CN1563023A - 3,6-bi(2'-hydroxy-5'-chlorphenyl)-S-tetrazine and accessory ingredient of transition metal, preparation and application - Google Patents
3,6-bi(2'-hydroxy-5'-chlorphenyl)-S-tetrazine and accessory ingredient of transition metal, preparation and application Download PDFInfo
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- CN1563023A CN1563023A CN 200410017445 CN200410017445A CN1563023A CN 1563023 A CN1563023 A CN 1563023A CN 200410017445 CN200410017445 CN 200410017445 CN 200410017445 A CN200410017445 A CN 200410017445A CN 1563023 A CN1563023 A CN 1563023A
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- 229910052723 transition metal Inorganic materials 0.000 title claims abstract description 41
- 150000003624 transition metals Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 15
- 239000004615 ingredient Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 103
- 239000000243 solution Substances 0.000 claims description 45
- 235000019441 ethanol Nutrition 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- -1 3 Chemical class 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000005406 washing Methods 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 229960000583 acetic acid Drugs 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 13
- OVFJHQBWUUTRFT-UHFFFAOYSA-N 1,2,3,4-tetrahydrotetrazine Chemical compound C1=CNNNN1 OVFJHQBWUUTRFT-UHFFFAOYSA-N 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 13
- 239000012362 glacial acetic acid Substances 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 7
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000013019 agitation Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000011010 flushing procedure Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000001093 anti-cancer Effects 0.000 abstract 2
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 238000003556 assay Methods 0.000 description 4
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 4
- 238000011275 oncology therapy Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 150000004905 tetrazines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- 150000000644 6-membered heterocyclic compounds Chemical class 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000008645 Joubert syndrome Diseases 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- HIPRDHDOPNHLNS-UHFFFAOYSA-N [Co+5] Chemical compound [Co+5] HIPRDHDOPNHLNS-UHFFFAOYSA-N 0.000 description 1
- NKIJNBRECMJRCM-UHFFFAOYSA-N [Ni+5] Chemical compound [Ni+5] NKIJNBRECMJRCM-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- CYCSEDRJRMCANL-UHFFFAOYSA-N iron(5+) Chemical compound [Fe+5] CYCSEDRJRMCANL-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 239000002760 rocket fuel Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention relates to a novel anti-cancer drug-3,6-di(2-hydroxy-5-chlorophenyl)-5-tetrazine and transtion metal coordination compound, its prepn. method, and its application. Experiment shows that, this coordination compound of said terazine and transition metal has obvious anti-cancer activity. This invention prepn. of coordination compound is of simple process. This invention can help to select new medicines.
Description
(1) technical field
The present invention relates to a kind of anticarcinogen 3, the title complex and the manufacture method thereof of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal, with and application in preparing cancer therapy drug.
(2) background technology
Tetrazine is the 6-membered heterocyclic compound that a class contains four nitrogen-atoms, and the S-tetrazine is the most stable in 3 kinds of isomerss.Germanization scholar Hantgsch had at first synthesized the S-tetrazine in 1900, and people find the S-tetrazine successively after the seventies in 20th century, although be aromatic hydrocarbons, (4+2) cycloaddition reaction can take place; The tetrazine derivatives of some special constructions has tangible antiviral activity, anti-tumor activity and can be as agricultural chemical insecticide, liquid crystal material and rocket fuel etc., thereby has caused people's extensive interest.
In the tetrazine analog derivative, filtered out some materials at present and had anti-tumor activity, N for example, N '-phenylbenzene-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-diformamide; 3, two (3-picoline-2 bases)-1,2,4 of 6-, the title complex of 5-tetrazine and transition metal, or the like.The S-tetrazine derivatives that contains the different structure of different substituents should have different biological activitys, screening by the tetrazine analog derivative, be expected to filter out the cancer therapy drug of high-efficiency low-toxicity, this will have very significant meaning, also will cause increasing scientific worker's concern.
(3) summary of the invention
The object of the invention provides a kind of new S-tetrazine kind anti-cancer drugs thing, and promptly 3, title complex of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal and preparation method thereof, and the application of this title complex in preparing cancer therapy drug.
For reaching the goal of the invention the technical solution adopted in the present invention be:
A kind of 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, described title complex has following general formula (I):
Wherein M is a transition-metal Fe
2+, Fe
3+, Co
2+, Ni
2+, Cu
2+, Pt
2+In a kind of, L is inorganic part Cl
-, Br
-, Ac
-, I
-, NO
3 -, SO
4 2-In a kind of, R is H or lone electron, x, y, z respectively are 1～5 number, a, b, c respectively are 0～10 number.
Preferably, described transition metal is Fe
3+, Co
2+, Ni
2+, Cu
2+In a kind of, described inorganic part is Cl
-, NO
3 -, Ac
-In a kind of.
A kind of preparation is described 3, the method for two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-, described method be with salicylic aldehyde and hydrazine hydrate in ethanolic soln, react the compound formula (II) that makes: 2,2 '-dihydroxy-benzene azine,
Reaction formula is shown in (A):
Compound formula (II) feeds chlorine and makes compound formula (III): α in Glacial acetic acid/acid anhydrides solvent, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-,
Reaction formula is shown in (B):
Compound (III) in ethanolic soln with hydrazine hydrate reacting generating compound formula (IV): 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine,
Reaction formula is shown in (C):
Compound (IV) is oxidized to the compound formula V with nitrous acid: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, 5-tetrazine.
Described nitrous acid is made by Sodium Nitrite and acetic acid reaction.
Reaction formula is shown in (D):
A kind of preparation is described 3, and the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal makes compound (IV) by preceding method: 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4,5-tetrazine, the salt M of compound (IV) and transition metal
eL
fCompound formula (I) is made in reaction in alcohol solvent: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal, wherein e, f respectively are 1～5 number.
Reaction formula is shown in (E):
Concrete, described method is carried out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-dihydroxy-benzene azine (II);
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, down feeds chlorine about 1 hour at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and in 10～20 ℃ of following chlorine 1.5～2 hours, with TLC point plate, observes the raw material spot and disappears and end, and stops logical chlorine, and placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines (III) of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4,5-tetrazine (IV);
(4) at normal temperatures, with 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV) are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF)
eL
fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number; Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour, with the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal.
A kind of preparation is described 3, and the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal makes compound (V) 3 by preceding method, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, the 5-tetrazine, the salt M of compound (V) and transition metal
eL
fCompound formula (I) is made in reaction in alcohol solvent: 3, and the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, wherein e, f respectively are 1～5 number.
Reaction formula is shown in (F):
Concrete, described method is carried out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-the dihydroxy-benzene azine;
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, feeds chlorine about 1 hour down at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and logical chlorine is 1.5～2 hours under 10～20 ℃; With TLC point plate, observe the raw material spot and only disappear, stop logical chlorine, placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine;
(4) compound (IV) and sodium nitrite in aqueous solution stir into suspension, add acetic acid, and in stirring at room 3 hours, solid filtering, washing obtained red crystals 3 with ethyl alcohol recrystallization, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-s-tetrazines (V) of 6-again;
(5) at normal temperatures, with 3, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines (V) of 6-are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF)
eL
fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number.Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour; With the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal.
Described 3, the title complex of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal is treated application in the medicine of leukemia, lung cancer or other tumour in preparation.
Of the present invention 3, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-are mainly reflected in the title complex of transition metal and the beneficial effect of preparation and application: (1) provides a kind of cancer therapy drug newly, that obvious antitumour activity is arranged; (2) preparation flow is simple, for new medicament screen provides the research basis.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment:
Embodiment 1: preparation 2,2 '-dihydroxy-benzene azine (II)
2.4g NH (85%)
2NH
2H
2The O aqueous solution (0.04mol) joins in the 24ml water, adds 5ml ethanol, stirs evenly into solution A, 9.8g salicylic aldehyde (0.08mol) is dissolved in the 4ml ethanol become solution B.B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours.Add 20ml water, suction filtration, with big water gaging flushing after drying get 2,2 '-dihydroxy-benzene azine 9.1 restrains, productive rate 95%, m.p.214～216 ℃.
Embodiment 2: preparation α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines (III) of α '-two chloro-
With 5.5g2,2 '-dihydroxy-benzene azine (0.023mol), be added in the mixed solution of 40ml Glacial acetic acid and 4.5ml acetic anhydride.Stirring makes suspension preferably.Fed chlorine about 1 hour down at 10～20 ℃, solution retrogradation this moment, but solid does not disappear.Add 40ml Glacial acetic acid and 4.5ml aceticanhydride.In 10～20 ℃ of following chlorine 1.5～2 hours.With TLC point plate, observe the raw material spot and only disappear, stop logical chlorine, placement is spent the night.Suction filtration, solid washing with alcohol, dry α, two (2 '-hydroxyl-5 '-chloro-phenyl-)-azines 5 grams of α '-two chloro-, yield 58%, m.p.175～178 ℃.
Embodiment 3: preparation 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV)
(3.8 grams 0.01mol) are dissolved in (20ml) in the ethanol, are heated to backflow, and (0.8 restrains, 0.012mol) to drip 80% hydrazine hydrate with III.Back flow reaction 45 minutes again after adding.Cool to room temperature with the solid filtering of separating out, is used washing with alcohol, dries to such an extent that yellow solid IV1.2 restrains yield 35%, m.p.250 ℃ (dec.).
Embodiment 4: preparation 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, 5-tetrazine (V)
(3.37 grams 0.01mol) add 25ml 10% sodium nitrite in aqueous solution (0.036mol) and stir into suspension compound IV, add 15ml acetic acid, again in stirring at room 3 hours.Solid filtering, washing obtain red crystals 1.1 grams with ethyl alcohol recrystallization.Yield 33%, m.p.238.5～240.5 ℃.IR(KBr)3443，3126，1613，1569，1477，1417，1303，1224，1140，1088，1046，941，898cm
-1；NMR(CDCl
3)：δ7.1(d，2H，Ar-H)，7.5(d，2H，Ar-H)，8.6(s，2H，Ar-H)，10.8(s，2H，OH)；M/Z(％)：334(M
+，7.55)，153(100.00)，125(56.36)，98(21.06)，63(61.50)。
Embodiment 5:3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the complex compound of 2-dihydro-S-tetrazine IV and transition metal.
At normal temperatures, with 0.5 gram 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV) are dissolved in and become solution A, 1.0g nickelous nitrate (Ni (NO in the 30ml tetrahydrofuran (THF) (THF)
3)
2) be dissolved in the 30ml ethanol and become solution B.Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour.With the solid filtering that generates, the washing of ethanol/water mixed solution obtains nickel-IV complex compound (VI).
CoCl is used in same operation
2Solution obtains cobalt-IV complex compound (VII);
Same operation is with Ni (OAc)
2Solution obtains nickel-IV complex compound (VIII);
Complex compound VI, VII, VIII molecular conductivity (s) and results of elemental analyses are as follows:
| Complex compound | Molecular formula | Molecular conductivity S.cm 2.mol -1 | Ultimate analysis (%) experimental value/calculated value | ||
| ????C | ????H | ????N | |||
| VI | Ni(NO 3) 2·IV 2·THF·1.5EtOH | ????33 | ????42.09/42.11 | ????3.12/3.74 | ????14.07/14.03 |
| VII | Co 2Cl·IV·EtOH·7H 2O | ????150 | ????25.13/24.99 | ????3.8/3.94 | ????7.23/7.29 |
| VIII | Ni(AcO) 2IV 2·4H 2O | ????43 | ????38.83/39.00 | ????3.13/3.72 | ????12.10/12.14 |
Embodiment 6:3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, the complex compound of 5-tetrazine (V) and transition metal
0.5 gram V is suspended in 1: 1 the ethanol/water mixture solution of 30ml.Slowly the aqueous sodium hydroxide solution of Dropwise 5 % to solid dissolves fully.This moment, solution PH was 6.5～7, was solution A; The 1g nickelous nitrate is dissolved in and is solution B in the water of 30ml.Under stirring at normal temperature, the A drips of solution is added in the B liquid, added the back restir 1.5 hours.With the solid filtering that generates, with behind ethanol/water (1: the 1) solvent wash the complex compound (IX) of nickel-(V);
Same operation gets the complex compound (X) of iron-(V) with liquor ferri trichloridi;
Same operation gets the complex compound (XI) of cobalt-(V) with cobalt chloride solution;
Complex compound VIII, IX, molecular conductivity and the results of elemental analyses of X are as follows:
| Complex compound | Molecular formula | Molecular conductivity S.cm 2.mol -1 | Ultimate analysis (%) experimental value/calculated value | ||
| ??C | ??H | ??N | |||
| IX | ????Ni 2(NO 3) 2·V·8H 2O | ????10 | ??28.66/28.62 | ??4.22/4.09 | ??9.30/9.55 |
| X | ????FeCl 3·(V) 3 | ????430 | ??43.61/43.20 | ??2.08/1.93 | ??14.83/14.40 |
| XI | ????Co 2Cl 2·V·3.5EtOH，4·H 2O | ????33 | ??32.98/33.39 | ??4.15/4.68 | ??-/7.42 |
To above-claimed cpd IV, V, and complex compound VI, IX, X, XI has measured compound respectively to P-388 mouse leukemia cell and the A-549 human lung carcinoma cell inhibiting rate in growth in vitro with tetrazolium enzyme reduction method (mtt assay) and sulphonyl rhodamine β protein staining method (srb assay).Its result is as follows:
Partly compound under different concns to the inhibiting rate of growth of cancer cells
| Complex compound | Mtt assay P-388 cell | Srb assay A-549 cell | ||||||||
| ??10 -4 | ??10 -5 | ??10 -6 | ??10 -7 | ??10 -8 | ??10 -4 | ??10 -5 | ??10 -6 | ??10 -7 | ??10 -8 | |
| ??IV | ??89.0 | ??0 | ??0 | ??0 | ??0 | ??65.3 | ??80.3 | ??0 | ??0 | ??0 |
| ??V | ??92.5 | ??90.7 | ??91.2 | ??88.0 | ??82.8 | ??57.6 | ??62.3 | ??16.4 | ??0 | ??0 |
| ??VI | ??95.5 | ??96.3 | ??94.4 | ??/ | ??94.0 | ??57.6 | ??69.0 | ??74.3 | ??71.5 | ??74.6 |
| ??IX | ??94.0 | ??95.9 | ??95.4 | ??93.2 | ??88.7 | ??79.1 | ??90.2 | ??79.8 | ??79.9 | ??77.5 |
| ??X | ??50.4 | ??95.6 | ??94.7 | ??93.7 | ??97.8 | ??96.8 | ??97.6 | ??91.2 | ??79.8 | ??77.5 |
| ??XI | ??91.7 | ??73.6 | ??92.4 | ??92.6 | ??87.2 | ??100 | ??100 | ??98.9 | ??97.2 | ??90.7 |
It is generally acknowledged that in concentration be 10-6mol/l, inhibiting rate reaches that to think then more than 50% that this compounds has potent.By this standard, ligand i V is invalid and part V has potent to P-388; No matter and 4 kinds of title complexs all have potent to P-388 or A-549.
Claims (10)
1. one kind 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described title complex has following general formula (I):
Wherein M is a transition-metal Fe
2+, Fe
3+, Co
2+, Ni
2+, Cu
2+, Pt
2+In a kind of, L is inorganic part Cl
-, Br
-, Ac
-, I
-, NO
3 -, SO
4 2-In a kind of, R is H or lone electron, x, y, z respectively are 1～5 number, a, b, c respectively are 0～10 number.
2. as claimed in claim 13, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described transition metal is Fe
3+, Co
2+, Ni
2+, Cu
2+In a kind of.
3. as claimed in claim 23, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described inorganic part is Cl
-, NO
3 -, Ac
-In a kind of.
4. one kind prepares as claimed in claim 13, the method of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-, it is characterized in that described method be with salicylic aldehyde and hydrazine hydrate in ethanolic soln, react the compound formula (II) that makes: 2,2 '-dihydroxy-benzene azine
Compound formula (II) feeds chlorine and makes compound formula (III): α in Glacial acetic acid/acid anhydrides solvent, two (2 '-hydroxyl-5-the chloro-phenyl-)-azines of α '-two chloro-,
Compound (III) in ethanolic soln with hydrazine hydrate reacting generating compound formula (IV): 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine,
Compound (IV) is oxidized to the compound formula V with nitrous acid: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, 5-tetrazine.
5. as claimed in claim 43, the preparation method of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-is characterized in that described nitrous acid is made by Sodium Nitrite and acetic acid reaction.
6. one kind prepares as claimed in claim 13, the method of the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, it is characterized in that making compound (IV): 3 by method as claimed in claim 4, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine, the salt M of compound (IV) and transition metal
eL
fCompound formula (I) is made in reaction in alcohol solvent: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal, wherein e, f respectively are 1～5 number.
7. as claimed in claim 63, the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described method carries out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-the dihydroxy-benzene azine;
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, down feeds chlorine about 1 hour at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and in 10～20 ℃ of following chlorine 1.5～2 hours, with TLC point plate, observes the raw material spot and disappears and end, and stops logical chlorine, and placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine;
(4) at normal temperatures, with 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV) are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF)
eL
fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number; Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour, with the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal.
8. one kind prepares as claimed in claim 13, the method of the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, it is characterized in that making compound (V) 3 by method as claimed in claim 5, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2,4,5-tetrazine, the salt M of compound (V) and transition metal
eL
fCompound formula (I) is made in reaction in alcohol solvent: 3, and the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, wherein e, f respectively are 1～5 number.
9. as claimed in claim 83, the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described method carries out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-the dihydroxy-benzene azine;
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, feeds chlorine about 1 hour down at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and logical chlorine is 1.5～2 hours under 10～20 ℃; With TLC point plate, observe the raw material spot and only disappear, stop logical chlorine, placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine;
(4) compound (IV) and sodium nitrite in aqueous solution stir into suspension, add acetic acid, and in stirring at room 3 hours, solid filtering, washing obtained red crystals 3 with ethyl alcohol recrystallization, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-s-tetrazines of 6-again;
(5) at normal temperatures, with 3, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines (V) of 6-are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF)
eL
fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number.Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour; With the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal.
10. described 3 as one of claim 1～3, the title complex of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal is treated application in the medicine of leukemia, lung cancer or other tumour in preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702122A (en) * | 2012-05-16 | 2012-10-03 | 南通大学 | Method for preparing tetrazine by oxidizing dihydro tetrazine |
| CN102911189A (en) * | 2012-10-16 | 2013-02-06 | 桂林理工大学 | Salicylaldehyde azine schiff base transition metal compound and application thereof |
| CN109134301A (en) * | 2018-10-12 | 2019-01-04 | 阜阳师范学院 | A kind of fluorescence probe preparation method and applications based on salicylide azine |
| CN110818908A (en) * | 2019-08-29 | 2020-02-21 | 杭州市富阳区浙工大银湖创新创业研究院 | Preparation method of metal organic framework material for detecting oxidizing gas |
-
2004
- 2004-03-31 CN CN 200410017445 patent/CN1279030C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702122A (en) * | 2012-05-16 | 2012-10-03 | 南通大学 | Method for preparing tetrazine by oxidizing dihydro tetrazine |
| CN102911189A (en) * | 2012-10-16 | 2013-02-06 | 桂林理工大学 | Salicylaldehyde azine schiff base transition metal compound and application thereof |
| CN109134301A (en) * | 2018-10-12 | 2019-01-04 | 阜阳师范学院 | A kind of fluorescence probe preparation method and applications based on salicylide azine |
| CN110818908A (en) * | 2019-08-29 | 2020-02-21 | 杭州市富阳区浙工大银湖创新创业研究院 | Preparation method of metal organic framework material for detecting oxidizing gas |
| CN110818908B (en) * | 2019-08-29 | 2021-12-17 | 杭州市富阳区浙工大银湖创新创业研究院 | Preparation method of metal organic framework material for detecting oxidizing gas |
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