Carbamidine derivative

A technology of amino and compound, applied in the field of imide urea derivatives and its preparation, can solve the problems of unsatisfactory clinical curative effect

Active Publication Date: 2018-11-13
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although great progress has been made in the treatment of tumors in recent years, the clinical efficacy is still unsatisfactory.

Method used

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  • Carbamidine derivative
  • Carbamidine derivative
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13047

[0065] The synthesis of embodiment 1 3047

[0066] Response 1

[0067]

[0068] Compound 1a (682 mg, 2 mmol) was dissolved in trifluoroacetic acid (13 mL), and then 30% H 2 o 2 , reacted overnight at 50°C, the reaction solution changed from turbid to a clear yellow solution, after the reaction was completed, it was quenched with saturated sodium sulfite solution, and after the KI starch test paper showed colorless, it was extracted with ethyl acetate (50mL*2), and the organic phase was extracted with Dry over anhydrous sodium sulfate, concentrate and column chromatography (petroleum ether→petroleum ether: ethyl acetate = 1 ether: ethyl: 1) to obtain light yellow solid 2a (500 mg, yield 67%).

[0069] response 2

[0070]

[0071] Ethylenediamine 1 (30mg, 0.5mmol) was added to a solution of compound 2a (170mg, 0.5mmol) in tetrahydrofuran (10mL), then 1N NaOH (0.4mL) was added, the reaction solution was stirred at room temperature for 0.5h, and the reaction solution was ...

Embodiment 23048

[0078] The synthesis of embodiment 2 3048

[0079] Response 1

[0080]

[0081] Propylenediamine (35mg, 0.5mmol) was added to compound 1 (170mg, 0.5mmol, the synthesis method is detailed in the synthesis of compound 2a in XSD3-047Final report) in tetrahydrofuran (10mL) solution, the reaction solution was stirred at room temperature for 0.5h, and the reaction The liquid was directly prepared to obtain 130 mg of the target product.

[0082] response 2

[0083]

[0084] Compound 2 (130mg, 0.33mmol) and compound 1a (100mg, 0.33mmol) in methanol (10mL) were stirred overnight at room temperature, the reaction solution was concentrated and then column chromatographed (petroleum ether → petroleum ether: ethyl acetate = 1 ether: ethyl ether) : 1) The target product 3 (78 mg, 45%) was obtained.

[0085] Response 3

[0086]

[0087] Trifluoroacetic acid (0.6 mL) was added to a solution of compound 3 (31 mg, 0.05 mmol) in dichloromethane (3 mL), stirred overnight at room temp...

Embodiment 33049

[0088] The synthesis of embodiment 3 3049

[0089]Response 1

[0090]

[0091] Compound 1 (384mg, 1mmol, see the final report of XSD3-047 for the preparation method) and compound 1 (100mg, 1.1mmol) in tetrahydrofuran (10mL) were stirred at room temperature for 48h, and the reaction solution was directly prepared to obtain the target product 2 (89mg, Yield 20%).

[0092] response 2

[0093]

[0094] The compound (89mg, 0.2mmol) was dissolved in THF (10mL), then adjusted to pH=12 with 1N NaOH solution, and continued to stir for 20min. The reaction was monitored by LCMS. After the reaction was completed, the reaction solution was adjusted to neutral with 0.5N HCl. After the reaction solution was concentrated, the target product (13 mg, yield 15%) was prepared by pre-HPLC. target compound 1 H-NMR (400MHz, DMSO-d6): δ(ppm): 11.47(s, 0.6H), 8.92(s, 1H), 7.50-7.09(m, 5H), 6.70(s, 1H), 6.28(s , 1H), 2.72-2.50 (m, 4H), 2.50 (m, 3H). MS: m / z 416.2 [M+1].

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Abstract

The invention relates to the field of drugs, in particular to a carbamidine derivative containing a furan structure and a composition of the carbamidine derivative. The derivative and the compositionthereof can be used for preparing drugs for treating a pathologic characteristic disease with an indoleamine 2,3-dioxygenase mediated tryptophan metabolic pathway. The invention further relates to a method for preparing the derivative and an intermediate thereof.

Description

technical field [0001] The invention relates to the field of medicines, in particular to imide urea derivatives and their preparation methods and uses. Background technique [0002] Indoleamine 2,3-dioxygenase is a monomeric enzyme containing heme, which can catalyze the indole epoxidation and cleavage of L-tryptophan to generate kynurenine. High expression of indoleamine 2,3-dioxygenase leads to local depletion of tryptophan in cells, induces T cell arrest in G1 phase, and thus inhibits T cell proliferation. On the other hand, indoleamine 2,3-dioxygenase-dependent tryptophan degradation leads to increased kynurenine levels and also induces oxygen free radical-mediated T cell apoptosis. Third, upregulating the expression of indoleamine 2,3-dioxygenase in dendritic cells strengthens local regulatory T cell (Treg)-mediated immunosuppression by degrading local tryptophan, prompting the body to respond to tumor-specific antigens peripheral immune tolerance. Indoleamine 2,3-di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61K31/4245A61P35/00A61P25/28A61P25/24A61P25/22A61P27/12A61P31/04A61P31/10A61P31/12A61P33/00
CPCC07D271/08A61P25/28A61P35/00A61P27/12A61P25/22A61P25/24A61P31/04A61P31/10A61P31/12A61P33/00A61K31/4245A61P27/02A61P31/00A61P35/04
Inventor 张贵民姚景春任玉珊
Owner LUNAN PHARMA GROUP CORPORATION
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