CN105037371A - Deuterated indoleamine-2,3-dioxygenase inhibitor - Google Patents

Deuterated indoleamine-2,3-dioxygenase inhibitor Download PDF

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CN105037371A
CN105037371A CN201510375004.2A CN201510375004A CN105037371A CN 105037371 A CN105037371 A CN 105037371A CN 201510375004 A CN201510375004 A CN 201510375004A CN 105037371 A CN105037371 A CN 105037371A
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compound
reaction solution
deuterated
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dioxygenase inhibitor
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钱珊
刘为峰
陈泉龙
何彦颖
张曼
王伟
杨羚羚
王周玉
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Xihua University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

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Abstract

The invention discloses a deuterated indoleamine-2,3-dioxygenase inhibitor, and the structure of the deuterated indoleamine-2,3-dioxygenase inhibitor is shown as the formula I in the description, wherein the R1 to R9 are respectively or simultaneously selected from hydrogen, C1 to C6 alkyl groups or C1 to C6 alkoxy groups. The deuterated compound, shown as the formula I, of the invention, has good IDO inhibitory activity, meanwhile, the metabolic stability of medicine is obviously improved, the medicine efficacy can be enabled to play for a long time, and the administration frequency and/or the dosage are reduced, thus the efficacy of clinical application of the medicine is improved. In the meanwhile, a preparation method of the deuterated indoleamine-2,3-dioxygenase inhibitor has the advantages of high yield, high purity, low energy consumption, few steps, easy and simple operation, low cost, environmental friendliness, safety and the like, and is very suitable for being applied in industries.

Description

A kind of deuterated indoles amine-2,3-dioxygenase inhibitor
Technical field
The present invention relates to a kind of deuterated indoles amine-2,3-dioxygenase inhibitor.
Background technology
IDO (Indoleamine2,3-dioxygenase, IDO) is indole ring oxicracking in the sour indoles amine molecules such as catalysis look ammonia, makes it by the catabolic rate-limiting enzyme of kynuric acid approach.IDO is in vivo in low expression level under normal circumstances.Most of tumour cell then can the high expression level IDO of composition, L-Trp is converted into N-formylkynurenine, reduce the Tryptophan concentration in cell micro-environment, the T cell synthesis that tryptophane is relied on is stagnated in the G1 phase, T cell propagation is suppressed, thus inhibits body immune system to the lethal effect of tumor tissues.Meanwhile, there is cytotoxicity in the meta-bolites of the lower tryptophane of IDO effect, can produce direct solvency action to T cell.Therefore, IDO exempts in tumour immunity and plays an important role in tumour generating process.
Suppress the activity of IDO effectively can stop the degraded of near tumor cells tryptophane, promote the propagation of T cell, thus enhancing body is to the attacking ability of tumour cell.The research and development of IDO inhibitor have become the hot fields of tumour immunotherapy.IDO inhibitor can also be share with chemotherapeutics, reduces the resistance of tumour cell, thus strengthens the anti-tumor activity of conventional cytotoxic therapy.Take the curative effect that IDO inhibitor also can improve the therapeutic vaccine of cancer patient simultaneously.
Except playing an important role in tumor cell drug resistance, IDO is also closely related to the multiple pathogenesis activating relevant disease with cellular immunization.IDO has been proved to be the target activating the major diseases such as relevant infection, malignant tumour, autoimmune disorder, acquired immune deficiency syndrome (AIDS) to cellular immunization.In addition, suppress IDO still for suffering from nervous system disorders as dysthymia disorders, the critical treatment strategy of the patient of alzheimer's disease.
The NLG919 developed by Newlink Genetics Corp. is the double inhibitor (WO2014159248A1) of a kind of IDO and tryptophane 2,3-dioxygenase (TDO), is just carrying out I phase clinical experiment at present.NLG919 all effectively can suppress the activity of IDO in vivo and in vitro, and mouse interior tumor cell volume can be caused to reduce 95%.But the major defect of NLG919 is that its metabolic stability is low, the time that medicine plays drug effect is shorter, and this improves dosage rate by needing and/or increases drug dose to ensure the drug effect of Clinical practice, inevitably increases the economical load of patient medication.
Therefore, high and indoles amine-2, the 3-dioxygenase inhibitor that metabolic stability is high of a kind of activity is needed to invent.
Summary of the invention
The object of the present invention is to provide a kind of deuterated indoles amine-2,3-dioxygenase inhibitor.
A kind of deuterated indoles amine-2,3-dioxygenase inhibitor provided by the invention, the structure of described indoles amine-2,3-dioxygenase inhibitor is such as formula shown in I:
Wherein, R 1~ R 9be selected from hydrogen, C respectively or simultaneously 1~ C 6alkyl or C 1~ C 6alkoxyl group.
Further, R 1~ R 9be hydrogen simultaneously.
Present invention also offers a kind of preparation method of deuterated indoles amine-2,3-dioxygenase inhibitor, the synthetic route of described preparation method is:
Wherein, R 1~ R 9be selected from hydrogen, C respectively or simultaneously 1~ C 6alkyl or C 1~ C 6alkoxyl group;
Described preparation method comprises the following steps:
A, compound 1, compound 2 with sodium hydride, react 6 hours ~ 18 hours in stirred at ambient temperature, obtain reaction solution in ether solvent; Reaction solution is separated, purifying, obtain compound 3;
Described compound 1, compound 2 are 1:1 ~ 3:1 ~ 5 with the mol ratio of sodium hydride; Described compound 1 is 1:5 ~ 15mmol/ml with the molecular volume ratio of ether solvent;
B, compound 3 and acetic acid, methanol mixed that step a is obtained, at 80 DEG C ~ 100 DEG C, stirring reaction 1 hour ~ 5 hours, obtains reaction solution; Reaction solution is separated, purifying, obtain compound 4;
Described compound 3 is 1:1 ~ 3mmol/ml with the molecular volume ratio of acetic acid; Described compound 3 is 1:5 ~ 10mmol/ml with the molecular volume ratio of methyl alcohol;
In organic solvent, at 0 DEG C ~ 40 DEG C, stirring reaction 0.5 hour ~ 5 hours, obtains reaction solution for the compound 4 that c, step b obtain and deuterated reagent; Reaction solution is separated, purifying, obtain compound 5, be deuterated indoles amine-2,3-dioxygenase inhibitor;
Described compound 4 is 1:1 ~ 5 with the mol ratio of deuterated reagent; Described compound 4 is 1:5 ~ 20mmol/ml with the molecular volume ratio of organic solvent.
Further,
In step a, described ether solvent is selected from any one or two kinds in tetrahydrofuran (THF), ether;
In step c, described deuterated reagent is selected from NaBD 4, LiAlD 4in any one or two kinds; Described organic solvent be selected from methyl alcohol, tetrahydrofuran (THF), ether any one or two or more.
Further, in step a, 12 hours ~ 18 hours time of stirring reaction.
Further,
In step a, described compound 1, compound 2 are 1:1.5 ~ 3:2 ~ 5 with the mol ratio of sodium hydride; Described compound 1 is 1:10 ~ 15mmol/ml with the molecular volume ratio of ether solvent;
In step b, described compound 3 is 1:2 ~ 3mmol/ml with the molecular volume ratio of acetic acid; Described compound 3 is 1:6 ~ 10mmol/ml with the molecular volume ratio of methyl alcohol;
In step c, described compound 4 is 1:2 ~ 3 with the mol ratio of deuterated reagent; Described compound 4 is 1:8 ~ 16mmol/ml with the molecular volume ratio of organic solvent.
Further,
In step a, reaction solution is separated, the step of purifying is: the solvent in removing reaction solution, obtains residue; Residue, with after saturated aqueous ammonium chloride dilution, with dichloromethane extraction, gets organic phase, and washing is dry, concentrated, obtains compound 3;
In step b, reaction solution is separated, the step of purifying is: cooled by reaction solution, the solvent in removing reaction solution, obtains residue; Residue is dissolved in ethyl acetate, and through unsaturated carbonate aqueous solutions of potassium, saturated common salt water washing, dry, concentrated, column chromatography purification, obtains compound 4;
In step c, reaction solution is separated, the step of purifying is: the solvent in removing reaction solution, obtains residue; Residue is dissolved in 2mol/L hydrochloric acid soln, stirs, after adding unsaturated carbonate aqueous solutions of potassium adjustment pH=6.5 ~ 7.5, with dichloromethane extraction, get organic phase, washing, dry, concentrated, column chromatography purification, obtains compound 5.
Compound shown in formula I is preparing the application in indoles amine-2,3-dioxygenase inhibitor class medicine.
Further, described indoles amine-2,3-dioxygenase inhibitor class medicine is treat and/or prevent the medicine that cellular immunization activates relevant infection, malignant tumour, autoimmune disorder, acquired immune deficiency syndrome (AIDS).
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition be with compound shown in formula I or its crystal formation, pharmacy acceptable salt, hydrate or solvate for activeconstituents, add the preparation that pharmaceutically conventional auxiliary material or complementary composition prepare.
Compound shown in the formula I that the present invention is deuterated, while there is good IDO inhibit activities, significantly improve the metabolic stability of medicine, medicine not only can be made to play drug effect for a long time, also reduce dosage rate and/or drug dose, improve the drug effect that clinical drug uses; Meanwhile, preparation method of the present invention, has the advantages such as yield is high, purity is high, energy consumption is low, step is few, easy and simple to handle, cost is low, environmental protection, safety, is applicable to very much the application in industry.
Obviously, according to foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, not departing under the present invention's above-mentioned basic fundamental thought prerequisite, the amendment of other various ways, replacement or change can also be made.
The embodiment of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
The raw material used in the specific embodiment of the invention, equipment are known product, obtain by buying commercially available prod.
Compound 1, compound 2 can be that method in 201280018684.7 prepares with reference to application number, also can obtain by buying commercially available prod.
Embodiment 1
Synthetic route:
1. the synthesis of compound 3
The 3mLTHF solution of compound 2 (1.5mmol) is joined in the 5mLTHF suspension of NaH (2.0mmol) in 0 DEG C, stir 30 minutes at 0 DEG C, again the 3mLTHF dropwise of compound 1 (1mmol) is joined in above-mentioned reaction solution, stirring at room temperature 12 hours, decompression revolves desolventizing, the saturated NH of residue 4after the dilution of the Cl aqueous solution, through CH 2cl 2extract 3 times, organic layer through saturated common salt water washing, Na 2sO 4drying, concentrates and obtains raw product 3.
2. the synthesis of compound 4
Be dissolved in 2mL Glacial acetic acid and 6mL methyl alcohol by above-mentioned raw product 3 (1mmol), stir 2 hours at 90 DEG C, reaction solution is cooled to room temperature, revolves desolventizing, and residue is dissolved in EtOAc, through saturated K 2cO 3, saturated common salt water washing, Na 2sO 4drying, concentrates and obtains raw product, obtain faint yellow solid 4 through column chromatography purification.
3. the synthesis of compound 5
By NaBD 4(0.75mmol) join in the 2mL methanol solution of compound 4 (0.25mmol) in 0 DEG C, 0 DEG C is stirred after 1 hour, revolves desolventizing, be dissolved in by residue in 2mol/L hydrochloric acid soln (2mL), stirring at room temperature 10 minutes, adds saturated K 2cO 3solution regulates pH to be 7, reaction solution CH 2cl 2extract 3 times, merge organic layer, organic layer through saturated common salt water washing, Na 2sO 4drying, concentrated, then obtain faint yellow solid 5 through column chromatography purification, yield 95%, purity 98%.
1hNMR (isomer mixture): 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 2.15 (m, 1H), 5.39 (t, 1H, J=5.4Hz), 7.18 (s, 1H), 7.25 (m, 1H), 7.36 (m, 1H), 7.45 (d, 1H, J=7.6Hz), 7.55 (d, 1H, J=7.6Hz), 7.82 (s, 1H).
ESI-MS:284.17(H +)。
Embodiment 2
1. the synthesis of compound 3
The 5mL diethyl ether solution of compound 2 (3.0mmol) is joined in the 5mL ether suspension of NaH (5.0mmol) in 0 DEG C, stirs 30 minutes at 0 DEG C.Again the 5mL diethyl ether solution of compound 1 (1mmol) is dropwise joined in above-mentioned reaction solution, stirring at room temperature 18 hours.Decompression revolves desolventizing, the saturated NH of residue 4after the dilution of the Cl aqueous solution, through CH 2cl 2extract 3 times.Organic layer through saturated common salt water washing, Na 2sO 4drying, concentrates and obtains raw product 3.
2. the synthesis of compound 4
Above-mentioned raw product 3 (1mmol) is dissolved in 3mL Glacial acetic acid and 10mL methyl alcohol, stirs 1 hour at 100 DEG C.Reaction solution is cooled to room temperature, revolves desolventizing.Residue is dissolved in EtOAc, through saturated K 2cO 3, saturated common salt water washing, Na 2sO 4drying, concentrates and obtains raw product.Faint yellow solid 4 is obtained through column chromatography purification.
3. the synthesis of compound 5
By NaBD 4(0.50mmol) join in the 4mL methanol solution of compound 4 (0.25mmol) in 0 DEG C, 30 DEG C are stirred after 0.5 hour, revolve desolventizing.Residue is dissolved in 2mol/L hydrochloric acid soln (2mL), stirring at room temperature 10 minutes.Add saturated K 2cO 3solution regulates pH to be 7.Reaction solution CH 2cl 2extract 3 times, merge organic layer.Organic layer through saturated common salt water washing, Na 2sO 4drying, concentrated, then obtain faint yellow solid 5 through column chromatography purification, yield 94%, purity 98%.
Embodiment 3
The synthesis of compound 5
By LiAlD 4(0.50mmol) join in the 2mL tetrahydrofuran solution of compound 4 (0.25mmol) in-20 DEG C, 0 DEG C is stirred after 1 hour, revolves desolventizing.Residue is dissolved in 2mol/L hydrochloric acid soln (2mL), stirring at room temperature 10 minutes.Filter, filtrate extracts 3 times through ethyl acetate, merges organic layer.Organic layer is successively through saturated K 2cO 3solution, saturated common salt water washing, Na 2sO 4drying, concentrated, then obtain faint yellow solid 5 through column chromatography purification, yield 92%, purity 98%.
Embodiment 4
The synthesis of compound 5
By LiAlD 4(0.50mmol) join in the 4mL diethyl ether solution of compound 4 (0.25mmol) in-20 DEG C, 0 DEG C is stirred after 1 hour, revolves desolventizing.Residue is dissolved in 2mol/L hydrochloric acid soln (2mL), stirring at room temperature 10 minutes.Filter, filtrate extracts 3 times through ethyl acetate, merges organic layer.Organic layer is successively through saturated K 2cO 3solution, saturated common salt water washing, Na 2sO 4drying, concentrated, then obtain faint yellow solid 5 through column chromatography purification, yield 93%, purity 98%.
In order to beneficial effect of the present invention is described, the invention provides following test example.
The external IDO inhibit activities of test example 1, the compounds of this invention
Test method:
0.5mL standard reaction mixture (containing 100mM potassium phosphate buffer, pH6.5,40mM xitix, 200mg/mL catalase, 20mM methylene blue and 0.05mMrhIDO) is joined in the solution containing substrate L-Trp and testing compound.Reaction solution adds 200mL 30% trichoroacetic acid(TCA) after cultivating 30 minutes at 37 DEG C stops.Be heated to 65 DEG C keep after 10 minutes, get 100mL supernatant liquor and be transferred in 96 orifice plates, the acetum adding 2% paradimethy laminobenzaldehyde of 100mL mixes.The absorbancy of the xanthein using microplate reader to be produced by kynurenine in wavelength 492nm place assaying reaction liquid.Contrast selects IDO inhibitor 1-methyl tryptophan, NLG919, and experimental result is in table 1.
The external IDO inhibit activities of table 1, different compound
Numbering Compound IC 50
1 The compounds of this invention 5 <1μM
2 1-methyl tryptophan 48μM
3 NLG919 <1μM
Experimental result shows, shown in the formula I that the present invention is deuterated, compound has good IDO inhibit activities, and its IDO vitro inhibition IC50 is less than 1 μM, is obviously better than the IDO inhibit activities of 1-methyl tryptophan, suitable with the IDO inhibit activities of NLG919.
Test example 2, the compounds of this invention metabolic condition in people's hepatomicrosome
Test method:
Get the NLG919 of 10 μ L and the phosphate buffered saline buffer (10 μMs of deuterated compound 5 respectively, pH7.4, containing 5%MeOH) join in 96 orifice plates, (protein concentration is 0.5mg/mL to add people's hepatomicrosome in 80 μ L/ holes again, microsome derives from Corning company), cultivate 10 minutes in 37 DEG C.Then, the NADPH degeneration system adding 10 μ L/ holes starts reaction, cultivates in 37 DEG C.
4 DEG C of acetonitrile solution termination reactions containing interior mark (100ng/mL tolbutamide and 100ng/mL Trate) in 300 μ L/ holes are added respectively at 0,5,10,20,30and60 minute.Sample jolting is after 5 minutes, in 4000rpm centrifugal 20 minutes.Get 100 μ L supernatant liquors and add 300 μ L ultrapure waters dilution (1:3), carry out LC/MS/MS analysis.
In Microsomal in vitro stability experiment, main matrix is microsome, and whether monitoring particulate body activity is in an experiment normal, can reflect that whether experimentation is normal.This experiment is for three kinds of main metabolic enzyme (3A4 in microsome, 2C9,2D6), select its specific substrate separately, i.e. testosterone (3A4 substrate), Propafenone (2D6 substrate) and diclofenac (2C9 substrate) are as positive control.
Based on the ratio of compound with interior target peak area, be calculated as follows the T of compound 1/2and clearance rate.
C t = C 0 &CenterDot; e - k e &CenterDot; t
C t = 1 2 C 0 , T 1 / 2 = L n 2 - k e = 0.693 - k e
CL int(mic)＝Vd·k e
Vd＝2mL/mg
Experimental result is as shown in table 2.
People's hepatomicrosome test result of table 2, different compound
As shown in Table 2, the T of compound shown in the formula I that the present invention is deuterated 1/2for 16.8min, residue percentage ratio (T=60min) is 11.1%, all much larger than the T of NLG919 1/2with residue percentage ratio (T=60min), this metabolic stability all indicating compound shown in the deuterated formula of the present invention I is significantly improved, drug effect can be played for a long time, reduce dosage rate and/or drug dose, improve the drug effect of Clinical practice.
T 1/2: the transformation period of medicine.Refer to that medicine maximum concentration in blood plasma reduces the time needed for half.T 1/2reflect the speed that medicine is eliminated in vivo, illustrate the relation between medicine time in vivo and Plasma Concentration, it is the Main Basis determining dosage, number of times.
In sum, compound shown in the formula I that the present invention is deuterated, while there is good IDO inhibit activities, significantly improve the metabolic stability of medicine, medicine not only can be made to play drug effect for a long time, also reduce dosage rate and/or drug dose, improve the drug effect that clinical drug uses; Meanwhile, preparation method of the present invention, has the advantages such as yield is high, purity is high, energy consumption is low, step is few, easy and simple to handle, cost is low, environmental protection, safety, is applicable to very much the application in industry.

Claims (10)

1. deuterated indoles amine-2, a 3-dioxygenase inhibitor, is characterized in that: the structure of described indoles amine-2,3-dioxygenase inhibitor is such as formula shown in I:
Wherein, R 1~ R 9be selected from hydrogen, C respectively or simultaneously 1~ C 6alkyl or C 1~ C 6alkoxyl group.
2. indoles amine-2,3-dioxygenase inhibitor according to claim 1, is characterized in that: R 1~ R 9be hydrogen simultaneously.
3. the preparation method of deuterated indoles amine-2, a 3-dioxygenase inhibitor, is characterized in that: the synthetic route of described preparation method is:
Wherein, R 1~ R 9be selected from hydrogen, C respectively or simultaneously 1~ C 6alkyl or C 1~ C 6alkoxyl group;
Described preparation method comprises the following steps:
A, compound 1, compound 2 with sodium hydride, react 6 hours ~ 18 hours in stirred at ambient temperature, obtain reaction solution in ether solvent; Reaction solution is separated, purifying, obtain compound 3;
Described compound 1, compound 2 are 1:1 ~ 3:1 ~ 5 with the mol ratio of sodium hydride; Described compound 1 is 1:5 ~ 15mmol/ml with the molecular volume ratio of ether solvent;
B, compound 3 and acetic acid, methanol mixed that step a is obtained, at 80 DEG C ~ 100 DEG C, stirring reaction 1 hour ~ 5 hours, obtains reaction solution; Reaction solution is separated, purifying, obtain compound 4;
Described compound 3 is 1:1 ~ 3mmol/ml with the molecular volume ratio of acetic acid; Described compound 3 is 1:5 ~ 10mmol/ml with the molecular volume ratio of methyl alcohol;
In organic solvent, at 0 DEG C ~ 40 DEG C, stirring reaction 0.5 hour ~ 5 hours, obtains reaction solution for the compound 4 that c, step b obtain and deuterated reagent; Reaction solution is separated, purifying, obtain compound 5, be deuterated indoles amine-2,3-dioxygenase inhibitor;
Described compound 4 is 1:1 ~ 5 with the mol ratio of deuterated reagent; Described compound 4 is 1:5 ~ 20mmol/ml with the molecular volume ratio of organic solvent.
4. preparation method according to claim 3, is characterized in that: in step a, and described ether solvent is selected from any one or two kinds in tetrahydrofuran (THF), ether;
In step c, described deuterated reagent is selected from NaBD 4, LiAlD 4in any one or two kinds; Described organic solvent be selected from methyl alcohol, tetrahydrofuran (THF), ether any one or two or more.
5. preparation method according to claim 3, is characterized in that: in step a, 12 hours ~ 18 hours time of stirring reaction.
6. preparation method according to claim 3, is characterized in that: in step a, and described compound 1, compound 2 are 1:1.5 ~ 3:2 ~ 5 with the mol ratio of sodium hydride; Described compound 1 is 1:10 ~ 15mmol/ml with the molecular volume ratio of ether solvent;
In step b, described compound 3 is 1:2 ~ 3mmol/ml with the molecular volume ratio of acetic acid; Described compound 3 is 1:6 ~ 10mmol/ml with the molecular volume ratio of methyl alcohol;
In step c, described compound 4 is 1:2 ~ 3 with the mol ratio of deuterated reagent; Described compound 4 is 1:8 ~ 16mmol/ml with the molecular volume ratio of organic solvent.
7. preparation method according to claim 3, is characterized in that: in step a, is separated reaction solution, the step of purifying is: the solvent in removing reaction solution, obtains residue; Residue, with after saturated aqueous ammonium chloride dilution, with dichloromethane extraction, gets organic phase, and washing is dry, concentrated, obtains compound 3;
In step b, reaction solution is separated, the step of purifying is: cooled by reaction solution, the solvent in removing reaction solution, obtains residue; Residue is dissolved in ethyl acetate, and through unsaturated carbonate aqueous solutions of potassium, saturated common salt water washing, dry, concentrated, column chromatography purification, obtains compound 4;
In step c, reaction solution is separated, the step of purifying is: the solvent in removing reaction solution, obtains residue; Residue is dissolved in 2mol/L hydrochloric acid soln, stirs, after adding unsaturated carbonate aqueous solutions of potassium adjustment pH=6.5 ~ 7.5, with dichloromethane extraction, get organic phase, washing, dry, concentrated, column chromatography purification, obtains compound 5.
8. compound shown in formula I is preparing the application in indoles amine-2,3-dioxygenase inhibitor class medicine.
9. application according to claim 8, is characterized in that: described indoles amine-2,3-dioxygenase inhibitor class medicine is treat and/or prevent the medicine that cellular immunization activates relevant infection, malignant tumour, autoimmune disorder, acquired immune deficiency syndrome (AIDS).
10. a pharmaceutical composition, it is characterized in that: described pharmaceutical composition be with compound shown in formula I or its crystal formation, pharmacy acceptable salt, hydrate or solvate for activeconstituents, add the preparation that pharmaceutically conventional auxiliary material or complementary composition prepare.
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WO2016165613A1 (en) 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as ido and tdo inhibitors
US10358451B2 (en) 2015-04-12 2019-07-23 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as IDO and TDO inhibitors
GB2548542A (en) * 2015-06-16 2017-09-27 Redx Pharma Plc Compounds
CN106256830A (en) * 2015-06-18 2016-12-28 成都海创药业有限公司 A kind of deuterated IDO inhibitor and its production and use
CN106256830B (en) * 2015-06-18 2019-03-08 成都海创药业有限公司 A kind of deuterated IDO inhibitor and its preparation method and application
JP2019504039A (en) * 2015-12-24 2019-02-14 ジェネンテック， インコーポレイテッド TDO2 inhibitor
JP7227005B2 (en) 2015-12-24 2023-02-21 ジェネンテック， インコーポレイテッド TDO2 inhibitor
CN105616408A (en) * 2016-01-11 2016-06-01 西华大学 Use of pyridino[3,4-b]indol derivative as IDO inhibitor
CN109689646A (en) * 2016-07-01 2019-04-26 纽弗姆制药有限公司 For treating the deuterated compound of pain
CN109689646B (en) * 2016-07-01 2022-09-02 纽弗姆制药有限公司 Deuterated compounds for the treatment of pain
CN109384791A (en) * 2017-08-09 2019-02-26 江苏恒瑞医药股份有限公司 A kind of crystal form and preparation method thereof of imidazo isoindoles derivative free alkali

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