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WO2012017891A1 - Dérivé de pyridylbenzofuranne - Google Patents

Dérivé de pyridylbenzofuranne Download PDF

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Publication number
WO2012017891A1
WO2012017891A1 PCT/JP2011/067092 JP2011067092W WO2012017891A1 WO 2012017891 A1 WO2012017891 A1 WO 2012017891A1 JP 2011067092 W JP2011067092 W JP 2011067092W WO 2012017891 A1 WO2012017891 A1 WO 2012017891A1
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pharmaceutically acceptable
acceptable salt
compound
group
compound according
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Japanese (ja)
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英郎 佐治
正博 小野
寛之 木村
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Kyoto University NUC
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Kyoto University NUC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a pyridylbenzofuran derivative and a composition for diagnosing amyloid-related diseases comprising the derivative.
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid
  • Non-Patent Document 16-18 -Ilvinyl) -N-methylbenzenamine
  • PIB analog 2- 3- [ 18 F] -fluoro-4-methylamino-phenyl) benzothiazole-6 All
  • FIG. 1 has been shown to be useful for imaging ⁇ -amyloid plaques in living brain tissue in phase 2 and phase 3 clinical trials.
  • Non-Patent Document 20 has been shown to be useful for imaging ⁇ -amyloid plaques in living brain tissue in phase 2 and phase 3 clinical trials.
  • Non-patent Document 21 The inventors evaluated a series of fluorinated benzofuran derivatives as candidates for 18 F-labeled tracers for imaging ⁇ -amyloid plaques with PET (Non-patent Document 21). These derivatives showed excellent affinity for A ⁇ aggregates both in vitro and in vivo. In particular, brain tissue by 4- (5- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) benzofuran-2-yl) -N, N-dimethylbenzenamine (FPHBF-1) (FIG. 2) Permeability was promising. However, this probe was not suitable for in vivo imaging because of slow drainage from normal mouse brain.
  • An object of the present invention is to provide a pyridylbenzofuran derivative suitable for in vivo ⁇ -amyloid plaque imaging.
  • the present inventors tried to develop a novel fluorinated pyridylbenzofuran derivative having low lipophilicity by replacing the phenyl group of phenylbenzofuran with a pyridyl group.
  • a new approach called core structure fluoro-PEGylation (FPEG) for labeling derivatives with 18 F has been developed by Kung et al. Since this approach provides a simple and convenient way to incorporate 18 F into the target without significantly increasing lipophilicity, we chose FPEG for labeling of pyridylbenzofuran derivatives.
  • the present inventors have developed a novel fluorinated ligand having a fluoropolyethyleneglycol side chain and a dimethylaminopyridyl group, 5- (5- (2- (2- (2-fluoroethoxy) ethoxy) ethoxy) benzofuran-2- Yl) -N, N-dimethylpyridin-2-amine (FPYBF-1) (FIG. 2) and several pyridylbenzofuran derivatives were synthesized. The first successful radiolabelling of pyridylbenzofuran derivatives was evaluated for in vivo imaging of ⁇ -amyloid plaques, completing the present invention.
  • R 1 is a hydroxy group, a C 1-10 alkoxy group and a formula: — (CH 2 CH 2 O) n —X (wherein n represents an integer of 1 to 10 and X represents a halogen atom).
  • R 2 is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents either a hydrogen atom or a C 1-3 alkyl group).
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a C 1-4 alkyl group, and a C 1-4 alkoxy group. Selected from) Or a pharmaceutically acceptable salt thereof.
  • the present invention also provides Formula (II) [Wherein R 1 represents a hydroxy group, a C 1-10 alkoxy group and a formula: — (CH 2 CH 2 O) n —X (wherein n represents an integer of 1 to 10, X represents a halogen atom Selected from the group consisting of: R 2 is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents a hydrogen atom or a C 1-3 alkyl group)] Or a pharmaceutically acceptable salt thereof.
  • the present invention also provides any of the aforementioned compounds or a pharmaceutically acceptable salt thereof, which is labeled with a radionuclide.
  • the present invention also provides a composition for diagnosing amyloid-related diseases, comprising any one of the aforementioned compounds labeled with a radionuclide or a pharmaceutically acceptable salt thereof.
  • the present invention also provides an imaging agent for amyloid plaques, comprising any one of the above compounds labeled with a radionuclide or a pharmaceutically acceptable salt thereof.
  • the present invention also includes: a. Introducing into the mammal a detectable amount of any of the aforementioned compounds labeled with a radionuclide or a pharmaceutically acceptable salt thereof; b. Leaving the compound for a time sufficient to bind to the amyloid plaque; and c. Detecting a compound bound to one or more amyloid plaques, a method for imaging amyloid plaques is provided.
  • the present invention makes it possible to image amyloid plaques in brain tissue and to diagnose diseases characterized by the presence of amyloid protein aggregates such as Alzheimer's disease.
  • R 1 is a hydroxy group, a C 1-10 alkoxy group and a formula: — (CH 2 CH 2 O) n —X (wherein n represents an integer of 1 to 10 and X represents a halogen atom).
  • R 2 is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents either a hydrogen atom or a C 1-3 alkyl group).
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a C 1-4 alkyl group, and a C 1-4 alkoxy group. Selected from) It is represented by
  • the compounds of the invention have the general formula (II) [Wherein R 1 represents a hydroxy group, a C 1-10 alkoxy group and a formula: — (CH 2 CH 2 O) n —X (wherein n represents an integer of 1 to 10, X represents a halogen atom Selected from the group consisting of: R 2 is a group represented by the formula: —NRaRb (wherein Ra and Rb each independently represents a hydrogen atom or a C 1-3 alkyl group)] It is.
  • Examples of the C 1-10 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a pentyl group.
  • Examples of the C 1-4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
  • halogen atoms include F, Cl, Br, and I.
  • X is F.
  • —NRaRb is —NH 2 , —NHCH 3 or —N (CH 3 ) 2 .
  • R 1 is — (CH 2 CH 2 O) n —X (wherein n represents an integer of 1 to 10 and X represents a halogen atom). n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In a preferred embodiment, n represents an integer of 1 to 3, 1 to 4, or 1 to 5.
  • a preferred compound of the present invention is FPYBF-1 or FPYBF-2 represented by the following formula.
  • R 1 is a C 1-10 alkoxy group, preferably a C 1-5 alkoxy group. In another aspect of this embodiment, R 1 is a C 1-3 alkoxy group.
  • a compound is “labeled with a radionuclide” when one or more atoms in the compound have the same atomic number but are substituted with radioactive isotopes having different mass numbers, or the compound is radioactive. It means that the nuclide is bound.
  • radioactive isotopes of atoms in the compound H, C, N, O, F, Cl, Br, and the radioisotopes of I, 2 H, 3 H, 11 C, 13 C, 14 C, 15 C, 15 O, 18 F, 36 Cl, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 11 C and 18 F are preferred.
  • radionuclide bonded to the compound of the present invention examples include 64 Cu, 67 Ga, 68 Ga, or 99m Tc, and 99m Tc is particularly preferable. These radionuclides can be substituted for the atoms in the compound of the present invention and bonded to the compound of the present invention by a method generally used for each radionuclide.
  • 99m Tc is usually bound to the unlabeled compound in the form of a complex.
  • Complexes containing 99m Tc include complexes containing 2-hydrazinopyridine (Liu S et al, Bioconjug Chem. 1996 Jan-Feb; 7 (1): 63-71), N- (2-mercaptoethyl) -2 Complexes containing — [(2-mercaptoethyl) amino] -acetamide (Zhen W et al, J Med Chem. 1999 Jul 29; 42 (15): 2805-15), 2,2 ′-(1,2-ethane Complex containing diyldiimino) bisethanethiol (Oya S et al, Nucl Med Biol. 1998 Feb; 25 (2): 135-40), tricarbonyl complex (Schibli R et al, Bioconjug Chem. 2000 May-Jun; 11 (3): 345-51) and the like (these documents are incorporated herein by reference).
  • Preferred labeling compounds of the present invention are as follows. [ 18 F] FPYBF-1 [ 18 F] FPYBF-2 [ 99m Tc] BAT-Bp [ 99m Tc] BAT-Bp-5
  • Examples of the “pharmaceutically acceptable salt” include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, sulfate, hydrochloride, nitrate, phosphate and the like. For example, but not limited to.
  • the present invention also relates to a composition for diagnosing amyloid-related diseases, comprising the compound of the present invention labeled with a radionuclide or a pharmaceutically acceptable salt thereof.
  • amyloid-related disease in the present invention means a disease in which the presence of amyloid protein aggregates is observed. Since the compound of the present invention binds to a protein having a ⁇ -sheet structure, the “amyloid-related diseases” in the present invention include amyloid proteins having a ⁇ -sheet structure such as tau, ⁇ -synuclein and prion in addition to ⁇ -amyloid. Diseases in which the presence of aggregates are observed.
  • the “amyloid-related disease” in the present invention includes Alzheimer's disease, Mediterranean fever, Maccle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloidosis Hereditary cerebral hemorrhage (including hereditary cerebral hemorrhage with Dutch or Icelandic amyloidosis), Down syndrome, scrapie, Buchie, Bachfeld-Jakob disease, Kuru, Gerstmann-Stroisler-Scheinker syndrome, medullary carcinoma of the thyroid, isolated These include atrial amyloid, ⁇ 2 -microglobulin amyloid in dialysis patients, inclusion body myositis, ⁇ 2 -amyloid deposition in muscle wasting disease, and Langerhans type II diabetes insulinoma.
  • the diagnostic composition of the present invention is particularly suitable for diseases in which the presence of ⁇ -amyloid (A ⁇ ) aggregates is observed, such as Alzheimer's disease, hereditary cerebral hemorrhage with Dutch amyloidosis, and Down's syndrome.
  • a ⁇ ⁇ -amyloid
  • precursor symptoms of diseases that are generally not recognized as “diseases” are also included in “amyloid-related diseases” in the present invention. Examples of prodromal symptoms of such diseases include mild cognitive impairment (MCI) seen before the onset of Alzheimer's disease.
  • MCI mild cognitive impairment
  • Diagnosis of amyloid-related diseases using the composition of the present invention is usually performed by administering the composition of the present invention to a subject to be diagnosed or a laboratory animal, and then taking a brain image, and the state of the compound of the present invention ( Quantity, distribution, etc.).
  • the composition of the present invention may contain a compound labeled with a ⁇ -emitting nuclide such as 123 I, 67 Ga, or 99m Tc when diagnosing by computer tomography (SPECT).
  • SPECT computer tomography
  • SPECT computer tomography
  • a diagnosis is performed by an imaging method (PET)
  • a compound labeled with a positron emitting nuclide such as 11 C, 13 N, 15 O, 18 F, 62 Cu, 68 Ga, or 76 Br may be included.
  • the method of administration of the composition of the present invention is not particularly limited, and is appropriately determined according to the type of compound and radionuclide and the condition of the subject, but is usually intradermal, intraperitoneal, vein, artery, or spinal fluid. Administered by injection or infusion.
  • the dose of the composition of the present invention is also appropriately determined according to the kind of the compound and radionuclide and the condition of the subject. For example, in the case of an adult, the dose of the compound of the present invention is 10 ⁇ 10 to 10 ⁇ 3 per day. mg, preferably 10 ⁇ 8 to 10 ⁇ 5 mg may be administered.
  • the composition of the present invention may contain, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, components usually contained in injection solutions or infusion solutions.
  • Such components include liquid carriers (for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol), antibacterial agents, Examples include a local anesthetic (eg, procaine hydrochloride, dibucaine hydrochloride), a buffer (eg, Tris-HCl buffer, Hepes buffer), and an osmotic pressure regulator (eg, glucose, sorbitol, sodium chloride).
  • liquid carriers for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol
  • antibacterial agents examples include a local anesthetic (
  • the present invention also relates to an amyloid plaque imaging agent comprising the compound of the present invention or a pharmaceutically acceptable salt thereof labeled with a radionuclide.
  • Amyloid plaques are formed by aggregation of amyloid proteins having a ⁇ -sheet structure. Examples of amyloid protein include ⁇ -amyloid, tau, ⁇ -synuclein, and prion.
  • the imaging agent of the present invention is particularly suitable for imaging amyloid plaques formed by ⁇ -amyloid.
  • the amyloid plaque imaging agent of the present invention can be prepared and used in the same manner as the composition for diagnosing amyloid-related diseases.
  • the present invention also provides a. Introducing a detectable amount of a compound of the present invention or a pharmaceutically acceptable salt thereof labeled with a radionuclide into a mammal; b. Leaving the compound for a time sufficient to bind to the amyloid plaque; and c. Detecting a compound bound to one or more amyloid plaques; A method for imaging amyloid plaques.
  • “Mammals” include, but are not limited to, humans, mice, rats, rabbits, dogs, monkeys. Preferably, the “mammal” is a human.
  • the labeling with the radionuclide and the detection of the labeled compound may be performed as described above. That is, SPECT and PET can be used for detection, and the radionuclide may be selected according to the detection method. Moreover, introduction into mammals may be performed as described for the composition for diagnosing amyloid-related diseases.
  • a detectable amount of a compound of the invention or a pharmaceutically acceptable salt thereof labeled with a radionuclide and “a sufficient amount of time for the compound to bind to amyloid plaques”
  • a person skilled in the art can appropriately determine depending on the compound used and the detection method. For example, the amount and time of these can be determined by introducing various concentrations of the labeled compound into the mammal of interest, and detecting this labeled compound with the selected detection method at various times after introduction. .
  • 5-methoxybenzofuran-2-boronic acid (576 mg, 3.0 mmol), 2-amino-5-iodopyridine (660 mg, 3.0 mmol), and Pd (Ph 3 ) 4 (366 mg, 0.3 mmol) (2 M
  • a solution of Na 2 CO 3 (aq) / dioxane 150 mL, 1: 1) was stirred at reflux overnight. The mixture was cooled to room temperature and 1 M NaOH (20 mL) was added. After extraction with ethyl acetate, the organic layer was dried over Na 2 SO 4 and filtered.
  • [ 18 F] Fluoride is produced by Cyclotron (CYPRIS HM-18, Sumitomo Heavy Industries, Ltd., Tokyo) via the 18 O (p, n) 18 F reaction, and as an aqueous solution in water rich in 18 O. -Passed through Pak Light QMA cartridge (Waters). The cartridge was dried with N 2 and 18 F activity was adjusted to 1.0 mL Kryptofix 222 / K 2 CO 3 solution (9.5 mg Kryptofix 222 and 1.7 mg K 2 CO 3 in acetonitrile / water (96/4). Elution). The solvent was removed at 120 ° C. under a stream of argon gas. The residue was dried twice under nitrogen gas flow at 120 ° C.
  • the eluted compound was purified by preparative HPLC [YMC-Pack Pro C18 column (20 mm ⁇ 150 mm), acetonitrile / water (60/40), flow rate 3.0 mL / min].
  • the retention time of the desired 18 F labeled product is 10.0 minutes.
  • the radiochemical purity and specific activity, analytical HPLC [YMC-Pack Pro C18 column (4.6 mm ⁇ 0.99 mm), acetonitrile / water (60/40), flow rate 1.0 mL / min] measured by, [18 F FPYBF-1 was obtained with a radiochemical purity> 99% and a specific activity of 242 GBq / ⁇ mol. Specific activity was assessed by comparing the UV peak intensity of the purified 18 F labeled compound with a known concentration of a reference non-radioactive compound.
  • [ 18 F] FPYBF-1 showed sufficiently high uptake (5.16% ID / g) in PET 2 minutes after injection, and radioactivity in the brain disappeared over time (2.44% ID / 60 at 60 minutes after injection). g). Since normal brain tissue does not have ⁇ -amyloid plaques that trap [ 18 F] FPYBF-1, radioactivity should be excreted very quickly. Thus, the rapid clearance of [ 18 F] FPYBF-1 from normal brain indicates that FPYBF-1 is suitable for detection of ⁇ -amyloid plaques in AD brain.
  • Non Patent Document 32 One way of selecting ligands having in vivo an appropriate kinetics is to use 2 min / brain 60 min ratios brain for the comparison of the discharge rate (brain 2 min / brain 60 min ratio) as an indicator (Non Patent Document 32).
  • the ratio of [ 18 F] FPYBF-1 to the brain 2 min / 60 min brain (2.1) is [ 18 F] BAY94-9172 (4.8) (Non-Patent Document 14) and [ 18 F] AV-45 (3.8) (Non- Although lower than that of Patent Document 16), it was improved compared with the previously reported value of [ 18 F] FPHBF-1 (1.0) (Non-Patent Document 21).
  • the [18 F] Preferred in vivo pharmacokinetic FPYBF-1 was achieved by changing the pyridyl group a [18 F] FPHBF-1 of the phenyl group.
  • the retention times of [ 18 F] FPYBF-1 and [ 18 F] FPHBF-1 are 14.8 minutes and 36.5 minutes, respectively, indicating that the lipophilicity of [ 18 F] FPYBF-1 is [ 18 F] FPHBF-1 Suggests lower than -1.
  • Lipophilicity is only one of the factors affecting the brain's uptake of compounds (Non-patent Document 4), but may explain the preferable pharmacokinetics of [ 18 F] FPYBF-1 in the brain. Bone uptake at 60 minutes has decreased (1.42% ID / g), indicating that there is little in vivo defluorination and relatively little interference with imaging. Suggest.
  • Tg2576 transgenic mice 36 months old, male
  • wild type mice 36 months old, male
  • 11.1 MBq [ 18 F] FPYBF-1 in 200 ⁇ L of 0.1% BSA solution
  • the animals were allowed to recover for 30 minutes and then killed by decapitation.
  • the brain was immediately removed and frozen in a dry ice / hexane bath. 20 ⁇ m sections were cut and exposed overnight to BAS imaging plates (Fuji Photo Film Co., Tokyo, Japan). In this way, an ex vivo film autoradiogram was obtained.
  • FPYBF-1 showed high affinity for in vitro A ⁇ aggregates and ⁇ -amyloid plaques in sections of autopsy AD brain. FPYBF-1 also showed good uptake in the brain (5.16% ID / g at 2 minutes after injection) and excellent binding to ⁇ -amyloid plaques ex vivo in transgenic mice.
  • 5-methoxybenzofuran-2-ylboronic acid (576 mg, 3.0 mmol), 5-iodopyridin-2-amine (660 mg, 3.0 mmol), and Pd (Ph 3 ) 4 (366 mg, 0.3 mmol) (2M Na
  • 2 CO 3 (aq) / dioxane 150 mL, 1: 1 was stirred at reflux overnight. After the mixture was cooled to room temperature, 1 M NaOH (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4 and filtered.
  • [ 18 F] Fluoride is produced by Cyclotron (CYPRIS HM-18, Sumitomo Heavy Industries, Ltd., Tokyo) via the 18 O (p, n) 18 F reaction, and as an aqueous solution in water rich in 18 O. -Passed through Pak Light QMA cartridge (Waters). The cartridge was dried with N 2 and 18 F activity was adjusted to 1.0 mL Kryptofix 222 / K 2 CO 3 solution (9.5 mg Kryptofix 222 and 1.7 mg K 2 CO 3 in acetonitrile / water (96/4). Elution). The solvent was removed at 120 ° C. under a stream of argon gas. The residue was dried twice under nitrogen gas flow at 120 ° C.
  • the residue was purified by preparative HPLC [YMC-Pack Pro C18 column (20 mm ⁇ 150 mm), acetonitrile / water (70/30), flow rate 4.0 mL / min].
  • the retention time of the desired 18 F labeled product is 13.3 minutes.
  • the radiochemical purity and specific activity, analytical HPLC [YMC-Pack Pro C18 column (4.6 mm ⁇ 0.99 mm), acetonitrile / water (50/50), flow rate 1.0 mL / min] measured by, [18 F ] FPYBF-2 was obtained with a radiochemical purity> 99% and a specific activity of 242 GBq / ⁇ mol. Specific activity was assessed by comparing the UV peak intensity of the purified 18 F labeled compound with a known concentration of a reference non-radioactive compound.
  • Re-BAT-Bp The synthesis of Re-BAT-Bp is shown in Scheme 3.
  • Scheme 3 Reagents: (a) Pd (Ph 3 P) 4 , 2 M Na 2 CO 3 (aq) / dioxane; (b) paraformaldehyde, sodium cyanoborohydride, acetic acid; (c) BBr 3 , CH 2 Cl 2 ; (d) 1,3-Dibromopropane, CH 3 CN, K 2 CO 3 ; (e) Tr-Boc-BAT, CH 3 CN, DIPEA; (f) Triethylsilane, TFA; (g) (Ph 3 P) 2 ReOCl 3 , AcONa, CH 2 Cl 2 / MeOH.
  • 5-methoxybenzofuran-2-boronic acid (576 mg, 3.0 mmol), 2-amino-5-iodopyridine (660 mg, 3.0 mmol), and Pd (Ph 3 ) 4 (366 mg, 0.3 mmol) (2 M
  • a solution of Na 2 CO 3 (aq) / dioxane 150 mL, 1: 1) was stirred at reflux overnight. The mixture was cooled to room temperature and 1 M NaOH (20 mL) was added. After extraction with ethyl acetate, the organic layer was dried over Na 2 SO 4 and filtered.
  • Binding test to A ⁇ aggregates in vitro As described in Example 1, binding tests were performed using 50 ⁇ L Re-BAT-Bp (0.008 pM-400 ⁇ M in 10% EtOH). The results are shown in FIG. The IC 50 of Re-BAT-Bp was 13.6 ⁇ 0.30 (nM).
  • Triethylsilane (10 ⁇ L) was mixed with a solution of compound 5 (0.5 mg) (in TFA (200 ⁇ L)), and then the solvent was removed under a stream of nitrogen gas. The residue was dissolved in acetonitrile (200 ⁇ L) and 0.1 M HCl (15 ⁇ L) and 99m TcGH solution (200 ⁇ L) were added. The reaction mixture was heated to 80-90 ° C. for 10 minutes. After cooling to room temperature, the mixture was purified by RP-HPLC to give [ 99m Tc] BAT-Bp.
  • Re-BAT-Bp-5 The synthesis of Re-BAT-Bp-5 is shown in Scheme 4.
  • Scheme 4 Reagents: (a) Pd (Ph 3 P) 4 , 2 M Na 2 CO 3 (aq) / dioxane; (b) paraformaldehyde, sodium cyanoborohydride, acetic acid; (c) BBr 3 , CH 2 Cl 2 ; (d) 1,5-Dibromopropane, CH 3 CN, K 2 CO 3 ; (e) Tr-Boc-BAT, CH 3 CN, DIPEA; (f) Triethylsilane, TFA; (g) (Ph 3 P) 2 ReOCl 3 , AcONa, CH 2 Cl 2 / MeOH.
  • Re-BAT-Bp-5 (6) To a solution of compound 5 (86.2 mg, 0.079 mmol) in TFA (3 mL) was added triethylsilane (0.29 mL) and stirred for 10 minutes, then the solvent was removed under a stream of nitrogen gas. The residue was dissolved in 10 mL CH 2 Cl 2 and (Ph 3 P) 2 ReOCl 3 (135 mg, 0.15 mmol) and 1 M sodium acetate (in methanol (5 mL)) were added. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. Ethyl acetate (60 mL) was added and the mixture was filtered.

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Abstract

La présente invention concerne : un dérivé de pyridylbenzofuranne ; et une composition pour le diagnostic des maladies associées à des substances amyloïdes, qui contient le dérivé.
PCT/JP2011/067092 2010-08-06 2011-07-27 Dérivé de pyridylbenzofuranne Ceased WO2012017891A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014132919A1 (fr) * 2013-02-28 2014-09-04 国立大学法人京都大学 Composition de diagnostic
JP2018523657A (ja) * 2015-08-18 2018-08-23 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 画像化のためのニトロキシドを含むアミロイド結合剤およびその治療的使用

Citations (5)

* Cited by examiner, † Cited by third party
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