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Compound capable of inhibiting IDO (indoleamine 2, 3-dioxyenase), and preparation method and application of compound

A technology for compounds and uses, applied in the field of medicine, can solve the problem of not finding a good IDO inhibitor, and achieve the effect of strong inhibitory activity and good application prospects

Active Publication Date: 2017-07-21
SHANGHAI JOYU PHARMATECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] IDO inhibitors as drugs have good application prospects in the pharmaceutical industry, but currently no good IDO inhibitors have been found as marketed drugs. In order to achieve better cancer treatment effects and better meet market demand, we hope to develop A new generation of selective IDO inhibitor with high efficiency and low toxicity

Method used

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  • Compound capable of inhibiting IDO (indoleamine 2, 3-dioxyenase), and preparation method and application of compound
  • Compound capable of inhibiting IDO (indoleamine 2, 3-dioxyenase), and preparation method and application of compound
  • Compound capable of inhibiting IDO (indoleamine 2, 3-dioxyenase), and preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0031] The method for preparing the compound represented by general formula (I) or its salt of the present invention includes the following steps:

[0032]

[0033] Under acidic conditions, compounds of general formula (Ia) are oxidized to compounds of general formula (Ib); compounds of general formula (Ib) react with compounds of general formula (Ic) under basic conditions to obtain compounds of general formula (Id); The compound of formula (Id) forms a ring under heating and basic conditions. The base under this condition is preferably N,N'-carbonyldiimidazole to obtain the compound of general formula (Ie); the compound of general formula (Ie) after ring formation is acidic Under conditions, the protective group on the amino group is removed to obtain the compound of general formula (If) or its salt; the basic solution of the compound of general formula (If) or its salt is reacted with the alcohol solution of chlorosulfonyl isocyanate at low temperature to obtain the general for...

Embodiment 1

[0046] trans-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-((sulfamoylamino)methyl)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide, the compound The preparation of 1, wherein the structural formula of compound 1 is as follows:

[0047]

[0048] The first step is to prepare compound lb:

[0049] The raw material compound la (500 mg, 1.46 mmol, prepared by referring to the method disclosed in P53 Example3 step A in the patent application "WO2010005958") was added to 7 mL of trifluoroacetic acid, and then 6 mL of hydrogen peroxide (30%) was added, and reacted at 45°C for 20 hours . After the reaction, the reaction was quenched by adding saturated sodium sulfite solution, extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B Compound lb (410 mg, yellow oil) was obtained with a y...

Embodiment 2

[0065] trans-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(2-(sulfamoylamino)ethyl)cyclohexyl)amino)-1,2,5-oxadiazole-3-carboximidamide, That is, the preparation of compound 2, wherein the structural formula of compound 2 is as follows:

[0066]

[0067] Using the synthesis method of Example 1, the second step raw material compound 1c was replaced with (Commercially available), compound 2 (73 mg, white solid) was prepared with a yield of 45%. MS m / z(ESI): 521.4[M+1] + , 1 HNMR (400MHz, DMSO-d6) δ 11.52 (s, 1H), 8.87 (s, 1H), 7.09-7.27 (m, 3H), 6.76-6.79 (m, 1H), 6.67 (s, 2H), 6.21 (t,1H),2.41(m,1H),1.20-1.83(m,11H),3.55(d,2H).

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Abstract

The invention discloses a compound capable of inhibiting IDO (indoleamine 2, 3-dioxyenase), and a preparation method and application of the compound. The structural general formula is shown as below; - is selected from a mixture of a cis-isomer, a trans-isomer or a cis-trans-isomer; R1 and R2 are independently selected from any one of hydrogen atoms, halogen, alkyl, alkoxy or halogenated alkyl; R3 is selected from any one of cyclopentyl, cyclohexyl, piperazinyl or piperidyl; the substitution position of the R3 is (1, 2), (1, 3) or (1, 4); m and n are selected from integers of 0-5 respectively. The compound capable of inhibiting the IDO has high inhibition activity on the IDO, can be used for preparing IDO inhibitors to prevent and / or treat diseases with pathological features of tryptophan metabolic pathways mediated by the IDO, and has quite good application prospect.

Description

Technical field [0001] The invention belongs to the field of medicine, and relates to a compound capable of inhibiting IDO, its preparation method and its application in medicine, for the treatment of diseases with the pathological characteristics of IDO-mediated tryptophan metabolism pathway, and the diseases include Cancer, Alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, psychological disorders, AIDS, etc. Background technique [0002] Cancer is one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The incidence of cancer in my country is generally on the rise. The incidence is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people in my country will have cancer and 3 million will die from cancer. The main reason is: old age Changes in urbanization, urbanization, industrialization and living habits. In the Chinese hospital drug market, the sales...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61K31/4245A61P35/00A61P35/02A61P37/02A61P25/28A61P25/22A61P25/24A61P25/00A61P31/18A61P27/12
CPCC07D271/08C07D271/04
Inventor 钟燕曹西蓉王永临
Owner SHANGHAI JOYU PHARMATECH LTD
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