CN105175410B - Compound in triazine class and preparation method thereof and antitumor application thereof - Google Patents
Compound in triazine class and preparation method thereof and antitumor application thereof Download PDFInfo
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Abstract
The invention provides a kind of compound in triazine class and its salt shown in formula I.Wherein, R is selected from H, C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl；Its salt is selected from hydrochloride, nitrate, phosphate, sulfate, hydrobromate, mesylate, tosilate, malate, tartrate or lactate.The compound is as the purposes in the medicine for preparing treating cancer.
Description
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field.More particularly to the compound in triazine class shown in Formulas I or its
Pharmacology or physiologically acceptable salt, its preparation method and they prepare treating cancer medicine in application.
Background technology
With the change of human habitat, living standard and life style and the progress of medical science, spectrum of disease there occurs
Significant change, general sexually transmitted disease is gradually controlled, and malignant tumour then turns into increasingly common and serious threat human life
One of with the principal disease of quality of life.At present in China or even the whole world, into causing, human death's is second largest for cancer
Reason.In recent years, the development of molecular weight tumor and molecular pharmacology constantly illustrates the essence of tumour, malignant tumour be body from
Body cell becomes uncontrolled propagation and the disease of diffusion, is a kind of cell propagation, the disease of disdifferentiation.Tumour is controlled
Treating includes surgical resection, radiotherapy and chemotherapy for being carried out with antineoplastic etc..The effect of these different treatment means
Fruit depends on the type and developing stage of tumour.On the whole, chemotherapeutic agent as primary treatments be only applicable to for
Number few several tumours such as leukaemia and lymphsystem tumor etc., and as surgical operation or the auxiliary treatment of radiotherapy,
Then it is applied to the tumour of many types.The Recent Progresses In The Development of antineoplastic is very rapid in recent years, have developed to one it is brand-new
Stage, the research and development focus of antineoplastic of today are transferred to from the cytotoxic drug that traditional selectivity is low, toxicity is big
Selected for the key enzyme of some intracellular signal transduction pathway related to tumor cell differentiation propagation as drug target, discovery
Property acts on efficient, less toxic, high specificity the new type antineoplastic medicine of specific target spot.
The content of the invention
The present invention seeks to open a kind of compound in triazine class with formula I, pharmacological testing proves, chemical combination of the invention
Thing or its there is excellent antitumor action.
The structure formula (I) of the triaizine compounds of the present invention is as follows：
R is H, C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl.
R preferably represents methyl or ethyl.
Preferable structural formula of compound is as follows：
The compounds of this invention (I) can be combined into salt with pharmaceutically acceptable acid.Pharmaceutically acceptable salt can be with
With organic or inorganic acid form.Such as can be by hydrochloride, nitrate, phosphate, sulfate, hydrobromate, mesylate, right
Toluene fulfonate, malate, tartrate or lactate and similar known acceptable acid forming salt.
Another aspect provides the method for preparing the compound described in formula I, it comprises the following steps：
1) 1,4- diazacyclos -1- Ethyl formates and ethyl chloride reaction generation compound VII；
2) reduction reaction generation compound VI occurs for compound VII；
3) bromination reaction generation compound V occurs for compound VI；
4) compound V prepares grignard reagent generation compound IV；
5) compound IV and three chlorotriazines reaction generation compound III；
6) compound III and morpholine reaction generation compound II；
7) compound II and substitution benzothiazole -2- acid reaction generation compounds I.
The reaction condition of the step 1) is：Pyridine is solvent, is reacted at room temperature 2~4 hours；
The reaction condition of the step 2) is：Methanol is solvent, and sodium borohydride is added at 0 DEG C, is reacted at room temperature 3~6 hours；
The reaction condition of the step 3) is：Acetic acid is solvent, adds hydrobromic acid, is reacted 6 hours under heated reflux condition；
The reaction condition of the step 4) is：Tetrahydrofuran is solvent, and iodine is initiator, small with magnesium chips reaction 5 at 45 DEG C
When；
The reaction condition of the step 5) is：Tetrahydrofuran is solvent, and three chlorotriazines are added at 0 DEG C, and room temperature reaction 2 is small
When；
The reaction condition of the step 6) is：DMF is solvent, adds potassium carbonate, reacts 8 at 110 DEG C
~12 hours；
The reaction condition of the step 7) is：Dioxane is solvent, in the presence of potassium carbonate and palladium catalyst, 90 DEG C
Reaction 12~24 hours.
The synthetic route of above-mentioned steps is as follows：
Wherein, R H, C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl.
It is yet another aspect of the present invention to provide a kind of pharmaceutical composition, and it includes one or more formulas of therapeutically effective amount
Compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier described in I.
Another aspect provides the compound described in formula I prepare treating cancer medicine in purposes,
The cancer is lung cancer, liver cancer or prostate cancer.
Embodiment
The structure and preparation method of the compound shown in formula I of the present invention are made with reference to embodiment further
Illustrate, but do not limit the present invention.
Prepare embodiment
Embodiment 1
Compound VII preparation
Compound VIII (159g, 0.924mol) is added in three-necked flask, pyridine (2.5L) is added, drips at room temperature
Add ethyl chloride (141.9,1.1mol), be added dropwise, continue to be stirred at room temperature 2 hours, TLC points plate (iodine colour developing) monitoring raw material
Spot disappears, and adds watery hydrochloric acid and ethyl acetate, extraction, stratification, separates organic layer, adds anhydrous sodium sulfate drying, mistake
Filter, filtrate decompression concentration, obtains compound as white solid VII 268.4g, yield 91%.
1H NMR (400MHz, DMSO-d6)：δppm 4.12(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)+.
Compound VI preparation
Compound VII (260g, 0.98mol) is added in absolute methanol 4L, be slowly added in batches sodium borohydride (93g,
2.45mol), it is stirred at room temperature 4 hours, TLC points plate (iodine colour developing) monitoring raw material spot disappears, and is concentrated under reduced pressure and removes most of first
Alcohol, 0 DEG C is cooled to, watery hydrochloric acid is added dropwise, has white solid precipitation, adds water and ethyl acetate, extracted, layering, separated organic
Phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain compound as white solid VI 171.8g, yield 79%.
1H NMR (400MHz, DMSO-d6)：δppm 4.59(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)+.
Compound V preparation
Compound VI (170g, 0.766mol) is added in acetic acid 2L, adds hydrobromic acid 1.5L, heating reflux reaction
6 hours, TLC points plate (iodine colour developing) monitoring raw material spot disappeared, and is concentrated under reduced pressure and removes most of solvent, then is cooled to less than 5 DEG C,
Saturated sodium bicarbonate aqueous solution is added dropwise, adjusts Ph=9, adds dichloromethane extraction, layering, separates organic phase, use anhydrous slufuric acid
Sodium is dried, and concentration, residue obtains off-white powder 178g, yield 82% with re-crystallizing in ethyl acetate.
1H NMR (400MHz, DMSO-d6)：δppm 4.24(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)+.
Compound IV preparation
Compound V (175g, 0.616mol) is added in 2.8L anhydrous tetrahydro furans, magnesium chips is added, adds iodine, add
Heat is reacted 5 hours to 45 DEG C, is cooled to room temperature, and reaction solution is directly used in react in next step.
Compound III preparation
Three chlorotriazines (109.8g, 0.6mol) are added in 900ml tetrahydrofurans, 0 DEG C is cooled to, is added dropwise to previous step
Reaction solution, continue room temperature reaction 2 hours, TLC points plate monitoring reaction product be not further added by, be added dropwise saturated ammonium chloride, add water
Extracted with ethyl acetate, layering, separate organic phase, add anhydrous magnesium sulfate, filtering, filtrate concentrates, and upper silicagel column is isolated
Light yellow compound III 178g, yield 84%.
1H NMR (400MHz, DMSO-d6)：δppm 3.86(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)+.
Compound II preparation
Compound III (152g, 0.43mol) and morpholine (37.5g, 0.43mol) are added to 1400ml N, N- dimethyl
In formamide, potassium carbonate (59g, 0.43mol) is added, is reacted 8 hours at 110 DEG C, TLC points plate monitoring raw material spot disappears, dense
Contracting removes partial solvent, adds water and ethyl acetate extraction, layering, separates organic layer, be washed with water and wash three times, use anhydrous slufuric acid
Sodium dries organic layer, concentration, residue absolute ethyl alcohol：Water=6:10(V:V) recrystallize, obtain compound as white solid II
125g, yield 72%.
1H NMR (400MHz, DMSO-d6)：δppm 3.85(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)+。
Compound I-1 preparation
Compound II (40.4g, 0.1mol) and 5- hydroxy benzos [d] thiazole -2- boric acid (19.5g, 0.1mol) are added
Into 700ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 12 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 29.0g, yield 56%.
1H NMR (400MHz, DMSO-d6)：δppm 7.92(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
Compound I-2 preparation
Compound II (40.4g, 0.1mol) and 5- propyl group benzo [d] thiazole -2- boric acid (23.7g, 0.1mol) are added
Into 700ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 12 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 29.3g, yield 55%.
1H NMR (400MHz, DMSO-d6)：δppm 7.93(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
Compound I-3 preparation
Compound II (40.4g, 0.1mol) and 5- ethyoxyls benzo [d] thiazole -2- boric acid (22.3g, 0.1mol) are added
Enter into 700ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 12 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 26.3g, yield 48%.
1H NMR (400MHz, DMSO-d6)：δppm 7.93(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
Compound I-4 preparation
Compound II (40.4g, 0.1mol) and 5- propoxyl group benzo [d] thiazole -2- boric acid (23.7g, 0.1mol) are added
Enter into 760ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 14 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 30.8g, yield 55%.
1H NMR (400MHz, DMSO-d6)：δppm 7.94(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
Compound I-5 preparation
Compound II (40.4g, 0.1mol) and 5- propoxyl group benzo [d] thiazole -2- boric acid (23.7g, 0.1mol) are added
Enter to 780ml1, in 4- dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 14 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 27.6g, yield 49.3%.
1H NMR (400MHz, DMSO-d6)：δppm 7.94(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
Compound I-6 preparation
Compound II (40.4g, 0.1mol) and 5- propoxyl group benzo [d] thiazole -2- boric acid (25.1g, 0.1mol) are added
Enter into 780ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 14 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 27.1g, yield 48.4%.
1H NMR (400MHz, DMSO-d6)：δppm 7.91(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
Compound I-7 preparation
By compound II (40.4g, 0.1mol) and 5- isopropoxies benzo [d] thiazole -2- boric acid (25.1g, 0.1mol)
Be added in 750ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 15 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 25.8g, yield 46.2%.
1H NMR (400MHz, DMSO-d6)：δppm 7.92(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
Compound I-8 preparation
By compound II (40.4g, 0.1mol) and 5- isopropoxies benzo [d] thiazole -2- boric acid (25.1g, 0.1mol)
Be added in 750ml Isosorbide-5-Nitraes-dioxane, add potassium carbonate (27.6g, 0.2mol) and tetrakis triphenylphosphine palladium (2.8g,
0.0025mol), reaction system is filled with inert gas, is reacted 18 hours at 90 DEG C, and TLC thirty monitors the disappearance of raw material spot, adds
Water and ethyl acetate, extract, layering, separate organic phase, then with saturated common salt water washing three times, organic phase is done with anhydrous sodium sulfate
It is dry, filter, concentration, residue re-crystallizing in ethyl acetate, filtering, filter cake is beaten with dichloromethane, obtains filter cake, reduced vacuum
It is dried to obtain white solid product 22.6g, yield 42.7%.
1H NMR (400MHz, DMSO-d6)：δppm 7.93(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：
Growth inhibition effect of the compounds of this invention to more plants of human tumor cells is evaluated using mtt assay.Method：In growth
(human lung cancer cell A549, human liver cancer cell HepG2 and Human Prostate Cancer Cells LNCap are with 1.5 × 10 for the cell of logarithmic phase4It is dense
Degree kind is in 96 orifice plates.Original culture medium is sucked after cell culture 24h is adherent.Experiment is divided into blank control group, drug-treated
Group.Blank group changes 1640 culture mediums containing 10% hyclone；Drug-treated group change containing concentration be 100 μM, 50 μM, 10 μ
M, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, the culture medium of 0.0001 μM and 0.00001 μM testing compound.After cultivating 96h, add
Enter concentration 5mg/mL MTT, continue to be put in CO2Incubator culture 4h, 100 μ L of supernatant are sucked then along nutrient solution top, are added
Enter 100 μ L DMSO, 10min is placed in dark place, determines light absorption value (wavelength 570nm) using ELIASA, and calculate carefully according to light absorption value
Born of the same parents' survival condition, each processing set 6 repeating holes.Cell survival rate (%)=Δ 0DDrug-treated/Δ0DBlank control×100。
8 kinds of compounds are calculated using the softwares of sigmaplot 10.0 respectively and suppress a variety of human tumor cell line cell growths
IC50Value is shown in Table 1.
IC50 value of the compounds of this invention of table 1 to a variety of human tumor cell lines
It is above-mentioned test result indicates that, before compound of the invention is to human lung cancer cell A549, human liver cancer cell HepG2 and people
Row adenocarcinoma cell LNCap has significant antiproliferative activity, these test result indicates that the compounds of this invention can be used for treating cancer,
Entity tumor is particularly treated, such as lung cancer, liver cancer and prostate cancer.
Claims (7)
1. a kind of compound in triazine class or its pharmaceutically acceptable salt, wherein described compound in triazine class has such as following formula I
Shown structure：
Wherein, R H, C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl；Its salt be selected from hydrochloride, nitrate, phosphate,
Sulfate, hydrobromate, mesylate, tosilate, malate, tartrate or lactate.
2. compound in triazine class or its pharmaceutically acceptable salt described in claim 1, wherein described compound in triazine class
Selected from following compounds and its salt：
The definition of its salt is as claimed in claim 1.
3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein described is pharmaceutically acceptable
Salt is hydrochloride.
4. the preparation method of compound according to claim 1, the synthetic route of this method is as shown in scheme 1：
1) 1,4- diazacyclos -1- Ethyl formates and ethyl chloride reaction generation compound VII；
2) reduction reaction generation compound VI occurs for compound VII；
3) bromination reaction generation compound V occurs for compound VI；
4) compound V prepares grignard reagent generation compound IV；
5) compound IV and three chlorotriazines reaction generation compound III；
6) compound III and morpholine reaction generation compound II；
7) compound II and substitution benzothiazole -2- acid reaction generation compounds I.
5. preparation method according to claim 4, wherein
The reaction condition of the step 1) is：Pyridine is solvent, is reacted at room temperature 2~4 hours；
The reaction condition of the step 2) is：Methanol is solvent, and sodium borohydride is added at 0 DEG C, is reacted at room temperature 3~6 hours；
The reaction condition of the step 3) is：Acetic acid is solvent, adds hydrobromic acid, is reacted 6 hours under heated reflux condition；
The reaction condition of the step 4) is：Tetrahydrofuran is solvent, and iodine is initiator, is reacted 5 hours with magnesium chips at 45 DEG C；
The reaction condition of the step 5) is：Tetrahydrofuran is solvent, and three chlorotriazines are added at 0 DEG C, is reacted at room temperature 2 hours；
The reaction condition of the step 6) is：DMF is solvent, adds potassium carbonate, reacts 8~12 at 110 DEG C
Hour；
The reaction condition of the step 7) is：Dioxane is solvent, in the presence of potassium carbonate and palladium catalyst, 90 DEG C of reactions
12~24 hours.
6. compound in triazine class according to claim 1 or its pharmaceutically acceptable salt are preparing treating cancer medicine
Using.
7. application according to claim 6, wherein the cancer is lung cancer, liver cancer or prostate cancer.
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| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Citations (2)
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101130913B1 (en) * | 2004-03-31 | 2012-03-28 | 젠야쿠코교가부시키가이샤 | 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 (2)
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| "PI3K-mTOR双重小分子抑制剂的研究进展";陈颖，等;《药学实践杂志》;20140905;第32卷(第5期);第332-336,359页 * |
| "抗癌药物磷脂酰肌醇3激酶抑制剂";王宇驰，等;《国外医药抗生素分册》;20081231;第29卷(第5期);第206-212页 * |
| "用于肿瘤治疗的PI3K/mTOR双重抑制剂的研究进展";赵金龙，等;《中南药学》;20140430;第12卷(第4期);第297-305页 * |
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