CN105616408A - Use of pyridino[3,4-b]indol derivative as IDO inhibitor - Google Patents

Use of pyridino[3,4-b]indol derivative as IDO inhibitor Download PDF

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CN105616408A
CN105616408A CN201610014976.3A CN201610014976A CN105616408A CN 105616408 A CN105616408 A CN 105616408A CN 201610014976 A CN201610014976 A CN 201610014976A CN 105616408 A CN105616408 A CN 105616408A
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CN105616408B (en
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钱珊
王周玉
杨羚羚
李国菠
张曼
王伟
何彦颖
陈泉龙
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Xihua University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

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Abstract

The invention discloses uses of pyridino[3,4-b]indol derivatives in preparation of IDO inhibitor medicines. A compound in the invention can be used for preventing and/or treating various diseases such as Alzheimer disease, cataracts, cellular immunity activation-related infections, autoimmune diseases, aids, cancers, depressions, tryptophan metabolic disorders or the like.

Description

Pyrido [3,4-b] indole derivatives is as the purposes of IDO inhibitor
Technical field
The present invention relates to pyrido [3,4-b] indole derivatives purposes as IDO inhibitor.
Background technology
IDO (Indoleamine2,3-dioxygenase, IDO) is indole ring oxicracking in the indole amine molecules such as catalysis tryptophan so that it is by the catabolic rate-limiting enzyme of kynurenine approach.
IDO exempts in tumour immunity and plays an important role in tumor generating process. Under normal circumstances, IDO is in vivo in low expression level, the high expressed IDO that most of tumor cells then can form, L-Trp is converted into N-formylkynurenine, reduce the Tryptophan concentration in cell micro-environment, the T cell synthesis that tryptophan relies on was stagnated in the G1 phase, and T cell propagation is suppressed, thus inhibiting the body immune system lethal effect to tumor tissues. Meanwhile, there is cytotoxicity in the metabolite of the lower tryptophan of IDO effect, T cell can produce direct dissolution.
Therefore, it is suppressed that the activity of IDO can stop the degraded of near tumor cells tryptophan effectively, the propagation of T cell is promoted, thus the attacking ability that enhancing body is to tumor cell. Further, IDO inhibitor can also be share with chemotherapeutics, reduces the drug resistance of tumor cell, thus strengthening 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 pathogenesis of the multiple disease relevant with cellular immunization activation. IDO has been found to the target being to activate the major diseases such as relevant infection, malignant tumor, autoimmune disease, acquired immune deficiency syndrome (AIDS) to cellular immunization. Simultaneously, it is suppressed that IDO still for suffering from nervous system disease such as depression, the critical treatment strategy of the patient of Alzheimer. Therefore, IDO inhibitor has wide potential applicability in clinical practice.
Summary of the invention
The invention provides the IDO inhibitor class medicine of a class brand new, they are all pyrido [3,4-b] indole derivativeses.
The invention provides compound shown in formula I or its pharmaceutically acceptable salt or its prodrug or its solvate purposes in preparation IDO inhibitor class medicine:
Wherein,
A indicate without or-OH adjacent on ring and-COOH replace orOne or more substituent groups on ring; Described substituent group is selected from halogen, trifluoromethyl, methyl, the alkyl of non-methyl, alkoxyl, ester group ,-OH ,-COOH ,-CONHOH ,-CH2COOH��-SO3H��-SO2NH2Or-BOOH;
B indicate without or withAt an arbitrary position and the aromatic ring closed or the aromatic ring of replacement, 5-membered aromatic or nonaromatic heterocycles, hexa-atomic fragrance or nonaromatic heterocycles, five yuan of saturated rings or hexa-atomic saturated rings;
L represents
When B indicate without time, in one end of L and pyrido [3,4-b] indole structure, the nitrogen-atoms on pyrrole ring is connected, the other end withRing is connected;
When B represent withAt an arbitrary position and the aromatic ring closed the or when aromatic ring of replacement, 5-membered aromatic or nonaromatic heterocycles, hexa-atomic fragrance or nonaromatic heterocycles, five yuan of saturated rings or hexa-atomic saturated rings, one end of L and pyrido [3,4-b] nitrogen-atoms on pyrrole ring is connected in indole structure, the other end withRing or ring B are connected;
X represents carbon or nitrogen.
Further, shown in the structure of described compound such as formula (I a) or formula (I b):
Wherein, X and A is as defined in claim 1.
Further, shown in the structure of described compound such as formula (I aa) or formula (I ba):
Wherein, R represents 1��3 substituent group on phenyl ring, and described substituent group is selected from halogen ,-COOH or-COORa; RaAlkyl selected from C1��6.
Further, described R represents 1 substituent group on phenyl ring, and described substituent group is selected from halogen ,-COOH or-COORa; RaAlkyl selected from C1��6.
Further, described halogen is selected from chlorine, RaSelected from methyl or ethyl.
It is further preferred that described compound is selected from one of compound:
Further, described medicine is the medicine that prevention and/or treatment Alzheimer, cataract, cellular immunization activate that relevant infection, autoimmune disease, acquired immune deficiency syndrome (AIDS), cancer, depression or tryptophan metabolism are abnormal.
Present invention also offers a kind of pharmaceutical composition, it is with aforesaid compound or its pharmaceutically acceptable salt for active component, adds the preparation that pharmaceutically acceptable adjuvant is prepared from.
Present invention also offers described pharmaceutical composition purposes in preparation IDO inhibitor class medicine.
Further, described medicine is the medicine that prevention and/or treatment Alzheimer, cataract, cellular immunization activate that relevant infection, autoimmune disease, acquired immune deficiency syndrome (AIDS), cancer, depression or tryptophan metabolism are abnormal.
Halogen of the present invention includes but not limited to fluorine, chlorine, bromine, iodine.
C of the present invention1��C6Alkyl refer to the alkyl of the straight or branched with 1��6 carbon atom, for instance methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, hexyl etc.
Described prodrug is the derivant of aforesaid compound, their own is likely to be of more weak activity or even without activity, but it is converted to corresponding biologically active form (such as by metabolism, solvolysis or other mode) upon administration, in physiological conditions.
Described preparation can include injection or oral formulations.
One or more compounds of the present invention can combine with one another use, it is possible to selects with other active agent any, the compound of the present invention is combined use, is used for preparing IDO inhibitor. If using one group of compound, then can by these compounds simultaneously, be administered respectively or in an orderly manner to study subject.
Pharmaceutically acceptable adjuvant of the present invention, refers to the material being included in dosage form in addition to the active ingredient (s.
Tests prove that, pyrido [3 provided by the invention, 4-b] indole derivatives IDO albumen is had excellence inhibitory action, may be used for treating multiple disease, as Alzheimer, cataract, cellular immunization activate infection, autoimmune disease, acquired immune deficiency syndrome (AIDS), cancer, depression or the tryptophan metabolism exception etc. be correlated with.
Simultaneously, pyrido provided by the invention [3,4-b] indole derivatives, this structure is the brand-new chemical constitution with IDO inhibitory activity, it is incorporated in same a part by the bridge crosslinking structure shown in L by pyrido [3,4-b] indole structure and another circulus. Therefore, the present invention is also that pyrido [3,4-b] indole structure provides new derivatization direction and purposes.
Obviously, the foregoing according to the present invention, according to ordinary technical knowledge and the customary means of this area, without departing under the above-mentioned basic fundamental thought premise of the present invention, it is also possible to make the amendment of other various ways, replacement or change.
The detailed description of the invention of form by the following examples, is described in further detail the foregoing of the present invention again. But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below. All technology realized based on foregoing of the present invention belong to the scope of the present invention.
Detailed description of the invention
The preparation of embodiment 1 the compounds of this invention key intermediate
1, the synthesis of 2-(9H-pyrido [3,4-b] indole-9-base) ethyl acetate (2)
To buy in lark prestige CAS as 244-63-3; Production code member is the starting compound 1 (0.50g of 230515,2.98mmol) with 60%NaH (0.24g, 5.96mmol) it is placed in round-bottomed flask, dissolved with 10mLDMF again, after stirring at normal temperature 2h, bromoacetate (0.49mL, 4.46mmol) is added drop-wise in above-mentioned reactant liquor, it is complete that room temperature reaction 5h, TLC detect raw material fundamental reaction.
Add water, be extracted with ethyl acetate 3 times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (CH2Cl2:CH3OH=60:1) purification, obtains faint yellow solid compound 2 (0.40g, yield 54%).
Compound 2:1HNMR(400MHz,CDCl3): �� 8.85 (s, 1H), 8.52 (d, J=5.0Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 7.99 (d, J=5.1Hz, 1H), 7.63 (t, J=7.8Hz, 1H), 7.42 (d, J=8.3Hz, 1H), 7.35 (t, J=7.5Hz, 1H), 5.10 (s, 1H), 4.25 (q, J=7.1Hz, 2H), 1.27 (t, J=7.1Hz, 3H).
2, the synthesis of 2-(9H-pyrido [3,4-b] indole-9-base) acetic acid (3)
With 5mL water and 5mL ethanol, compound 2 (0.20g, 0.79mmol) and NaOH (0.10g, 2.37mmol) are dissolved, be warming up to 100 DEG C of reaction 2h, TLC detection raw material reactions complete.
Reactant liquor is cooled to room temperature afterwards, and decompression is distilled off solvent, adds water, having white solid to precipitate out when pH being adjusted to 6��7 with rare HCl, filter, vacuum drying oven dries to obtain compound as white solid 3 (0.16g, yield 90%), purity detects more than 90% through HPLC.
3, the synthesis of (1-(tert-butoxy carbonyl) amino) ethanol-(4-toluenesulfonic acid) ester (6)
To buy in Rui Ouke science and technology CAS as 26690-80-2; Production code member is raw material (tertbutyloxycarbonyl) ethylaminoethanol (5.00g of R0K11845-2,31.06mmol) and TsCl (11.88g, 62.12mmol) be dissolved in 20mL pyridine, reaction 12h, TLC detection is stirred at room temperature and reacts completely.
Decompression is distilled off a part of pyridine, add water, being extracted with ethyl acetate 3 times, organic layer is dried over magnesium sulfate, crude product obtains compound as white solid 6 (4.89g, yield 50%) through silica gel column chromatography (petroleum ether: ethyl acetate=3:1) purification after concentration.
4, the synthesis of t-butoxy (2-(9H-pyrido [3,4-b] indole-9-base) ethyl) carbamate (7)
By compound 1 (0.50g, 2.98mmol) with 60%NaH (0.24g, 5.96mmol) it is placed in round-bottomed flask, dissolved with 10mLDMF again, after 45 DEG C of stirring 2h, then compound 6 (2.81g, 8.94mmol) is added in above-mentioned reactant liquor, 16h, TLC detection raw material fundamental reaction is stirred at room temperature complete.
Add water, be extracted with ethyl acetate 3 times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (CH2Cl2:CH3OH=30:1) purification obtains faint yellow solid compound 7 (0.74g, yield 77%).
Compound 7:1HNMR(400MHz,CDCl3): �� (ppm) 8.92 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 8.17 (d, J=7.8Hz, 1H), 7.98 (dd, J=5.2Hz, 0.8Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.55 (d, J=8.3Hz, 1H), 7.33 (t, J=7.8Hz, 1H), 4.65 (s, br, 1H), 4.59 (t, J=5.7Hz, 2H), 3.62 (q, J=6.0Hz, 2H), 1.45 (s, 9H).
5, the synthesis of 2-(9H-pyrido [3,4-b] indole-9-base) ethyl-1-amino (8)
First with the CH of 10mL2Cl2Being dissolved by compound 7 (0.21g, 0.66mmol), add 1.60mL trifluoroacetic acid under stirring at room temperature, after reaction 5h, it is complete that TLC detects raw material reaction.
Decompression is distilled off solvent, uses saturated NaHCO3Being adjusted to pH is 8, extraction into ethyl acetate 3 times, organic layer is dried over magnesium sulfate, after concentration faint yellow solid compound 8 (0.12g, yield 86%).
The synthesis of embodiment 2N-benzyl-2-(9H-pyrido [3,4-b] indole-9-base) acetamide (5a)
First use 2mLCH2Cl2By compound 4 (0.05g, 0.22mmol) dissolve, it is gradually added benzylamine (0.05mL under stirring at 0 DEG C, 0.44mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 0.05g, 0.27mmol), 1-hydroxy benzo triazole (HOBT, 0.04g, 0.27mmol) with N, N-diisopropylethylamine (DIEA, 0.09mL, 0.44mmol), finish, be warming up to be stirred at room temperature reaction 12h, TLC detect display react completely.
Add water, with dichloromethane extraction three times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (CH2Cl2:CH3OH=60:1) purification obtains compound as white solid 5a (0.04g, yield 58%).
Compound 5a: purity is 98% through HPLC test;1HNMR(400MHz,CDCl3): �� (ppm) 8.91 (s, 1H), 8.55 (d, J=5.2Hz, 1H), 8.19 (d, J=8.0Hz, 1H), 7.99 (d, J=5.2Hz, 1H), 7.67 (t, J=8.0Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.40 (t, J=8.0Hz, 1H), 7.70-7.08 (m, 5H), 6.04 (s, br, 1H), 5.11 (s, 2H), 4.44 (d, J=4.0Hz, 2H).13CNMR(100MHz,CDCl3): �� 167.3,141.1,140.3,137.3,136.5,131.7,129.2,128.7,127.6,12 7.3,122.2,121.7,121.1,114.8,109.4,47.2,43.4; ESI-MSm/z:316.14 [M+H].
The synthesis of embodiment 3N-(pyridine-3-methylene)-2-(9H-pyrido [3,4-b] indole-9-base) acetamide (5b)
First use 2mLCH2Cl2By compound 4 (0.03g, 0.13mmol) dissolve, it is gradually added pyridine-3-methylamine (0.03g under stirring at 0 DEG C, 0.26mmol), EDCI (0.03g, 0.16mmol), HOBT (0.02g, 0.16mmol) and DIEA (0.06mL, 0.26mmol), finishing, after being warming up to room temperature, stirring reaction 12h, TLC detection reacts completely.
Add water, use CH2Cl2Extract three times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (CH2Cl2:CH3OH=10:1) purification obtains compound as white solid 5b (0.03g, yield 71%).
Compound 5b: purity is 98% through HPLC test;1HNMR(400MHz,CDCl3): �� (ppm) 8.80 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 8.39 (d, J=4.7Hz, 1H), 8.28 (d, J=1.7Hz, 1H), 8.14 (d, J=7.8Hz, 1H), 7.92 (d, J=5.2Hz, 1H), 7.65 (t, J=7.6Hz, 1H), 7.46-7.43 (m, 2H), 7.38 (t, J=7.6Hz, 1H), 7.16 (q, J=7.7Hz, J=4.6Hz, 1H), 6.42 (s, br, 1H), 5.06 (s, 2H), 4.41 (d, J=6.0Hz, 2H).13CNMR(100MHz,CDCl3):��167.6,148.8,148.7,141.1,140.1,136.4,135.3,133.3,131.5,129.3,129.2,123.5,122.2,121.6,121.1,114.7,109.3,47.1,40.8.LC-MSm/z:317.12[M+H]��
The synthesis of embodiment 4N-(4-chlorphenyl)-2-(9H-pyrido [3,4-b] indole-9-base) acetamide (5c)
First use 2mLCH2Cl2By compound 4 (0.03g, 0.13mmol) dissolve, it is gradually added chlorobenzylamine (0.04g under stirring at 0 DEG C, 0.26mmol), EDCI (0.03g, 0.16mmol), HOBT (0.02g, 0.16mmol) and DIEA (0.06mL, 0.26mmol), finish, be warming up to be stirred at room temperature reaction 12h, TLC detection react completely.
Add water, with dichloromethane extraction three times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (CH2Cl2:CH3OH=40:1) purification obtains compound as white solid 5c (0.03g, yield 65%).
Compound 5c: purity is 98% through HPLC test;1HNMR(400MHz,CDCl3): �� (ppm) 8.78 (s, 1H), 8.43 (d, J=5.2Hz, 1H), 8.28 (d, J=8.0Hz, 1H), 7.87 (d, J=5.2Hz, 1H), 7.58 (t, J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.30 (d, J=7.6Hz, 2H), 7.15 (d, J=7.6Hz, 2H), 5.80 (s, br, 1H), 5.08 (s, 2H), 4.34 (d, J=4.0Hz, 2H).13CNMR(100MHz,CDCl3): �� 168.8,142.1,140.8,138.8,138.7,135.9,132.2,130.7,130.6,12 7.5,125.2,123.7,120.4,116.8,109.4,108.2,46.2,43.4; ESI-MSm/z:350.10 [M+H].
Embodiment 53-((2-(9H-pyrido [3,4-b] indole-9-base) acetylamino) methyl) synthesis of ethyl benzoate (5d) and 3-((2-(9H-pyrido [3,4-b] indole-9-base) acetylamino) methyl) benzoic acid (5e)
First use 3mLCH2Cl2By 3-amine methyl-benzoic acid-ethyl ester (0.04g, 0.22mmol) dissolve, it is gradually added compound 4 (0.10g, 0.44mmol), EDCI (0.05g, 0.27mmol), HOBT (0.04g under stirring at 0 DEG C, 0.27mmol) with DIEA (0.09mL, 0.44mmol), finish, be warming up to room temperature, stirring reaction 12h, TLC detection reacts completely.
Adding water, with dichloromethane extraction three times, after organic layer drying, concentration, crude product is through column chromatography (CH2Cl2:CH3OH=30:1) purification obtains white solid 5d (0.05g, yield 63%). Purity is 98% through HPLC test.
With 2mL water and 2mL ethanol, compound 5d (0.05g, 0.22mmol) and NaOH (0.03g, 0.67mmol) is dissolved, be warming up to 100 DEG C of back flow reaction 2h, TLC detection raw material reactions complete.
Reactant liquor is cooled to room temperature, and decompression adds water after solvent is distilled off, and has white solid to precipitate out when pH being adjusted to 6��7 with rare HCl, and filtration, vacuum drying oven dries to obtain white powder 5e (0.04g, yield 85%).
Compound 5e: purity is 98% through HPLC test;1HNMR(400MHz,DMSO-d6): �� (ppm) 9.00 (s, 1H), 8.94 (t, J=5.8Hz, 1H), 8.40 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.14 (d, J=5.2Hz, 1H), 7.91 (s, 1H), 7.83 (d, J=7.6Hz, 1H), 7.66-7.59 (m, 2H), 7.52 (d, J=7.6Hz, 1H), 7.45 (t, J=7.6Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 5.26 (s, 2H), 4.40 (d, J=5.8Hz, 2H).13CNMR(100MHz,DMSO-d6):��167.8,167.6,141.8,140.1,139.2,137.3,133.3,132.2,131.5,129.1,128.8,128.6,128.4,128.0,122.3,121.1,120.2,115.0,110.6,46.2,42.5.ESI-MSm/z:360.13[M+H]��
Embodiment 64-((2-(9H-pyrido [3,4-b] indole-9-base) acetylamino) methyl) synthesis of ethyl benzoate (5g) and 4-((2-(9H-pyrido [3,4-b] indole-9-base) acetylamino) methyl) benzoic acid (5f)
According to the method for embodiment 5, substitute 3-amine methyl-benzoic acid-ethyl ester with 4-amine methyl-benzoic acid-ethyl ester, obtain compound 5g (0.06g, yield 86%). According to the method for embodiment 6, with compound 5g alternative compounds 5d. Obtain compound 5f (0.05g, yield 88%).
Compound 5f: purity is 98% through HPLC test;1HNMR(400MHz,DMSO-d6): �� (ppm) 12.87 (s, br, 1H), 9.07 (s, 1H), 8.96 (t, J=6.0Hz, 1H), 8.44 (d, J=5.2Hz, 1H), 8.32 (d, J=7.8Hz, 1H), 8.24 (d, J=5.2Hz, 1H), 7.89 (d, J=8.2Hz, 2H), 7.70-7.63 (m, 2H), 7.39 (d, J=8.2Hz, 2H), 7.34 (t, J=6.8Hz, 1H), 5.29 (s, 2H), 4.40 (d, J=5.8Hz, 2H).13CNMR(100MHz,DMSO-d6):��167.8,167.6,144.7,142.1,138.2,137.2,132.5,131.7,129.8,129.2,128.7,127.7,122.6,121.0,120.5,115.3,110.8,46.3,42.6.ESI-MSm/z:360.13[M+H]��
The synthesis of embodiment 7N-(2-(9H-pyrido [3,4-b] indole-9-base) ethyl) Benzoylamide (10a)
First use 2mLCH2Cl2By compound 8 (0.03g, 0.14mmol) dissolve, it is gradually added benzoic acid (0.03g under stirring at 0 DEG C, 0.28mmol), EDCI (0.03g, 0.17mmol), HOBT (0.025g, 0.17mmol) and DIEA (0.06mL, 0.28mmol), finish, be warming up to room temperature reaction 12h, TLC detection and react completely. Add water, with dichloromethane extraction three times, organic layer is dried over magnesium sulfate, after concentration through silica gel column chromatography (CH2Cl2:CH3OH=15:1) purification obtains faint yellow solid 10a (0.03g, yield 68%).
Compound 10a: purity is 99% through HPLC test;1HNMR(400MHz,CDCl3): �� (ppm) 8.93 (s, 1H), 8.38 (d, J=5.2Hz, 1H), 8.16 (d, J=7.9Hz, 1H), 7.96 (d, J=5.2Hz, 1H), 7.62-7.56 (m, 4H), 7.47 (t, J=7.2Hz, 1H), 7.38-7.30 (m, 3H), 6.69 (t, J=5.2Hz, 1H), 4.72 (t, J=6.0Hz, 2H), 3.95 (q, J=6.0Hz, 2H) .ESI-MSm/z:316.14 [M+H].
The synthesis of embodiment 83-((2-(9H-pyrido [3,4-b] indole-9-base) ethyl) carbamyl) benzoic acid (10b)
First use 2mLCH2Cl2By compound 8 (0.03g, 0.14mmol) dissolve, it is gradually added M-phthalic acid (0.07g under stirring at 0 DEG C, 0.41mmol), EDCI (0.03g, 0.17mmol), HOBT (0.025g, 0.17mmol) and DIEA (0.06mL, 0.28mmol), finish, be warming up to room temperature reaction 12h, TLC detection and react completely. Add water, with dichloromethane extraction three times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (CH2Cl2:CH3OH=5:1) purification obtains faint yellow solid 10b (0.02g, yield 40%).
Compound 10b: purity is 99% through HPLC test;1HNMR(400MHz,DMSO-d6): �� (ppm) 9.03 (s, 1H), 8.83 (t, J=5.5Hz, 1H), 8.35 (d, J=5.2Hz, 1H), 8.26 (m, 2H), 8.12 (d, J=5.2Hz, 1H), 8.03 (d, J=7.7Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.72 (d, J=8.3Hz, 1H), 7.58-7.50 (m, 2H), 7.26 (t, J=7.4Hz, 1H), 4.71 (t, J=6.0Hz, 2H), 3.74 (q, J=6.0Hz, 2H) .ESI-MSm/z:358.13 [M-H].
The synthesis of embodiment 94-((2-(9H-pyrido [3,4-b] indole-9-base) ethyl) carbamyl) benzoic acid (10c)
According to the method for embodiment 8, substitute M-phthalic acid with p-phthalic acid. Obtain compound 10c (0.03g, yield 31%).
Compound 10c: purity is 99% through HPLC test;1HNMR(400MHz,DMSO-d6): �� (ppm) 12.98 (s, br, 1H), 9.15 (s, 1H), 8.81 (t, J=5.8Hz, 1H), 8.42 (d, J=5.4Hz, 1H), 8.33 (d, J=7.8Hz, 1H), 8.29 (d, J=5.4Hz, 1H), 7.92 (d, J=8.5Hz, 2H), 7.77 (d, J=8.4Hz, 1H), 7.66 (d, J=8.5Hz, 2H), 7.62 (t, J=8.5Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 4.75 (t, J=5.8Hz, 2H), 3.76 (q, J=6.0Hz, 2H).13CNMR(100MHz,DMSO-d6):��167.2,166.6,142.2,138.3,136.8,136.7,133.4,131.5,129.6,129.5,129.2,127.7,122.8,120.7,120.4,115.7,110.7,42.8,39.2.ESI-MSm/z:358.13[M-H]��
Embodiment 10 the compounds of this invention inhibitory activity to IDO albumen
Recombined human IDO albumen through escherichia coli expression, nickel affinity chromatography purification and obtain. The experiment of IDO inhibitory activity is adopted L-Trp as substrate by compound. Testing compound is dissolved in 10%DMSO solution and is configured to diluent. Take 5 �� L diluents to join in 100 �� L reaction systems. Containing 0.5%DMSO, 40nmol/LIDO, 900 ��m of ol/LL-tryptophan in 100 �� L reaction systems, and other reactions concurrent (kaliumphosphate buffer, ascorbic acid, catalase, methylene blue). Reactant mixture, in 37 degree of lower cultivations 180 minutes, adds trichloroacetic acid and terminates reaction. TecanInfiniteM1000 microplate reader is used to measure the concentration of the N-formoxyl kynurenin produced at 321nm place, thus evaluating the compound inhibitory activity to IDO. Negative control thing is to replace IDO with the buffer of 5 �� L. Using IDO inhibitor INCB024360 as positive control, verify that whether the IDO Activity determination system that this experiment is set up is effective.
Each concentration sets up three wells. Software GraphpadPrism is used to carry out data analysis. Without in the reactant liquor of testing compound, absorbance (At) it is defined as 100% activity. Without in the reactant liquor of IDO, absorbance (Ab) it is defined as 0% activity. For testing compound, the computing formula of activity is: %activity=[(A-Ab)/(At-Ab)] �� 100, wherein A is the absorbance of the reactant liquor containing testing compound. The computing formula of suppression ratio is: %inhibition=100-%activity.
By above experimental technique, test the inhibitory activity for IDO of the compound in the present invention. Particular compound inhibitory activity under 1 ��M, 10 ��Ms, 100 ��Ms concentration is in Table 1.
Wherein A represent suppression ratio more than 40%, B represent that suppression ratio is that 30%-40%, C represent that suppression ratio is that 20%-30%, D represent that suppression ratio is 10%-20%; E represents that suppression ratio is less than 10%; * represent that sample dissolubility is bad; ND represents and does not test. Positive control is suppression ratio when 0.05 ��M in concentration is 46%.
Table 1 the compounds of this invention inhibitory activity to IDO
Result shows, IDO is all had certain inhibitory activity by the compound of the present invention. Wherein, the structure of L isTime 5 series compound activity better, for instance compound 5d that carboxyl or ester group replace, 5e, 5f and 5g; Especially compound 5f, its under the concentration of 100 ��Ms to the suppression ratio of IDO more than 40%, effect is very notable.
In sum, pyrido [3 provided by the invention, 4-b] indole derivatives, IDO is had the inhibitory action of excellence, may be used for treating multiple disease, as Alzheimer, cataract, cellular immunization activate infection, autoimmune disease, acquired immune deficiency syndrome (AIDS), cancer, depression or the tryptophan metabolism exception etc. be correlated with.

Claims (10)

1. compound shown in formula I or its pharmaceutically acceptable salt or its prodrug or its solvate purposes in preparation IDO inhibitor class medicine:
Wherein,
A indicate without or-OH adjacent on ring and-COOH replace orOne or more substituent groups on ring; Described substituent group is selected from halogen, trifluoromethyl, methyl, the alkyl of non-methyl, alkoxyl, ester group ,-OH ,-COOH ,-CONHOH ,-CH2COOH��-SO3H��-SO2NH2Or-BOOH;
B indicate without or withAt an arbitrary position and the aromatic ring closed or the aromatic ring of replacement, 5-membered aromatic or nonaromatic heterocycles, hexa-atomic fragrance or nonaromatic heterocycles, five yuan of saturated rings or hexa-atomic saturated rings;
L represents
When B indicate without time, in one end of L and pyrido [3,4-b] indole structure, the nitrogen-atoms on pyrrole ring is connected, the other end withRing is connected;
When B represent withAt an arbitrary position and the aromatic ring closed the or when aromatic ring of replacement, 5-membered aromatic or nonaromatic heterocycles, hexa-atomic fragrance or nonaromatic heterocycles, five yuan of saturated rings or hexa-atomic saturated rings, one end of L and pyrido [3,4-b] nitrogen-atoms on pyrrole ring is connected in indole structure, the other end withRing or ring B are connected;
X represents carbon or nitrogen.
2. purposes according to claim 1, it is characterised in that: the structure of described compound such as formula (I a) or shown in formula (I b):
Wherein, X and A is as defined in claim 1.
3. purposes according to claim 2, it is characterised in that: the structure of described compound such as formula (I aa) or shown in formula (I ba):
Wherein, R represents 1��3 substituent group on phenyl ring, and described substituent group is selected from halogen ,-COOH or-COORa; RaAlkyl selected from C1��6.
4. purposes according to claim 3, it is characterised in that: described R represents 1 substituent group on phenyl ring, and described substituent group is selected from halogen ,-COOH or-COORa; RaAlkyl selected from C1��6.
5. the purposes according to claim 3 or 4, it is characterised in that: described halogen is selected from chlorine, RaSelected from methyl or ethyl.
6. purposes according to claim 5, it is characterised in that: described compound is selected from one of compound:
7. the purposes according to claim 1-6 any one claim, it is characterised in that: described medicine is the medicine that prevention and/or treatment Alzheimer, cataract, cellular immunization activate that relevant infection, autoimmune disease, acquired immune deficiency syndrome (AIDS), cancer, depression or tryptophan metabolism are abnormal.
8. a pharmaceutical composition, it is characterised in that: it is with the compound described in any one of claim 1-6 or its pharmaceutically acceptable salt for active component, adds the preparation that pharmaceutically acceptable adjuvant is prepared from.
9. the purposes in preparation IDO inhibitor class medicine of the pharmaceutical composition described in claim 8.
10. want the purposes described in 9 according to right, it is characterised in that: described medicine is the medicine that prevention and/or treatment Alzheimer, cataract, cellular immunization activate that relevant infection, autoimmune disease, acquired immune deficiency syndrome (AIDS), cancer, depression or tryptophan metabolism are abnormal.
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CN101932325A (en) * 2007-11-30 2010-12-29 新联基因公司 Ido inhibitors
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CN110294714A (en) * 2018-03-22 2019-10-01 西华大学 Imidazoles methylamine like derivative and its synthetic method with indoles amine -2,3- dioxygenase (IDO) inhibitor activity
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