CN101830792A - Vitamin K3 derivatives serving as IDO inhibitor - Google Patents
Vitamin K3 derivatives serving as IDO inhibitor Download PDFInfo
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- CN101830792A CN101830792A CN201010166116A CN201010166116A CN101830792A CN 101830792 A CN101830792 A CN 101830792A CN 201010166116 A CN201010166116 A CN 201010166116A CN 201010166116 A CN201010166116 A CN 201010166116A CN 101830792 A CN101830792 A CN 101830792A
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Abstract
The invention belongs to the technical fields of medicaments and intermediate synthesis, and in particular relates to vitamin K3 derivatives and a preparation method thereof. The 1,4-naphthoquinone derivatives are conveniently synthesized by using 2-bromine-1,4-naphthoquinone as raw materials through one-step reaction. The vitamin K3 derivatives synthesized by the method contain vitamin K3 structures and can be used as medicaments and important synthesized intermediates. The method for preparing the vitamin K3 derivatives has the characteristics of simple operation, mild condition, low cost, high yield, and the like, has wide application prospect, and is easy for industrialized production. An IDO inhibitor synthesized by the method and containing the vitamin K3 structure can be applied to the treatment of diseases with IDO-mediated tryptophan metabolic pathway pathologic features, wherein the diseases at least comprise tumor diseases, cancers, Alzheimer, autoimmune diseases, cataracts, mood disorders, depression, and anxiety disorder.
Description
Technical field
The invention belongs to medicine and intermediate synthesis technical field, be specifically related to a kind of vitamin K 3 derivatives serving and IDO inhibitor thereof.
Background technology
Indoleamine 2,3-is two to be added oxydase (Indoleamine 2, and 3-dioxygenase IDO) is distributed widely in the many tissues and cell of humans and animals, are that catalysis tryptophane unique beyond the liver is along the catabolic rate-limiting enzyme of kynurenine pathway
[1]IDO is low expression level under standard state, expressing significantly under inflammation or infectious condition increases
[2]The pathogenesis of IDO and multiple disease is closely related, has been proved to be the target of major diseases such as cancer, alzheimer's disease, dysthymia disorders, cataract
[3-9]Therefore the IDO inhibitor is the medicine that has potentiality, seeks highly active IDO inhibitor and has important significance for theories and using value.
IDO is the oxydo-reductase that a kind of cell includes heme, is made up of 403 amino acid
[10], comprising two folding α-Luo Xuanjiegou territories, the macrostructure territory comprises the catalysis pocket, and hydrogen bond, salt bridge, effect such as hydrophobic can be in the catalysis pocket take place with IDO in substrate
[11]Heme between two structural domains, Fe
2+Ionic oxide formation is Fe
3+The time IDO inactivation and IDO easily autoxidation, so the body domestic demand relies on reductive agent reactivate such as flavine, replacements such as external available xitix.Existing IDO inhibitor mainly obtains by the means of chemosynthesis or natural extract.
Vitamin K3 is the important natural product of a class, and this compounds is widespread in nature, and shows the anti-tumor immunotherapy activity in medicine and other fields.Vitamin K3 has been proved its main pharmacodynamics group for naphthaquinone, extensively exists at medicine and intermediate synthetic technology.Naphthaquinone also exists among many other important vitamines families, as vitamin-E, vitamin K etc.
[12]The phenolic compound anticancer research comes into one's own day by day, and many phenolic compounds have restraining effect to tumour cell, laboratory animal tumour and the human tumor of vitro culture, and phenolic compound has obvious inhibition to tumour cell and normal cell is had no side effect simultaneously.The vitamin K3 stand-in are in that pharmaceutically especially antitumor application prospect is extensive, have become one of major fields of drug research and exploitation in recent years, have shown wide development potentiality.The synthetic document of vitamin K 3 derivatives serving seldom and lacks high yield, synthetic bibliographical information simple to operate.Contain vitamin K3 and aromatic ring structure in synthetic pyrroles of the present invention-2-formic acid aromatic ester structure, can be used as the IDO inhibitor, can be used to have the disease of pathological characteristics of the tryptophan metabolism approach of IDO mediation, comprise the treatment of major diseases such as cancer, acquired immune deficiency syndrome (AIDS), alzheimer's disease, dysthymia disorders and cataract.
Reference:
[1]Yamamoto，S.；Hayashi，O.J.Biol.Chem.，1967，242，5260-5266.
[2]Bianchi，M.；Bertini，R.；Ghezzi，P.Biochem.Biophys.Res.Commun.，1988，152，237-242.
[3]Bodaghi，B.；Goureauo，O.；Zipeto，D.et?al.J.Immunol，1999，162，957-964.
[4]Roye，J.；Taikawa，O.；Kranz，D.M.，et?al.Neuroscience?Lett.，2005，387，95-99.
[5]Munn，D.H.；Shatizadeh，E.；Attwod，J.T.，et?al.J.Exp.Med.，1999，189，1363-1372.
[6]Munn，D.H.；Zhou，M.；Attwood，J.T.，et?al.Science，1998，281，1191-1193.
[7]Friber，G.M.；Jennings，R.；Alsarraaj，M.FRIBERG?M.，et?al.Int.J.Cancer，2002，101，151-155.
[8]Terness，P.；Chuang，J.J.；Bauer，T.，et?al.Blood，2005，105，2480-2486.
[9]Katz，B.J.；Muller，A.J.；Prendergast，G.C.Immunological?Rev.，2008，222，206-221.
[10] Xie Qichao, Wang Lingli, Chen Zhengtang etc., wall bulletin, 2008,21,73-75. are given birth in medical research
[11]Sugimoto，H.；Oda，S.；Otsuki，T.，et?al.Proc.Natl.Acad.Sci.USA，2006，103，2611-2616.
[12]Kumar，S?J.et?al.，J?Med?Chem，2008，51(6)，1706-1718.
Summary of the invention
The object of the invention is to provide a kind of IDO inhibitor and preparation method who contains the vitamin K3 structure.
Synthetic vitamin K3 stand-in of the present invention, its general structure is as follows:
Wherein, R is-H-CH
3,-Br etc.
The present invention is with potential prodrug 2-bromo-1, and 4-naphthoquinones and phenol are raw material, and dimethyl formamide (DMF) organic solvent commonly used is made one step of solvent selectivity and realized 2-bromo-1, the one-tenth ether reaction of 4-naphthoquinones, fragrant phenols, and its reaction scheme is as follows:
Wherein, R is-H-CH
3,-Br etc.
The preparation method of the vitamin K3 stand-in that the present invention proposes, concrete steps are as follows:
The first step: add dimethyl formamide in the exsiccant round-bottomed flask, add fragrant phenol and Anhydrous potassium carbonate respectively, TLC tracking monitor sylvite generates, and treats after magnetic agitation 1-2 hour that it generates phenol sylvite;
Second step: with 2-bromo-1, the 4-naphthoquinones adds in the above-mentioned reaction system, and after room temperature reaction 3-4 hour, the reaction of TLC tracking monitor is carried out fully, adds water quencher reaction and carries out aftertreatment;
The 3rd step: add the ethyl acetate extraction organic layer, use saturated sodium bisulfite, saturated common salt water washing again, anhydrous sodium sulfate drying is that leacheate carries out the column chromatography for separation purification promptly with ethyl acetate and sherwood oil.
Among the present invention, described fragrant phenol be in phenol derivatives or the naphthols etc. any, wherein phenol derivatives comprises phenol, p-cresol, p bromophenol etc.
Among the present invention, when using fragrant phenol as reaction reagent, temperature of reaction is a room temperature, and the reaction times is 4-18 hour.
Among the present invention, the mol ratio of described fragrant phenol and Anhydrous potassium carbonate is 1: 3-5, and 2-bromo-1, the mol ratio of 4-naphthoquinones and fragrant phenol is 1: 1-1.5, the volume ratio of ethyl acetate and sherwood oil is 1: 3-1: 8.
Among the present invention, a kind of IDO inhibitor, its application in the medicine of the disease for preparing the pathological characteristics for the treatment of the tryptophan metabolism approach with IDO mediation, such disease comprises neoplastic disease, cancer, alzheimer's disease, autoimmune disorder, cataract, mood disorder, dysthymia disorders, anxiety disorder at least.
The invention has the advantages that:
The present invention is with potential prodrug 2-bromo-1, and 4-naphthoquinones, fragrant phenolic compound are raw material, and single step reaction had both got product.This synthetic route have raw material be easy to get, easy and simple to handle, reaction conditions is gentle, the reaction times is short, save solvent and reduce advantages such as pollution, is convenient to suitability for industrialized production.This synthetic product has the pharmacophore of vitamin K3, fragrant phenol, has extensive prospect aspect anti-tumor immunotherapy.
Embodiment
Followingly further specify the present invention, but can not limit content of the present invention by embodiment.
Embodiment 1: the preparation of Compound I
In the exsiccant round-bottomed flask of 50mL, add 4mL dimethyl formamide (DMF), the Anhydrous potassium carbonate that adds 18mg (0.1mmol) p bromophenol and 42mg (0.3mmol) respectively, TLC tracking monitor sylvite generates, magnetic agitation is treated its generation phenol sylvite after 1 hour after; With 24mg (0.1mmol) 2-bromo-1,4-naphthoquinones impouring system, system presents brown, and room temperature reaction is after 3 hours, the reaction of TLC tracking monitor is carried out fully, with 20mL water quencher post-reaction treatment, add ethyl acetate, separate obtaining organic layer, after adding saturated sodium bisulfite, saturated common salt washing again, use anhydrous sodium sulfate drying, with ethyl acetate: sherwood oil=1: 8 is that leacheate carries out column chromatography for separation and purifies and promptly get Compound I 40mg, productive rate 75%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)：δ＝6.00(1H，s)，7.03-7.05(2H，d，J＝8.5Hz)，7.58-7.60(2H，d，J＝8.5Hz)，7.76-7.78(2H，m)，8.06(1H，m)，8.20(1H，m).
Embodiment 2: the preparation of Compound I I
Add 4mL DMF in the exsiccant round-bottomed flask of 50mL, add the Anhydrous potassium carbonate of 16mg (0.15mmol) p-cresol and 62mg (0.45mmol) respectively, TLC tracking monitor sylvite generates, magnetic agitation is treated its generation phenol sylvite after 2.5 hours after; With 24mg (0.1mmol) 2-bromo-1,4-naphthoquinones impouring system, system presents brown, and room temperature reaction is after 4 hours, the reaction of TLC tracking monitor is carried out fully, with 20mL water quencher post-reaction treatment, add ethyl acetate, separate obtaining organic layer, after adding saturated sodium bisulfite, saturated common salt washing again, anhydrous sodium sulfate drying, with ethyl acetate: sherwood oil=1: 8 is that leacheate carries out column chromatography for separation and purifies and promptly get Compound I I 30mg, productive rate 70%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)：δ＝2.39(3H，s)，6.00(1H，s)，7.00-7.03(2H，d，J＝8.5Hz)，7.23-7.27(2H，d，J＝8.5Hz)，7.75-7.77(2H，m)，8.05(1H，m)，8.22(1H，m)
Embodiment 3: the preparation of compound III
Add 4mL DMF in the exsiccant round-bottomed flask of 50mL, add the Anhydrous potassium carbonate of 14mg (0.15mmol) phenol and 62mg (0.45mmol) respectively, TLC tracking monitor sylvite generates, magnetic agitation is treated its generation phenol sylvite after 1 hour after; With 24mg (0.1mmol) 2-bromo-1,4-naphthoquinones impouring system, system presents red sauce, behind the room temperature reaction 1.5 hours, the reaction of TLC tracking monitor is carried out fully, with 20mL water quencher reaction, aftertreatment, add ethyl acetate, separate to obtain organic layer, add saturated sodium bisulfite, saturated common salt washing again after, anhydrous sodium sulfate drying, with ethyl acetate: sherwood oil=1: 7 is that leacheate carries out column chromatography for separation and purifies and promptly get compound III 24mg, productive rate 81%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)：δ＝6.00(1H，s)，7.13-7.15(2H，d)，7.32(1H，d)，7.08(d，J＝8.8Hz，7.44-7.47(2H，t)，7.74-7.76(2H，t)，8.06(1H，d，J＝9.0Hz)，8.19(1H，d，J＝9.0Hz)
Embodiment 4:IDO suppresses active and detects
Structure, the expression in intestinal bacteria, extraction and the purifying that contains the plasmid of people IDO gene all by report methods such as Littlejohn carry out (Takikawa O, Kuroiwa T, Yamazaki F, et al.J.Biol.Chem.1988,263,2041-2048.).Isolating each component and monomeric compound detect according to the method for introducing the inhibition activity of IDO.On 96 orifice plates with 50mM potassium phosphate buffer (pH 6.5), the 40mM vitamins C, 400 μ g/ml catalases, 20 μ M methylene blues and IDO enzyme mix.In above-mentioned mixed solution, add substrate L-tryptophane and testing sample.Be reflected at and carried out under 37 ℃ 60 minutes, add 30% (w/v) trichoroacetic acid(TCA) and make reaction terminating.96 orifice plates heated 15 minutes down at 65 ℃, made it to finish the conversion from the formylkynurenine to the kynurenine, and the 6000g rotation is 5 minutes then.Every hole is taken out 100 μ l supernatant liquors and is transferred in the 96 new orifice plates, add 2% (w/v) right-acetic acid solution of (dimethylamino) phenyl aldehyde, kynurenine reacts the yellow color of producing with it and can use microplate reader to observe at 490nm, and the gained result utilizes the IC50 software for calculation to calculate.Utilize aforesaid method, the IDO of Compound I-III is suppressed activity measure, its IC50 is as follows, and with IDO inhibitor 1-methyl tryptophan (1-MT, commercially available) general in present experiment in vivo and vitro thing in contrast.
The IDO of synthetic compound suppresses active as follows among the foregoing description 1-3:
IC50(μg/ml)
1-MT 34.6
Compound I 40.8
Compound I I 68.5
Compound III 81.8
Claims (6)
1. vitamin K 3 derivatives serving is characterized in that its compound structure general formula is as follows:
Wherein, R is-H-CH3 ,-Br etc.
2. the preparation method of a vitamin K 3 derivatives serving as claimed in claim 1 is characterized in that concrete steps are as follows:
The first step: add dimethyl formamide in the exsiccant round-bottomed flask, add fragrant phenol and Anhydrous potassium carbonate respectively, TLC tracking monitor sylvite generates, and treats after magnetic agitation 1-2 hour that it generates phenol sylvite;
Second step: with 2-bromo-1, the 4-naphthoquinones adds in the above-mentioned reaction system, and after room temperature reaction 3-4 hour, the reaction of TLC tracking monitor is carried out fully, adds water quencher reaction and carries out aftertreatment;
The 3rd step: add the ethyl acetate extraction organic layer, use saturated sodium bisulfite, saturated common salt water washing again, anhydrous sodium sulfate drying is that leacheate carries out the column chromatography for separation purification promptly with ethyl acetate and sherwood oil.
3. according to the preparation method of vitamin K 3 derivatives serving as claimed in claim 2, it is characterized in that described fragrant phenol be in phenol derivatives or the naphthols etc. any.
4. according to the preparation method of vitamin K 3 derivatives serving as claimed in claim 2, it is characterized in that the described fragrant phenol of use of working as reaction reagent, temperature of reaction is a room temperature, and the reaction times is 4-10 hour.
5. according to the preparation method of vitamin K 3 derivatives serving as claimed in claim 2, the mol ratio that it is characterized in that described fragrant phenol and Anhydrous potassium carbonate is 1: 3-5, and 2-bromo-1, the mol ratio of 4-naphthoquinones and fragrant phenol is 1: 1-1.5, the volume ratio of ethyl acetate and sherwood oil is 1: 3-1: 8.
6. one kind has the IDO inhibitor of derivative according to claim 1, it is characterized in that its application in the medicine of the disease for preparing the pathological characteristics for the treatment of the tryptophan metabolism approach with IDO mediation, such disease comprises neoplastic disease, cancer, alzheimer's disease, autoimmune disorder, cataract, mood disorder, dysthymia disorders, anxiety disorder at least.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552228A (en) * | 2010-12-30 | 2012-07-11 | 浙江大学 | Application of vitamin K to preparation of pyruvate kinase inhibitor |
| WO2012166862A1 (en) * | 2011-06-01 | 2012-12-06 | Wisconsin Alumni Research Foundation | Compositions and methods for treating alzheimer's disease |
| CN108785350A (en) * | 2017-04-28 | 2018-11-13 | 苏州凯祥生物科技有限公司 | Purposes of the Cortex Periplocae Radicis extract in preparing IDO inhibitor |
-
2010
- 2010-05-10 CN CN201010166116A patent/CN101830792A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552228A (en) * | 2010-12-30 | 2012-07-11 | 浙江大学 | Application of vitamin K to preparation of pyruvate kinase inhibitor |
| CN102552228B (en) * | 2010-12-30 | 2013-09-18 | 浙江大学 | Application of vitamin K in preparation of pyruvate kinase inhibitor |
| WO2012166862A1 (en) * | 2011-06-01 | 2012-12-06 | Wisconsin Alumni Research Foundation | Compositions and methods for treating alzheimer's disease |
| US8980884B2 (en) | 2011-06-01 | 2015-03-17 | Wisconsin Alumni Research Foundation | Methods for treating Alzheimer's disease |
| US9522124B2 (en) | 2011-06-01 | 2016-12-20 | Wisconsin Alumni Research Foundation | Methods for treating Alzheimer's disease |
| CN108785350A (en) * | 2017-04-28 | 2018-11-13 | 苏州凯祥生物科技有限公司 | Purposes of the Cortex Periplocae Radicis extract in preparing IDO inhibitor |
| CN108785350B (en) * | 2017-04-28 | 2021-09-21 | 苏州凯祥生物科技有限公司 | Use of cortex Periplocae Radicis extract in preparing IDO inhibitor |
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Application publication date: 20100915 |