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Novel molecular probes

A technology selected from compounds, applied in the field of characterization, localization and separation of new molecular probes for γ-secretase, and detection, which can solve the problems of uncurable and unobtainable diseases

Inactive Publication Date: 2008-01-30
ASTRAZENECA AB +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Treatments that effectively prevent AD or reverse the clinical symptoms and underlying pathophysiology are currently unavailable, and experts consider the disease currently incurable

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0081] Example 1: 5-((3aR,6S,6aS)-2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid {5-[2-((6R,7S)-7-{(S)-2-[2-(3-benzoyl-phenyl)-acetamido]-propionylamino}-8-oxo -6-Phenyl-7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl)-acetylamino]-pentyl}-amide (1)

[0082] in N 2 Under atmosphere, to 5-((3aS, 4S, 6aR)-2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid (5-{2-[(6R , 7S)-7-((S)-2-amino-propionylamino)-8-oxo-6-phenyl-7,8-dihydro-6H-5-oxa-9-azabenzo Cyclohepten-9-yl]-acetylamino}-pentyl)-amide ( 1h ) (66mg, 0.096mmol) in DMF (2mL) cold solution (0°C), was added m-benzoylphenylacetic acid (used similarly to J.A.

[0083] Zderic, the procedure described in J.Org.Chem., 1961, 26, 635, prepared from m-methylbenzophenone) (24mg, 0.100mmol), HOBt (19mg, 0.140mmol), i-Pr 2 EtN (40 μL, 0.230 mmol) and EDAC-HCl (27 mg, 0.141 mmol). The mixture was stirred overnight at ambient temperature, diluted with EtOAc (30 mL), then washed with 20% K 2 CO 3 Aqueous so...

Embodiment 2

[0112] Example 2: 5-((3aR,6S,6aS)-2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid {5-[2-((6R,7S)-7-{(S)-2-[2-(4-benzoyl-phenyl)-acetylamino]-propionylamino}-8-oxo -6-Phenyl-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetylamino]-pentyl}-acyl Amines (2)

[0113] Using a procedure similar to that of Example (1), the difference is that p-benzoylphenylacetic acid (using the procedure described by J.A.Zderic, J.Org.Chem., 1961, 26, 1635, derived from Ketone preparation) (24mg, 0.100mmol) as the acid component, the title compound was isolated by preparative RPHPLC to give the title compound as an off-white solid ( 2 ) (48 mg, 53%). 1 H NMR (300.132MHz, MeOH) δ7.76(d, J=7.0Hz, 2H), 7.72(d, J=8.2Hz, 2H), 7.64(t, J=7.4Hz, 1H), 7.52(t, J=7.5Hz, 2H), 7.47-7.26(m, 10H), 7.21(d, J=7.1Hz, 1H), 5.66(d, J=7.1Hz, 1H), 5.27-5.07(m, 1H), 4.67(d, J=16.4Hz, 1H), 4.45(dd, J=7.8, 5.0Hz, 1H), 4.38(d, J=16.4Hz, 1H), 4.31-4.18(m, 2H), 3.58(s , 2H), 3.21(t, J=6.8Hz, 2H), 3.1...

Embodiment 3

[0115] Example 3: 5-((3aR,6S,6aS)-2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoic acid {5-[2-((6R,7S)-7-{(S)-2-[2-(4-azido-phenyl)-acetylamino]-propionylamino}-8-oxo- 6- Phenyl-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetylamino]-pentyl}-amide (3)

[0116] Using a procedure similar to that described in Example (1), the difference is that p-azidophenylacetic acid (using the procedure described by R.Seyer, J.Med.Chem., 1994, 37, 1841, derived from p-aminobenzene Acetic acid) (20 mg, 0.113 mmol) as the acid component, the title compound was isolated by preparative RPHPLC to give the title compound as an off-white solid ( 3 ) (68 mg, 74%). 1H NMR (300.132MHz, MeOH) δ7.47-7.30(m, 9H), 7.27(d, J=8.4Hz, 2H), 6.99(d, J=8.4Hz, 2H), 5.65(d, J=7.1 Hz, 1H), 5.16 (d, J=7.1Hz, 1H), 4.69 and 4.39 (AB, J=16.4Hz, 2H), 4.46 (dd, J=7.8, 4.8Hz, 1H), 4.27 (dd, J =7.9, 4.5Hz, 1H), 4.20(q, J=7.2Hz, 1H), 3.45(s, 2H), 3.30-3.05(m, 6H), 2.90(dd, J=12.7, 5.0Hz, 1H) , 2.68(d, J...

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Abstract

The present invention relates to novel molecular probes having the formula (I) (I) useful for the characterization, detection, localization and isolation of the secretase enzyme.

Description

field of invention [0001] The present invention relates to novel molecular probes for the detection, characterization, localization and isolation of gamma-secretase. Background of the invention [0002] Alzheimer's disease (AD) is a progressive, neurodegenerative disorder clinically characterized by progressive loss of memory, cognition, reasoning, judgment, and emotional stability. AD is a common cause of dementia in humans and is the leading cause of death in the United States. AD has been observed in races and ethnic groups worldwide and AD presents as a major public health problem worldwide. There are currently no treatments available to effectively prevent AD or reverse the clinical symptoms and underlying pathophysiology, and experts believe that the disease is currently incurable. [0003] The histopathology of AD is manifested by characteristic lesions, called amyloid plaques (or senile plaques) and neurofibrillary tangles, which occur in areas of the brain associa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D267/14C07F5/02
CPCC07D495/04C07K5/0806C07K5/0827C07D413/14C07F5/022C07D267/14
Inventor 巴里·格林伯格丹尼尔·C·希尔罗伯特·雅各布斯桑格拉姆·S·西索迪亚
Owner ASTRAZENECA AB