WO2007139149A1 - Composé pour réactif biologique - Google Patents

Composé pour réactif biologique Download PDF

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Publication number
WO2007139149A1
WO2007139149A1 PCT/JP2007/060989 JP2007060989W WO2007139149A1 WO 2007139149 A1 WO2007139149 A1 WO 2007139149A1 JP 2007060989 W JP2007060989 W JP 2007060989W WO 2007139149 A1 WO2007139149 A1 WO 2007139149A1
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Prior art keywords
group
ethyl
compound
imidazole
methyl
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English (en)
Japanese (ja)
Inventor
Teiji Kimura
Toshiki Kurokawa
Takeo Sasaki
Yoshiyuki Murata
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to a compound for a biological reagent. More specifically, a biological reagent compound that can be used as a biological reagent useful for elucidating the mechanism of amyloid beta tank (A ⁇ protein) formation, and A The present invention relates to a method for elucidating the mechanism of j8 protein production, and a kit for elucidating the mechanism of A ⁇ protein production, comprising the compound for biological reagent.
  • Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles as well as neuronal degeneration and loss.
  • symptomatic treatment with symptom ameliorating agents represented by acetylcholine esterase inhibitors, and a fundamental therapeutic agent that suppresses the progression of the disease has been developed!
  • Development of a method for controlling the cause of the pathogenesis is necessary for the creation of a therapeutic agent for Alzheimer's disease.
  • 8 protein which is a metabolite of amyloid precursor protein ( ⁇ ⁇ ⁇ ), is thought to be greatly involved in the degeneration and loss of neurons and the appearance of dementia symptoms (see Non-Patent Documents 1 and 2, for example) .
  • the main component of the 8 protein is ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ 40, which has 40 amino acids, and 42 ⁇ 42, which has 2 amino acids added to the C-terminal.
  • ⁇ 40 and 42 are highly cohesive (see, for example, Non-Patent Document 3), are the main constituents of the elderly population (see, for example, Non-Patent Documents 3, 4, and 5), and are also familial Alach Mutations in the sputum and presenelin genes found in Imah's disease are known to increase these sputum ⁇ 40 and 42 (see, for example, Non-Patent Documents 6, 7, and 8). Therefore, compounds that reduce the production of Aj840 and 42 are expected to be used as an Alzheimer's disease progression inhibitor or preventive agent.
  • a j8 is produced by APP being cleaved by beta secretase and then cleaved by gamma secretase. From this, gamma cell is used to reduce A ⁇ production.
  • Attempts have been made to create inhibitors of secretase and beta-secretase.
  • Many of these secretase inhibitors already known include peptides such as L-685, 458 (see, for example, Non-Patent Document 9) and LY-411575 (see, for example, Non-Patent Documents 10, 11, and 12). Or peptidomimetics.
  • This synamido compound is a compound that strongly suppresses the production of ⁇ 40 and 42, and is expected as a therapeutic or prophylactic agent for diseases caused by ⁇ ⁇ ⁇ represented by Alzheimer's disease.
  • Patent Document 1 For the above-mentioned cinnamidi compound (Patent Document 1) that suppresses the production of A ⁇ 40 and 42, the search for the target protein using a biological reagent has not yet been made.
  • Non-patent literature l Klein WL, 7 others, Alzheimer's disease -affected brain: Pre sence oi oligomeric A ⁇ ligands (DDLs suggests a molecular basi s for reversible memory loss, Proceeding National Academy of Science USA 2003 , Sep 2; 100 (18), p. 10417-10422.
  • DDLs Pre sence oi oligomeric A ⁇ ligands
  • Non-Patent Document 2 Nitsch RM, 16 others, Antibodies against ⁇ -amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 3 8, p. 547-554.
  • Non-Patent Document 3 Jarrett JT, 2 others, The carboxy terminus of the ⁇ amyl oid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimers' disease, Biochemistry, 199 3, 32 (18), p.4693-4697.
  • Patent Document 4 Glenner GG, 1 other, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular a myloid protein, Biochemical and oiophysical research communication s, 1984, May 16, 120 (3), p. 885— 890.
  • Non-Patent Document 5 Masters CL, 5 others, Amyloid plaque core protein in Alzh eimer disease and Down syndrome, Proceeding National Academy of Science USA, 1985, Jun, 82 (12), p.4245-4249.
  • Non-Patent Document 6 Gouras GK, 11 others, Intraneuronal ⁇ 42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156 (1), p. 15-20.
  • Non-Patent Document 7 Scheuner D, 20 others, Secreted amyloid ⁇ -protein simila r to that in the senile plaques of Alzheimer's disease is increased d in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine , 1996, Aug, 2 (8), p. 864-870.
  • Non-Patent Document 8 Forman MS, 4 others, Differential effects of the Swedish mutant amyloid precursor protein on ⁇ -amyloid accumulation and secretion in neurons and nonneuronal cells, The Journal of Biolog ical Chemistry, 1997, Dec 19, 272 (51) , p. 32247-32253.
  • Non-Patent Document 9 Shearman MS, 9 others, L— 685, 458, an Aspartyl Protease
  • Non-Patent Document 10 Shearman MS, 6 others, Catalytic Site -Directed ⁇ — Seer etase Complex Inhibitors Do Not Discriminate Pharmacologically be etweeen Notch S3 and ⁇ — APP Clevages, Biochemistry, 2003, Jun 24, 42 (24), p. 7580-7586.
  • Patent Literature ll Lanz TA, 3 others, Studies of A j8 pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque ⁇ free) Tg 2576 mice using the y—secretase inhibitor N2— [(2S) — 2— (3, 5— difluorophenyl) — 2— hydroxyethanoyl] — Nl— [(7S) —5— methyl— 6— ox o— 6, 7— dihydro— 5H— dibenzo [b, d] azepin— 7— yl] — L— alaninamide (LY— 411575), The journal of pharmacology and experimental thera peutics, 2004, Apr, 309 (1), p. 49— 55.
  • Non-Patent Document 12 Wong GT, 12 others, Chronic treatment with the ⁇ — seer etase inhibitor LY—411, 575 inhibits ⁇ -amyloid peptide productio n and alters lymphopoiesis and intestinal cell differentiation, The j ournal of biological chemistry, 2004, Mar 26, 279 (13), p. 12876— 12 882.
  • Non-Patent Document 13 Li YM, 17 others, Photoactivated ⁇ -secretase inhibitors di rected to the active site covalently label presenilin 1, Nature, 200
  • Patent Document 1 International Publication No. WO2005Z115990 Pamphlet
  • Patent Document 2 International Publication No. WO00Z019210 Pamphlet
  • An object of the present invention is to provide a compound for a biological reagent comprising the above-mentioned cinnamidi compound that suppresses the production of A ⁇ 40 and 42 as a constituent component.
  • a further object of the present invention is to provide a method for analyzing the production mechanism of ⁇ protein by searching for a target protein of a cinnamidine compound using this biological reagent compound as a chemical probe.
  • a further object of the present invention is to provide a kit for analyzing the production mechanism of A
  • the present inventors have intensively studied for the purpose of solving the above problems, and have constructed a compound for a biological reagent containing a cinnamide compound as a constituent component. By using the product, it was found that the production mechanism of ⁇ protein can be analyzed, and the present invention has been completed.
  • the present invention relates to the following compounds 1) to 14) for biological reagents or salts thereof.
  • Ar represents an imidazolyl group which may be substituted with 1 to 3 substituents selected from the following substituent group A1;
  • Ar may be substituted with 1 to 3 substituents selected from the following substituent group A2.
  • X is c ⁇ c or one CR 2 — CR 3 —
  • R 2 and IT represent a substituent selected from the following substituent group A3,
  • R 1 represents a group selected from the following substituent group A4; X may be substituted with a protein labeling group or a group containing a protein labeling group, C1
  • the C1 6 alkylene group is a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a C1 6 alkyl group (the C 1-6 alkyl group is It may be substituted with a hydroxyl group, and the same carbon atom on the C1 6 alkylene group may be substituted with 1 or 2 carbon atoms, and the two C1 6 alkyl groups may be bonded together with a cyclic group (the cyclic group).
  • a methylene group on the ring may be substituted with 1 oxygen atom)), a C 1-6 alkoxy group, an amino group (the amino group is C1— A group selected from the group of A5 and 1 or 3 selected from the substituent group A5, or 5 or a group of 14-membered non-aromatic heterocyclic groups. Force is also selected 1 or 3 and may be substituted with 3 substituents;
  • X is a single bond, an imino group which may be substituted with a substituent selected from substituent group A5,-
  • Ar may be substituted with 1 to 3 substituents selected from Substituent Group A5 6 to 6
  • a 14-membered aromatic hydrocarbon group or a substituent group selected from 1 to 3 substituents selected from the substituent group A5, 5 or 14 represents a 14-membered aromatic heterocyclic group;
  • R 4 represents a substituent selected from the substituent group A3;
  • Z represents a single bond, CO, one (CH) n— (here Te, n is 1 to an integer of 3) or - in CR3 ⁇ 4 6 (wherein, R 5 and R 6 represents a substituent selected from lower Symbol Substituent Group A4) indicates; Z is a single Bond, one O, one NR
  • n an integer of 1 to 3
  • R 7 and R 8 represent a substituent which is also selected from the following substituent group A4 force) or —O;
  • X is
  • A represents a single bond, a protein labeling group or a group containing a protein labeling group;
  • A represents a single bond or a linker;
  • A represents a single bond or a cleavable linker
  • A is a hydrogen atom, fishing tag group, detectable marker, solid support or solid phase
  • Substituent group A1 halogen atom, cyano group, nitro group, C3-8 cycloalkyl group, C2-6 alkyl group, C2-6 alkyl group, C1-6 alkoxy group, C3-8 cycloalkoxy group, A formyl group, a C1 6 alkyl carbo group and a C 1-6 alkyl group (the C 1 6 alkyl group includes a halogen atom, a hydroxyl group, a cyano group, a C 16 alkoxy group, a C 3-8 cycloalkyl group, a C 1 6 alkyl carbo -Which may be substituted with 1 to 3 substituents selected from the group consisting of a thiol group), a protein labeling group, a group containing a protein labeling group, and a group to be bound to a solid phase carrier;
  • Substituent group A2 halogen atom, hydroxyl group, cyano group, C1 6 alkoxy group (the C1 6 alkoxy group is a halogen atom, cyano group, C1-6 alkoxy group, C2-6 alkyl group, C2-6 alkyl group) Group may be substituted with 1 or 3 substituents selected from the group consisting of a C1-8 group and a C3-8 cycloalkyl group), a C3-8 cycloalkoxy group, a C2-6 alkoxy group, a C2— 6 groups containing an alkyloxy group, a protein labeling group and a protein labeling group;
  • Substituent group A3 substituted with 1 to 3 substituents selected from halogen atom, substituent group A5 ⁇ 6 to 14-membered aromatic hydrocarbon ring group, selected from substituent group A5 1 V, and may be substituted with 3 substituents, 5 or 14-membered aromatic heterocyclic group, C1-6 alkyl group (the C16 alkyl group includes a formyl group, a halogen atom, a hydroxyl group, and a protecting group).
  • V 5 or 14-membered aromatic heterocyclic group, substituted with 1 to 3 substituents selected from substituent group A5 A 6 to 14-membered non-aromatic hydrocarbon ring group , A substituent selected from the substituent group A5, and a substituent substituted with 3 substituents, a 5-membered, 14-membered non-aromatic heterocyclic group and —X—A (where X is an imino A group, —O or —S, and A is substituted with 1 or 3 substituents selected from the substituent group A5, 6 or 14 membered aromatic hydrocarbon ring or 5 represents a 14-membered aromatic heterocyclic group (may be substituted with 1 to 3 substituents selected from the group of groups), a C 1-6 alkoxy group, a protein label A group comprising a group and a protein labeling group;
  • Substituent group A4 hydrogen atom, halogen atom, hydroxyl group, cyano group, nitro group, C3-8 cycloalkyl group, C2-6 alkyl group, C2-6 alkyl group, C3-8 cycloalkoxy group, C3 — 8 cycloalkylthio group, formyl group, C16 alkyl carbonyl group, C1-6 alkylthio group, C16 alkyl sulfier group, C16 alkylsulfol group, hydroxyimino group, C 1-6 alkoxyimino group May be substituted with 1 to 3 substituents selected from Substituent Group A5, or may be substituted with C1-6 alkyl group, 1 or 3 substituents selected from Substituent Group A5 C1-6 alkoxy group, 1 selected from substituent group A5
  • Substituent group A5 halogen atom, hydroxyl group, cyan group, nitro group, C3-8 cycloalkyl group, C2-6 alkyl group, C2-6 alkyl group, C3-8 cycloalkoxy group, C3-8 group Chloalkylthio group, formyl group, C16 alkyl carbonyl group, C16 alkylthio group, C1-6 alkylsulfur group, C1-6 alkylsulfol group, hydroxyimino group, C2-6 alkke Groups containing a ruoxy group, a C2-6 alkyloxy group, a C3-8 cycloalkylsulfuryl group, a C3-8 cycloalkylsulfol group, a protein labeling group and a protein labeling group.
  • Chloalkylthio group formyl group, C16 alkyl carbonyl group, C16 alkylthio group, C1-6 alkylsulfur
  • the basic force represented by the formula (II) is selected from the substituent group A5 and may be substituted with 1 or 4 substituents,
  • R 9 represents a substituent selected from the substituent group A4, and R 4 , X, X and Ar are
  • Ar may be substituted with 1 to 3 substituents selected from Substituent Group A2.
  • R 1U represents a C1-C6 alkyl group optionally substituted by a hydrogen atom or a hydroxyl group, and A, A, A and A have the above-mentioned meanings.
  • the linker of A is L4-L1-L2-L3- (where L4 may have a substituent).
  • Heterocycle, C1 20 alkylene group, C2-20 alkylene group, and C2-20 alkylylene group, L1 and L3 are each substituted with a single bond, —O—, —S—, C16 alkyl group NH-OC (0) NH-NHC (0) 0 NHC (0) NH NHC (O) C (0) NH C (O) or
  • R represents a C1-C6 alkyl group
  • L2 represents a single bond, one (CH 2 CH 2 O 3
  • L3 may be a halogen atom, a hydroxyl group, or a heterocyclic group, and L1 and L3 may form a ring with an adjacent group), A compound for biological reagent or a salt thereof according to any one of 1) to 8).
  • the cleavable linker of A is S—S, —O Si—O or —sugar residue—.
  • a compound for biological reagent or a salt thereof according to any one of 1) to 9) above.
  • the fishing tag group of A is Piotin, or 3— (4,4
  • a detectable marker is radiolabeled group, fluorescent labeling group, chemiluminescent group, heavy metal
  • Group power The compound for biological reagent or salt thereof according to any one of 1) to 12) above, which is selected.
  • Group power The compound for biological reagent or salt thereof according to any one of 1) to 12) above, which is selected.
  • the present invention relates to a method for analyzing the production mechanism of the A
  • R 1 represents a C1-C6 alkyl group optionally substituted with a hydrogen atom or a hydroxyl group, and A, A, A and A have the above-mentioned meanings]
  • 8 protein production composed of X, X and Ar The method according to any one of 15) to 17) above, wherein the target protein of the portion to be exhibited is searched and the suppression mechanism of A
  • the present invention relates to the following kit 19).
  • a kit for analyzing the production mechanism of A ⁇ protein comprising the biological reagent compound or salt thereof according to any one of 1) to 14) above.
  • the present invention relates to the following compounds for biological reagents or salts thereof which do not have the action of suppressing the production of
  • the compound for biological reagent or the salt thereof according to 20) above which is a compound or a salt thereof.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., preferably a fluorine atom, a chlorine atom, or a bromine atom.
  • C1-6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms, and preferred groups include, for example, a methyl group, an ethyl group, an n propyl group, an i propyl group, and an n butyl group.
  • C16 alkoxy group refers to a group in which a hydrogen atom of an alkyl group having 1 to 6 carbon atoms is substituted with an oxygen atom.
  • Preferred groups include, for example, a methoxy group, an ethoxy group, n Propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec butoxy group, tertiary butoxy group, n-pentoxy group, i-pentoxy group, sec pentoxy group, tertiary pentoxy group, n— Hexoxy, i-hexoxy, 1,2-dimethylpropoxy, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1, 1,2- Trimethylpropoxy group, 1,1,2-trimethylpropyloxy group, 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2-ethylbutoxy group, 1,3 dimethylbutoxy group, 2-methylpen
  • C 1-6 alkylsulfonyl group refers to a group in which one hydrogen atom is substituted with a sulfonyl group in an alkyl group having 1 to 6 carbon atoms.
  • Preferred groups include, for example, Examples thereof include a methanesulfol group and an ethanesulfol group.
  • amino group refers to an amino group that may be substituted with 1 or 6 alkyl groups, and is a preferred group. Examples thereof include an amino group, a methylamino group, an ethylamino group, a propylamino group, and a dimethylamino group.
  • C2-6 alkenyl group refers to a alkenyl group having 2 to 6 carbon atoms, and preferred groups include, for example, a bur group, a allyl group, a 1 probe group, an isopropyl group.
  • Base group 1-butene-1-yl group, 1-butene-2-yl group, 1-butene-3-yl group, 2-butene-1-yl group, 2-butene-2-yl group
  • linear or branched alkenyl groups such as a group.
  • C2-6 alkyl group refers to an alkyl group having 2 to 6 carbon atoms, and preferred groups include, for example, an ethur group, a 1 propyl group, and a 2-propyl group. And linear or molecular chain alkyl groups such as a group, butynyl group, pentynyl group, and hexyl group.
  • C3-8 cycloalkyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms. Preferred examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclobenthyl group, and a cyclohexyl group. Group, cycloheptyl group, cyclooctyl group and the like.
  • C16 alkylthio group refers to a group in which one hydrogen atom is substituted with a sulfur atom in an alkyl group having 1 to 6 carbon atoms.
  • Preferred groups include, for example, a methylthio group, an ethylthio group, n Propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, tertiary butylthio group, n-pentylthio group, i-pentylthio group, neopentylthio group, n-hexylthio group, 1-methylpropylthio group, etc. .
  • C16 alkyl sulfiel group refers to a group in which one hydrogen atom is substituted with a sulfiel group in an alkyl group having 1 to 6 carbon atoms.
  • Preferred examples of the group include a methyl sulfiel group.
  • Ethylmethylsulfuryl group n-propylsulfiel group, i-propylsulfiel group, n-butylsulfiel group, i-butylsulfiel group, tertiary-butylsulfiel group, n-pentylsulfur Fier, i-pentylsulfi -L group, neopentyl sulfier group, n-hexyl sulfier group, 1-methylpropyl sulfier group and the like.
  • C 1-6 alkyl carbo group refers to a group in which one hydrogen atom is substituted with a carbo yl group in an alkyl group having 1 to 6 carbon atoms. Examples include a acetyl group, propionyl group, and petityl group.
  • C3-8 cycloalkoxy group refers to a cyclic alkyl group having 3 or 8 carbon atoms, in which one hydrogen atom is substituted with an oxygen atom
  • Preferable groups include, for example, a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, a cycloheptyloxy group, a cyclooctoxy group, and the like.
  • C3-8 cycloalkylthio group refers to a cyclic alkyl group having 3 or 8 carbon atoms, wherein one hydrogen atom is substituted with a sulfur atom
  • Preferred groups include, for example, cyclopropylthio group, cycloptylthio group, cyclopentylthio group, cyclohexylthio group, cycloheptylthio group, cyclooctylthio group and the like.
  • C16 alkoxyimino group refers to a group in which a hydrogen atom of an imino group is substituted with a C16 alkoxy group, and preferred groups include, for example, a methoxyimino group and an ethoxyimino group.
  • C2-6 alkyloxy group refers to a group in which one hydrogen atom is substituted with an oxygen atom in an alkenyl group having 2 to 6 carbon atoms.
  • C2-6 alkyloxy group refers to a group in which one hydrogen atom is substituted with an oxygen atom in an alkyl group having 2 to 6 carbon atoms.
  • Examples thereof include straight-chain or branched alkynyloxy groups such as an ethuroxy group, a 1-propyloxy group, a 2-propyloxy group, a butyroxy group, a pentynyloxy group, and a hexynyloxy group.
  • C3-8 cycloalkylsulfier group refers to a group in which one hydrogen atom is substituted with a sulfinyl group in a cyclic alkyl group having 3 or 8 carbon atoms
  • Preferable groups include, for example, cyclopropylsulfuryl group, cycloptylsulfuryl group, cyclopentylsulfuryl group, cyclohexylsulfuryl group, cycloheptylsulfuryl group, cyclooctylsulfuryl group and the like.
  • C3-8 cycloalkylsulfol group refers to a group in which one hydrogen atom is substituted with a sulfonyl group in a cyclic alkyl group having 3 or 8 carbon atoms.
  • Preferred examples of the group include, for example, a cyclopropylsulfol group, a cycloptylsulfol group, a cyclopentylsulfol group, a cyclohexylsulfol group, a cycloheptylsulfol group, and a cyclooctylsulfol group.
  • the “6 or 14-membered cyclic aromatic hydrocarbon ring group” means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having 6 or 14 carbon atoms, Preferred examples of the group include a phenyl group, an indur group, a naphthyl group, an azulenyl group, a heptalyl group, a biphenyl group, a fluorine group, a phenol group, a phenanthryl group, an anthracene group.
  • Monocyclic, bicyclic or tricyclic 6 or 14 membered aromatic hydrocarbon ring groups such as
  • the "5 or 14-membered aromatic heterocyclic group” refers to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group having 5 and 14 carbon atoms, which is preferable in the group.
  • the group include a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazol group, a virazolinyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an indolyl group, an isoindolyl group, an indolizyl group, a purinyl group, and an indazolyl group.
  • quinolyl group isoquinolyl group, quinolidyl group, phthalazinyl group, naphthyridyl group, quinoxalinyl group, quinazolinyl group, cinnolyl group, pteridyl group, imidazotriazyl group, virazinopyridazini
  • Nitrogen-containing aromatics such as ruthel groups, talidyl groups, phenanthryl groups, carbazolyl groups, perimidyl groups, phenanthral groups, phenacyl groups, etc.
  • Primitive ring group sulfur-containing aromatic heterocyclic group such as chael group and benzocher group; oxygen-containing aromatic group such as furyl group, biranyl group, cyclopentabiral group, benzofuran group and isobenzofuranyl group Heterocyclic group: thiazolyl group, isothiazolyl group, benzthiazol group, benzthiadiazolyl group, phenothiazyl group, isoxazolyl group Group such as nitrogen atom, sulfur atom, and oxygen nuclear energy such as benzene, furazal group, phenoxazyl group, biazoloxazolyl group, imidazothiazolyl group, thienofuryl group, furopyrrolyl group, pyridoxadiyl group, etc.
  • An aromatic complex ring group containing two or more different atoms can be mentioned.
  • the "6- to 14-membered non-aromatic hydrocarbon ring group” refers to a 6- to 14-cyclic aliphatic hydrocarbon group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group , Cycloheptyl group, cyclooctyl group, spiro [3.4] octal group, decane group, indanyl group, 1-acenaphthyl group, cyclopentacyclootatur group, benzocyclooctenyl group, indur group , Tetrahydronaphthyl group, 6, 7, 8, 9-tetrahydra 5H benzocycloheptyl group, 1,4-dihydronaphthalyl group, etc., cyclic aliphatic carbonization consisting of 6 to 14 carbon atoms It means a hydrogen group.
  • a "5 or 14-membered non-aromatic heterocyclic group” means that 1) the number of atoms constituting the ring is 5, and 14; and 2) 1 to 5 atoms in the atoms constituting the ring Containing, for example, a nitrogen atom, a hetero atom such as O or S, etc. 3)
  • the ring may contain one or more carbonyl groups, double bonds or triple bonds, Not only a 14-membered non-aromatic heterocyclic monocyclic group, but also a saturated heterocyclic group condensed with an aromatic hydrocarbon cyclic group, or a saturated hydrocarbon cyclic group or saturated heterocyclic group condensed with an aromatic heterocyclic group.
  • a ring group is shown.
  • 5- to 14-membered non-aromatic heterocyclic group examples include azetidyl ring, pyrrolidyl ring, piberidyl ring, azepar ring, azo-ring ring, tetrahydrofuranyl ring, tetrahydrovillar.
  • heterocyclic group means a 5- or 14-membered aromatic heterocyclic group or a 5- or 14-membered non-aromatic heterocyclic group.
  • Preferable groups in the "hydroxyl group having a protecting group” include, for example, a methoxymethyl ether group, a tetrahydrovinyl ether group, a tertiary butyl ether group, a aryl ether group, a benzoate group, an acetate group, a formate group, and a crotonate group.
  • Protein labeling group means a group that chemically irreversibly binds to an amino acid residue of a protein.
  • a protein labeling group include a photoaffinity labeling group and a chemical affinity group.
  • Specific examples of the photoaffinity labeling group include a benzoyl group, a benzophenone group, an azide group, a carborazide group, a diaziridine group, an enone group, a diazo group, and a nitro group.
  • the chemical affinity group include a ketone group substituted with a halogen atom, a strong rubamoyl group or ester group, an alkylthio group, and an oxylan group.
  • the photoaffinity labeling group preferred by the photoaffinity labeling group is particularly preferably a benzophenone group, a benzoyl group, an azide group, a carborazide group, a diaziridin group, an enone group, a diazo group, or a nitro group.
  • the "group containing a protein labeling group” means that the above-described protein labeling group is an appropriate linker (for example, a linker for A described later), a 6 to 14-membered aromatic hydrocarbon ring group,
  • C5 C6 alkyl group CI—C6 alkoxy group, C2—C6 alkenyl group, C2—C 6 substituted or directly substituted via a 14-membered aromatic heterocyclic group Alkynyl group, phenol group, naphthyl group, benzoyl group and the like can be mentioned.
  • the "group to be bound to a solid phase carrier” means a group that can be bound to a solid phase carrier having a functional group.
  • a solid phase carrier has an amino group, a carbonyl group, an ester group, a carboxyl group, an isocyanate group, etc.
  • the solid phase carrier has a carboxyl group, the amino group, etc.
  • Group or alkynyl group In the case where it has, a strong solid phase carrier such as a halogen atom, methanesulfonate group or azide group may contain an amino group, a hydroxyl group, a thiol group and the like when it has a halogen atom.
  • the substituent group Al, the substituent group A2, the substituent group A3, the substituent group A4 and the substituent group A5 represent the following groups.
  • Substituent group A1 is a halogen atom, cyano group, nitro group, C3-8 cycloalkyl group, C2-6 alkyl group, C2-6 alkyl group, C1-6 alkoxy group, C3-8 Cycloalkoxy group, formyl group, C1 6 alkyl carbo group and C1 6 alkyl group (the C1 6 alkyl group is a halogen atom, a hydroxyl group, a cyano group, a C1 6 alkoxy group, a C3-8 cycloalkyl group and a C1 6 alkyl group)
  • a protein labeling group a group containing a protein labeling group, and a group to be bound to a solid phase carrier.
  • Substituent group A2 is a halogen atom, a hydroxyl group, a cyano group, a C16 alkoxy group (the C16 alkoxy group is a halogen atom, a cyano group, a C1-6 alkoxy group, a C2-6 alkoxyl group, C2 — Group power consisting of 6 alkyl groups and C3-8 cycloalkyl groups (which may be substituted with 1 to 3 substituents selected), C3-8 cycloalkoxy groups, C2-6 alkyloxy groups and C2 — A group containing a 6 alkyloxy group, a protein labeling group and a protein labeling group.
  • Substituent group A3 may be substituted with 1 to 3 substituents selected from halogen atom and substituent group A5.
  • 6 to 14-membered aromatic hydrocarbon ring group substituent group A5 1 or 3 selected from the following: 5- or 14-membered aromatic heterocyclic group, C1-6 alkyl group (wherein the C16 alkyl group is a formyl group, a halogen atom) Atom, hydroxyl group, hydroxyl group with protecting group, cyano group, C2-6 alkyl group, C2-6 alkyl group, C3-8 cycloalkyl group, C1-6 alkoxy group, C1-6 alkylthio group, C1— 6 alkylsulfier group, C16 alkylsulfol group, C16 alkylcarbonyl group, amino group (the amino group may be optionally substituted with a C16 alkyl group having 1 to 5 halogen atoms) 1 or 3 selected from the substituent group A5, 6 or 14 and substituted
  • Substituent may be substituted with 1 to 3 substituents selected from hydrocarbon ring group, substituent group A5! /, 5 or 14 membered aromatic heterocyclic group, 1 group selected from substituent group A5 , Then 3 substitutions Substituted with a group ⁇ 6 or 14 membered non-aromatic hydrocarbon ring group, selected from substituent group A5 1 or 3 A membered non-aromatic heterocyclic group and —X—A (wherein X represents an imino group, —O or —S, and A represents one or three substituents selected from substituent group A 5) 6 or 6 or 14-membered aromatic hydrocarbon ring group or 5 or 14-membered aromatic heterocyclic group) And a group containing a C 1-6 alkoxy group, a protein labeling group, and a protein labeling group.
  • Substituent group A4 includes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C3-8 cycloalkyl group, a C2-6 alkyl group, a C2-6 alkyl group, and a C3-8 Cycloalkoxy group, C3—8 cycloalkylthio group, formyl group, C1 6 alkyl carbo group, C1 6 alkylthio group, C1 6 alkyl sulfier group, C1 6 alkyl sulfol group, hydroxyimino group, C 1— 6Alkoxyimino group, optionally substituted with 1 to 3 substituents selected from Substituent Group A5 C 1-6 alkyl group, substituted with 1 or 3 substituents selected from Substituent Group A5 C1-6 alkoxy group, which may be substituted with 1 or 2 substituents selected from substituent group A5, or may
  • Substituent group A5 is a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C3-8 cycloalkyl group, a C2-6 alkyl group, a C2-6 alkyl group, a C3-8 cycloalkoxy group, C3-8 cycloalkylthio group, formyl group, C1 6 alkyl carbo group, C1 6 alkyl Thio group, CI 6 alkyl sulfier group, C 16 alkyl sulfo group, hydroxyimino group, C 2-6 alkyloxy group, C 2-6 alkyloxy group, C 3-8 cycloalkyl sulfier group and C 3— 8 represents a group containing a cycloalkylsulfol group, a protein labeling group and a protein labeling group.
  • a protein labeling group As a group, a protein labeling group, a group containing a protein labeling group, or a group to be bonded to a solid phase carrier may be substituted.
  • Ar is an imidazolyl group which may be substituted with 1 to 3 substituents selected from the substituent group A1. is there.
  • Ar is preferably an imidazolyl group which may be substituted with one or two substituents selected from the substituent group A1.
  • Ar is a hydrogen atom, a halogen atom, a C3-8 cycloalkyl group, a C2-6 alkene.
  • the force is also selected 1 Substituted with 2 substituents
  • An imidazolyl group which may be substituted, or an imidazolyl group substituted with an azide group as a protein labeling group is more preferred
  • Ar is selected from a hydrogen atom, a halogen atom, a C3-8 cycloalkyl group and a C16 alkyl group. 1 or 2 may be substituted with 2 substituents! ⁇ More preferred is an imidazolyl group.
  • Ar is selected from the substituent group A2.
  • Ar is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, C1-6
  • the C16 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of C2-6 alkyl group, C2-6 alkyl group and C3-8 cycloalkyl group
  • a pyridyl group, a pyrimidyl group or a phenyl group which may be substituted with 1 to 3 substituents selected from a C2-6 alkyloxy group and a C2-6 alkyloxy group, or
  • a group having a protein labeling group a pyridinyl group, a pyrimidinyl group or a phenyl group substituted by an alkoxy group having an oxysilane group is more preferred.
  • a pyridyl group, a pyrimidyl group or a phenyl group which may be substituted with 3 to 3 substituents is more preferable.
  • pyridinyl pyrimidinyl or phenol groups that may be
  • R 1 is a group selected from the substituent group A4.
  • R 1 is a hydrogen atom or a C 1-6 alkyl group (the C 1-6 alkyl group is a hydroxyl group, a C 3-8 cycloalkyl group, a C 3-8 cycloalkoxy group, a C 1-6 alkylthio group, an amino group (the The amino group may be substituted with a C16 alkyl group having 1 to 5 halogen atoms as appropriate), or may be substituted with 1 or 3 substituents selected from Substituent Group A6.
  • X is a protein labeling group or tamper.
  • C1-6 alkylene group (the C1-6 alkylene group is a halogen atom, hydroxyl group, cyano group, C3-8 cycloalkyl group, C3-8 Cyclo An alkoxy group, a formyl group, a C16 alkyl group (the C16 alkyl group may be substituted with a hydroxyl group, and the same carbon atom on the C16 alkylene group may be substituted by 1 or 2;
  • the two C16 alkyl groups may form a cyclic group (which may be substituted with an oxygen atom having a methylene group on the ring of the cyclic group) together with the carbon atom to be bonded) , C1-6 alkoxy group, amino group (the amino group may be substituted with C1-6 alkyl group) and substituent group A5 selected from 1 to 3 substituents However, it is 5 or 1 and may be substituted with 1 or 3 substituents selected from the group consisting of 14-membered non-aromatic heterocyclic groups.
  • C16 alkylene group may be substituted by 1 or 2 and the two C16 alkyl groups may be bonded together with a carbon atom to which a cyclic group (the cyclic group is substituted).
  • X is preferably a C1-6 alkylene group (the C1-6
  • the alkylene group is preferably a C16 alkyl group (the C16 alkyl group may be substituted with a hydroxyl group! /,)!).
  • X is selected from a single bond and substituent group A5
  • R 4 represents a substituent selected from the substituent group A3;
  • Z represents a single bond, one CO—, one (CH 2) n— (here
  • n is 1 to an integer of 3) or - in CR3 ⁇ 4 6 (wherein, R 5 and R 6 represents a substituent selected from lower Symbol Substituent Group A4) indicates; Z is a single Bond, one O—, one NR
  • n represents an integer of 1 to 3
  • —CR 7 R 8 — (wherein R 7 and R 8 represent a substituent which is also selected from the following substituent group A4 force) or —O—.
  • X, X and Ar are
  • Formula ( ⁇ ) may be substituted with 1 or 4 substituents selected from Substituent Group A5, and
  • R 9 represents a substituent selected from the substituent group A4, and R 4 , X, X and Ar are
  • cyclic group represented by formula ( ⁇ ) may be substituted with a substituent of 1 or 4 selected from the substituent group A5.
  • R represents a C1-C6 alkyl group which may be substituted with a hydroxyl group
  • A, A, A and A have the aforementioned meanings.
  • the corresponding component is preferred ⁇ .
  • A represents a single bond, a protein labeling group or a group containing a protein labeling group.
  • A represents a single bond or a linker.
  • Linkers are well known in the art and include, for example, ordinary bonds (eg, ester, amide, force rubamate, ether, thioether, urea, alkyl groups having an amine group, alkaryl groups).
  • L4 is a heterocyclic ring which may have a substituent, a C1 20 alkyl group, a C2-20 alkyl group; , And C2—20 alkyl groups, L1 and L3 are each a single bond, 1 O, 1 S, 1 NH, 1 OC (0) N, 1 NC (0) 0—, 1 NC (0) N, 1 NC (O) —, 1 C (0) N, 1 C (O) or
  • L2 represents a C2-20 alkylene group, a C2-20 alkylene group, a C2-20 alkylene group, or — (CH CH 0) p
  • L3 may be a single bond, a halogen atom, a hydroxyl group, or a heterocyclic group, and L1 and L3 may form a ring with an adjacent group) Preferred linkers are listed.
  • examples of the heterocyclic ring when L3 is a heterocyclic group include triazole.
  • Examples of the case where L1 and L3 may form a ring with an adjacent group include a piperazine group.
  • A is a single bond or a cleavable linker.
  • a cleavable linker refers to a portion that does not contain a fishing tag group, a detectable marker, or a solid phase carrier from the complex after the compound for biological reagent forms a complex with a target protein. Cleavage by chemical reaction, enzyme reaction, etc. It means the best linker.
  • the chemical reaction or enzyme reaction for cleaving the linker is selected so that it is specific to the intended cleavage of the bond and does not cause an unintended reaction on the complex. Examples of such a cleavable linker include S—S—, —0-Si— o, and one monosaccharide residue.
  • a monosaccharide residue specifically,
  • monosaccharides such as glucose group and galactose group, or disaccharides such as ratatose.
  • A is a fishing tag group, and is detectable.
  • a marker, a solid phase carrier, or a group to be bound to a solid phase carrier is shown.
  • the term “phishing tag group” means a group used for separating the complex of the biological reagent compound and the target protein to separate the protein force without forming a complex. Phishing tag groups include, for example, piotin, 3-(4,4-difluoro-1,5, dimethyl-1,4H—3a, 4a-diaza, 4-bora, s-indacene, 3-yl) propiol groups.
  • a detectable marker means a radioactive label, a fluorescent label, a chemiluminescent label, a heavy metal ion, and the like.
  • detectable markers include radioactive labeling groups such as 125 I, 32 P, 3 H, and “C; fluorescein, rhodamine, downsyl, umbelliferone, 7—trotroazal, 3— (4, 4— Difluoro-5,7-dimethyl-4H-3a, 4a-diaza 4-bora s-indacene 3-yl) propiol and other fluorescent labeling groups; luminiferin, luminol and other chemiluminescent groups; lanthanoid metal ions Heavy metal ions such as radium ions, etc.
  • Solid phase carrier means a solid carrier that can be bonded to a linker having a functional group, such as glass beads, glass beds, microbe. Examples include titer plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, nylon beds.
  • X is a protein labeling group or tan
  • A binds the solid phase carrier or the solid phase carrier.
  • A is preferably the linker.
  • the compound for biological reagent of formula (I) of the present invention may be in the form of a salt.
  • hydrofluoric acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate
  • Inorganic acids such as salts; organic carboxylates such as acetate, oxalate, maleate, tartrate, fumarate, citrate; methanesulfonate, trifluoromethanesulfonate, ethanesulfonate
  • Organic sulfonates such as acid salts, benzene sulfonates, toluene sulfonates and camphor sulfonates; amino acid salts such as aspartate and glutamate; quaternary amine salts; alkali metal salts such as sodium salts and potassium salts And alkaline earth metal salts such as magnesium salts such
  • A is used for fishing.
  • tag group is one having piotin or 3- (4,4-difluoro-5,7-dimethyl-4H—3a, 4 a diaza-4-bora-s indacene-3-yl) propiol group.
  • Specific examples include the following compounds.
  • a protective group known to those skilled in the art suitable for each step in conveniently producing the compound of the present invention for example, T. Greene et al., “Protective Groups in Organic Synthesis” (John Wiley & Sons. Inc., New York, Needless to say, it includes a protection reaction step and a deprotection reaction step as appropriate.
  • Y and Y are hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.
  • Alkyl tin groups such as logogen atoms, trifluoromethanesulfonic acid ester groups and trimethyltin groups, alkyne groups such as boronic acid groups, boronic acid ester groups and acetylene groups, alkene groups such as vinyl groups, azide groups, carboxyl groups, amino acids Group and hydroxyl group.
  • [General production method 1] is an example of a method for producing a compound of the general formula (I) by condensing the compound (4) and the compound (5) according to [Step 1-3].
  • the compound of the general formula (I) can be prepared by condensing the compound (4) and the compound (5) according to [Step 1-3]. That is, [Step 1-3] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and known methods described in many literatures can be used. For example, i) a method in which a carboxylic acid compound is converted into an acid halide, and then the acid halide compound is reacted with an amine compound under basic conditions (for example, “New Experimental Chemistry Course edited by Japan Chemical Society”).
  • the acid halogenation reaction is a method of converting the compound (4) (where Y represents a carboxyl group) into an acid halide.
  • the solvent and reaction temperature used in this reaction vary depending on the starting materials and are not particularly limited. There is no particular limitation, and a known method can be used.
  • the compound (a) is a known method.
  • the compound (a) is a known method.
  • the solvent to be used varies depending on the starting material and is not particularly limited, but is preferably an inert solvent such as, for example, chloride methylene, toluene, tetrahydrofuran or the like.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably ice-cold to 100 ° C.
  • the base to be used varies depending on the starting materials and is not particularly limited.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent! However, preferably, for example, methylene chloride, toluene, tetrahydrofuran, 1,4-dioxane, water, etc. Or a mixture of them.
  • a base may be used as a solvent.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably ice-cold to 100 ° C. This reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatographic techniques. Desirably, by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction is carried out, for example, when Y of compound (4) is an amino group or a hydroxyl group, and Y of compound (5)
  • the condensing agent to be used varies depending on the starting materials and is not particularly limited. However, for example, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) is preferable. And carbodiimide or benzotriazole-1-yloxytris (dimethylamino) phospho-hexafluorophosphate.
  • N-hydroxysuccinimide, N-hydroxybenzotriazole, etc. may be added in an amount of 1.0 to 2.0 equivalents relative to compound (4).
  • the solvent to be used varies depending on the starting material and the condensing agent to be used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • methylene chloride 1, 2— Halogen solvents such as dichloroethane or polar solvents such as tetrahydrofuran, N, N-dimethylformamide.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably ice-cold to 100 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction is carried out, for example, when Y of compound (4) is an amino group and Y of compound (5) is a carboxy group.
  • iii) is a condensation reaction using the Mizorogi-Heck reaction.
  • Mizorogi-In the case of the Heck reaction preferably, for example, compound (4) (where Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group) )
  • compound (4) where Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group
  • the solvent to be used varies depending on the starting material and the transition metal catalyst to be used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • acetonitrile, tetrahydrofuran, 1, 4 — Examples include dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, N, N-dimethylformamide and the like.
  • the transition metal catalyst used is preferably, for example, a palladium complex, and more preferably, for example, palladium acetate ( ⁇ ), dichlorobis (triphenylphosphine) palladium ( ⁇ ), tetrakis (triphenyl).
  • Known palladium complexes such as phosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0) can be mentioned.
  • a phosphorus ligand preferably, for example, triphenylphosphine, trio-tolylphosphine, tritertiarybutylphosphine, 2- (ditertiarybutylphosphine) is used.
  • Ino) bifuel etc. may be added as appropriate.
  • a preferable result may be given in the presence of a base, and the base to be used is not particularly limited as long as it is used in this reaction-like coupling reaction.
  • the base to be used is not particularly limited as long as it is used in this reaction-like coupling reaction.
  • triethylamine, N examples thereof include N-diisopropylethylamine, N, N-dicyclohexylmethylamine, tetraptylammonium chloride and the like.
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to 150 ° C., for example.
  • This reaction is preferably performed in an inert gas atmosphere, more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction may be carried out, for example, when Y in compound (4) is an alkene group and Y in compound (5) is a chlorine atom.
  • the desired compound of the general formula (I) can be efficiently obtained even by a combination of a halogen atom such as a 12 atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group.
  • a halogen atom such as a 12 atom, a bromine atom or an iodine atom
  • a sulfonate group such as a triflate group.
  • iv) is a condensation reaction using the Suzuki-Kajiura reaction.
  • Suzuki-Kajiura reaction preferably, for example, compound (4) (wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group).
  • Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group.
  • Solvents used include starting materials, use The starting material is not particularly limited as long as it varies depending on the transition metal catalyst to be used and does not inhibit the reaction but dissolves the starting material to some extent. Preferably, for example, acetonitrile, tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxyethane , Benzene, toluene, xylene, 1-methyl-2-pyrrolidone, N, N dimethylformamide, water, or a mixed solvent thereof.
  • the transition metal catalyst used is preferably, for example, a known paradium complex, and more preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphenylphosphine) palladium ( ⁇ ), tetrakis (triphenyl).
  • Known palladium complexes such as -lphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and the like.
  • a phosphorus ligand preferably, for example, triphenylphosphine, tritolylphosphine, tricyclohexylphosphine, treater tributylphosphine, etc.
  • a phosphorus ligand preferably, for example, triphenylphosphine, tritolylphosphine, tricyclohexylphosphine, treater tributylphosphine, etc.
  • a quaternary ammonium salt preferably, for example, a salted tetratetramyl ammonium, a odorized tetraptyl ammonium or the like may be appropriately added.
  • the base to be used varies depending on the starting material, the solvent to be used, etc., and is not particularly limited.
  • sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, sodium carbonate, cesium carbonate, potassium phosphate and the like can be mentioned.
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to reflux of the solvent, for example.
  • This reaction is preferably performed, for example, in an inert gas atmosphere, and more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques.
  • the reaction is completed in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques.
  • Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • Y of the compound (4) is a boronic acid or boronic acid ester group
  • Y of the compound (5) is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or bird
  • v) is a condensation reaction using the fungus head reaction.
  • fungus head reaction preferably, for example, compound (4) (where Y is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group).
  • compound (4) where Y is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group.
  • compound (5) wherein Y represents An acetylene group
  • the solvent to be used varies depending on the starting material and the transition metal catalyst to be used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • acetonitrile, tetrahydrofuran, 1 , 4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, etc. more preferably, for example, tetrahydrofuran, 1, 4-Dioxane, 1-methyl-2-pyrrolidone, N, N-dimethylformamide and the like.
  • the transition metal catalyst used is preferably, for example, a known palladium complex, and more preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphenylphosphine) palladium ( ⁇ ), tetrakis (triphenyl).
  • palladium complexes such as -lphosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0) can be mentioned.
  • a phosphorus ligand preferably, for example, triphenylphosphine, trio-trinolephosphine, tricyclohexylphosphine, treater tributylphosphine, etc.
  • this reaction is carried out according to necessity, such as a halogenated metal or a quaternary ammonium salt, preferably, for example, copper iodide (1), lithium chloride, tetrafluorobutyl ammonium fluoride or acid salt.
  • Silver (I) or the like can also be added.
  • there may be a preferable result in the presence of a salt group and the base used in this case is not particularly limited as long as it is used in the coupling reaction like this reaction.
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to reflux of the solvent.
  • This reaction is preferably performed, for example, in an inert gas atmosphere, and more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques.
  • this reaction is 1 to 24 Completing in time, the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • Stille reaction preferably, for example, compound (4) (wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group).
  • compound (4) wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group.
  • compound (4) wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group.
  • compound (5) wherein Y represents a trialkyltin group
  • the solvent to be used varies depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the transition metal catalyst used is, for example, a palladium complex, preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphenylphosphine) palladium ( ⁇ ), tetrakis (triphenylphosphine) palladium (0 ), Tris (dibenzylideneacetone) dipalladium (0) and the like, and more preferably, for example, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) di palladium (0). Palladium (0) etc. are mentioned.
  • This reaction is preferably performed, for example, in an inert gas atmosphere, and more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably from room temperature to the reflux temperature of the solvent. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction may be carried out, for example, when Y of compound (4) is a trialkyltin group, Y of compound (5)
  • Examples of vii) include 1) amination reaction using a transition metal catalyst, or 2) amination reaction by nucleophilic substitution reaction.
  • compound (4) (wherein Y represents a chlorine atom, a bromine atom, a halogen atom such as an iodine atom, or a sulfonate group such as a triflate group).
  • Y represents a chlorine atom, a bromine atom, a halogen atom such as an iodine atom, or a sulfonate group such as a triflate group.
  • the solvent to be used is not particularly limited as long as it varies depending on the starting material and does not inhibit the reaction and dissolves the starting material to some extent.
  • the transition metal catalyst to be used is, for example, a palladium complex, and preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphosphine) palladium ( ⁇ ), tetrakis (triphenylphosphine) palladium (0 ), Tris (dibenzylideneacetone) dipalladium (0) and the like, and more preferable examples include tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone), and the like. Examples include dipalladium (0).
  • a phosphorus ligand preferably, for example, triphenylphosphine, tri o-tolyl phosphine, treater butyl phosphine, 2- (ditertiary butyl phosphino) Biphenyl, 2,2,1bis (diphenylphosphino) -1,1,1, binaphthyl, 1,2-bis (diphenylphosphino) ethane or 1,1,1bis (diphenylphosphino) phenol ) Etc.
  • a phosphorus ligand preferably, for example, triphenylphosphine, tri o-tolyl phosphine, treater butyl phosphine, 2- (ditertiary butyl phosphino) Biphenyl, 2,2,1bis (diphenylphosphino) -1,1,1, binaphthyl, 1,2-bis (diphenylphosphino) ethane or 1,1,1bis (
  • a preferable result may be obtained in the presence of a base, and the base to be used is not particularly limited as long as it is used in this reaction-like coupling reaction.
  • sodium hydroxide is used.
  • This reaction is preferably performed, for example, in an inert gas atmosphere, and more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, It is preferably room temperature to the reflux temperature of the solvent.
  • reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction may be carried out, for example, when Y in compound (4) is an amino group, Y in compound (5) is a halogen atom such as a chlorine atom, bromine atom or iodine atom, or
  • the desired compound of the general formula (I) can be efficiently obtained even by a combination of a sulfonate group such as a rate group.
  • compound (4) (wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group).
  • Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group.
  • a solvent in a solvent.
  • the solvent to be used varies depending on the starting material and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • acetonitrile, tetrahydrofuran, 1,4-dioxane examples include 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyridone, and N, N-dimethylformamide.
  • a preferable result may be given in the presence of a base, and the base to be used is not particularly limited as long as it is used in a coupling reaction like this reaction.
  • water is used.
  • reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to the reflux temperature of the solvent. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Desirably, by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization. In addition, this reaction is carried out, for example, when Y of compound (4) is an amino group and Y of compound (5) is a salt.
  • a desired compound of the general formula (I) can be efficiently obtained by a combination of a halogen atom such as a 12 atom, bromine atom or iodine atom, or a sulfonate group such as a triflate group.
  • a halogen atom such as a 12 atom, bromine atom or iodine atom
  • a sulfonate group such as a triflate group.
  • compound (4) (wherein represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group),
  • compound (5) (where Y represents a hydroxyl group) in the presence of compound (4) as a solvent
  • Examples of the solvent to be used include a stirring method, and are not particularly limited as long as they vary depending on the starting materials and can dissolve the starting materials to some extent without inhibiting the reaction.
  • acetonitrile, tetrahydrofuran are used.
  • the transition metal catalyst to be used is, for example, a palladium complex, and preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphenylphosphine) palladium ( ⁇ ), tetrakis (triphenylphosphine) palladium (0) And known palladium complexes such as tris (dibenzylideneacetone) dipalladium (0), and more preferably, for example, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium ( 0) and the like.
  • palladium complex preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphenylphosphine) palladium ( ⁇ ), tetrakis (triphenylphosphine) palladium (0)
  • known palladium complexes such as tris (dibenzylideneacetone) dipalladium (0),
  • a phosphorus ligand preferably, for example, triphenylphosphine, tri -.- tolylphosphine, treater butylphosphine, 2- (ditertiary butylphosphine) is used.
  • Bifeninole 2, 2, 1 Bis (diphenylphosphino) 1, 1, 1 Binaphthyl, 1, 2-bis (diphenylphosphino) ethane, [2,-(Ditert-butylphosphino) ] -2-Dimethylamino 1,1'-binaphthyl or 1,1,1bis (diphenylphosphino) phenol etc.) may be added as appropriate.
  • a preferable result may be obtained in the presence of a base, and the base to be used is not particularly limited as long as it is used in a coupling reaction like this reaction.
  • This reaction is preferably performed, for example, in an inert gas atmosphere, and more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction temperature should be a temperature that is sufficient to complete the coupling reaction, and is preferably room temperature to the reflux temperature of the solvent. Under preferred reaction conditions, the reaction is complete in 1-24 hours The progress of the reaction can be monitored by a known chromatography technique. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction may be carried out, for example, when Y of compound (4) is a hydroxyl group and Y of compound (5)
  • compound (4) (wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group). , 1.0-5.0 equivalents of compound (5) with respect to compound (4) (where Y is water
  • a solvent in a solvent.
  • the solvent used varies depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • acetonitrile, tetrahydrofuran, 1,4 dioxane, 1, Examples include 2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, and N, N dimethylformamide.
  • a preferable result may be obtained in the presence of a base, and the base to be used is not particularly limited as long as it is used in a coupling reaction like this reaction.
  • Examples thereof include sodium, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and sodium tertiary butoxide.
  • good results can be obtained by adding 0.1 to 10.0 equivalents of metal copper or copper halide (preferably, for example, copper chloride, copper iodide, etc.) to compound (4).
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to the reflux temperature of the solvent. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours and the progress of the reaction can be monitored by known chromatographic techniques.
  • by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • this reaction may be performed, for example, by Y of compound (4) being a hydroxyl group and Y of compound (5) being a salt.
  • a desired compound of the general formula (I) can be efficiently obtained by a combination of a halogen atom such as a 12 atom, bromine atom or iodine atom, or a sulfonate group such as a triflate group.
  • Compound (4) can be produced by a known method described in International Publication No. WO2005Z115990. For example, it can be produced by the method of the following scheme.
  • a protective group such as a carboxyl group such as a group, an ethyl group, a benzyl group, an aryl group, a trifluoromethyl group, a tertiary butyl group, a methoxymethyl group or a tertiary butyldimethylsilyl group]
  • Compound (5) is commercially available, or when not commercially available, it can be synthesized, for example, by the method of the following scheme.
  • Sulfide group such as lupoxyl group, amino group, hydroxyl group, thiol, alkyne group such as azide, acetylene group, alkene group such as vinyl group, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • a sulfonate group such as a halogen atom or a triflate group is shown.
  • these functional groups may have a protective group as appropriate.
  • Compound (5) was prepared by coupling compound (d) and compound (e) according to [Step 5-1] to give compound (a), and then combining compound (a) and compound (c) with [Step 5— It can be prepared by coupling according to 2].
  • the compound (f) and the compound (c) are coupled according to [Step 5-2], led to the compound (b), and then the compound (b) and the compound (d) are cut according to [Step 5-1]. It can be similarly prepared by pulling.
  • the reaction i) comprises an acid halogenation reaction followed by a condensation reaction.
  • the halogenating agent used depends on the starting material, and in particular Although not limited, preferred are, for example, salt and salt, salt and oxalyl.
  • the solvent used varies depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an inert solvent such as methylene chloride, toluene, tetrahydrofuran or the like. is there.
  • a catalytic amount of N, N-dimethylformamide or the like may be added as appropriate.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably ice-cold to 100 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • the obtained acid halide is converted into acid halide and acidogen in the presence of 1.0 to: LO. 0 equivalents of compound (e), compound (c) or compound (b) (where Y, Y or Y is an amino group or hydroxyl group)
  • the base to be used varies depending on the starting material and is not particularly limited, but preferably, for example, pyridine, lutidine, quinoline, isoquinoline, triethylamine, N, N-diisopropylethylamine, sodium hydroxide, hydroxide Potassium and the like.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably, for example, methylene chloride, toluene, tetrahydrofuran, 1,4-dioxane, water, etc., or The mixture.
  • a base may be used as a solvent.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably ice-cold to 100 ° C., for example.
  • This reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored by a known chromatographic technique. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization. Further, in this reaction, even when the combination of the carboxyl group and the amino group or hydroxyl group is reversed, a desired coupling product can be obtained efficiently.
  • the compound (d), the compound (a), or the compound (f) (wherein Y, Y and Y represent a carboxyl group) and the compound (d) Compound (a) is In the presence of 1.0 to 2.0 equivalents of a condensing agent relative to compound (f), 0.5 to 2.0, etc. relative to compound (d), compound (a) or compound (f) Compound (e), compound (c) or compound (b) (wherein Y, Y, or Y represents an amino group or a hydroxyl group).
  • the condensing agent to be used varies depending on the starting material and is not particularly limited, but preferably, for example, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3, -dimethylaminopropyl) carbodiimide Benzotriazole-1-yloxytris (dimethylamino) phospho-hexafluorophosphate, and the like.
  • N-hydroxysuccinimide, N-hydroxybenzotriazole and the like may be added in an amount of 1.0 to 2.0 equivalents.
  • the solvent to be used varies depending on the starting material and the condensing agent to be used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • methylene chloride, 1, 2— Examples include halogen solvents such as dichloroethane or polar solvents such as tetrahydrofuran, N, N-dimethylformamide.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably ice-cold to 100 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • the reaction is easy to use and has the ability to stir.
  • the solvent used preferably in the presence of a solvent varies depending on the starting material and can dissolve the starting material to some extent without inhibiting the reaction. Is not particularly limited, but preferably, for example, jetyl ether, tetrahydrofuran, etc. It is.
  • the reaction temperature should be a temperature that is sufficient to complete the reaction without promoting the formation of the preferred! / ⁇ by-product, and is from room temperature to 100 ° C. Under preferred reaction conditions, the reaction is complete in 30 minutes to 24 hours, and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • reaction of iii) is carried out by reacting compound (f) (wherein Y represents a thiol group) and compound (c) (
  • the desired coupling compound can be obtained.
  • the technique to do is mentioned.
  • the metal catalyst used preferably includes, for example, copper (II) sulfate, copper iodide (1), copper bromide (I), copper (I) chloride and the like.
  • ascorbic acid sodium ascorbate may be added as appropriate in order to allow the reaction to proceed efficiently.
  • the solvent to be used varies depending on the starting material and the metal catalyst used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to 150 ° C.
  • a preferable result may be obtained in the presence of a base, and the base to be used is not particularly limited as long as it is used in a coupling reaction like this reaction, but preferably, for example, triethylamine.
  • reaction is complete in 1-36 hours and the progress of the reaction can be monitored by known chromatographic techniques. Hope The minor by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as z and crystallization.
  • this reaction involves reacting compound (f) (where Y represents an azide group) and compound (c)
  • Y represents an alkyne group.
  • a compound (a) (where Y
  • ⁇ represents an azide group.
  • a pulling grade can be obtained.
  • this reaction can efficiently obtain a desired coupling product even when the combination of an azide group and an alkyne group is reversed.
  • the solvent to be used varies depending on the starting material and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • acetonitrile, tetrahydrofuran, 1,4 dioxane, 1, Examples include 2-dimethoxyethane, benzene, toluene, xylene, 1-methyl 2-pyrrolidone, and N, N-dimethylformamide.
  • the transition metal catalyst to be used varies depending on the starting material and is not particularly limited, but is preferably, for example, a palladium complex, and more preferably, for example, palladium acetate ( ⁇ ), dichroic bis (triphenylphosphine) paradi Well-known noradium complexes such as um ( ⁇ ), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like can be mentioned.
  • a phosphorus ligand preferably, for example, triphenyl phosphine, tri-o-tolyl phosphine, treater butyl phosphine, 2- (di-tertiary butyl phosphino) Biphenyl, 2,2,1bis (diphenylphosphino) 1,1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane or 1,1'-bis (diphenylphosphino) phthalcene) Etc.
  • a base to be used is not particularly limited as long as it is used in this reaction-like coupling reaction.
  • sodium hydroxide, barium hydroxide examples include potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and sodium tertiary butoxide.
  • This reaction is preferably performed, for example, in an inert gas atmosphere, and more preferably, for example, in a nitrogen or argon atmosphere.
  • the reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to the reflux temperature of the solvent. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by conventional chromatographic techniques or techniques known to those skilled in the art such as Z and crystallization.
  • This reaction is carried out by reacting compound (f) (where Y is a chlorine atom, bromine atom, iodine atom, etc.)
  • Y is a halogen atom such as a chlorine atom, bromine atom or iodine atom, or a triflate group
  • ⁇ represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group
  • a desired coupling product can be obtained efficiently.
  • the desired coupling can be efficiently performed even in the combination of a leaving group such as a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group and an alkene group.
  • a leaving group such as a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group such as a triflate group and an alkene group.
  • a grade can be obtained.
  • A4 is a solid phase carrier
  • the solid phase carrier is mixed with a solvent, homogenized, and then subjected to filtration, whereby a purification operation can be easily performed.
  • Q_ ⁇ XI people ⁇ + ⁇ 9 - ⁇ 2 - ⁇ 10 is about 1 '— 3 ] people ⁇ ⁇ ⁇ - ⁇ ⁇ — ⁇ - ⁇ ⁇ "- ⁇ 3 - ⁇ 12
  • ⁇ , ⁇ , ⁇ , ⁇ and ⁇ are hydrogen atom, fluorine atom, chlorine atom, bromine atom,
  • Halogen atoms such as iodine atoms, alkyltin groups such as trifluoromethanesulfonic acid ester groups and trimethyltin groups, alkyne groups such as boronic acid groups, boronic acid ester groups, and acetylene groups, alkene groups such as vinyl groups, and azides
  • a sulfide group such as a group, carboxyl group, amino group, hydroxyl group and thiol.
  • the above [General production method 2] shows an example of the preparation method of the general formula (I) as an alternative method. That is, the compound (4) and the compound (g) are condensed according to the method of [Step 1-3] and led to the compound (h), and according to the above [Step 5-1], the compound (h) and the compound ( This shows a method for producing a compound of general formula (I) by condensing compound (j) and compound (k) according to the above [Step 5-2] by condensing i) to compound (j). is there.
  • There are no particular limitations as long as the conditions are the same as in this step, and known methods described in many literatures can be used (for example, Y. Feng, “Bioorg. Med. Chem. Lett.”, 1998). , 8 ⁇ , p881-884).
  • the compound (g), compound (i), and compound (k) used in this step are commercially available, or commercially available raw materials are converted into protection / deprotection reactions known to those skilled in the art (for example, T. Greene et al., fprote ctive Groups in Organic Synthesis J (see John Wiley & Sons. Inc., New York, 1981).
  • 16 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom, an alkyltin group such as a trifluoromethanesulfonic acid ester group or a trimethyltin group, a boronic acid group, a boronic acid ester group, or an acetylene group
  • an alkyne group such as alkene, a alkene group such as a bur group, a sulfide group such as an azide group, a carboxyl group, an amino group, a hydroxyl group, and a thiol.
  • the above [General production method 3] shows an example of the preparation method of the general formula (I) as an alternative method. That is, according to the above [Step 5-2], the compound (1) and the compound (m) are condensed and converted into the compound (n), and then the compound (n) is converted according to the above [Step 5-1].
  • This shows a method for producing a compound of general formula (I) by condensing with compound (h). If the conditions of this process There is no particular limitation, and known methods described in many literatures can be used (for example, PJ DeLaLuz, “: Bioconjugate Chem.”, 1995, 6 ⁇ , p558-566).
  • the compound (1) and compound) used in this step are commercially available, or commercially available raw materials are protected or protected using a protection / deprotection reaction known to those skilled in the art (for example, T. Greene et al., Rp ro tective It can be prepared by subjecting to uroups m Organic synthesisj (see John Wiley & Sons. Inc., -Yup York, 1981).
  • 8 protein can be analyzed using the compound for biological reagent of formula (I) or a salt thereof. That is, according to the present invention, a method for analyzing the production mechanism of A
  • a method for analyzing the production mechanism of A ⁇ protein is provided.
  • Ar is represented by the formula ( ⁇ ).
  • cells or cell components that are considered to contain a protein involved in the production mechanism of A ⁇ protein include cells or cell components known to produce ⁇
  • a photoaffinity labeling group When a photoaffinity labeling group is used as the protein labeling group, reversibly bound target protein and the photoaffinity labeling group are cross-linked by photoreaction by irradiating with light after incubating.
  • the biological reagent compound of formula (I) or a salt thereof to which the target protein is bound is used, for example, when piotin is used as A in the biological reagent compound of formula (I) or a salt thereof.
  • the target protein can be identified by subjecting the compound for biological reagent of formula (I) or a salt thereof to which the target protein is bound to Western blotting. In these methods, when a cleavable linker is used as A in the compound for biological reagent of formula (I) or a salt thereof, it is captured on an affinity column, etc.
  • the compound for biological reagent of the formula (I) or the salt thereof to which the collected target protein is bound can be released by cleaving the cleavable linker to release the portion to which the target protein is bound.
  • the target tank bonded to the compound for biological reagent of formula (I) or a salt thereof is substantially the same as described above. You can search for identification and analysis.
  • a solid phase carrier is used as A in the compound for biological reagent of formula (I) or a salt thereof.
  • the target column is obtained by affinity column chromatography using the compound for biological reagent of the formula (I) containing the solid phase carrier or a salt thereof as the affinity column.
  • the target protein can be identified by capturing and collecting the compound for biological reagent of formula (I) or its salt to which the protein is bound.
  • A is a single bond, and Ar, Ar, X, R 1 X, X and Ar are all substituted as a protein labeling group.
  • a compound for a biological reagent of the formula (I) or a salt thereof is used.
  • the affinity column chromatography using an avidin column in which avidin, streptavidin, etc. are bound to a carrier is added with the compound for biological reagent of formula (I) or a salt thereof bound to the target protein.
  • the compound for the biological reagent of formula (I) or the salt thereof bound to the target protein can be captured and collected.
  • an azide group is used as a group to be bonded to a solid phase carrier
  • a solid phase carrier having an acetylene group is used as a solid phase carrier, and they are reacted to form a target protein
  • Examples include a method in which a complex of a compound for biological reagent of formula (I) or a salt thereof is bound to a solid phase carrier, and then the solid phase carrier force is isolated. Even when a group to be bonded to a solid phase carrier other than the azide group is used, the reaction can be similarly performed using a solid phase carrier having a group to be bonded to the group.
  • a group that binds to a solid phase carrier such as an acetylene group or a vinyl group at the end of the molecule, which may be present in the biological reagent compound of formula (I) or a salt molecule thereof, is used.
  • a complex of the target protein and the biological reagent compound of formula (I) or a salt thereof is bound to the solid phase carrier by reacting with the solid phase carrier having a group that binds to the group.
  • An example is a method of isolating from a carrier.
  • Ar substituent group A1 in the compound for biological reagent of formula (I) or a salt thereof is a group that binds to a solid phase carrier, the solid phase having the group and the group that binds to the group.
  • the complex of the target protein and the compound for biological reagent of formula (I) or a salt thereof is bound to the solid phase carrier, and then the solid phase carrier force is isolated by can do.
  • the biological reagent compound represented by formula (1) which has a function of suppressing A protein production
  • a compound for a biological reagent or a salt thereof which is a compound for a biological reagent represented by the formula (1) and has no action to suppress A ⁇ protein production.
  • the same method is used for both biological reagent compounds or their salts, and the two are compared to identify the target protein, making the target protein more efficient and accurate. Can be identified.
  • Is a compound for a biological reagent which is a compound for a biological reagent and has no action to suppress A ⁇ protein production, or a salt thereof.
  • R 1 represents a C1-C6 alkyl group optionally substituted with a hydrogen atom or a hydroxyl group, and A, A, A and A have the above-mentioned meanings]
  • Such a compound include, for example, the following compounds.
  • the present invention provides a kit for analyzing the production mechanism of A
  • This kit contains other reagents for identifying and analyzing the target protein as necessary, for example, antibodies against gamma selector, beta selector, etc., and their constituents preserilin, dicastrin, etc. An antibody may be included. Further, it may contain a reagent for detecting a labeling group, a buffer solution, a surfactant and the like, which are usually used in an assembly system.
  • BW 300 manufactured by Fuji Silysia was used as a carrier unless otherwise specified.
  • LC MS High-pressure liquid chromatography that separates the target compound using mass spectrum.
  • the elution solvent used was a linear gradient system of 10% to 99% of 0.1% trifluoroacetic acid-containing water and 0.1% trifluoroacetic acid-containing acetonitrile.
  • Trinormal butylphosphine (2.06 mL) was added dropwise at ⁇ 20 ° C. to a solution of benzoyl chloride (2 g) in THF (30 mL). After the reaction solution was stirred at ⁇ 20 ° C. for 20 minutes, 4-ethylphenylmagnesium bromide (15 mL: 0.5M THF solution) was added to the reaction solution, and the reaction solution was further stirred at ⁇ 20 ° C. for 10 minutes. After stirring, the reaction solution was added to a mixed solution of 1N hydrochloric acid aqueous solution and jetyl ether, and the organic layer was partitioned. Jetyl ether was added to the water layer, and the organic layer was distributed.
  • the obtained organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 325 mg of the racemic isomer of the title compound.
  • the obtained racemate (325 mg) was fractionated with Daicel CHIRALCEL TM OD (2 cm X 25 cm: mobile phase; ethanol), and the title optically active substance (125 mg;> 99% ee) and retention time 7.6 min.
  • the title optically active substance (117 mg;> 99% ee ) having a retention time of 19.2 minutes was obtained.
  • the physical properties of the title optically active substance with a retention time of 7.6 minutes are as follows.
  • the physical properties of the title optically active substance with a retention time of 19.2 minutes are as follows.
  • ⁇ 9 ⁇ ' ⁇ ) 99 ⁇ ⁇ : ( ⁇ ⁇ ) g (10Q0) HPVN-H X , [H + + PV] 8I6 z / rai SPV-ISa
  • the obtained organic layer was washed with a mixed solution of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified using silica gel chromatography (elution solvent: heptane acetate ethyl system) to obtain an alcohol form.
  • Water (10 mL) and p-toluenesulfonic acid monohydrate (500 mg) were sequentially added to a THF (90 mL) solution of the obtained alcohol, and the reaction solution was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate.
  • a saturated aqueous solution of ammonium chloride was added to the reaction solution, the reaction vessel was removed from the cooling bath, and the mixture was extracted three times with ethyl acetate.
  • the obtained organic layer was washed with a mixed solution of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified using silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain an alcohol form.
  • the residue was purified using silica gel chromatography (elution solvent: heptane ethyl acetate system) to obtain a ketone body.
  • Tetraptyl ammonium fluoride (1M THF solution, 8 mL) was added to a THF (30 mL) solution of the ketone body obtained by the above operation, and the reaction solution was stirred at room temperature for 1.5 hours.
  • the solvent of the reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: heptane monoacetate system) to obtain 2.05 g of the title compound.
  • the physical properties of this product are as follows.
  • reaction solution was directly purified using silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane acetate ethyl THF system) to obtain 386 mg of the title compound.
  • carrier Chromatorex NH; elution solvent: heptane acetate ethyl THF system
  • the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain an aldehyde form.
  • acetone 5 mL
  • 2-methyl-2-butene 400 L
  • sodium dihydrogen phosphate dihydrate 55 mg
  • sodium chlorite 70 mg
  • sodium dihydrogen phosphate dihydrate 30 mg
  • sodium chlorite 35 mg
  • a saturated salt aqueous solution and chloroform were added to the reaction solution, and the organic layer was partitioned.
  • the obtained organic layer was washed successively with a mixed solution of hydrochloric acid (2N aqueous solution) and saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure.
  • Trimethylsilyl diazomethane (2M hexane solution, 500 ⁇ L) was added to a methanol (4 mL) solution of the residue obtained by the above operation, and the reaction solution was stirred at room temperature.
  • Trimethylsilyldiazomethane (2 ⁇ hexane solution) was added to the reaction solution until the disappearance of the raw material was confirmed by TLC (a total of 1.5 mL was added for 500 L, lmL).
  • a small amount of acetic acid was added to the reaction solution, and after confirming that the reaction solution became yellow solution transparent, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added, and the organic layer was partitioned. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated salt.
  • the mixture was washed successively with a mixed solution of aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
  • N-Hydroxysuccinimidebiotin (20 mg) and triethylamine (25 ⁇ L) were successively added to a DMF (2 mL) solution of the obtained residue, and the reaction solution was stirred at room temperature for 1 hour. Further, triethylamine (25 L) was added to the reaction solution, and the reaction solution was stirred at room temperature for 12.5 hours. The reaction mixture was filtered, and the filtrate was purified by LC MS to give 8.7 mg of the title compound.
  • the physical properties of this product are as follows.
  • Example 25 6 yl) pentanoylamino 1 succinic acid ⁇ 4- ⁇ i4- i (S)-1— ⁇ 3— ⁇ ⁇ — “3 methoxy ( 4- methyl-iH-imidazole 1-yl) : Nyl ⁇ ( ⁇ ) -methylidene ⁇ — 2-oxopiperidine 1-yl ⁇ ethyl ⁇ benhanyl ⁇ benzyl ⁇ methylamide trifluoroacetate synthesis
  • the obtained crude product was neutralized with a small amount of saturated aqueous sodium hydrogen carbonate, and extracted three times with black mouth form to which a small amount of methanol was added.
  • the obtained organic layer was concentrated to obtain 9.4 mg of the title compound.
  • the physical properties of this product are as follows.

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Abstract

L'invention concerne un composé destiné à un réactif biologique, ce composé étant représenté par la formule ci-jointe, dans laquelle R10 représente un groupe alkyle C1-C6 pouvant être substitué par un groupe hydroxyle; A1 représente une liaison simple, un groupe de marquage d'affinité ou un groupe contenant un groupe de marquage d'affinité; A2 représente une liaison simple ou un lieur; A3 représente une liaison simple ou un lieur clivable; et A4 représente un groupe étiquette de pêche ('fishing tag'), un groupe de marquage ou un support solide. L'utilisation de ce composé pour le criblage d'une protéine cible d'un agent thérapeutique ou prophylactique contre une maladie neurodégénérative due à l'amyloïde bêta (Aβ) permet d'analyser le mécanisme de production d'Aβ ou le mécanisme d'action de l'agent thérapeutique ou prophylactique contre la maladie neurodégénérative.
PCT/JP2007/060989 2006-05-31 2007-05-30 Composé pour réactif biologique Ceased WO2007139149A1 (fr)

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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010038686A1 (fr) 2008-09-30 2010-04-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé d'aminodihydrothiazine fusionné inédit
WO2010098488A1 (fr) 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Composé arylimidazole et leur utilisation en tant qu'inhibiteurs de production de la protéine amyloïde bêta
WO2010098495A1 (fr) 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Dérivés d'imidazolylpyrazine
US7897627B2 (en) 2007-12-21 2011-03-01 Hoffmann-La Roche Inc. Heteroaryl derivatives as orexin receptor antagonists
US7923450B2 (en) 2008-01-11 2011-04-12 Hoffmann-La Roche Inc. Modulators for amyloid beta
WO2012039371A1 (fr) 2010-09-22 2012-03-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de cyclopropane
US8188101B2 (en) 2008-11-06 2012-05-29 Astrazeneca Ab Dihydropyridopyrimidines for the treatment of AB-related pathologies
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
US8389717B2 (en) 2008-10-09 2013-03-05 Hoffmann-La Roche Inc. Modulators for amyloid beta
WO2013051639A1 (fr) 2011-10-07 2013-04-11 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de pyrazoloquinoline
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
EP2615090A1 (fr) 2009-02-26 2013-07-17 Eisai R&D Management Co., Ltd. Composés hétérocycliques fusionnés contenant de l'azote et leur utilisation en tant qu'inhibiteurs de production de bêta-amyloïdes
WO2013115162A1 (fr) 2012-01-31 2013-08-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de sitaxsentan
WO2013115163A1 (fr) 2012-01-31 2013-08-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de paroxétine
WO2013191144A1 (fr) 2012-06-21 2013-12-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 Nouveau dérivé d'indanesulfamide
WO2014129477A1 (fr) 2013-02-20 2014-08-28 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de pyridine monocyclique
WO2014133022A1 (fr) 2013-02-28 2014-09-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de tétrahydroimidazo[1,5-d][1,4]oxazépine
WO2014163146A1 (fr) 2013-04-05 2014-10-09 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de pyridinylpyrazoloquinoline
WO2014195323A1 (fr) 2013-06-04 2014-12-11 Acturum Life Science AB Composés de pyrimidine et leur utilisation comme modulateurs de la gamma-sécrétase
WO2014195322A1 (fr) 2013-06-04 2014-12-11 Acturum Life Science AB Composés triazole et utilisation de ces derniers en tant que modulateurs de la gamma-sécrétase
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
WO2015098853A1 (fr) 2013-12-25 2015-07-02 エーザイ・アール・アンド・ディー・マネジメント株式会社 COMPOSÉ (6S,9aS)-N-BENZYL-6-[(4-HYDROXYPHÉNYL)MÉTHYL]-4,7-DIOXO-8-({6-[3-(PIPÉRAZINE-1-YL)AZÉTIDINE-1-YL]PYRIDINE-2-YL}MÉTHYL)-2-(PROP-2-EN-1-YL)-OCTAHYDRO-1H-PYRAZINO[2,1-c][1,2,4]TRIAZINE-1-CARBOXAMIDE
US9611254B2 (en) 2013-06-04 2017-04-04 Acturum Life Science AB Triazole compounds and their use as gamma secretase modulators
JP2017512834A (ja) * 2014-03-19 2017-05-25 アミディス・ダイアグノスティックス・インコーポレイテッド アミロイド標的剤及びその使用方法
WO2018009627A1 (fr) 2016-07-07 2018-01-11 Bristol-Myers Squibb Company Urées cycliques spiro fusionnées en tant qu'inhibiteurs de rock
US9938288B1 (en) 2017-04-05 2018-04-10 President And Fellows Of Harvard College Macrocyclic compound and uses thereof
WO2018187331A1 (fr) 2017-04-05 2018-10-11 President And Fellows Of Harvard College Composé macrocyclique et utilisations correspondantes
WO2019049869A1 (fr) 2017-09-07 2019-03-14 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé pentacyclique
WO2019099646A1 (fr) 2017-11-15 2019-05-23 President And Fellows Of Harvard College Composés macrocycliques et utilisations de ces composés
US10344038B2 (en) 2015-04-30 2019-07-09 President And Fellows Of Harvard College Chromium-mediated coupling and application to the synthesis of halichondrins
WO2019151241A1 (fr) 2018-01-31 2019-08-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Activateur d'aldh2
US10392400B2 (en) 2016-11-11 2019-08-27 President And Fellows Of Harvard College Palladium-mediated ketolization
US10556910B2 (en) 2014-06-30 2020-02-11 President And Fellows Of Harvard College Synthesis of halichondrin analogs and uses thereof
WO2020179780A1 (fr) 2019-03-05 2020-09-10 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé hétérocyclique pentacyclique
WO2022014680A1 (fr) 2020-07-17 2022-01-20 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de pipéridine substitué et son application
US11498892B2 (en) 2017-07-06 2022-11-15 President And Fellows Of Harvard College Fe/Cu-mediated ketone synthesis
US11548898B2 (en) 2017-07-06 2023-01-10 President And Fellows Of Harvard College Synthesis of halichondrins
CN117561264A (zh) * 2021-04-14 2024-02-13 勃林格殷格翰国际有限公司 作为TRPA1抑制剂的3H,4H,5H,6H,7H‐嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮衍生物
WO2025053163A1 (fr) 2023-09-05 2025-03-13 セレイドセラピューティクス株式会社 Composé ou sel de celui-ci, son procédé de production, composition pharmaceutique contenant un composé ou un sel de celui-ci et son procédé de production
US12478693B2 (en) 2018-05-31 2025-11-25 Amydis, Inc. Compositions and methods for detection of traumatic brain injury

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003524601A (ja) * 1998-09-30 2003-08-19 エラン ファーマシューティカルズ，インコーポレイテッド 生物学的試薬およびβ−アミロイドペプチドの生成機構の決定法
WO2005115990A1 (fr) * 2004-05-26 2005-12-08 Eisai R & D Management Co., Ltd. Composé de cinnamide
JP2006053092A (ja) * 2004-08-13 2006-02-23 Fuji Photo Film Co Ltd バイオセンサー

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003524601A (ja) * 1998-09-30 2003-08-19 エラン ファーマシューティカルズ，インコーポレイテッド 生物学的試薬およびβ−アミロイドペプチドの生成機構の決定法
WO2005115990A1 (fr) * 2004-05-26 2005-12-08 Eisai R & D Management Co., Ltd. Composé de cinnamide
JP2006053092A (ja) * 2004-08-13 2006-02-23 Fuji Photo Film Co Ltd バイオセンサー

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KORNILOVA A.Y., PNAS, vol. 102, no. 9, 2005, pages 3230 - 3235, XP003019709 *
LI Y.-M., NATURE, vol. 405, no. 6787, 2000, pages 689 - 694, XP001026218 *

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US7897627B2 (en) 2007-12-21 2011-03-01 Hoffmann-La Roche Inc. Heteroaryl derivatives as orexin receptor antagonists
US7923450B2 (en) 2008-01-11 2011-04-12 Hoffmann-La Roche Inc. Modulators for amyloid beta
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
WO2010038686A1 (fr) 2008-09-30 2010-04-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé d'aminodihydrothiazine fusionné inédit
US8389717B2 (en) 2008-10-09 2013-03-05 Hoffmann-La Roche Inc. Modulators for amyloid beta
US8188101B2 (en) 2008-11-06 2012-05-29 Astrazeneca Ab Dihydropyridopyrimidines for the treatment of AB-related pathologies
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
EP2615090A1 (fr) 2009-02-26 2013-07-17 Eisai R&D Management Co., Ltd. Composés hétérocycliques fusionnés contenant de l'azote et leur utilisation en tant qu'inhibiteurs de production de bêta-amyloïdes
WO2010098495A1 (fr) 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Dérivés d'imidazolylpyrazine
WO2010098488A1 (fr) 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Composé arylimidazole et leur utilisation en tant qu'inhibiteurs de production de la protéine amyloïde bêta
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
WO2012039371A1 (fr) 2010-09-22 2012-03-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de cyclopropane
WO2013051639A1 (fr) 2011-10-07 2013-04-11 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de pyrazoloquinoline
WO2013115162A1 (fr) 2012-01-31 2013-08-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de sitaxsentan
WO2013115163A1 (fr) 2012-01-31 2013-08-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de paroxétine
WO2013191144A1 (fr) 2012-06-21 2013-12-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 Nouveau dérivé d'indanesulfamide
WO2014129477A1 (fr) 2013-02-20 2014-08-28 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de pyridine monocyclique
WO2014133022A1 (fr) 2013-02-28 2014-09-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de tétrahydroimidazo[1,5-d][1,4]oxazépine
WO2014163146A1 (fr) 2013-04-05 2014-10-09 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composé de pyridinylpyrazoloquinoline
WO2014195323A1 (fr) 2013-06-04 2014-12-11 Acturum Life Science AB Composés de pyrimidine et leur utilisation comme modulateurs de la gamma-sécrétase
US9718805B2 (en) 2013-06-04 2017-08-01 Acturum Life Science AB Triazole compounds and their use as gamma secretase modulators
US9439904B2 (en) 2013-06-04 2016-09-13 Acturum Life Science AB Pyrimidine compounds and their use as gamma secretase modulators
US9611254B2 (en) 2013-06-04 2017-04-04 Acturum Life Science AB Triazole compounds and their use as gamma secretase modulators
WO2014195322A1 (fr) 2013-06-04 2014-12-11 Acturum Life Science AB Composés triazole et utilisation de ces derniers en tant que modulateurs de la gamma-sécrétase
WO2015098853A1 (fr) 2013-12-25 2015-07-02 エーザイ・アール・アンド・ディー・マネジメント株式会社 COMPOSÉ (6S,9aS)-N-BENZYL-6-[(4-HYDROXYPHÉNYL)MÉTHYL]-4,7-DIOXO-8-({6-[3-(PIPÉRAZINE-1-YL)AZÉTIDINE-1-YL]PYRIDINE-2-YL}MÉTHYL)-2-(PROP-2-EN-1-YL)-OCTAHYDRO-1H-PYRAZINO[2,1-c][1,2,4]TRIAZINE-1-CARBOXAMIDE
JP2020143086A (ja) * 2014-03-19 2020-09-10 アミディス・ダイアグノスティックス・インコーポレイテッド アミロイド標的剤及びその使用方法
JP7124006B2 (ja) 2014-03-19 2022-08-23 アミディス・ダイアグノスティックス・インコーポレイテッド アミロイド標的剤及びその使用方法
JP2017512834A (ja) * 2014-03-19 2017-05-25 アミディス・ダイアグノスティックス・インコーポレイテッド アミロイド標的剤及びその使用方法
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