CN101812008A - IDO inhibitor containing pyrrole-2-aryl structure and preparation method thereof - Google Patents
IDO inhibitor containing pyrrole-2-aryl structure and preparation method thereof Download PDFInfo
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- CN101812008A CN101812008A CN201010166134A CN201010166134A CN101812008A CN 101812008 A CN101812008 A CN 101812008A CN 201010166134 A CN201010166134 A CN 201010166134A CN 201010166134 A CN201010166134 A CN 201010166134A CN 101812008 A CN101812008 A CN 101812008A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 14
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Abstract
The invention belongs to the technical field of medicine and midbody synthesis, and particularly relates to an IDO inhibitor containing a pyrrole-2-aryl structure and a preparation method thereof. Pyrrole-2-formic acid and phenol are adopted as raw materials, under the existence of N, N'-dicyclohexylcarbodiimide (DCC) and 2-dimethylamino pyridine (DMAP), the Pyrrole-2-formic acid and the phenol are undertaken the esterification to synthesize pyrrole-2-aryl compound. The IDO inhibitor has the advantages of simple operation, moderate condition, low cost, high yield and the like, has promising prospect and is easy to realize the industrialized production. The synthesized pyrrole-2-aryl structure contains pyrrole-2-formic acid and aromatic ring structure and can be used as the IDO inhibitor. The IDO inhibitor is applicable to the treatment of disease with the pathological feature of tryptophan metabolic pathway which is mediated by IDO. The disease at least comprises tumorous diseases, cancers, Alzheimer disease, autoimmune diseases, cataract, mood disorder, depression and anxiety disorders.
Description
Technical field
The invention belongs to medicine and intermediate synthesis technical field, be specifically related to the IDO inhibitor and the preparation method of a kind of pyrroles of containing-2-formic acid aromatic ester structure.
Background technology
Indoleamine 2, (Indoleamine 2 for the 3-dioxygenase, 3-dioxygenase is the enzyme that a kind of cell contains heme IDO), but is that unique catalysis tryptophan metabolism makes it decompose the rate-limiting enzyme that generates a series of meta-bolitess that comprise quinolinic acid along kynurenine pathway beyond the liver
[1]
IDO is relevant with a lot of physiological and pathological processes.The syncytionboph-oblast of the pregnant mouse Study of model being found female tire interface forms consistent with the dynamic change that antigen presenting cell can synthesize IDO and IDO expression with the embryo, if the effect of specific inhibition IDO, then can cause the mouse miscarriage, show that IDO can make fetus avoid the repulsion of parent, keeps the formation of female tire interface immune deviation
[2]Illustrating that IDO is relevant with the immunological tolerance of body immune system, is a kind of immunomodulatory enzyme.It is relevant to its supervision and the immunologic escape phenomenon of killing and wounding that IDO and tumour cell are escaped body immune system.Discovery various human solid tumor cell (cervical cancer, cancer of the stomach, colorectal carcinoma, melanoma and carcinoma of the pancreas etc.) high expression level IDO such as Uyttenhove make local T cell proliferation be subjected to press down, thereby the mediation tumour cell is escaped immune attack
[3]IDO participates in regulating the reaction of T cell.The T cell is exhausted responsive especially to tryptophane, when tryptophane concentration was low, T cell proliferation will be still in the G1 phase, and IDO can cut off the activation of T cell by the degraded tryptophane.Based on this mechanism, IDO protection fetus avoids parent and repels, and has also mediated the tumour immunity escape.
The kynurenine pathway of tryptophan metabolism is unusual, is accompanied by the rise of active raising of IDO and quinolinic acid level usually, and is closely related with neural system inflammation and neurological sexual disorder
[4]Directly and indirectly evidence shows that all IDO and kynurenine pathway play a significant role in the pathogenesis of alzheimer's disease
[5-6]Tryptophane concentration in the patients with Alzheimer disease blood becomes negative correlation with the degree of its cognitive defect
[7], kynurenine concentration is higher than the normal people in the serum, and the level of degree that raises and cognitive defect is closely related
[8-9]IDO content is abundanter than the normal people in the patients with Alzheimer disease brain: IDO and quinolinic acid all have expression in microglia, stellate cell and the neuronal cell of patients with Alzheimer disease hippocampus lamina corticalis, and content is the highest in the microglia around senile plaque, the stellate cell
[10]. beta-amyloyd polypeptide A β (1-42) can activate former people microglia of being commissioned to train foster, the expression of inducing IDO
[11-12]
Interferon-gamma can be induced the expression of IDO, and during the continuous activation that the plain γ of high levels of interference stimulates, IDO has reduced the availability of free serum tryptophane.Thereby, also reduced the generation of serotonin.With the generation that these variations that combine help neurological, psychiatric disorders of accumulating such as the kynurenine metabolite with neural activity of quinolinic acid, and be the factor of multiple mood disorder, also be the related indication factor of some chronic diseases with IDO activation and tryptophane degraded feature, described chronic disease is acquired immune deficiency syndrome (AIDS) (AIDS), broad variety dysthymia disorders, alzheimer's disease and cancer for example
[13]Draw.
The IDO activity also relates to the generation of the nuclear cataract relevant with the age.IDO is first enzyme in the biosynthesizing of lens middle-ultraviolet lamp filter, and is rate-limiting enzyme.Ultraviolet filter compound (kynurenine and 3-hydroxykynurenine heteroside) from the tryptophane degraded is modified the protein that is present in people's lens.The amount of these ultraviolet filter compounds increased with the age and to have reported that these ultraviolet filter compounds can cause being called the lens of the nuclear cataract relevant with the age muddy gradually
[14]
The IDO inhibitor can be treated tumour.There are some researches show the IDO inhibitor 1-methyl tryptophan (1-MT) of generally acknowledging at present in the external immunostimulating susceptibility that can strengthen tumour cell to the T cell, can delay the growth of tumour cell and the antitumous effect of enhancing chemotherapeutics in the animal model in vivo, and nearly all spontaneous tumor is worked
[15]The IDO inhibitor can be treated the disease of pathological characteristics that mood disorder and other have the tryptophan metabolism approach of IDO mediation, comprising: AIDS, nerve degenerative diseases (alzheimer's disease, Huntington Chorea and Parkinson's disease), dysthymia disorders, cataract, yellow and the autoimmune disorder relevant with the age.
IDO and multiple disease incidence mechanism are closely related, be proved to be the target of major diseases such as cancer, alzheimer's disease, dysthymia disorders, cataract, the IDO inhibitor has broad application prospects as medicine, but do not have suitable IDO inhibitor to can be used as the medicine listing so far, therefore seeking new and effective IDO inhibitor has important significance for theories and using value.
Reference:
[1]MacKenzie，C.R.et.al.Current?Drug?Metabolism，2007，8：237-244.
[2]David，H.M.；et?al.，Science，1998，281：5380.
[3]Uyttenhov，C，et?al.Nat?Med，2003，9：1269-1274.
[4]Heyes，M.P.，et?al.，Brain，1992，115：1249-1273.
[5]Guillemin，G.J.et?al..Redox?Rep?2002，7，199-20.
[6]Stone，T.W.，et?al.，J.Alzheimers?Dis.2001，3：355-66.
[7]Widner?B，et?al.，Adv?Exp?Med?Biol?1999，467：133-8.
[8]Baran?H，et?al.，J.Neural?Transm?1999，106：165-81.
[9]Widner?B，et?al.，J?Neural?Transm?2000，107：343-53.
[10]Guillemin，G.J.et?al.，Neuropathology?and?Applied?Neurobiology?2005，31：395-404.
[11]Guillemin?G.J.，et?al.，Neuro?Report?2003，14：2311-2315.
[12]Walker?D.G.，et?al.，J.Leukoc.Biol.2006，79：596-610.
[13]Schroecksnadel?K.，et?al.，.Clin?Exp?Immunol.2005，140(1)：41-45.
[14]Takikawa?O，et?al.，Exp?Eye?Res.2001，72(3)：271-7.
[15]Friberg?M，et?al.Int?J?Cancer，2002，101：151-155.
Summary of the invention
The object of the invention is to provide a kind of pyrroles-2-formic acid aromatic ester compound and preparation method.
Pyrroles-2-formic acid aromatic ester compound that the present invention proposes, its general structure is as follows:
Wherein, Ar is a phenyl, and p-methylphenyl is to bromophenyl or naphthyl etc.
The present invention is a raw material with pyrroles-2-formic acid, aromatic series phenols, pass through N, N '-dicyclohexylcarbodiimide (DCC), right-Dimethylamino pyridine (DMAP) do dehydrating agent, organic solvent commonly used such as benzene is made the esterification that one step of solvent selectivity realizes pyrroles-2-formic acid, aromatic series phenols, and its reaction scheme is as follows:
Wherein, Ar is a phenyl, and p-methylphenyl is to bromophenyl or naphthyl etc.
The preparation method of pyrroles-2-formic acid aromatic ester compound that the present invention proposes, concrete steps are as follows:
The first step: add benzene, pyrroles-2-formic acid, aromatic series phenol, right-Dimethylamino pyridine (DMAP) in the exsiccant round-bottomed flask, wherein the mol ratio of pyrroles-2-formic acid and aromatic series phenol is 1: 0.9-1: 1.1;
Second step: at room temperature magnetic agitation carries out adding N after 10-20 minute, and N '-dicyclohexylcarbodiimide (DCC) reacts under the room temperature, and TLC follows the tracks of extent of reaction;
The 3rd step: after question response was finished, pressure reducing and steaming solvent, residue were with ethyl acetate: sherwood oil=1: 1-1: 9 is that leacheate carries out column chromatography for separation and purifies promptly.
The phenol of aromatic series described in the present invention be in phenol, p-cresol, p bromophenol, the naphthyl alcohol any.
When using aromatic series phenol as reaction reagent, temperature of reaction is a room temperature among the present invention, and the reaction times is 4-24 hour.
In the leacheate, ethyl acetate and sherwood oil volume ratio are 1: 1-1: 9 described in the present invention.
The mol ratio of pyrroles described in the present invention-2-formic acid and aromatic series phenol is 1: 1, the mol ratio of pyrroles-2-formic acid and right-Dimethylamino pyridine (DMAP) is 1: 1-1: 1.2, pyrroles-2-formic acid and N, the mol ratio of N '-dicyclohexylcarbodiimide (DCC) is 1: 1-1: 1.2.
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.
Pyrroles disclosed by the invention-2-formic acid aromatic ester can be used as the IDO inhibitor.Pyrroles-2-formic acid is a kind of important heteroaromatic organic monoacid, the phenolic compound anticancer research comes into one's own day by day, 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.Pyrroles-2-formic acid aromatic ester pharmaceutically especially aspect the anti-tumor immunotherapy application prospect extensive, become one of major fields of drug research and exploitation in recent years, shown wide development potentiality.The synthetic document of pyrroles-2-formic acid aromatic ester compound seldom and lacks high yield, synthetic bibliographical information simple to operate.Pyrroles-2-formic acid aromatic ester 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, comprises the treatment of major diseases such as cancer, acquired immune deficiency syndrome (AIDS), alzheimer's disease, dysthymia disorders and cataract.
The invention has the advantages that:
The present invention is a raw material with potential prodrug pyrroles-2-formic acid, aromatic series phenolic compound, uses right-Dimethylamino pyridine (DMAP) and N, and N '-dicyclohexylcarbodiimide (DCC) does dehydrating agent.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.
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 25mL, add 3mL benzene, 33mg (0.3mmol) pyrroles-2-formic acid, 0.3mmol phenol, 40mg (0.33mmol) right-Dimethylamino pyridine (DMAP), at room temperature magnetic agitation carries out adding after 10 minutes 68mg (0.33mmol) N, N '-dicyclohexylcarbodiimide (DCC), react under the room temperature, TLC follows the tracks of extent of reaction.After question response was finished, pressure reducing and steaming solvent, residue were with ethyl acetate: sherwood oil=1: 3 be leacheate carry out column chromatography for separation purify promptly get silicagel column separate Compound I 42mg, yield 83%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)δ：0.88(3H，t，J＝7.4Hz)，1.28-1.95(12H，m)，4.31(2H，t，J＝76.6Hz)，6.92(1H，d，J＝14.3Hz)，7.14(1H，d，J＝14.3Hz)，7.36(2H，d，J＝8.1Hz)，8.00(2H，d，J＝8.4Hz)。
Embodiment 2: the preparation of Compound I I
In the exsiccant round-bottomed flask of 25mL, add 3mL benzene, 33mg (0.3mmol) pyrroles-2-formic acid, 0.3mmol p-cresol, 40mg (0.33mmol) right-Dimethylamino pyridine (DMAP), at room temperature magnetic agitation carries out adding after 10 minutes 68mg (0.33mmol) N, N '-dicyclohexylcarbodiimide (DCC), react under the room temperature, TLC follows the tracks of extent of reaction.After question response was finished, pressure reducing and steaming solvent, residue were with ethyl acetate: sherwood oil=1: 3 be leacheate carry out column chromatography for separation purify promptly get silicagel column separate Compound I I 51mg, yield 86%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)δ：9.46(s，1H)，7.19(d，J＝8.3Hz，2H)，7.14-7.09(m，1H)，7.06(d，J＝8.4Hz，2H)，6.98(dd，J＝4.0，2.6Hz，1H)，6.32(dt，J＝3.5，2.5Hz，1H)，2.35(s，3H)。
Embodiment 3: the preparation of compound III
In the exsiccant round-bottomed flask of 25mL, add 3mL benzene, 33mg (0.3mmol) pyrroles-2-formic acid, 52mg (0.3mmol) p bromophenol, 40mg (0.33mmol) right-Dimethylamino pyridine (DMAP), at room temperature magnetic agitation carries out adding after 15 minutes 68mg (0.33mmol) N, N '-dicyclohexylcarbodiimide (DCC), react under the room temperature, TLC follows the tracks of extent of reaction.After question response was finished, pressure reducing and steaming solvent, residue were with ethyl acetate: sherwood oil=1: 6 be leacheate carry out column chromatography for separation purify promptly get silicagel column separate compound III 75mg, yield 95%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)δ：9.39(s，1H)，7.51(d，J＝8.8Hz，2H)，7.12(d，J＝3.0Hz，1H)，7.08(d，J＝8.8Hz，2H)，7.03(s，1H)，6.38-6.30(m，1H)。
Embodiment 4: the preparation of compound IV
In the exsiccant round-bottomed flask of 25mL, add 3mL benzene, 33mg (0.3mmol) pyrroles-2-formic acid, 0.3mmol naphthyl alcohol, 40mg (0.33mmol) right-Dimethylamino pyridine (DMAP), at room temperature magnetic agitation carries out adding after 10 minutes 68mg (0.33mmol) N, N '-dicyclohexylcarbodiimide (DCC), react under the room temperature, TLC follows the tracks of extent of reaction.After question response was finished, pressure reducing and steaming solvent, residue were with ethyl acetate: sherwood oil=1: 7 be leacheate carry out column chromatography for separation purify promptly get silicagel column separate compound IV 60mg, yield 81%.
Characterization data is as follows:
1H?NMR(500MHz，CDCl
3)δ＝9.50(s，1H)，7.95(d，J＝7.8Hz，1H)，7.88(dd，J＝7.2，1.7Hz，1H)，7.76(d，J＝8.3Hz，1H)，7.57-7.41(m，3H)，7.34(dd，J＝7.4，0.7Hz，1H)，7.27(ddd，J＝3.8，2.4，1.5Hz，1H)，6.98(td，J＝2.7，1.5Hz，1H)，6.37(dt，J＝3.7，2.6Hz，1H)
Embodiment 5: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-IV 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 1-5:
IC50(g/ml)
1-MT 34.6
Compound I 120.8
Compound I I 53.2
Compound III 36.8
Compound IV 320.2
Claims (7)
1. pyrroles-2-formic acid aromatic ester compound is characterized in that this compound structure general formula is as follows:
Wherein, Ar is a phenyl, and p-methylphenyl is to bromophenyl or naphthyl etc.
2. the preparation method of pyrroles as claimed in claim 1-2-formic acid aromatic ester compound is characterized in that concrete steps are as follows:
The first step: add benzene, pyrroles-2-formic acid, aromatic series phenol, right-Dimethylamino pyridine in the exsiccant round-bottomed flask, wherein the mol ratio of pyrroles-2-formic acid and aromatic series phenol is 1: 0.9-1: 1.1
Second step: at room temperature magnetic agitation carries out adding N after 10-20 minute, and N '-dicyclohexylcarbodiimide reacts under the room temperature, and TLC follows the tracks of extent of reaction;
The 3rd step: after question response was finished, pressure reducing and steaming solvent, residue were that leacheate carries out the column chromatography for separation purification promptly with the ethyl acetate/petroleum ether.
3. according to the preparation method of pyrroles as claimed in claim 2-2-formic acid aromatic ester compound, it is characterized in that described aromatic series phenol be in other aromatic series phenol such as phenol derivatives or naphthols any.
4. according to the preparation method of pyrroles as claimed in claim 2-2-formic acid aromatic ester compound, it is characterized in that when using aromatic series phenol as reaction reagent, temperature of reaction is a room temperature, the reaction times is 4-24 hour.
5. according to the preparation method of pyrroles as claimed in claim 2-2-formic acid aromatic ester compound, it is characterized in that in the described leacheate that ethyl acetate and sherwood oil volume ratio are 1: 1-1: 9.
6. according to the preparation method of pyrroles as claimed in claim 2-2-formic acid aromatic ester compound, the mol ratio that it is characterized in that described pyrroles-2-formic acid and aromatic series phenol is 1: 1, the mol ratio of pyrroles-2-formic acid and right-Dimethylamino pyridine is 1: 1-1: 1.2, pyrroles-2-formic acid and N, the mol ratio of N '-dicyclohexylcarbodiimide is 1: 1-1: 1.2.
7. IDO inhibitor with compound as claimed in 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105209443A (en) * | 2013-03-15 | 2015-12-30 | 百时美施贵宝公司 | Inhibitors of indoleamine 2,3-dioxygenase (IDO) |
| CN108794376A (en) * | 2018-04-28 | 2018-11-13 | 北京施安泰医药技术开发有限公司 | Carboxamides derivatives, its pharmaceutical composition, preparation method and purposes |
-
2010
- 2010-05-10 CN CN201010166134A patent/CN101812008A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105209443A (en) * | 2013-03-15 | 2015-12-30 | 百时美施贵宝公司 | Inhibitors of indoleamine 2,3-dioxygenase (IDO) |
| CN108794376A (en) * | 2018-04-28 | 2018-11-13 | 北京施安泰医药技术开发有限公司 | Carboxamides derivatives, its pharmaceutical composition, preparation method and purposes |
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