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Novel heterocyclic derivative with CDK (cyclin-dependent kinase) 4/6 and HDAC (histone deacetylase) inhibitory activities

A CH2, heteroaromatic ring technology, applied in the field of novel heterocyclic derivatives and pharmaceutical compositions thereof, can solve the problems of enhanced deacetylation, increased DNA and histone attraction, unfavorable tumor suppressor gene expression and the like

Inactive Publication Date: 2017-06-13
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In tumor cells, the overexpression of HDAC leads to enhanced deacetylation, which restores the positive charge of histones, thereby increasing the attractive force between DNA and histones, making the relaxed nucleosomes very compact, which is not conducive to some tumors repress gene expression

Method used

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  • Novel heterocyclic derivative with CDK (cyclin-dependent kinase) 4/6 and HDAC (histone deacetylase) inhibitory activities
  • Novel heterocyclic derivative with CDK (cyclin-dependent kinase) 4/6 and HDAC (histone deacetylase) inhibitory activities
  • Novel heterocyclic derivative with CDK (cyclin-dependent kinase) 4/6 and HDAC (histone deacetylase) inhibitory activities

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preparation example Construction

[0021] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0022] The invention also relates to novel intermediates and / or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.

[0023] Both intermediates and final products can be worked up and / or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

[0024] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

[0025] The following examples are only used to illustrate the present invention and do not limit the present invention in any way.

Embodiment 1

[0026] Example 1 8-((4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino)phenyl)amino) - Preparation of methyl 8-oxooctanoate

[0027]

[0028] Step 1.1: Preparation of 8-((4-aminoaniline)amino)-8-oxooctanoic acid methyl ester

[0029]

[0030]Add monomethyl suberate (3.97 g, 21.3 mmol), p-phenylenediamine (2.31 g, 21.3 mmol), DMF 30 mL and DIPEA (13 mL, 74.4 mmol) into a 500 mL single-necked bottle. Stir at room temperature for 5 minutes. Add EDCI (4.5 g, 23.4 mmol) and stir overnight at room temperature. After the reaction was completed, ammonium chloride aqueous solution (30 g ammonium chloride, 300 mL water) was slowly added dropwise. After the drop was completed, the mixture was stirred at room temperature for 2 h, filtered, and the solid was collected and vacuum-dried to obtain 3.19 g of a pink solid, with a yield of 51%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.42 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.47 (d, J = 8.5 Hz, 2H), 4.82 (s, 2H)...

Embodiment 2

[0034] Example 2 N-1-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino)phenyl)- Preparation of N-8-Hydroxyaminooxyoctanoic Acid Amide

[0035]

[0036] Add 8-((4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino)benzene Base)amino)-methyl 8-oxooctanoate (250 mg, 0.47 mmol), hydroxylamine aqueous solution (50%, 2 ml), methanol 5 mL, heated to reflux, and reacted overnight. After the reaction, the solvent was removed, and the residue was purified by column chromatography to obtain 199 mg, yield = 79.4%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.74 (s, 1H), 9.44 (s, 1H), 8.72 (s, 1H), 7.81 – 7.65 (m, 2H), 7.60 – 7.44 (m, 2H), 6.57 ( s, 1H), 4.83 – 4.64 (m, 1H), 3.06 (s, 6H), 2.47 (m, 2H), 2.27 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.3 Hz, 1H), 1.97 (dq, J = 14.6, 7.4 Hz, 5H), 1.73 – 1.45 (m, 6H), 1.34 – 1.26 (m, 4H).

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Abstract

The invention relates to a novel heterocyclic derivative having a formula (I) and salt. The novel heterocyclic derivative comprises pharmaceutical salt, wherein R1, R2, R3, R4, X, Z and L are defined in the text. Compounds of the novel heterocyclic derivative are a CDK (cyclin-dependent kinase) 4 / 6 inhibitor and an HDAC (histone deacetylase) inhibitor and can be used for treating diseases mediated by CDK4 / 6 and HDAC and disturbances, such as cancer including mantle cell lymphoma, liposarcomata, non-small cell lung cancer, melanomas, squamous cell esophagus cancer and breast cancer. The invention also relates to a pharmaceutical composition containing the compounds provided by the invention, and also relates to application of the compounds or pharmaceutical composition containing the compounds provided by the invention to treatment of related disturbances. <FORMULA I>.

Description

technical field [0001] The present invention relates to novel heterocyclic derivatives and their pharmaceutical compositions, especially novel heterocyclic derivatives and their pharmaceutical compositions as CDK4 / 6 or HDAC inhibitors. The invention also relates to the use of these compounds and compositions in the treatment of hyperproliferative disorders such as cancer. Background technique [0002] Cyclin-dependent kinase (CDK) is a kind of serine (Ser) / threonine (Thr) kinase, as an important signal transduction molecule in cells, and CDK-cyclin formed by cyclin Complex, involved in cell growth, proliferation, dormancy or apoptosis. During the process of the cell cycle, cyclins are periodically and continuously expressed and degraded, and are respectively bound to the CDKs activated by them instantaneously. Through CDK activity, they catalyze the phosphorylation of different substrates, and realize the promotion and transformation of different phases of the cell cycle. ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04
Inventor 向荣范艳李永涛郭庆祥黄志
Owner NANKAI UNIV
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