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Heterocyclic compound and p27Kip1 degradation inhibitor

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

Active Publication Date: 2016-07-13
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 p27Kip1 degradation inhibitor
  • Heterocyclic compound and p27Kip1 degradation inhibitor
  • Heterocyclic compound and p27Kip1 degradation inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0321] Step 1-1-1

[0322] Ethyl 4-fluoro-3-nitrobenzoate

[0323] [chem 30]

[0324]

[0325] Suspend 4-fluoro-3-nitrobenzoic acid (150 g, 0.810 mol) in ethanol (1000 ml), add concentrated sulfuric acid (25 ml) 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 air-dried to obtain the title compound (160 g, 93%) as a yellow solid.

[0326] 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).

[0327] Mass spectrum, m / z: 213 (M + ), 185, 168 (base peak).

[0328] Step 1-1-2

[0329] 4-Methylamino-3-nitrobenzoic acid ethyl ester

[0330] [chem 31]

[0331]

[0332] 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), and Under i...

Embodiment 1-2～1-6

[0357] 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.

[0358] [Table 9]

[0359] Table 9

[0360]

[0361] Synthetic route 2

[0362] [chem 35]

[0363]

[0364] (In the formula, R represents an alkyl group, and R' represents an alkyl or alkoxyalkyl group)

Embodiment 2-1

[0366] Step 2-1-1

[0367] 1,2-Dimethyl-1H-benzimidazole-5-carboxylic acid ethyl ester

[0368] [chem 36]

[0369]

[0370] 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 to 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.

[0371] 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 = 6.9 Hz, 3H).

[0372] Mass spectrum, m / z: 218 (M + ), 173 (base peak).

[0373] Step 2-1-2

[0374] (1,2-Dimethyl-1H-benzimidazol-5-yl)methanol

[0375] [chem 37]

[0376]

[0377] Using ethyl 1,2-dimethyl-1...

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PUM

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Abstract

A novel heterocyclic compound or a salt thereof useful for selectively inhibiting the degradation of p27Kip1 is provided. The compound or the salt thereof is represented by the following formula (1), wherein A represents an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group, the group A may have a substituent; the ring B represents a 5- to 8-membered monocyclic heterocyclic ring or a condensed ring containing the monocyclic heterocyclic ring, the ring B may have a substituent; the ring C represents an aromatic ring, the ring C may have a substituent; L represents a linker comprising a main chain having 3 to 5 atoms selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, wherein at least one atom in the main chain is a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, the linker L may have a substituent; and n is 0 or 1.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201180032088.X with the same title of invention. The original international application number is PCT / JP2011 / 065148, and the international filing date is July 1, 2011. technical field [0002] The present invention relates to a heterocyclic compound that specifically binds ubiquitin protein kinase (SCF Skp2 ), the constituent protein Skp2, for example inhibits 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 disintegration inhibitors), and prophylactic and / or therapeutic agents (for example, anticancer agents) for cell proliferative diseases. Background technique [0003] p27 Kip1 Is a cyclin-dependent kinase inhibitor (CDK in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D487/04C07D403/12C07D498/04C07D231/56A61K31/427A61K31/4184A61K31/416A61K31/5383A61P35/00A61P3/10A61P3/04A61P15/00A61P13/08A61P29/00
CPCC07D231/56C07D403/12C07D417/12C07D487/04C07D498/04A61P3/04A61P3/10A61P13/08A61P15/00A61P29/00A61P35/00A61P43/00C07D207/34C07D231/40C07D277/20C07D277/42C07D307/68C07D405/14C07D409/12C07D417/14C07D471/04C07D491/052A61K31/4184A61K31/437C07D235/06C07F5/025
Inventor 内田裕朝乌章松井照明
Owner ASKA PHARMACEUTICAL CO LTD
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