CN102579452A - Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor - Google Patents
Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor Download PDFInfo
- Publication number
- CN102579452A CN102579452A CN2012100185916A CN201210018591A CN102579452A CN 102579452 A CN102579452 A CN 102579452A CN 2012100185916 A CN2012100185916 A CN 2012100185916A CN 201210018591 A CN201210018591 A CN 201210018591A CN 102579452 A CN102579452 A CN 102579452A
- Authority
- CN
- China
- Prior art keywords
- ido
- formula
- chemical compound
- inhibitor
- tryptanthrin compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DXSBFTGUEOWLSD-YHYXMXQVSA-N O/N=C\C(Nc(cc1)ccc1F)=O Chemical compound O/N=C\C(Nc(cc1)ccc1F)=O DXSBFTGUEOWLSD-YHYXMXQVSA-N 0.000 description 1
Abstract
The invention relates to a preparation method of tryptanthrin compound and a new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor, in particular to an application of tryptanthrin compound in preparing IDO inhibitor and in preparing medicine for preventing and/or treating diseases having pathological characteristics of tryptophan metabolic disturbance mediated by IDO. The structure of the tryptanthrin compound is shown in formula A, wherein R1 and R2 are respectively and independently selected from hydrogen, nitryl, C1 to C5 alkyl, halogen or piperazinyl. The tryptanthrin compound can be used as an IDO inhibitor with high activity and is used for treating diseases having pathological characteristics of tryptophan metabolic disturbance mediated by IDO such as tumor, cancer, Alzheimer disease, autoimmune disease, cataract, mental block, tristimania, anxiety neurosis, acquired immure deficiency syndrome (AIDS) and other serious diseases, and as a medicinal resource which is very difficult to get, the tryptanthrin compound has good potential on researching and developing new medicine.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to the method for preparing and the new purposes in preparation IDO inhibitor thereof of couroupitine A compounds.
Background technology
Indoleamine 2; (Indoleamine 2, and 3-dioxygenase IDO) is the enzyme that a kind of cell contains heme for the 3-dioxygenase; Be that but unique catalysis tryptophan metabolism makes it decompose the rate-limiting enzyme (MacKenzie that generates a series of metabolites that comprise quinolinic acid along kynurenine pathway beyond the liver; C.R.et.al.Current Drug Metabolism, 2007,8:237-244.).From nineteen nineties; Indoleamine 2,3-is two to be added oxidase (indoleamine 2,3-dioxygenase; IDO) and the kynurenine pathway of catalysis tryptophan metabolism (Kynurenine pathway, the important function that KP) in the various diseases process, is risen causes people's attention day by day.
IDO is relevant with a lot of physiological and pathological processes.The pregnant mouse Study of model is found that the syncytionboph-oblast at female tire interface and antigen presenting cell can synthesize IDO; And the dynamic change that IDO expresses forms consistent with the embryo; If the effect of specific inhibition IDO then can cause the mice miscarriage, show that IDO can make fetus avoid the repulsion of parent; Keep formation (David, the H.M. of the interface immune deviation of female tire; Et al., Science, 1998,281:5380.).Explaining that IDO is relevant with the immunologic tolerance of body immune system, is a kind of immunomodulating enzyme.It is relevant to its supervision and the immunologic escape phenomenon of killing and wounding that IDO and tumor cell are escaped body immune system.Uyttenhove etc. find various human solid tumor cell (cervical cancer, gastric cancer, colon cancer, melanoma and cancer of pancreas etc.) high expressed IDO antigen; Make the local T cell proliferation receive to press down; Thereby the mediation tumor cell is escaped immune attack (Uyttenhov, C, et al.Nat Med; 2003,9:1269-1274.).IDO participates in regulating the reaction of T cell.The T cell is exhausted responsive especially to tryptophan, when tryptophan concentration was low, the T cell proliferation will be still in G
1Phase, IDO can cut off the activation of T cell through the degraded tryptophan.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, with nervous system inflammation and neurological sexual disorder closely related (Heyes, M.P., et al., Brain, 1992,115:1249-1273).Direct and indirect evidence all shows IDO and kynurenine pathway in the pathogenesis of Alzheimer, play a significant role (Guillemin, G.J.et al.Redox Rep 2002,7,199-20; Stone, T.W., et al., J.Alzheimers Dis.2001,3:355-66).Tryptophan concentration in the patients with Alzheimer disease blood becomes negative correlation (Widner B, et al., Adv Exp Med Biol 1999 with the degree of its cognitive defect; 467:133-8); Kynurenin concentration is higher than the normal person in the serum, and the degree that raises and level closely related (Baran H, the et al. of cognitive defect; J.Neural Transm 1999,106:165-81; Widner B, et al., JNeural Transm 2000,107:343-53).IDO content is abundanter than the normal person in the patients with Alzheimer disease brain: IDO and quinolinic acid all have expression in microglia, spider cell and the neuronal cell of patients with Alzheimer disease hippocampus cortical layer; The highest (the Guillemin of content in microglia around senile plaque, the spider cell; G.J.et al.; Neuropathology and AppliedNeurobiology 2005,31:395-404).Beta-amyloyd polypeptide A β (1-42) can activate former people's microglia of being commissioned to train foster, and (NeuroReport 2003,14:2311-2315 for Guillemin G.J., et al. to induce the expression of IDO; Walker D.G., et al., J.Leukoc.Biol.2006,79:596-610).
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 tryptophan.Thereby, also reduced the generation of 5-hydroxy tryptamine.These change with the accumulating of kynurenin metabolite with neural activity such as quinolinic acid and combine; Help the generation of neurological, psychiatric disorders; And be the factor of multiple mental maladjustment; Also be the related indication inducement of some chronic diseases with IDO activation and tryptophan degraded characteristic, said chronic disease is AIDS (AIDS), polytype depression, Alzheimer and cancer (Schroecksnadel K., et al. for example; Clin Exp Immunol.2005,140 (1): 41-45).
The IDO activity also relates to the generation of the nuclear cataract relevant with the age.IDO is first enzyme in the crystalline lens middle-ultraviolet lamp filter biosynthesis, and is rate-limiting enzyme.Ultraviolet filter chemical compound (kynurenin and 3-hydroxykynurenine heteroside) modification from the tryptophan degraded is present in the protein in people's crystalline lens.The amount of these ultraviolet filter chemical compounds increased with the age; And reported that these ultraviolet filter chemical compounds can cause being called as muddy gradually (the Takikawa O of crystalline lens of the nuclear cataract relevant with the age; Et al., Exp Eye Res.2001,72 (3): 271-7).
The IDO inhibitor can be treated tumor.Existing research shows that the IDO inhibitor 1-methyl tryptophan (1-MT) of generally acknowledging at present is in the external immunostimulating sensitivity that can strengthen tumor cell to the T cell; In animal model, can delay the growth of interior tumor cell and the antitumous effect of enhancing chemotherapeutics; And to nearly all spontaneous tumor (Friberg M that works; Et al.Int J Cancer, 2002,101:151-155).The IDO inhibitor can be treated the disease of pathological characteristics that mental maladjustment and other have the tryptophan metabolism approach of IDO mediation, comprising: AIDS, neurodegenerative diseases (Alzheimer, Huntington Chorea and parkinson disease), depression, cataract, yellow and the autoimmune disease 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, depression, 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.Existing research shows that IDO inhibitor 1-MT (1-methyl tryptophan) is in the external immunostimulating sensitivity that can strengthen tumor cell to the T cell; In animal model, can delay the growth of interior tumor cell and the antitumous effect of enhancing chemotherapeutics, and nearly all spontaneous tumor is all worked, this has brought new hope for immunization therapy of tumor.D-1-MT is listed in RAID (rapid access tointervention development) plan by national cancer institute, and gets into the I clinical trial phase in the autumn in 2007.Regrettably existing IDO inhibitor mostly suppresses to render a service low, and 1-MT is as IDO inhibitor commonly used in the various experiment in vivo and vitro, and it suppresses constant K i and also is merely 34 μ M.Therefore, find that new and effective IDO inhibitor has major application and is worth.
Couroupitine A is the indole quinazoline Alkaloid, and its chemical name is indole [2, a 1-b] quinazoline-6, the 12-diketone.Couroupitine A is a kind of xanchromatic acicular crystal, mainly is present in Acanthaceous indigo, polygonum tinctorium ait., Isatis indigotica Fort. etc. and produces (Honda G.et al.Planta Medica, 1980,38 (3): 275-276.) in the blue plant.In addition, also can from the fermentation liquid of microorganism, extract (Hosoe T, et al.Mycopathologia, 1999,144 (1): 9-12).In recent years, the home and abroad scholar has carried out part Study to the pharmacology of couroupitine A, and its effect mainly shows antibiotic, antiinflammatory, antitumor and parasiticide (Oberthur C, et al.Fitoterapia, 2005,76 (3-4): 324-332; Motoki T, et al.Biol Pharm Bull, 2005,28 (2): aspect such as 260-266).Though from the metabolite of blue plant of product such as polygonum tinctorium ait., Acanthaceous indigo, Isatis indigotica Fort. and microorganism, can extract couroupitine A, separation process is long, extraction ratio is low, be difficult to satisfy the demand of research and clinical application.Have only that weak point consuming time, yield are high through exploring, the easy synthetic approach that is easy to get could provide more resources for couroupitine A, make its further development and application become possibility.Generally speaking, couroupitine A is a kind of very rare medicine resource, has the potentiality of excellent research and developing new drug.
Summary of the invention
In order to overcome the defective of prior art; The present invention provides a kind of new pharmaceutical applications of couroupitine A compounds; Said couroupitine A compounds can be used as IDO inhibitor more efficiently, and then is used for preparing the application of medicine of the disease of the disorderly pathological characteristics of tryptophan metabolism with IDO mediation.
Above-mentioned purpose of the present invention realizes through following technical scheme.
On the one hand, the invention provides the purposes of chemical compound shown in the formula A in preparation IDO inhibitor,
Wherein, R
1, R
2Be independently selected from hydrogen, nitro, C respectively
1-C
5Alkyl, halogen or piperazinyl.
On the other hand, the present invention also provides chemical compound shown in the formula A to prevent and/or treat the purposes in the medicine of disease of the disorderly pathological characteristics of tryptophan metabolism with IDO mediation in preparation.Preferably, said disease is selected from tumor, cancer, Alzheimer, autoimmune disease, cataract, mental maladjustment, depression, anxiety neurosis, AIDS.
In formula A, preferably, R
1, R
2Be independently selected from hydrogen, methyl, fluorine, chlorine, bromine and piperazinyl respectively.More preferably, the structure of chemical compound shown in the formula A is suc as formula shown in A1 or the A2:
The structure of chemical compound is following shown in the preferred formula A of the present invention:
Experiment shows; The present invention finds that after deliberation said couroupitine A derivant can be used as highly active IDO inhibitor; 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 tumor, cancer, Alzheimer, autoimmune disease, cataract, mental maladjustment, depression, anxiety neurosis and AIDS, it has the potentiality of excellent research and developing new drug as very rare medicine resource.
The specific embodiment
Followingly further specify the present invention, do not require the scope protected but do not limit the present invention through embodiment.
If no special instructions, involved reagent or raw material is commercially available in following examples.
Embodiment 1: the preparation of couroupitine A (formula I)
In the exsiccant round-bottomed flask of 25mL, add 3mL toluene, 163mg (1mmol) isatoic anhydride (opening up the chemical industry company limited), 147mg (1mmol) isatin (available from Aladdin reagent company limited), 505mg (5mmol) triethylamine available from last Haikang; Be warming up to 110 ℃ then, after refluxing and stirring reaction 3-4h, TLC detect and show that reaction is accomplished; The pressure reducing and steaming solvent; Residue gets formula I chemical compound 228mg, yield 92% with ethyl alcohol recrystallization.
Characterization data is following:
1H-NMR (400MHz, CDCl
3) δ=8.64 (d, 1H), 8.45 (d, 1H), 8.04 (d, 1H), 7.92 (d, 1H), 7.88 (t, 1H), 7.80 (t, 1H), 7.69 (t, 1H), 7.44 (t, 1H).
The preparation of embodiment 2:8-methyltryptamine ketone (formula II)
In the exsiccant round-bottomed flask of 25mL, add 3mL toluene, 163mg (1mmol) isatoic anhydride, 161mg (1mmol) 5-methyl isatin (available from Qingdao Union Fine Chemical Co., Ltd.), 505mg (5mmol) triethylamine; Be warming up to 110 ℃ then, after refluxing and stirring reaction 3-4h, TLC detect and show that reaction is accomplished; The pressure reducing and steaming solvent; Residue gets formula II chemical compound 235mg, yield 90% with ethyl alcohol recrystallization.
Characterization data is following:
1H-NMR (400MHz, CDCl
3) δ=8.49 (d, 1H), 8.43 (d, 1H), 8.02 (d, 1H), 7.84 (t, 1H), 7.67 (m, 2H), 7.59 (d, 1H), 2.46 (s, 3H).
The preparation of embodiment 3:8-fluorine couroupitine A (formula III)
In the exsiccant round-bottomed flask of 25mL, add 3mL toluene, 163mg (1mmol) isatoic anhydride, (its preparation method sees also step (2), 505mg (5mmol) triethylamine of embodiment 5 to 165mg (1mmol) 5-fluoro indigo red; Be warming up to 110 ℃ then, after refluxing and stirring reaction 3-4h, TLC detect and show that reaction is accomplished; The pressure reducing and steaming solvent; Residue gets formula III chemical compound 242mg, yield 91% with ethyl alcohol recrystallization.
Characterization data is following:
1H-NMR (400MHz, CDCl
3) δ=8.64 (m, 1H), 8.44 (d, 1H), 8.03 (d, 1H), 7.87 (t, 1H), 7.70 (t, 1H), 7.58 (m, 1H), 7.49 (m, 1H).
Synthesizing of embodiment 4:8-bromine couroupitine A (formula IV)
(1) synthesizing bromine isonitroso acetanilide
In the 500mL round-bottomed flask, add 16.5g (0.1mol) Chloral and 220mL water; Add the 15g sodium sulfate crystal then successively; 17.1g (0.1mol) dilute hydrochloric acid solution that is made into of para-bromoaniline (available from Aladdin reagent company limited) and 60mL water and 10mL concentrated hydrochloric acid adds 20.8g (0.3mol) oxammonium hydrochloride. at last and is dissolved in the solution of processing in the 95mL water.Backflow 40-45min.In heating process, separate out small amount of crystalline, make crystallization complete with the flowing water cooling solution.Filter, dry, subsequent use.
(2) 5-bromoisatin is synthetic
In the 100mL three-necked bottle of reflux condenser, magneton, thermometer is housed; Add the 25.5mL concentrated sulphuric acid, it is exsiccant to bromine isonitroso acetanilide to add 8.7g (0.036mol) then under the room temperature, control adding speed (adding about 20min); Make temperature keep 65 ℃, reaction 1h.Then with the reactant mixture cool to room temperature, and pour in the trash ice that is equivalent to 10～12 times of reactant volumes, filtration under diminished pressure after half an hour, with cold water washing for several times, flush away sulphuric acid at air drying, obtains 5-bromoisatin.
(3) 8-bromine couroupitine A (IV) is synthetic
With 5-bromoisatin 2.25g (0.01mol), isatoic anhydride 1.63g (0.01mol), the stirring magneton is equipped with in 20mL toluene and triethylamine 5.05g (0.05mol) adding; In the 100mL three-necked bottle of condensing tube and thermometer, reflux 3h, cooling; Filter; Recrystallization obtains the yellow green acicular crystal, i.e. 8-bromine couroupitine A shown in the formula IV.
Characterization data is following:
1H-NMR (400MHz, CDCl
3) δ=8.56 (d, 1H), 8.44 (d, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.82-7.96 (m, 2H), 7.66-7.76 (m, 1H).
Synthesizing of embodiment 5:2-fluorine couroupitine A (formula V)
(1) synthesizing fluorine isonitroso acetanilide
In the 500mL round-bottomed flask, add 16.5g (0.1mol) Chloral (available from Aladdin reagent company limited) and 220mL water; Add the 15g sodium sulfate crystal then successively; 11.1g (0.1mol) dilute hydrochloric acid solution that is made into of para-fluoroaniline (available from Aladdin reagent company limited) and 60mL water and 10mL concentrated hydrochloric acid adds 20.8g (0.3mol) oxammonium hydrochloride. at last and is dissolved in the solution of processing in the 95mL water.Backflow 40-45min.In heating process, separate out small amount of crystalline, make crystallization complete with the flowing water cooling solution.Filter, dry, subsequent use.
(2) the 5-fluoro indigo red is synthetic
In the 100mL three-necked bottle of reflux condenser, magneton, thermometer is housed; Add the 25.5mL concentrated sulphuric acid, it is exsiccant to fluorine isonitroso acetanilide 1 to add 6.55g (0.036mol) then under the room temperature, control adding speed (adding about 20min); Make temperature keep 65 ℃, reaction 1h.Then with the reactant mixture cool to room temperature, and pour in the trash ice that is equivalent to 10～12 times of reactant volumes, filtration under diminished pressure after half an hour, with cold water washing for several times, flush away sulphuric acid at air drying, obtains the 5-fluoro indigo red.
(3) 6-fluoro indigo red anhydride is synthetic
In the 100mL round-bottomed flask, add 1.65g (0.01mol) 5-fluoro indigo red, the 10mL acetic anhydride, the 0.1mL concentrated sulphuric acid drips the new Peracetic Acid 4mL (HOAc: H that disposes under the stirring at room
2O
2=8: 9).60-70 ℃ is reacted 4h down.Cooling is filtered, washing, 5%NaHCO
3Solution is washed, and washing again gets pressed powder 6-fluoro indigo red anhydride after the drying.
(4) 2-fluorine couroupitine A (V) is synthetic
With isatin 1.47g (0.01mol), 6-fluoro indigo red anhydride 1.81g (0.01mol), the stirring magneton is equipped with in 20mL toluene and triethylamine 5.05g (0.05mol) adding; In the 100mL three-necked bottle of condensing tube and thermometer, reflux 3h, cooling; Filter; Recrystallization obtains the yellow green acicular crystal, i.e. 2-fluorine couroupitine A shown in the formula V.
Characterization data is following:
1H-NMR (400MHz, DMSO-d
6) δ=8.46-8.51 (m, 1H), 8.02-8.08 (m, 2H), 7.82-7.94 (m, 3H), 7.48-7.54 (m, 1H).
Embodiment 6:2,8-difluoro couroupitine A (formula VI) synthetic
(1) synthesizing fluorine isonitroso acetanilide
In the 500mL round-bottomed flask, add 16.5g (0.1mol) Chloral and 220mL water; Add the 15g sodium sulfate crystal then successively, the dilute hydrochloric acid solution that 11.1g (0.1mol) para-fluoroaniline and 60mL water and 10mL concentrated hydrochloric acid are made into adds 20.8g (0.3mol) oxammonium hydrochloride. at last and is dissolved in the solution of processing in the 95mL water.Backflow 40-45min.In heating process, separate out small amount of crystalline, make crystallization complete with the flowing water cooling solution.Filter, dry, subsequent use.
(2) the 5-fluoro indigo red is synthetic
In the 100mL three-necked bottle of reflux condenser, magneton, thermometer is housed; Add the 25.5mL concentrated sulphuric acid, it is exsiccant to fluorine isonitroso acetanilide 1 to add 6.55g (0.036mol) then under the room temperature, control adding speed (adding about 20min); Make temperature keep 65 ℃, reaction 1h.Then with the reactant mixture cool to room temperature, and pour in the trash ice that is equivalent to 10～12 times of reactant volumes, filtration under diminished pressure after half an hour, with cold water washing for several times, flush away sulphuric acid at air drying, obtains the 5-fluoro indigo red.
(3) 6-fluoro indigo red anhydride is synthetic
In the 100mL round-bottomed flask, add 1.65g (0.01mol) 5-fluoro indigo red, the 10mL acetic anhydride, the 0.1mL concentrated sulphuric acid drips the new Peracetic Acid 4mL (HOAc: H that disposes under the stirring at room
2O
2=8: 9).60-70 ℃ is reacted 4h down.Cooling is filtered, washing, 5%NaHCO
3Solution is washed, and washing again gets pressed powder 6-fluoro indigo red anhydride after the drying.
Synthesizing of (4) 2,8-difluoro couroupitine As (VI)
With 5-fluoro indigo red 1.65g (0.01mol), 6-fluoro indigo red anhydride 1.81g (0.01mol), the stirring magneton is equipped with in 20mL toluene and triethylamine 5.05g (0.05mol) adding; In the 100mL three-necked bottle of condensing tube and thermometer, reflux 3h, cooling; Filter, recrystallization obtains the yellow green acicular crystal; Be 2 shown in the formula VI, 8-difluoro couroupitine A.
Characterization data is following:
1H-NMR (400MHz, DMSO-d
6) δ=8.46-8.52 (m, 1H), 8.03-8.10 (m, 2H), 7.51-7.80 (m, 3H).
The preparation of embodiment 7:7-chlorine couroupitine A (formula VII)
In the exsiccant round-bottomed flask of 25mL, add 3mL toluene, 163mg (1mmol) isatoic anhydride, 181mg (1mmol) 4-chlorisatide (becoming the chemical industry company limited), 505mg (5mmol) triethylamine available from Shanghai nation; Be warming up to 110 ℃ then, after refluxing and stirring reaction 3-4h, TLC detect and show that reaction is accomplished; The pressure reducing and steaming solvent; Residue gets chemical compound 225mg shown in the VI, yield 80% with ethyl alcohol recrystallization.
Characterization data is following:
1H-NMR (400MHz, CDCl
3) δ=8.47 (d, 1H), 8.34 (d, 1H), 7.95 (d, 2H), 7.86 (m, 1H), 7.76 (m, 1H), 7.54 (m, 1H).
The preparation of embodiment 8:7-piperazine couroupitine A (formula VIII)
In the exsiccant round-bottomed flask of 25mL, add 10mL NMP, 283mg (1mmol) 7-chlorine couroupitine A, 252mg (1.3mmol) anthalazine (available from Aladdin reagent company limited), react under 70 ℃, TLC follows the tracks of extent of reaction.After question response is accomplished, chloroform extraction, with chloroform: methanol=95: 5 is that leacheate carries out column chromatography for separation and purifies and promptly get the 7-piperazine couroupitine A 200mg shown in the formula VIII, yield 60%.
Characterization data is following:
1H-NMR (400MHz, CDCl
3) δ=6.74-8.35 (m, 7H), 3.37 (t, 4H), 3.09 (m, 4H).
Embodiment 9:IDO suppresses active Preliminary detection
Structure, the expression in escherichia coli, extraction and the purification 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 kaliumphosphate buffer (pH 6.5), the 40mM vitamin C, 400 μ g/ml catalases, 20 μ M methylene blues and IDO enzyme mix.In above-mentioned mixed liquor, add substrate L-tryptophan and testing sample.Be reflected at and carry out 60min under 37 ℃, add 30% (w/v) trichloroacetic acid and make reaction terminating.96 orifice plates heat 15min down at 65 ℃, make it to accomplish the conversion from the formylkynurenine to the kynurenin, then 6000rpm rotation 5min.Every hole is taken out 100 μ l supernatant and is transferred in the 96 new orifice plates, add 2% (w/v) right-acetic acid solution of dimethylamino benzaldehyde, kynurenin reacts the yellow color of producing with it and can use ELIASA under 490nm, to observe.Preliminary detection shows that couroupitine A derivant (formula I-VIII) all has IDO and suppresses active.
Whether embodiment 10: be the judgement of reversible inhibitor
Under the situation of fixing inhibitor concentration, with enzyme and the inhibitor reaction and the assaying reaction speed of a series of variable concentrations.To enzyme concentration (v～[E]) mapping, can judge whether be reversible inhibitor with response speed according to the characteristic of curve.
Reaction condition: in the reaction system of 500 μ l, add 50mM kaliumphosphate buffer (pH6.5), 40mM vitamin C earlier; 400 μ g/ml catalases, 20 μ M methylene blues, 300mM substrate L-tryptophan or add the 100mM inhibitor simultaneously; Mixed liquor is incubated 5min for 37 ℃, in above-mentioned mixed liquor, adds the IDO enzyme of different volumes more respectively, is reflected at and carries out 30min under 37 ℃; Add 30% (w/v) trichloroacetic acid, 200 μ l and make reaction terminating; Reaction system makes it to accomplish the conversion from the formylkynurenine to the kynurenin at 65 ℃ of heating 15min, then 12000rpm rotation 10min; Get supernatant right with equal-volume 2% (w/v)-acetic acid solution of dimethylaminobenzaldehyde mixes, and detects the reading of wavelength 490nm with ELIASA.Be figure with v～[E].Detection shows that couroupitine A derivant (I-VIII) is reversible IDO inhibitor.
Embodiment 11: inhibitor type is judged and K
iPH-value determination pH
In the reaction system of 500 μ l, add 50mM kaliumphosphate buffer (pH 6.5), 40mM vitamin C earlier; 400 μ g/ml catalases, 20 μ M methylene blues add 100,250 respectively, 300mM substrate L-tryptophan; Under a concentration of substrate, in each tube reaction system, add the chemical compound of variable concentrations respectively, 37 ℃ of insulations of mixed liquor 5min; In above-mentioned mixed liquor, add 10 μ lIDO (about 20nM) again, be reflected at and carry out 30min under 37 ℃, add 30% (w/v) trichloroacetic acid, 200 μ l and make reaction terminating; Reaction system makes it to accomplish the conversion from the formylkynurenine to the kynurenin at 65 ℃ of heating in water bath 15min, then the centrifugal 10min of 12000rpm; Get supernatant and equal-volume 2% (w/v) right-reaction of the acetic acid solution mixing of dimethylaminobenzaldehyde, detect the reading of wavelength 490nm with ELIASA.With the inhibitor type of Dixon graphing method (1/v～[I]) judgement chemical compound, with S/v～[I] mapping, the K of the agent that is inhibited
iValue.
Embodiment 12: the external IC of half effective inhibition concentration
50Mensuration
First with 50mM kaliumphosphate buffer (pH 6.5), 40mM vitamin C, 400 μ g/ml catalases, 20 μ M methylene blues, substrate L-tryptophan 150mM and inhibitor mixed.Inhibitor concentration is selected 100,200,400,600,800,1000,1200 μ M for use, and 37 ℃ of insulations of mixed liquor 5min adds the IDO enzyme again in above-mentioned mixed liquor.Be reflected at and carry out 30min under 37 ℃; Add 30% (w/v) trichloroacetic acid, 200 μ l and make reaction terminating, reaction system makes it to accomplish the conversion from the formylkynurenine to the kynurenin at 65 ℃ of heating 15min; 12000rpm rotates 10min then; Get 200 μ l supernatants right with equal-volume 2% (w/v)-acetic acid solution of dimethylaminobenzaldehyde mixes, kynurenin reacts the yellow color of generation with it and can use ELIASA under 490nm, to detect, the gained result utilizes IC
50Computing software.It is following that this measures mechanism:
λ
max＝490nm
Embodiment 13: half effective inhibition concentration cell IC
50Mensuration
Utilize liposome Lipofectamin 2000 mediations plasmid pcDNA3.1-hIDO wink to change the HEK293 cell.It is high sugared DMEM that the cellular level inhibitor activity is measured HEK 293 cell culture mediums that adopt, and contains the 50U/mL penicillin, 50U/mL streptomycin, 10%FBS, 37 ℃, 5%CO
2Cultivate.Behind the cell transfecting plasmid 24h, add medicine to be measured, hatch a period of time after; Get supernatant in another 96 orifice plate; Add 10 μ L 30% (w/v) trichloroacetic acids, make it to accomplish the conversion of formylkynurenine at 65 ℃ of heating 15min, then the centrifugal 10min of 12000rpm to kynurenin; Get equal-volume 2 ‰ (w/v) right-acetic acid solution of dimethylaminobenzaldehyde mixes colour developing, adopts ELIASA under 490nm, to detect light absorption value at last.
Utilize the method for the foregoing description 10-13, the IDO of formula I-VIII chemical compound suppressed activity measure, and with IDO inhibitor 1-methyl tryptophan (1-MT, commercially available) general in the present experiment in vivo and vitro as tester, mensuration result such as table 1.
Table 1: the IDO of formula I-VIII chemical compound suppresses active
ND representes not survey in the table 1.
Embodiment 14: the leukemic effect of anti-mice P388
1. cell line
The mouse lymphocyte leukaemia is P388, available from Nanjing Kai Ji biotech firm.
2. laboratory animal
6～8 age in week the DBA/2 mice, inbred line, the SPF level, 100, male and female half and half, individual quality (22.0 ± 1.6) g, available from Shanghai Slac Experimental Animal Co., Ltd., the quality certification number: SCXK (Shanghai) 2007-0005.All mices are all raised the barrier environment Animal Lab. in Shenyang Pharmaceutical University's Experimental Animal Center.
3.P388 leukemia mouse modeling method
Get the P388 leukaemia of the exponential phase of In vitro culture, after normal saline washing 2 times, inoculating cell about 1 * 10 in 2 DBA/2 mouse peritoneals respectively
6Individual, put to death back extraction ascites under aseptic condition on the 8th day, it is translucent to be creamy white, and putting and using normal saline adjustment cell density in the sterile chamber is 5 * 10
6Individual/mL, to get a little suspension and carry out trypan blue dyeing, light microscopic is counting down, and viable count should be more than 95%, then with above-mentioned tumor cell suspension every mouse peritoneal injection (ip) 0.2mL (about 1 * 10 under aseptic condition
6Individual cell), inoculate 100 altogether.
4. test grouping, administration and test method
20%DMSO preparation is diluted to the working solution of debita spissitudo according to the mice body weight with normal saline during experiment, and the DMSO maximum concentration is no more than 10%.100 postvaccinal mices of success are divided into 10 groups at random, i.e. blank group, solvent control group, formula I, II, III, IV, V, VI, VII, VIII chemical compound group (35mg/kg), 10 every group, male and female half and half.Inoculate and begin administration next day.In experiment administration in the 1st～7 day, blank group, every ip in mice normal saline 0.2ml/d; Solvent control group, every ip in mice 10%DMSO 0.2mL/d; Formula I, II, III, IV, V, VI, VII, VIII chemical compound group, every corresponding medicine 35mg/kg of ip in mice, final volume 0.2mL.
Leukemia mouse increase in life span computational methods: experiment mice lotus tumor life cycle is from inoculation calculating on the same day.Increase in life span=(experimental group mean survival time (MST)-matched group mean survival time (MST))/matched group mean survival time (MST) * 100%
5. result
Table 2
The growth of two control group mice ascites is rapid, and the 8th day promptly visible obvious bulge of abdominal part in inoculation back is slow in action, the visible a large amount of muddy bloody ascites of the intracavity of cutting open the belly after the death, and the visible crisp tumor agglomerate of more greyish white chromaticness of the outer mesentery of intestinal adheres to.Each administration group mice stops the administration postabdomen swells gradually, eight groups of equal visible abdominal tympanitess about 12d, and also visible a large amount of bloody ascites of intraperitoneal after death, the tumor agglomerate is less.
6. discuss
Show according to the result, but explain that chemical compound of the present invention has good antitumor action the life cycle of formula I, II, III, IV, V, VI, VII, the equal significant prolongation P388 leukemia mouse of VIII chemical compound in P388 leukemia mouse body.
Embodiment 15: to the influence of A Er the silent learning and memory in rats ability in sea
1. main agents and instrument
Quinolinic acid (QA): Sigma company provides.Test kit (Tunnel): Wuhan Boster Biological Technology Co., Ltd. provides, production code member MK1020.Brain solid positioner NARISHIGE SN-2 type.The Morris water maze: pharmacology teaching and research room of Chinese Medical Sciences University makes.
2. laboratory animal
100 of male Wistar rats, male and female half and half, body weight (280 ± 10) g is provided by Chinese Medical Sciences University experimental animal center.
3. animal grouping, modelling and medication
100 rats are divided 10 groups at random, promptly false injured group, model group, formula I, II, III, IV, V, VI, VII, VIII chemical compound group (50mg/kg), 10 every group, rat body weight no difference of science of statistics between group.
Except that blank control group, laboratory animal is anaesthetized with 3% pentobarbital sodium 1ml/kg ip; Be fixed on the brain solid positioner, calvarium medisection is with reference to rat brain stereotaxic atlas (AP 0.2mm; ML2.5mm, DV 4.5mm), behind the three-dimensional location, bilateral Hippocampus CA1 district; Skull left by brill, with the vertical inserting needle of 2 μ l microsyringes, will use 0.01mol/L (pH 7.4) the dissolved QA 2 μ l of PBS buffer (containing 150nmol QA) slowly to inject bilateral Hippocampus CA1 district; False injured group is injected 0.01mol/L (pH 7.4) PBS 2 μ l, and every side injection length is 5min, let the acupuncture needle remain at a certain point 5min; Block up skull with the dentistry mudding after pulling out pin, skin suture after the partly sterilised, the intramuscular injection penicillin is protected from infection for three days on end.1 week of postoperative is respectively organized administration according to dosage, and false injured group, model group give distilled water 2ml/ and only irritate stomach, continuous 2 weeks.
Morris water maze test method: after 1 week of medication, every rat incidence hair is positioned navigation with common hair dye blacking; Laboratory temperature adds milk powder 1kg at 24～25 ℃ during test in the water maze, washes open with hot water, and water adds to and exceeds security platform 1cm again, and water temperature remains on about 22 ℃.Mounted camera head is connected with computer monitor and printer.Indicate four place of entry in the four corners of the world in the pond, the pond is divided into 4 quadrants, SW, NW, SE, NE; Security platform is positioned at the SW quadrant, the 23cm apart from the center of circle, fix security platform after; Towards pool wall rat is put into water from 4 quadrant place of entry respectively, the record rat from place of entry begin to find platform the time ask (incubation period, SPL), (animal is if can not find security platform in the 2min to induce number of times; Then it is put back into security platform by the experimenter), index such as motion path, as the location school grade.Let rat free swimming 5min to be familiar with environment in first day; Second day begins one period of every day; Train 4 times for every section; For three days on end, carried out space exploration experiment (promptly removing the ratio that security platform is observed swimming distance with total distance of the inherent platform quadrant of Mus 2min) on the 5th day to detect rat spatial memory ability.Each equal 5 groups of parallel carrying out.
4, experimental result
Table 3
* compare P＜0.05 or 0.01 with model group
Formula I, II, III, IV, V, VI, VII, VIII chemical compound cause the influence (orientation navigation test) of AD learning and memory in rats process to QA damage Hippocampus: the treatment group is than model group minimizing incubation period; The navigation path contraction; Induce number of times to reduce; Induce percentage ratio to reduce (chi-square criterion, table 3 is seen in P＜0.05).Formula I, II, III, IV, V, VI, VII, VIII chemical compound cause the influence (space exploration test) of AD rat memory intensity to QA damage Hippocampus: model group rats'swimming route all quadrants is almost average; Still than the blind search security platform, span security platform position once in a while just; Each treatment group rat has clearer and more definite search purpose, and the swimming route mainly concentrates on the security platform quadrant, crosses over security platform position number of times obviously more than model group (seeing table 3).
5, conclusion
Experiment display model group rat space orientation memory ability receives grievous injury, each treatment group space orientation memory ability than the model group rat in obvious improvement, suitable with the positive drug therapeutic effect.Prove that chemical compound of the present invention all has certain therapeutical effect to AD rat due to the QA.
Embodiment 16: to the influence of cataract rat lens
1. reagent and instrument:
Sodium selenite crystalline solid (Na
2SeO
35H
2O) and the sheet of recovering lost eyesight (Beilin Pharmaceutical Co., Ltd., Xi'an).Malonaldehyde (MDA) and superoxide dismutase (SOD) testing cassete (bio-engineering research institute is built up in Nanjing).756MC type ultraviolet-uisible spectrophotometer (Shanghai Precision Scientific Apparatus Co., Ltd).Digital display constant temperature three usefulness water tanks (the bank head state Rui Shiyanyiqichang of Jintan City, Jiangsu).Micropipettor (Qiujing Bio-Chemical Reagent Instrument Co., Ltd., Shanghai).YZ-5CSI type slit lamp microscope (Suzhou Medical Instruments Factory).
2. animal:
100 of healthy pure lines Wiatar rat neonatal rats, the male and female dual-purpose, Mus is 10 days age, and individual quality 14～16g is provided by Chinese Medical Sciences University's Experimental Animal Center.
3. divide into groups and the cataract modelling:
The Wistar rat is divided into 10 groups at random, i.e. matched group, model group, formula I-VIII chemical compound group (every group of 50mg/kg), 10 every group.Divide cage to feed with breast milk and plain particles feedstuff, freely drink water.To model group and low dose of (3.46mg/kg body weight) sodium selenite of formula I-VIII chemical compound group rat nape portion subcutaneous injection, the next day 1 time, continuous 3 times.Control rats is left intact.Lenticular opacity was the modeling success with the variation of slit lamp microscope observation crystalline lens in the 3rd day after the last administration.
4. administration and test method:
Each administration group is according to dosage carried out administration, 1 time/day, continues for 2 weeks; Matched group and model group rat do not give any medicine free diet drinking-water.
(1) crystalline lens form gross examination of skeletal muscle: behind the rat Cheng Mo, weekly with behind the U.S. Dolly eye drop mydriasis, with the examination with slitlamp microscope rat lens and take pictures.The muddy degree of crystalline lens is divided into 0～V phase: 0 phase was that crystalline lens is transparent; The I phase is dispersed in tiny cavity for the crystalline lens peripheral cortical; The II phase is the intensive circlewise medium cavity of crystalline lens peripheral cortical; The III phase is except that the intensive cavity of crystalline lens peripheral cortical, and the partial cortical lamellar is muddy; The IV phase is nucleus lentis and examines all cortex muddinesses; The V phase is that crystalline lens is muddy fully.
(2) preparation of crystalline lens homogenate: take by weighing the double eyeball crystalline lens and put into 5ml homogenate cup; Adding 8.6g/L ice normal saline by a certain percentage smashs 1.5min with temperature control multi-purpose high speed tissue mashing machine to pieces with 10000r/min and processes 3.5% crystalline lens homogenate; With 2000r/min low-speed centrifugal 8min, separation of supernatant MDA content to be measured and SOD are active then.
(3) MDA content and SOD are active in the crystalline lens detects: get serum 100 μ l, crystalline lens homogenate supernatant 100 μ l; Detect MDA content; Get serum 30 μ l, crystalline lens homogenate supernatant 30 μ l detection SOD activity, detailed process is operated by MDA and SOD testing cassete description.Carry out colorimetric determination with 756MC type ultraviolet-uisible spectrophotometer.
5. result
Table 4: the last eventually muddy degree of respectively organizing rat lens of experiment
In phase, the control rats crystalline lens is transparent all the time at laboratory observation; Intensive cavity appears in model group rat lens peripheral cortical, the partial cortical lamellar is muddy, is III～V phase; Formula I, II, III, IV, V, VI, VII, the muddy degree of VIII chemical compound group rat lens alleviate than model group is obvious, are 0～III phase.
Table 5: the active comparison of MDA content and SOD in rat blood serum and the crystalline lens (x ± s)
The detection of MDA content finds that MDA is starkly lower than model group in formula I, II, III, IV, V, VI, VII, the VIII chemical compound group crystalline lens, and difference has significance (P＜0.05).The active detection of SOD finds that the SOD activity is apparently higher than model group in formula I, II, III, IV, V, VI, VII, the VIII chemical compound group crystalline lens, and difference has significance (P＜0.05).
6. conclusion
Chemical compound of the present invention can alleviate the lenticular opacity degree, this effect maybe with SOD in its increase crystalline lens with reduce MDA content, thereby play antagonism and to alleviate peroxide injury relevant.
Embodiment 17: to the antidepressant effect of mice depression model
1. laboratory animal
Male SPF level Kunming mouse, body constitution amount 20～25g purchases the Experimental Animal Center in Chinese Medical Sciences University.
2. animal divides into groups
, experiments all mice is carried out neuroethology test and screening before dividing into groups with corresponding instrument; Rejecting differs greatly; Again that difference is less mice filters out 90 altogether, divides 9 groups at random; Be blank control group, formula I, II, III, IV, V, VI, VII, VIII chemical compound group (every group of 60mg/kg), 10 every group.
3. test method:
(1) mouse tail suspension experiment (Tail Suspension Test, TST)
4 groups of mices conformed for 1 week, and the single cage of 24h animal is raised before the experiment, and water is can't help in fasting.Test each group on the same day according to dosage requires gastric infusion, behind administration 1h, with adhesive plaster mouse tail is being sticked at outstanding tail balance bracket apart from tail point 2cm place; Do not make the mouse tail distortion folding; The suspension downwards of its head is hangs shape by the feet, head distance desktop 15cm, every mouse tail suspension 6min; Preceding 2min adapts to, the accumulative total dead time in the 4min of record back (fixed finger mice all limbs except that breathing are all motionless).
(2) mouse swimming test (Forced Swimming Test, FST)
4 groups of mices conformed for 1 week, and the 24h animal carries out swimming instruction 15min before the experiment, and the raising of single cage, and water is can't help in fasting.During experiment each is organized the single about 18cm of diameter that only puts into of mice behind the administration 1h according to dosage; Depth of water 18cm; In the bulge of water temperature (25 ± 1) ℃; Begin to calculate the accumulative total dead time in the 4min of back (floating motionless state only exposes the nostril and keeps breathing, and extremity paddling once in a while are unlikely to sink to keep health) after adapting to 2min.
4. result
Table 6
It is as shown in the table for the result, with blank group compared, and the dead time that formula I, II, III, IV, V, VI, VII, VIII flower chemical compound group all can shorten mice swimming and hang tail, do not see difference between three groups.
5. conclusion
Result of the test shows that chemical compound of the present invention can resist the depressive symptom that mice is caused because of forced swimming and outstanding tail.
Embodiment 18: to the influence of mice anxiety behavior
1. instrument
Unite prologue experiment video analytic system (Cornbined Open Field Test AnalysisSystem), Jiliang Software Sci-Tech Co., Ltd., Shanghai produces.
2. animal and grouping
90 of Male Kunming strain mice, body constitution amount (20 ± 2) g purchases the Experimental Animal Center in Chinese Medical Sciences University.The mice adaptability is divided into 9 groups after raising for 1 week at random, and promptly blank control group, formula I, II, III, IV, V, VI, VII, VIII chemical compound group (60mg/kg) begin to carry out mice and unite prologue behavior detection behind the administration 1h.
3. test method
Mice is put the center district that unites the experimental box of beginning that the people is equipped with the 16 hole plates of 40cm * 40cm, pick up counting simultaneously.Unite in the prologue experimental box and be mounted with RF transmitter and camera head, effectively various spontaneous activity behaviors and the exploratory heading behavior of record mice simultaneously.The degree of depth in hole is 2.2cm, is mounted with infrared ray in the 1cm depths, when the exploratory heading degree of depth of mice surpasses 1cm, because by the infrared ray blocking-up, instrument will write down an exploratory heading behavior automatically, and accumulative total exploratory heading number of times.Every mice carries out the 6min record continuously, keeps external environment quiet during operation, puts into the Excreta of cleaning out case before the mice at every turn, guarantees the objectivity of every batch of detection as far as possible.
4. result
Table 7
1. the central area activity time relatively: formula I, II, III, IV, V, VI, VII, VIII chemical compound group and blank control group relatively have significant difference (P＜0.05); 2. central area activity distance relatively: formula I, II, III, IV, V, VI, VII, VIII chemical compound group and blank control group relatively have significant difference (P＜0.05); 3. shuttle back and forth time ratio: formula I, II, III, IV, V, VI, VII, VIII chemical compound group and blank control group relatively have significant difference (P＜0.05).
Table 8
Formula I, II, III, IV, V, VI, VII, VIII chemical compound group and blank control group relatively have significant difference (P＜0.05).
5. conclusion:
In this animal spontaneous behaviour of uniting prologue detects, tentative confirmation chemical compound of the present invention the behavior of anxiety mice is had the improvement effect.
Embodiment 19: to the influence of adjuvant arthritis rat model
1. laboratory animal
5～6 monthly age of SPF level the male wistar rat, body constitution amount (180 ± 20) g, Chinese Medical Sciences University's Experimental Animal Center provides.
2. reagent and instrument
Liquid paraffin, chemical reagent factory in Tianjin produces; Medicinal lanoline, Shanghai China prosperous lanoline factory produces; Intradermal injection is used bacillus calmette-guerin vaccine, and Shanghai Vaccine and Serum Institute produces.The 1/100mm digimatic calipers, measurer factory in Tianjin produces.
3. modeling and grouping administration
(1) preparation of Freund ' s Freund's complete adjuvant:
Get 1 part after the anhydrous lanolin heating is dissolved and place mortar, cooling slightly adds 2 parts of liquid paraffin while grinding.After grinding 30min, 70 ℃ of hot 10min altogether take out the back then and add bacillus calmette-guerin vaccine or deactivation tubercule bacillus 7.5mg by every milliliter behind the autoclaving 1h, grind evenly, put 4 ℃ of refrigerators and preserve subsequent usely, shake up before the use.
(2) animal divides into groups and administration:
After 100 rat adaptabilities are fed 3d, be divided into 10 groups at random, promptly blank control group, model group, compound I～VIII organize (every group of 50mg/kg), 10 every group.Each treated animal all in cause scorching before 1h begin gastric infusion, 1 time/d of administration after the modeling, continuous 3d.
(3) adjuvant-induced arthritis modelling:
Right back sufficient intradermal injection Freund ' the s Freund's complete adjuvant of rat except that the normal control group (0.05mL/ only).Normal control group injection isometric(al) normal saline.
(4) observation index:
Injection parapodum pawl swelling degree (constitutional pathological changes): respectively at cause scorching before with cause scorching back 18,36,72h measures vola thickness with the slide calliper rule method, and calculates the swelling degree.
Vola thickness before vola thickness-injection after swelling degree=injection.
4. result:
Table 9: compound I～VIII is to the influence (n=10) of adjuvant arthritis rat model primary affection
Annotate: compare * P＜0.05 or P＜0.01 with model group
Shown in the result as above shows, compare, all can significantly suppress the swelling (P＜0.05 or P＜0.01) of the adjuvant arthritis rat model modeling parapodum palm behind compound I～VIII group administration 36h with model group.
5. conclusion
This experimental result shows that chemical compound gastric infusion of the present invention has significant therapeutical effect to adjuvant arthritis rat model primary affection, can suppress immune inflammation.
Claims (9)
1. the purposes of chemical compound shown in the formula A in preparation IDO inhibitor,
Wherein, R
1, R
2Be independently selected from hydrogen, nitro, C respectively
1-C
5Alkyl, halogen or piperazinyl.
2. purposes according to claim 1 is characterized in that R
1, R
2Be independently selected from hydrogen, methyl, fluorine, chlorine, bromine and piperazinyl respectively.
3. purposes according to claim 1 and 2 is characterized in that, the structure of chemical compound shown in the formula A is suc as formula shown in A1 or the A2:
4. according to each described purposes in the claim 1 to 3, it is characterized in that the structure of chemical compound shown in the formula A is following:
5. chemical compound shown in the formula A prevents and/or treats the purposes in the medicine of disease of the disorderly pathological characteristics of tryptophan metabolism with IDO mediation in preparation,
Wherein, R
1, R
2Be independently selected from hydrogen, nitro, C respectively
1-C
5Alkyl, halogen or piperazinyl.
6. purposes according to claim 5 is characterized in that said disease is selected from tumor, cancer, Alzheimer, autoimmune disease, cataract, mental maladjustment, depression, anxiety neurosis, AIDS.
7. according to claim 5 or 6 described purposes, it is characterized in that R
1, R
2Be independently selected from hydrogen, methyl, fluorine, chlorine, bromine and piperazinyl respectively.
8. according to each described purposes in the claim 5 to 6, it is characterized in that the structure of chemical compound shown in the formula A is suc as formula shown in A1 or the A2:
9. according to each described purposes in the claim 5 to 7, it is characterized in that the structure of chemical compound shown in the formula A is following:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210018591.6A CN102579452B (en) | 2012-01-20 | 2012-01-20 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210018591.6A CN102579452B (en) | 2012-01-20 | 2012-01-20 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102579452A true CN102579452A (en) | 2012-07-18 |
| CN102579452B CN102579452B (en) | 2014-05-14 |
Family
ID=46469059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210018591.6A Active CN102579452B (en) | 2012-01-20 | 2012-01-20 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102579452B (en) |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054870A (en) * | 2013-01-08 | 2013-04-24 | 复旦大学 | Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor |
| CN103570726A (en) * | 2013-07-15 | 2014-02-12 | 上海天慈生物谷生物工程有限公司 | N-alkyl tryptanthrin derivative, as well as preparation method and application thereof |
| CN105153148A (en) * | 2015-06-18 | 2015-12-16 | 玉林师范学院 | Tryptanthrin alkaloid salt, and preparation method and application thereof |
| CN105330666A (en) * | 2015-11-27 | 2016-02-17 | 西北大学 | Novel tryptanthrin derivative, synthetic method and medicinal application thereof |
| CN105829312A (en) * | 2013-11-12 | 2016-08-03 | 复旦大学 | N-benzyl tryptanthrin derivative, and preparation method and application thereof |
| WO2017114260A1 (en) * | 2015-12-30 | 2017-07-06 | 苏州康正生物医药有限公司 | Uses of tryptanthrin and derivative thereof in preparing hldo2 inhibitor |
| CN107260743A (en) * | 2016-04-05 | 2017-10-20 | 北京大学 | Azatryptamine ketone derivatives as IDO1 and/or TDO inhibitor purposes |
| WO2018071873A2 (en) | 2016-10-13 | 2018-04-19 | Juno Therapeutics, Inc. | Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators |
| WO2018113624A1 (en) | 2016-12-20 | 2018-06-28 | 深圳微芯生物科技有限责任公司 | Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity |
| CN110283192A (en) * | 2019-07-18 | 2019-09-27 | 同济大学 | A kind of preparation method and application of the tryptamines ketone derivatives of boronic acid containing |
| CN110437233A (en) * | 2019-06-21 | 2019-11-12 | 同济大学 | A kind of tryptamines ketone derivatives and its preparation method and application containing olefin(e) acid |
| WO2020063618A1 (en) | 2018-09-27 | 2020-04-02 | 深圳微芯生物科技股份有限公司 | Quinolone derivative having indoleamine-2,3-dioxygenase inhibited activity |
| CN111187785A (en) * | 2020-02-12 | 2020-05-22 | 浙江中医药大学 | Cloning expression and application of serpentis grass tryptophan decarboxylase gene OpTDC2 |
| CN111808078A (en) * | 2020-06-22 | 2020-10-23 | 济南爱思医药科技有限公司 | Lenalidomide derivative for inhibiting IDO1 activity and preparation method and application thereof |
| CN114874219A (en) * | 2022-04-15 | 2022-08-09 | 安徽瀚海博兴生物技术有限公司 | 2-aminobenzene sulfonamide substituted tryptanthrin derivative and preparation and application thereof |
| CN115710276A (en) * | 2022-11-21 | 2023-02-24 | 贵州大学 | 7-fatty amine substituted tryptanthrin derivative, preparation method and application thereof |
| CN117298119A (en) * | 2023-11-28 | 2023-12-29 | 云南中医药大学 | Application of tryptanthrin derivative in preparation of drug-resistant candida albicans drug |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2369448A1 (en) * | 1999-04-14 | 2000-10-19 | Max Zeller Sohne Ag | Medicament for inhibiting nf-kb |
-
2012
- 2012-01-20 CN CN201210018591.6A patent/CN102579452B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2369448A1 (en) * | 1999-04-14 | 2000-10-19 | Max Zeller Sohne Ag | Medicament for inhibiting nf-kb |
| CA2369448C (en) * | 1999-04-14 | 2008-08-19 | Max Zeller Sohne Ag | Medicament for inhibiting nf-kb |
Non-Patent Citations (2)
| Title |
|---|
| 梅虎等: "原子类型电拓扑状态指数预测吲哚喹唑啉衍生物的抗癌性", 《物理化学学报》 * |
| 缪珊等: "色胺酮的研究进展", 《中国药理学通报》 * |
Cited By (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054870A (en) * | 2013-01-08 | 2013-04-24 | 复旦大学 | Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor |
| US9630969B2 (en) | 2013-07-15 | 2017-04-25 | Shanghai Tin Tsz Bio Valley Biological Engineering Co., Ltd | N-alkyl tryptanthrin derivative, preparation method for same, and application thereof |
| CN103570726A (en) * | 2013-07-15 | 2014-02-12 | 上海天慈生物谷生物工程有限公司 | N-alkyl tryptanthrin derivative, as well as preparation method and application thereof |
| WO2015007249A1 (en) * | 2013-07-15 | 2015-01-22 | 上海天慈生物谷生物工程有限公司 | N-alkyl tryptanthrin derivative, preparation method for same, and application thereof |
| CN103570726B (en) * | 2013-07-15 | 2016-04-06 | 上海天慈生物谷生物工程有限公司 | N-alkyl couroupitine A derivative and its preparation method and application |
| US10059712B2 (en) | 2013-11-12 | 2018-08-28 | Fudan University | N-benzyl tryptanthrin derivative, and preparation method and application thereof |
| CN105829312A (en) * | 2013-11-12 | 2016-08-03 | 复旦大学 | N-benzyl tryptanthrin derivative, and preparation method and application thereof |
| JP2016535788A (en) * | 2013-11-12 | 2016-11-17 | フーダン ユニヴァーシティＦｕｄａｎ Ｕｎｉｖｅｒｓｉｔｙ | N-benzyltryptanthrin derivative, and preparation method and use thereof |
| CN105153148A (en) * | 2015-06-18 | 2015-12-16 | 玉林师范学院 | Tryptanthrin alkaloid salt, and preparation method and application thereof |
| CN105330666A (en) * | 2015-11-27 | 2016-02-17 | 西北大学 | Novel tryptanthrin derivative, synthetic method and medicinal application thereof |
| CN105330666B (en) * | 2015-11-27 | 2018-10-30 | 西北大学 | Tryptamines ketone derivatives, synthetic method and its pharmaceutical usage |
| WO2017114260A1 (en) * | 2015-12-30 | 2017-07-06 | 苏州康正生物医药有限公司 | Uses of tryptanthrin and derivative thereof in preparing hldo2 inhibitor |
| CN106928229A (en) * | 2015-12-30 | 2017-07-07 | 苏州康正生物医药有限公司 | The purposes of couroupitine A and its derivative in hIDO2 inhibitor is prepared |
| CN107260743B (en) * | 2016-04-05 | 2020-01-31 | 北京大学 | Use of azatryptanthrin derivatives as IDO1 and/or TDO inhibitors |
| CN107260743A (en) * | 2016-04-05 | 2017-10-20 | 北京大学 | Azatryptamine ketone derivatives as IDO1 and/or TDO inhibitor purposes |
| US10669273B2 (en) | 2016-04-05 | 2020-06-02 | Peking University | Use of aza-tryptanthrin derivatives as inhibitors of IDO1 and/or TDO |
| WO2018071873A2 (en) | 2016-10-13 | 2018-04-19 | Juno Therapeutics, Inc. | Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators |
| US11896615B2 (en) | 2016-10-13 | 2024-02-13 | Juno Therapeutics, Inc. | Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators |
| EP4190335A1 (en) | 2016-10-13 | 2023-06-07 | Juno Therapeutics, Inc. | Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators |
| WO2018113624A1 (en) | 2016-12-20 | 2018-06-28 | 深圳微芯生物科技有限责任公司 | Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity |
| US10604529B2 (en) | 2016-12-20 | 2020-03-31 | Shenzhen Chipscreen Biosciences Co., Ltd. | Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity |
| WO2020063618A1 (en) | 2018-09-27 | 2020-04-02 | 深圳微芯生物科技股份有限公司 | Quinolone derivative having indoleamine-2,3-dioxygenase inhibited activity |
| CN110437233A (en) * | 2019-06-21 | 2019-11-12 | 同济大学 | A kind of tryptamines ketone derivatives and its preparation method and application containing olefin(e) acid |
| CN110437233B (en) * | 2019-06-21 | 2022-01-07 | 同济大学 | Tryptanthrin derivative containing olefine acid and preparation method and application thereof |
| CN110283192A (en) * | 2019-07-18 | 2019-09-27 | 同济大学 | A kind of preparation method and application of the tryptamines ketone derivatives of boronic acid containing |
| CN111187785B (en) * | 2020-02-12 | 2021-07-16 | 浙江中医药大学 | Cloning expression and application of serpentis grass tryptophan decarboxylase gene OpTDC2 |
| CN111187785A (en) * | 2020-02-12 | 2020-05-22 | 浙江中医药大学 | Cloning expression and application of serpentis grass tryptophan decarboxylase gene OpTDC2 |
| CN111808078A (en) * | 2020-06-22 | 2020-10-23 | 济南爱思医药科技有限公司 | Lenalidomide derivative for inhibiting IDO1 activity and preparation method and application thereof |
| CN114874219A (en) * | 2022-04-15 | 2022-08-09 | 安徽瀚海博兴生物技术有限公司 | 2-aminobenzene sulfonamide substituted tryptanthrin derivative and preparation and application thereof |
| CN114874219B (en) * | 2022-04-15 | 2023-04-28 | 安徽瀚海博兴生物技术有限公司 | 2-aminobenzene sulfonamide substituted tryptanthrin derivative and preparation and application thereof |
| CN115710276A (en) * | 2022-11-21 | 2023-02-24 | 贵州大学 | 7-fatty amine substituted tryptanthrin derivative, preparation method and application thereof |
| CN115710276B (en) * | 2022-11-21 | 2024-04-05 | 贵州大学 | 7-fatty amine substituted tryptamine ketone derivative, preparation method and application thereof |
| CN117298119A (en) * | 2023-11-28 | 2023-12-29 | 云南中医药大学 | Application of tryptanthrin derivative in preparation of drug-resistant candida albicans drug |
| CN117298119B (en) * | 2023-11-28 | 2024-01-23 | 云南中医药大学 | Application of tryptanthrin derivative in preparation of drug-resistant candida albicans drug |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102579452B (en) | 2014-05-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102579452B (en) | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor | |
| CN102532144B (en) | Novel indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof | |
| CN106866571A (en) | Heterocyclic urea compound and its pharmaceutical composition and application | |
| CN104367575B (en) | A kind of Bouchardatine and Bouchardatine derivatives and its preparation method and application | |
| CN103502219A (en) | Novel small-molecules as therapeutics | |
| CN103054870A (en) | Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor | |
| CN106008581A (en) | BODIPY derivative containing six trifluoromethyl groups and preparation and application of BODIPY derivative | |
| CN109912607A (en) | Porphyrin-Chrysin compound and its anti-tumor activity | |
| CN101619089B (en) | Anticancer drug CL168, synthesis method and application thereof | |
| CN107759642A (en) | A kind of double glycosylation benzo phenoxazine class sensitising agents and its preparation method and application | |
| CN108586443A (en) | A kind of drug and preparation method thereof of prevention lung bronchogenic carcinoma | |
| CN104974108B (en) | Series connection double thiazole class compound of one kind 2,2 ' and its production and use | |
| CN115124531A (en) | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof | |
| CN105198714B (en) | Red bayberry 01 derivatives and its preparation method and application | |
| US20210038535A1 (en) | Pharmaceutical compound for treating colorectal cancer | |
| CN108904499B (en) | A kind of medical usage for the tetrahydro isoquinoline compound that hydroxyl replaces | |
| CN106995452B (en) | Double target spot inhibitor of a kind of thieno [3,2 d] miazines EGFR/ErbB2 and its production and use | |
| CN1199946C (en) | Specific indole compound and its preparation and use in treating and preventing cancers | |
| CN106831779B (en) | The noval chemical compound of a kind of jak kinase inhibitor | |
| CN103880700B (en) | O-cinnamoyl-fluorobenzene salicylamide compound and in the application of preparing in medicament for resisting cervical cancer | |
| CN106397432B (en) | A kind of compound as JAK inhibitor | |
| CN108947904A (en) | A kind of compound containing seven membered lactams rings and its application | |
| CN103880793B (en) | Containing furan imine compound and its production and use | |
| CN104356108B (en) | Heteroaromatic dibenzo ton compound and preparation method and application | |
| CN109053570A (en) | The antitumor action of tetrahydroisoquinoline structural compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210319 Address after: 110000 No.10 Xuelian street, Sujiatun District, Shenyang City, Liaoning Province Patentee after: SHENYANG XINMA PHARMACEUTICAL Co.,Ltd. Address before: 110016 No.25, Fuxin 2nd Street, Heping District, Shenyang City, Liaoning Province Patentee before: TIANJIN NANKAI SHARE PHARMACEUTICAL SCIENCE & TECHNOLOGY Co.,Ltd. |