Aryl thiourea and preparation method and application thereof

An aryl thiourea and aryl technology, which is used in the synthesis and inhibition of VEGFR-2, new aryl thiourea compounds, and the field of anti-tumor drugs, can solve the problem of unpredictable thiourea compounds with VEGFR kinase inhibitory activity and its application. Drug safety performance and other issues

Inactive Publication Date: 2010-06-09
CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN1972925A discloses a class of bisaryl urea derivatives with VEGFR kinase inhibitory effect, but the various group compounds defined by the substituents in the general formula have never been implemented, and have large property differences from the disclosed substituent compounds, Therefore, we cannot predict whether the thiourea compound contained in the general formula has VEGFR kinase inhibitory activity and its drug safety performance

Method used

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  • Aryl thiourea and preparation method and application thereof
  • Aryl thiourea and preparation method and application thereof
  • Aryl thiourea and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Synthesis of Intermediate III

[0052] step 1:

[0053] In a 250mL three-neck flask, replace the air with nitrogen, and 2 Add 36mLSOCl under protection 2 , carefully drop into 1.2mL of dry DMF, control the temperature at 42°C, stir for 10min, then slowly add 12g of 2-pyridinecarboxylic acid (completely added within 30min), then raise the temperature to 72°C, stir for 16h, cool to room temperature, add 100mL of toluene , concentrated to 40mL under reduced pressure, then added 60mL of toluene and concentrated to 40mL, repeated the above process once, a small amount of red solid appeared, filtered with suction, washed the solid with 50mL of toluene, placed the filtrate in a 250mL flask, and slowly added 40mL of methanol in an ice-water bath , stirred for 10 minutes, removed the ice bath, stirred at room temperature for 45 minutes, then placed in an ice-water bath for 5 minutes, added 40 mL of diethyl ether, a white precipitate precipitated, filtered, washed the...

Embodiment 2

[0058] The synthesis of embodiment 2 intermediate II isothiocyanates

[0059] method 1:

[0060] Add 1.85g of p-methoxyaniline, 6.3mL of triethylamine and 20mL of toluene into a 100mL single-necked bottle, and add 2.7mL of CS dropwise within 20min while stirring at room temperature 2 After the addition, the reaction at room temperature was continued until a large amount of solid precipitated. Cool the above reaction solution under an ice-water bath, slowly add 15 mL of toluene solution containing 1.48 g of trimeric phosgene (BTC) dropwise, continue to react at room temperature for about 4 hours after the addition, filter, wash the filter residue twice with toluene, and distill the filtrate under reduced pressure to obtain The crude product was separated by silica gel column chromatography (pure PE) to obtain 1.86 g of colorless liquid II-1 with a yield of 75.1%. 1 HNMR (600MHz, CDCl3): δ3.79(s, 3H), 6.83-6.84(d, 2H), 7.13-7.15(d, 2H).

[0061] Method 2:

[0062] Add 0.89g ...

Embodiment 3

[0063] Example 3 Preparation of Compound 1

[0064]

[0065] In a 25mL single-necked bottle, 73mg of intermediate III was dissolved in 5mL of DMF, and 71mg of p-trifluoromethoxybenzene isothiocyanate dissolved in 5mL of DMF was added dropwise under cooling and stirring in an ice-water bath. After completion, extracted with ethyl acetate, washed with saturated brine, anhydrous Na 2 SO 4 After drying, it was separated by silica gel column chromatography (PE:EA=2:1 (v / v)) to obtain 76 mg of light gray powder with a yield of 52.8%. 1H NMR (600MHz, DMSO-d6): δ2.96-2.97(d, 3H), 7.01-7.02(m, 1H), 7.05-7.06(d, 2H), 7.18-7.19(d, 2H), 7.42- 7.45(t, 4H), 7.62(d, 1H), 8.11-8.12(br d, 1H), 8.39-8.40(d, 1H), 8.64(s, 1H), 8.70(s, 1H).

[0066] MS (ESI): 461.06 (M-H)

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Abstract

The invention discloses aryl thiourea and a preparation method and applications thereof. The aryl thiourea is a compound shown in the general formula I. The new compound-aryl substituted thiourea shows very high activity of inhibiting the growth of tumor cells and especially has significant effect of inhibiting the growth of HUVEC cells with high expression of VEGFR, wherein IC 50 is more than 70% in 10mu g / ml. The invention also provides a preparation method of the compound.

Description

technical field [0001] The present invention relates to a new compound of aryl thiourea, its synthesis and its use for inhibiting VEGFR-2, more specifically, it is a compound containing aryl thiourea as an efficient antineoplastic drug targeting VEGFR and its synthesis and use, which belongs to medicine field. Background technique [0002] Vascular Endothelial Growth Factor Receptor (VEGFR) tyrosine kinase is currently the most concerned target for anti-tumor drug design because of its key role in mediating tumor angiogenesis [Sebolt-Leopold, J.S.; English, J.M., Mechanisms of drug inhibition of signaling molecules. Nature 2006, 441, (7092), 457-62]. This growth factor receptor family has now discovered three regulatory transmembrane glycoprotein receptors [Neufeld, G.; Cohen, T.; Gengrinovitch, S.; Poltorak, Z., Vascular endothelial growth factor (VEGF) and its receptors. FASEB J1999, 13, (1), 9-22.]: VEGFR-1 (Fms-like Tyrosine Kinase, Flt-1), VEGFR-2 (Kinase Insert Domai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81C07D401/12A61K31/44A61K31/4439A61K31/444A61P43/00A61P35/00
Inventor 金毅姬建新李炎飞左承森
Owner CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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