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A kind of novel benzimidazole-pyrimidine amine derivative and its application

A technology of drugs and compounds, applied in the field of benzimidazole-pyrimidinamine derivatives, to achieve the effects of increasing concentration, reducing first-pass metabolism, reducing drug toxicity and other side effects

Active Publication Date: 2018-01-26
河南英诺唯医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to its toxicity, such as high incidence of hematological toxicity (leukocyte, neutrophil and thrombocytopenia, anemia), as well as diarrhea, nausea, vomiting and fatigue, about 30% of patients developed grade III neutropenia Cells decreased, and 8% of patients developed grade III diarrhea and fatigue

Method used

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  • A kind of novel benzimidazole-pyrimidine amine derivative and its application
  • A kind of novel benzimidazole-pyrimidine amine derivative and its application
  • A kind of novel benzimidazole-pyrimidine amine derivative and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0049] Preparation of [5-(4-pentadeuterioethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2- Methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine

[0050]

[0051] N 2 Under atmosphere, in 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole (1.5g), 5-( 4-Pentadeuterioethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (1.1 g) in 1,4-dioxane (20 mL), was added cesium carbonate (3.0 g) in portions , tris(dibenzylideneacetone)dipalladium (0.2 g), and 4,5-bis(benzoylthio)-9,9-dimethylxanthene (0.2 g). The mixture was heated at 110° C. for 2 hours, and the reaction was monitored by TLC. After cooling to room temperature, the reaction solution was poured into ice water (50 mL) with stirring. This system was extracted with dichloromethane (30 mL X 3). The organic phases were combined, washed with brine (20 mL X 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.8 g of a brown viscous ...

Embodiment 1b

[0054] Preparation of [5-(4-pentadeuterioethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2- Methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine methanesulfonate

[0055]

[0056] N 2 Under atmosphere, in [5-(4-pentadeuteroethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl -2-Methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine (0.7 g) in dichloromethane (10 mL) and methanol (10 mL) was added methanesulfonic acid ( 10mL). The solution was stirred at room temperature for 1 hour and the solvent was removed. After washing several times with methyl tert-butyl ether, 0.9 g of the title compound was obtained.

[0057] 1 H-NMR (CD 3 OD-d4)δ8.58(b,1H),8.32(s,1H),8.26(b,2H),7.87-7,78(m,2H),4.98-4.92(m,1H),3.67(brs ,2H), 3.50-3.42(m,2H), 3.22-3.09(m,6H), 2.71(d,6H), 1.72(d,6H).

[0058] Preparation of intermediate 5-(4-pentadeuteroethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine

[0059] N 2 Under atmosphere, in a degassed solut...

Embodiment 2a

[0068] Preparation of [5-(4-(2,2,2-trideuteroethyl)-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro- 3-isopropyl-2-methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine

[0069]

[0070] It was prepared according to the method described in Example 1, except that 1-(2,2,2-trideuteroethyl)piperazine was used instead of 1-pentadeuteroethylpiperazine to obtain the target product.

[0071] MS (ES+): m / z = 510.2 (M+H).

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Abstract

The invention provides a deuterated benzimidazole-pyrilamine derivative which is a compound shown in formula (I) shown in the specification or a pharmaceutically acceptable salt, a monocrystal substance or a polymorphic substance of the compound as well as an application of the derivative to preparation of drugs for treating cancer, and further provides pharmaceutical composition containing the compound. R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 refer to hydrogen or deuterium independently, and at least one deuterium is contained in total. The deuterated benzimidazole-pyrilamine derivative mesylate prolongs half-life periods of the drugs, prolongs the retention time of the drugs in human bodies and increases concentration of the drugs in blood, so that the better curative effect can be realized.

Description

technical field [0001] The invention belongs to the field of heterocyclic drugs, in particular to a novel benzimidazole-pyrimidinamine derivative and its application. Background technique [0002] At present, the morbidity and mortality of female breast cancer in the United States are ranked 2nd and 3rd respectively; in my country, breast cancer is the malignant tumor with the 1st incidence rate and 4th mortality rate among women, and its incidence rate is increasing year by year. It is estimated that the incidence of breast cancer in Chinese cities will reach 53.87 / 100,000 in 2015, and the incidence in rural areas will reach 40.14 / 100,000. That is, in 2015, the estimated number of new breast cancer cases in China will be 560,000-750,000. This is a huge amount, which also means that more and more effective therapeutic drugs are needed for the treatment of breast cancer. [0003] With the in-depth research on breast cancer, according to the expression of three specific recepto...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCC07D401/14
Inventor 彭快
Owner 河南英诺唯医药科技有限公司
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