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5-position ring substituted 2, 4-diaminopyrimidine compound with phenylglycinol structure, preparation and application thereof

A compound and metabolite technology, applied in the field of 2,4-diaminopyrimidine compounds, can solve the problems of lethal myelosuppressive toxicity, potential safety hazards, poor selectivity, etc.

Active Publication Date: 2019-01-15
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that FLT3 activating mutation is one of the important factors of leukocyte proliferation and poor prognosis in AML, which makes the treatment of AML patients face great challenges
[0005]In view of the fact that FLT3 activating mutations lead to poor efficacy in AML, the development of targeted FLT3 inhibitors has become a hot spot in the research of anticancer drugs
FLT3 first-generation inhibitors such as Sunitinib, sorafenib, these inhibitors have inhibitory effect on FLT3, but also have good activity on other targets, with poor selectivity
Second-generation FLT3 inhibitors with relatively high selectivity, such as AC220 and PLX3397, have entered clinical research, but these inhibitors only show a short-term response, and soon drug resistance problems will affect the curative effect
In addition, the most advanced clinical research compounds such as AC220 and PKC412 have dual inhibitory activities of c-KIT and FLT3 kinases, which are easy to cause synthetic lethal myelosuppressive toxicity, and there are great safety risks

Method used

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  • 5-position ring substituted 2, 4-diaminopyrimidine compound with phenylglycinol structure, preparation and application thereof
  • 5-position ring substituted 2, 4-diaminopyrimidine compound with phenylglycinol structure, preparation and application thereof
  • 5-position ring substituted 2, 4-diaminopyrimidine compound with phenylglycinol structure, preparation and application thereof

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preparation example Construction

[0113] The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by the direct salt-forming reaction between the free base of the compound and an inorganic or organic acid. The inorganic or organic acid may be selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid acid and p-toluenesulfonic acid etc.

[0114] Since the compound of the present invention has excellent inhibitory activity against FLT3 kinase (Kinase) and mutant FLT3-ITD, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, And the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used to treat, prevent and relieve diseases rela...

Embodiment 1

[0131]

[0132] Synthesis of Compound 1-3:

[0133] Weigh compound 1-1 (4.5g, 20mmol), compound 1-2 (3.3g, 24mmol) in a single-necked bottle, add absolute ethanol, and then add N,N-diisopropylethylamine (6.6ml , 40mmol), stirred at room temperature for 6h. After the reaction, a large amount of white solids precipitated, and were filtered by suction to obtain compound 1-3, 5.48 g. The mother liquor obtained by suction filtration was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Separation by column chromatography gave Compound 1-3, 1.04g.

[0134] Synthesis of compounds 1-4:

[0135] Weigh compound 1-3 (78mg, 0.24mmol), compound 3-fluoro-4-(4-methyl-1-piperazinyl) aniline (42mg, 0.2mmol) in a one-mouth bottle, add 3ml of isopropanol, Then D(+)-10-camphorsulfonic acid (93mg, 0.4mmol) was added, and the mixture was refluxed at 85°C overnight. After...

Embodiment 17

[0145]

[0146] Weigh compound 1-4 (100mg, 0.2mmol), compound 17-1 (36mg, 0.26mmol) in a single-necked bottle, add Pd(OAc) 2 (26mg, 0.12mmol), S-Phos (98mg, 0.24mmol), potassium phosphate (106mg, 0.50mmol). Then add 6ml tetrahydrofuran and 1ml water as solvent, nitrogen protection, react at 90°C for 4h. After the reaction, extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound S17, 54mg, compound S17 as a yellow solid. analyze data: 1 H NMR (400MHz, DMSO-d 6 )δ9.61(s,1H),9.57(s,1H),8.51(s,1H),7.71(d,J=3.8Hz,1H),7.57(d,J=15.8Hz,1H),7.46( d, J=7.4Hz, 3H), 7.35(t, J=7.6Hz, 2H), 7.25(d, J=7.2Hz, 2H), 7.13(d, J=3.8Hz, 1H), 6.91(t, J=9.4Hz, 1H), 5.32(s, 1H), 5.19(t, J=5.2Hz, 1H), 3.78(ddt, J=40.0, 11.3, 5.5Hz, 2H), 2.97(s, 4H), 2.50(d,J=5.2Hz,4H),2.24(s,3H).

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Abstract

The invention discloses a 5-position ring substituted 2, 4-diaminopyrimidine compound with phenylglycinol structure, preparation and application thereof. The structure of the compound provided by theinvention is shown as general formula I, and the definitions of all substituent groups are described as the specification and claims. The compound shows remarkable inhibitory activity on Tel-BaF3-FLT3and BaF3-FLT3-ITD mutant cells, shows weak activity on Tel-BaF3-cKIT cells, and has good selectivity, thus being a very potential FLT3 inhibitor.

Description

technical field [0001] The invention relates to a class of 2,4-diaminopyrimidine compounds with a phenylglycinol structure substituted by a 5-position ring, a preparation method and an application. Background technique [0002] Acute myeloid leukemia (AML) is the most common malignant proliferative disease among adult leukemias, accounting for 80-90%. In the United States, more than 10,000 people are newly diagnosed with leukemia each year, which is similar to the annual number of leukemia deaths. At present, the main treatment options for AML are chemotherapy and hematopoietic stem cell transplantation. However, this type of treatment lacks continuous effectiveness and is poorly tolerated by elderly patients. For patients under the age of 60, the 5-year survival rate is only 40%. In recent years, protein kinase inhibitors have been a hot spot in the development of anti-tumor drugs. Studies have found that more than 70% of AML patients and acute lymphoblastic leukemia (ALL)...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D401/04C07D403/04C07D405/04C07D409/04C07D405/14A61K31/506A61K31/5377A61P35/02A61P35/00A61P19/08
CPCC07D239/48C07D401/04C07D403/04C07D405/04C07D405/14C07D409/04
Inventor 张翱宋子兰邢莉魏曼曼
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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