CN106866648B - 1 inhibitor of phthalimide class indoles amine -2,3- dioxygenase and application thereof - Google Patents
1 inhibitor of phthalimide class indoles amine -2,3- dioxygenase 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
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Abstract
The present invention relates to field of medicinal chemistry, and in particular to a kind of IDO1 inhibitor (I) and preparation method with phthalimide structure, the wherein same specification of the definition of X, R.Pharmacodynamics test proves that the compound of the present invention can be used for treating the disease of the pathological characteristics of the tryptophan metabolic pathway of IDO1 mediation, such as malignant tumour, autoimmune disease, alzheimer's disease and schizophrenia.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of IDO1 inhibitor with phthalimide structure
And preparation method.
Background technique
Indoles amine -2,3- dioxygenase (Indoleamine 2,3-dioxygenase, IDO) is that intracellular one kind contains
There is the metabolic enzyme of heme, it is the important composition of kynurenine pathway that it, which is the key that mediate tryptophan metabolism rate-limiting enzyme,
Part.IDO since 2003 are found, studied extensively by academia and pharmaceutical industry by the important target spot as medicament research and development.
The first step of tryptophan degradation is that tryptophan is oxidized to N- formoxyl-L- kynurenin, it is by IDO and color ammonia
Acid -2,3- dioxygenase (tryptophan 2,3-dioxygenase, TDO) both heme dependent form dioxygenases
What one such mediation generated.In both dioxygenases, IDO is considered as the inspection for adjusting the oxidation reaction and occurring
Point, there is the performance with effect is the main reason for human body generates immunosupress power.IDO is further divided into IDO1 and IDO2.
IDO1 is in low expression level in vivo under normal circumstances, when interferon (IFN-α, IFN-β and IFN-γ), interleukin (IL-1 and
IL-2), when the cytokine profiles such as tumor necrosis factor (TNF) induction IDO1 level increases, tryptophan will be extensively metabolized, from
And inhibiting human body to the immune response of the pathogen such as parasitics, viral, bacillary, fungoid, human body will exempt from morbid state
Epidemic disease holddown.
The high expression of IDO1 reduces the concentration of tryptophan in cell micro-environment in most of tumour cells, so that color ammonia
The T cell synthesis that acid relies on was stagnated in the G1 phase, and T cell proliferation is suppressed, to inhibit the immune system of human body to tumour
The lethal effect of tissue.Meanwhile having cytotoxic tryptophan metabolite and can generate direct dissolution to T cell and making
With.Therefore, IDO1 is exempted in the occurrence and development with tumour in tumour immunity and is played an important role.
In some chronic diseases such as acquired immunodeficiency syndrome (AIDS), multiple types depression, Alzheimer
In disease etc., IDO1 is also considered as one of the reason of promoting progression of the disease.High-caliber interferon-induced IDO1 high expression.Dry
Under the continuous activation for disturbing element, IDO1 reduces the availability of free serum tryptophan, to reduce the generation of serotonin.Add
The Kynurenine metabolism object with neural activity accumulation, a variety of neurological conditions and mental handicape generation one touching is
Hair.
Since IDO1 has been demonstrated closely related with a variety of disease incidence mechanism, IDO1 inhibitor can be used for treating
IDO1 mediate tryptophan metabolic pathway pathological characteristics disease, these diseases include and be not limited only to malignant tumour, from
Body immunity disease, alzheimer's disease and schizophrenia.IDO1 inhibitor has wide development prospect as drug, so
And there is not suitable IDO1 inhibitor to list as drug so far, therefore find new and effective IDO1 inhibitor with weight
The theory significance and application value wanted.
Summary 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 representative-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 methods of compound (I), comprising:
Wherein X, R are as defined above.
Compound and NaNO shown in Formula II2Compound shown in the production that reacts III, preferably 0~5 DEG C of reaction temperature,
Reaction time preferably 12~for 24 hours, reaction dissolvent is the mixed solvent that concentrated hydrochloric acid and acetic acid form.NaCl is added in reaction.
Compound shown in formula III reacts compound shown in production IV with the amine containing R group, and reaction temperature preferably 25~
30 DEG C, reaction time preferably 1~3h, reaction dissolvent is ethyl acetate, methylene chloride etc..Inorganic base or organic is additionally added in reaction
Alkali, such as sodium carbonate, sodium bicarbonate, triethylamine.
Compound shown in formula IV flows back allosteric into compound shown in Formula V, and preferably 80~100 DEG C of reaction temperature, the reaction time
It is preferred that 12~20h, reaction dissolvent is water, ethyl alcohol etc..Inorganic base, such as sodium hydroxide, potassium hydroxide are additionally added in reaction.
The phthalic anhydride that the compound as shown in Formula V of general formula shown in Formulas I and X replace, which flows back, to be generated, and reaction temperature is excellent
110~120 DEG C, reaction time preferably 12~20h are selected, 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 also includes compound of Formula I pharmaceutically acceptable salt etc..
Compound of the present invention can add pharmaceutically acceptable carrier and common pharmaceutical formulation, such as piece is made
Fragrance, sweetener, liquid or solid filler or diluent can be added in agent, capsule, pulvis, syrup, liquor, suspending agent, injection
Etc. common medicinal supplementary materials.
The administration mode of compound of the present invention clinically can be using modes such as oral, injections.
Generally, the compound of the present invention is for when treating, people to be 1mg~1000mg/ days with dosage range.It can also basis
The difference and disease severity of dosage form, dosage exceed the range.
It is the pharmacology test and result of part of compounds of the present invention below:
(1) measurement experiment of IDO1 inhibitory activity
There is the human indoleamine 2,3-dioxygenase (IDO) of N- terminal His tag in expression in escherichia coli, extract and pure
Change IDO1.The oxidation scission of the pyrrole ring of IDO1 catalysis tryptophan indole ring obtains N '-formoxyl kynurenin.On 96 orifice plates
By 50mM kaliumphosphate buffer (pH 6.5), 40mM vitamin C, 400 μ g/mL catalases, 20 μM of methylenum careuleum and IDO1 enzyme
Mixing.Substrate L-Trp and sample to be tested are added into above-mentioned mixed liquor.Reaction carries out 60min at 37 DEG C, is added 30%
(w/v) trichloroacetic acid makes reaction terminating.96 orifice plates heat 15min at 65 DEG C, are allowed to complete to urinate from formylkynurenine to dog
The conversion of propylhomoserin, then 6000rpm rotates 10min.Every hole is taken out 100 μ L supernatants and is transferred in 96 new orifice plates, is added 2%
(w/v) the 100 μ L of acetic acid solution of p- (dimethylamino) benzaldehyde, kynurenin, which reacts, generates the usable enzyme of yellow color
It marks instrument to observe in 480nm, acquired results utilize IC50(nM) software for calculation calculates.Using the above method, the IDO1 of compound is pressed down
Activity processed is measured, IC50(nM) as follows, and use be currently in the IDO inhibitor NLG-919 of Phase I clinical trial as pair
According to.It 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)
Seen from table 1, part of compounds of the present invention has good inhibitory activity to IDO1.
(2) measurement experiment of the IDO1 inhibitory activity based on Hela cell
At 37 DEG C, cell is stored in, 5%CO is provided2The wet incubator of control in.It is measured as follows: by 5000/ hole
Density, by Hela cell inoculation in 96 well culture plates, and overnight incubation.Second day, by IFN-γ (final concentration 50ng/mL) and
The serial dilutions (200 μ L culture medium of total volume) of compound add to cell.After incubating 48h, by 140 μ L supernatants/Kong Yizhi
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 ammonia generated
Acid is hydrolyzed to kynurenin.Then reaction mixture is centrifuged to remove sediment by 10min with 6000rpm.By 100 μ L supernatants
Liquid/hole moves in another 96 orifice plate, mixes with 100 μ L2% (w/v) paradime thylaminobenzaldehydes in acetic acid, measures in 480nm
The yellow that kynurenin generates.Make standard with L- kynurenin.With 100 μ L culture mediums prepare titer (240,120,60,30,
15,7.5,3.75,1.87 μM), and they are mixed with 2% isometric (w/v) paradime thylaminobenzaldehyde.It measures each dense
Inhibition percentage under degree obtains IC using nonlinear regression analysis data50(μM) value, and with being currently in Phase I clinical trial
IDO inhibitor NLG-919 as control.It the results are shown in Table 2.
IDO1 inhibitory activity IC of the part of compounds of the present invention of table 2 based on Hela cell50(μM)
As can be seen from Table 2, part of compounds of the present invention has good inhibitory activity to IDO1.
(3) experiment in vivo of the anti-tumor activity of IDO1 inhibitor
Growth animated period mouse melanoma cells B16F10 is collected, cell suspension is aseptically prepared into, is inoculated in
C57BL6 mouse oxter.C57BL6 mice-transplanted tumor vernier caliper measurement transplantable tumor diameter, to tumour growth to a certain size
Afterwards by animal packet, every group 5.Use the method for measurement knurl footpath, the antitumor effect of dynamic observation subject.Blank control is given
Give equal dosage 0.5%CMC (sodium carboxymethylcellulose), gastric infusion；Compound group is injected intraperitoneally, and once every other day, is continued
15 days.Since measurement tumour major diameter (a) and minor axis (b) the same day is administered, every other day measurement is primary, gross tumor volume=ab2/2。
Lotus knurl C57BL6 mouse is put to death after 15 days, and separates tumor mass weighing.The data obtained carries out statistical procedures, calculates tumour inhibiting rate, and
It uses and is currently in the IDO inhibitor NLG-919 of Phase I clinical trial as control.It the results are shown in Table 3, Fig. 1 and Fig. 2
The growth inhibition ratio of the B16F10 transplantable tumor of the representative compound CPUL-I021 of the present invention of table 3
By Fig. 1, Fig. 2 and table 3 as it can be seen that the compounds of this invention has good inhibitory activity to the growth of malignant tumour.
(4) pharmacokinetic studies of IDO1 inhibitor in rats
SD rat 10 are chosen, male, 180~200g of weight, stomach-filling or vein are given compound CPUL-I021, be shown in Table
4:
The administrations of 4 compound CPUL-I021 of table in rats
Gastric infusion is formulated as suspension with 1%MC, and intravenous injection is with DMSO:30%PEG400 (5:95) preparation.Test
Preceding fasting 12h, free water.2h is unified after administration feeds.It takes a blood sample after administration according to following time point: when gastric infusion group is taken a blood sample
Between point be after administration 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and for 24 hours；Intravenously administrable group blood sampling time point is after being administered
0.25,0.5,1.0,2.0,4.0,6.0,8.0 and for 24 hours.At above-mentioned time point through rat eye rear vein beard extracting vein blood
0.3mL is placed in EDTA-2K test tube, and 11000rpm is centrifuged 5min, and separated plasma is placed in -20 DEG C of refrigerators and freezes.Using LC/
MS/MS method measures 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 TmaxFor measured value；Area under the drug-time curve AUC0-tValue is calculated using trapezoidal method；
AUC0-∞=AUC0-t+Ct/ke, Ct is that the last one can measure the blood concentration at time point, keFor 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=(AUCStomach-filling×DVein)/(AUCVein×DStomach-filling) × 100%.It the results are shown in Table 5 and table 6.
The pharmacokinetic parameters after 10mg/kg CPUL-I021 are administered in 5 rat oral gavage of table
The pharmacokinetic parameters after 1mg/kg CPUL-I021 are administered in 6 rat vein of table
Detailed description of the invention
Fig. 1 is separation tumor mass weighing after putting to death lotus knurl C57BL6 mouse
Fig. 2 is gross tumor volume and administration number of days relationship
Specific embodiment
Embodiment 1
The preparation of 4- amino -3- (N '-hydroxyl amidino groups) -1,2,5- oxadiazoles (II)
Sodium nitrite (20.7g, 300mmol) and 40mL water are added in 500mL reaction flask, 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, is cooled to 0 DEG C, hydrochloric acid hydroxyl is added dropwise
The aqueous solution of amine (23g, 340mmol) stirs 30min, and 20 DEG C or less adjust pH to 10 with 10N sodium hydroxide, rises to 35 DEG C instead
2h is answered, reflux 2h is reheated.It being cooled to room temperature, reaction solution is extracted with 20mL ethyl acetate, and evaporating solvent under reduced pressure obtains white solid,
Water layer is stood overnight, solid is precipitated, is filtered, washing, filter cake merges dry white powder with white solid is evaporated under reduced pressure to
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- chloro 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 are added to 250mL
It answers in bottle, rises to 45 DEG C of stirring and dissolvings, be added solid sodium chloride (5.12g, 87.5mmol), stirring and dissolving, be cooled to 0 DEG C, analysis
The aqueous solution of sodium nitrite (2.00g, 29mmol) is slowly added dropwise in white solid out, and 0 DEG C of 3h stirred below is warmed to room temperature, and takes out
Filter, filter cake washing, re crystallization from toluene obtain 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 ethyl alcohol are added in 100mL reaction flask, stirred, at room temperature successively slowly
40% methylethylolamine solution (0.48g, 6.2mmol) and triethylamine (1.25g, 12.4mmol) is added dropwise, 3h is stirred at room temperature, depressurizes
Solvent is evaporated off, ethyl acetate stirring is added, filters, filtrate water and saturated sodium-chloride water solution respectively wash 1 time, anhydrous sodium sulfate
Dry organic layer, evaporating solvent under reduced pressure obtain yellow oil (0.68g, 70.1%).HRMS m/z[M+H]+calculated
for C4H7N5O2:157.0602,found:157.0600。
The preparation of 4- methylamino -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 flask, potassium hydroxide is slowly added dropwise under stirring
The 3mL aqueous solution of (0.73g, 13mmol), is heated to reflux 14h, after completion of the reaction through TLC detection, is cooled to room temperature, with acetic acid second
Ester extracts (5 × 4mL), merges organic phase, and anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure obtain light 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- oxadiazoles -3- base) 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 reaction
In bottle, return stirring about 8h after completion of the reaction through TLC detection is cooled to room temperature, evaporating solvent under reduced pressure, column chromatographic purifying obtains 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
It is replaced outside methylamine with ethamine (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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
It is replaced outside methylamine with cyclopropylamine (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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
It is replaced outside methylamine with n-propylamine (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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
It is replaced outside methylamine with tert-butylamine (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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
It is replaced outside methylamine with cyclohexylamine (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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
It is replaced outside methylamine with 4- oxygen azo-cycle hexane (6.2mmol), with method synthesis identical with compound CPUL-I001
It closes object 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
It is replaced outside methylamine with aniline (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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
It is replaced outside methylamine with benzylamine (6.2mmol), synthesizes compound in method identical with compound CPUL-I001
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 anhydride replace phthalic anhydride outside, with compound CPUL-
Identical method synthesis compound CPUL-I010 (0.31g, 14.5%) of I001.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 anhydride replace phthalic anhydride outside, with compound CPUL-
Identical method synthesis compound CPUL-I011 (0.41g, 17%) of I001.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-cycle hexane (6.2mmol) replace methylamine, 4- chloride anhydride replace phthalic anhydride outside, with compound
Identical method synthesis compound CPUL-I012 (0.39g, 16.5%) of CPUL-I001.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 anhydride replace phthalic anhydride outside, with compound CPUL-
Identical method synthesis compound CPUL-I013 (0.34g, 14.5%) of I001.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- bromobenzene acid anhydride replace phthalic anhydride outside, with compound CPUL-
Identical method synthesis compound CPUL-I014 (0.38g, 15.5%) of I001.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- bromobenzene acid anhydride replace phthalic anhydride outside, with compound CPUL-
Identical method synthesis compound CPUL-I015 (0.46g, 17%) of I001.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-cycle hexane (6.2mmol) replace methylamine, 4- bromobenzene acid anhydride replace phthalic anhydride outside, with compound
Identical method synthesis compound CPUL-I016 (0.39g, 15%) of CPUL-I001.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- bromobenzene acid anhydride replace phthalic anhydride outside, with compound CPUL-
Identical method synthesis compound CPUL-I017 (0.40g, 15%) of I001.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-
Identical method synthesis compound CPUL-I018 (0.29g, 14%) of I001.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
Identical method synthesis compound CPUL-I019 (0.33g, 14.5%) of CPUL-I001.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-cycle hexane (6.2mmol) replace methylamine, 4- methyl phthalic anhydride replace phthalic anhydride outside, with chemical combination
Identical method synthesis compound CPUL-I020 (0.33g, 15.5%) of object CPUL-I001.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-
Identical method synthesis compound CPUL-I021 (0.36g, 16%) of I001.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 representative-NH2、
N represents 0~3；
M represents 0 or 1.
2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein X represents methyl.
3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R is represented
4. the preparation method of the compound of claim 1,2 or 3, comprising:
Wherein the definition of X, R are the same as 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 that treatment IDO1 is mediated
The purposes of the drug of the disease of the pathological characteristics of metabolic pathway.
7. the purposes of claim 6, the disease of the pathological characteristics for the tryptophan metabolic pathway that wherein IDO1 is mediated is pernicious swollen
Tumor.
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| 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 |
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|---|---|---|---|---|
| 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 |
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