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Spiro compound taking as indoleamine-2, 3-dioxygenase inhibitor

A compound, C3-C6 technology, applied to the active ingredients of heterocyclic compounds, drug combination, organic chemistry, etc.

Inactive Publication Date: 2019-08-23
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 1937, Kotake et al. purified the protein from rabbit intestines and discovered for the first time that TDO was mainly expressed in the liver of mammals. It has not been found that he is closely related to the immune system.

Method used

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  • Spiro compound taking as indoleamine-2, 3-dioxygenase inhibitor
  • Spiro compound taking as indoleamine-2, 3-dioxygenase inhibitor
  • Spiro compound taking as indoleamine-2, 3-dioxygenase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Example 1: N-(4-chlorophenyl)-6-(quinolin-4-yl)spiro[3.3]heptane-2-carboxamide (compound 1)

[0148]

[0149] The first step: (1-hydroxymethyl-3,3-dimethoxycyclobutyl)methanol

[0150]

[0151] Lithium aluminum hydride (28.81g, 759.7mmol) was added in batches to a three-necked flask containing tetrahydrofuran (1500mL), and then slowly added dropwise with isopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (99.57g, 345.3mmol) in tetrahydrofuran (500mL). Stirring at room temperature for 12h, TLC showed that the reaction was complete. Add saturated sodium potassium tartrate solution (27 mL) dropwise under ice-cooling to quench, and stir at room temperature for 1 h. After suction filtration, the filter cake was washed with dichloromethane / methanol (10:1, 200 mL×5), the organic phase filtrates were combined, and spin-dried to obtain a colorless and transparent oily product (59.8 g, yield 95%).

[0152] 1 H NMR (400MHz, CDCl 3 ): δ1.94(s,4H),3.12(s,6H),3.70(s,4H,)...

Embodiment 2

[0191] The preparation of embodiment 2 (±) (cis / trans) N-(4-chlorophenyl)-6-(quinolin-4-yl)spiro[2.5]octane-1-carboxamide

[0192]

[0193] The first step: ethyl 2-(1,4-dioxaspiro[4.5]dec-8-ylidene) ethyl acetate

[0194]

[0195] Under ice-cooling, dissolve sodium hydrogen (52mg, 0.88mmol) and triethyl phosphonoacetate (52mg, 0.83mmol) in 5mL of N,N-dimethylformamide, stir for half an hour, then add compound 1,4 -Dioxaspiro[4.5]dec-8-one (100 mg, 0.65 mmol) was dissolved in 2 mL of N,N-dimethylformamide and added dropwise to the reaction solution, and stirring was continued at room temperature for 1 hour. Quenched by adding 50mL, extracted with ethyl acetate (20mL x 3), combined organic layers, washed with brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and passed through a column (PE:EA=3:1) to obtain a white oil (128mg ,88%). 1 H NMR (400MHz, CDCl3): δ5.60(s,1H),4.05-4.11(m,2H),3.91-3.92(d,4H),2.95(t,3H),2.31(t,3H),1.67 -1.73(m,4H),1.19-1.23(m,3H)...

Embodiment 3

[0225] activity test

[0226] (1) Induced expression and purification method of IDO protein

[0227] First, the IDO gene was amplified by PCR, and the amplified PCR product was recovered, and then the pET28a plasmid (purchased from Shanghai Baoman Biotechnology Co., Ltd.) and the product recovered from IDO gel were digested with two restriction enzymes, EcoR I and Xho I. (37°C, enzyme digestion for 2h), gel run, recovery, T4 ligase linked overnight ligation product was added to DH5α competent, placed on ice for 30min, heat shock at 42°C for 90s, shake the plate, pick a single clone, PCR identification , Sequencing identification, all correct, that is, the pET28a-IDO plasmid was successfully constructed.

[0228] Shake the constructed BL21 containing the pET28a-IDO plasmid at 37°C to OD 600 0.6-0.8, add hemin (hemin) and 0.5mM IPTG (isopropyl-β-D-thiogalactoside) to a final concentration of 40 μM, induce at 16°C for 20h; after induction, at 4°C , 6000rpm centrifugation to coll...

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Abstract

The invention discloses a spiro compound taking as an indoleamine-2, 3-dioxygenase inhibitor, and a preparation method thereof. The structure of the inhibitor is represented by general formula I, wherein Ar, E, Y, X, C, D, W, B, ring A and ring B are defined in the patent specification and claims. The compound with the general formula I can be taken as an indoleamine-2, 3-dioxygenase inhibitor inpreparation of medicines used for preventing and / or treating indoleamine-2, 3-dioxygenase mediated diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an IDO inhibitor containing a spiro ring structure and a preparation method thereof. Background technique [0002] Indoleamine-2,3-dioxygenase (Indoleamine-2,3-dioxygenase, IDO) is a monomeric enzyme containing heme first discovered in cells by the Hayaishi group in 1967. The cDNA-encoded protein is composed of Composed of 403 amino acids, with a molecular weight of 45kDa, it is the rate-limiting enzyme for the catabolism of the tryptophan-kynurenine pathway, and is widely expressed in various mammalian tissues (Hayaishi O. et al Science, 1969, 164, 389-396). In the cells of tumor patients, IDO often plays an important physiological role in inducing immune tolerance in the tumor microenvironment, and its mediated tryptophan (Trp)-kynurenine (Kynurenine, Kyn) metabolic pathway participates in tumor Immune escape, and IDO also plays an important role in in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/12C07D215/18C07D405/04C07D401/04A61K31/47A61K31/4709A61P35/00A61P25/00A61P31/18A61P27/02A61P25/22A61P25/24A61P25/28A61P37/00
CPCC07D215/12C07D215/18C07D405/04C07D401/04A61P27/02A61P25/00A61P25/22A61P25/24A61P25/28A61P31/18A61P35/00A61P37/00C07D471/10C07D215/14A61K31/47A61K31/4709C07D401/08C07D401/12
Inventor 王召印郭巍柴永帅
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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