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Heterocyclic compound, and p27 kip1 degradation inhibitor

A compound and heterocyclic technology, applied in the field of heterocyclic compounds and p27Kip1 decomposition inhibitors, can solve problems such as undocumented relationships

Active Publication Date: 2013-03-20
ASKA PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its relationship with intracellular proteins is not documented

Method used

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  • Heterocyclic compound, and p27 kip1 degradation inhibitor
  • Heterocyclic compound, and p27 kip1 degradation inhibitor
  • Heterocyclic compound, and p27 kip1 degradation inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0324] Step 1-1-1

[0325] Ethyl 4-fluoro-3-nitrobenzoate

[0326] [chem 30]

[0327]

[0328] Suspend 4-fluoro-3-nitrobenzoic acid (150g, 0.810mol) in ethanol (1000ml), add concentrated sulfuric acid (25ml) dropwise, and heat to reflux for 8 hours. After standing to cool, it was concentrated under reduced pressure, and water was added with stirring. The precipitate was separated by filtration, washed with water and ventilated to dry to obtain the title compound (160 g, 93%) as a yellow solid.

[0329] 1 H-NMR (DMSO-d 6 ) δ: 8.56 (dd, J=2.3, 7.3Hz, 1H), 8.35-8.31 (m, 1H), 7.76-7.71 (m, 1H), 4.37 (q, J=7.3Hz, 2H), 1.35 (t , J=7.3Hz, 3H).

[0330] Mass spectrum, m / z: 213 (M + ), 185, 168 (base peak).

[0331] Step 1-1-2

[0332] 4-Methylamino-3-nitrobenzoic acid ethyl ester

[0333] [chem 31]

[0334]

[0335] Dissolve ethyl 4-fluoro-3-nitrobenzoate (10.0 g, 46.9 mmol) prepared in the above step 1-1-1 in methanol (40 ml), add triethylamine (10 ml, 70.4 mmol), an...

Embodiment 1-2～1-6

[0360] Instead of the 40% methylamine-methanol solution as the ring-forming component, or ethyl 4-fluoro-3-nitrobenzoate as the monocyclic compound, the compounds shown in the table below were used. 1-1 is operated in the same way to obtain the target bicyclic compound.

[0361] [Table 9]

[0362] Table 9

[0363]

[0364] Synthetic route 2

[0365] [chem 35]

[0366]

[0367] (In the formula, R represents an alkyl group, and R' represents an alkyl or alkoxyalkyl group)

Embodiment 2-1

[0369] Step 2-1-1

[0370] 1,2-Dimethyl-1H-benzimidazole-5-carboxylic acid ethyl ester

[0371] [chem 36]

[0372]

[0373] Ethyl 3-amino-4-methylaminobenzoate (1.00 g, 5.15 mmol) prepared in step 1-1-3 was dissolved in acetic anhydride (4 ml), and heated under reflux for 19 hours. After standing to cool, it was neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate. Dry over anhydrous magnesium sulfate, then concentrate. Purification by silica gel column chromatography (chloroform:methanol=10:1) gave the title compound (1.15 g, quantitative) as a light brown oil.

[0374] 1 H-NMR (CDCl 3 ) δ: 8.39 (d, J=1.5Hz, 1H), 7.98 (dd, J=1.5, 8.5Hz, 1H), 7.28 (d, J=8.5Hz, 1H), 4.39 (q, J=6.9Hz, 2H), 3.75 (s, 3H), 2.62 (s, 3H), 1.41 (t, J=6.9Hz, 3H).

[0375] Mass spectrum, m / z: 218 (M + ), 173 (base peak).

[0376] Step 2-1-2

[0377] (1,2-Dimethyl-1H-benzimidazol-5-yl)methanol

[0378] [chem 37]

[0379]

[0380] Using ethyl 1,2-dimet...

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PUM

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Abstract

Provided are a novel heterocyclic compound and salt thereof applicable in the selective inhibition of the degradation of p27Kip1. The compound and the salt thereof are represented in formula (1). [In the formula: A represents an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, and group A can have a substituent group; ring B represents a 5- to 8- membered monocyclic heterocyclic ring or a condensed ring containing this monocyclic heterocyclic ring, and ring B can have a substituent group; ring C represents an aromatic ring, and ring C can have a substituent group; L represents a linker having 3-5 atoms in the main chain selected from carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms, and having at least one heteroatom selected from nitrogen atoms, oxygen atoms, and sulfur atoms, and linker L can have a substituent group; and n represents 0 or 1.]

Description

technical field [0001] The present invention relates to a heterocyclic compound that specifically binds ubiquitin protein kinase (SCF Skp2 ), the constituent protein Skp2, for example inhibits the release from SCF Skp2 p27 in complex Kip1 dissociates, and consequently, inhibits p27 Kip1 Proceeding of ubiquitination and simultaneous inhibition of p27 induced by the proteasome Kip1 The decomposition of the present invention also relates to the p27 containing the compound Kip1 ubiquitination inhibitor (or p27 Kip1 decomposition inhibitors), and prophylactic and / or therapeutic agents (for example, anticancer agents) for cell proliferative diseases. Background technique [0002] p27 Kip1 is a cyclin-dependent kinase inhibitor (CDK inhibitor) that acts as a factor that negatively regulates cell cycle progression. According to clinical studies, in highly malignant cancer cells due to p27 Kip1 hyperlysis of p27 Kip1 expression decreased. In addition, it is revealed that th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34A61K31/341A61K31/415A61K31/4178A61K31/426A61K31/427A61K31/437A61K31/498A61K31/5383A61K31/55A61P3/10A61P29/00A61P35/00A61P43/00C07D231/40C07D277/20C07D277/42C07D307/68C07D403/12C07D405/14C07D409/12C07D417/12C07D417/14C07D471/04C07D487/04C07D491/052C07D498/04
CPCC07D231/40C07D207/34C07D307/68C07D471/04C07F5/025C07D403/12C07D409/12C07D277/42C07D417/14C07D277/20C07D405/14C07D491/052C07D417/12C07D487/04C07D498/04C07D231/56A61P3/04A61P3/10A61P13/08A61P15/00A61P29/00A61P35/00A61P43/00A61K31/4184A61K31/437C07D235/06
Inventor 内田裕朝乌章松井照明
Owner ASKA PHARMACEUTICAL CO LTD
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