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N-alkyl tryptanthrin derivative, as well as preparation method and application thereof

A technology of alkyl and alkoxy groups, which is applied in the field of N-alkyl tryptanthrin derivatives and their preparation, and can solve problems such as insufficient development of tryptanthrin series compounds

Active Publication Date: 2014-02-12
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, domestic and foreign scholars have conducted some research on the pharmacology of tryptophan, and its effects are mainly manifested in antibacterial, anti-inflammatory, anti-tumor and anti-parasitic aspects. The results show that tryptophan is a very rare medicinal resources, has good potential for research and development of new drugs, but the development of tryptanthrin series compounds is insufficient, and further research and development of high-efficiency tryptanthrin derivatives with new structures is needed in this field

Method used

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  • N-alkyl tryptanthrin derivative, as well as preparation method and application thereof
  • N-alkyl tryptanthrin derivative, as well as preparation method and application thereof
  • N-alkyl tryptanthrin derivative, as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0062] The preparation method of the compound of formula I includes:

[0063]

[0064] (a) The compound of formula II undergoes an oxidation reaction to produce a compound of formula III;

[0065]

[0066] (b) The compound of formula III is reacted with fluoroisatin or isatin to produce compound of formula IV; and

[0067]

[0068] (c) The compound of formula IV undergoes substitution reaction to obtain the compound of formula I,

[0069] In each formula, R 1 , R 2 Independently selected from H, Br or I, and R 1 , R 2 Not at the same time as H;

[0070] T 1 , T 2 The definition of Z is as mentioned above.

[0071] Generally, in step a), the compound of formula II is oxidized in an organic solvent in the presence of an oxidizing agent at 20°C to 30°C for 2 to 3 hours to obtain a compound of formula III. The organic solvent is preferably selected from dichloromethane, tetrahydrofuran, methanol, ethanol, 1,4-dioxane, toluene, acetonitrile, isopropanol, n-propanol, acetic acid; the oxidizin...

Embodiment 1

[0086]

[0087] Compound 1 ((500mg, 2.2mmol) was suspended in 10ml of dry dichloromethane, and m-chloroperoxybenzoic acid (0.76g, 4.4mmol, 85%) was added in batches at zero degrees Celsius. Stir at room temperature for 2 Hours later. TLC(CH 2 Cl 2 / MeOH=50 / 1, Rf0.4) After the completion of the reaction was detected, the white solid formed by the reaction was filtered, and then washed with 10 ml of ethyl acetate three times to obtain compound 2 (420 mg, 79%).

[0088]

[0089] A mixture of compound 2 (3g, 12.4mmol), 5-fluoroisatin (2g, 12.4mmol) and triethylamine (3.6ml, 24.8mmol) was suspended in dry toluene (12ml) and heated at 110°C for 4 After hours, the solvent was distilled off under reduced pressure. The yellow solid was dissolved in 2 ml of dichloromethane, and then 2 ml of ethyl acetate was added. The yellow solid formed was filtered and used with 2 ml of ethyl acetate. After washing three times, the obtained yellow solid is compound 3 (1.9 g, 44%).

[0090] 1 H NMR(400MHz...

Embodiment 2

[0098]

[0099] Under nitrogen protection, compound 3 (100mg, 0.29mmol), N-Methylpiperazine (N-methylpiperazine, 58mg, 0.58mmol), Pd(OAc) 2 (Palladium acetate, 20mg, 0.087mmol), BINAP ((±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 84mg, 0.14mmol) and Cs 2 CO 3 (189mg, 0.58mmol) was suspended in anhydrous toluene (5ml) and heated at 110°C for 16 hours. TLC(CH 2 Cl 2 / MeOH=15 / 1, Rf0.4) indicates that the reaction is complete. After the solvent is evaporated under reduced pressure, 20 ml of dichloromethane is added to the resulting black solid, washed with water and brine, and dried. The black solid obtained after concentration is used Silica gel column (CH 2 Cl 2 / MeOH=15 / 1) separated to obtain compound 6 as a red solid.

[0100] 1 H NMR(400MHz, CDCl 3 )δ8.64(dd,J=8.8,4.1Hz,1H),7.90(d,J=9.1Hz,1H),7.76(d,J=2.9Hz,1H),7.57(dd,J=6.6,2.7 Hz,1H),7.47(td,J=8.7,2.7Hz,1H),7.39(dd,J=9.1,3.0Hz,1H),3.57-3.43(m,4H),2.69-2.57(m,4H) , 2.40(s,3H).

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Abstract

The invention discloses an N-alkyl tryptanthrin derivative, as well as a preparation method and an application thereof. The structure of the N-alkyl tryptanthrin derivative is as shown in a formula I, wherein T1, T2 and Z are as defined in description and claims. The N-alkyl tryptanthrin derivative disclosed by the invention can be used as a high-activity IDO (indoleamine 2, 3-dioxygenase) inhibitor, and can be used for preparing medicaments for preventing and / or treating diseases with pathological characteristics of IDO-mediated tryptophan metabolic ways.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an N-alkyltryptamine derivative, and a preparation method and application thereof. Background technique [0002] Indoleamine2,3-dioxygenase (IDO) is an enzyme that contains heme in the cell. It is the only enzyme outside the liver that can catalyze the metabolism of tryptophan to make it along with kynurenine. The pathway breaks down to generate a series of rate-limiting enzymes including quinolinic acid (MacKenzie et al. Current Drug Metabolism, 2007, 8:237-244.). Since the 1990s, indoleamine 2,3-dioxygenase and its kynurenine pathway (KP), which catalyzes the metabolism of tryptophan, have played an important role in various diseases. Increasingly arouse people's attention. [0003] Indoleamine 2,3-dioxygenase IDO catalyzes the oxidation reaction of the essential amino acid-amino acid to N-formylkynurenine through hydrogen peroxide, and is responsible for cleaning up tryptophan in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P35/00A61P27/12A61P25/24A61P25/22A61P31/18A61P37/00A61P25/28A61P25/18
CPCC07D487/04A61P25/18A61P25/22A61P25/24A61P25/28A61P27/12A61P31/18A61P35/00A61P37/00
Inventor 李函璞匡春香李健之
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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