CN102702121B - Hydroxy phenyl tetrazine diformamide and Synthesis and applications between a kind of compound - Google Patents
Hydroxy phenyl tetrazine diformamide and Synthesis and applications between a kind of compound Download PDFInfo
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- CN102702121B CN102702121B CN201210100382.6A CN201210100382A CN102702121B CN 102702121 B CN102702121 B CN 102702121B CN 201210100382 A CN201210100382 A CN 201210100382A CN 102702121 B CN102702121 B CN 102702121B
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- dimethyl
- compound
- diformamide
- tetrazine
- hydroxy phenyl
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- 150000001875 compounds Chemical class 0.000 title abstract description 38
- CMLXNYZCFJJOCE-UHFFFAOYSA-N C(=O)N.C(=O)N.OC1=C(N=NN=N1)C1=CC=CC=C1 Chemical compound C(=O)N.C(=O)N.OC1=C(N=NN=N1)C1=CC=CC=C1 CMLXNYZCFJJOCE-UHFFFAOYSA-N 0.000 title description 5
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 206010000210 abortion Diseases 0.000 claims description 12
- 231100000176 abortion Toxicity 0.000 claims description 12
- 206010017758 gastric cancer Diseases 0.000 claims description 12
- 201000011549 stomach cancer Diseases 0.000 claims description 12
- 208000011580 syndromic disease Diseases 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 abstract description 32
- LKQNEFXKCOFFCO-UHFFFAOYSA-N 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine Chemical compound CC1NN=C(C)N=N1 LKQNEFXKCOFFCO-UHFFFAOYSA-N 0.000 abstract description 29
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 14
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 abstract description 13
- CKRZKMFTZCFYGB-UHFFFAOYSA-N N-phenylhydroxylamine Chemical class ONC1=CC=CC=C1 CKRZKMFTZCFYGB-UHFFFAOYSA-N 0.000 abstract description 13
- 201000005202 lung cancer Diseases 0.000 abstract description 13
- 208000020816 lung neoplasm Diseases 0.000 abstract description 13
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 abstract description 13
- 239000003054 catalyst Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 3
- 206010033128 Ovarian cancer Diseases 0.000 abstract description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 201000008275 breast carcinoma Diseases 0.000 abstract description 3
- 201000007270 liver cancer Diseases 0.000 abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 3
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- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 238000013461 design Methods 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000001514 detection method Methods 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 230000000259 anti-tumor effect Effects 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 230000000452 restraining effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- -1 1,2,4,5-tetrazine compound Chemical class 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- OVFJHQBWUUTRFT-UHFFFAOYSA-N 1,2,3,4-tetrahydrotetrazine Chemical compound C1=CNNNN1 OVFJHQBWUUTRFT-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000005907 cancer growth Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
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- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 206010057362 Underdose Diseases 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 235000021050 feed intake Nutrition 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- HTJMXYRLEDBSLT-UHFFFAOYSA-N 1,2,4,5-tetrazine Chemical compound C1=NN=CN=N1 HTJMXYRLEDBSLT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical class NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 1
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- PGLPNLGHVCQLRH-UHFFFAOYSA-N CN1N=CN=NC1C Chemical compound CN1N=CN=NC1C PGLPNLGHVCQLRH-UHFFFAOYSA-N 0.000 description 1
- 239000005654 Clofentezine Substances 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- UXADOQPNKNTIHB-UHFFFAOYSA-N clofentezine Chemical compound ClC1=CC=CC=C1C1=NN=C(C=2C(=CC=CC=2)Cl)N=N1 UXADOQPNKNTIHB-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of N as shown in formula I
1, N
4-two (3-hydroxy phenyls)-3, 6-dimethyl-1, 2, 4, 5-tetrazine-1, 4-diformamide compound and its production and use, the preparation of this compound is with 3, 6-dimethyl-1, 6-dihydro-1, 2, 4, 5-tetrazine, two (trichloromethyl) carbonic ether is raw material, under basic catalyst effect, in organic solvent and a hydroxyanilines carry out reaction and prepare, the compounds of this invention is applied to preparation treatment and prevention people cancer of the stomach, human ovarian cancer, people's liver cancer, human breast carcinoma or people's lung cancer disease medicament, the present invention is reasonable in design, preparation method is easy, easy handling, raw material is easy to get and production cost is lower, be suitable for industrial applications, screening for antitumor drug provides new kind,
Description
(1) technical field
The present invention relates to hydroxy phenyl tetrazine diformamide (i.e. N between a kind of new compound
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide) and preparation method thereof, and the application of described compound in the medicine of preparation prevention or treatment tumor disease.
(2) background technology
Tetrazine kind compound has many good physical propertiess, spectral quality and higher reactive behavior, and especially the tetrazine derivatives of some special constructions has obvious antiviral activity, anti-tumor activity, and can be used as agricultural chemicals and sterilant.Such as agricultural chemicals existing two kinds (clofentezine and fluorine mite piperazine) listing at present, an existing kind (antitumour drug Temozolomide) listing of medicine.
1978, bibliographical information 3,6-hexichol alkynyl-six hydrogen-1,2,4,5-tetrazine had anti-tumor activity and (consults Eremeev, A.V.; Tikhomirova, D.A.; Tyusheva, V.A.; Liepins, F.Khim.Geterotsikl.Soedin, 1978,753.), this is that 1,2,4,5-tetrazine kind compound is in the news first and may has potential anti-tumor activity.Afterwards, 1,2,4, the 5-tetrazine kind compound reporting some ad hoc structures successively has anti-tumor activity, and 3,6-two (2-hydroxyl-5-chloro-phenyl-)-1,2,4,5-tetrazines such as with anti-tumor activity (consult Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006,16 (14), 3702.), 1-isobutyryl-3,6-phenylbenzene-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine (consults Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2005,15 (12), 3714.) and N
1, N
4-two (aminomethyl phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (consult Hu, W.-X.; Rao, G.-W.; Sun, Y.-Q.Bioorg.Med.Chem.Lett.2004,14 (5), 1177.) etc., but great majority 1,2,4,5-tetrazine compound does not have anti-tumor activity.
(3) summary of the invention
The object of the present invention is to provide hydroxy phenyl tetrazine diformamide and preparation method thereof between a kind of new compound with antitumour activity, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide and preparation method thereof, the screening for antitumor drug provides new kind.This compound is under doses, have good inhibiting rate to human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, MCF-7 cell strainHJ2mm or human lung cancer cell lines A-549, it is to the IC of human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 five kinds of JEG-3
50be respectively 3.81 μMs, 6.56 μMs, 3.33 μMs, 7.96 μMs and 5.55 μMs.The present invention is reasonable in design, and preparation method is easy, easy handling, and raw material is easy to get and production cost is lower, is suitable for industrial applications.
The technical solution used in the present invention is as follows:
Hydroxy phenyl tetrazine diformamide between a kind of new compound provided by the invention, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide compound, it has having structure formula I:
N of the present invention
1, N
4-two (3-hydroxy phenyls)-3, 6-dimethyl-1, 2, 4, 5-tetrazine-1, the preparation method of 4-diformamide (I) is as follows: under-10 ~ 0 DEG C of condition, by 3 shown in formula II, 6-dimethyl-1, 6-dihydro-1, 2, 4, 5-tetrazine, two (trichloromethyl) carbonic ether (triphosgene, BTC), basic catalyst adds in organic solvent A, after adding, heating reflux reaction 4 ~ 12 hours, after reaction terminates, reaction solution is cooled to about 5 DEG C, normally cool to 4 ~ 6 DEG C, logical nitrogen, the solution of the organic solvent B of hydroxyanilines between dripping again, after dripping off, reflux 12 ~ 48 hours, react complete, after steaming desolventizes, residue recrystallization or column chromatography are obtained the N shown in formula I
1, N
4-two (3-hydroxy phenyls)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-diformamide compound, described basic catalyst is one of following: pyridine, triethylamine, quinoline, potassium hydroxide, sodium hydroxide, N, N-xylidene(s), DMAP or 4-pyrollidinopyridine,
Preparation N of the present invention
1, N
4-two (3-hydroxy phenyl)-3,6-the reaction of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I) as shown in following reaction formula:
The feed intake ratio of amount of substance of 3,6-dimethyl-1,6-dihydros-1,2,4,5-tetrazine (II) of the present invention and two (trichloromethyl) carbonic ether, basic catalyst, a hydroxyanilines is 1 ﹕ 0.67 ~ 2 ﹕ 0.1 ~ 1 ﹕ 2 ~ 6.The cumulative volume consumption of described organic solvent A and organic solvent B counts 13 ~ 75ml/g with 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine quality shown in formula II.
The present invention reacts organic solvent A used and organic solvent B and is independently selected from one of following separately: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or tetrahydrofuran (THF).
Concrete, the present invention prepares N
1, N
4-two (3-hydroxy phenyls)-3, 6-dimethyl-1, 2, 4, 5-tetrazine-1, the method of 4-diformamide (I) recommends to carry out as follows: to dissolve shown in formula II 3 by organic solvent A 1, 6-dimethyl-1, 6-dihydro-1, 2, 4, 5-tetrazine and basic catalyst, obtain containing 3, 6-dimethyl-1, 6-dihydro-1, 2, 4, the solution of 5-tetrazine and basic catalyst, two (trichloromethyl) carbonic ether and organic solvent A 2 are placed in reactor, stir at-10 ~ 0 DEG C, described in slow dropping containing 3, 6-dimethyl-1, 6-dihydro-1, 2, 4, the solution of 5-tetrazine and basic catalyst, 10 ~ 80min feeds in raw material complete, reflux 4 ~ 12 hours, TLC tracing detection, after reaction terminates, reaction solution is cooled to about 5 DEG C, normally drop to 4 ~ 6 DEG C, logical nitrogen, between dripping, hydroxyanilines is dissolved in the solution of organic solvent B again, after dripping off, reflux 12 ~ 48 hours, TLC tracing detection, react complete, after steaming desolventizes, residue recrystallization or column chromatography are obtained the N shown in formula I
1, N
4-two (3-hydroxy phenyls)-3, 6-dimethyl-1, 2, 4, 5-tetrazine-1, 4-diformamide compound, described basic catalyst is one of following: pyridine, triethylamine, quinoline, potassium hydroxide, sodium hydroxide, N, N-xylidene(s), DMAP or 4-pyrollidinopyridine, described organic solvent A 1 is identical organic solvent with organic solvent A 2, organic solvent B and organic solvent A 1 are identical or different organic solvent, organic solvent A 1, organic solvent A 2 is unified be selected from one of following: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or tetrahydrofuran (THF), described organic solvent B is selected from one of following: methylene dichloride, chloroform, toluene, methyl alcohol, ethanol or tetrahydrofuran (THF), the cumulative volume consumption of described organic solvent A 1 and organic solvent A 2 counts 10 ~ 50ml/g with 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine quality shown in formula II, the volumetric usage of described organic solvent B is with shown in formula II 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine quality counts 3 ~ 25ml/g, described organic solvent A 1 consumption is dissolving 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine and basic catalyst, 3,6-described dimethyl-1,6-dihydro-1, the feed intake ratio of amount of substance of 2,4,5-tetrazine (II) and two (trichloromethyl) carbonic ether, basic catalyst, 2-hydroxyanilines is 1 ﹕ 0.67 ~ 2 ﹕ 0.1 ~ 1 ﹕ 2 ~ 6.
Residue recrystallization described in method of the present invention carries out as follows: get and steam the residue after desolventizing in reaction flask, add recrystallization solvent, stirring heating, reflux 5 ~ 10 minutes, filtered while hot removing insolubles, filtrate cools, and separates out solid, refilter, filter cake is dried and is obtained the N shown in formula I
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide compound; Described recrystallization solvent is one of following: methyl alcohol, ethanol, sherwood oil, ethyl acetate, methylene dichloride, chloroform or tetrahydrofuran (THF), is preferably methyl alcohol, ethanol, ethyl acetate, methylene dichloride or tetrahydrofuran (THF).
Residue column chromatography described in method of the present invention carries out as follows: get and steam the residue after desolventizing in single port bottle, add organic solvent C to be dissolved, obtain lysate, then in lysate, add the column chromatography silica gel of 1.5 ~ 2 times amount of residue quality, after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then be that the sherwood oil of 0.5 ~ 10:1 and ethyl acetate mixture are for eluent with volume ratio, directly carry out wash-out, TLC tracing detection, the elutriant collected containing the compound shown in formula I is detected according to TLC, collection liquid is dry, obtain the N shown in formula I
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide compound, described organic solvent C is one of following: methyl alcohol, ethanol, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO).
Organic solvent A of the present invention (organic solvent A 1 and organic solvent A 2), organic solvent B, the represented organic solvent all referred to for reacting, here letter does not refer in particular to the implication of certain some organic solvent, letter is just answered clear for the ease of table, is used for distinguishing these organic solvents and appears in different reactions steps.
N of the present invention
1, N
4-two (3-hydroxy phenyls)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-diformamide (I) can be applicable to the medicine preparing prevention or treatment tumor disease, the application particularly in the medicine preparing prevention or treatment people cancer of the stomach, human ovarian cancer, people's liver cancer, human breast carcinoma or people's lung cancer disease.
Compound provided by the invention is under doses, have good inhibiting rate to human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, MCF-7 cell strainHJ2mm or human lung cancer cell lines A-549, described compound is to the IC of human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 five kinds of JEG-3
50be respectively 3.81 μMs, 6.56 μMs, 3.33 μMs, 7.96 μMs and 5.55 μMs, and with the compounds of this invention similar not necessarily there is antitumour activity with other amine for compound that substrate synthesizes or antitumour activity is lower.
Beneficial effect of the present invention is mainly reflected in: (1) the invention provides a kind of tetrazine compound of antitumour activity that is novel, that had, the N namely shown in formula I
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide compound; For the screening of cancer drug provides new variety; (2) the invention provides the preparation method of this tetrazine compound, this preparation method is simple, easy handling, and raw material is easy to get and production cost is lower, is suitable for practicality, is expected to be applied in the medicine of preparation prevention or treatment tumor disease.
(4) accompanying drawing explanation
Compound N in Fig. 1 embodiment 9
1, N
4-two (4-ethoxyl phenenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (III), N
1, N
4-dimethyl-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (IV), N
1, N
4-two (4-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (V), N
1, N
4-di-sec-butyl-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (VI) and N
1, N
4the chemosynthesis reaction schema of-di-t-butyl-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (VII).
(5) embodiment
The present invention is further described in conjunction with specific embodiments, and following embodiment illustrates of the present invention, instead of limits the present invention by any way.
3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) prepare reference literature (Sun, Y.Q.; Hu, W.X.; Yuan, Q.Synth.Commun.2003,33,2769.) method prepares.
Embodiment 1:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 2.16 grams of (17.8mmol) N, N-xylidene(s) is dissolved in 50 milliliters of dichloromethane solutions makes solutions preparatory (namely containing 3,6-dimethyl-1,6-dihydro-1,2, the solution of 4,5-tetrazine and basic catalyst), add two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and methylene dichloride 20 milliliters in 250 milliliters of there-necked flasks successively, stir at 0 DEG C, slowly drip solutions preparatory.After adding in 10min, TLC tracing detection, back flow reaction 4 hours.Then be cooled to 5 DEG C, logical nitrogen, then drip hydroxyanilines between 3.90 grams (35.7mmol) and be dissolved in the solution that 20 milliliters of methylene dichloride obtain.After dripping off, TLC tracing detection, reflux 48 hours, steam except methylene dichloride, residue column chromatography, namely get and steam the residue after desolventizing and add 20 ml methanol solvents and dissolved, obtain lysate, then in lysate, add 2.2 grams of silica gel (300 ~ 400 order gross porosity (zcx.II) type column chromatography silica gel), after mixing, steaming desolventizes, obtain the mixture of dry residue and silica gel, mixture is filled post, then with the sherwood oil of volume ratio 1:2 and ethyl acetate mixture for eluent, wash-out, TLC tracing detection, the elutriant collected containing the compound shown in formula I is detected according to TLC, collection liquid is dry, obtain white solid 0.42 gram, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-diformamide (I), yield 6.2% is (with formula II 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine amount of substance meter, lower same), fusing point 236 ~ 238 DEG C.
1HNMR(500MHz,CDCl
3)δ:2.40(s,6H,CH
3),6.48-6.50(m,2H,C
6H
4),6.97-6.99(m,2H,C
6H
4),7.09(t,2H,J＝8.0Hz,C
6H
4),7.17(t,2H,J＝2.3Hz,C
6H
4),9.14(s,2H),9.40(s,2H)。
Embodiment 2:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.98 gram of (12.4mmol) pyridine are dissolved in 10 ml methanol makes solutions preparatory, adds two (trichloromethyl) carbonic ether 3.54 grams (11.9mmol) and methyl alcohol 10 milliliters in 50 milliliters of there-necked flasks successively, stir at-5 DEG C, slowly drip solutions preparatory.After adding in 10min, TLC tracing detection, back flow reaction 10 hours.Then be cooled to 6 DEG C, logical nitrogen, then drip hydroxyanilines between 5.84 grams (53.5mmol) and be dissolved in the solution that 6 milliliters of ethanol obtain.After dripping off, TLC tracing detection, reflux 27 hours, steam except methyl alcohol and ethanol, residue adds 20 milliliters of chloroforms, stirring heating, backflow 5 ~ 10min, filtered while hot removing insolubles, filtrate cools, and separates out solid, filter, filter cake 50 DEG C oven dry, obtains white solid 2.05 grams, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 30.1%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 3:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.91 gram of (7.4mmol) DMAP are dissolved in 40 milliliters of chloroformic solutions makes solutions preparatory, adds two (trichloromethyl) carbonic ether 4.30 grams (14.5mmol) and chloroform 20 milliliters in 100 milliliters of there-necked flasks successively, stir at-10 DEG C, slowly drip solutions preparatory.After adding in 40min, TLC tracing detection, back flow reaction 8 hours.Then be cooled to 6 DEG C, logical nitrogen, then drip hydroxyanilines between 7.77 grams (71.2mmol) and be dissolved in the solution that 10 milliliters of chloroforms obtain.After dripping off, TLC tracing detection, reflux 12 hours, steams except chloroform, residue 20 milliliters of ethyl alcohol recrystallizations, and other operations, with embodiment 2, obtain white solid 0.70 gram, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 10.3%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 4:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 1.75 grams of (13.5mmol) quinoline are dissolved in 40 milliliters of tetrahydrofuran solutions makes solutions preparatory, adds two (trichloromethyl) carbonic ether 9.06 grams (30.5mmol) and tetrahydrofuran (THF) 30 milliliters in 250 milliliters of there-necked flasks successively, stir at-8 DEG C, slowly drip solutions preparatory.After adding in 30min, TLC tracing detection, back flow reaction 12 hours.Then be cooled to 4 DEG C, logical nitrogen, then drip hydroxyanilines between 9.72 grams (89.1mmol) and be dissolved in the solution that 30 milliliters of chloroforms obtain.After dripping off, TLC tracing detection, reflux 28 hours, steams except tetrahydrofuran (THF) and chloroform, residue 20 milliliters of re-crystallizing in ethyl acetate, and other operations, with embodiment 2, obtain white solid 1.07 grams, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 15.7%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 5:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 1.60 grams of (10.8mmol) 4-pyrollidinopyridine are dissolved in 80 milliliters of ethanolic solns makes solutions preparatory, adds two (trichloromethyl) carbonic ether 8.00 grams (27.0mmol) and ethanol 20 milliliters in 250 milliliters of there-necked flasks successively, stir at 0 DEG C, slowly drip solutions preparatory.After adding in 80min, TLC tracing detection, back flow reaction 6 hours.Then be cooled to 5 DEG C, logical nitrogen, then drip hydroxyanilines between 11.67 grams (106.9mmol) and be dissolved in the solution that 40 milliliters of ethanol obtain.After dripping off, TLC tracing detection, reflux 36 hours, steams except ethanol, residue 20 milliliters of tetrahydrofuran (THF) recrystallizations, and other operations, with embodiment 2, obtain white solid 1.35 grams, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I).Yield 19.8%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 6:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.18 gram of (1.78mmol) triethylamine are dissolved in 50 milliliters of toluene solutions makes solutions preparatory, adds two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and toluene 50 milliliters in 250 milliliters of there-necked flasks successively, stir at-10 DEG C, slowly drip solutions preparatory.After adding in 70min, TLC tracing detection, back flow reaction 12 hours.Then be cooled to 5 DEG C, logical nitrogen, then drip hydroxyanilines between 5.84 grams (53.5mmol) and be dissolved in the solution that 50 milliliters of toluene obtain.After dripping off, TLC tracing detection, reflux 18 hours, steams except toluene, residue 20 milliliters of methylene dichloride recrystallizations, and other operations, with embodiment 2, obtain the white solid shown in formula I 0.82 gram, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 12.0%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 7:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.36 gram of (9.0mmol) sodium hydroxide are dissolved in 50 milliliters of toluene solutions makes solutions preparatory, adds two (trichloromethyl) carbonic ether 10.60 grams (35.7mmol) and toluene 50 milliliters in 250 milliliters of there-necked flasks successively, stir at-10 DEG C, slowly drip solutions preparatory.After adding in 70min, TLC tracing detection, back flow reaction 12 hours.Then be cooled to 5 DEG C, logical nitrogen, then drip hydroxyanilines between 5.84 grams (53.5mmol) and be dissolved in the solution that 50 milliliters of toluene obtain.After dripping off, TLC tracing detection, reflux 18 hours, steams except toluene, residue 20 ml methanol recrystallizations, and other operations, with embodiment 2, obtain the white solid shown in formula I 1.22 grams, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 17.9%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 8:N
1, N
4-two (3-hydroxy phenyl)-3,6-preparation of dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I)
By 2.00 grams of (17.8mmol) 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.20 gram of (3.6mmol) potassium hydroxide are dissolved in 40 milliliters of tetrahydrofuran solutions makes solutions preparatory, adds two (trichloromethyl) carbonic ether 9.06 grams (30.5mmol) and tetrahydrofuran (THF) 30 milliliters in 250 milliliters of there-necked flasks successively, stir at-8 DEG C, slowly drip solutions preparatory.After adding in 30min, TLC tracing detection, back flow reaction 12 hours.Then be cooled to 4 DEG C, logical nitrogen, then drip hydroxyanilines between 9.72 grams (89.1mmol) and be dissolved in the solution that 30 milliliters of chloroforms obtain.After dripping off, TLC tracing detection, reflux 29 hours, steam except tetrahydrofuran (THF) and chloroform, residue column chromatography (eluent is sherwood oil: ethyl acetate=10:1 (volume ratio)), residue 20 milliliters of methylene dichloride dissolve, and other operations are with embodiment 1, obtain white solid 1.87 grams, i.e. N
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (I), yield 27.4%, fusing point 236 ~ 238 DEG C.
1hNMR is with embodiment 1.
Embodiment 9: antitumour activity vitro test
1) compound (I) obtained for embodiment 1 people's cancer of the stomach, human ovarian cancer, people's liver cancer, human breast carcinoma and human lung carcinoma cell line biological activity test have been carried out.Result display compound (I) all has significant antitumour activity to human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, MCF-7 cell strainHJ2mm or human lung cancer cell lines A-549.
Testing method: Sulforhodamine B (sulforhodamineB, SRB) protein staining method
Cell strain: human stomach cancer cell line SGC-7901, abortion syndrome HO-8910 and HepG2 cell lines
Action time: 72 hours
Testing method: tetrazolium (Methyl-Thiazol-Tetrozolium, MTT) reduction method
Cell strain: MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549
Action time: 72 hours
Compound (I) obtained for embodiment 1 DMSO (dimethyl sulfoxide (DMSO)) is dissolved (consumption of DMSO with can dissolved compound) configuration concentrated solution, then by concentrated solution substratum (the RPMI-1640 substratum of Gibco company production or DMEM substratum; The preparation of substratum: containing 800,000 units of Penicillin in every 1000mL substratum, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum) be diluted to working concentration (as 10
-5, 5 × 10
-6, 2.5 × 10
-6, 1.25 × 10
-6, 6.25 × 10
-7, 10
-4, 10
-6, 10
-7with 10
-8molL
-1; 50 μ g/mL, 5 μ g/mL, 0.5 μ g/mL and 0.05 μ g/mL), then respectively antitumour activity test is carried out to human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549.The result of test is as shown in following table 1, table 2 and table 3:
Table 1 compound (I) is to the restraining effect of SGC-7901 and HO-8910 growth of cancer cells
Table 2 compound (I) is to the restraining effect of HepG2 growth of cancer cells
Table 3 compound (I) is to the restraining effect of MCF-7 and A-549 growth of cancer cells
2) according to embodiment 1, between inciting somebody to action, hydroxyanilines replaces by 4-phenetidine, methylamine, 4-hydroxyanilines, sec-butylamine or TERTIARY BUTYL AMINE respectively, and other operations, with embodiment 1, have synthesized compound N respectively
1, N
4-two (4-ethoxyl phenenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (III), N
1, N
4-dimethyl-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (IV), N
1, N
4-two (4-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (V), N
1, N
4-di-sec-butyl-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (VI) and N
1, N
4-di-t-butyl-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide (VII), building-up reactions as shown in Figure 1.
According to aforesaid method, obtained compound (III) and (IV) MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 biological activity test are carried out, result show compound (III) and (IV) to MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 inhibition very poor, its antitumour activity can not show a candle to compound (I).Concrete outcome is as shown in table 4 below:
Table 4 compound (III) and (IV) are to the restraining effect of MCF-7 and A-549 growth of cancer cells
According to aforesaid method, obtained compound (V), (VI) and (VII) human stomach cancer cell line SGC-7901 and abortion syndrome HO-8910 biological activity test are carried out, result shows that compound (V), (VI) and (VII) inhibition to human stomach cancer cell line SGC-7901 and abortion syndrome HO-8910 are very poor, and its antitumour activity can not show a candle to compound (I).Concrete outcome is as shown in table 5 below:
Table 5 compound (V), (VI) and (VII) are to the restraining effect of SGC-7901 and HO-8910 growth of cancer cells
Above-mentioned experiment shows: compound (I) is to human stomach cancer cell line SGC-7901, abortion syndrome HO-8910, HepG2 cell lines, the restraining effect of MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 growth is remarkable, and restraining effect that the compound of other 2 similar (III) and (IV) grow MCF-7 cell strainHJ2mm and human lung cancer cell lines A-549 is all not obvious, the compound (V) of 3 similar, (VI) and (VII) restraining effect that human stomach cancer cell line SGC-7901 and abortion syndrome HO-8910 are grown all not obvious.
Claims (2)
1. the N as shown in formula I
1, N
4-two (3-hydroxy phenyl)-3,6-dimethyl-1,2,4,5-tetrazines-Isosorbide-5-Nitrae-diformamide compound:
2. a N according to claim 1
1, N
4-two (3-hydroxy phenyls)-3,6-dimethyl-1,2,4,5-tetrazine-1, the application of 4-diformamide (I) in the medicine of preparation prevention or treatment tumor disease, is characterized in that the JEG-3 of described tumour is one of following: human stomach cancer cell line SGC-7901 or abortion syndrome HO-8910.
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| CN105949139B (en) * | 2016-05-06 | 2018-01-16 | 浙江工业大学 | A kind of sec-butyl diphenyl tetrazine benzamide compound and preparation and application |
| CN105949140B (en) * | 2016-05-06 | 2019-05-31 | 浙江工业大学 | A kind of diphenyl tetrazine diformamide compound and preparation and application |
| CN105968063B (en) * | 2016-05-06 | 2019-02-01 | 浙江工业大学 | A kind of di-sec-butyl diphenyl tetrazine diformamide compound and preparation and application |
| CN105968064B (en) * | 2016-05-06 | 2019-02-01 | 浙江工业大学 | Two tolyl tetrazine diformamide compounds of one kind and preparation and application |
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