Heterocyclic compounds and inhibitors of p27kip1 breakdown

Abstract

The present invention provides novel heterocyclic compounds or salts thereof for selectively inhibiting the decomposition of p27Kip1. The compound or its salt is represented by the following formula (1) (in the formula, A represents an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group, and the group A may have a substituent; the ring B represents a 5-8 membered monocyclic ring Formula heterocycle or a condensed ring containing the monocyclic heterocycle, ring B may have a substituent; ring C represents an aromatic ring, and ring C may have a substituent; L represents that its main chain has a carbon atom, a nitrogen atom, A linking group consisting of 3 to 5 atoms of oxygen atom and sulfur atom and having at least one heteroatom selected from nitrogen atom, oxygen atom and sulfur atom, the linking group L may have a substituent; n is 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 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

[0002] p27 Kip1 Is a cyclin-dependent kinase inhibitor (CDK inhibitor) that is 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 the development, r...

Examples

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...

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 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

[0002] p27 Kip1 Is a cyclin-dependent kinase inhibitor (CDK inhibitor) that is 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 the development, r...

Examples

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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