Efficient IDO/TDO double inhibitor containing nitrogen heterocyclic helix structure

A cycloalkyl and heteroaryl technology, applied in the field of high-efficiency IDO/TDO inhibitors and its preparation, can solve problems such as cell dysfunction

Inactive Publication Date: 2018-05-11
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Therefore, its deficiency can lead to

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  • Efficient IDO/TDO double inhibitor containing nitrogen heterocyclic helix structure
  • Efficient IDO/TDO double inhibitor containing nitrogen heterocyclic helix structure
  • Efficient IDO/TDO double inhibitor containing nitrogen heterocyclic helix structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0253] Preparation of (cis / trans) 3-phenylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol

[0254]

[0255] The first step: (cis / trans) 1-(2-bromophenyl)-3-hydroxycyclobutanenitrile

[0256]

[0257] Add the compound 2-bromobenzylcyanide (10.2g, 52.0mmol) into the reaction flask, cool to minus 78 degrees, add methyllithium (44mL, 52.0mmol) dropwise, after the dropwise addition, stir at this temperature for 1 hour, add Epichlorohydrin (5.3g, 57.2mmol), stirred at this temperature for 3 hours, TLC detected that the raw material disappeared, then added dropwise methylmagnesium bromide Grignard reagent (19ml, 57.2mmol), after the dropwise addition, naturally returned to room temperature , and then slowly warming up to 60 degrees, stirring overnight. TLC monitors that the reaction is complete. Under cooling in an ice bath, 2N hydrochloric acid solution was added dropwise, and the pH of the reaction system was adjusted to about 7. Ethyl acetate (150 mL) and water (150 ...

Embodiment 2

[0294] (cis / trans)(3-fluorophenyl)(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)methanol

[0295]

[0296] Step 1: (cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl methanesulfonate

[0297]

[0298] (cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol (212mg, 1.0mmol) was dissolved in 5mL of dichloromethane, triethylamine ( 202mg, 2.0mmol), methanesulfonyl chloride (216mg, 1.5mmol) was added dropwise, after the dropwise completion, it was naturally returned to room temperature, and reacted for 1 hour in total. Add saturated brine 10mL, respectively add dichloromethane 2x 20mL for extraction, combine the organic phases to obtain the target compound (300mg, yield 100%).

[0299] MS ESI: m / z=291.0, [M+H] + .

[0300] The second step: spiro[cyclobutane 1,5'-imidazo[5,1-α]is indole]-3-carbonitrile

[0301]

[0302] The product of the first step (300mg, 1.0mmol) was dissolved in 10mL of DMF, sodium cyanide (150mg, 3.0mmol) was added, heated to 100°C...

Embodiment 3

[0324] (cis / trans) 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoind Indole]-3-ol

[0325]

[0326] According to the conditions in the eighth step of Example 1, the target compound was obtained as a white solid (10 mg, Yield 29%).

[0327] 1 H NMR (400MHz, CDCl 3 ):δ8.35(s,1H),7.42-7.41(m,1H),7.37-7.35(m,1H),7.34-7.31(m,1H),7.27-7.25(m,1H),7.18(s ,1H),5.75(s,1H),3.86(s,4H),3.15(d,2H),2.64(d,2H),2.40-2.36(m,4H),1.83-1.80(m,2H).

[0328] MS ESI: m / z=351.2, [M+H] + .

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Abstract

The present invention discloses an efficient IDO/TDO double inhibitor containing a nitrogen heterocyclic helix structure, and in particular, relates to a compound of formula (I) or pharmaceutically acceptable salt, stereoisomers, or tautomers, or prodrugs thereof. The compound of the formula (I) can be used as an indoleamine-2,3-dioxygenase inhibitor and tryptophan-2,3-dioxygenase for preparationof drugs for prevention and/or treatment of indoleamine-2,3-dioxygenase and tryptophan-2,3-dioxygenase-mediated diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a high-efficiency IDO / TDO inhibitor containing nitrogen heterocyclic helical 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 ID...

Claims

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Application Information

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IPC IPC(8): C07D487/10A61K31/4192A61K31/4188A61K31/4439A61P35/00
CPCC07B2200/07C07D487/10A61K31/4188A61K31/4192A61K31/4439A61P35/00
Inventor 王召印郭巍朱继东胡新波
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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