CN103897011A - CDDO imidazole derivatives as well as preparation method and application thereof - Google Patents
CDDO imidazole derivatives as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN103897011A CN103897011A CN201410142477.3A CN201410142477A CN103897011A CN 103897011 A CN103897011 A CN 103897011A CN 201410142477 A CN201410142477 A CN 201410142477A CN 103897011 A CN103897011 A CN 103897011A
- Authority
- CN
- China
- Prior art keywords
- acid
- preparation
- cddo
- compound
- adopting
- 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.)
- Pending
Links
- SMHXSOKKHVQCMW-UHFFFAOYSA-N BrCCC[n]1cncc1 Chemical compound BrCCC[n]1cncc1 SMHXSOKKHVQCMW-UHFFFAOYSA-N 0.000 description 2
- OYMIUINVKWBIGL-UHFFFAOYSA-N Cc1c[n](CCCBr)cn1 Chemical compound Cc1c[n](CCCBr)cn1 OYMIUINVKWBIGL-UHFFFAOYSA-N 0.000 description 1
- DQISUDOBLBZIDY-UHFFFAOYSA-N Cc1nc(C(OC)=O)c[n]1CCCBr Chemical compound Cc1nc(C(OC)=O)c[n]1CCCBr DQISUDOBLBZIDY-UHFFFAOYSA-N 0.000 description 1
- XGDRLCRGKUCBQL-UHFFFAOYSA-N N#Cc1c(C#N)nc[nH]1 Chemical compound N#Cc1c(C#N)nc[nH]1 XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 1
- LAXFBCLMFGCAMP-UHFFFAOYSA-N N#Cc1c(C#N)nc[n]1CCCBr Chemical compound N#Cc1c(C#N)nc[n]1CCCBr LAXFBCLMFGCAMP-UHFFFAOYSA-N 0.000 description 1
- RYZVYLGJZFNBND-UHFFFAOYSA-N OCCC[n]1cncc1 Chemical compound OCCC[n]1cncc1 RYZVYLGJZFNBND-UHFFFAOYSA-N 0.000 description 1
- KOGZSTVKCCNIIR-UHFFFAOYSA-N [O-][N+](c1c[n](CCCCBr)cn1)=O Chemical compound [O-][N+](c1c[n](CCCCBr)cn1)=O KOGZSTVKCCNIIR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses novel CDDO imidazole derivatives with a structure shown in the general formula (I), or pharmaceutically acceptable salts of the novel CDDO imidazole derivatives, and a preparation method and medicine application of the novel CDDO imidazole derivatives, belonging the field of biological medicine. The preparation method of the compounds is mild in reaction conditions, lowly-toxic in adopted reagent, easily-available in raw materials and convenient in after-treatment. Pharmacological experimental studies show that the compounds disclosed by the invention have excellent anti-tumor activity, and can be used as anti-tumor medicaments.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to a class CDDO (2-cyano group-3,12-dioxo volatile oil-1,9 (11)-diene-28-carboxylic acid) imdazole derivatives and preparation method thereof; The invention still further relates to this compounds in the application of preparing in antitumor drug.
Background technology
Oleanolic Acid (Oleanolic acid, OA) is a kind of Triterpenoids sapogenins compounds, extensive in distributed in nature, and aboundresources, has multiple biological activity.Its anti-tumor activity and mechanism of action are subject to domestic and international investigator's extensive attention (Mol Cancer Ther.2007,6,154-162.) in recent years.Honda seminar is unremittingly devoted to structure of modification and the antitumor activity of OA during the last ten years, this has caused having 2-cyano group-3 of special construction fragment, 12-dioxo volatile oil-1, the discovery of 9 (11)-diene-28-carboxylic acid (CDDO), CDDO shows good anti-inflammatory and anti-tumor activity, has its particular mechanism of many target spots.Then, this seminar is take CDDO as lead compound, to its C
17position carboxyl modified obtains multiple derivative, and activity improves greatly, as CDDO-Me, and CDDO-Im etc., the CDDO-Im especially with imidazole ring demonstrates the activity higher than CDDO-Me in rodent experiment, and toxicity is lower.But, CDDO-Im less stable, the CDDO-Im of solid form decomposes rotten (Cancer Res.2008,68.6727.) in 4 ℃ of next years.
In order to find, activity is stronger, the better CDDO derivative of stability, Honda etc. have found novel C DDO imdazole derivatives (1) (Bioorganic & Medicinal Chemistry Letters.2011 that ethynyl replaces, 21,2188-2191.).Although compound 1 is active suitable with CDDO-Im, and stability increases compared with CDDO-Im, and this compound still contains unsettled acylimidazole structure, and preparation is difficult.Therefore, the novel C DDO imdazole derivatives of searching stable in properties, easy preparation is still extremely important.
Summary of the invention
The present invention discloses a class novel C DDO imdazole derivatives, its preparation method and medicinal use first.The preparation method's reaction conditions gentleness adopting, agents useful for same low toxicity, raw material is easy to get, convenient post-treatment.Pharmacological evaluation shows, the compounds of this invention has good anti-tumor activity, actively improves or quite, can be used as antitumor drug application compared with CDDO-Me.
One of object of the present invention is to provide the CDDO imdazole derivatives shown in a kind of general formula I or its pharmacy acceptable salt:
Wherein: R
1and R
2be selected from respectively F-; Cl-; Br-; I-; F
3c-; F
2hC-; FH
2c-; NC-; O
2n-;
wherein R
5, R
6be selected from respectively the straight or branched alkyl of hydrogen or 1 to 7 carbon atom;
R
3: work as R
4with imidazole ring N
1while being connected, R
3do not exist; Otherwise, R
3be selected from the straight or branched alkyl of hydrogen or 1 to 7 carbon atom;
R
4be selected from the straight or branched aliphatic hydrocarbon fragment containing 1 to 8 carbon atom.
Concretely, compound shown in general formula I is preferably from following compounds:
Another object of the present invention is to provide one of preparation method of compound shown in general formula I, it is characterized in that, CDDO and II or its organic acid or inorganic acid salt become ester under acid binding agent, obtain target compound I.
Wherein, X is Cl, Br, I; R
1, R
2, R
3and R
4same as described above.
The acid binding agent adopting be selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, DBU or N-methylmorpholine wherein one or more.The solvent adopting be selected from DMF, DMSO, DMAC, acetone, acetonitrile, pyridine, toluene, benzene, dimethylbenzene, Isosorbide-5-Nitrae-dioxane, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF) or ether wherein one or more.The temperature of reaction adopting is 0 ℃-140 ℃.Be selected from wherein one of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, methylsulfonic acid, trifluoroacetic acid, oxalic acid, propanedioic acid, succinic acid, tartrate, pyruvic acid with the organic acid of II salify.Be selected from wherein one of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid with the mineral acid of II salify.
Another object of the present invention is to provide compound shown in general formula I preparation method two, it is characterized in that, compound III becomes ester with IV under anhydrous condition and acid binding agent, obtains target compound I.
Wherein, R
1, R
2, R
3and R
4same as described above.
The acid binding agent adopting be selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, DBU or N-methylmorpholine wherein one or more.The anhydrous solvent adopting be selected from methylene dichloride, chloroform, ether, tetrahydrofuran (THF), ethyl acetate, acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, benzene or dimethylbenzene wherein one or more.The temperature of reaction adopting is-10 ℃ to 50 ℃.
A further object of the present invention is to provide a kind of the compounds of this invention containing effective dose and the pharmaceutical composition that pharmaceutically acceptable carrier is made.The compounds of this invention can be made different dosage form separately or with one or more pharmaceutical carriers, and such as tablet, capsule, granule, liquid preparation etc. are used for clinical oral administration, injection or topica.In these different preparations, the content of the compounds of this invention can be 0.1%-99.9%.The dosage of the compounds of this invention can be 0.001-10000mg/kg/0.3 days, can appropriateness adjust according to clinical needs.
A further object of the present invention is to provide the compounds of this invention in the application of preparing in antitumor drug.The compounds of this invention can be separately or with conventional clinically antitumor drug as combined utilization such as alkylating agent, antimetabolite, antitumor antibiotics, anti-tumor botanical, hormoness, in addition can also with radiotherapy combined utilization.
Below part pharmacological evaluation and the result of representative compound of the present invention:
Blue colorimetry (MTT) in vitro tests of tetramethyl-nitrogen azoles
Operation adopts mtt assay to carry out anti-tumor activity test to part representative compound of the present invention routinely, chooses CDDO and CDDO-Me as positive control drug.CDDO and CDDO-Me in I phase clinical study, are used for the treatment of noumenal tumour and lymphoma at present.
Material
Instrument: Bechtop (Su Jing is safe and sound for SW-CJ-1FD, AIRTECH), constant temperature CO
2incubator (3111; Thermo; the U.S.), inverted biologic microscope (IX71; OLYMPUS; Japan), enzyme-linked immunosorbent assay instrument (Model680; BIO-RAD, U.S.), dull and stereotyped shaking table (Kylin-bell lab Instruments), high-pressure sterilizing pot (YXO.SG41.280, Shanghai China line), whizzer (SIGMA).
Reagent: DMEM (GIBCO), foetal calf serum (GIBCO), trypsin SIGMA), DMSO (SIGMA).
Cell strain: HepG2 cell lines, mouse melanin tumor cell strain B16.
Method
By frozen cell strain recovery, be placed in constant temperature CO
2in incubator, cultivate, change liquid every day once, get in the time that exponential phase of growth is in good condition and can put plate until it.Add 1ml0.25% tryptic digestive juice, digestion 1-2min, examine under a microscope cell state, when becoming when circle shrinks, attached cell can absorb Digestive system, add 1-2ml 10%DMEM substratum to make cell suspension, carry out cell counting, calculate the amount of required cell suspension according to every hole 5000 (HepG2 cell) or 4000 (B16 cell) individual cell count and total hole count, by this cell suspension inoculation on 96 orifice plates, 100 μ l/ holes, use PBS fluid-tight around, put constant temperature CO
2in incubator, cultivate 18h.
Prepare the tested medicine of 10 μ M with 2%DMEM substratum, absorb substratum, add positive control drug CDDO, CDDO-Me and tested medicine, 150 μ l/ holes, 3 multiple holes of each medicine, cultivate 48 hours.MTT reagent is joined in 96 orifice plates, and 30 μ l/ holes, continue to hatch 4 hours.Absorb substratum in plate, every hole adds 150 μ l DMSO, and dull and stereotyped shaking table jolting 10min makes dissolving crystallized.Survey every hole light absorption value with enzyme-linked immunosorbent assay instrument at wavelength 570nm place, and calculate cell inhibitory rate by following formula.3 primary dcreening operation result mean values are its final inhibiting rate, and primary dcreening operation inhibiting rate is greater than 60% compound and carries out concentration gradient screening (5 times of dilutions), in order to calculating the IC of tested medicine
50value (graphpad computed in software), repeat for 3 times experimental result by the final IC of survey compound
50value.
Result
Inhibiting rate (%) to HepG2 cell when table 1. test-compound concentration is 10 μ M
Inhibiting rate (%) to B16 cell when table 2. test-compound concentration is 10 μ M
Table 3. part test-compound IC
50value (HepG2 cell)
Tentatively tumor cytotoxicity Journal of Sex Research shows, selected representative compound improves compared with positive control drug CDDO, CDDO-Me the inhibition activity of HepG2 and B16 cell or be suitable with it.
Embodiment
In order further to illustrate the present invention, enumerate a series of embodiment below.These embodiment are illustrative, not should be understood to limitation of the present invention.
Embodiment 1: intermediate CDDO's is synthetic
With reference to method described in Chinese patent CN102070697A, for raw material synthesizes and obtains white solid through 11 steps, be accredited as CDDO through analytical procedures such as mass spectrum, hydrogen spectrums with Oleanolic Acid (Tianfeng Biological Science & Technology Co., Ltd., Xi'an, specification 98%).
ESI-MS：490.2[M-H]
-，492.3[M+H]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，5.98(1H，s)，3，0-3.05(2H，m)，1.89-1.99(2H，m)，1.56，1.48，1.35，1.17，1.0，0.91(each3H，s)
Embodiment 2: the preparation (compound number: II-1, lower same) of intermediate 1-(2-bromotrifluoromethane) imidazoles hydrobromate
In a single neck bottle, add imidazoles (6mmol, 0.41g), KHCO
3(25.6mmol, 2.56g), Bu
4n
+br
-(0.128mmol, 0.042g), glycol dibromide 16ml.Under room temperature, react 10.5h, add CH
2cl
235ml, water repeatedly washs, until TLC shows inclusion-free.Organic phase adds 40%HBr7.8ml, stirs, and is statically placed in refrigerator a few hours.Water intaking phase, concentrated, obtain reddish-brown solid.For several times, vacuum-drying obtains pink solid 0.51g to the washing of 10-15ml ether, productive rate 33.2%.ESI-MS: bromine isotope characteristic ion peak 174.9,177[M+H]
+, when detection, use deionized water dissolution sample.
Reaction formula is as follows:
Embodiment 3:I-1's is synthetic
0.0491g CDDO (0.1mmol) is dissolved in to 2ml DMF, adds 0.0552g K
2cO
3(0.4mmol) and 0.004g KI (0.024mmol), stir, add 1-(2-bromotrifluoromethane) imidazoles hydrobromate, room temperature reaction.Show that reaction is complete until TLC analyzes, add CH
2cl
235ml dilution, washes 5-6 time.Organic phase is spin-dried for.Preparative TLC obtains white solid 32mg, productive rate 54.7%.
ESI-MS：586.7[M+H]
+；620.7[M+Cl]
-
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.52(1H，s)，7.03(1H，s)，6.95(1H，s)，5.98(1H，s)，4.35(2H，m)，4.27(2H，m)，1.49，1.18，1.11，0.92(each3H，s)。
Embodiment 4: the preparation (II-2) of intermediate 1-(3-bromopropyl) imidazoles hydrobromate
The preparation of 4.13-(1-imidazolyl) methyl propionate
Imidazoles 0.335g (5mmol) and methyl acrylate 0.86g (10mmol) are dissolved in to 6ml acetonitrile, and back flow reaction 22h, is then spin-dried for reaction solution, adds ethyl acetate 40ml, and saturated NaCl liquid washing for several times.Organic phase anhydrous Na SO
4dry, be spin-dried for, obtain 0.57 gram of white solid, productive rate 74%.ESI-MS：155.1[M+H]
+
The preparation of 4.23-(1-imidazolyl) propyl alcohol
In 50ml two neck bottles, add LiAlH
40.63g, then drips anhydrous THF15ml, and stirring at room temperature 5 minutes, is then cooled to 0-5 ℃.The anhydrous THF liquid that is dissolved with imidazolylpropionic acid methyl esters 1.1g is slowly added dropwise to reaction solution.Maintain 0-5 ℃ 5 minutes, be then warming up to 70 ℃.After 4.5h, TLC shows that reaction is complete.Be cooled to 0 ℃, under rapid stirring, be added dropwise to successively water 0.63ml, 15%NaOH solution 0.63ml, water 0.63ml.Diatomite aided filter, a small amount of ethyl acetate is repeatedly cleaned filter cake, and merging filtrate, is spin-dried for, and obtains 0.8 gram of brown oil, crosses post and separates to obtain 0.38 gram of sterling, productive rate 43%.
ESI-MS：127.1[M+H]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：7.45(1H，s)，7.0(1H，s)，6.92(1H，s)，4.10(2H，t，J＝6.75)，3.57(2H，t，J＝5.9)，1.97(2H，m)
The preparation (II-2) of 4.31-(3-bromopropyl) imidazoles hydrobromate
It is 40% HBr that 0.15 gram of 3-(1-imidazolyl) propyl alcohol (1.19mmol) is dissolved in to 0.872ml massfraction, is added dropwise to vitriol oil 0.11ml, and 130 ℃ of reaction 6.5h, add CH
2cl
260ml, ice bath is lowered PH near neutral.Organic phase washing 3-4 time, to inclusion-free.At once add 0.54ml40%HBr acidifying, water intaking layer, adds a small amount of acetone, and 70 ℃ are spin-dried for.Obtain 1-(3-bromopropyl) imidazoles hydrobromate.
Embodiment 5:I-2's is synthetic
With reference to the preparation method of I-1, make target compound I-214mg.
ESI-MS：600.4[M+H]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(s，1H)，7.49(s，1H)，7.09(s，1H)，6.92(s，1H)，6.0(s，1H)，4.11(m，4H)，2.90(d，1H，J＝4.5)，2.13(m，2H)，1.50，1.19，0.93(each3H，s)
Embodiment 6: the preparation (II-3) of intermediate 1-(4-brombutyl) imidazoles hydrobromate
With reference to the method for making of 1-(2-bromotrifluoromethane) imidazoles hydrobromate, imidazoles (6mmol, 0.41g) is dissolved in to 10ml CH
2cl
2, add Isosorbide-5-Nitrae-dibromobutane 0.93ml (7.8mmol), KHCO
32.56g (25.6mmol), Bu
4n
+br
-0.042g (0.128mmol), room temperature reaction 68h.Use 50ml CH
2cl
2dilution, washes repeatedly, until inclusion-free.Organic phase adds 40%HBr3.9ml at once, adds water 10ml, fully stir, and water intaking phase, 70 ℃ are spin-dried for, and obtain 0.396 gram of orange red thick thing, productive rate 23.3%.
Embodiment 7:I-3's is synthetic
With reference to the method for making of I-1, make target compound I-3.
ESI-MS：636.4[M+Na]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.50(1H，s)，7.08(1H，s)，6.93(1H，s)，5.98(1H，s)，4.13(2H，m)，4.0(2H，t)，2.88(1H，m)，2.1(1H，s)，1.49，1.18，0.89(each3H，s)
Embodiment 8: the preparation (II-4) of intermediate 1-(2-bromotrifluoromethane)-4-methylimidazole hydrobromate
With reference to the method for making of 1-(2-bromotrifluoromethane) imidazoles hydrobromate, obtain 0.321 gram of red-brown dope, productive rate 19.9% by 0.492 gram of 4-methylimidazole (6mmol).
Embodiment 9:I-4's is synthetic
With reference to the method for making of I-1, make target compound I-454mg, productive rate 90%.
ESI-MS：600.4[M+H]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.42(1H，s)，6.66(1H，s)，5.97(1H，s)，4.32(2H，m)，4.18(2H，m)，2.20(3H，s)，1.49，0.92(each3H，s)
Embodiment 10: the preparation (II-5) of intermediate 1-(3-bromopropyl)-4-methylimidazole hydrobromate
With reference to the method for making of 1-(2-bromotrifluoromethane) imidazoles hydrobromate, 4-methylimidazole (6mmol, 0.492g) is dissolved in to 10ml CH
2cl
2, add 1,3-dibromopropane 3.1ml (30mmol), KHCO
31.28g (12.8mmol), Bu
4n
+br
-0.042g (0.128mmol), room temperature reaction 46h.Stopped reaction, uses 50mlCH
2cl
2dilution, washes repeatedly, until inclusion-free.Organic phase adds 40%HBr8.5ml, water intaking phase, and 70 ℃ are spin-dried for, and obtain the thick thing of scarlet, and vacuum-drying obtains 0.81 gram, productive rate 47.7%.
ESI-MS: bromine isotope characteristic peak 203,205[M+H]
+
Embodiment 11:I-5's is synthetic
With reference to the method for making of I-1, make target compound I-5.
ESI-MS：614.4[M+H]
+，636.4[M+Na]
+，652.4[M+K]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.37(1H，s)，?6.62(1H，s)，5.99(1H，s)，3.95-4.17(4H，m)，2.90(1H，d，J＝4.29)，2.23(3H，s)，1.49，1.18，0.93(each3H，s)
Embodiment 12: the preparation (II-6) of intermediate 1-(4-brombutyl)-4-methylimidazole hydrobromate
According to the method for making of embodiment 10II-5, make this intermediate.
Embodiment 13:I-6's is synthetic
With reference to the method for making of I-1, make target compound I-6.
ESI-MS：650.4[M+Na]
+，666.4[M+K]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.37(1H，s)，6.63(1H，s)，5.98(1H，s)，4.07-4.17(2H，m)，3.86-3.93(2H，m)，2.90(1H，d，J＝5.04)，1.49，1.19，0.92(each3H，s)。
Embodiment 14: the preparation (II-7) of intermediate 1-(2-bromotrifluoromethane)-4-nitroimidazole
14.14-the preparation of nitroimidazole
The vitriol oil (98%, the 30ml) solution of imidazoles (10 grams) is warming up to 70 ℃, slowly drips concentrated nitric acid (65-68%, 30ml), finish and be warming up to 95 ℃ of reactions, produce reddish-brown gas, with the absorption of NaOH solution.After 5.5h, stop heating, in impouring frozen water, adjust PH to 3-4, filter, filter cake washing secondary, is dried to obtain light green powder, and 9.96 grams, productive rate 60.2%.
ESI-MS：111.9[M-H]
-
The preparation of 14.21,4-Nitroimidazole
7 grams of 4-nitroimidazoles are dissolved in to 50ml CH
3cOOH, 0 ℃ drips nitrosonitric acid 5.4ml, in 5min, finishes.After 0.5h, add aceticanhydride 12ml at 15 ℃, in 10min, add.Room temperature reaction 48h.In reaction solution impouring 126ml frozen water, leave standstill, filter, filter cake is white solid, 3.9 grams.Filtrate is used 250ml CH
2cl
2extract 6 times.Saturated NaCl liquid washing three times for extraction liquid.Organic phase is spin-dried for, and obtains 4.1 grams of fine acicular white crystals, totally 8 grams of gained filter cakes before adding, productive rate 82%.For subsequent use.
The preparation of 14.31-(2-hydroxyethyl)-4-nitroimidazole
Cryosel is bathed (5 ℃), 0.72 gram of Isosorbide-5-Nitrae-Nitroimidazole is joined in batches in methanol/water (each 5ml) solution of thanomin (0.278 gram).Rise to room temperature reaction, after about 16h, TLC detection reaction is complete.Be spin-dried for reaction solvent, recrystallizing methanol, obtains garnet needle.
ESI-MS：158[M+H]
+。
The preparation of 14.41-(2-bromotrifluoromethane)-4-nitroimidazole
0.314 gram of 1-(2-hydroxyethyl)-4-nitroimidazole (2mmol) is dissolved in to 1.28ml40%HBr (8.8mmol), then drips the vitriol oil 90 microlitres.125 ℃ of reactions, until TLC shows that raw material effect is complete.Cooling, adjust PH to neutral, use 40ml CH
2cl
2extraction, saturated NaHCO
3and saturated common salt water washing, organic phase is spin-dried for to obtain 0.15 gram of faint yellow solid, productive rate 34.1%.
ESI-MS: bromine isotope characteristic peak 220,221.9[M+H]
+.
Embodiment 15:I-7's is synthetic
0.0491 gram of CDDO (0.1mmol) is dissolved in 3ml dry toluene, adds DBU (1,8-diazabicylo, 11 carbon-7-alkene) 15 microlitres, then adds the anhydrous toluene solution of 1-(2-bromotrifluoromethane)-4-nitroimidazole.Be warming up to 117 ℃ of back flow reaction, after 4h, TLC monitoring shows that reaction is complete, is spin-dried for reaction solution, and Preparative TLC obtains white solid I-7 (49mg, productive rate 77.8%).
ESI-MS：631.6[M+H]
+；665.5[M+Cl]
-
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.81(1H，d，J＝1.47Hz)，7.48(1H，d，J＝1.47Hz)，6.0(1H，s)，4.42(4H，m)，1.48，1.08，0.92(each3H，s)。
Embodiment 16: the preparation (II-8) of intermediate 1-(3-bromopropyl)-4-nitroimidazole
The preparation of 16.11-(3-hydroxypropyl)-4-nitroimidazole
With reference to the preparation method of 1-(2-hydroxyethyl)-4-nitroimidazole, productive rate 55%.
The preparation of 16.21-(3-bromopropyl)-4-nitroimidazole
With reference to the preparation method of 1-(2-bromotrifluoromethane)-4-nitroimidazole, obtain tenne dope, productive rate 83%.
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：7.83(1H，d，J＝1.29)，7.52(1H，d，J＝1.29)，4.29(2H，t，J＝6.63)，3.38(2H，t，J＝6.12)，2.39(2H，m，J1＝6.6，J2＝6.2)
Embodiment 17:I-8's is synthetic
With reference to the method for making of I-7, make white solid 40mg, productive rate 40%.
ESI-MS：645.6[M+H]
+；679.6[M+Cl]
-
H
1-NMR(300MHz，CDCl3，TMS)，δppm：8.05(1H，s)，7.75(1H，d，J＝1.47)，7.45(1H，d，J＝1.44)，6.02(1H，s)，4.14(4H，m)，2.22(2H，m)，1.51，1.19，0.94(each3H，s)。
Embodiment 18: the preparation (II-9) of intermediate 1-(4-brombutyl)-4-nitroimidazole
0.6786 gram of 4-nitroimidazole (6mmol) is dissolved in to 10ml CH
2cl
2with the mixed solution of 4ml acetone, add successively Isosorbide-5-Nitrae-dibromobutane 0.93ml (7.8mmol), K
2cO
31.656 grams (12mmol), Bu
4n
+br
-0.042 gram (0.128mmol), room temperature reaction 50h.Reaction solution adds 80ml CH
2cl
2dilution, washes 3 times, and organic phase is concentrated.Rapid column chromatography obtains yellow-green liquid, 46 ℃ of vacuum-dryings, the 0.84 gram of yellow-green colour oily matter that spends the night to obtain, productive rate 56.5%.
ESI-MS: bromine isotope characteristic peak 270,272[M+Na]
+.
Embodiment 19:I-9's is synthetic
With reference to the method for making of I-1, make target compound I-9.
ESI-MS：681.4[M+Na]
+，697.3[M+K]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.79(1H，d，J＝1.44)，7.46(1H，d，J＝1.47)，6.0(1H，s)，4.07-4.21(4H，m)，2.83(1H，d，J＝4.05)，2.06(1H，s)，1.48，1.18，0.92(each3H，s)
Embodiment 20: the preparation (II-10) of intermediate 1-(2-bromotrifluoromethane) imidazoles-4-methyl-formiate
The preparation of 20.1 imidazole-4,5-dicarboxylic acids
Under room temperature, 5g benzoglyoxaline (0.0423mol) is dissolved in 55ml water, adds vitriol oil 70ml, finally slowly adds K
2cr
2o
737 grams.Be warming up to 95 ℃ and maintain 15 minutes, then in impouring frozen water.Be placed in refrigerator cooling number hour, suction filtration, washing repeatedly, obtains light green solid.
The preparation of 20.2 imidazoles-4-formic acid
1.97 grams of imidazole-4,5-dicarboxylic acids are dissolved in 75ml aceticanhydride, back flow reaction.Solution becomes coffee-like liquid from white opacity liquid.After reaction 6h, filtered while hot, filtrate adds 30ml water, under room temperature, stirs and spends the night.Then at 95 ℃, react 1h, be cooled to room temperature.Add 30ml ethanol, 1.8 grams of gacs, react 0.5h at 78 ℃.Filtered while hot, filtrate is cooled to room temperature and is then placed in refrigerator.Separate out 0.38 gram of white granular solid, productive rate 26.5%.
ESI-MS：113[M+H]
+，111.1[M-H]
-
The preparation of 20.3 imidazoles-4-methyl-formiate
0.1g imidazoles-4-formic acid is dissolved in to 3ml methyl alcohol, under room temperature, adds vitriol oil 0.1ml, after be warming up to reaction solution reflux.After 13h, reaction solution is spin-dried for, and adds 30ml ethyl acetate, and 4ml water, uses K
2cO
3adjust PH to weakly alkaline, organic layer is spin-dried for, and obtains 0.045 gram of white solid, productive rate 40.1%.
ESI-MS：149[M+Na]
+
Synthesizing of 20.41-(2-bromotrifluoromethane) imidazoles-4-methyl-formiate
Imidazoles-4-methyl-formiate 0.03 gram (0.25mmol) is dissolved in to 2ml DMF, adds successively glycol dibromide 0.0433ml (0.5mmol), K
2cO
30.1035 gram (0.75mmol), Bu
4n
+br
-0.0023 gram (0.006mmol), room temperature reaction 48h.Add CH
2cl
2dilution, washing (10ml × 5), anhydrous sodium sulfate drying.Organic phase is spin-dried for, and then separates and makes product through 100-200 order silica gel column chromatography.
ESI-MS: bromine isotope characteristic peak 255,257[M+Na]
+
Embodiment 21:I-10's is synthetic
According to the method for making preparation of I-1.
ESI-MS：666.3[M+Na]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.75(1H，d，J＝3.57，7.59(1H，d，J＝3.45)，5.98(1H，s)，4.67(2H，m)，4.41(2H，m)，3.88(3H，s)，2.78(1H，d，J＝4.26)，1.49(3H，s)，0.91(3H，s)。
Embodiment 22: the preparation (II-11) of intermediate 1-(3-bromopropyl) imidazoles-4-methyl-formiate
With reference to the method for making of 1-(2-bromotrifluoromethane) imidazoles-4-methyl-formiate, obtain 0.027 gram of sterling, productive rate 20% by 0.07 gram of imidazoles-4-methyl-formiate.
ESI-MS: bromine isotope characteristic peak 269,271[M+Na]
+
Embodiment 23:I-11's is synthetic
According to the method for making preparation of I-1.
ESI-MS：680.4[M+Na]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.76(1H，s)，7.58(1H，s)，5.99(1H，s)，4.38(2H，m)，4.11(2H，m)，3.87(3H，s)，2.94(1H，d，J＝4.8)，2.18(2H，m)，1.50，1.32，1.18，0.93(each3H，s)
Embodiment 24: the preparation (II-12) of intermediate 1-(4-brombutyl) imidazoles-4-methyl-formiate
According to the method for making preparation of 1-(2-bromotrifluoromethane) imidazoles-4 methyl-formiate.
ESI-MS: bromine isotope characteristic peak 283,285[M+Na]
+
Embodiment 25:I-12's is synthetic
According to the method for making of I-1.
ESI-MS：694.4[M+Na]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.74(1H，s)，7.58(1H，s)，5.98(1H，s)，4.34(2H，m)，4.12(2H，m)，3.87(3H，s)，2.91(1H，d，J＝4.7)，1.50，1.19，0.92(each3H，s)
Embodiment 26: intermediate 1-(3-bromopropyl)-4, the preparation (II-13) of 5-dicyano imidazole
By 0.177 gram 4,5-dicyano imidazole (1.5mmol) is dissolved in 10ml acetone, adds successively 0.414 gram of K
2cO
3(3mmol), 0.032 gram of Bu
4n
+br
-(0.09mmol), 0.168ml 1,3-dibromopropane (1.65mmol).Back flow reaction 17.5h, TLC monitoring shows that reaction is complete.Column chromatography obtains white solid.
ESI-MS: bromine isotope characteristic peak 273,275[M+Cl]
-
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：7.78(1H，s)，4.42(2H，t，J＝6.75)，3.37(2H，t，J＝5.85)，2.44(2H，m，J1＝5.82，J2＝6.6)
Embodiment 27:I-13's is synthetic
With reference to the method for making of I-1, make target compound I-13.
ESI-MS：672.4[M+Na]
+，688.4[M+K]
+
H
1-NMR(300MHz，CDCl
3，TMS)，δppm：8.05(1H，s)，7.74(1H，s)，6.01(1H，s)，4.13-4.35(4H，m)，2.87(1H，d，J＝4.44)，2.27(2H，m)，1.50，1.31，1.27，1.19，1.04，1.02，0.93(each3H，s)
Embodiment 28: intermediate 1-(4-brombutyl)-4, the preparation (II-14) of 5-dicyano imidazole
According to 1-(3-bromopropyl)-4, the method for making of 5-dicyano imidazole.
ESI-MS: bromine isotope characteristic peak 287,289[M+Cl]
-
Embodiment 29:I-14's is synthetic
With reference to the method for making of I-1, make target compound I-14
ESI-MS：686.4[M+Na]
+，702.4[M+K]
+
H
1-NMR(300MHz，CDC]
3，TMS)，δppm：8.05(1H，s)，7.75(1H，s)，5.99(1H，s)，4.10-4.24(4H，m)，2.83(1H，d，J＝4.29)，2.06(1H，s)，1.57，1.51，1.19，0.92(each3H，s)
Embodiment 30:I-15's is synthetic
Dried CDDO (0.0491g, 0.1mmol) is dissolved in to the anhydrous CH of 5ml
2cl
2, at 0 ℃, drip one of the dry DMF of oxalyl chloride 90 microlitres and catalytic amount.Finish, room temperature reaction spends the night.Then be spin-dried for reaction solution, remove unnecessary oxalyl chloride, add anhydrous CH
2cl
25ml, and triethylamine 0.042ml (0.3mmol), DMAP0.61mg.At 0 ℃, add 0.0168 gram of methyl alcohol of 1-Methylimidazole-2-(0.15mmol).After transfer room temperature to, after 2h, react complete.Be spin-dried for, Preparative TLC obtains white solid.
ESI-MS：608.3[M+Na]
+
H
1-NMR(300MHz，25℃，TMS)，δppm：8.05(1H，s)，7.0(1H，d，J?＝1.08)，6.89(1H，d，J＝0.99)，5.94(1H，s)，5.21(2H，m，J＝13.02)，3.73(1H，s)，2.89(1H，d，J＝4.68)，1.48，0.91(each3H，s)
Claims (10)
1. the CDDO imdazole derivatives shown in a general formula I or its pharmacy acceptable salt:
Wherein: R
1and R
2be selected from respectively F-; Cl-; Br-; I-; F
3c-; F
2hC-; FH
2c-; NC-; O
2n-;
wherein R
5, R
6be selected from respectively the straight or branched alkyl of hydrogen or 1 to 7 carbon atom;
R
3: work as R
4with imidazole ring N
1while being connected, R
3do not exist; Otherwise, R
3be selected from the straight or branched alkyl of hydrogen or 1 to 7 carbon atom;
R
4be selected from the straight or branched aliphatic hydrocarbon fragment containing 1 to 8 carbon atom.
2. CDDO imdazole derivatives described in claim 1, is selected from following compounds:
3. a preparation method for compound described in claim 1, is characterized in that, CDDO and II or its organic acid or inorganic acid salt become ester under acid binding agent, obtain target compound I;
Wherein, X is selected from Cl, Br, I; R
1, R
2, R
3and R
4as mentioned above.
4. according to the preparation method described in claim 3, it is characterized in that, the acid binding agent adopting be selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, DBU or N-methylmorpholine wherein one or more.
5. according to the preparation method described in claim 3, it is characterized in that, the solvent adopting be selected from DMF, DMSO, DMAC, acetone, acetonitrile, pyridine, toluene, benzene, dimethylbenzene, Isosorbide-5-Nitrae-dioxane, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF) or ether wherein one or more; The temperature of reaction adopting is 0 ℃-140 ℃.
6. according to the preparation method described in claim 3, it is characterized in that, be selected from wherein one of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid with the mineral acid of II salify; Be selected from wherein one of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, methylsulfonic acid, trifluoroacetic acid, oxalic acid, propanedioic acid, succinic acid, tartrate, pyruvic acid with the organic acid of II salify.
7. a preparation method for compound described in claim 1, is characterized in that, compound III becomes ester with IV under anhydrous condition and acid binding agent, obtains corresponding target compound I;
Wherein, R
1, R
2, R
3and R
4as mentioned above.
8. according to the preparation method described in claim 7, it is characterized in that, the acid binding agent adopting be selected from salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, DBU or N-methylmorpholine wherein one or more.
9. according to the preparation method described in claim 7, it is characterized in that, the anhydrous solvent adopting be selected from methylene dichloride, chloroform, ether, tetrahydrofuran (THF), ethyl acetate, acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, benzene or dimethylbenzene wherein one or more; The temperature of reaction adopting is-10 ℃ to 50 ℃.
Described in claim 1 or 2 compound in the purposes of preparing in antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410142477.3A CN103897011A (en) | 2014-04-10 | 2014-04-10 | CDDO imidazole derivatives as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410142477.3A CN103897011A (en) | 2014-04-10 | 2014-04-10 | CDDO imidazole derivatives as well as preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103897011A true CN103897011A (en) | 2014-07-02 |
Family
ID=50988623
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410142477.3A Pending CN103897011A (en) | 2014-04-10 | 2014-04-10 | CDDO imidazole derivatives as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103897011A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008650A (en) * | 2016-05-13 | 2016-10-12 | 中国药科大学 | Oleanane derivative |
| CN108440636A (en) * | 2018-04-26 | 2018-08-24 | 泰州学院 | A kind of CDDO-Me derivatives, preparation method and medical usage |
| CN109336944A (en) * | 2018-11-13 | 2019-02-15 | 中国药科大学 | Celastrol imdazole derivatives and preparation method thereof and purposes |
| CN111393500A (en) * | 2020-03-09 | 2020-07-10 | 丁晔 | Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof |
| CN112851694A (en) * | 2021-01-18 | 2021-05-28 | 邓颖菁 | Quinolinylbenzimidazole corrosion inhibitor and preparation method thereof |
| CN113061113A (en) * | 2021-04-07 | 2021-07-02 | 中北大学 | Preparation method of 4-nitroimidazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009146216A2 (en) * | 2008-04-18 | 2009-12-03 | Reata Pharmaceuticals. Inc. | Antioxidant inflammation modulators: novel derivatives of oleanolic acid |
| CN102164941A (en) * | 2008-04-18 | 2011-08-24 | 里亚塔医药公司 | Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring |
| CN103665087A (en) * | 2012-09-03 | 2014-03-26 | 上海源力生物技术有限公司 | Terpenoid and application thereof in medicine |
-
2014
- 2014-04-10 CN CN201410142477.3A patent/CN103897011A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009146216A2 (en) * | 2008-04-18 | 2009-12-03 | Reata Pharmaceuticals. Inc. | Antioxidant inflammation modulators: novel derivatives of oleanolic acid |
| CN102164941A (en) * | 2008-04-18 | 2011-08-24 | 里亚塔医药公司 | Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring |
| CN103665087A (en) * | 2012-09-03 | 2014-03-26 | 上海源力生物技术有限公司 | Terpenoid and application thereof in medicine |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008650A (en) * | 2016-05-13 | 2016-10-12 | 中国药科大学 | Oleanane derivative |
| CN106008650B (en) * | 2016-05-13 | 2018-05-04 | 中国药科大学 | A kind of oleanane derivative |
| CN108440636A (en) * | 2018-04-26 | 2018-08-24 | 泰州学院 | A kind of CDDO-Me derivatives, preparation method and medical usage |
| CN109336944A (en) * | 2018-11-13 | 2019-02-15 | 中国药科大学 | Celastrol imdazole derivatives and preparation method thereof and purposes |
| CN109336944B (en) * | 2018-11-13 | 2021-04-27 | 中国药科大学 | Tripterine imidazole derivative and preparation method and application thereof |
| CN111393500A (en) * | 2020-03-09 | 2020-07-10 | 丁晔 | Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof |
| WO2021179884A1 (en) * | 2020-03-09 | 2021-09-16 | 丁晔 | Oleanolic acid derivative having conjugated diene structure c ring, and preparation method therefor and use thereof |
| CN111393500B (en) * | 2020-03-09 | 2021-09-28 | 丁晔 | Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof |
| CN112851694A (en) * | 2021-01-18 | 2021-05-28 | 邓颖菁 | Quinolinylbenzimidazole corrosion inhibitor and preparation method thereof |
| CN113061113A (en) * | 2021-04-07 | 2021-07-02 | 中北大学 | Preparation method of 4-nitroimidazole |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103897011A (en) | CDDO imidazole derivatives as well as preparation method and application thereof | |
| EP3394033B1 (en) | Heterocyclic compounds as immunomodulators | |
| EP3277689B1 (en) | Heterocyclic compounds as lsd1 inhibitors | |
| CN104470921B (en) | Thiophene miazines derivate, preparation method therefor, and medical application thereof | |
| AU2018219967B2 (en) | Stable crystal form of tipiracil hydrochloride and crystallization method for the same | |
| CN102146081B (en) | Indoleacetic acid derivatives and preparation method and application thereof | |
| CN105153136B (en) | Brefeldin A ester derivative and its preparation and application | |
| CN102295635B (en) | Antitumor medicament tetralin amide compounds and pharmaceutically acceptable salts thereof as well as preparation method and application of antitumor medicament tetralin amide compounds | |
| CN102286055B (en) | B-drop-3, 6-disubstituted cholestane compound and preparation method and application thereof to preparation of antitumor drug | |
| CN102241726B (en) | Glycyrrhetinic acid derivative and application thereof as antitumor medicament | |
| WO2020034987A1 (en) | Prodrug containing glucuronide derivative of jak inhibitor, preparation method therefor, and uses thereof | |
| CN114133390A (en) | Harmine derivative and preparation method and application thereof | |
| CN104447937B (en) | Cholestane benzimidazoles compound and its production and use drops in a kind of B- | |
| CN103254139A (en) | Novel <18>F marked 4-aminoquinazoline derivatives, and preparation methods and tumor PET development application thereof | |
| CN108264500B (en) | Substituted 2-aminopyridines and preparation method thereof | |
| CN114507190B (en) | Deuterated 1, 4-benzodiazepine-2, 5-diketone compound and application thereof | |
| CN102887869A (en) | Application of 3-acylamino-1,2,4-phentriazines to preparation of tumor sensitizer | |
| CN103483158A (en) | Diphenylethane derivatives and application thereof | |
| CN103739635B (en) | A kind of purification process of mannose triflate intermediate | |
| CN101967148A (en) | New18F substituted p-toluenesulfonyloxy labeled pyrazolo [1,5-a] pyrimidines and their preparation and application | |
| CN112920241B (en) | Benzimidazole derivative BI308 and preparation method and application thereof | |
| CN103254188B (en) | A kind of preparation method of Azilsartan derivative | |
| CN106349180A (en) | 4,5-diphenyl isoxazole derivative as well as preparation method and application thereof | |
| CN112375112B (en) | Benzimidazole derivative BI361 and preparation method and application thereof | |
| CN102702116A (en) | 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140702 |
|
| RJ01 | Rejection of invention patent application after publication |