CN105949221A - Spiro indol-2-ketone derivative as well as preparation method and application of derivative as anti-cancer drug - Google Patents
Spiro indol-2-ketone derivative as well as preparation method and application of derivative as anti-cancer drug Download PDFInfo
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Abstract
The invention provides a novel 3-substituted-7-aryl formyl spiro[1,2,4-triazole[3,4-b] [1,3,4] thiadiazine-6, 3'-indol]-2'-ketone derivative shown in the formula (I). In the formula (I), a substituent R1 represents alkyl or aryl of H and C1-6; R2 represents alkyl, alkoxy, hydroxyl, a nitrile group, carboxyl or sulfonyl of H, F, Cl, Br and C1-6. The 3-substituted-7-aryl formyl spiro[1,2,4-triazole[3,4-b] [1,3,4] thiadiazine-6, 3'-indol]-2'-ketone derivative has certain inhibition activity on cancer cells, a synthesis method is simple, materials are easy to obtain, and the novel 3-substituted-7-aryl formyl spiro[1,2,4-triazole[3,4-b] [1,3,4] thiadiazine-6, 3'-indol]-2'-ketone derivative can be used for preparation of the anti-cancer drug.
Description
Technical field
The present invention relates to a kind new medicine compounds, specifically, relate to a kind of 3-replace-7-sweet-smelling formacyl spiral shell [1,2,
4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one derivant and preparation method thereof and as cancer therapy drug
Application.
Background technology
Cancer is one of principal disease of current serious threat human health and life security.The research of cancer therapy drug with open
Send out the focus that always chemist and medicine scholar pay close attention to.Find selectivity efficient, high and the little cancer therapy drug of toxic and side effects is
One of direction is wanted in the life of drug development research.
A kind of Benzazole compounds of Isatin (2,3-indolinedione), is to come from marine organisms Lobster and maintain it to survive
Necessary a kind of natural marine antibiotic.Having confirmed the Indigo Naturalis played a major role in Chinese medicine DANGGUI LUHUI WAN, it resists
The effective ingredient of tumor is exactly a kind of Isatin derivant indirubin, and chronic myelocytic leukemia (CML) is had by this compound
Obvious inhibitory action [Biochem. Biophys. Res. Commun., 2000, 276(1), 379-84], also it is me
State creates I class PTS.Research find Isatin derivant have suppression cyclin dependent kinase (CDKs),
The effect of the vascular endothelial growth factor receptor (VEGFR) of Stat3 and promotion tumor-blood-vessel growth, has antitumor widely
Specificity.This analog derivative can be by being combined in the ATP-binding site of some important cells cycle regulators, to experimentally
Solid tumor play inhibitory action, they can also by directly suppression people's epithelial cancer cells Src kinases, thus suppress transcribe because of
Sub-Stat3 phosphorylation, makes two kinds of Stat3 target genes (anti-apoptotic proteins Mcl-1 and survivin protein) express and declines, thus
Apoptosis-induced generation.But due to indirubin poorly water-soluble, and gastrointestinal side effect is obvious, and therefore, its clinical practice is substantially subject to
Limit.Therefore with Isatin as lead compound, carry out structural modification, find antitumor drug novel, safe and efficient and become
Important topic for the domestic and international scientists study in this field.
Summary of the invention
It is an object of the invention to provide a kind of novel 3-and replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b]
[1,3,4] thiadiazine-6,3 '-indole]-2 '-one derivant.
The purpose of the present invention lie also in a kind of 3-of offer replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,
The preparation method of 4] thiadiazine-6,3 '-indole]-2 '-one derivant.
The purpose of the present invention lie also in offer above-mentioned 3-replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,
4] thiadiazine-6,3 '-indole]-2 ' application in preparing antitumor drug of the-one derivant.
The above-mentioned purpose of the present invention is achieved by below scheme:
A kind of 3-replaces-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one spreads out
Biology, its chemical structural formula shown in formula I:
In formula (I), substituent R1It is H, C1-6Alkyl or aryl；R2It is H, F, Cl, Br, C1-6Alkyl, alkoxyl, hydroxyl,
Itrile group, carboxyl or sulfonic group.
Above-mentioned 3-replacement-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-
The preparation method of ketone derivatives, reaction expression is:
Specifically comprise the following steps that
(1) by indole-2,3-dione 1 and 5-substituted-4-amino-3-sulfydryl-1,2,4-triazoles 2 are dissolved in absolute methanol, and it is right to add
Toluenesulfonic acid, refluxes 4-5 hour at 55-65 DEG C, cooling precipitation, filter Schiff's base 3-((5-replaces-3-sulfydryl-4H-1,2,
4-triazole-4-yl) imino group) indol-2-one 3.
(2) by above-mentioned Schiff's base 3-((5-replaces-3-sulfydryl-4H-1,2,4-triazole-4-yl) imino group) indol-2-one 3 He
2-bromine substituted acetophenone is dissolved in absolute methanol, adds triethylamine, refluxes 1-2 hour at 60-65 DEG C, cooling precipitation, is collected by filtration
Solid, oxolane and methanol miscible fluid recrystallization both 3-replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,
4] thiadiazine-6,3 '-indole]-2 '-one derivant.
Beneficial effects of the present invention: be experimentally confirmed, the 3-of the present invention replaces-7-sweet-smelling formacyl spiral shell [1,2,4-triazole
[3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one derivant has good inhibitory activity to tumor cell.Can be used for
The medicine of preparation suppression tumor cell.And synthetic method is simple, and material is easy to get, provide a kind of new for solving antitumor drug
Development approach.
Detailed description of the invention
In order to be better understood from the present invention, now provide preparation 3-and replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b]
[1,3,4] thiadiazine-6,3 '-indole]-2 ' embodiment of-one derivant, the present invention includes but bad is limited to this preparation method.
Embodiment 1:3-ethyl-7-(4-anisoyl base)-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-
6,3 '-indole]-2 ' synthesis of-one (Ia).
By indole dione 1 (2 mmol) and 5-ethyl-3-sulfydryl-4-amino-1,2,4-triazole 2(2.2 mmol) it is dissolved in 5
In mL methanol, adding p-methyl benzenesulfonic acid (0.04 mmol), in 65 DEG C of backflows, TCL follows the tracks of reaction process, and reaction cools down after terminating
To room temperature, a large amount of indigo red solid is had to separate out.Filter, filtering residue washing with alcohol 2-3 time, dry to obtain intermediate product 3-((5-second
Base-3-sulfydryl-4H-1,2,4-triazole-4-yl) imino group) indol-2-one isatin color Schiff's base solid 3
Weigh intermediate product 3-obtained above ((5-ethyl-3-sulfydryl-4H-1,2,4-triazole-4-yl) imino group) indole-2-
Ketone (1 mmol) is put in reaction bulb, dissolves with 5 mL methanol, is added dropwise over triethylamine (0.1 mmol), 10 mins are stirred at room temperature
After, add the bromo-4 '-methoxyacetophenone of 2-(0.11 mmol), 65 DEG C of backflows.TLC follows the tracks of reaction, and reaction is cooled to after terminating
Room temperature, has a large amount of white solid to separate out.Filtering, oxolane/recrystallizing methanol obtains white solid 3-ethyl-7-(4-methoxy benzene
Formoxyl)-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one, its chemical structural formula such as formula
(Ia) shown in, productivity: 87%.
1 H NMR (500 MHz, DMSO) δ: 10.86 (s, 1H ), 7.94 (d, J = 6.9 Hz, 2H), 7.29
(d, J = 5.8 Hz, 1H), 7.16 (m, 2H), 7.09 (d, J = 7.1 Hz, 2H), 6.92 (s, 2H),
5.86 (s, 1H), 3.86 (s, 3H), 2.60 (m, 2H), 1.07 (s, 3H);13C NMR (125 MHz, DMSO)
δ 192.15, 172.23, 164.27, 154.76, 142.38, 140.25, 131.17, 130.29, 127.17,
126.76, 123.94, 121.67, 114.44, 110.19, 59.86, 55.75, 42.10, 17.22, 11.14;
ESI MS m/z: 421 (M+H)+.
Embodiment 2:3-ethyl-7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-
The synthesis of 2 '-one (Ib).
The preparation method of the present embodiment is in addition to replacing the bromo-4 '-methoxyacetophenone of 2-with the bromo-1-Phenylethanone. of 2-, and remaining is with real
Execute example 1, finally tan crystals 3-ethyl-7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,
3 '-indole]-2 '-one, shown in its chemical structural formula such as formula (Ib), productivity: 82%.
1H NMR (500 MHz, DMSO) δ 10.92 (s, 1H), 7.97 (d, J = 4.5 Hz, 2H), 7.71
(d, J = 3.8 Hz, 1H), 7.31 (m, 1H), 7.27 (m, 2H), 7.12 (d, J = 5.6 Hz, 2H),
6.94 (s, 2H), 5.87 (s, 1H), 2.61 (dd, J = 13.2, 6.6 Hz, 2H), 1.07 (s, 3H);13CNMR (125 MHz, DMSO) δ 194.32, 172.21, 154.89, 142.29, 140.13, 134.52,
130.35, 129.09, 128.65, 126.73, 125.09, 124.09, 121.80, 110.31, 60.27, 48.78,
42.16, 17.24; ESI MS m/z: 391 (M+H)+.
Embodiment 3:3-(4-anisyl)-7-benzoyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-
Indole]-2 ' synthesis of-one (Ic).
The preparation method of the present embodiment is except replacing 5-second by 5-(4-anisyl)-3-sulfydryl-4-amino-1,2,4-triazole
Base-3-sulfydryl-4-amino-1,2,4-triazole；The bromo-1-Phenylethanone. of 2-replaces outside the bromo-4 '-methoxyacetophenone of 2-, and remaining is with implementing
Example 1, finally obtains tan crystals 3-(4-anisyl)-7-benzoyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiophene two
Piperazine-6,3 '-indole]-2 '-one, shown in its chemical structural formula such as formula (Ic), productivity: 82%.
1H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 7.95 (d, J = 7.5 Hz, 2H), 7.79
(d, J = 8.9 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 3H), 7.28
(dd, J = 15.2, 7.5 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 6.95 (m, 1H), 6.90 (d,J = 7.8 Hz, 1H), 6.02 (s, 1H), 3.76 (s, 3H); 13C NMR (125 MHz, DMSO) δ 193.72
, 172.17 , 160.28 , 151.80 , 142.38 , 142.19 , 134.71, 134.16 , 130.43 ,
129.16 , 128.94 , 128.68 , 126.60 , 123.96 , 121.77 , 118.54 , 114.01, 110.27
, 60.22 , 55.20, 43.68; ESI MS m/z: 469 (M+H)+.
Embodiment 4:3-(4-tolyl)-7-benzoyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-Yin
Diindyl]-2 ' synthesis of-one (Id).
The preparation method of the present embodiment is except replacing 5-second by 5-(4-tolyl)-3-sulfydryl-4-amino-1,2,4-triazole
Base-3-sulfydryl-4-amino-1,2,4-triazole；2-bromoacetophenone replaces outside the bromo-4 '-methoxyacetophenone of 2-, remaining same embodiment
1, finally yellow crystals 3-(4-tolyl)-7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,
3 '-indole]-2 '-one, shown in its chemical structural formula such as formula (Id), productivity: 67%.
1H NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 7.95 (d, J = 7.4 Hz, 2H), 7.73
(t, J = 7.3 Hz, 3H), 7.62 (s, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.29 (t, J = 8.2
Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.95 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.7
Hz, 1H), 6.05 (s, 1H), 3.37 (s, 1H), 2.30 (s, 3H). 13C NMR (125 MHz, DMSO) δ
193.71, 172.14, 152.04, 142.52, 142.38, 139.44, 134.69, 134.19, 130.43,
129.15, 129.08, 128.67, 128.30, 127.38, 127.13, 126.57, 123.95, 123.39,
121.77, 110.27, 60.24, 43.75, 20.88; ESI MS m/z: 453 (M+H)+.
Embodiment 5:3-(3-chlorphenyl)-7-(4-anisoyl base)-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiophene two
The synthesis of piperazine-6,3 '-indole]-2 '-one (Ie).
The preparation method of the present embodiment is except replacing 5-second by 5-(3-chlorphenyl)-3-sulfydryl-4-amino-1,2,4-triazole
Outside base-3-sulfydryl-4-amino-1,2,4-triazole, remaining is with embodiment 1, finally obtains white crystal 3-(3-chlorphenyl)-7-(4-
Anisoyl base)-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one, its chemical structural formula
As shown in formula (Ie), productivity: 83%.
1H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.88
(t, J = 11.0 Hz, 2H), 7.68 (s, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
6.3 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.01 (s, 1H), 3.87 (s, 3H); 13C NMR
(125 MHz, DMSO) δ 191.77, 173.50, 164.05, 150.92, 146.12, 142.16, 133.16,
130.99, 130.66, 130.30, 129.75, 127.82, 127.10, 126.67, 125.77, 124.74,
124.73, 121.94, 114.14, 110.36, 63.34, 55.71, 49.72; ESI MS m/z: 503 (M+H)+.
Embodiment 6:3-(3-tolyl)-7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-Yin
Diindyl]-2 ' synthesis of-one (If).
The preparation method of the present embodiment is except replacing 5-second by 5-(3-tolyl)-3-sulfydryl-4-amino-1,2,4-triazole
Base-3-sulfydryl-4-amino-1,2,4-triazole；The bromo-1-Phenylethanone. of 2-replaces outside the bromo-4 '-methoxyacetophenone of 2-, and remaining is with implementing
Example 1, finally white crystal 3-(3-tolyl)-7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-
6,3 '-indole]-2 '-one, shown in its chemical structural formula such as formula (If), productivity: 82%.
1H NMR (500 MHz, DMSO) δ 10.86 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 7.5
Hz, 1H), 7.61 (d, J = 10.7 Hz, 1H), 7.57 (d, J = 7.5 Hz, 3H), 7.44 (t, J =
7.8 Hz, 2H), 7.30 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.21 (t, J =
7.9 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.73 (d, J =
7.8 Hz, 1H), 5.98 (s, 1H), 2.28 (s, 3H);13C NMR (125 MHz, DMSO) δ 191.63,
173.56, 164.06, 152.46, 145.38, 142.23, 137.69, 130.97, 130.47, 130.12,
128.38, 127.92, 127.04, 125.87, 124.99, 124.67, 124.45, 121.89, 114.16,
110.29, 63.45, 49.97, 20.94; ESI MS m/z: 453 (M+H)+.
Embodiment 7:7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one (Ig)
Synthesis.
The preparation method of the present embodiment is except replacing 5-ethyl-3-sulfydryl-4-ammonia by 3-sulfydryl-4-amino-1,2,4-triazole
Base-1,2,4-triazoles, the bromo-1-Phenylethanone. of 2-replaces outside the bromo-4 '-methoxyacetophenone of 2-, and remaining is with embodiment 1, finally obtains yellow
Crystal 7-benzoyl-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one, its chemical constitution
Shown in formula such as formula (Ig), productivity: 80%.
1H NMR (500 MHz, DMSO) δ 10.93 (s, 1H), 8.61 (s, 1H), 7.97 (d, J = 7.7
Hz, 2H), 7.72 (m, 1H), 7.57 (t, J = 7.7 Hz, 2H), 7.45 (s, 1H), 7.31 (t, J =
7.7 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.94 (t, J = 8.6 Hz, 2H), 5.98 (m,
1H); 13C NMR (125 MHz, DMSO) δ 194.15, 172.15, 143.08, 142.33, 140.08, 134.60,
134.45, 130.41, 129.11, 128.68, 126.51, 124.20, 121.83, 110.29, 60.00, 42.86;
ESI MS m/z: 363 (M+H)+.
Embodiment 8:3-(3-tolyl)-7-(4-anisoyl base)-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiophene two
The synthesis of piperazine-6,3 '-indole]-2 '-one (Ih).
The preparation method of the present embodiment is except replacing 5-second by 5-(3-tolyl)-3-sulfydryl-4-amino-1,2,4-triazole
Outside base-3-sulfydryl-4-amino-1,2,4-triazole, remaining is with embodiment 1, finally greyish white crystal 3-(3-tolyl)-7-(4-
Anisoyl base)-spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one, its chemical structural formula
As shown in formula (Ih), productivity: 75%.
1H NMR (500 MHz, DMSO) δ 10.89 (s, 1H), 7.68 (d, J = 9.1 Hz, 3H), 7.56
(d, J = 7.6 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.22 (dd, J = 15.8, 7.8 Hz,
2H), 7.01 (d, J = 8.9 Hz, 2H), 6.85 (t, J = 7.7 Hz, 1H), 6.79 (m, 2H), 5.87
(d, J = 23.7 Hz, 1H), 3.83 (s, 3H), 2.24 (s, 3H);13C NMR (125 MHz, DMSO) δ
191.63, 173.56, 164.06, 152.46, 145.38, 142.23, 137.69, 130.97, 130.47,
130.12, 128.38, 127.92, 127.04, 125.87, 124.99, 124.67, 124.45, 121.89,
114.16, 110.29, 63.45, 55.70, 49.97, 20.94; ESI MS m/z: 483 (M+H)+.
Below by compound experiment example and activity experiment example, the present invention is described in further detail.
Use mtt assay, 12 kinds of synthesized target product 3-are replaced-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b]
[1,3,4] thiadiazine-6,3 '-indole]-2 '-one has carried out the experiment of active anticancer.DU145(carcinoma of prostate with people), MCF-
7(breast carcinoma), EC109(esophageal squamous cell carcinoma), MGC803(gastric cancer) be material to be tested.Collect logarithmic (log) phase cell, thin with trypsinization
Born of the same parents, adjust concentration of cell suspension to 2 × 104Individual/mL, is dispensed in 96 orifice plates, and every hole adds 200 μ L；In 5%CO2, incubate for 37 DEG C
Educate half a day, be paved with at the bottom of hole to cell monolayer, the sample of addition variable concentrations, every hole 100 μ l, if 3 parallel holes；Then at 5%
CO2, hatch four days for 37 DEG C, observe under inverted microscope；Every hole adds 20 μ l MTT solution (5 mg/ml, i.e. 0.5%MTT), continues
Continuous cultivation 4 h, if medicine can react with MTT, can first be centrifuged and discard culture fluid afterwards, after carefully rushing 2-3 time with PBS, add
Culture fluid containing MTT, terminates cultivating, carefully sucks culture fluid in hole；Every hole adds 180 μ l dimethyl sulfoxide, puts on shaking table low
Speed vibration 10 min, make crystal fully dissolve.At wavelength 550 nm, the light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument.
With reference to comparison (without sample, sample replaces with the solvent dissolving it, and other condition is just the same), calculate suppression ratio IC50, survey
Test result is shown in Table 1.
Table 1 3-replacement-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-
The anti-tumor activity of ketone derivatives
As it can be seen from table 1 3-replaces-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-Yin
Diindyl]-2 '-one derivant has a suppression tumor promotion, and wherein the tumor promotion inhibition of compound Ia and Ig is best, particularly
Compound Ig per is for above-mentioned cell DU145(carcinoma of prostate), MCF-7(breast carcinoma), EC109(esophageal squamous cell carcinoma), MGC803(stomach
Cancer) IC50Value is respectively less than positive control 5-Fu (5-fluorouracil).
Claims (6)
1. a 3-replaces-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one
Derivant, its chemical structural formula shown in formula I:
In formula (I), substituent R1It is H, C1-6Alkyl or aryl；R2It is H, F, Cl, Br, C1-6Alkyl, alkoxyl, hydroxyl, nitrile
Base, carboxyl or sulfonic group.
2. a 3-replaces-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one
The preparation method of derivant, it is characterised in that comprise the steps:
(1) 5-being replaced-3-sulfydryl-4-amino-1,2,4-triazole and 2,3-indole dione is dissolved in reaction dissolvent, in heating
Under counterflow condition react, after react, cooling precipitation solid, filter intermediate product 3-((3-sulfydryl-5-replacement-4H-1,
2,4-triazole-4-yl) imino group) indol-2-one；
(2) by above-mentioned intermediate product 3-((3-sulfydryl-5-replaces-4H-1,2,4-triazole-4-yl) imino group) indol-2-one
It is dissolved in reaction dissolvent with 2-bromine substituted acetophenone, is heated to reflux, after having reacted, cooling precipitation, solid is collected by filtration, heavily ties
Brilliant 3-replaces-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,3 '-indole]-2 '-one derives
Thing.
3. 3-as claimed in claim 2 replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,
3 '-indole]-2 ' preparation method of-one derivant, it is characterised in that in step (1), the catalyst used by condensation reaction is to first
Benzenesulfonic acid, whipping temp is 60-65 DEG C, and mixing time is 4-5 hour, and reaction dissolvent is absolute methanol.
4. 3-as claimed in claim 2 replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,
3 '-indole]-2 ' preparation method of-one derivant, it is characterised in that in step (2), the alkali used by nucleophilic substitution is three second
Amine, whipping temp is 60-65 DEG C, and mixing time is 1-2 hour, and reaction dissolvent is methanol.
5. 3-as claimed in claim 1 replace-7-sweet-smelling formacyl spiral shell [1,2,4-triazole [3,4-b] [1,3,4] thiadiazine-6,
3 '-indole]-2 ' application in preparing antitumor drug of the-one derivant.
Application the most according to claim 5, it is characterised in that the dosage form of described antitumor drug be tablet, pill, capsule,
Injection, suspending agent or Emulsion.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108341831A (en) * | 2018-05-11 | 2018-07-31 | 贵州医科大学 | 7H- [1,2,4] triazole [3,4-b] [1,3,4] thiadiazine-phenylhydrazone type compound |
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| WO2011067185A1 (en) * | 2009-12-02 | 2011-06-09 | F. Hoffmann-La Roche Ag | Spiroindolinone pyrrolidines |
| CN104650096A (en) * | 2015-02-12 | 2015-05-27 | 贵州大学 | Compound containing isopentene ketone group five-membered ring pyrrole spiro ring oxoindole as well as preparation method and application of compound |
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| WO2011067185A1 (en) * | 2009-12-02 | 2011-06-09 | F. Hoffmann-La Roche Ag | Spiroindolinone pyrrolidines |
| CN104650096A (en) * | 2015-02-12 | 2015-05-27 | 贵州大学 | Compound containing isopentene ketone group five-membered ring pyrrole spiro ring oxoindole as well as preparation method and application of compound |
Non-Patent Citations (1)
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| N. I. GAPONENKO，等: "Synthesis of spiro[indole-3,3´-[1,3,4]thiadiazino[3,2-a]benzimidazoles] and spiro[indole-3,6´-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines]", 《RUSSIAN CHEMICAL BULLETIN》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108341831A (en) * | 2018-05-11 | 2018-07-31 | 贵州医科大学 | 7H- [1,2,4] triazole [3,4-b] [1,3,4] thiadiazine-phenylhydrazone type compound |
| CN108341831B (en) * | 2018-05-11 | 2020-10-09 | 贵州医科大学 | 7H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine-phenylhydrazone type compounds |
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