CN105541825A - Preparation method of triazole derivatives and application of triazole derivatives as drugs - Google Patents

Preparation method of triazole derivatives and application of triazole derivatives as drugs Download PDF

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CN105541825A
CN105541825A CN201511016420.XA CN201511016420A CN105541825A CN 105541825 A CN105541825 A CN 105541825A CN 201511016420 A CN201511016420 A CN 201511016420A CN 105541825 A CN105541825 A CN 105541825A
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phenyl
methyl
compound
triazole
dihydroquinazoline
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张惠斌
周金培
赵雷磊
张兵
徐斌
韩丽
杨一飞
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention relates to a preparation method of triazole derivatives and medical application of the triazole derivatives. The invention particularly relates to triazole derivatives disclosed as general formula (I) and pharmaceutical salts thereof or a pharmaceutical composition containing the triazole derivatives or pharmaceutical salts thereof, and a preparation method thereof, and further relates to application of the triazole derivatives and pharmaceutical salts thereof or pharmaceutical composition containing the triazole derivatives and pharmaceutical salts thereof as a BET inhibitor in treating multiple tumors.

Description

Triazole derivatives preparation method and the purposes as medicine thereof
Technical field
The present invention relates to pharmaceutical synthesis field, specifically, the present invention relates to triazole compound and pharmaceutical composition and its thereof pharmaceutical use as BET inhibitor.
Background technology
Epigenetic phenomenon comprises DNA modification, histone modification, Chromatin Remodeling and non-coding RNA and regulates (ncRNA) etc.Acetylation of histone is a kind of histone modification mode of most study, acetylize can in and the positive charge of Methionin band, weaken the avidity of DNA and histone; make chromatin Structure loose; be in open state, be conducive to genetic transcription, Chromatin Remodeling and DNA repair.In addition, acetyl-l-lysine can also for providing identification and binding site containing the histone acetyl base recognin of Bromodomain structural domain, and be beneficial to recognin and raise associated protein, regulatory gene is transcribed.
Research in recent years finds the potential novel targets becoming research and development antitumor drug of BET family protein in histone acetyl base recognin.BET family protein comprises four albumen (BRD2, BRD3, BRD4 and BRDT), each albumen comprise two independently Bromodomain structural domain (BD1, BD2) be used for identifying the terminated acetylated lysine sites of histone.Bromodomain structural domain be a high conservative by the protein function structural domain of about 110 Amino acid profiles; albumen is by four α spiral (Z; A; B; C) and two Loop (ZA; BC) form, can hydrophobic region be formed, to identify and in conjunction with acetylizad lysine residue.Human genome is encoded 61 kinds of Bromodomain structural domains altogether, is distributed in 46 kinds of different functional proteins.
BET albumen can regulate and control transcribing (as proto-oncogene c-MYC) of multiple downstream gene; and BET albumen can also identify and in conjunction with the transcription factor of acetylation modification on karyomit(e) (as GATA-1; NF κ B); common regulatory gene is transcribed; affect generation and the pathogenesis of numerous disease, particularly relate to tumour and inflammation.The c-MYC albumen of c-MYC coding is the main regulatory factors of cell proliferation, wide participation kinds of tumors generation evolution, and is closely related with tumor pharmacother reactivity.Suppress the activity of c-MYC can the proliferate of remarkable inhibition tumor cell, this discovery points out c-MYC to be a potential antitumor target spot.But, because the ligand binding region of c-MYC albumen is indefinite, and from high-resolution composite structure, also cannot find out the site of applicable organic molecule combination, the serious development hindering micromolecular inhibitor.Research finds, BET family protein BRD4, regulation and control c-MYC genetic transcription.Therefore, the combination of design small molecules BET inhibitor interference BRD4 and acetylated histones, will likely suppress c-MYC genetic transcription, reach antitumor object.By to leukemia cell; lymphoma cell and multiple myeloma cells research find; BET inhibitor (+)-JQ1 can affect BRD4 and be combined with acetylated histones; remarkable downward c-MYC genetic transcription; the propagation of inhibition tumor cell; and lower to normal cytotoxicity, show that BET inhibitor promises to be effective medicine of c-MYC high expression level tumour.
In addition, research finds BRD3 and BRD4 and NUT gene possibility producer transposition in organism, thus forms fusion gene BRD3-NUT and BRD4-NUT, and express a kind of high tumorigenicity fusion rotein, this albumen and center line cancer (NMC) are formed closely related.There is no such patient of effective pharmacological agent at present, and traditional chemotherapy and radiation means are nearly unavailable to patient.BET inhibitor promises to be the active drug for the treatment of NMC patient.
Summary of the invention
An object of the present invention is to provide tolyltriazole compounds or its salt pharmaceutically accepted.
Another object of the present invention is to provide this compounds and is preparing the purposes in medicine.This compounds can effectively combine the albumen with Bromodomain structural domain, thus regulates the signal path in downstream, plays specific function, may be used for treating the various diseases relevant to Bromodomain domain protein.This compounds can disturb has the BRD4 of Brodomain structural domain and the combination of acetylated histones, and then lowers transcribing of oncogene target gene relevant with other, therefore can become effective medicine of tumour.
Another object of the present invention is to provide and comprises the pharmaceutical composition of this compounds as activeconstituents.
To achieve these goals, the invention provides the triazole compound shown in following general formula (I) or its pharmacy acceptable salt:
Wherein:
R 1independently be selected from the alkyl of hydrogen atom, 1-6 carbon;
R 2independently be selected from olefin carboxylic acid's ester of fluorine substituted-phenyl, chlorine substituted-phenyl, the alkyl-substituted phenyl of 1-6 carbon, the alkoxy substituted phenyl of 1-6 carbon, trifluoromethyl substituted-phenyl, the alkyl carboxylic acid of 1-6 carbon, the alkyl carboxylic acid ester of 1-6 carbon, the alkylamide of 1-6 carbon, the olefin carboxylic acid of 1-6 carbon or 1-6 carbon;
N is the integer of 1 to 6.
Preferably, in general formula (I) compound:
R 1independently be selected from the alkyl of hydrogen atom, 1-3 carbon;
R 2independently be selected from olefin carboxylic acid's ester of fluorine substituted-phenyl, chlorine substituted-phenyl, the alkyl-substituted phenyl of 1-3 carbon, the alkoxy substituted phenyl of 1-3 carbon, trifluoromethyl substituted-phenyl, the alkyl carboxylic acid of 1-3 carbon, the alkyl carboxylic acid ester of 1-3 carbon, the alkylamide of 1-3 carbon, the olefin carboxylic acid of 1-3 carbon or 1-3 carbon;
N is the integer of 1 to 4.
More preferably, in general formula (I) compound:
R 1independently be selected from hydrogen atom, methyl;
R 2independently be selected from fluorine substituted-phenyl, chlorine substituted-phenyl, methyl substituted phenyl, methoxy substitution phenyl, trifluoromethyl substituted-phenyl, acetoxyl, methyl acetate, acetyl-pyrrole;
N is the integer of 1 to 2.
Preferred compound of the present invention includes, but are not limited to:
6-(3,5-dimethyl isoxazole)-4-phenyl-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(4-p-methoxy-phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-p-methoxy-phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-p-methoxy-phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(2-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(4-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(2,4 difluorobenzene base)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-aminomethyl phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(4-trifluoromethyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-trifluoromethyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(2-trifluoromethyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-1-methyl 4-phenyl-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole-4-base)-3-((1-(2-oxo-2-(pyrrolidyl-1-base)-ethyl)-1H-1,2,3-triazole-4-base) methyl 4-phenyl-3,4-dihydroquinazoline-2 (1H)-one.
The structure of compound is:
Compound shown in general formula (I) can contain asymmetric or chiral centre, therefore can exist with different stereoisomeric forms in any ratio.All stereoisomeric forms in any ratio of the compounds of this invention, include but not limited to diastereomer, enantiomer and atropisomer and their mixture (as racemoid), include within the scope of the invention.
Compound shown in general formula (I) can also exist with different tautomeric form, and all these forms includes within the scope of the present invention.Belong to the constitutional isomer that " tautomer " or " tautomeric form " refers to the different-energy mutually transformed via low energy barrier.
Compound shown in general formula (I) can exist with nonsolvated forms and the solvation form containing pharmaceutically acceptable solvent (as water, ethanol etc.), the present invention includes solvation and nonsolvated forms.
Compound shown in general formula (I) can be formed " pharmacy acceptable salt " with mineral acid or organic acid, described mineral acid as: hydrochloric acid, Hydrogen bromide, phosphoric acid and sulfuric acid, described organic acid is as xitix, hydrochloric acid, citric acid, tartrate, lactic acid, toxilic acid, propanedioic acid, fumaric acid, oxalic acid, oxysuccinic acid, oxyacetic acid, succsinic acid, propionic acid, acetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid etc.
Compound shown in general formula of the present invention (I) can synthesize by comprising chemical field those methods well-known, especially synthesizes according to explanation of the present invention.Raw material generally can from commercial source as An Naiji, Sigma obtain, or use method well known to those skilled in the art to be easy to preparation.
The compound that general formula provided by the invention (I) represents can be prepared by the synthetic route shown in following reaction equation.
Step a: compd A and N-bromo-succinimide are obtained by reacting compd B;
Step b: compd B and t-butyl sulfonamide are obtained by reacting Compound C;
Step c: obtain Compound D by sodium borohydride reduction Compound C;
Steps d: Compound D and bromo alkyne reaction obtain compd E;
Step e: compd E and triphosgene are obtained by reacting compound F 17-hydroxy-corticosterone;
Step f: compound F 17-hydroxy-corticosterone and trinitride are obtained by reacting G;
Step g: compound G and 3,5-dimethyl isoxazole-4-pinacol borate are obtained by reacting chemical combination H;
Step h: compound H and idoalkane are obtained by reacting the compound that general formula (I) represents;
Wherein, R 1, R 2described above with the definition of n.
Another object of the present invention is to provide the triazole compound shown in general formula (I) or its pharmacy acceptable salt is treated and the purposes in the medicine of Bromodomain domain protein relative disease in preparation.
Compound shown in general formula (I) or its pharmacy acceptable salt can effectively combine the albumen with Bromodomain structural domain, thus regulate the signal path in downstream, play specific function, can be used for treating the various diseases relevant to Bromodomain domain protein.As this compounds can disturb, there is the BRD4 of Bromodomain structural domain and the combination of acetylated protein, and then lower transcribing of oncogene C-MYC target gene relevant with it, therefore can become effective medicine of tumour.
Therefore, another object of the present invention is to provide the compound shown in general formula (I) or the purposes of its pharmacy acceptable salt in the medicine of preparation treatment tumour.Described tumour can be but is not limited to multiple myeloma, cancer of the stomach, lung cancer, mammary cancer, the esophageal carcinoma, colorectal carcinoma, medulloblastoma, acute myeloblastic leukemia, chronic leukemia, prostate cancer, hepatoma, renal cell carcinoma, cervical cancer, skin carcinoma, ovarian cancer, colorectal carcinoma, neurospongioma, thyroid carcinoma or carcinoma of the pancreas.
Another object of the present invention is to provide a kind of pharmaceutical composition, it comprises the compound shown in a kind of general formula (I) or its pharmacy acceptable salt for the treatment of significant quantity, and pharmaceutically acceptable auxiliary material.
Another object of the present invention is to provide a kind of prevention or treatment and the method for Bromodomain domain protein relative disease, and described method comprises the compounds shown in general formula (I) of administering therapeutic significant quantity or its pharmacy acceptable salt or aforementioned pharmaceutical compositions of the present invention to patient.
Embodiment
Do not need to further describe, think that those skilled in the art are by description above, farthest can utilize the present invention.Therefore, the embodiment provided below is only illustrate the present invention further, and does not mean that and limit the scope of the invention by any way.
Raw material can obtain from commercial channels, or is prepared by methods known in the art, or prepares according to methods described herein.
The structure of compound is determined by nucleus magnetic resonance (1H-NMR) and/or mass spectrum (MS).It is that mensuration solvent is deuterochloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6), and TMS is interior mark by ACF-300BRUK type nuclear magnetic resonance analyser that NMR measures.The mensuration HP1100 type mass spectrograph of MS.Column chromatography adopts 200-300 order silica gel (Haiyang Chemical Plant, Qingdao's production).
Preparation embodiment:
Embodiment 1:
Synthetic route is:
Reagent and condition: a) N-bromo-succinimide, methylene dichloride ,-10 DEG C; B) t-butyl sulfonamide, tetraethyl titanate, tetrahydrofuran (THF) acetonitrile, 70 DEG C; C) sodium borohydride, tetrahydrofuran (THF), water, room temperature; D) 3-propargyl bromide, sodium hydride, DMF, 0 DEG C; E) triphosgene, tetrahydrofuran (THF), room temperature; F) aziminobenzene, Salzburg vitriol, sodium ascorbate, methylene dichloride, methyl alcohol, water, room temperature; G) 3,5-dimethyl isoxazole-4-pinacol borates, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, salt of wormwood, toluene, methyl alcohol, DMF, nitrogen, 80 DEG C.
A) by 2-aminobenzophenone (5g, 25.35mmol) be dissolved in 60ml methylene dichloride, 10min is stirred in-10 DEG C of cold-traps, add N-bromo-succinimide (4.74g in batches, 26.62mmol), continue to react after 2 hours in cold-trap, add 30ml water, with dichloromethane extraction, saturated common salt is washed, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, petrol ether/ethyl acetate (V/V=20/1-10/1) wash-out is used to obtain 2-amino-5-bromine benzophenone 6g, for yellow solid, yield 85.71%. 1HNMR(300MHz，DMSO)δ7.68-7.48(m，5H)，7.42(dd，J＝8.9，2.4Hz，1H)，7.31(d，J＝2.4Hz，1H)，7.24(s，2H)，6.86(d，J＝8.9Hz，1H).
B) by 2-amino-5-bromine benzophenone (6g, 21.73mmol), t-butyl sulfonamide (10.53g, 86.91mmol) with tetraethyl titanate (19.83g, 86.91) 50ml tetrahydrofuran (THF) is dissolved in successively, be heated to 70 DEG C of stirring reactions 48 hours, add 30ml water and 50ml ethyl acetate, solid is had to separate out, by reaction solution suction filtered through kieselguhr, collect filtrate, be extracted with ethyl acetate, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, petrol ether/ethyl acetate (V/V=3/1-1/1) wash-out is used to obtain N-(2-amino-5-bromine phenylbenzene) methylene radical t-butyl sulfonamide 7.7g, for yellow foamy solid, yield 93.42%.
C) by N-(2-amino-5-bromine phenylbenzene) methylene radical t-butyl sulfonamide (7.7g, 20.3mmol) be dissolved in 49ml tetrahydrofuran (THF) and 1ml water, stirred at ambient temperature, add sodium borohydride (3.07g in batches, 81.2mmol), continue stirring at room temperature 4 hours, add 30ml water, be extracted with ethyl acetate, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, obtaining N-(2-amino-5-bromine phenylbenzene) methyl tertbutyl sulfinyl amine 7.6g, is white solid, yield 98.18%. 1HNMR(300MHz，DMSO)δ7.42-7.20(m，5H)，7.13-7.00(m，2H)，6.60(d，J＝8.5Hz，1H)，5.95(d，J＝5.9Hz，1H)，5.47(d，J＝6.0Hz，1H)，5.25(s，2H)，1.13(s，9H).
D) by N-(2-amino-5-bromine phenylbenzene) methyl tertbutyl sulfinyl amine (2g, 5.24mmol) with 3-propargyl bromide (0.93g, 7.87mmol) be dissolved in 10mlN, N-dimethyl formamide, 5min is stirred in 0 DEG C of ice bath, add 60% sodium hydride (0.63g in batches, 15.73mmol), continue to stir 1 hour in 0 DEG C of ice bath, add 30ml water, be extracted with ethyl acetate, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, petrol ether/ethyl acetate (V/V=6/1-5/1) wash-out is used to obtain N-(2-amino-5-bromine phenylbenzene) methyl-N-proyl t-butyl sulfonamide 1.9g, for yellow solid, yield 86.38%. 1HNMR(300MHz，DMSO)δ7.41-7.27(m，5H)，7.15(dd，J＝8.6，2.2Hz，2H)，6.62(d，J＝8.6Hz，1H)，5.82(s，1H)，5.31(s，2H)，4.07-3.97(m，1H)，3.42(d，J＝20.7Hz，1H)，3.26(d，J＝2.3Hz，1H)，1.03(d，J＝8.4Hz，9H).
E) by N-(2-amino-5-bromine phenylbenzene) methyl-N-proyl t-butyl sulfonamide (1.8g, 4.29mmol) be dissolved in 20ml tetrahydrofuran (THF), stirring at room temperature, add triphosgene (1.91g, 6.44mmol), stirring at room temperature 2 hours, concentrating under reduced pressure reaction solution, has solid to separate out, add 20ml water, adjust pH to 7 with saturated sodium carbonate, have a large amount of solid to separate out, suction filtration, drying obtains the bromo-4-phenyl of 6--3-proyl-3,4-dihydroquinazoline-2 (1H)-one 1.25g is light yellow solid, yield 85.35%. 1HNMR(300MHz，DMSO)δ9.83(s，1H)，7.55-7.17(m，7H)，6.81(d，J＝8.5Hz，1H)，5.81(s，1H)，4.66(dd，J＝17.7，2.5Hz，1H)，3.41(dd，J＝17.7，2.3Hz，1H)，3.23(t，J＝2.4Hz，1H).
F) by bromo-for 6-4-phenyl-3-proyl-3, 4-dihydroquinazoline-2 (1H)-one (0.2g, 0.58mmol) with aziminobenzene (0.1g, 0.87mmol) be dissolved in 3ml methylene dichloride, the mixed solution of 3ml methyl alcohol and 2ml water, stirring at room temperature, add Salzburg vitriol (0.0146g, 0.058mmol), stirring at room temperature 20min, add sodium ascorbate (0.046g, 0.234mmol), stirring at room temperature 2 hours, concentrating under reduced pressure reaction solution, solid is had to separate out, add 10ml water, suction filtration, with sherwood oil filter wash cake, drying obtains the bromo-4-phenyl of 6--3-((1-phenyl-1H-1, 2, 3-triazole) methyl)-3, 4-dihydroquinazoline-2 (1H)-one 0.25g, for light yellow solid, yield 92.65%. 1HNMR(300MHz，DMSO)δ9.77(s，1H)，8.68(s，1H)，7.88(d，J＝8.1Hz，2H)，7.58(t，J＝7.7Hz，2H)，7.47(t，J＝7.4Hz，1H)，7.41-7.25(m，7H)，6.80(d，J＝8.5Hz，1H)，5.70(s，1H)，5.22(d，J＝15.3Hz，1H)，3.89(d，J＝15.3Hz，1H).
G) by bromo-for 6-4-phenyl-3-((1-phenyl-1H-1, 2, 3-triazole) methyl)-3, 4-dihydroquinazoline-2 (1H)-one (0.24g, 0.52mmol), 3, 5-dimethyl isoxazole-4-pinacol borate (0.23g, 1.04mmol), [1, 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (0.038g, 0.052mmol) with salt of wormwood (0.144g, 1.04mmol) be dissolved in 1mlN, dinethylformamide, the mixed solution of 1ml methyl alcohol and 3ml toluene, nitrogen protection, be heated to 70 DEG C of stirring reactions 24 hours, add 10ml water and 10ml ethyl acetate, by solution suction filtered through kieselguhr, collect filtrate, be extracted with ethyl acetate, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, petrol ether/ethyl acetate (V/V=2/1-1/1) wash-out is used to obtain 6-(3, 5-dimethyl isoxazole)-4-phenyl-3-((1-phenyl-1H-1, 2, 3-triazole) methyl)-3, 4-dihydroquinazoline-2 (1H)-one 0.13g, for white solid, yield 52.32%. 1HNMR(300MHz，DMSO)δ9.76(s，1H)，8.72(s，1H)，7.88(d，J＝7.5Hz，2H)，7.58(s，2H)，7.42(tt，J＝14.8，7.5Hz，5H)，7.29(d，J＝6.9Hz，1H)，7.19(s，1H)，7.13(d，J＝8.2Hz，1H)，6.92(d，J＝8.2Hz，1H)，5.77(s，1H)，5.27(d，J＝15.4Hz，1H)，3.93(d，J＝15.4Hz，1H)，2.27(s，3H)，2.10(s，3H).
Following compounds is prepared according to the method identical with preparing embodiment 1:
Embodiment 13:
Synthetic route is:
Reagent and condition: a) methyl iodide, sodium hydride, DMF, 0 DEG C.
A) by 6-(3, 5-dimethyl isoxazole)-4-phenyl-3-((1-phenyl-1H-1, 2, 3-triazole) methyl)-3, 4-dihydroquinazoline-2 (1H)-one (0.12g, 0.25mmol) with methyl iodide (0.071g, 0.5mmol) be dissolved in 2mlN, in dinethylformamide, 5min is stirred in 0 DEG C of ice bath, add 60% sodium hydride (0.03g in batches, 0.018mmol), continue to react after 2 hours in ice bath, add 10ml water, solid is had to separate out, suction filtration, with sherwood oil filter wash cake, drying obtains 6-(3, 5-dimethyl isoxazole)-1-methyl 4-phenyl-3-((1-phenyl-1H-1, 2, 3-triazole) methyl)-3, 4-dihydroquinazoline-2 (1H)-one 0.11g, for white solid, yield 89.05%. 1HNMR(300MHz，DMSO)δ8.69(s，1H)，7.86(d，J＝7.9Hz，2H)，7.58(t，J＝7.7Hz，2H)，7.48(d，J＝7.1Hz，1H)，7.43-7.23(m，7H)，7.08(d，J＝8.3Hz，1H)，5.80(s，1H)，5.26(d，J＝15.6Hz，1H)，4.08(d，J＝15.3Hz，1H)，3.36(s，3H)，2.31(s，3H)，2.14(s，3H).
Embodiment 14:
Synthetic route is:
Reagent and condition: a) ethyl azidoacetate, Salzburg vitriol, sodium ascorbate, methylene dichloride, methyl alcohol, water, room temperature; B) hydronium(ion) Lithium Oxide 98min, methyl alcohol, water, room temperature; C) Pyrrolidine, O-benzotriazole-tetramethyl-urea phosphofluoric acid ester, diisopropyl ethyl amine, DMF, room temperature; D) 3,5-dimethyl isoxazole-4-pinacol borates, [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, salt of wormwood, toluene, methyl alcohol, DMF, nitrogen, 80 DEG C.
A) by bromo-for 6-4-phenyl-3-proyl-3, 4-dihydroquinazoline-2 (1H)-one (0.25g, 0.73mmol) with ethyl azidoacetate (0.14g, 1.1mmol) be dissolved in 3ml methylene dichloride, the mixed solution of 3ml methyl alcohol and 2ml water, stirring at room temperature, add Salzburg vitriol (0.018g, 0.073mmol), stirring at room temperature 20min, add sodium ascorbate (0.058g, 0.293mmol), stirring at room temperature 2 hours, with dichloromethane extraction, saturated common salt is washed, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, methylene chloride/methanol (V/V=100/1-80/1) wash-out is used to obtain 2-(4-((the bromo-2-oxo of 6--4-phenyl-1, 4-dihydroquinazoline-3 (2H)) methyl)-1H-1, 2, 3-triazole ethyl acetate 0.3g, for light yellow solid, yield 87.06%. 1HNMR(300MHz，DMSO)δ9.73(s，1H)，8.00(s，1H)，7.41-7.25(m，7H)，6.78(d，J＝8.4Hz，1H)，5.62(s，1H)，5.33(s，2H)，5.12(d，J＝15.3Hz，1H)，4.16(q，J＝7.1Hz，2H)，3.77(d，J＝15.4Hz，1H)，1.20(t，J＝7.1Hz，3H).
B) by 2-(4-((the bromo-2-oxo of 6--4-phenyl-1, 4-dihydroquinazoline-3 (2H)) methyl)-1H-1, 2, 3-triazole ethyl acetate (0.3g, 0.637mmol) with hydronium(ion) Lithium Oxide 98min (0.053g, 1.28mmol) be dissolved in 6ml methyl alcohol and 3ml water mixed liquid, stirring at room temperature 1 hour, concentrating under reduced pressure reaction solution, solid is had to separate out, add 5ml water, pH to 3 is adjusted with 1mol/L hydrochloric acid, a large amount of white solid is had to separate out, suction filtration, with sherwood oil filter wash cake, drying obtains 2-(4-((the bromo-2-oxo of 6--4-phenyl-1, 4-dihydroquinazoline-3 (2H)) methyl)-1H-1, 2, 3-triazole acetic acid 0.24g, for white solid, yield 85.07%. 1HNMR(300MHz，DMSO)δ13.82-13.05(m，1H)，9.76(s，1H)，7.99(s，1H)，7.38-7.25(m，7H)，6.78(d，J＝8.5Hz，1H)，5.64(s，1H)，5.22(s，2H)，5.12(d，J＝15.3Hz，1H)，3.76(d，J＝15.3Hz，1H).
C) by 2-(4-((the bromo-2-oxo of 6--4-phenyl-1, 4-dihydroquinazoline-3 (2H)) methyl)-1H-1, 2, 3-triazole acetic acid (0.137g, 0.309mmol), Pyrrolidine (0.026g, 0.371mmol), O-benzotriazole-tetramethyl-urea phosphofluoric acid ester (0.14g, 0.371mmol) with diisopropyl ethyl amine (0.08g, 0.619mmol) be dissolved in 2mlN, dinethylformamide, stirring at room temperature 2 hours, add 10ml water, be extracted with ethyl acetate, saturated common salt is washed, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, methylene chloride/methanol (V/V=80/1-40/1) wash-out is used to obtain the bromo-3-of 6-((1-(2-oxo-2-(pyrrolidyl-1-base)-ethyl)-1H-1, 2, 3-triazole-4-base) methyl)-4-phenyl-3, 4-dihydroquinazoline-2 (1H)-one 0.1g, for light yellow solid, yield 65.17%. 1HNMR(300MHz，DMSO)δ9.75(s，1H)，7.89(s，1H)，7.40-7.26(m，7H)，6.78(d，J＝8.5Hz，1H)，5.64(s，1H)，5.30(s，2H)，5.14(d，J＝15.4Hz，1H)，3.75(d，J＝15.4Hz，1H)，3.50(t，J＝6.8Hz，2H)，3.30(d，J＝6.9Hz，2H)，1.90(dd，J＝13.0，6.3Hz，2H)，1.80(dd，J＝13.3，6.6Hz，2H).
D) by bromo-for 6-3-((1-(2-oxo-2-(pyrrolidyl-1-base)-ethyl)-1H-1, 2, 3-triazole-4-base) methyl)-4-phenyl-3, 4-dihydroquinazoline-2 (1H)-one (0.09g, 0.181mmol), 3, 5-dimethyl isoxazole-4-pinacol borate (0.081g, 0.363mmol), [1, 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (0.026g, 0.036mmol) with salt of wormwood (0.05g, 0.363mmol) be dissolved in 1mlN, dinethylformamide, the mixed solution of 1ml methyl alcohol and 3ml toluene, nitrogen protection, be heated to 70 DEG C of stirring reactions 24 hours, add 10ml water and 10ml ethyl acetate, by solution suction filtered through kieselguhr, collect filtrate, be extracted with ethyl acetate, collected organic layer, anhydrous sodium sulfate drying, pressure reducing and steaming organic solvent, residue is by silica gel column chromatography purifying, ethyl acetate/methanol (V/V=40/1) wash-out is used to obtain 6-(3, 5-dimethyl isoxazole-4-base)-3-((1-(2-oxo-2-(pyrrolidyl-1-base)-ethyl)-1H-1, 2, 3-triazole-4-base) methyl)-4-phenyl-3, 4-dihydroquinazoline-2 (1H)-one 0.05g, for light yellow solid, yield 53.8%. 1HNMR(300MHz，DMSO)δ9.70(s，1H)，7.90(s，1H)，7.43-7.35(m，4H)，7.32-7.26(m，1H)，7.16(s，1H)，7.14-7.09(m，1H)，6.90(d，J＝8.2Hz，1H)，5.71(s，1H)，5.29(s，2H)，5.19(d，J＝15.3Hz，1H)，3.78(d，J＝15.2Hz，1H)，3.50(t，J＝6.7Hz，2H)，3.29(d，J＝6.8Hz，2H)，2.28(s，3H)，2.11(s，3H)，1.90(dd，J＝13.1，6.5Hz，2H)，1.79(dd，J＝13.4，6.3Hz，2H).
Pharmacologically active embodiment 1: the enzyme level determination of activity of compound
It is AlphaScreen detection technique that the binding activities of compound and BRD4 albumen n end second bromodomain structural domain (hereinafter referred to as BRD4 (BD2)) tests what adopt.Compound primary dcreening operation concentration is 1 μM, its IC of compound determination that under this condition, inhibiting rate is greater than 70% 50value.Preparation HEPES damping fluid (50mMHEPES, 100mMNaCl, 0.1%BSA, 0.05%CHAPS, pH7.5) for the preparation of BRD4 (BD2) albumen, Biotin mark histone H 4, testing compound (DMSO0.1%), donorbeads and acceptorbeads solution.Get 384 orifice plate one piece, according to layout, point testing compound hole, blank control wells (min, max), positive drug control wells on plate.Add the compound solution 5 μ L of different concns respectively to testing compound hole and positive drug hole, blank adds damping fluid 5 μ L (DMSO0.1%).Continue to add BRD4 (BD2) protein solution 5 μ L to each hole except blank control wells (min), add damping fluid 5 μ L to blank control wells (min).Incubated at room temperature is after 15 minutes, every hole adds the histone H 4 solution 5 μ L of Biotin mark, after continuing at room temperature to hatch 1 hour, add donorbeads and acceptorbeads solution 15 μ L, lucifuge incubated at room read fluorescence values with the Alphamode (λ ex=680, λ em=570) of EnSpire detector after 1 hour.
Numerical value process: inhibiting rate=(Max-Signal)/(Max-Min) × 100%
Wherein: the histone H 4 that Max:Biotin marks and the value that albumen is combined completely
The histone H 4 background values of Min:Biotin mark
Signal: the value under compound respective concentration
S curve is done with compound concentration and corresponding inhibiting rate.Obtain the IC of respective compound 50.
With the biological activity result that following table 1 obtains in pharmacological test example 1 for compound that the present invention is prepared in embodiment.
Table 1
Note: " NT " represents do not have test I C 50.
Part of compounds primary dcreening operation concentration listed by table 1 is show the inhibiting rate suitable with positive control (+)-JQ1, part of compounds IC under 1 μM 50suitable with (+)-JQ1, demonstrate stronger activity, show that compound of the present invention can effectively combine the albumen with bromodomian structural domain at enzyme level, therefore compound of the present invention can become antineoplastic active drug.
Pharmacologically active embodiment 2: Compound cellular level activity measures
The Activity determination of Compound cellular level adopts Celltiter-Glo fluorocyte viability examination method.The MV4-11 cell being in logarithmic phase is seeded to 96 well culture plates, after overnight incubation, adds testing compound 37 DEG C, 5%CO 2hatch 72h, after terminating, detect first 30 minutes and at room temperature balance mensuration reagent.Every hole adds 30uLCelltiter-Glo reagent, rocks 96 orifice plate, 10 minutes inducing cell lysis.96 orifice plates are at room temperature hatched and within 2 minutes, carrys out stable fluorescent signal.Envision detector is used to read fluorescence values.
Numerical value process: inhibiting rate=(Maxsignal-Compoundsignal)/(Maxsignal-Minsignal) × 100%
Wherein: the maximum value that Maxsignal:DMSO reads on
Minsignal: the minimum value only having medium effect
Compoundsignal: the value under compound respective concentration
S curve is done with compound concentration and corresponding inhibiting rate.Obtain the IC of respective compound 50.
With following table 2 for the present invention prepares the biological activity result that part of compounds in embodiment obtains in Pharmacological Examples 2.
Table 2
Compound IC 50(μM)
Embodiment 1 0.0652
The IC of compound listed by table 2 50numerical value, show that compound of the present invention can effectively combine the albumen with bromodomain structural domain at cell levels, therefore compound of the present invention can become effective medicine of tumour.

Claims (9)

1. the triazole compound shown in a general formula (I) and pharmaceutically useful salt thereof:
Wherein:
R 1independently be selected from the alkyl of hydrogen atom, 1-6 carbon;
R 2independently be selected from olefin carboxylic acid's ester of fluorine substituted-phenyl, chlorine substituted-phenyl, the alkyl-substituted phenyl of 1-6 carbon, the alkoxy substituted phenyl of 1-6 carbon, trifluoromethyl substituted-phenyl, the alkyl carboxylic acid of 1-6 carbon, the alkyl carboxylic acid ester of 1-6 carbon, the alkylamide of 1-6 carbon, the olefin carboxylic acid of 1-6 carbon or 1-6 carbon;
N is the integer of 1 to 6.
2. compound according to claim 1 and pharmaceutically useful salt thereof, wherein:
R 1independently be selected from the alkyl of hydrogen atom, 1-3 carbon;
R 2independently be selected from olefin carboxylic acid's ester of fluorine substituted-phenyl, chlorine substituted-phenyl, the alkyl-substituted phenyl of 1-3 carbon, the alkoxy substituted phenyl of 1-3 carbon, trifluoromethyl substituted-phenyl, the alkyl carboxylic acid of 1-3 carbon, the alkyl carboxylic acid ester of 1-3 carbon, the alkylamide of 1-3 carbon, the olefin carboxylic acid of 1-3 carbon or 1-3 carbon;
N is the integer of 1 to 4.
3. compound according to claim 2 and pharmaceutically useful salt thereof, wherein:
R 1independently be selected from hydrogen atom, methyl;
R 2independently be selected from fluorine substituted-phenyl, chlorine substituted-phenyl, methyl substituted phenyl, methoxy substitution phenyl, trifluoromethyl substituted-phenyl, acetoxyl, methyl acetate, acetyl-pyrrole;
N is the integer of 1 to 2.
4. according to the compound described in claim 1-3 and pharmaceutically useful salt thereof, wherein, described compound is one of following compounds or its pharmacologically acceptable salt:
6-(3,5-dimethyl isoxazole)-4-phenyl-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(4-p-methoxy-phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-p-methoxy-phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-p-methoxy-phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(2-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(4-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(2,4 difluorobenzene base)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-aminomethyl phenyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(4-trifluoromethyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(3-trifluoromethyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-4-(2-trifluoromethyl)-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole)-1-methyl 4-phenyl-3-((1-phenyl-1H-1,2,3-triazole) methyl)-3,4-dihydroquinazoline-2 (1H)-one;
6-(3,5-dimethyl isoxazole-4-base)-3-((1-(2-oxo-2-(pyrrolidyl-1-base)-ethyl)-1H-1,2,3-triazole-4-base) methyl 4-phenyl-3,4-dihydroquinazoline-2 (1H)-one.
5. the preparation method of the compound shown in general formula (I) according to any one of claim 1-4, is prepared by following methods:
Step a: compd A and N-bromo-succinimide are obtained by reacting compd B;
Step b: compd B and t-butyl sulfonamide are obtained by reacting Compound C;
Step c: obtain Compound D by sodium borohydride reduction Compound C;
Steps d: Compound D and bromo alkyne reaction obtain compd E;
Step e: compd E and triphosgene are obtained by reacting compound F 17-hydroxy-corticosterone;
Step f: compound F 17-hydroxy-corticosterone and trinitride are obtained by reacting G;
Step g: compound G and 3,5-dimethyl isoxazole-4-pinacol borate are obtained by reacting chemical combination H;
Step h: compound H and idoalkane are obtained by reacting the compound that general formula (I) represents;
Wherein, R 1, R 2described above with the definition of n.
6. the compound shown in general formula (I) according to any one of claim 1-4 or its pharmacy acceptable salt are in preparation treatment and the purposes in the medicine of bromodomain domain protein relative disease.
7. the compound shown in general formula (I) according to any one of claim 1-4 or its pharmacy acceptable salt purposes in the medicine of preparation treatment tumour.
8. purposes according to claim 7, wherein, described tumour can be but is not limited to multiple myeloma, cancer of the stomach, lung cancer, mammary cancer, the esophageal carcinoma, colorectal carcinoma, medulloblastoma, acute myeloblastic leukemia, chronic leukemia, prostate cancer, hepatoma, renal cell carcinoma, cervical cancer, skin carcinoma, ovarian cancer, colorectal carcinoma, neurospongioma, thyroid carcinoma or carcinoma of the pancreas.
9. a pharmaceutical composition, it comprises one or more compounds shown in general formula (I) according to any one of claim 1-4 or its pharmacy acceptable salt for the treatment of significant quantity, and pharmaceutically acceptable auxiliary material.
CN201511016420.XA 2015-12-28 2015-12-28 Preparation method of triazole derivatives and application of triazole derivatives as drugs Pending CN105541825A (en)

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CN106749513A (en) * 2017-01-23 2017-05-31 中国药科大学 Bifunctional molecule and its preparation and application based on the induction BET degradeds of VHL parts
CN107056772A (en) * 2017-01-23 2017-08-18 中国药科大学 Bifunctional molecule and its preparation and the application of BET degradeds are induced based on cereblon parts
CN107056771A (en) * 2017-01-23 2017-08-18 中国药科大学 Bromodomain albumen bivalent inhibitors and its preparation method and application
CN108440503A (en) * 2018-04-10 2018-08-24 张海英 The preparation method of the disubstituted quinazoline medicinal compound of the parent nucleus containing triazole
CN114437041A (en) * 2022-02-25 2022-05-06 湖北科技学院 4-tetrazolyl substituted-3, 4-dihydroquinazoline derivatives with anti-tumor activity and preparation method and application thereof

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CN101679318A (en) * 2007-04-05 2010-03-24 美国西门子医疗解决公司 Development of molecular imaging probes for carbonic anhydrase-IX using click chemistry
WO2014154762A1 (en) * 2013-03-27 2014-10-02 Boehringer Ingelheim International Gmbh Dihydroquinazolinone analogues as brd4 inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106749513A (en) * 2017-01-23 2017-05-31 中国药科大学 Bifunctional molecule and its preparation and application based on the induction BET degradeds of VHL parts
CN107056772A (en) * 2017-01-23 2017-08-18 中国药科大学 Bifunctional molecule and its preparation and the application of BET degradeds are induced based on cereblon parts
CN107056771A (en) * 2017-01-23 2017-08-18 中国药科大学 Bromodomain albumen bivalent inhibitors and its preparation method and application
CN108440503A (en) * 2018-04-10 2018-08-24 张海英 The preparation method of the disubstituted quinazoline medicinal compound of the parent nucleus containing triazole
CN114437041A (en) * 2022-02-25 2022-05-06 湖北科技学院 4-tetrazolyl substituted-3, 4-dihydroquinazoline derivatives with anti-tumor activity and preparation method and application thereof
CN114437041B (en) * 2022-02-25 2023-11-10 湖北科技学院 4-tetrazolyl substituted-3, 4-dihydroquinazoline derivative with antitumor activity, and preparation method and application thereof

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