CN105175410A - Triazine compound and preparing method and antineoplastic application thereof - Google Patents
Triazine compound and preparing method and antineoplastic application thereof Download PDFInfo
- Publication number
- CN105175410A CN105175410A CN201510665477.6A CN201510665477A CN105175410A CN 105175410 A CN105175410 A CN 105175410A CN 201510665477 A CN201510665477 A CN 201510665477A CN 105175410 A CN105175410 A CN 105175410A
- Authority
- CN
- China
- Prior art keywords
- compound
- salt
- hours
- solvent
- reaction
- 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
- CNNYVKBYJPMHRX-UHFFFAOYSA-N CCS(N1CCN(Cc2nc(Cl)nc(N3CCOCC3)n2)CCC1)(=O)=O Chemical compound CCS(N1CCN(Cc2nc(Cl)nc(N3CCOCC3)n2)CCC1)(=O)=O CNNYVKBYJPMHRX-UHFFFAOYSA-N 0.000 description 1
- RSVSTBSRCAKKGG-UHFFFAOYSA-N COc1ccc2[s]c(-c3nc(N4CCOCC4)nc(CN(CCC4)CCN4C=O)n3)nc2c1 Chemical compound COc1ccc2[s]c(-c3nc(N4CCOCC4)nc(CN(CCC4)CCN4C=O)n3)nc2c1 RSVSTBSRCAKKGG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a triazine compound shown in the formula I and a salt thereof (see the formula in the description). R is selected from H, a C1-C2 alkyl group and a C3-C4 straight-chain alkyl group or branched chain alkyl group; the salt is selected from hydrochloride, nitrate, phosphate, sulfate, hydrobromide, mesylate, tosilate, malate, tartrate and lactate. The compound is used for preparing a drug for treating cancers.
Description
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field.Be specifically related to the compound in triazine class shown in formula I or its pharmacology or physiologically acceptable salt, its preparation method and their application in the medicine preparing Therapeutic cancer.
Background technology
Along with the change of human habitat, standard of living and mode of life and the progress of medical science, spectrum of disease there occurs significant change, general transmissible disease is controlled gradually, and malignant tumour then becomes day by day common and one of principal disease of serious threat human life and quality of life.At present in China and even the whole world, cancer has become to cause the second largest reason of human death.In recent years, the essence of tumour is constantly illustrated in the development of molecular weight tumor and molecular pharmacology, and malignant tumour is the disease that body own cells becomes uncontrolled proliferation and spreading, is the disease of a class cell proliferation, prosoplasia.To the chemotherapy etc. that the treatment of tumour comprises surgical resection, radiotherapy and carries out with antitumour drug.The effect of these different treatment meanss depends on type and the developmental stage of tumour.On the whole, chemotherapeutic agent is only applicable to several tumours few in number as leukemia and lymphsystem tumor etc. as primary treatments, and as surgical operation or radiocurable assisting therapy, is then applicable to eurypalynous tumour perhaps.The Recent Progresses In The Development of antitumor drug is very rapid in recent years, develop into a brand-new stage, low from traditional selectivity, that toxicity the is large cytotoxic drug of research and development focus of antitumor drug of today is transferred to and is bred the key enzyme of relevant intracellular signal transduction pathway as drug target for some and tumor cell differentiation, finds that selectively acting is in the new type antineoplastic medicine of efficient, low toxicity, the high specificity of specific target spot.
Summary of the invention
The present invention seeks to disclose the compound in triazine class that a class has general formula I, pharmacological testing proves, compound of the present invention or its there is excellent antitumor action.
The structural formula (I) of triaizine compounds of the present invention is as follows:
R is H, C
1~ C
2alkyl, C
3~ C
4straight chained alkyl or branched-chain alkyl.
R preferably represents methyl or ethyl.
Preferred structural formula of compound is as follows:
The compounds of this invention (I) can with pharmaceutically acceptable acid in conjunction with salify.Pharmaceutically acceptable salt can use organic or inorganic acid form.Such as can form salt by hydrochloride, nitrate, phosphoric acid salt, vitriol, hydrobromate, mesylate, tosilate, malate, tartrate or lactic acid salt and similar known acceptable acid.
Another aspect provides the method for the compound prepared described in general formula I, it comprises the steps:
1) Isosorbide-5-Nitrae-diazacyclo-1-ethyl formate and ethyl chloride reacting generating compound VII;
2) there is reduction reaction generation compound VI in compound VI I;
3) compound VI generation bromination reaction generates compound V;
4) compound V prepares grignard reagent generation compound IV;
5) compound IV and three chlorotriazine reacting generating compound III;
6) compound III and morpholine reacting generating compound II;
7) Compound II per generates Compound I with replacement benzothiazole-2-acid reaction.
Described step 1) reaction conditions be: pyridine is solvent, room temperature reaction 2 ~ 4 hours;
Described step 2) reaction conditions be: methyl alcohol is solvent, adds sodium borohydride at 0 DEG C, room temperature reaction 3 ~ 6 hours;
Described step 3) reaction conditions be: acetic acid is solvent, adds Hydrogen bromide, under heated reflux condition react 6 hours;
Described step 4) reaction conditions be: tetrahydrofuran (THF) is solvent, and iodine is initiator, reacts 5 hours at 45 DEG C with magnesium chips;
Described step 5) reaction conditions be: tetrahydrofuran (THF) is solvent, adds three chlorotriazines at 0 DEG C, room temperature reaction 2 hours;
Described step 6) reaction conditions be: DMF is solvent, adds salt of wormwood, at 110 DEG C react 8 ~ 12 hours;
Described step 7) reaction conditions be: dioxane is solvent, under the existence of salt of wormwood and palladium catalyst, 90 DEG C of reactions 12 ~ 24 hours.
The synthetic route of above-mentioned steps is as follows:
Wherein, R is H, C
1~ C
2alkyl, C
3~ C
4straight chained alkyl or branched-chain alkyl.
Another aspect of the present invention provides a kind of pharmaceutical composition, and it comprises the compound described in one or more general formula Is or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
Another aspect provides the purposes of compound in the medicine preparing Therapeutic cancer described in general formula I, described cancer is lung cancer, liver cancer or prostate cancer.
Embodiment
Below in conjunction with embodiment, the structure of the compound shown in general formula I of the present invention and preparation method are further elaborated, but do not limit the present invention.
Preparation embodiment
Embodiment 1
The preparation of compound VI I
By compound VI II (159g, 0.924mol) join in there-necked flask, add pyridine (2.5L) again, ethyl chloride (141.9 is dripped under room temperature, 1.1mol), dropwise, continue stirring at room temperature 2 hours, TLC point plate (iodine colour developing) monitoring raw material spot disappears, add dilute hydrochloric acid and ethyl acetate, extraction, stratification, separate organic layer, add anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain compound as white solid VII268.4g, yield 91%.
1HNMR(400MHz，DMSO-d6)：δppm4.12(t,2H),3.61(t,2H),3.09(m,2H),2.98-2.86(m,4H),2.64(m,2H),1.68(m,2H),1.29(m,3H),1.27(m,3H)；ESI/MS：m/z＝265(M+H)+。
The preparation of compound VI
By compound VI I (260g, 0.98mol) join in anhydrous methanol 4L, slowly add sodium borohydride (93g, 2.45mol), stirring at room temperature 4 hours in batches, TLC point plate (iodine colour developing) monitoring raw material spot disappears, concentrating under reduced pressure removes most of methyl alcohol, is cooled to 0 DEG C, drips dilute hydrochloric acid, adularescent solid is separated out, add water and ethyl acetate again, extraction, layering, separate organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain compound as white solid VI171.8g, yield 79%.
1HNMR(400MHz，DMSO-d6)：δppm4.59(s,2H),3.60(t,2H),3.08(m,2H),2.99-2.87(m,4H),2.65(m,2H),1.96(s,1H),1.69(m,2H),1.28(m,3H)；ESI/MS：m/z＝223(M+H)+。
The preparation of compound V
By compound VI (170g, 0.766mol) join in acetic acid 2L, add Hydrogen bromide 1.5L again, heating reflux reaction 6 hours, TLC point plate (iodine colour developing) monitoring raw material spot disappears, concentrating under reduced pressure removes most of solvent, then is cooled to less than 5 DEG C, drips saturated sodium bicarbonate aqueous solution, regulate Ph=9, add dichloromethane extraction, layering, separate organic phase, with anhydrous sodium sulfate drying, concentrated, residuum re-crystallizing in ethyl acetate obtains off-white color solid 178g, yield 82%.
1HNMR(400MHz，DMSO-d6)：δppm4.24(s,2H),3.59(t,2H),3.07(m,2H),2.98-2.84(m,4H),2.64(m,2H),1.70(m,2H),1.29(m,3H)；ESI/MS：m/z＝285(M+H)+。
The preparation of compound IV
Joined in 2.8L anhydrous tetrahydro furan by compound V (175g, 0.616mol), add magnesium chips, then add iodine, be heated to 45 DEG C, react 5 hours, be cooled to room temperature, reaction solution is directly used in next step reaction.
The preparation of compound III
Three chlorotriazines (109.8g, 0.6mol) are joined in 900ml tetrahydrofuran (THF), is cooled to 0 DEG C, be added dropwise to the reaction solution of previous step, continue room temperature reaction 2 hours, TLC point plate monitoring reaction product no longer increases, drip saturated ammonium chloride, add water and extraction into ethyl acetate, layering, separate organic phase, add anhydrous magnesium sulfate, filter, filtrate concentrates, upper silicagel column is separated and obtains light yellow compound III178g, yield 84%.
1HNMR(400MHz，DMSO-d6)：δppm3.86(s,2H),3.61(t,2H),3.09(m,2H),2.99-2.86(m,4H),2.65(m,2H),1.71(m,2H),1.30(m,3H)；ESI/MS：m/z＝354(M+H)+。
The preparation of Compound II per
By compound III (152g, 0.43mol) with morpholine (37.5g, 0.43mol) join 1400mlN, in dinethylformamide, add salt of wormwood (59g, 0.43mol), react 8 hours at 110 DEG C, TLC point plate monitoring raw material spot disappears, and concentrated remove portion solvent, adds water and extraction into ethyl acetate, layering, separate organic layer, then wash three times with water, use anhydrous sodium sulfate drying organic layer, concentrated, residuum dehydrated alcohol: water=6:10 (V:V) recrystallization, obtains compound as white solid II125g, yield 72%.
1HNMR(400MHz，DMSO-d6)：δppm3.85(s,2H),3.60(t,2H),3.51(t,4H),3.12(m,2H),2.95-2.81(m,4H),2.89(t,4H),2.64(m,2H),1.69(m,2H),1.31(m,3H)；ESI/MS：m/z＝405(M+H)+。
The preparation of Compound I-1
By Compound II per (40.4g, 0.1mol) with 5-hydroxy benzo [d] thiazole-2-boric acid (19.5g, 0.1mol) join 700ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 12 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 29.0g, yield 56%.
1HNMR(400MHz，DMSO-d6)：δppm7.92(d,1H),7.61(s,1H),7.38(d,1H),3.86(s,2H),3.62(t,2H),3.52(t,4H),3.13(m,2H),2.96-2.80(m,4H),2.87(t,4H),2.66(m,2H),2.32(s,1H),1.71(m,2H),1.32(m,3H)；ESI/MS：m/z＝520(M+H)+。
Embodiment 2
The preparation of Compound I-2
By Compound II per (40.4g, 0.1mol) with 5-propyl group benzo [d] thiazole-2-boric acid (23.7g, 0.1mol) join 700ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 12 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 29.3g, yield 55%.
1HNMR(400MHz，DMSO-d6)：δppm7.93(d,1H),7.62(s,1H),7.41(d,1H),3.87(s,2H),3.63(t,2H),3.54(t,4H),3.47(s,3H),3.15(m,2H),2.97-2.80(m,4H),2.88(t,4H),2.67(m,2H),1.70(m,2H),1.31(m,3H)；ESI/MS：m/z＝534(M+H)+。
Embodiment 3
The preparation of Compound I-3
By Compound II per (40.4g, 0.1mol) with 5-oxyethyl group benzo [d] thiazole-2-boric acid (22.3g, 0.1mol) join 700ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 12 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 26.3g, yield 48%.
1HNMR(400MHz，DMSO-d6)：δppm7.93(d,1H),7.62(s,1H),7.41(d,1H),3.87(s,2H),3.63(t,2H),3.54(t,4H),3.47(s,3H),3.15(m,2H),2.97-2.80(m,4H),2.88(t,4H),2.67(m,2H),1.70(m,2H),1.31(m,3H)；ESI/MS：m/z＝548(M+H)+。
Embodiment 4
The preparation of Compound I-4
By Compound II per (40.4g, 0.1mol) with 5-propoxy-benzo [d] thiazole-2-boric acid (23.7g, 0.1mol) join 760ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 14 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 30.8g, yield 55%.
1HNMR(400MHz，DMSO-d6)：δppm7.94(d,1H),7.61(s,1H),7.40(d,1H),3.81(t,2H),3.63(t,2H),3.55(t,4H),3.47(s,3H),3.15(m,2H),2.98-2.81(m,4H),2.88(t,4H),2.67(m,2H),1.70(m,2H),1.63(m,2H),1.45(t,3H),1.30(m,3H)；ESI/MS：m/z＝562(M+H)+。
Embodiment 5
The preparation of Compound I-5
By Compound II per (40.4g, 0.1mol) with 5-propoxy-benzo [d] thiazole-2-boric acid (23.7g, 0.1mol) join 780ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 14 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 27.6g, yield 49.3%.
1HNMR(400MHz，DMSO-d6)：δppm7.94(d,1H),7.61(s,1H),7.40(d,1H),3.65(m,1H),3.55(t,4H),3.27(t,2H),3.15(m,2H),2.98-2.81(m,4H),2.88(t,4H),2.67(m,2H),1.63(m,2H),1.45(t,6H),1.30(m,3H)；ESI/MS：m/z＝562(M+H)+。
Embodiment 6
The preparation of Compound I-6
By Compound II per (40.4g, 0.1mol) with 5-propoxy-benzo [d] thiazole-2-boric acid (25.1g, 0.1mol) join 780ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 14 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 27.1g, yield 48.4%.
1HNMR(400MHz，DMSO-d6)：δppm7.91(d,1H),7.60(s,1H),7.41(d,1H),3.58(t,2H),3.54(t,4H),3.28(t,2H),3.16(m,2H),2.99-2.82(m,4H),2.89(t,4H),2.67(m,2H),1.64(m,2H),1.57～1.45(m,4H),1.32(m,3H),1.17(t,3H)；ESI/MS：m/z＝576(M+H)+。
Embodiment 7
The preparation of Compound I-7
By Compound II per (40.4g, 0.1mol) with 5-isopropoxy benzo [d] thiazole-2-boric acid (25.1g, 0.1mol) join 750ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 15 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 25.8g, yield 46.2%.
1HNMR(400MHz，DMSO-d6)：δppm7.92(d,1H),7.61(s,1H),7.38(d,1H),3.59(m,1H),3.56(t,4H),3.28(t,2H),3.16(m,2H),2.99-2.82(m,4H),2.89(t,4H),2.67(m,2H),1.64(m,2H),1.56(m,2H),1.32(m,3H),1.26(d,3H),1.16(t,3H)；ESI/MS：m/z＝576(M+H)+。
Embodiment 8
The preparation of Compound I-8
By Compound II per (40.4g, 0.1mol) with 5-isopropoxy benzo [d] thiazole-2-boric acid (25.1g, 0.1mol) join 750ml1, in 4-dioxane, add salt of wormwood (27.6g again, 0.2mol) with tetrakis triphenylphosphine palladium (2.8g, 0.0025mol), reaction system is filled with rare gas element, react 18 hours at 90 DEG C, TLC monitors the disappearance of raw material spot thirty, add water and ethyl acetate, extraction, layering, separate organic phase, use saturated common salt water washing again three times, organic phase anhydrous sodium sulfate drying, filter, concentrated, residuum re-crystallizing in ethyl acetate, filter, filter cake methylene dichloride is pulled an oar, obtain filter cake, reduced vacuum drying obtains white solid product 22.6g, yield 42.7%.
1HNMR(400MHz，DMSO-d6)：δppm7.93(d,1H),7.60(s,1H),7.38(d,1H),3.57(t,4H),3.29(t,2H),3.18(m,2H),2.95-2.80(m,4H),2.81(t,4H),2.64(m,2H),1.62(m,2H),1.33(m,3H),1.29(s,9H)；ESI/MS：m/z＝576(M+H)+。
Compound activity is tested:
Mtt assay is adopted to evaluate the compounds of this invention to the growth-inhibiting effect of many strains human tumor cells.Method: (human lung cancer cell A549, human liver cancer cell HepG2 and Human Prostate Cancer Cells LNCap are with 1.5 × 10 to be in the cell growing logarithmic phase
4concentration kind is in 96 orifice plates.Original substratum is sucked after cell cultures 24h is adherent.Test is divided into blank group, drug treating group.Blank group changes 1640 substratum containing 10% foetal calf serum; It is 100 μMs that drug treating group is changed containing concentration, 50 μMs, 10 μMs, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, the substratum of 0.0001 μM and 0.00001 μM testing compound.After cultivating 96h, add the MTT of concentration 5mg/mL, continue to be put in CO
24h cultivated by incubator, then sucks 100 μ L supernatants along nutrient solution top, adds 100 μ LDMSO, 10min is placed in dark place, utilize microplate reader to measure light absorption value (wavelength 570nm), and calculate cell survival according to light absorption value, 6 repeating holes are established in each process.Cell survival rate (%)=Δ 0D
drug treating/ Δ 0D
blank× 100.
Sigmaplot10.0 software is adopted to calculate the IC of 8 kinds of compounds suppression various human tumor cell line Growth of Cells respectively
50value is in table 1.
Table 1 the compounds of this invention is to the IC50 value of various human tumor cell line
Above-mentioned experimental result shows, compound of the present invention has significant antiproliferative activity to human lung cancer cell A549, human liver cancer cell HepG2 and Human Prostate Cancer Cells LNCap, these experimental results show that the compounds of this invention can be used for Therapeutic cancer, particularly treat noumenal tumour, as lung cancer, liver cancer and prostate cancer.
Claims (7)
1. compound in triazine class or its pharmacy acceptable salt, wherein said compound in triazine class has as shown in the formula the structure shown in I:
Wherein, R is H, C
1~ C
2alkyl, C
3~ C
4straight chained alkyl or branched-chain alkyl; Its salt is selected from hydrochloride, nitrate, phosphoric acid salt, vitriol, hydrobromate, mesylate, tosilate, malate, tartrate or lactic acid salt.
2. compound in triazine class according to claim 1 is selected from shrimps compound and salt thereof:
The definition of its salt as claimed in claim 1.
3. compound according to claim 1 or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is hydrochloride.
4. the preparation method of compound according to claim 1, the synthetic route of the method as shown in scheme 1:
1) Isosorbide-5-Nitrae-diazacyclo-1-ethyl formate and ethyl chloride reacting generating compound VII;
2) there is reduction reaction generation compound VI in compound VI I;
3) compound VI generation bromination reaction generates compound V;
4) compound V prepares grignard reagent generation compound IV;
5) compound IV and three chlorotriazine reacting generating compound III;
6) compound III and morpholine reacting generating compound II;
7) Compound II per generates Compound I with replacement benzothiazole-2-acid reaction.
5. preparation method according to claim 4, wherein
Described step 1) reaction conditions be: pyridine is solvent, room temperature reaction 2 ~ 4 hours;
Described step 2) reaction conditions be: methyl alcohol is solvent, adds sodium borohydride at 0 DEG C, room temperature reaction 3 ~ 6 hours;
Described step 3) reaction conditions be: acetic acid is solvent, adds Hydrogen bromide, under heated reflux condition react 6 hours;
Described step 4) reaction conditions be: tetrahydrofuran (THF) is solvent, and iodine is initiator, reacts 5 hours at 45 DEG C with magnesium chips;
Described step 5) reaction conditions be: tetrahydrofuran (THF) is solvent, adds three chlorotriazines at 0 DEG C, room temperature reaction 2 hours;
Described step 6) reaction conditions be: DMF is solvent, adds salt of wormwood, at 110 DEG C react 8 ~ 12 hours;
Described step 7) reaction conditions be: dioxane is solvent, under the existence of salt of wormwood and palladium catalyst, 90 DEG C of reactions 12 ~ 24 hours.
6. compound in triazine class according to claim 1 or its pharmacy acceptable salt are in the application preparing Therapeutic cancer medicine.
7. application according to claim 6, wherein said cancer is lung cancer, liver cancer or prostate cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510665477.6A CN105175410B (en) | 2015-10-14 | 2015-10-14 | Compound in triazine class and preparation method thereof and antitumor application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510665477.6A CN105175410B (en) | 2015-10-14 | 2015-10-14 | Compound in triazine class and preparation method thereof and antitumor application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105175410A true CN105175410A (en) | 2015-12-23 |
| CN105175410B CN105175410B (en) | 2018-01-05 |
Family
ID=54897923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510665477.6A Active CN105175410B (en) | 2015-10-14 | 2015-10-14 | Compound in triazine class and preparation method thereof and antitumor application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105175410B (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622528A (en) * | 2016-02-01 | 2016-06-01 | 白玲强 | Compound for treating pulmonary hypertension and application thereof |
| CN108285446A (en) * | 2018-04-26 | 2018-07-17 | 湖南华腾制药有限公司 | A kind of crystal form of compound in triazine class |
| CN108285447A (en) * | 2018-04-26 | 2018-07-17 | 湖南华腾制药有限公司 | A kind of crystal form of compound in triazine class |
| CN108358910A (en) * | 2018-04-24 | 2018-08-03 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108409725A (en) * | 2018-05-04 | 2018-08-17 | 湖南华腾制药有限公司 | A kind of deuterated anticancer drug and application thereof |
| CN108503633A (en) * | 2018-04-24 | 2018-09-07 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108558855A (en) * | 2018-05-04 | 2018-09-21 | 湖南华腾制药有限公司 | A kind of crystal form of triazines hydrochloride compound |
| CN108558856A (en) * | 2018-05-04 | 2018-09-21 | 湖南华腾制药有限公司 | A kind of crystal form of triazines hydrobromate compound |
| CN108586446A (en) * | 2018-04-20 | 2018-09-28 | 湖南华腾制药有限公司 | Compound in triazine class and preparation method thereof and antitumor application thereof |
| CN108658968A (en) * | 2018-04-24 | 2018-10-16 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108658967A (en) * | 2018-04-24 | 2018-10-16 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108658969A (en) * | 2018-04-24 | 2018-10-16 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN110208449A (en) * | 2019-05-24 | 2019-09-06 | 湖南华腾制药有限公司 | The analyzing detecting method of triaizine compounds |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1271355A (en) * | 1997-07-24 | 2000-10-25 | 全药工业株式会社 | Heterocyclic compounds and antitumor agent containing the same as active ingredient |
| CN1538967A (en) * | 2001-04-27 | 2004-10-20 | ������ҩ��ҵ��ʽ���� | Heterocyclic compound and antitumour agent containing the same as active ingredient |
| WO2005095389A1 (en) * | 2004-03-31 | 2005-10-13 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compound and anti-malignant-tumor agent containing the same as active ingredient |
-
2015
- 2015-10-14 CN CN201510665477.6A patent/CN105175410B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1271355A (en) * | 1997-07-24 | 2000-10-25 | 全药工业株式会社 | Heterocyclic compounds and antitumor agent containing the same as active ingredient |
| CN1538967A (en) * | 2001-04-27 | 2004-10-20 | ������ҩ��ҵ��ʽ���� | Heterocyclic compound and antitumour agent containing the same as active ingredient |
| WO2005095389A1 (en) * | 2004-03-31 | 2005-10-13 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compound and anti-malignant-tumor agent containing the same as active ingredient |
Non-Patent Citations (3)
| Title |
|---|
| 王宇驰，等: ""抗癌药物磷脂酰肌醇3激酶抑制剂"", 《国外医药抗生素分册》 * |
| 赵金龙，等: ""用于肿瘤治疗的PI3K/mTOR双重抑制剂的研究进展"", 《中南药学》 * |
| 陈颖，等: ""PI3K-mTOR双重小分子抑制剂的研究进展"", 《药学实践杂志》 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622528A (en) * | 2016-02-01 | 2016-06-01 | 白玲强 | Compound for treating pulmonary hypertension and application thereof |
| CN105622528B (en) * | 2016-02-01 | 2017-12-15 | 新乡医学院第一附属医院 | A kind of compound for treating pulmonary hypertension and its application |
| CN108586446A (en) * | 2018-04-20 | 2018-09-28 | 湖南华腾制药有限公司 | Compound in triazine class and preparation method thereof and antitumor application thereof |
| CN108503633A (en) * | 2018-04-24 | 2018-09-07 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108358910A (en) * | 2018-04-24 | 2018-08-03 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108658968A (en) * | 2018-04-24 | 2018-10-16 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108658967A (en) * | 2018-04-24 | 2018-10-16 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108658969A (en) * | 2018-04-24 | 2018-10-16 | 湖南华腾制药有限公司 | A kind of process for purification of compound in triazine class |
| CN108285447A (en) * | 2018-04-26 | 2018-07-17 | 湖南华腾制药有限公司 | A kind of crystal form of compound in triazine class |
| CN108285446A (en) * | 2018-04-26 | 2018-07-17 | 湖南华腾制药有限公司 | A kind of crystal form of compound in triazine class |
| CN108409725A (en) * | 2018-05-04 | 2018-08-17 | 湖南华腾制药有限公司 | A kind of deuterated anticancer drug and application thereof |
| CN108558855A (en) * | 2018-05-04 | 2018-09-21 | 湖南华腾制药有限公司 | A kind of crystal form of triazines hydrochloride compound |
| CN108558856A (en) * | 2018-05-04 | 2018-09-21 | 湖南华腾制药有限公司 | A kind of crystal form of triazines hydrobromate compound |
| CN110208449A (en) * | 2019-05-24 | 2019-09-06 | 湖南华腾制药有限公司 | The analyzing detecting method of triaizine compounds |
| CN110208449B (en) * | 2019-05-24 | 2021-07-02 | 湖南华腾制药有限公司 | Method for analyzing and detecting triazine compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105175410B (en) | 2018-01-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105175410A (en) | Triazine compound and preparing method and antineoplastic application thereof | |
| CN102675323B (en) | Pyrrole-[2, 1-f] [1, 2 and 4] triazine derivative and antitumor effect thereof | |
| CN102603743B (en) | Anti-tumor benzazepine[f]azulene derivative, preparation method thereof, and purpose thereof | |
| CN103044395B (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN102911118B (en) | Benzo-azepine type derivative and preparation method and purpose thereof | |
| CN103396386A (en) | Di-substituted dinaphtho-[2,1-b:1',2'-d] furan derivative as well as preparation method and application thereof | |
| CN104558094A (en) | Sapogenin derivative, preparation method of derivative and application thereof in preparation of antitumor drugs | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN108530436B (en) | Pyrazole compound and preparation method and application thereof | |
| EP4063361A1 (en) | Crystal forms of fused ring compound, and composition thereof, preparation method therefor and application thereof | |
| CN112876456A (en) | Cinnoline compound PI3K kinase inhibitor, preparation method thereof and application thereof in pharmacy | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN101967163B (en) | Platinum (II) anti-cancer compound with selectivity for cancer cells | |
| CN106883230B (en) | 7- aniline benzo pyridine compounds and their and its preparation method and application | |
| CN108586446A (en) | Compound in triazine class and preparation method thereof and antitumor application thereof | |
| CN105037265A (en) | Preparation method of quinolinone derivative containing chalcone framework, and application of the quinolinone derivative in anti-cancer medicines | |
| CN105418517B (en) | Novel quinazoline derivative LU1509 as well as preparation method and application thereof | |
| CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof | |
| US9120816B2 (en) | Oxanorbornadiene derivatives and their anticancer activities | |
| CN110590852B (en) | Platinum complex with antitumor activity and preparation method thereof | |
| CN102268003A (en) | Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof | |
| CN105461642B (en) | Novel quinazoline derivative LU1505 as well as preparation method and application thereof | |
| CN105503747B (en) | A kind of quinazoline derivant LU1507 and its preparation method and application | |
| CN105399689B (en) | A kind of novel quinazoline quinoline derivant LU1503 and its preparation method and application | |
| CN105384699B (en) | A kind of novel quinazoline quinoline derivant LU1501 and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Luo Rong Inventor after: Deng Zeping Inventor after: Chen Fangjun Inventor after: Li Shuyun Inventor before: Chen Fangjun Inventor before: Li Shuyun |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Triazine compound and preparing method and antineoplastic application thereof Effective date of registration: 20200318 Granted publication date: 20180105 Pledgee: Bank of Changsha Limited by Share Ltd science and Technology Branch Pledgor: HUNAN HUATENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2020980000827 |