CN106866648A - Phthalimide class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof - Google Patents
Phthalimide class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof Download PDFInfo
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to medicinal chemistry art, and in particular to a kind of IDO1 inhibitor (I) and preparation method with phthalimide structure, the same specification of definition of wherein X, R.Pharmacodynamics test proves that compound of the invention can be used for the disease of the pathological characteristicses of the tryptophan metabolic pathway for treating IDO1 mediations, such as malignant tumour, autoimmune disease, alzheimer's disease and schizophrenia.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of IDO1 inhibitor with phthalimide structure
And preparation method.
Background technology
Indoles amine -2,3- dioxygenases (Indoleamine 2,3-dioxygenase, IDO) are that intracellular one kind contains
There is the metabolic enzyme of heme, it is the crucial rate-limiting enzyme for mediating tryptophan metabolism, is the important composition of kynurenine pathway
Part.Since IDO was found from 2003, it is widely studied by academia and pharmaceutical industry as the important target spot of medicament research and development.
The first step of tryptophan degradation is that tryptophan is oxidized into N- formoxyl-L- kynurenins, and it is by IDO and color ammonia
Acid -2,3- dioxygenases (tryptophan 2,3-dioxygenase, TDO) both heme dependent form dioxygenases
What a kind of mediation therein was produced.In both dioxygenases, IDO is considered as to adjust the inspection that the oxidation reaction occurs
Point, it is the main cause of human body generation immunosupress power that it is present with the performance of effect.IDO is further divided into IDO1 and IDO2.
IDO1 is in vivo low expression level under normal circumstances, when interferon (IFN-α, IFN-β and IFN-γ), interleukin (IL-1 and
IL-2 when), the cytokine profiles such as TNF (TNF) induction IDO1 levels are raised, tryptophan will be extensively metabolized, from
And suppressing immune response of the human body to the pathogen such as parasitics, viral, bacillary, fungoid, human body will exempt from ill
Epidemic disease holddown.
The concentration of tryptophan during the expression high of IDO1 reduces cell micro-environment in most of tumour cells so that color ammonia
The T cell synthesis that acid is relied on was stagnated in the G1 phases, and T cell propagation is suppressed, so as to inhibit the immune system of human body to tumour
The lethal effect of tissue.Meanwhile, having cytotoxic tryptophan metabolite can produce directly dissolving to make to T cell
With.Therefore, IDO1 plays an important role in tumour immunity is exempted and tumour develops.
In some chronic diseases such as acquired immunodeficiency syndrome (AIDS), polytype depression, alzheimer
In disease etc., IDO1 is also considered as one of the reason for promoting disease development.High-caliber interferon-induced IDO1 expression high.Dry
Disturb under the continuous activation of element, IDO1 reduces the availability of free serum tryptophan, so as to reduce the generation of serotonin.Plus
The Kynurenine metabolism thing with neural activity accumulation, the generation one of various neurological conditions and mental handicape touches i.e.
Hair.
Because IDO1 has been demonstrated closely related with various disease incidence mechanism, therefore IDO1 inhibitor can be used to treat
The disease of the pathological characteristicses of the tryptophan metabolic pathway of IDO1 mediations, these diseases include and are not limited only to malignant tumour, oneself
Body immunity disease, alzheimer's disease and schizophrenia.IDO1 inhibitor has wide DEVELOPMENT PROSPECT as medicine, so
And do not there is suitable IDO1 inhibitor to be listed as medicine so far, therefore new and effective IDO1 inhibitor is found with weight
The theory significance and application value wanted.
The content of the invention
The invention discloses a kind of compound containing phthalimide class formation, structural formula is as follows：
X represents hydrogen, halogen or methyl；
R representatives-NH2、
N represents 0~3；
M represents 0 or 1.
Wherein X preferably represents methyl.
R is preferably represented
Currently preferred part of compounds is as follows：
The invention also discloses the preparation method of compound (I), including：
Wherein X, R are as defined above.
Compound shown in Formula II and NaNO2Compound shown in the production that reacts III, preferably 0~5 DEG C of reaction temperature,
Reaction time preferably 12~24h, reaction dissolvent is the mixed solvent that concentrated hydrochloric acid and acetic acid are constituted.NaCl is added in reaction.
Compound shown in formula III and compound shown in the amine reaction production IV containing R group, reaction temperature preferably 25~
30 DEG C, reaction time preferably 1~3h, reaction dissolvent is ethyl acetate, dichloromethane etc..Inorganic base or organic is additionally added in reaction
Alkali, such as sodium carbonate, sodium acid carbonate, triethylamine.
The backflow of compound shown in formula IV becomes compound, reaction temperature preferably 80~100 DEG C, reaction time shown in constitutional formula V
It is preferred that 12~20h, reaction dissolvent is water, ethanol etc..Inorganic base, such as NaOH, potassium hydroxide are additionally added in reaction.
Formula shown in Formulas I compound can be generated as shown in Formula V with the phthalic anhydride backflow of X substitutions, and reaction temperature is excellent
110~120 DEG C are selected, reaction time preferably 12~20h, reaction dissolvent is acetic acid, concentrated hydrochloric acid, trifluoroacetic acid etc..
Compound of Formula I can be purified using common separation method, such as recrystallization, column chromatography.
The present invention is also including compound of Formula I pharmaceutically acceptable salt etc..
Compound of the present invention can add pharmaceutically acceptable carrier and be made common pharmaceutical formulation, such as piece
Agent, capsule, pulvis, syrup, liquor, suspending agent, injection, can add spices, sweetener, liquid or solid filler or diluent
Etc. common medicinal supplementary material.
Compound of the present invention administering mode clinically can be using modes such as oral, injections.
Usually, when compound of the invention is used to treat, people's dosage range is 1mg~1000mg/ days.Also dependent on
The difference and disease severity of formulation, dosage exceed the scope.
The following is the pharmacology test and result of part of compounds of the present invention：
(1) determination experiment of IDO1 inhibitory activity
There is the IDO (IDO) of N- terminal His tags in expression in escherichia coli, extract and pure
Change IDO1.The oxidation scission of the pyrrole ring of IDO1 catalysis tryptophan indole rings obtains N '-formoxyl kynurenin.On 96 orifice plates
By 50mM kaliumphosphate buffers (pH 6.5), 40mM vitamin Cs, 400 μ g/mL catalases, 20 μM of methylenum careuleum and IDO1 enzymes
Mixing.To addition substrate L-Trp and testing sample in above-mentioned mixed liquor.Reaction carries out 60min at 37 DEG C, adds 30%
(w/v) trichloroacetic acid makes reaction terminating.96 orifice plates heat 15min at 65 DEG C, are allowed to complete urinated from formylkynurenine to dog
The conversion of propylhomoserin, then 6000rpm rotation 10min.100 μ L of supernatant liquid are taken out per hole to be transferred in 96 new orifice plates, add 2%
(w/v) the μ L of acetic acid solution 100 of p- (dimethylamino) benzaldehyde, kynurenin reacts generation yellow color and enzyme can be used
Mark instrument is observed in 480nm, and acquired results utilize IC50(nM) software for calculation is calculated.Using the above method, the IDO1 suppressions to compound
Activity processed is measured, its IC50(nM) it is as follows, and with being currently in the IDO inhibitor NLG-919 of Phase I clinical trial as right
According to.The results are shown in Table 1.
Inhibitory activity IC of the part of compounds of the present invention of table 1 to IDO150(nM)
From table 1, part of compounds of the present invention has good inhibitory activity to IDO1.
(2) determination experiment of the IDO1 inhibitory activity based on Hela cells
At 37 DEG C, cell is stored in offer 5%CO2The wet incubator of control in.It is carried out as follows measure：By 5000/ hole
Density, Hela cells are seeded in 96 well culture plates, and overnight incubation.Second day, by IFN-γ (final concentration 50ng/mL) and
The serial dilutions (the μ L culture mediums of cumulative volume 200) of compound add to cell.After incubating 48h, 140 μ L of supernatant liquid/hole is moved to
In 96 new orifice plates.10 μ L6.1N trichloroacetic acids are mixed into each hole, incubating 30min at 50 DEG C makes the N- formoxyl dog urinary ammonias of generation
Acid is hydrolyzed to kynurenin.Then reactant mixture is centrifuged to remove sediment by 10min with 6000rpm.By 100 μ L of supernatant
Liquid/hole is moved in another 96 orifice plate, is mixed with 100 μ L2% (w/v) paradime thylaminobenzaldehydes in acetic acid, in 480nm measurements
The yellow that kynurenin is produced.Make standard with L- kynurenins.With 100 μ L culture mediums prepare titer (240,120,60,30,
15th, 7.5,3.75,1.87 μM), and they are mixed with 2% isometric (w/v) paradime thylaminobenzaldehyde.Determine each dense
Suppression percentage under degree, using nonlinear regression analysis data, obtains IC50(μM) value, and with being currently in Phase I clinical trial
IDO inhibitor NLG-919 as control.The results are shown in Table 2.
The part of compounds of the present invention of table 2 is based on the IDO1 inhibitory activity IC of Hela cells50(μM)
From table 2, part of compounds of the present invention has good inhibitory activity to IDO1.
(3) experiment in vivo of the antitumor activity of IDO1 inhibitor
Growth animated period mouse MC B16F10 is collected, cell suspension is aseptically prepared into, is inoculated in
C57BL6 mouse oxter.C57BL6 mice-transplanted tumors vernier caliper measurement transplantable tumor diameter, treat tumour growth to a certain size
Afterwards by animal packet, every group 5.Use the method in measurement knurl footpath, the dynamic observation antineoplastic effect of tested thing.Blank is given
The dosage 0.5%CMC (sodium carboxymethylcellulose), gastric infusion such as give；Compound group carries out intraperitoneal injection, once every other day, continues
15 days.Tumour major diameter (a) and minor axis (b) are measured since the same day is administered, is every other day measured once, gross tumor volume=ab2/2。
Lotus knurl C57BL6 mouse are put to death after 15 days, and separates tumor mass and weighed.The data obtained carries out statistical procedures, calculates tumour inhibiting rate, and
With being currently in the IDO inhibitor NLG-919 of Phase I clinical trial as control.The results are shown in Table 3, Fig. 1 and Fig. 2
The growth inhibition ratio of the B16F10 transplantable tumors of the representative compound CPUL-I021 of the present invention of table 3
From Fig. 1, Fig. 2 and Biao 3, growth of the compounds of this invention to malignant tumour has good inhibitory activity.
(4) IDO1 inhibitor pharmacokinetic studies in rats
SD rats 10 are chosen, male, 180~200g of body weight, gavage or vein give compound CPUL-I021, be shown in Table
4：
The compound CPUL-I021 of table 4 administrations in rats
Gastric infusion is formulated as suspension with 1%MC, is injected intravenously with DMSO:30%PEG400 (5:95) prepare.Experiment
Preceding fasting 12h, free water.2h unifications feed after administration.Taken a blood sample according to following time point after administration：When gastric infusion group is taken a blood sample
Between point for administration after 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24h；After intravenously administrable group blood sampling time point is for administration
0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24h.At above-mentioned time point through rat eye rear vein beard extracting vein blood
0.3mL, is placed in EDTA-2K test tubes, and 11000rpm centrifugation 5min, separated plasma is placed in -20 DEG C of refrigerators and freezes.Using LC/
MS/MS methods determine the concentration of compound CPUL-I021 in rat plasma.Medicine after administration is calculated for power using non-compartment model
Learn parameter.Up to Cmax CmaxWith peak time TmaxIt is measured value；Area under the drug-time curve AUC0-tValue is calculated using trapezoidal method；
AUC0-∞=AUC0-t+Ct/ke, Ct is that last can measure the blood concentration at time point, keIt is elimination rate constant；Eliminate half
Decline phase t1/2=0.693/ke；Mean residence time MRT=AUMC/AUC.Clearance rate CL=D/AUC0-∞；Vdss Vss
=CL × MRT；Absolute bioavailability F=(AUCGavage×DVein)/(AUCVein×DGavage) × 100%.The results are shown in Table 5 and table 6.
Pharmacokinetic parameters after the rat oral gavage of table 5 administration 10mg/kg CPUL-I021
Pharmacokinetic parameters after the rat vein of table 6 administration 1mg/kg CPUL-I021
Brief description of the drawings
Fig. 1 is that separation tumor mass is weighed after putting to death lotus knurl C57BL6 mouse
Fig. 2 is gross tumor volume and administration number of days relation
Specific embodiment
Embodiment 1
The preparation of 4- amino -3- (N '-hydroxyl amidino groups) -1,2,5- oxadiazoles (II)
Natrium nitrosum (20.7g, 300mmol) and 40mL water are added in 500mL reaction bulbs, stirring and dissolving, at room temperature
Hydrochloric acid (2N) solution of malononitrile (9.9g, 150mmol) is slowly added dropwise, is stirred overnight at room temperature, be cooled to 0 DEG C, hydrochloric acid hydroxyl is added dropwise
The aqueous solution of amine (23g, 340mmol), stirs 30min, and less than 20 DEG C adjust pH to 10 with 10N NaOH, rise to 35 DEG C instead
2h is answered, backflow 2h is reheated.Room temperature is cooled to, reaction solution is extracted with 20mL ethyl acetate, removes solvent under reduced pressure and obtain white solid,
Water layer is stood overnight, solid is separated out, suction filtration, washing, filter cake and vacuum distillation obtain white solid and merge dry white powder
Shape solid (14.9g, 69.5%).1H NMR(300MHz,DMSO-d6)δ:10.46(s,1H,-OH),6.24(s,2H,-NH2),
6.02(s,2H,-NH2)ppm.HRMS m/z[M+H]+calculated for C3H5N5O2:143.0516,found:
143.0518。
The preparation of 4- amino -3- chloros first oximido -1,2,5- oxadiazoles (III)
By II (4.18g, 29.2mmol), 58.4mL water, it is anti-that the 6N hydrochloric acid of 29.7mL acetic acid and 14.6mL is added to 250mL
Answer in bottle, rise to 45 DEG C of stirring and dissolvings, add solid sodium chloride (5.12g, 87.5mmol), stirring and dissolving to be cooled to 0 DEG C, analysis
Go out white solid, be slowly added dropwise the aqueous solution of natrium nitrosum (2.00g, 29mmol), 0 DEG C of 3h stirred below is warmed to room temperature, takes out
Filter, filter cake washing, re crystallization from toluene obtains white powdery solids (2.52g, 53.2%).1H NMR(300MHz,DMSO-d6)δ:
13.39(s,1H,-OH),6.29(s,2H,-NH2)ppm.HRMS m/z[M+H]+calculated for C3H3ClN4O2:
161.9872,found:161.9872。
Embodiment 2
The preparation of compound CPUL-I001
The preparation of 4- amino -3- (N- methyl-N '-hydroxyl amidino groups) -1,2,5- oxadiazoles (IV-1)
III (1.0g, 6.2mmol) and 40mL ethanol are added in 100mL reaction bulbs, are stirred, it is slow successively at room temperature
40% methylethylolamine solution (0.48g, 6.2mmol) and triethylamine (1.25g, 12.4mmol) is added dropwise, 3h is stirred at room temperature, depressurize
Solvent is evaporated off, ethyl acetate stirring, suction filtration, filtrate water and saturated sodium-chloride water solution respectively washing 1 time, anhydrous sodium sulfate is added
Organic layer is dried, solvent is removed under reduced pressure and is obtained yellow oil (0.68g, 70.1%).HRMS m/z[M+H]+calculated
for C4H7N5O2:157.0602,found:157.0600。
The preparation of 4- methylaminos -3- (N '-hydroxyl amidino groups) -1,2,5- oxadiazoles (V-1)
IV-1 (0.68g, 4.3mmol) and 9mL water are added in 50mL reaction bulbs, potassium hydroxide is slowly added dropwise under stirring
The 3mL aqueous solution of (0.73g, 13mmol), is heated to reflux 14h, through TLC detections after completion of the reaction, is cooled to room temperature, uses acetic acid second
Ester extract (5 × 4mL), merge organic phase, anhydrous sodium sulfate drying, remove under reduced pressure solvent obtain pale yellow oil (0.46g,
67.5%).HRMS m/z[M+H]+calculated for C4H7N5O2:157.0608,found:157.0600。
The system of 2- [(4- methylamino -1,2,5- oxadiazole -3- bases) first oximido] iso-indoles -1,3- diketone (CPUL-I001)
It is standby
By V-1 (0.46g, 3mmol), 20mL acetic acid and phthalic anhydride (0.88g, 6mmol) are added to 100mL reactions
In bottle, about 8h is refluxed, through TLC detections after completion of the reaction, is cooled to room temperature, remove solvent under reduced pressure, column chromatography purifies light
Yellow solid (0.25g, 29%).m.p.203-204℃,1H NMR(300MHz,DMSO-d6)δ:12.61(s,1H,-OH),
7.87-7.95 (m, 2H ,-ArH), 7.64-7.67 (m, 2H ,-ArH), 5.41 (m, 1H ,-NH-), 2.33 (d, J=4.5Hz,
3H,-CH3)ppm.HRMS m/z[M+H]+calculated for C12H9N5O4:287.0650,found:287.0655。
Embodiment 3
The preparation of compound CPUL-I002
Replaced outside methylamine with ethamine (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I002 (0.28g, 15%).m.p.199-200℃,1H NMR(300MHz,DMSO-d6)δ:13.01(s,1H,-OH),
7.91-8.02(m,2H,-ArH),7.73-7.77(m,2H,-ArH),6.21(m,1H,-NH-),2.43(m,2H,-CH2-),
2.29 (t, J=4.7Hz, 3H ,-CH3)ppm.HRMS m/z[M+H]+calculated for C12H9N5O4:301.0806,
found:301.0811。
Embodiment 4
The preparation of compound CPUL-I003
Replaced outside methylamine with cyclopropylamine (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I003 (0.28g, 14.5%).m.p.169-171℃,1H NMR(300MHz,DMSO-d6)δ:13.71(s,1H,-OH),
7.81-8.03(m,4H,-ArH),6.63(bs,1H,-NH-),2.67-2.74(m,1H,-CH-),0.67-0.78(m,4H,-
CH2-CH2-)ppm.HRMS m/z[M+H]+calculated for C14H11N5O4:313.0884,found:313.0867。
Embodiment 5
The preparation of compound CPUL-I004
Replaced outside methylamine with n-propylamine (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I004 (0.31g, 16%).m.p.197-198℃,1H NMR(300MHz,DMSO-d6)δ:13.61(s,1H,-OH),
7.97-8.05 (m, 2H ,-ArH), 7.84-7.87 (m, 2H ,-ArH), 6.41 (bs, 1H ,-NH-), 3.28 (q, J=6.5Hz,
2H,-CH2-),1.63-1.70(m,2H,-CH2-), 0.92 (t, J=7.3Hz, 3H ,-CH3)ppm.HRMS m/z[M+H]+
calculated for C14H13N5O4:315.0873,found:315.0869。
Embodiment 6
The preparation of compound CPUL-I005
Replaced outside methylamine with tert-butylamine (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I005 (0.32g, 15.5%).m.p.136-138℃,1H NMR(300MHz,DMSO-d6)δ:13.67(s,1H,-OH),
7.85-7.97(m,4H,-ArH),5.80(s,1H,-NH-),1.40(s,9H,-C(CH3)3)ppm.HRMS m/z[M+H]+
calculated for C15H15N5O4:329.1197,found:329.1196。
Embodiment 7
The preparation of compound CPUL-I006
Replaced outside methylamine with cyclohexylamine (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I006 (0.32g, 14.5%).m.p.202-203℃,1H NMR(300MHz,(CD3)2CO-d6)δ:8.14-8.17(m,
1H ,-ArH), 7.98-8.01 (m, 1H ,-ArH), 7.88-7.90 (m, 2H ,-ArH), 5.71 (d, J=6.9Hz, 1H ,-NH-),
3.55(bs,1H,-CH-),2.11-2.17(m,2H,-CH2-),1.77-1.80(m,2H,-CH2-),1.31-1.68(m,6H,-
CH2-CH2-CH2-)ppm.HRMS m/z[M+H]+calculated for C17H17N5O4:355.1353,found:
355.1353。
Embodiment 8
The preparation of compound CPUL-I007
Replaced outside methylamine with 4- oxygen azo-cycles hexane (6.2mmol), with compound CPUL-I001 identical method synthesisization
Compound CPUL-I007 (0.28g, 13%).m.p.190-192℃,1H NMR(300MHz,DMSO-d6)δ:13.72(s,1H,-
OH),7.81-8.06(m,4H,-ArH),3.64-3.74(m,4H,-CH2-O-CH2-), 3.31 (t, J=4.2Hz, 4H ,-CH2-
N-CH2-)ppm.HRMS m/z[M+H]+calculated for C15H13N5O5:343.0989,found:343.0992。
Embodiment 9
The preparation of compound CPUL-I008
Replaced outside methylamine with aniline (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I008 (0.32g, 15%).m.p.182-184℃,1H NMR(300MHz,DMSO-d6)δ:8.69(s,1H,-NH-),
7.98-8.06 (m, 2H ,-ArH), 7.84-7.89 (m, 2H ,-ArH), 7.66 (d, J=7.9Hz, 2H ,-ArH), 7.41 (t, J=
7.6Hz, 2H ,-ArH), 7.08 (t, J=7.3Hz, 1H ,-ArH) ppm.1H RMS m/z[M+H]+calculated for
C17H11N5O4:349.0884,found:349.0916。
Embodiment 10
The preparation of compound CPUL-I009
Replaced outside methylamine with benzylamine (6.2mmol), compound is synthesized with compound CPUL-I001 identicals method
CPUL-I009 (0.35g, 15.5%).m.p.195-197℃,1H NMR(300MHz,DMSO-d6)δ:7.97-8.06(m,2H,-
), ArH 7.82-7.89 (m, 2H ,-ArH), 7.24-7.43 (m, 5H ,-ArH), 7.10 (t, J=6.2Hz, 1H ,-NH-), 4.53
(d, J=6.1Hz, 2H ,-CH2-)ppm.HRMS m/z[M+H]+calculated for C18H13N5O4:363.1040,found:
363.1045。
Embodiment 11
The preparation of compound CPUL-I010
With propylamine (6.2mmol) replace methylamine, 4- chloride anhydrides replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I010 (0.31g, 14.5%).m.p.120-122℃,1H NMR(300MHz,
DMSO-d6)δ:14.00(s,1H,-OH),7.90-8.09(m,3H,-ArH),6.42(bs,1H,-NH-),3.26(bs,2H,-
CH2-),1.63-1.67(m,2H,-CH2-),0.91(bs,3H,-CH3)ppm.HRMS m/z[M+H]+calculated for
C14H12ClN5O4:349.0651,found:349.0686。
Embodiment 12
The preparation of compound CPUL-I011
With cyclohexylamine (6.2mmol) replace methylamine, 4- chloride anhydrides replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I011 (0.41g, 17%).m.p.200-202℃,1H NMR(300MHz,
DMSO-d6)δ:14.00(s,1H,-OH),8.03-8.06(m,2H,-ArH),7.93-7.96(m,1H,-ArH),5.96(d,J
=7.6Hz, 1H ,-NH-), 3.31-3.43 (m, 1H ,-CH-), 2.00-2.04 (m, 2H ,-CH2-),1.71-1.75(m,2H,-
CH2-),1.31-1.63(m,6H,-CH2-CH2-CH2-)ppm.HRMS m/z[M+H]+calculated for C17H16ClN5O4:
389.0964,found:389.0978。
Embodiment 13
The preparation of compound CPUL-I012
With 4- oxygen azo-cycles hexane (6.2mmol) replace methylamine, 4- chloride anhydrides replace phthalic anhydride outside, with compound
CPUL-I001 identicals method synthesizes compound CPUL-I012 (0.39g, 16.5%).m.p.176-178℃,1H NMR
(300MHz,DMSO-d6)δ:13.90(s,1H,-OH),7.93-8.08(m,3H,-ArH),3.73(bs,4H,-CH2-O-
CH2-),3.31(bs,4H,-CH2-N-CH2-)ppm.HRMS m/z[M+H]+calculated for C15H12ClN5O5:
377.0600,found:377.0600。
Embodiment 14
The preparation of compound CPUL-I013
With aniline (6.2mmol) replace methylamine, 4- chloride anhydrides replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I013 (0.34g, 14.5%).m.p.207-209℃,1H NMR(300MHz,
DMSO-d6)δ:8.77 (s, 1H ,-NH-), 8.06 (s, 1H ,-ArH), 7.95 (d, J=7.5Hz, 1H ,-ArH), 7.88 (d, J=
6.8Hz, 1H ,-ArH), 7.67 (d, J=7.8Hz, 2H ,-ArH), 7.39 (t, J=7.6Hz, 2H ,-ArH), 7.06 (t, J=
7.1Hz,1H,-ArH)ppm.HRMS m/z[M+H]+calculated for C17H10ClN5O4:383.0494,found:
383.0512。
Embodiment 15
The preparation of compound CPUL-I014
With propylamine (6.2mmol) replace methylamine, 4- bromobenzenes acid anhydride replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I014 (0.38g, 15.5%).m.p.130-132℃,1H NMR(300MHz,
DMSO-d6)δ:14.00 (s, 1H ,-OH), 7.93-8.21 (m, 3H ,-ArH), 6.43 (t, J=5.3Hz, 1H ,-NH-), 3.24-
3.31(m,2H,-CH2-),1.63-1.70(m,2H,-CH2-), 0.92 (t, J=7.4Hz, 3H ,-CH3)ppm.HRMS m/z[M+
H]+calculated for C14H12BrN5O4:393.0145,found:393.0148。
Embodiment 16
The preparation of compound CPUL-I015
With cyclohexylamine (6.2mmol) replace methylamine, 4- bromobenzenes acid anhydride replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I015 (0.46g, 17%).m.p.188-190℃,1H NMR(300MHz,
CDCl3)δ:7.77-8.23(m,3H,-ArH),5.30(bs,1H,-NH-),3.58(bs,1H,-CH-),2.15-2.21(m,
2H,-CH2-),1.70-1.78(m,2H,-CH2-),1.25-1.66(m,6H,-CH2-CH2-CH2-)ppm.HRMS m/z[M+H]+
calculated for C17H16BrN5O4:433.0458,found:433.0462。
Embodiment 17
The preparation of compound CPUL-I016
With 4- oxygen azo-cycles hexane (6.2mmol) replace methylamine, 4- bromobenzenes acid anhydride replace phthalic anhydride outside, with compound
CPUL-I001 identicals method synthesizes compound CPUL-I016 (0.39g, 15%).m.p.189-191℃,1H NMR
(300MHz,DMSO-d6)δ:13.95 (s, 1H ,-OH), 7.91-8.21 (m, 3H ,-ArH), 3.73 (t, J=4.2Hz, 4H ,-
CH2-O-CH2-), 3.31 (t, J=4.1Hz, 4H ,-CH2-N-CH2-)ppm.HRMS m/z[M+H]+calculated for
C15H12BrN5O5:421.0095,found:421.0098。
Embodiment 18
The preparation of compound CPUL-I017
With aniline (6.2mmol) replace methylamine, 4- bromobenzenes acid anhydride replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I017 (0.40g, 15%).m.p.237-239℃,1H NMR(300MHz,
DMSO-d6)δ:8.69 (s, 1H ,-NH-), 7.95-8.06 (m, 3H ,-ArH), 7.68 (d, J=7.9Hz, 2H ,-ArH), 7.40
(t, J=7.8Hz, 2H ,-ArH), 7.07 (t, J=7.3Hz, 1H ,-ArH) ppm.HRMS m/z [M+H]+calculated for
C17H10BrN5O4:426.9989,found:427.0004。
Embodiment 19
The preparation of compound CPUL-I018
With propylamine (6.2mmol) replace methylamine, 4- methyl phthalic anhydride replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I018 (0.29g, 14%).m.p.123-125℃,1H NMR(300MHz,
CDCl3)δ:7.68-8.08 (m, 2H ,-ArH), 7.57 (d, J=7.8Hz, 1H ,-ArH), 5.46 (bs, 1H ,-NH-), 3.40-
3.43(m,2H,-CH2-),2.54(s,3H,-CH3),1.74-1.81(m,2H,-CH2-), 1.03 (t, J=7.4Hz, 3H ,-
CH3)ppm.HRMS m/z[M+H]+calculated for C15H15N5O4:329.1197,found:329.1205。
Embodiment 20
The preparation of compound CPUL-I019
With cyclohexylamine (6.2mmol) replace methylamine, 4- methyl phthalic anhydride replace phthalic anhydride outside, with compound
CPUL-I001 identicals method synthesizes compound CPUL-I019 (0.33g, 14.5%).m.p.201-203℃,1H NMR
(300MHz,CDCl3),δ:7.89-8.05 (m, 1H ,-ArH), 7.66-7.81 (m, 1H ,-ArH), 7.55 (d, J=7.9Hz,
1H ,-ArH), 5.36 (d, J=5.6Hz, 1H ,-NH-), 3.57 (bs, 1H ,-CH-), 2.53 (s, 3H ,-CH3),2.15-2.18
(m,2H,-CH2-),1.69-1.77(m,2H,-CH2-),1.24-1.65(m,6H,-CH2-CH2-CH2-)ppm.HRMS m/z[M+
H]+calculated for C18H19N5O4:369.1510,found:369.1507。
Embodiment 21
The preparation of compound CPUL-I020
With 4- oxygen azo-cycles hexane (6.2mmol) replace methylamine, 4- methyl phthalic anhydride replace phthalic anhydride outside, with chemical combination
Thing CPUL-I001 identicals method synthesizes compound CPUL-I020 (0.33g, 15.5%).m.p.176-178℃,1H NMR
(300MHz,DMSO-d6)δ:13.58 (s, 1H ,-OH), 7.74-7.96 (m, 3H ,-ArH), 3.73 (t, J=4.8Hz, 4H ,-
CH2-O-CH2-), 3.31 (t, J=4.4Hz, 4H ,-CH2-N-CH2-),2.49(s,3H,-CH3)ppm.HRMS m/z[M+H]+
calculated for C16H15N5O5:357.1146,found:357.1150。
Embodiment 22
The preparation of compound CPUL-I021
With aniline (6.2mmol) replace methylamine, 4- methyl phthalic anhydride replace phthalic anhydride outside, with compound CPUL-
I001 identicals method synthesizes compound CPUL-I021 (0.36g, 16%).m.p.206-208℃,1H NMR(300MHz,
(CD3)2CO-d6)δ:12.58 (s, 1H ,-OH), 8.38 (s, 1H ,-NH-), 8.03 (dd, J=8.0Hz, 5.4Hz, 1H ,-ArH),
7.88 (d, J=8.4Hz, 1H ,-ArH), 7.71-7.75 (m, 3H ,-ArH), 7.44 (t, J=8.1Hz, 2H ,-ArH), 7.11
(t, J=7.3Hz, 1H ,-ArH), 2.57 (s, 3H ,-CH3)ppm.HRMS m/z[M+H]+calculated for C18H13N5O4:
363.1040,found:363.1041。
Claims (7)
1. compounds of formula I or its pharmaceutically acceptable salt：
X represents hydrogen, halogen or methyl；
R representatives-NH2、
N represents 0~3；
M represents 0 or 1.
2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein X represent methyl.
3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R are represented
4. the preparation method of the compound of claim 1,2 or 3, including：
Wherein the definition of X, R is with claim 1.
5. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used
The carrier of receiving.
6. the compound or its pharmaceutically acceptable salt of claim 1,2 or 3 are used to prepare the tryptophan for the treatment of IDO1 mediations
The purposes of the medicine of the disease of the pathological characteristicses of metabolic pathway.
7. the purposes of claim 6, the disease of the pathological characteristicses of the tryptophan metabolic pathway of wherein IDO1 mediations is pernicious swollen
Knurl.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018072697A1 (en) * | 2016-10-17 | 2018-04-26 | 上海医药集团股份有限公司 | Oxadiazole ring-containing compound, preparation method therefor, and intermediate, composite, and application thereof |
| CN109748911A (en) * | 2017-11-06 | 2019-05-14 | 中国药科大学 | A kind of IDO inhibitor containing triazole, preparation method and its medical usage |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101212967A (en) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
| CN105481789A (en) * | 2014-09-15 | 2016-04-13 | 中国科学院上海有机化学研究所 | Indoleamine-2, 3-dioxygenase inhibitor and preparation method thereof |
-
2017
- 2017-01-03 CN CN201710001222.9A patent/CN106866648B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101212967A (en) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
| CN105481789A (en) * | 2014-09-15 | 2016-04-13 | 中国科学院上海有机化学研究所 | Indoleamine-2, 3-dioxygenase inhibitor and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| UTE F. ROHRIG ET AL.: "Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors", 《J. MED. CHEM.》 * |
| 徐跃洋等: "吲哚胺-2，3-双加氧酶IDO1抑制剂研究进展", 《中国新药杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018072697A1 (en) * | 2016-10-17 | 2018-04-26 | 上海医药集团股份有限公司 | Oxadiazole ring-containing compound, preparation method therefor, and intermediate, composite, and application thereof |
| CN109748911A (en) * | 2017-11-06 | 2019-05-14 | 中国药科大学 | A kind of IDO inhibitor containing triazole, preparation method and its medical usage |
| CN109748911B (en) * | 2017-11-06 | 2022-03-11 | 中国药科大学 | Triazole-containing IDO inhibitor, and preparation method and medical application thereof |
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