Oxadiazole-contained cyclic compound, preparation method, intermediates, compositions and application thereof

A technology containing an oxadiazole ring and a compound is applied in the fields of drug combination, compounds containing elements of Group 3/13 of the periodic table, chemical instruments and methods, and can solve the problems of IDO inhibitor activity and unsatisfactory pharmacokinetic properties.

Active Publication Date: 2018-04-24
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is that the existing IDO inhibitor activity and pharmacokinetic properties are not ideal, for this reason, the present invention provides a kind of oxadiazole-containing Cyclic compound, preparation method, intermediate, composition and application, the compound has high inhibitory activ

Method used

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  • Oxadiazole-contained cyclic compound, preparation method, intermediates, compositions and application thereof
  • Oxadiazole-contained cyclic compound, preparation method, intermediates, compositions and application thereof
  • Oxadiazole-contained cyclic compound, preparation method, intermediates, compositions and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0555]

[0556] first step:

[0557] Malononitrile (compound shown in formula 1-a) was dissolved in water (280mL), heated to 45°C, added sodium nitrite (15.2g, 220mmol), and stirred until the solution was clear. Cool the solution to 0°C, add concentrated hydrochloric acid (13.2mL), stir in the ice bath for 5 minutes, remove the ice bath and stir for 1.5 hours, add 50% aqueous hydroxylamine solution (19.8g, 599 mmol) at 0°C, and warm to room temperature And stirred for 1 hour, heated to reflux and stirred for 24 hours. The reaction solution was cooled to room temperature, and a white solid was precipitated, which was filtered to obtain the compound 4-aminoethyl-N'-hydroxyl-1,2,5-oxadiazole-3-carboxamidine (25g) shown in 1-b, a white solid . 1 H NMR (400MHz, DMSO) δ 10.46 (s, 1H), 6.27 (s, 2H), 6.18 (s, 2H). LC-MS: m / z: (M+H)+=144.0.

[0558] Step two:

[0559] 4-aminoethyl-N'-hydroxyl-1,2,5-oxadiazole-3-carboxamidine (25g, 174.7mmol) (compound as shown in formula 1-b) is...

preparation example 2

[0569]

[0570] first step:

[0571]The compound (2.6g, 16mmol) shown as formula 1-c was dissolved in dry dichloromethane (40mL), under ice-cooling, 2-methylthio-1-ethylamine (1.6g, 17.6mmol) was added In the reaction solution, after stirring for ten minutes, triethylamine (2.424 g, 24 mmol) was added and reacted for 1 hour. After the reaction was completed, dichloromethane was distilled off under reduced pressure, ethyl acetate was added, the organic phase was washed once with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure to obtain the formula 2-a The compound 4-amino-N'-hydroxy-N-(2-methylthioethyl)-1,2,5-oxadiazole-3-carboxamidine (3.128g) was yellow oil. 1H NMR(400MHz,CD3Cl)δ6.75(s,1H),5.74(s,1H),5.16(s,2H),3.84(q,2H),2.72(t,2H),2.12(s,3H) .

[0572] Step two:

[0573] The compound represented by Formula 2-a (1 g, 4.6 mmol) was added to 15 mL of water, ...

preparation example 3

[0584]

[0585] first step:

[0586] The method is the same as that described in the first step of Preparation Example 2. Using 1-c as the starting substrate, the compound 4-amino-N'-hydroxyl-N-(2-methoxyethyl)-1,2,5-oxadiazole- 3-Formamidine (6.6g), yellow oil. 1H NMR (400MHz, DMSO) δ10.67(s,1H),6.28(s,2H),6.14(t,J=6.4Hz,1H),3.54(dd,J=12.0,5.9Hz,2H),3.38 (t, J=5.7Hz, 2H), 3.22(s, 3H).LC-MS: m / z: (M+H)+=202.0.

[0587] Step two:

[0588] The method is described in the second step of Preparation Example 2. Using 3-a as the starting material, the compound N'-hydroxyl-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3- Formamidine (6.06g), yellow oil. 1H NMR (400 MHz, DMSO) δ10.54(s, 1H), 6.23(s, 2H), 6.16(t, J=5.8Hz, 1H), 3.52(t, J=5.3Hz, 2H), 3.39( dd, J=11.0, 5.4Hz, 2H), 3.29(s, 3H). LC-MS: m / z: (M+H)+=202.0.

[0589] third step:

[0590] The method is described in the third step of Preparation Example 2. Using 3-b as the starting material, the compound N-hydroxyl-4-((2...

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Abstract

The invention discloses an oxadiazole-contained cyclic compound, a preparation method, intermediates, compositions and application thereof. The medically acceptable salts, the enantiomer, the diastereoisomer, the tautomer, the solvate, the metabolite or the prodrug of the dthe oxadiazole-contained cyclic compound shown as the formula I is high in inhibitory activity on IDO (dioxygenase) at a molecular level and a cellular level and significant in proliferation inhibition effects on cancer cells related to IDO activity at an animal level and good in liver microsome stability of human, mouse andthe like, has no significant inhibition over metabolic enzymes and achieves good absorption properties and high bioavailability in rats and mice as well as good druggability.

Description

technical field [0001] The invention relates to a compound containing an oxadiazole ring, a preparation method, an intermediate, a composition and an application. Background technique [0002] The human immune system is not only responsible for defending against microbial invasion, but also clearing the changed host components from the body. There is an anti-tumor immune mechanism in the body. When the immune surveillance function is weakened due to the immune system itself or tumor cells, it provides favorable conditions for the occurrence of tumors. The combination of the defects of the patient's tumor cells and the dysfunction of the immune system promotes the crazy growth of the tumor. If the killing weapons in the body can be mobilized, it will be the most effective and safest way to treat tumors. T cells play a central role in the process of immunotherapy for tumors. Studies have shown that the G1 phase of the T cell cycle depends on the concentration of tryptophan. ...

Claims

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Application Information

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IPC IPC(8): C07D413/06C07D271/08C07F7/10C07D413/12C07F5/02C07C391/00C07F9/653A61K31/4245A61K31/695A61K31/675A61K31/541A61K31/454A61K31/4439A61K31/69A61P35/00A61P35/02C07D413/04C07D317/30
CPCC07C391/00C07D271/08C07D317/30C07D413/04C07D413/06C07D413/12C07F5/025C07F7/10C07F9/65318A61K31/4245A61K31/4439A61K31/454A61K31/541A61K31/675A61K31/69A61K31/695A61P25/28A61P27/02A61P35/00A61P35/02C07F5/02C07F9/653Y02P20/54Y02P20/55
Inventor 王倩夏广新石辰张霖舒思杰张冰宾周佳玲陈娜张乐多毛煜刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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