CN106831711A - Oxygen derivative of benzo [e] [1,2,4] triazine 1 and combinations thereof and application - Google Patents
Oxygen derivative of benzo [e] [1,2,4] triazine 1 and combinations thereof and application Download PDFInfo
- Publication number
- CN106831711A CN106831711A CN201611260249.1A CN201611260249A CN106831711A CN 106831711 A CN106831711 A CN 106831711A CN 201611260249 A CN201611260249 A CN 201611260249A CN 106831711 A CN106831711 A CN 106831711A
- Authority
- CN
- China
- Prior art keywords
- cancer
- hydrogen
- hydroxyl
- alkyl
- triazine
- 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
- 0 *NCCCCN(*)c1ccnc2c1ccc(Cl)c2 Chemical compound *NCCCCN(*)c1ccnc2c1ccc(Cl)c2 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
3 [(amino of 7 chloroquinoline 4) butylamine base] oxygen derivatives of 7 substitution benzo [e] [1,2,4] triazine 1 the present invention relates to one kind as shown in formula (1), its pharmaceutically acceptable salt, ester, solvate:R1Selected from hydrogen, hydroxyl, C1‑C6Alkyl, fluorine, chlorine and bromine;R2Selected from hydrogen, C1‑C12Alkyl or hydroxyl;R3Selected from hydrogen, C1‑C12Alkyl or hydroxyl.Present invention also offers a kind of composition, including 3 [(amino of 7 chloroquinoline 4) butylamine base] 7 substitution benzos [e] [1 shown in formula (1), 2,4] the oxygen derivative of triazine 1, its pharmaceutically acceptable salt, ester, solvate and pharmaceutically acceptable auxiliary material:Wherein, R1Selected from hydrogen, hydroxyl, C1‑C6Alkyl, fluorine, chlorine or bromine;R2Selected from hydrogen, C1‑C12Alkyl or hydroxyl;R3Selected from hydrogen, C1‑C12Alkyl or hydroxyl.The present invention is also claimed 3 [(amino of 7 chloroquinoline 4) butylamine base] 7 substitution benzos [e] [1; 2; 4] the oxygen derivative of triazine 1, the application of its pharmaceutically acceptable salt, ester, solvate in anti-tumor medicine is prepared.
Description
Technical field
The present invention relates to pharmaceutical field, more particularly to a kind of benzo [e] [1,2,4] triazine -1- oxygen derivatives and combinations thereof
Thing and application.
Background technology
The life of the cancer serious harm mankind and health, are one of global maximum public health problems.The whole world is annual
Newly-increased cancer patient more than 14,000,000, every year because the people of cancer mortality is more than 8,200,000.The annual pathogenesis of cancer of China and dead people
, respectively more than 4,300,000 and 2,800,000 people, the situation is tense for number.Malignant tumour (also referred to as cancer) is mainly because cell proliferation machinery loses
Adjust and hinder the disease of normal cell function, may locally invade profit normal structure and via lymphatic system, body-internal-circulation system
It is transferred to other positions.With to Developing restraint signal it is insensitive, do not controlled by growth signals and the characteristics of infinite multiplication, have
Resistance apoptosis, the ability for promoting angiogenesis, invasion and attack and migration.
Cell autophagy be cell under conditions of nutrient deprivation or ambient pressure, organelle (such as endoplasm of itself of degrading
Net, mitochondria etc.) or protein masses, to maintain the process of self-energy and metabolism.In mammalian cell, lure
The general molecule mechanism for leading autophagy is:Under the conditions of hungry or ambient pressure, various signal gatherings cause in mTORC1
MTORC1 dissociates from ULK compounds so that ULK hyperphosphorylations, then phosphorylation Ambra1 so that Beclin1-
Ambra1-PIK3C3 compounds are transferred to endoplasmic reticulum from micro-pipe, constitute the core of autophagosome.Then Atg5-Atg12 compounds with
And LC3 completes the extension of autophagic vacuole, ripe autophagic vacuole is combined completion degraded with lysosome.It is generally acknowledged that autophagy is cell pair
In the effecting reaction of environmental change, survival and death to cell play very important effect, current study show that autophagy with
There is substantial connection in various diseases of the mankind, especially malignant tumour.
Autophagy is not also fully aware of at present with the relation of death of neoplastic cells.There are some researches show autophagy is cell death
A kind of mode, it is similar to apoptosis, it is named as II type programmed cell death.Suppress the generation of autophagy by inducing cell apoptosis,
So as to suppress the generation of tumour.
Chloroquine is a kind of wide variety of anti-malaria medicaments, and research shows chloroquine by improving lysosome pH value, suppression
The fusion of autophagosome processed and lysosome and the degraded of autophagy lyase vivo protein, are a kind of autophagy inhibitors.Amaradi etc. sends out
Existing 5 μm of chloroquines of ol/L can suppress autophagy degradation mechanism, promote the apoptosis of tumor cells of p53 mediations
(J.Clin.Invest.2007,117:326-336);Maclean etc. thinks that the chloroquine (50 μm of ol/L) of high concentration can directly lead
Cause death of neoplastic cells (J Clin Invest, 2008,118:79-88);Chaachouay studies discovery 3-MA
The breast cancer cell MDA-MB-231 that (3-MA) and chloroquine suppress radioresistance can improve radiosusceptibility (Radiother
Oncol,2011,99:287-292).Chloroquine forms therapeutic alliance medicine with Treated with Chemotherapeutic Drugs as autophagy inhibitor, and
Into the clinical I/II experimental stages.
The content of the invention
In order to solve the above technical problems, deriving it is an object of the invention to provide a kind of benzo [e] [1,2,4] triazine -1- oxygen
Thing and combinations thereof and application, free radical active cell is produced using benzo [e] [1,2,4] triazine -1- oxides in the cell
Autophagy, suppresses with reference to chloroquine class autophagy inhibitor to cell autophagy signal path, so as to trigger Apoptosis, realizes killing
Tumour cell, the purpose for suppressing tumour growth.
On the one hand, the invention provides one kind as shown in formula (1) 3- [(7- chloroquinoline -4- amino) butylamine base] -7-
Substitution-benzo [e] [1,2,4] triazine -1- oxygen derivatives, its pharmaceutically acceptable salt, ester, solvate:
Wherein, R1Selected from hydrogen, hydroxyl, C1-C6Alkyl, fluorine, chlorine or bromine;
R2Selected from hydrogen, C1-C12Alkyl or hydroxyl;
R3Selected from hydrogen, C1-C12Alkyl or hydroxyl.
Further, in one embodiment, R1It is hydrogen, R2It is hydrogen, R3It is hydrogen, its structural formula is as follows:
Further, in another specific embodiment, R1It is methyl, R2It is hydrogen, R3It is hydrogen, its structural formula is as follows:
Further, in one embodiment, R1It is chlorine, R2It is hydrogen, R3It is hydrogen, its structural formula is as follows:
On the other hand, present invention also offers a kind of composition, including the 3- [(7- chloroquinoline -4- ammonia shown in formula (1)
Base) butylamine base] -7- substitution-benzos [e] [1,2,4] triazine -1- oxygen derivatives, its pharmaceutically acceptable salt, ester, solvent are closed
Thing and pharmaceutically acceptable auxiliary material:
Wherein, R1Selected from hydrogen, hydroxyl, C1-C6Alkyl, fluorine, chlorine or bromine;
R2Selected from hydrogen, C1-C12Alkyl or hydroxyl;
R3Selected from hydrogen, C1-C12Alkyl or hydroxyl.
Further, auxiliary material is starch, pregelatinized starch, dextrin, sucrose, dried starch, Sodium Hydroxymethyl Stalcs, low substitution hydroxyl
One or more in propyl cellulose, gas-producing disintegrant and PVPP.
It yet still another aspect, the present invention is also claimed a kind of 3- [(7- chloroquinoline -4- amino) butylamine base] -7- substitutions-benzene
And [e] [1,2,4] triazine -1- oxygen derivatives, its pharmaceutically acceptable salt, ester, solvate are preparing anti-tumor medicine
In application.
Further, tumour is solid tumor.
Further, tumour is non-small cell lung cancer, incidence cancer, liver cancer, prostate cancer, bone and soft tissue sarcoma, straight
Intestinal cancer, malignant mela noma, brain tumor, cancer of pancreas, cancer of the esophagus, colorectal cancer, breast cancer, the cancer of the uterus, oophoroma or main peritoneal cancer.
Further, the formulation of anti-tumor medicine be tablet, capsule, pill, suppository, aerosol, granule, dissipate
Agent, mixture, syrup, oral liquid, injection, syrup, vina, tincture, distillate medicinal water or film.
Further, the administering mode of anti-tumor medicine is oral, injection, implantation, external application, spraying or sucks.
The present invention, as parent molecule, benzo [e] [1,2,4] three is introduced in its branched fraction using autophagy inhibitor chloroquine
Piperazine -1- oxygen units.Benzo [e] [1,2,4] triazine -1- oxygen can produce hydroxyl radical free radical, hydroxyl in intracellular by cromoci reduction
The base freely further generation of inducing DNA chain fracture, so as to trigger cell autophagy;Due to the presence of chloroquine precursor structure, to thin
Born of the same parents' autophagy signal path is suppressed, and triggers Apoptosis, is realized killing tumour cell, is suppressed the purpose of tumour growth.
By such scheme, the present invention at least has advantages below:
Compared with the chloroquine class medicine used by current clinic, 3- [(7- chloroquinoline -4- amino) butylamine base] -7- of the invention
Substitution-benzo [e] [1,2,4] the triazine cytotoxicity of -1- oxygen derivative for A549 is bigger, can significantly more kill lung
Cancer cell;Cytotoxicity experiment result shows, in the case where parent compound is nontoxic to non-small cell lung cancer, chlorine of the invention
ID of the quinoline analog derivative to A549 cells50At 25 μM or so, and it is relatively small for normal cell toxicity;The acute and Asia of mouse
Acute experiment result shows that chloroquine analog derivative of the invention is acute for animal and long term toxicity is smaller.
Described above is only the general introduction of technical solution of the present invention, in order to better understand technological means of the invention,
And can be practiced according to the content of specification, below with presently preferred embodiments of the present invention and coordinate detailed description as after.
Description of reference numerals
Fig. 1 is cytotoxicity test result of the compound of the invention to Calu-1 cells;
Fig. 2 is cytotoxicity test result of the compound of the invention to Beas-2B cells;
Fig. 3 is cytotoxicity test result of the compound of the invention to A549 cells;
Fig. 4 is to carry out Acute toxicity experimental test result to mouse using compound 3;
Fig. 5 is that medicine subacute toxicity test test result is carried out to mouse using compound 3;
Fig. 6 is compound Westernblotting experimental results of the invention.
Specific embodiment
With reference to embodiment, specific embodiment of the invention is described in further detail.Following examples are used for
The present invention is illustrated, but is not limited to the scope of the present invention.
3- [(7- chloroquinoline -4- amino) butylamine base] -7- substitution-benzos [e] [1,2,4] triazine -1- oxygen of the invention spreads out
Biological synthetic route is as follows:
In above-mentioned preparation method, with 4,7- dichloroquinolines for raw material, reacted at high temperature with butanediamine derivatives reaction
Generation 4- (amine butyl) amido -7- chloroquines quinoline derivant (A);4- (amine butyl) amido -7- chloroquines quinoline derivant (A) is in triethylamine
In the presence of with product (I) needed for 7- substitution -3- chloro- 1,2,4- BTA -1- oxides reaction generations.
Preparation (the R of the 3- of embodiment 1 [(7- chloroquinoline -4- amino) butylamine base]-benzo [e] [1,2,4] triazine -1- oxygen1
=H)
Weigh (1g, 5.05mmol) 4,7- dichloroquinolines to be placed in 50mL there-necked flasks, add 1.74g's under argon gas protection
Butanediamine, heats 6-8h under the conditions of 110 DEG C, after completion of the reaction, is down to room temperature, adds dichloromethane, is spin-dried for solvent, Ran Houjia
Enter ethyl acetate, suction filtration obtains light yellow solid, column chromatography purifying, DCM:Me=20:1 obtains 1.13g compounds 4- (amine fourths
Base) amido -7- chloroquinolines, yield 86%.Its nuclear-magnetism test result is as follows:
1H NMR (400MHz, DMSO-d6) δ=8.40 (d, J=5.4Hz, 1H), 8.35 (d, J=9.0Hz, 1H), 7.78
(d, J=2.0Hz, 1H), 7.44 (dd, J=9.0,2.0Hz, 1H), 6.49 (d, J=5.4Hz, 1H), 3.30 (t, J=5.9Hz,
2H), 2.82 (t, J=6.8Hz, 2H), 1.70 (s, 4H).
Weigh the BTA -1- oxides of 3- chloro- 1,2,4- and (68mg, 0.275mmol) of (50mg, 0.275mmol)
Above-mentioned 4- (amine butyl) chloroquinoline of amido -7 be placed in the single port bottle of 50mL, add 10mL DME, and 0.5mL triethylamine,
5h is heated to reflux under the conditions of 80 DEG C.After completion of the reaction, be spin-dried for solvent, dichloromethane and with water extraction, saturated aqueous common salt washing,
Organic layer anhydrous sodium sulfate.After being spin-dried for, column chromatography purifying, PE:EA=5:1-2:1, obtain the 3- [(7- chloroquinoline -4- ammonia of 80mg
Base) butylamine base]-benzo [e] [1,2,4] triazine -1- oxygen (hereinafter referred to as compound 1), yield 78%.Its nuclear-magnetism and mass spectrometric measurement
Result is as follows:
1H NMR (400MHz, DMSO-d6) δ=9.58 (s, 1H), 8.67 (d, J=9.1Hz, 1H), 8.50 (d, J=
7.0Hz, 1H), 8.08 (dd, J=14.3,5.2Hz, 2H), 7.99 (s, 1H), 7.75 (t, J=7.2Hz, 1H), 7.68 (dd, J
=9.1,1.8Hz, 1H), 7.54-7.37 (m, 1H), 7.31 (t, J=7.5Hz, 1H), 6.87 (d, J=7.1Hz, 1H), 3.61-
3.53 (m, 2H), 3.40 (d, J=5.5Hz, 2H), 1.85-1.67 (m, 4H).
MS:[M+1]+:395.27 (100%).
The 3- of embodiment 2 [(7- chloroquinoline -4- amino) butylamine base] -7- methyl-benzo [e] [1,2,4] triazine -1- oxygen
Prepare (R1=CH3)
Weigh (1g, 5.05mmol) 4,7- dichloroquinolines to be placed in 50mL there-necked flasks, add 1.74g's under argon gas protection
Butanediamine, heats 6-8h under the conditions of 110 DEG C, after completion of the reaction, is down to room temperature, adds dichloromethane, is spin-dried for solvent, Ran Houjia
Enter ethyl acetate, suction filtration obtains light yellow solid, column chromatography purifying, DCM:Me=20:1 obtains 1.13g compounds 4- (amine fourths
Base) amido -7- chloroquinolines.
Weigh the chloro- 7- methyl isophthalic acids of 3-, 2,4- BTA -1- oxides (50mg, 0.275mmol) and above-mentioned 4- (amine fourths
Base) chloroquinoline of amido -7 (68mg, 0.275mmol) is placed in the single port bottle of 50mL, adds the DME of 10mL, and 0.5mL three second
Amine, 5h is heated to reflux under the conditions of 80 DEG C.After completion of the reaction, be spin-dried for solvent, dichloromethane and with water extraction, saturated aqueous common salt water
Wash, organic layer anhydrous sodium sulfate.After being spin-dried for, column chromatography purifying, PE:EA=5:1-2:1, obtain 80mg 3- [(7- chloroquinolines-
4- amino) butylamine base] -7- methyl-benzo [e] [1,2,4] triazine -1- oxygen (hereinafter referred to as compound 2), yield 79%.Its core
Magnetic and mass spectrometric measurement result are as follows:
1H NMR(400MHz,DMSO-d6) δ=8.43 (t, J=7.1Hz, 2H), 8.34 (s, 1H), 7.94-7.78 (m,
3H), 7.59 (d, J=8.5Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.42 (d, J=8.6Hz, 1H), 6.64 (d, J=
6.1Hz, 1H), 3.43 (d, J=5.8Hz, 1H), 3.39 (d, J=5.9Hz, 1H), 2.43 (s, 2H), 1.74 (s, 4H).13C
NMR(100MHz,DMSO-d6)δ159.16(s),152.74(s),148.28(s),145.00(s),138.08(s),135.65
(s),135.00(s),130.04(s),126.20(s),125.42(s),124.23(s),118.92(s),117.03(s),
99.04(s),45.75(s),42.85(s),34.16(s),31.74(s),26.41(s),25.53(s),21.15(s)。
MS:[M+1]+:409.27 (100%).
The system of the 3- of embodiment 3 [(7- chloroquinoline -4- amino) butylamine base] -7- chloro- benzo [e] [1,2,4] triazine -1- oxygen
Standby (R1=Cl)
Weigh (1g, 5.05mmol) 4,7- dichloroquinolines to be placed in 50mL there-necked flasks, add 1.74g's under argon gas protection
Butanediamine, heats 6-8h under the conditions of 110 DEG C, after completion of the reaction, is down to room temperature, adds dichloromethane, is spin-dried for solvent, Ran Houjia
Enter ethyl acetate, suction filtration obtains light yellow solid, column chromatography purifying, DCM:Me=20:1 obtains 1.13g compounds 4- (amine fourths
Base) amido -7- chloroquinolines.
Weigh 3,7- bis- chloro- 1,2,4- BTA -1- oxides (50mg, 0.275mmol) and above-mentioned 4- (amine butyl)
The chloroquinoline of amido -7 (68mg, 0.275mmol) is placed in the single port bottle of 50mL, add 10mL DME, and 0.5mL triethylamine,
5h is heated to reflux under the conditions of 80 DEG C.After completion of the reaction, be spin-dried for solvent, dichloromethane and with water extraction, saturated aqueous common salt washing,
Organic layer anhydrous sodium sulfate.After being spin-dried for, column chromatography purifying, PE:EA=5:1-2:1, obtain the 3- [(7- chloroquinoline -4- ammonia of 80mg
Base) butylamine base] -7- chloro- benzo [e] [1,2,4] triazine -1- oxygen (hereinafter referred to as compound 3), yield 73%.Its nuclear-magnetism and matter
Spectrum test result is as follows:
1H NMR(400MHz,DMSO-d6) δ=9.01 (s, 1H), 8.57 (d, J=9.1Hz, 1H), 8.47 (d, J=
6.7Hz, 1H), 8.12 (dd, J=9.4,2.3Hz, 2H), 7.98 (d, J=2.1Hz, 1H), 7.76 (dd, J=9.0,2.4Hz,
1H), 7.66 (dd, J=9.0,2.0Hz, 1H), 7.55 (d, J=9.0Hz, 1H), 6.75 (d, J=6.7Hz, 1H), 3.45 (d,
J=5.8Hz, 2H), 3.41 (d, J=5.9Hz, 2H), 2.43 (m, 2H), 1.74 (m, 2H).13C NMR(100MHz,DMSO-
d6)δ159.50(s),154.49(s),145.12(s),141.44(s),137.19(s),136.40(s),128.47(s),
126.40(s),126.07(s),121.33(s),119.39(s),116.36(s),98.91(s),45.71(s),42.65(s),
34.15(s),31.34(s),25.23(s),21.19(s)。
MS:[M+1]+:429.30 (100%).
Embodiment 4
3- [(7- chloroquinoline -4- amino) butylamine base]-benzo [e] [1,2,4] triazine -1- oxygen and the first of 2 equivalents of 1 equivalent
The aldehyde aqueous solution, in weakly alkaline environment, condensation turn into inferior amine salt, further with Pd/C hydrogen reducings can obtain corresponding R2,
R3 methyl products, its structural formula is as follows:
Wherein, R1It is hydrogen, R2It is methyl, R3It is methyl.
Embodiment 5
3- [(7- chloroquinoline -4- amino) butylamine base] -7- methyl-benzo [e] [1,2,4] triazine -1- oxygen and 2 of 1 equivalent
The formalin of equivalent, in weakly alkaline environment, condensation turns into inferior amine salt, is further obtained with Pd/C hydrogen reducings
Corresponding R2, R3 methyl product, its structural formula is as follows:
Wherein, R1It is methyl, R2It is methyl, R3It is methyl.
Embodiment 6
3- [(7- chloroquinoline -4- amino) butylamine base] the chloro- benzos of -7- [e] [1,2,4] triazine -1- oxygen of 1 equivalent and 2 is worked as
The formalin of amount, in weakly alkaline environment, condensation turns into inferior amine salt, is further obtained with phase with Pd/C hydrogen reducings
R2, R3 the methyl product answered, its structural formula are as follows:
Wherein, R1It is chlorine, R2It is methyl, R3It is methyl.
Embodiment 7
The compound 1 that is synthesized using embodiment 1-3 respectively, compound 2, compound 3 are thin to Calu-1, Beas-2B, A549
Born of the same parents carry out cytotoxicity test, as a result as Figure 1-3.Fig. 1 a are the cytotoxicity experiment of Calu-1, test result indicate that and
Blank control group is compared, and compound 1, compound 2, the cytotoxicity of compound 3 are significantly increased, and compound 3 cell toxicant
Property it is maximum;Fig. 1 b are the cytotoxicity experiment of Calu-1, test result indicate that under different drug concentrations, compound 3 it is thin
Cellular toxicity is significantly greater than compound 2.Ctrl represents blank control group in Fig. 1 a, and C represents clinical conventional chloroquine in figure.Fig. 2 a are
The toxicity test of Bease-2B cells, test result indicate that compared with blank control group, compound 1, compound 2, compound 3
Cytotoxicity is significantly increased, and the cytotoxicity of compound 3 is maximum;Fig. 2 b are the cytotoxicity experiment of Bease-2B, experiment
Result shows that under different drug concentrations the cytotoxicity of compound 3 is significantly greater than compound 2.Ctrl represents sky in Fig. 2 a
White control group, C represents clinical conventional chloroquine in figure.Fig. 3 a be A549 cytotoxicity experiments, test result indicate that with blank pair
Compared according to group, compound 1, compound 2, the cytotoxicity of compound 3 are significantly increased, and the cytotoxicity of compound 3 is maximum;
Fig. 3 b are the cytotoxicity experiment of A549, test result indicate that under different drug concentrations, the cytotoxicity of compound 3 is obvious
More than compound 2, Ctrl represents blank control group in Fig. 3 a, and C represents clinical conventional chloroquine in figure.It can be seen that
Compared with common clinical application chloroquine, 3- [(7- chloroquinoline -4- amino) butylamine base] -7- substitution-benzos [e] of the invention
[1,2,4] triazine -1- oxygen derivative all has very strong lethality for non-small cell lung cancer cell Calu-1 and A549, wherein
Compound 3 is maximum for the cytotoxicity of lung carcinoma cell.
Acute toxicity experiment is carried out using 3 pairs of males (♂) of chemical combination and female (♀) mouse, as a result as shown in Figure 4.Figure
Middle Ctrl (♀) represents female mice physiological saline negative control group, and DMSO (♂) represents male mice DMSO gavage groups in figure.From
In figure it can be seen that new chloroquine class medicine in compound 3 organ index of mouse can be made to reduce, but with physiological saline with
DMSO group mouse are compared, and the survival rate for mouse does not influence significantly, illustrate the medicine for mouse acute toxicity not
Greatly.
Subacute toxicity test is carried out to mouse using compound 3, compound 3 is various by gavage and tail vein injection
Method is processed mouse, as a result as shown in Figure 5.Result shows that compound 3 is little for the survival rate influence of mouse, explanation
The medicine does not have obvious long term toxicity for mouse.
The compound 1 that is synthesized using embodiment 1-3 respectively, compound 2, compound 3 carry out Western to mouse
Blotting is tested, as a result as shown in Figure 6.Ctrl groups are blank control group in Fig. 6, hungry+to change with larva starvation group as positive control
Compound 3 represents Nature enemy group+3- [(7- chloroquinoline -4- amino) butylamine base] -7- substitution-benzos [e] [1,2,4] triazine -1-
Oxygen derivative, A groups represent benzo [e] [1,2,4] triazine -1- oxides, and C groups represent chloroquine gavage group.Compared with chloroquine, 3-
[(7- chloroquinoline -4- amino) alkylamino radical] -7- substitution-benzos [e] [1,2,4] triazine -1- oxygen derivatives have substantially for autophagy
Inhibitory action.This medicine can in the cell produce free radical to swash by using benzo [e] [1,2,4] triazine -1- oxides
Living cells autophagy, the suppression with reference to chloroquine class autophagy inhibitor to cell autophagy path, inducing cell apoptosis are realized killing tumour
The purpose of cell, reaches the effect for suppressing tumour.
The above is only the preferred embodiment of the present invention, is not intended to limit the invention, it is noted that for this skill
For the those of ordinary skill in art field, on the premise of the technology of the present invention principle is not departed from, can also make it is some improvement and
Modification, these are improved and modification also should be regarded as protection scope of the present invention.
Claims (8)
1. 3- [(7- chloroquinoline -4- amino) butylamine base] -7- substitution-benzos [e] [1,2,4] triazine as shown in formula (1) of one kind -
1- oxygen derivatives, its pharmaceutically acceptable salt, ester, solvate:
Wherein, R1Selected from hydrogen, hydroxyl, C1-C6Alkyl, fluorine, chlorine or bromine;
R2Selected from hydrogen, C1-C12Alkyl or hydroxyl;
R3Selected from hydrogen, C1-C12Alkyl or hydroxyl.
2. a kind of composition, it is characterised in that:Taken including 3- [(7- chloroquinoline -4- amino) butylamine the base] -7- shown in formula (1)
Generation-benzo [e] [1,2,4] triazine -1- oxygen derivatives, its pharmaceutically acceptable salt, ester, solvate and pharmaceutically acceptable
Auxiliary material:
Wherein, R1Selected from hydrogen, hydroxyl, C1-C6Alkyl, fluorine, chlorine or bromine;
R2Selected from hydrogen, C1-C12Alkyl or hydroxyl;
R3Selected from hydrogen, C1-C12Alkyl or hydroxyl.
3. composition according to claim 2, it is characterised in that:The auxiliary material is starch, dextrin, sucrose, methylol shallow lake
One or more in powder sodium, low-substituted hydroxypropyl cellulose, gas-producing disintegrant and PVPP.
4. 3- [(7- chloroquinoline -4- amino) butylamine base] -7- substitution-benzos [e] [1,2,4] three according to claim 1
Piperazine -1- oxygen derivatives, the application of its pharmaceutically acceptable salt, ester, solvate in anti-tumor medicine is prepared.
5. application according to claim 4, it is characterised in that:Tumour is solid tumor.
6. application according to claim 5, it is characterised in that:Tumour is non-small cell lung cancer, incidence cancer, liver cancer, preceding
Row gland cancer, bone and soft tissue sarcoma, the carcinoma of the rectum, malignant mela noma, brain tumor, cancer of pancreas, cancer of the esophagus, colorectal cancer, breast cancer,
The cancer of the uterus, oophoroma or main peritoneal cancer.
7. application according to claim 4, it is characterised in that:The formulation of the anti-tumor medicine be tablet, capsule,
Pill, suppository, aerosol, granule, powder, mixture, syrup, oral liquid, injection, syrup, vina, tincture, distillate medicinal water or
Film.
8. application according to claim 4, it is characterised in that:The administering mode of the anti-tumor medicine is oral, note
Penetrate, be implanted into, external application, spraying or suction.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611260249.1A CN106831711B (en) | 2016-12-30 | 2016-12-30 | Benzo [ e ] [1,2,4] triazine-1-oxy derivatives, and compositions and uses thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611260249.1A CN106831711B (en) | 2016-12-30 | 2016-12-30 | Benzo [ e ] [1,2,4] triazine-1-oxy derivatives, and compositions and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106831711A true CN106831711A (en) | 2017-06-13 |
CN106831711B CN106831711B (en) | 2021-08-24 |
Family
ID=59115082
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201611260249.1A Active CN106831711B (en) | 2016-12-30 | 2016-12-30 | Benzo [ e ] [1,2,4] triazine-1-oxy derivatives, and compositions and uses thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106831711B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1237963A (en) * | 1996-09-25 | 1999-12-08 | 曾尼卡有限公司 | Qinoline derivatives inhibiting effect of growth factors such as VEGF |
WO2004026846A1 (en) * | 2002-09-17 | 2004-04-01 | Auckland Uniservices Limited | Dna-targeted benzotriazine 1,4-dioxides and their use in cancer therapy |
-
2016
- 2016-12-30 CN CN201611260249.1A patent/CN106831711B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1237963A (en) * | 1996-09-25 | 1999-12-08 | 曾尼卡有限公司 | Qinoline derivatives inhibiting effect of growth factors such as VEGF |
WO2004026846A1 (en) * | 2002-09-17 | 2004-04-01 | Auckland Uniservices Limited | Dna-targeted benzotriazine 1,4-dioxides and their use in cancer therapy |
Also Published As
Publication number | Publication date |
---|---|
CN106831711B (en) | 2021-08-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107213466B (en) | A kind of column aromatic hydrocarbons compound, preparation method, pharmaceutical composition and purposes | |
CN107721959B (en) | Myricetin derivative, its preparation method, and its application in treating colitis, preventing and treating colitis cancer transformation and treating colorectal cancer | |
CN104523664B (en) | Curcumin anti-tumor drug and its application | |
CN106749089A (en) | The preparation of new fluoro thiazole hydrazone compounds and its application in antineoplastic | |
CN104230952A (en) | Compound containing pyrimidine skeleton, and preparation method and use of compound | |
CN110041375A (en) | Compound, preparation method and its application in preparation of anti-tumor drugs with asymmetric monosubstituted naphthalimide tetravalence platinum structure | |
CN107334767B (en) | A kind of application of pyridazinone compound in oncotherapy | |
CN106083704A (en) | 3,5 (E) two aryl methylene N cyclopropyl piperidine 4 ketone compounds is as the application of Hsp90 inhibitor | |
CN106748939B (en) | A kind of novel bromine phenol thiosemicarbazide compound and its preparation and drug and purposes | |
CN104211661A (en) | Chalcone compound, preparation method and medicinal application thereof | |
CN108030777B (en) | Chloroguanide application in preparation of anti-tumor drugs | |
CN106831711A (en) | Oxygen derivative of benzo [e] [1,2,4] triazine 1 and combinations thereof and application | |
RO129522A0 (en) | N-()-1-methyl-1h-pyrazole-4-carboxamide derivatives as antitumour agents | |
CN111217825B (en) | 4-O-aminopropyl earth licorice A derivative and preparation and application thereof | |
CN103864776B (en) | A kind of Tegafur derivative containing 1,3,4-thiadiazoles heterocycle and amide group | |
CN111704634A (en) | Metal complex containing tridentate ligand and xanthine derivative ligand as well as preparation method and medical application of metal complex | |
CN104926804A (en) | Compounds with anti-tumor effect, and preparation method and application of compounds | |
CN115990162B (en) | Application of 4-hydroxy-2-pyridone alkaloid in preparation of medicines for treating gastric cancer | |
CN103880793B (en) | Containing furan imine compound and its production and use | |
CN103351383A (en) | 5-fluorouracil nitroxyl-free-radical anti-tumor drug | |
CN113069451B (en) | Preparation method of pyrrole-2-sulfonamide compound and application of pyrrole-2-sulfonamide compound in preparation of antitumor drugs | |
CN103772317B (en) | 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound and preparation method thereof and purposes | |
CN109846818B (en) | Injection of antineoplastic medicine with ubenimex structure and preparation method thereof | |
CN106866694B (en) | Oridonin Schiff base derivatives and its preparation method and application | |
CN101116664B (en) | Application of compound 1-( 4-chloroaniline )-4-( 4-picoline )-2, 3-naphthyridine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |