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Five-membered six-membered heterocyclic compound as well as preparation method and application thereof

A compound and heterocyclic group technology, applied in the field of five-membered six-membered heterocyclic compounds and their preparation, can solve problems such as treatment failure, poor overall prognosis, and central nervous system infiltration

Active Publication Date: 2019-04-02
浙江星浩澎博医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

With the deepening of studies on the pathogenesis of leukemia, chemotherapy regimens, specific targeted therapy, and hematopoietic stem cell transplantation, the cure rate of ALL has increased significantly, and the long-term disease-free survival rate has reached 70-80%, but there are still 20-30% Treatment failure due to relapse in children
Among them, the age of onset of T-ALL is relatively old, and the number of white blood cells at the first diagnosis is often greater than 50×10 9 / L, high tumor burden, rapid disease progression, and prone to mediastinal and central nervous system infiltration, with unique clinical, immunological, cytogenetic and molecular biological characteristics different from B-ALL: rapid cell mutation, The low apoptosis rate and many residual leukemia clones determine that it is prone to relapse (up to 30%) and early relapse, with poor prognosis. Compared with B-ALL, the overall prognosis is poor

Method used

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  • Five-membered six-membered heterocyclic compound as well as preparation method and application thereof
  • Five-membered six-membered heterocyclic compound as well as preparation method and application thereof
  • Five-membered six-membered heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] The synthesis of embodiment 1, DB1976

[0113] DB1976 is prepared by the following synthetic route:

[0114]

[0115] Synthesis of Compound 2:

[0116] 4-Amino-3-nitro-benzamidine hydrochloride 1 (108.3 mg, 0.50 mmol) was dissolved in 10.7 mL of absolute ethanol, followed by the addition of 10% palladium on carbon (10.8 mg). After the system was completely replaced with hydrogen, the mixture was stirred at room temperature for 24 hours. Then the palladium carbon was removed by filtration, and the filtrate was spin-dried under vacuum to obtain yellow compound 2 (98.6 mg, quantitative reaction).

[0117] 1 H NMR (400MHz, CD 3 OD) δ7.11(dd, J=2.4,8.4Hz,1H),7.06(d,J=2.4Hz,1H),6.73(d,J=8.4Hz,1H); 13 C NMR (100MHz, CD 3 OD) δ 167.7, 143.9, 135.3, 121.3, 116.3, 115.4, 115.2; HRMS (ESI) m / z: calculated value of C 25 h 26 N 3 o 8 [M+NH 4 ] + = 496.1714, found value = 496.1715.

[0118] Synthesis of Compound 4:

[0119]Dissolve selenophene 3 (670.0mg, 5.10mmol) a...

Embodiment 2

[0126] Embodiment 2: the synthesis of compound 8

[0127] The preparation of compound 2 was the same as in Example 1.

[0128]

[0129] Synthesis of compound 7:

[0130] Dissolve 2,2-diselenol 6 (130.0mg, 5mmol) and tetramethylethylenediamine (711.0mg, 6.12mmol) in 1.6mL of anhydrous n-hexane, and completely replace the system with argon, then Argon gas was passed into the reaction solution for 6 minutes, and the reaction system was cooled to minus 4°C with an ice-salt bath, and the n-hexane solution of tert-butyllithium (8.5 mL, 1.3M) was slowly added to the reaction system dropwise, and the addition was completed. Afterwards, the reaction system was slowly warmed up to room temperature and refluxed for 30 minutes. 6.5 mL of freshly distilled THF was added, and the temperature of the reaction system was lowered to minus 40°C, and anhydrous N,N-dimethylformamide (1.49 g, 20.4 mmol) was slowly added dropwise into the reaction system.

[0131] After the addition, the react...

Embodiment 3

[0135] The compounds in Table 1 were prepared according to the same method as in Example 1. Wherein, for preparing compound 2 from compound 1, the non-hydrochloride salt structure of compound 1 is adopted:

[0136]

[0137] Other preparation conditions are with embodiment 1.

[0138] Table 1: Specific compounds and their mass spectral data

[0139]

[0140]

[0141]

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Abstract

The invention relates to a general formula (I) compound and pharmaceutically acceptable salts thereof as well as a preparation method and application thereof. In the general formula (I) compound, X is-aryl-, -heteroaryl-, -heteroaryl-heteroaryl-, and heterocyclyl-; R1is same or different and is independently selected from H, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halogen, amino, sulfo, nitro, -CN, -CO-R, -CO-OR, -O-R, aryl, heteroaryl and heterocyclyl, wherein R is a C1-6 alkyl, aryl, heteroaryl and heterocyclyl; and R2 is same or different and is independently selected from thegroup consisting of H, C1-6 alkyl, and C1-6 alkoxy. The compound can be used to treat tumor.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a class of five-membered and six-membered heterocyclic compounds, a preparation method thereof and an application for treating tumors. Background technique [0002] Tumor is a heterogeneous tissue. Basic medical research believes that the growth of tumor is the result of the proliferation and differentiation of a small part of tumor cells with stem cell properties in tumor tissue, thus putting forward the "tumor stem cell hypothesis": cancer stem cell (cancer stem cell) Heterogeneous division occurs during the proliferation of CSCs. One CSC divides to form a new CSC and another daughter cell that can eventually differentiate into various cells including tumor cells. As a result, the number of CSCs is maintained stable and tumors are generated. The number of CSCs is extremely rare, and its tumorigenic ability is hundreds of times higher than that of ordinary tumor cells, which is the basis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D421/14C07D403/14C07D491/056C07D495/04C07D493/04C07D517/04C07D409/14C07D401/14C07D471/04C07D235/18A61K31/4184A61K31/4439A61K31/4375A61P35/00A61P35/02A61P37/06A61P17/06A61P25/00
CPCC07D235/18C07D401/14C07D403/14C07D405/14C07D409/14C07D421/14C07D471/04C07D491/056C07D493/04C07D495/04C07D517/04
Inventor 吴虹祝海川张刘珍吴祎琳雷晓光唐毓良
Owner 浙江星浩澎博医药有限公司
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