygen atom Child, a sulfur atom, One SO-, -S0 2 _, - NH- , -NR 7 - (. Wherein,: R 7 is showing a ⁇ alkyl), One Co_, -OCO-, One C0 2 -, One CONR 8 — or one NR 8 CO— (wherein R 8 represents a hydrogen atom or alkyl),
  • R 8 which may be identical or different, it it a hydrogen atom or an alkyl or become R 8 and R 9 gar ⁇ They may form a ring with the atoms to which they are attached.
  • the “substituent” is not particularly limited, and includes, for example, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), ( 6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl) , N-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl Xyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl
  • C 3 8 cycloalkyl e.g., cyclopropyl, cyclobutyl, shea Kuropenchiru, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru, norbornene two Le, bicyclo [ 2.2.1] heptyl or bicyclo [2.2.2] Okuchiru etc.
  • C 3 8 cycloalkyl O alkoxy e.g., cyclopropyl O alkoxy, Shikurobu Chiruokishi, Puchiruo carboxymethyl cyclopentyloxy Ruo alkoxy, cyclohexane Kishiruokishi, cyclohexylene , Cyclooctyloxy, norbornyloxy, bicyclo [2.2.1] butyloxy or bicyclo [2.2.2] octyloxy, etc.), — 6-halo Alkyl (for example, the above-mentioned Ct-6 alkyl
  • Amino e.g., Mechiruamino, Echiruamino, Jimechirua Mino, Jechiruamino, propylamino, isopropyl ⁇ Mino, Puchiruamino, diisopropylamino etc.
  • mono- or di- (c 3 - 8 cycloalkyl) Amino e.g., cyclopropyl ⁇ Mino , Cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, norbornylamino, bicyclo [2.2.1] heptylamino, bicyclo [2.2.2] octylamino, dicyclo Propylamino, dicyclobutylamino, dicyclopentylamino, dicyclohexylamino, dicycloheptylamino, dicycloo
  • (C i- 6 alkyl) aminocarbonyl (for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, sec-butylaminocarbonyl, tert-butyl) Aminocarbonyl, dimethylaminocarbonyl, acetylaminocarbonyl, ethylmethylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, diisopropylaminocarbonyl, etc.)
  • C e - 1 4 Ariru ⁇ amino carbonyl (e.g., phenylalanine ⁇ amino carbonyl, 1 one naphthyl ⁇ amino carbonyl, 2-naphthyl ⁇ amino carbonyl, 1-Antori Rua amino carbonyl, etc.), Shiano, C 7 _ 2 0 Aralkyl (e.g., benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 1- (1-naphthyl) ) Ethyl, 2— (1—naphthyl) ethyl,
  • Aralkyl e.g., benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-phenylpropy
  • the amino acid residue may be of natural or non-natural origin, and the amino group contained in the amino acid residue may be protected with a protecting group (for example, tert-butoxycarbonyl group and the like).
  • a protecting group for example, tert-butoxycarbonyl group and the like.
  • Hydroxy, mercapto, C i _ 6 alkylthio e.g., methylthio, Echiruchio, propylthio, isopropoxy Ropiruchio, Puchiruchio etc.
  • substituents may be further substituted with the above-mentioned substituents, and the kind and number of the substituents are not particularly limited, and one to three substituents are present at the substitutable positions.o
  • substituents examples include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a Ci- 6 alkyl [if necessary, the above halogen atom, the above de-e alkoxy or phenyl ( If necessary, the above halogen atom, Alkyl, C i- 4 alkoxy or trifluoromethyl), one R A1 , one S (0) 2 R A2 ,
  • halogen atom for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.
  • Ci- 6 alkyl if necessary, the above halogen atom, the above de-e alkoxy or phenyl ( If necessary, the above halogen atom, Alkyl, C i- 4 alkoxy or trifluoromethyl
  • R A14 , R A15 and R A16 are independently the above halogen atom or — 6 alkyl (optionally substituted by the above C alkoxy) or phenyl (optionally the above halogen Atom, alkyl, substituted with Ci- 4 alkoxy or trifluoromethyl);
  • R A2 and R A6 are independently the Ci-e alkyl [optionally the C ⁇ _ 6 alkoxy, or phenyl (optionally the halogen atom, ⁇ alkyl, C i_ 4 alkoxy or Torifuruo And it may be substituted with methyl.). ]
  • R A7 represents a hydrogen atom, if the CI_ 6 alkyl [required, the an alkoxy or phenyl (optionally the halogen atom, the alkyl, optionally substituted on Symbol C Bok 4 alkoxy or triflate Ruo B methyl . it may be) in replacement which may also be or the CI- C6 alkoxy [unsubstituted or optionally the C Bok 6 alkoxy, or phenyl (necessary, the halogen atom, ( ⁇ - 47 alkyl, C 4 May be substituted with alkoxy or trifluoromethyl).
  • substituents include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), -cycloalkyl, one heterocyclic group, aryl, —OH, —OH, —O—Ci-ealkyl, Aryl, _0-cycloalkyl, 10-heterocyclic group, -NH-aryl, —NH-cycloalkyl, —NH-heterocyclic group, 1 NH 2 , 1 NH—Ci- 6 alkyl, 1 N (C Medicine 6 alkyl) 2, -CONH 2, one CONH- CI- C6 alkyl, - NHCO- (6 alkyl, -CON (C x _ 6 alkyl) 2, - C0 2 - d- 6 alkyl, - C0 2 H, —S0 3 H, —S0 2 NH 2 , 1 N 0 2 and
  • substituents examples include alkyl, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), an alkyl (eg, trifluoromethyl), and a C-OH-substituted C atom.
  • a halogen atom eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.
  • alkyl eg, trifluoromethyl
  • C-OH-substituted C atom 6 alkyl, C i_ 6 alkyl substituted with 1 COOH, — alkyl substituted with CONH 2 and C i- 6 alkyl substituted with 1 CN [alkyl is as defined above].
  • examples of the substituent include a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), - OH, - CN, One N_ ⁇ 2, One NH 2, One CONH 2, -C0 2 - alkyl , A halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a C i_ 3 alkyl, —0— (halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom) , phenyl substituted with a group selected from is optionally may CI- 3 alkyl) and single so 2 _ substituted by an iodine atom, etc.) (which may be substituted by a halogen atom C i-3 alkyl) No.
  • a halogen atom e.g., fluor
  • examples of the substituent include a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), - R B1, C 2 _ 6 alkenyl (wherein, C 2 _ 6 alkenyl, the above “(3 ⁇ 6 alkyl "is alkenyl having carbon number 2 to 6 straight or branched chain have a double bond at any position of the" C 2 _ 6 alkyl ".
  • a halogen atom e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom
  • C 2 _ 6 alkenyl wherein, C 2 _ 6 alkenyl, the above “(3 ⁇ 6 alkyl "is alkenyl having carbon number 2 to 6 straight or branched chain have a double bond at any position of the" C 2 _ 6 alkyl ".
  • C 2 _ 6 alkynyl (where C 2 _ 6 alkynyl is a straight-chain or straight-chain having a triple bond at any position of “C 2 — 6 alkyl” of “( ⁇ _ 6 alkyl)” It is an alkynyl having a branched chain carbon number of 2 to 6.
  • the position and number of the triple bond are not particularly limited.
  • —OH, —SH, one N (R B2 ) 2 —CHO,
  • One S0 2 NR B2 — R B1 or — S0 2 — NR B2 — (optionally substituted aryl) includes: R B 1 is optionally substituted — 6 alkyl, and 1? ⁇ 2 and 11 ⁇ are the same or different and are each a hydrogen atom or ( ⁇ 6 alkyl; or R B2 and R B3 is the above defined "heteroaryl but" ring formed together with the atom to which they are bonded in R B2 and R B 3 gar ⁇ "they are attached to optionally form a ring together with the atom (Te summer together "Ring group” includes "nitrogen-containing saturated heterocycle").
  • the "oxidizable nitrogen atom" contained in the formula is known to those skilled in organic synthesis. Means that it may be oxidized by the above method.
  • the "oxidizable nitrogen atom” is not particularly limited as long as it is a nitrogen atom.
  • the “oxidizable nitrogen atom” is preferably a compound represented by the general formula (1): Is a bonded nitrogen atom.
  • a nitrogen atom contained in the heterocyclic group (including heteroaryl) represented by B is also preferable.
  • the ring A good Ariru preferably have a substituent, as of V, a C bets 6 alkylene preferably have a substituent, especially methylene down among them (one CH 2 -) is preferable.
  • aryl of the “aryl which may have a substituent” represented by Ar
  • phenyl is preferable
  • the “substituent” is preferably a chlorine atom.
  • 3,4-dichlorophenyl is preferable.
  • Ra and Rb are preferably both hydrogen atoms.
  • p represents an integer of 0 to 2, and is preferably 1.
  • m represents an integer of 0 to 5, preferably an integer of 0 to 3, and more preferably 0.
  • n represents an integer of 0 to 5, preferably an integer of 1 to 5, more preferably an integer of 1 to 4, and still more preferably 1.
  • W is preferably one CH, —CH 2 —, one N, —NH— or an oxygen atom, more preferably one CH or one CH 2 —, and even more preferably one CH ⁇ .
  • X is preferably a bond, —NH—, —NR 1 — (wherein R 1 represents alkyl), —CO—, —CONH—, —NHCO—, —NR 2 CONR 3 — (wherein , R 2, R 3, which may be the same or different and is shown it hydrogen atom or alkyl Le), an oxygen atom, a sulfur atom, one SO_, -. S0 2 _ one NHS0 2 - or an S0 2 NH—, more preferably _CO—, one CONH—,
  • Y is preferably a bond, —NH—, —N 4 — (wherein R 4 represents alkyl), one CO—, one CONH—, one NHCO—, and —NR 5 CONR e — (wherein , R 5, R 6, which may be the same or different, it indicates it hydrogen atom or alkyl Le), an oxygen atom, a sulfur atom, -. SO-, one S0 2 -, - NHS0 2 - or one S0 2 NH—, more preferably a bond, an oxygen atom or a sulfur atom, more preferably a sulfur atom.
  • Z is preferably a bond, may be substituted - 4 alkylene, SansoHara child, a sulfur atom, One SO-, One S0 2 -, One NH-, -NR 7 - (R 7 is alkyl ), One CO—, one Q 2 — (CH 2 ) q — or one (CH 2 ) q -Q 2- Q 2 is, _NH-, -N 7 - (wherein, R 7 represents an alkyl.), An oxygen atom, a sulfur atom, one SO- or _S0 2 - indicates, q is an integer of 1 to 4. And more preferably a bond.
  • A is preferably a bond, arylene optionally having substituent (s), heteroarylene optionally having substituent (s) or cycloalkylene optionally having substituent (s), and Preferred is arylene which may have a bond or a substituent or heteroarylene which may have a substituent, and even more preferably, it has a bond or a substituent.
  • Heterogenes are good and still more preferably heteroarylenes which may have a substituent.
  • thiazolylene, oxadiazolylene for example, 1,3,4-oxadiazolylene and the like
  • thiadiazolylene for example, 1,3,4-thiadiazolylene and the like
  • B is preferably aryl which may have a substituent, heteroaryl which may have a substituent or cycloalkyl which may have a substituent, and more preferably has a substituent. And heteroaryl which may have a substituent.
  • aryl which may have a substituent
  • heteroaryl which may have a substituent.
  • phenyl, pyridyl, pyrazinyl, thiaziazolyl (for example, 1,3,4-thiadiazolyl, etc.) and benzothiazolyl are preferred.
  • Amino e.g., (imidazo 1-yl 2-ylmethyl) amino, (imidazoyl 4-ylmethyl) amino, etc., heteroaryl carboxamide (eg, imidazole-4-ylcarboxamide, etc.), amino acid residue amino (eg, L-aralanylamino, etc.)
  • the heteroaryl which may have a substituent represented by B, N-oxidepyridyl is preferable.
  • Preferred compounds of the general formula (1) include:
  • N_ [1— (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — (4-phenylthiazo-1-ru-2-ylthio) acetamide
  • the compound of the general formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate (eg, an ethanol solvate). Objects are also included in the present invention.
  • 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 also included in the present invention.
  • the compound of the general formula (1) can be produced by the following methods (1) to (8) and methods according to these methods, and is used in the following methods (1) to (8)
  • the starting compounds can be obtained by methods known to those skilled in the art of organic synthesis, and methods according to the methods described in Patent Documents 1 to 15 (Patent Documents 1 to 15 are incorporated herein by reference). And the like.
  • the compound of the general formula (1) is shown in a preferred embodiment so that those skilled in the art can easily understand the production method of the compound of the present invention. That is, in the general formula (1), the group:
  • substitutedaryl including heteroarylene
  • Acid, hydrogen halide, etc. means a substituent necessary for constructing a heteroaryl by a condensation reaction accompanied by elimination.
  • Specific examples of the above “substituents required for heteroaryl construction” include any of a combination of promoacetyl and thioamide when constructing thiazolyl, and hydrazide when constructing 1,3,4-oxoxadiazole.
  • a salt thereof eg, an acid addition salt (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.)
  • a base addition salt for example, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, etc.
  • a suitable solvent which does not inhibit the reaction for example, dichloromethane, dichloroethane, chloroform.
  • Halogenated hydrocarbons such as, for example, or any mixed solvent of these
  • an oxidizing agent such as methylbenzoate perbenzoic acid
  • a carboxylic acid solvent such as acetic acid, trifluoroacetic acid, or formic acid.
  • the reaction is usually carried out at a temperature of 30 to 80 ° C, preferably at a temperature of 110 to 60 ° C, for 0.5 to 24 hours by using an oxidizing agent such as plain water. Equation (1):
  • the substituent when an amino group which does not participate in the reaction is present in the reactant, the substituent may be protected with an appropriate protecting group, then the reaction may be carried out, and the protecting group may be removed after the reaction.
  • the protecting group for the amino group used in this case include tert-butoxycarbonyl (B oc), benzyloxycarbonyl and other such sulfamates, formyl, acetyl, trifluoroacetyl, benzoyl and other amides, benzyl, P— And arylalkyl such as methoxybenzyl and trityl.
  • Removal of these protecting groups can be performed, for example, by solvolysis using an acid such as hydrochloric acid, formic acid, or trifluoroacetic acid, or a base such as sodium hydroxide or lithium hydroxide, reduction using a metal hydride complex, or palladium.
  • an acid such as hydrochloric acid, formic acid, or trifluoroacetic acid
  • a base such as sodium hydroxide or lithium hydroxide
  • reduction using a metal hydride complex or palladium.
  • Catalytic reduction using carbon catalyst or Raney nickel, 2 It can be performed by oxidation using 3-dichloro-5,6-dicyanor ⁇ -benzoquinone or the like.
  • the compound when X is -CONH-, the compound can also be synthesized by the following method.
  • an acid addition salt thereof eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.
  • a suitable solvent for example, tetrahydrofuran (hereinafter abbreviated as THF), dichloromethane, ⁇ , ⁇ -dimethylformamide (hereinafter abbreviated as DMF) or a mixed solvent of any of these), triethylamine
  • THF tetrahydrofuran
  • DMF dichloromethane
  • DMF ⁇ , ⁇ -dimethylformamide
  • EDC Ethylcarboimide
  • its hydrochloride 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline
  • DPPA isoptyl chloroformate
  • getyl acetyl chloride trimethyl acetyl chloride and the like.
  • Alone or N-hydroxys Cucinimide hereinafter abbreviated as HONSu
  • hydroxybenzotriazole hereinafter abbreviated as HOBT
  • HOOBT benzotriazine
  • DMAP 4-dimethylaminopyridine
  • the compound represented by the general formula (1) can be obtained by performing the same reaction as the reactive derivative (for example, acid chloride, acylimidazole, etc.) using the compound of the general formula (3). .
  • this reaction is carried out in a suitable solvent that does not hinder the reaction (eg, THF, dichloromethane, chloroform, benzene, or any mixed solvent thereof) in the presence of a tertiary amine such as triethylamine or pyridine.
  • a suitable solvent that does not hinder the reaction eg, THF, dichloromethane, chloroform, benzene, or any mixed solvent thereof.
  • a tertiary amine such as triethylamine or pyridine.
  • the compound represented by the general formula (1) can be obtained by performing the same reaction as the reactive derivative (acid chloride, acylimidazole, etc.) using the compound of the general formula (6).
  • Y represents _NH—, an oxygen atom or a sulfur atom.
  • an acid addition salt thereof for example, hydrochloride, hydrobromide
  • a suitable solvent that does not interfere with the reaction for example, Chloromethane, chloroform, dichloroethane, geethylether, dimethylformamide, water or a mixture of any of these
  • L 1 represents a leaving group such as chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and other symbols are as defined above.
  • a salt thereof with an acid eg, hydrochloride, acetate, hydrobromide, sulfate, oxalate, etc.
  • triethylamine pyridine
  • DMAP potassium carbonate
  • hydrogen carbonate By reacting in the presence of a base such as sodium and sodium hydroxide under ice cooling or at room temperature for 1 to 24 hours, the general formula (1):
  • A represents heteroarylene which may have a substituent in the general formula (1), it can be synthesized by the following method. That is, the general formula (9):
  • A represents heteroarylene which may have a substituent, and other symbols are as defined above).
  • B represents a heteroaryl which may have a substituent in the general formula (1), it can also be synthesized by the following method.
  • G 3 represents a substituent necessary for building a heteroaryl
  • an acid addition salt thereof for example, hydrochloride, hydrobromide, sulfate, sulfuric acid
  • ⁇ represents —Q 2 — (CH 2 ) q— , wherein Q 2 represents —NH—, —NR 7 — (wherein R 7 represents alkyl), an oxygen atom or Represents a sulfur atom, and q represents an integer of 1 to 4.
  • Q 2 represents —NH—, —NR 7 — (wherein R 7 represents alkyl), an oxygen atom or Represents a sulfur atom, and q represents an integer of 1 to 4.
  • G 5 represents —NH 2 , —NHR 7 (where R 7 represents alkyl), —OH or one SH, and the other symbols are as defined above.
  • an acid addition salt thereof eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.
  • a suitable solvent that does not inhibit the reaction eg, dichloromethane, chloroform-form
  • L 2 represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and other symbols are as defined above).
  • Compound or its acid addition salt eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.
  • base eg, triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogencarbonate, hydroxide
  • Z is —Q 2 _ (CH 2 ) q — [wherein Q 2 is one NH—, one NR 7 — (wherein, R 7 represents alkyl.), An oxygen atom or sulfur Represents an atom, and q represents an integer of 1 to 4. ]. Other symbols are as defined above. ] The compound represented by these is obtained.
  • Z is one (CH 2 ) q -Q 2- , wherein Q 2 is one NH—, —NR 7 — (where R 7 represents alkyl), and an oxygen atom Or a sulfur atom, and q represents an integer of 1 to 4.
  • Q 2 is one NH—, —NR 7 — (where R 7 represents alkyl), and an oxygen atom Or a sulfur atom, and q represents an integer of 1 to 4.
  • R 7 represents alkyl
  • q represents an integer of 1 to 4.
  • L 3 represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and other symbols are as defined above).
  • Compound or its acid addition salt eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.
  • a suitable solvent that does not interfere with the reaction (eg, dichloromethan, chloroform, dichloroform) Even, getyl ether, water or a mixed solvent of any of these) in the general formula (16):
  • G 6 represents —NH 2 , one NHR 7 (where R 7 represents alkyl), one OH or —SH, and the other symbols are as defined above.
  • R 7 represents alkyl
  • the other symbols are as defined above.
  • the reaction is performed under ice-cooling or at room temperature for 1 to 24 hours to obtain the general formula (1):
  • Z is, - (CH 2) q _Q 2 - [ wherein, Q 2 one NH-, -NR 7 - (. Wherein, R 7 is showing a alkyl), an oxygen atom or a sulfur atom And q represents an integer of 1 to 4. ].
  • R 7 is showing a alkyl
  • q represents an integer of 1 to 4.
  • Other symbols are as defined above. ] The compound represented by these is obtained.
  • the nitrogen atom in the portion (N ⁇ 0) may not be oxidized, and in such a case, the reaction of the above methods (2) to (8) is performed using a compound in which the nitrogen atom is not oxidized. Thereafter, the nitrogen atom (which is not particularly limited as long as it is a nitrogen atom) contained in the obtained product is oxidized by the method (1) or a method analogous to the method (1) and a method known in the art. Is also good. Further, as the starting compound, a compound in which another nitrogen atom is oxidized by a method known in the art may be used.
  • Examples of the pharmaceutically acceptable salt of the compound of the general formula (1) include an acid addition salt with an inorganic acid or an organic acid.
  • the compound of the general formula (1) can be converted into an inorganic acid (eg, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, etc.), organic acids (for example, acetic acid, trifluoroacetic acid, tosylic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, It can be converted to a salt by treating with ascorbic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid, camphorsulfonic acid, ascorbic acid, and the like.
  • an inorganic acid eg, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric
  • a pharmaceutically acceptable salt of the compound of general formula (1) is a base addition salt (Eg, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, etc.). Hydrates and solvates (for example, ethanol solvates) of the compound of the general formula (1) are also included in the present invention.
  • the compound of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization and column chromatography.
  • a conventional method such as recrystallization and column chromatography.
  • the obtained product is a racemic form, it is separated into a desired optically active substance by, for example, fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier. can do.
  • Individual diastereomers can be separated by means such as fractional crystallization or column chromatography. These can also be obtained by using an optically active starting compound or the like.
  • Stereoisomers can be isolated by recrystallization, column chromatography, or the like.
  • the compound of the present invention can be used in a pharmaceutically acceptable carrier (eg, excipient, binder, disintegrant, corrigent, etc.).
  • a pharmaceutically acceptable carrier eg, excipient, binder, disintegrant, corrigent, etc.
  • Compositions or preparations eg, tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs obtained by mixing with pharmaceutical agents, flavoring agents, emulsifiers, diluents, solubilizing agents, etc. Preparations, suspensions, solutions, injections, drops, suppositories, etc.) orally or parenterally.
  • parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like.
  • the active ingredient compound may comprise at least one excipient, for example, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans , Pectins, tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers
  • Such dosage forms may also contain additional additives (eg, inert diluents, lubricants such as magnesium stearate, Preservatives such as parabens and sorbins, antioxidants such as ascorbic acid, heart tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, perfumes Agent etc.).
  • additional additives eg, inert diluents, lubricants such as magnesium stearate, Preservatives such as parabens and sorbins, antioxidants such as ascorbic acid, heart tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, perfumes Agent etc.
  • Tablets and pills can additionally be prepared with enteric coating.
  • Solutions for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which are inert diluents commonly used in the art, such as water. May be included.
  • Injectable preparations should be prepared using known dispersing or wetting agents and suspending agents and by methods known in the art. Can be.
  • the preparation for injection may also be, for example, a sterile injectable solution or suspension using a diluent or a solvent such as water. Examples of the vehicle or solvent that can be used include water, Ringer's solution, isotonic saline and the like.
  • sterile, fixed oils can be employed as a solvent or suspending medium.
  • any bland fixed oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides.
  • Suppositories for rectal administration are solid at room temperature, including the drug and suitable nonirritating excipients, for example, cocoa balm and polyethylene glycols, but are liquid at intestinal tract temperatures and intrarectal. It can be manufactured by mixing with a substance that releases the drug by melting it.
  • the dosage depends on the patient's age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated at that time. It is determined in consideration of other factors.
  • the compound of the present invention is low-toxic and can be used safely.
  • the daily dose varies depending on the condition and weight of the patient, the type of the compound, the administration route and the like. 1 to 1
  • 0.000 mg / kg body weight / day preferably 0.05 to 50 mg / kg body weight / day, administered once to several times a day, and parenterally subcutaneously or intravenously.
  • Diseases that can be treated and / or prevented include, for example, diseases in which cells with chemokine receptors play an important role in the onset, progression, and maintenance of the disease state, such as atherosclerosis and rheumatoid arthritis , Osteoarthritis, psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergy, ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis Rejection at the time of organ transplant surgery, human immunodeficiency syndrome, and the like.
  • diseases in which cells with chemokine receptors play an important role in the onset, progression, and maintenance of the disease state, such as atherosclerosis and rheumatoid arthritis , Osteoarthritis, psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergy,
  • the 1 H-NMR spectrum of the compound was measured at 300 MHz. Chemical shifts in ifi-NMR were expressed in relative per million (d) values in ppm using tetramethylsilane (TMS) as the internal standard. Coupling constants indicate trivial multiplicity in hertz (Hz), s (single rate), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet). ), Brs (broad singlet), etc. Column chromatography was performed using silica gel manufactured by Fuji Silicon Chemicals.
  • the obtained solid was dissolved in chloroform and purified by silica gel column chromatography using a mixed solvent of chloroform and ethanol as an eluent. The solvent was distilled off from the eluate to give the title compound (43 lmg) as a pale-yellow solid.
  • Human eosinophils were isolated from anticoagulated peripheral blood of healthy humans by the CD16 negative selection method (for example, J. Immunol. Methods, 145, 105-110, 1991). Separated eosinophils (2 x 10 5 ), 50 pmo 1 / L [ 125 I]-eot axin (2000 Ci / mmoL, manufactured by Amersham Pharmacia Biotech) and 0.1 mL of test compound Buffer solution (50 mmol / L HEPES, 1 mmol / L CaCl 2 , 5 mmol / L MgCl 2 , 0.5% serum albumin (BSA), 0.1% sodium azide, pH 7.6 ) And incubated at 25 ° C for 1 hour in a multi-screen plate (Millipore).
  • Buffer solution 50 mmol / L HEPES, 1 mmol / L CaCl 2 , 5 mmol / L MgCl 2 , 0.5% serum albumin (BSA), 0.
  • Eosinophils isolated from peripheral blood of a healthy individual were suspended in a measurement buffer (hanks s' ba 1 anced sal tso lut ion containing 10 mmol / L HE PES and 0.5%% serum albumin). The mixture was turbid and incubated at 37 ° C. for 45 minutes in the presence of 5 ⁇ mo 1 / L Fura-2AM (manufactured by Dojindo Laboratories).
  • the cells were washed three times with a measurement buffer to remove Fura-2AM that was not taken up into the cells.
  • FDSS6000 manufactured by Hamamatsu Photonics KK. That is, a cell suspension (0.1 mL) loaded with Fura-2AM was placed in a 96-well plate for measurement, set on the FDSS6000, and the fluorescence intensity by the excitation light at wavelengths of 340 11111 and 380 nm was measured. The intracellular calcium concentration was calculated by measuring and calculating the ratio of the fluorescence intensity to the excitation light of the two wavelengths.
  • the agonist used CCL11 (0.3 nmol / L), which is a selective ligand for CCR3, and the gonist activity was determined by treating eosinophils with various concentrations of the compound of the present invention 5 minutes before stimulation with the agonist. 50 % inhibition rate (IC 50 value) of the increase in intracellular calcium concentration at that time.
  • Table 2 The agonist used CCL11 (0.3 nmol / L), which is a selective ligand for CCR3, and the gonist activity was determined by treating eosinophils with various concentrations of the compound of the present invention 5 minutes before stimulation with the agonist. 50 % inhibition rate (IC 50 value) of the increase in intracellular calcium concentration at that time.
  • diseases in which cells having chemokine receptors play an important role in the onset, progress, and maintenance of the disease state for example, atherosclerosis, rheumatoid arthritis, osteoarthritis, Psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergy, ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis, rejection during organ transplant surgery Reaction and / or human immunodeficiency syndrome can be treated and / or prevented.

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Abstract

La présente invention se rapporte à un composé représenté par la formule (I) dans laquelle chaque symbole est tel que défini dans le descriptif, à condition qu'au moins un des atomes d'azote de la formule ait été oxydé. Cette invention concerne ce composé, son isomère optique ou son sel pharmaceutiquement acceptable. Il est ainsi possible d'utiliser des médicaments qui présentent une affinité pour un récepteur de chimiokine et qui peuvent être employés dans le traitement et/ou la prévention des maladies immunes et inflammatoires. Formule (I)
PCT/JP2003/013591 2002-10-25 2003-10-24 Composes de n-oxyde WO2004037817A1 (fr)

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WO2007102768A1 (fr) * 2006-03-07 2007-09-13 Astrazeneca Ab Dérivés de pipéridine, leur procédé de synthèse, leur emploi en tant qu'agents thérapeutiques et les compositions pharmaceutiques les incluant
WO2007102767A1 (fr) * 2006-03-07 2007-09-13 Astrazeneca Ab Dérivés de pipéridine, leur procédé de synthèse, leur emploi en tant qu'agents thérapeutiques et les compositions pharmaceutiques les incluant
US7456193B2 (en) 2002-10-23 2008-11-25 Sanofi-Aventis Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
US8044206B2 (en) 2003-03-07 2011-10-25 Astellas Pharma Inc. Nitrogen—containing heterocyclic derivatives having 2,6-disubstituted styryl
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US8569343B2 (en) 2007-03-12 2013-10-29 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8673920B2 (en) 2009-05-06 2014-03-18 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8952166B2 (en) 2012-07-26 2015-02-10 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999990B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999991B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
US9056859B2 (en) 2010-10-29 2015-06-16 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9062070B2 (en) 2011-08-19 2015-06-23 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9073882B2 (en) 2010-10-27 2015-07-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9108947B2 (en) 2011-10-31 2015-08-18 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9139585B2 (en) 2011-10-31 2015-09-22 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9206199B2 (en) 2011-12-16 2015-12-08 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9493474B2 (en) 2011-10-31 2016-11-15 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9527830B2 (en) 2011-09-16 2016-12-27 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9573961B2 (en) 2012-12-19 2017-02-21 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9604998B2 (en) 2013-02-18 2017-03-28 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9751881B2 (en) 2013-07-31 2017-09-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9765074B2 (en) 2013-03-15 2017-09-19 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9777002B2 (en) 2012-11-29 2017-10-03 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US10160751B2 (en) 2015-02-12 2018-12-25 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
WO2021040519A1 (fr) * 2019-08-26 2021-03-04 Stichting Vumc Inhibition de la sécrétion mycobactérienne de type vii
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV

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WO2000068203A1 (fr) * 1999-05-07 2000-11-16 Takeda Chemical Industries, Ltd. Composes cycliques et leurs utilisations
WO2001014333A1 (fr) * 1999-08-24 2001-03-01 Astrazeneca Uk Limited Composes de piperidine substitues utiles comme modulateurs de l'activite de recepteurs de chimiokine
GB2373186A (en) * 2001-02-23 2002-09-18 Astrazeneca Ab Pharmaceutical combinations of a CCR3 antagonist and a compound which is usefulreatment of asthma, allergic disease or inflammation

Cited By (46)

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Publication number Priority date Publication date Assignee Title
US7456193B2 (en) 2002-10-23 2008-11-25 Sanofi-Aventis Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics
US8044206B2 (en) 2003-03-07 2011-10-25 Astellas Pharma Inc. Nitrogen—containing heterocyclic derivatives having 2,6-disubstituted styryl
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles
WO2007102767A1 (fr) * 2006-03-07 2007-09-13 Astrazeneca Ab Dérivés de pipéridine, leur procédé de synthèse, leur emploi en tant qu'agents thérapeutiques et les compositions pharmaceutiques les incluant
WO2007102768A1 (fr) * 2006-03-07 2007-09-13 Astrazeneca Ab Dérivés de pipéridine, leur procédé de synthèse, leur emploi en tant qu'agents thérapeutiques et les compositions pharmaceutiques les incluant
US9512135B2 (en) 2007-03-12 2016-12-06 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10143690B2 (en) 2007-03-12 2018-12-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8569343B2 (en) 2007-03-12 2013-10-29 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10307416B2 (en) 2007-03-12 2019-06-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8946285B2 (en) 2007-03-12 2015-02-03 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8952032B2 (en) 2007-03-12 2015-02-10 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
US9458166B2 (en) 2007-03-12 2016-10-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9827239B2 (en) 2007-03-12 2017-11-28 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9233167B2 (en) 2007-03-12 2016-01-12 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9233168B2 (en) 2007-03-12 2016-01-12 Nektar Therapeutics Oligomer-opioid agonist conjugates
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
US9018211B2 (en) 2009-05-06 2015-04-28 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8673920B2 (en) 2009-05-06 2014-03-18 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
US9073882B2 (en) 2010-10-27 2015-07-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9056859B2 (en) 2010-10-29 2015-06-16 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9062070B2 (en) 2011-08-19 2015-06-23 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9527830B2 (en) 2011-09-16 2016-12-27 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999990B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999991B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9493474B2 (en) 2011-10-31 2016-11-15 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9139585B2 (en) 2011-10-31 2015-09-22 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9108947B2 (en) 2011-10-31 2015-08-18 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9206199B2 (en) 2011-12-16 2015-12-08 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9206198B2 (en) 2012-07-26 2015-12-08 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8952166B2 (en) 2012-07-26 2015-02-10 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9777002B2 (en) 2012-11-29 2017-10-03 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9573961B2 (en) 2012-12-19 2017-02-21 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9604998B2 (en) 2013-02-18 2017-03-28 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9765074B2 (en) 2013-03-15 2017-09-19 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9751881B2 (en) 2013-07-31 2017-09-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US10160751B2 (en) 2015-02-12 2018-12-25 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10611769B2 (en) 2015-04-28 2020-04-07 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US11084826B2 (en) 2015-04-28 2021-08-10 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV
WO2021040519A1 (fr) * 2019-08-26 2021-03-04 Stichting Vumc Inhibition de la sécrétion mycobactérienne de type vii

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