CN107118209A - Pyridine a pair of horses going side by side [3,4-b] indoles carbamide compounds and its purposes as IDO inhibitor - Google Patents
Pyridine a pair of horses going side by side [3,4-b] indoles carbamide compounds and its purposes as IDO inhibitor Download PDFInfo
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- CN107118209A CN107118209A CN201610103753.4A CN201610103753A CN107118209A CN 107118209 A CN107118209 A CN 107118209A CN 201610103753 A CN201610103753 A CN 201610103753A CN 107118209 A CN107118209 A CN 107118209A
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- 0 *c1ccc*(CNC(N2*C2)=O)c1 Chemical compound *c1ccc*(CNC(N2*C2)=O)c1 0.000 description 10
- RYOXKQYCZDTIJJ-UHFFFAOYSA-N NC(NCC[n]1c(C=NCC2)c2c2ccccc12)=[U] Chemical compound NC(NCC[n]1c(C=NCC2)c2c2ccccc12)=[U] RYOXKQYCZDTIJJ-UHFFFAOYSA-N 0.000 description 1
- PVIAUEWEXVRHPE-UHFFFAOYSA-N NCC[n]1c(cccc2)c2c2ccncc12 Chemical compound NCC[n]1c(cccc2)c2c2ccncc12 PVIAUEWEXVRHPE-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
It is specifically substituted in the 9- positions of parallel [3, the 4-b] indoles of pyridine the invention discloses parallel [3,4-b] the indoles carbamide compounds of pyridine, and connecting bridge is ureas structure.The invention also discloses the preparation method of the compound and the purposes as IDO inhibitor.The compound of the present invention can be used for preventing and/or treat a variety of diseases, and such as Alzheimer disease, cataract, cellular immunity activation related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism is abnormal.
Description
Technical field
The present invention relates to parallel [3,4-b] the indoles carbamide compounds of pyridine, its preparation method and the purposes as IDO inhibitor are further related to.
Background technology
IDO (Indoleamine 2,3-dioxygenase, IDO) is indole ring oxicracking in the indoles amine molecules such as catalysis tryptophan, makes it by the rate-limiting enzyme of kynurenine approach catabolism.
IDO plays an important role in tumour immunity exemption and tumour generating process.Under normal circumstances, IDO is in low expression level in vivo, and the high expression IDO that most of tumour cells can then be constituted, L-Trp is converted into N- formylkynurenines, reduce the Tryptophan concentration in cell micro-environment, so that the T cell synthesis that tryptophan is relied on was stagnated in the G1 phases, T cell propagation is suppressed, so as to inhibit body immune system to the lethal effects of tumor tissues.Meanwhile, there is cytotoxicity in the metabolite of the lower tryptophan of IDO effects, can produce direct dissolution to T cell.
Therefore, the degraded of near tumor cells tryptophan can effectively be prevented by suppressing IDO activity, promote the propagation of T cell, so as to strengthen attacking ability of the body to tumour cell.Also, IDO inhibitor can also be shared with chemotherapeutics, the drug resistance of tumour cell is reduced, so as to strengthen the antitumor activity of conventional cytotoxic therapy.Take the curative effect that IDO inhibitor can also improve the therapeutic vaccine of cancer patient simultaneously.
Except being played an important role in terms of tumor cell drug resistance, pathogenesis of the IDO also to a variety of diseases related with cellular immunity activation is closely related.IDO have been found to be the major diseases such as infection, malignant tumour, autoimmune disease, the AIDS related to cellular immunity activation target.Meanwhile, suppress IDO still for the nervous system disease such as depression, the critical treatment strategy of the patient of Alzheimer disease.Therefore, IDO inhibitor has wide potential applicability in clinical practice.
The content of the invention
To solve the above problems, invention broadly provides the new IDO inhibitor class medicine of a class, they are parallel [3,4-b] the indoles carbamide compounds of pyridine.It is specifically substituted in the 9- positions of parallel [3, the 4-b] indoles of pyridine, and connecting bridge is ureas structure.
The invention provides a kind of compound or its pharmaceutically acceptable salt or its solvate, shown in the structure such as formula (I) of the compound：
A indicate without orOn ring adjacent-OH and-COOH substitutions orOne or more substituents on ring；The substituent is selected from halogen, alkyl, alkoxy, ester group ,-OH ,-COOH ,-SO3H or-SO2NH2；
X represents carbon or nitrogen；
N represents 0 or 1.
In specific a kind of embodiment of the invention, when X is selected from nitrogen,For 3- pyridine radicals.
Further, A indicate without orOn ring adjacent-OH and-COOH substitutions orOne or more substituents on ring；The substituent is selected from-COOH or ester group-COOR, R are selected from the alkyl of C1~4.
Further, the quantity of the substituent is 1 or 2.
Further, it is characterised in that：N is selected from 0.
Further, it is characterised in that：A is representedOn at least one-COOH substitution.
Further, the structure of the compound is one of following structure：
Present invention also offers the method for compound shown in a kind of formula (I), it is characterised in that：Comprise the steps：
(1)
Compound 2 is prepared using (tertbutyloxycarbonyl) ethylaminoethanol and paratoluensulfonyl chloride as raw material；
(2)
It is that raw material prepares compound 3 with compound 1 and compound 2, sloughs the blocking group on amino and obtain compound 4；
(3)
Compound 5-ic is prepared using compound 5 and Triphosgene as raw material；N=0 or 1；
(4)
Compound shown in formula (I) is prepared using compound 4 and compound 5-ic as raw material；
Wherein, it is its ester-formin in the raw material 5 used in step (3) when the group that A is represented includes-COOH structures, also, the step of also including hydrolyzing the ester group after step (4).
In some specific embodiments of the invention, A is selected from-COOR.The ester type compound of final product can as when A is selected from-COOH respective compound prepare intermediate, such as compound 6bEt, 6cEt, 6gEt, 6hEt can prepare intermediate as compound 6b, 6c, 6g and 6h, further by the conventional ester hydrolysis technological means in this area, ester hydrolysis reaction is prepared.In another example, it is compound 6d and 6e in invention specific embodiment, the initiation material of step (3) is its lactone form when A represents adjacent hydroxyl and carboxyl.
Present invention also offers the purposes of the compound or its pharmaceutically acceptable salt or its prodrug or its solvate on IDO inhibitor class medicine is prepared.
Further, the medicine is that prevention and/or treatment Alzheimer disease, cataract, cellular immunity activate the abnormal medicine of related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism.
Present invention also offers a kind of pharmaceutical composition, it is, using described compound or its pharmaceutically acceptable salt as active component, to add the preparation that pharmaceutically acceptable auxiliary material is prepared from.
Wherein, the composition is that treatment or prevention and/or treatment Alzheimer disease, cataract, cellular immunity activate the abnormal medicine of related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism
The prodrug is the derivative of aforesaid compound, their own may be with weaker activity or even without activity, but upon administration, it is converted to corresponding biologically active form (such as by metabolism, solvolysis or other mode) in physiological conditions.
Described preparation can include injection or oral formulations.
Key intermediate and compound in the present invention are separated and purified, and used mode is the Isolation and purification method commonly used in organic chemistry.
One or more compounds of the present invention can be used in conjunction with one another, and also may be selected the compound of the present invention being used in combination with any other active agent, for preparing IDO inhibitor.If using one group of compound, these compounds can simultaneously, respectively or in an orderly manner to study subject be administered.
Pharmaceutically acceptable auxiliary material of the present invention, refers to the material being included in addition to the active ingredient (s in formulation.
Tests prove that, pyridine a pair of horses going side by side [3 that the present invention is provided, 4-b] indoles carbamide compounds have excellent inhibitory action to IDO, it can be used for preventing and/or treat a variety of diseases, such as Alzheimer disease, cataract, cellular immunity activation related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism is abnormal.
In the present invention, the connotation of english abbreviation is as follows：
Ts：P-toluenesulfonyl.
Boc：Tert- butoxy carbonyl.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, under the premise of above-mentioned basic fundamental thought of the invention is not departed from, the modification of other diversified forms can also be made, replaces or changes.
The embodiment of form, is described in further detail again to the above of the invention by the following examples.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.All technologies realized based on the above of the present invention belong to the scope of the present invention.
Embodiment
The reagent and raw material are all from commercially available commodity, in addition to specially the initiation material in source is labelled with, and remaining reagent is purchased from Chengdu Ke Long chemical reagents corporations.
The preparation of the compounds of this invention key intermediate of embodiment 1
1st, the synthesis of (1- (tert- butoxy carbonyl) amino) ethanol-(4- toluenesulfonic acids) ester (2)
To buy in Rui Ouke science and technology No. CAS be 26690-80-2；Production code member is R0K11845-2 raw material (tertbutyloxycarbonyl) ethylaminoethanol (5.00g, 31.06mmol) with TsCl (11.88g, 62.12mmol) it is dissolved in 20mL pyridines, reaction 12h, TLC detection reaction is stirred at room temperature complete.
Vacuum distillation removes a part of pyridine, adds water, is extracted with ethyl acetate 3 times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography (petroleum ether:Ethyl acetate=3:1) compound as white solid 2 (4.89g, yield 50%) is purified to obtain.
2nd, the synthesis of t-butoxy (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) carbamate (3)
By lark prestige, No. CAS is 244-63-3；Production code member is the 230515 (0.50g of starting compound 1,2.98mmol) with 60%NaH (0.24g, 5.96mmol) it is placed in round-bottomed flask, dissolved again with 10mLDMF, after 45 DEG C of stirring 2h, then by the above-mentioned reaction solution of compound 2 (2.81g, 8.94mmol) addition, 16h is stirred at room temperature, TLC detections raw material fundamental reaction is 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) faint yellow solid compound 3 (0.74g, yield 77%) is purified to obtain.
Compound 3：1H NMR(400MHz,CDCl3):δ (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)
3rd, the synthesis of 2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl -1- amino (4)
First use 10mL CH2Cl2Compound 3 (0.21g, 0.66mmol) dissolving is added after 1.60mL trifluoroacetic acids, reaction 5h under stirring at room temperature, TLC detection raw material reactions are complete.
Vacuum distillation removes solvent, uses saturation NaHCO3PH is adjusted to for 8, ethyl acetate is extracted 3 times, organic layer is dried over magnesium sulfate, after concentration faint yellow solid compound 4 (0.12g, yield 86%).
The synthesis of the 1- of embodiment 2 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- phenylureas (6a)
15mLCH is dissolved in by aniline 5a (0.02mL, 2.19mmol)2Cl2With 15mL saturations NaHCO3The in the mixed solvent of the aqueous solution, adds TCL after Triphosgene (0.22g, 0.72mmol), equality of temperature stirring reaction 15min and shows complete reaction under being stirred at 0 DEG C.
Reaction solution is poured into separatory funnel, collected organic layer, dry, be concentrated to give phenylisocyanate crude product, not purified direct throwing next step.
Phenylisocyanate (0.02g, 0.15mmol) and compound 4 (0.03g, 0.14mmol) are dissolved in 4mLCH2Cl2, it is placed in TCL after 0 DEG C of stirring reaction 10h and shows complete reaction.
Reaction solution is directly spin-dried for obtaining crude product, crude product is through column chromatography (CH2Cl2:CH3OH=15:1) white solid powder 6a (0.05g, yield 98%) is purified to obtain.
Compound 6a：Purity is 99% through HPLC tests；1H NMR(400MHz,CDCl3):δ (ppm) 8.81 (s, 1H), 8.25 (d, J=5.2Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 7.86 (d, J=5.2Hz, 1H), 7.62-7.55 (m, 2H), 7.33-7.29 (m, 2H), 7.20 (t, J=8.0Hz, 2H), 7.09 (d, J=7.6Hz, 2H), 7.01 (t, J=6.0Hz, 2H), 5.26 (t, J=5.8Hz, 1H), 4.55 (t, J=5.8Hz, 2H), 3.65 (q, J=5.8Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)156.0,141.5,140.7,138.5,136.8,132.8,129.1,128.9,127.9,122.5,121.7,120.8,120.1,118.4,115.1,110.6,43.1,39.0.ESI-MS m/z:331.15[M+H]。
The 1- of embodiment 3 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) and -3- (3- carbethoxyl groups)-phenylurea (6bEt) and 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- carboxyls)-phenylureas (6b) synthesis
3- aminobenzoic acids (0.04g, 0.27mmol) are dissolved with 3mL ethanol, 0 DEG C of stirring is lower to add thionyl chloride (0.05mL, 0.68mmol), is warmed to room temperature stirring reaction 7h, and TCL shows complete reaction.
Solvent is removed in rotation, uses saturation NaHCO3PH to 7~8 is adjusted, ethyl acetate is extracted 3 times, uses saturated common salt water washing, is dried, concentration obtains pale yellow oil 3- benzocaines (0.04g, yield 84%).
According to the method for embodiment 2, aniline is replaced with 3- benzocaines 5b, compound 1- (2- (9H- pyridos [3 are made, 4-b] indoles -9- bases) ethyl) -3- (3- carbethoxyl groups)-phenylurea 6bEt, white solid (0.09g, yield 98%).
With 5mL water and 5mL ethanol by 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- carbethoxyl groups)-phenylurea (0.08g, 0.21mmol) with NaOH (0.03g, 0.63mmol) dissolve, it is warming up to 100 DEG C of reaction 2h, TLC detection raw material reactions complete.
Reaction solution is cooled to room temperature afterwards, vacuum distillation removes solvent, adds water, there is white solid precipitation when pH being adjusted into 6~7 with dilute HCl, filtered, vacuum drying chamber it is dry white solid 6b (0.07g, yield 90%).
Compound 6bEt：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):(the s of δ (ppm) 12.80, br, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.38 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.13 (d, J=5.2Hz, 1H), 8.03 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.63-7.56 (m, 2H), 7.49 (d, J=7.8Hz, 1H), 7.36-7.27 (m, 2H), 6.31 (t, J=6.0Hz, 1H), 4.61 (t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 3.55 (q, J=6.0Hz, 2H), 1.20 (t, J=6.8Hz, 3H)
Compound 6b：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):δ (ppm) 12.80 (s, br, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.38 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.13 (d, J=5.2Hz, 1H), 8.03 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.63-7.56 (m, 2H), 7.49 (d, J=7.8Hz, 1H), 7.36-7.27 (m, 2H), 6.31 (t, J=6.0Hz, 1H), 4.61 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)168.2,155.9,141.3,141.0,138.9,136.8,133.1,132.2,129.2,128.8,127.7,122.5,122.4,122.3,120.9,120.0,119.0,115.0,110.5,43.0,39.0.ESI-MS m/z:375.14[M+H]。
The 1- of embodiment 4 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) and -3- (4- carbethoxyl groups)-phenylurea (6cEt) and 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carboxyls)-phenylureas (6c) synthesis
According to the method for embodiment 3,3- Aminobenzoates 5b is substituted with PABA ethyl ester 5c.
Obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carbethoxyl groups)-phenylurea 6cEt, white solid (0.10g, total recovery 92%).
Obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carboxyls)-phenylurea 6c, white solid (0.09g, four step yields 90%).
Compound 6cEt：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):δ (ppm) 9.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.14 (s, 1H), 7.81 (d, J=7.6Hz, 2H), 7.74 (d, J=7.6Hz, 1H), 7.61 (t, J=6.0Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.29 (t, J=6.0Hz, 1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 3.55 (q, J=6.0Hz, 2H), 1.20 (t, J=6.8Hz, 3H)
Compound 6c：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):δ (ppm) 9.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.14 (s, 1H), 7.81 (d, J=7.6Hz, 2H), 7.74 (d, J=7.6Hz, 1H), 7.61 (t, J=6.0Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.29 (t, J=6.0Hz, 1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)167.6,155.6,145.1,141.4,138.7,137.0,132.9,130.9,128.8,127.8,123.4,122.4,120.9,120.0,117.3,115.1,110.5,43.0,39.0.ESI-MS m/z:375.14[M+H]。
The synthesis of the 1- of embodiment 5 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- hydroxyl -4- carboxyls)-phenylurea (6d)
According to the method for embodiment 2, with 6- amino -2,2- dimethyl -4- oxygen -4H- benzos [1,3] dioxin -4- ketone 5d (being made by WO2006125805 methods) substitutes aniline 5a, obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (2,2- dimethyl -4- oxygen -4H- benzos [1,3] dioxin -7- bases) urea (0.05g, total recovery 98%).
By 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (2,2- dimethyl -4- oxygen -4H- benzos [1,3] dioxin -7- bases) urea (0.05g, 0.12mmol) it is dissolved in 1mL tetrahydrofurans, 1mL KOH (0.03g, 0.6mmol) aqueous solution is added, is stirred at reflux overnight.
It is cooled to room temperature, it is 1 that reaction solution is acidified into pH, and ethyl acetate is extracted 3 times, merges organic layer, through saturated common salt water washing, is dried, is concentrated to give white solid 6d (0.04g, yield 90%)
Compound 6d：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):δ (ppm) 12.50 (br, 1H), 9.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.77 (d, J=7.6Hz, 1H), 7.61 (t, J=6.0Hz, 1H), 7.49 (d, J=7.6Hz, 2H), 7.29 (t, J=6.0Hz, 1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H) .ESI-MS m/z:389.13[M-H].
The synthesis of the 1- of embodiment 6 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- carboxyl -4- hydroxyls)-phenylurea (6e)
According to the method for embodiment 5, with compound 5e alternative compounds 5d, obtain 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- carboxyl -4- hydroxyls)-phenylurea 6e white solids (0.05g, total recovery 98%).
Compound 6e：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):δ (ppm) 12.50 (br, 1H), 9.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.73 (d, J=7.6Hz, 1H), 7.64 (t, J=6.0Hz, 1H), 7.52 (d, J=7.6Hz, 2H), 7.23 (t, J=6.0Hz, 1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H) .ESI-MS m/z:389.13[M-H].
The synthesis of the 1- of embodiment 7 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- benzyls urea (6f)
According to the method for embodiment 2, aniline 5a is substituted with benzylamine 5f, 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- benzyl urea 6f white solids (0.06g, total recovery 92%) are obtained.
Compound 6f：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):δ (ppm) 9.05 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.27 (d, J=7.8Hz, 1H), 8.15 (d, J=5.2Hz, 1H), 7.81 (s, 1H), 7.80 (d, J=7.0Hz, 1H), 7.64 (d, J=8.3Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.40-7.42 (m, 2H), 7.23 (t, J=7.6Hz, 1H), 6.51 (t, J=5.8Hz, 1H), 6.13 (t, J=5.6Hz, 1H), 4.51 (t, J=6.0Hz, 2H), 4.20 (d, J=5.8Hz, 2H), 3.41 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)158.6,141.9,141.5,138.7,136.7,133.0,132.0,131.2,128.9,128.8,128.3,128.0,127.8,122.4,120.8,119.9,115.0,110.6,43.4,43.0.ESI-MS m/z:345.15[M+H]。
The 1- of embodiment 8 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) and -3- (3- carbethoxyl groups)-benzyl urea (6gEt) 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- carboxyls)-benzyl urea (6g) synthesis
According to the method for embodiment 3,3- carboxyanilinos (i.e. 3- aminobenzoic acids) are substituted with 3- carboxyl benzylamines 5g.
Obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carbethoxyl groups)-phenylurea 6gEt white solids (0.07g, total recovery 91%).
Obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- carboxyls)-benzyl urea 6g white solids (0.06g, total recovery 90%).
Compound 6gEt：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):(the br of δ (ppm) 12.80, 1H), 9.06 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H), 7.85 (s, 1H), 7.81 (d, J=7.0Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.46-7.40 (m, 2H), 7.28 (t, J=7.6Hz, 1H), 6.56 (t, J=5.8Hz, 1H), 6.15 (t, J=5.6Hz, 1H), 4.54 (t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 4.25 (d, J=5.8Hz, 2H), 3.48 (q, J=6.0Hz, 2H), 1.20 (t, J=6.8Hz, 3H)
Compound 6g：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):(the br of δ (ppm) 12.80, 1H), 9.06 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H), 7.85 (s, 1H), 7.81 (d, J=7.0Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.46-7.40 (m, 2H), 7.28 (t, J=7.6Hz, 1H), 6.56 (t, J=5.8Hz, 1H), 6.15 (t, J=5.6Hz, 1H), 4.54 (t, J=6.0Hz, 2H), 4.25 (d, J=5.8Hz, 2H), 3.48 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)167.9,158.6,141.9,141.5,138.7,136.7,133.0,132.0,131.2,128.9,128.8,128.3,128.0,127.8,
122.4,120.8,119.9,115.0,110.6,43.4,43.0.ESI-MS m/z:387.15[M-H]。
The 1- of embodiment 9 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) and -3- (4- carbethoxyl groups)-benzyl urea (6hEt) and 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carboxyls)-benzyl urea (6h) synthesis
According to the method for embodiment 4,4- carboxyanilinos are substituted with 4- carboxyl benzylamines 5h.
Obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carbethoxyl groups)-benzyl urea 6hEt white solids (0.07g, total recovery 93%).
Obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (4- carboxyls)-benzyl urea 6h white solids (0.06g, total recovery 90%).
Compound 6hEt：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):(the s of δ (ppm) 12.80, br, 1H), 9.07 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H), 7.88 (d, J=8.2Hz, 2H), 7.71 (d, J=8.3Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.31-7.28 (m, 1H), 7.25 (d, J=8.2Hz, 2H), 6.52 (t, J=6.0Hz, 1H), 6.17 (t, J=6.0Hz, 2H), 4.55 (t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 4.24 (t, J=6.0Hz, 2H), 3.50 (q, J=6.0Hz, 2H), 1.20 (t, J=6.8Hz, 3H)
Compound 6h：Purity is 99% through HPLC tests；1H NMR(400MHz,DMSO-d6):(the s of δ (ppm) 12.80, br, 1H), 9.07 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H), 7.88 (d, J=8.2Hz, 2H), 7.71 (d, J=8.3Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.31-7.28 (m, 1H), 7.25 (d, J=8.2Hz, 2H), 6.52 (t, J=6.0Hz, 1H), 6.17 (t, J=6.0Hz, 2H), 4.55 (t, J=6.0Hz, 2H), 4.24 (t, J=6.0Hz, 2H), 3.50 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)167.7,158.6,146.6,141.5,138.5,136.8,132.9,129.8,129.5,128.8,127.9,127.3,122.4,120.8,119.9,115.1,110.6,43.5,43.1.ESI-MS m/z:387.15[M-H]。
The synthesis of the 1- of embodiment 10 (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- pyridines) MUs (6j)
According to the method for embodiment 2, aniline is substituted with 3- aminomethyl-pyridines 5j, obtain compound 1- (2- (9H- pyridos [3,4-b] indoles -9- bases) ethyl) -3- (3- pyridines) MU 6j white solids (0.06g, yield 98%)
Compound 6j：Purity is 98% through HPLC tests；1H NMR(400MHz,CDCl3):(the s of δ (ppm) 8.80, 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), 7.52 (t, J=7.6Hz, 1H), 7.40-7.42 (m, 2H), 7.23 (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), 4.51 (t, J=6.0Hz, 2H), 3.41 (q, J=6.0Hz, 2H) .LC-MS m/z:346.16[M+H].
Inhibitory activity of the compounds of this invention of embodiment 11 to IDO albumen
Recombined human IDO albumen is obtained through Bacillus coli expression, nickel affinity chromatographic purifying.Compound is used as substrate to the experiment of IDO inhibitory activity using L-Trp.Testing compound is dissolved in 10%DMSO solution and is configured to dilution.5uL dilutions are taken to be added in 100 μ L reaction systems.Contain 0.5%DMSO, 40nmol/L IDO, 900 μm of ol/L L-Trps, and other reaction concurrents (kaliumphosphate buffer, ascorbic acid, catalase, methylene blue) in 100 μ L reaction systems.Reactant mixture adds trichloroacetic acid terminating reaction in being cultivated 180 minutes under 37 degree.The concentration of the N- formoxyl kynurenins produced is determined at 321nm using Tecan Infinite M1000 ELIASAs, so as to evaluate inhibitory activity of the compound to IDO.Negative control thing is to replace IDO with 5 μ L buffer solution.The IDO inhibitor INCB024360 of clinical III phases verifies whether the IDO Activity determinations system that this experiment is set up is effective as positive control.
Each concentration sets up three wells.Data analysis is carried out using software Graphpad Prism.In the reaction solution without testing compound, absorbance (At) it is defined as 100% activity.In the reaction solution without IDO, absorbance (Ab) it is defined as 0% activity.For testing compound, active calculation formula is：%activity=[(A-Ab)/(At-Ab)] × 100, wherein A is the absorbance of the reaction solution containing testing compound.The calculation formula of inhibiting rate is：%inhibition=100-%activity.
By above experimental method, the inhibitory activity that the part of compounds in the present invention is directed to IDO is tested.Specific inhibitory activity of portion's compound under 1 μM, 10 μM, 100 μM of concentration is shown in Table 1.
Wherein A represents that inhibiting rate is more than 80%, B and represents that inhibiting rate is 20-80%, and C represents that inhibiting rate is 10-19%；D represents that inhibiting rate is less than 10%；Inhibiting rate of the positive control when concentration is 0.05 μM is 46%.
Inhibitory activity of the compounds of this invention of table 1 to IDO
Pyridine [3,4-b] indoles carbamide compounds show the inhibitory activity different degrees of to IDO.When the aromatic rings non-polar group on side chain, activity is mostly relatively low；When the aromatic rings on side chain has carboxyl, hydroxyl substitution, activity substantially increase；When carboxyl replaces between the aromatic rings on side chain is (6b), preferably activity is obtained, inhibiting rate is more than 80% under 100 μM of concentration.Meanwhile, 6i and 6j result are also shown, during group aromatic rings or aromatic heterocycle on side chain, its inhibitory activity is suitable.
Tests prove that, pyridine a pair of horses going side by side [3 that the present invention is provided, 4-b] indoles carbamide compounds have excellent inhibitory action to IDO, it can be used for preventing and/or treat a variety of diseases, such as Alzheimer disease, cataract, cellular immunity activation related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism is abnormal.
Claims (10)
1. a kind of compound or its pharmaceutically acceptable salt or its solvate, shown in the structure such as formula (I) of the compound：
A indicate without orOn ring adjacent-OH and-COOH substitutions orOne or more substituents on ring；The substituent is selected from halogen, alkyl, alkoxy, ester group ,-OH ,-COOH ,-SO3H or-SO2NH2；
X represents carbon or nitrogen；
N represents 0 or 1.
2. compound according to claim 1, it is characterised in that：A indicate without orOn ring adjacent-OH and-COOH substitutions orOne or more substituents on ring；The substituent is selected from-COOH or ester group-COOR, R are selected from the alkyl of C1~4.
3. compound according to claim 2, it is characterised in that：The quantity of the substituent is 1 or 2.
4. the compound according to claim any one of 1-3, it is characterised in that：N is selected from 0.
5. the compound according to claim any one of 1-3, it is characterised in that：A is representedOn at least one-COOH substitution.
6. compound according to claim 1, it is characterised in that：The structure of the compound is one of following structure：
7. a kind of method of compound shown in formula (I), it is characterised in that：Comprise the steps：
(1)
Compound 2 is prepared using (tertbutyloxycarbonyl) ethylaminoethanol and paratoluensulfonyl chloride as raw material；
(2)
It is that raw material prepares compound 3 with compound 1 and compound 2, sloughs the blocking group on amino and obtain compound 4；
(3)
Compound 5-ic is prepared using compound 5 and Triphosgene as raw material；N=0 or 1；
(4)
Compound shown in formula (I) is prepared using compound 4 and compound 5-ic as raw material；
Wherein, it is its ester-formin in the raw material 5 used in step (3) when the group that A is represented includes-COOH structures, also, the step of also including hydrolyzing the ester group after step (4).
8. the purposes of any one of the claim 1-7 compounds or its pharmaceutically acceptable salt or its prodrug or its solvate on IDO inhibitor class medicine is prepared.
9. purposes according to claim 8, it is characterised in that：The medicine is that prevention and/or treatment Alzheimer disease, cataract, cellular immunity activate the abnormal medicine of related infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism.
10. a kind of pharmaceutical composition, it is characterised in that：It is, using the compound or its pharmaceutically acceptable salt described in claim any one of 1-6 as active component, to add the preparation that pharmaceutically acceptable auxiliary material is prepared from.
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| CN101932325A (en) * | 2007-11-30 | 2010-12-29 | 新联基因公司 | Ido inhibitors |
| CN105906531A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of pimavanserin intermediate |
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| CN101932325A (en) * | 2007-11-30 | 2010-12-29 | 新联基因公司 | Ido inhibitors |
| CN105906531A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of pimavanserin intermediate |
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| CN111153850A (en) * | 2020-01-17 | 2020-05-15 | 中国药科大学 | Indole compound, preparation method thereof, pharmaceutical composition and application |
| WO2021143936A1 (en) * | 2020-01-17 | 2021-07-22 | 中国药科大学 | Indole compounds, preparation method therefor, and pharmaceutical composition and use thereof |
| CN111153850B (en) * | 2020-01-17 | 2021-08-13 | 中国药科大学 | Indole compound, preparation method thereof, pharmaceutical composition and application |
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