CN105968127B - A kind of azacyclo- transition metal Zn complex containing multiple coordination sites, preparation method and application - Google Patents
A kind of azacyclo- transition metal Zn complex containing multiple coordination sites, preparation method and application Download PDFInfo
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- 229910052723 transition metal Inorganic materials 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- -1 ethyl imidazol Chemical compound 0.000 claims abstract description 39
- 230000002218 hypoglycaemic effect Effects 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- IQUVMOWIZMLZIA-VOTSOKGWSA-N 6-[(e)-2-phenylethenyl]pyrimidine-2,4,5-triamine Chemical compound NC1=NC(N)=C(N)C(\C=C\C=2C=CC=CC=2)=N1 IQUVMOWIZMLZIA-VOTSOKGWSA-N 0.000 claims abstract description 5
- DTMHTVJOHYTUHE-UHFFFAOYSA-N thiocyanogen Chemical compound N#CSSC#N DTMHTVJOHYTUHE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011701 zinc Substances 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 50
- 239000000243 solution Substances 0.000 claims description 45
- 239000003446 ligand Substances 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 21
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 19
- 239000013078 crystal Substances 0.000 claims description 19
- 229910052725 zinc Inorganic materials 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 239000008236 heating water Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 4
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052737 gold Inorganic materials 0.000 claims description 3
- 239000010931 gold Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical group [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 2
- 229960001763 zinc sulfate Drugs 0.000 claims description 2
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 150000003851 azoles Chemical class 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 150000003751 zinc Chemical class 0.000 claims 1
- 102000004139 alpha-Amylases Human genes 0.000 abstract description 19
- 108090000637 alpha-Amylases Proteins 0.000 abstract description 19
- 229940024171 alpha-amylase Drugs 0.000 abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 abstract description 4
- 229960002632 acarbose Drugs 0.000 abstract description 4
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 10
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- 235000019698 starch Nutrition 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 229910017464 nitrogen compound Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- WDMUXYQIMRDWRC-UHFFFAOYSA-N 2-hydroxy-3,4-dinitrobenzoic acid Chemical class OC(=O)C1=CC=C([N+]([O-])=O)C([N+]([O-])=O)=C1O WDMUXYQIMRDWRC-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 241000208340 Araliaceae Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010059892 Cellulase Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of azacyclo- transition metal Zn complex containing multiple coordination sites, preparation method and application, described azacyclo- transition metal Zn complex is 1 (methyl of BTA 1) 1 (2 ethyl imidazol(e)) Zn complex, and molecular formula is [Zn (SCN)2(C12H13N5)2].Azacyclo- transition metal Zn complex prepared by the present invention, i.e. 1 (methyl of BTA 1) 1 (2 ethyl imidazol(e)) Zn complex, there is stronger inhibitory action to alpha amylase, 1 (methyl of BTA 1) 1 (2 ethyl imidazol(e)) or transition metal salt is significantly larger than used alone to the inhibitory action of alpha amylase, is also better than conventional hypoglycemic medicine acarbose.This shows that azacyclo- transition metal Zn complex of the invention has good blood sugar reducing function, can be effectively used for preparing treatment diabetes medicament, is to treat the innovation on diabetes medicament.
Description
Technical field
The present invention relates to a kind of azacyclo- transition metal Zn complex containing multiple coordination sites, preparation method and application, category
In pharmaceutical technology field.
Background technology
Diabetes are a kind of metabolic diseases being characterized with hyperglycaemia.Long-standing hyperglycaemia during diabetes, easily
Cause various tissues, particularly eye, kidney, heart, blood vessel, the chronic lesion of nerve and dysfunction.At present, the whole world of diabetes
Illness rate is in the rapid increase phase, and China has become the most country of diabetic in the world.According to relevant report,
Among numerous diabetics, diabetes B patient has accounted for 90%-95%, and due to the concealment of its pathogenic factor, morbidity is just
Phase symptom is not obvious, the reason such as caused complication is more and serious, and diabetes B, which has become, threatens the main of human health
One of disease.
The method that the treatment for diabetes B is taken at present mainly has：OHA, insulin injection, pancreas are moved
Plant the methods such as operation, motor adjustment, dietary adjustments.But hypoglycemic after the meal is slow, diabetes B is to pancreas because these treatment methods are present
The strong stress resistance of island element, hypoglycemic effect are not substantially and the shortcomings of hypoglycemic cost prohibitive, therefore these treatment methods can not be preferable
The hypoglycemic needs for meeting patient.At present, the critical path for finding new drug is turned into by the drug screening of target spot of enzyme or acceptor.
Alpha-amylase (α-amylase) is a kind of Endoglucanases, α-Isosorbide-5-Nitrae-glucoside bond in energy hydrolysis starch molecule, will
Starch is degraded step by step.Therefore under alpha-amylase existence condition, soluble starch and test sample are added, by determining by alphalise starch
The amount of the reduced sugar of enzyme degraded generation evaluates the activity of test sample, i.e., using evaluating in vitro the inhibitory action of alpha-amylase
The hypoglycemic activity of some medicines, is a kind of common method of testing.
Heterocyclic nitrogen compound have it is very strong match somebody with somebody bit function, the compound can be steady with many transition metal generating structures
Fixed complex；As hypoglycemic medicine can with the emulative binding site for occupying carbohydrate, postpone substrate hydrolysis so as to
Reach the effect of hypoglycemic.In addition, also there are some researches show some transition metal such as copper, zinc, chromium, vanadium etc. also have good hypoglycemic
Activity.The complex of zinc also result in the concern of vast researcher as the research of hypoglycemic medicine in recent years.But it is due to
Transition metal large dose oral administration can produce toxic action to human body, and be imitated using asymmetric heterocyclic nitrogen compound hypoglycemic merely
The reason such as really less desirable.Therefore asymmetric heterocyclic nitrogen compound is made into complex with transition metal reaction just becomes
One effective way solving the above problems.
The content of the invention
In order to solve the above problems, it is an object of the invention to provide a kind of azacyclo- transition metal zinc containing multiple coordination sites
Complex, preparation method and application, the complex preparation method are simple, with good blood sugar reducing function.
To achieve these goals, the technical solution adopted in the present invention is：
A kind of azacyclo- transition metal Zn complex containing multiple coordination sites, described azacyclo- transition metal Zn complex
For 1- (BTA -1- methyl) -1- (2- ethyl imidazol(e)s) Zn complex, molecular formula is [Zn (SCN)2(C12H13N5)2]；Its
In, C12H13N5For ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s), molecular structural formula is：
Described ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) preparation method, including following step
Suddenly：
(1) 11.9g BTAs, 30ml water and 30ml formaldehyde are mixed, heating stirring makes solid dissolving, in 80 DEG C of bars
Heating water bath 1h under part, cooling, is filtrated to get product as white needles, white crystal, as hydroxyl is obtained with re-crystallizing in ethyl acetate
Methyl benzotriazazole；
(2) methylol BTA 7.4g is added in single port bottle, 25ml SOCl is added dropwise2, mixing is stirred after completion of dropwise addition
Mix 30min, 80 DEG C of backflow 3h；Excessive SOCl is boiled off with Rotary Evaporators2, obtain white crystal, as chloromethyl benzo three
Nitrogen azoles；
(3) 2- ethyl imidazol(e) 40mmol are taken, are dissolved in 20ml DMSO, the NaOH 80mmol pulverized is added, is heated to 60
DEG C, 40mmol chloromethyl BTAs are added, 60 DEG C of heating water bath 1h are cooled to room temperature, pour into 100g frozen water, stir
Mix, precipitate, suction filtration, precipitation is washed with water 3 times, obtains crude product；
(4) crude product is recrystallized in ethyl acetate, obtains lacteous crystal, as ligand 1-(BTA-1- methyl)-
1- (2- ethyl imidazol(e)s).
A kind of preparation method of the azacyclo- transition metal Zn complex containing multiple coordination sites, comprises the following steps：
(1) transition metal zinc salt 0.02-0.04mmol accurately is weighed, is dissolved in 4-6ml solvents, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.02-0.03mmol is accurately weighed, is dissolved
In 4-6ml solvents, ligand solution is obtained；
(3) 0.02-0.03mmol KSCN accurately are weighed, is dissolved in 1-2ml water, obtains KSCN solution；And KSCN is molten
Liquid is added in zinc solution, obtains mixed solution；
(4) ligand solution is added in mixed solution, be well mixed, filtering, filtrate solubilizer to 14-18ml, at room temperature
Stand, to colourless rectangle crystal is separated out, produce.
Described transition metal zinc salt is zinc sulfate, zinc acetate, zinc nitrate or zinc chloride.
The solvent of step (1), (2) and (4) is one or both of water, methanol, ethanol, dimethyl sulfoxide (DMSO), acetonitrile
Mixture.
It is preferred that, the preparation method of the described azacyclo- transition metal Zn complex containing multiple coordination sites, including it is following
Step：
(1) Zn (Ac) is accurately weighed20.02mmol, is dissolved in 4ml methanol, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.02mmol is accurately weighed, 4ml is dissolved in
In methanol, ligand solution is obtained；
(3) 0.02mmol KSCN accurately are weighed, is dissolved in 1ml water, obtains KSCN solution；And add KSCN solution
In zinc solution, mixed solution is obtained；
(4) ligand solution is added in mixed solution, be well mixed, filtering, filtrate adds methanol to 14ml, quiet at room temperature
Put, to colourless rectangle crystal is separated out, produce.
A kind of application of azacyclo- transition metal Zn complex containing multiple coordination sites in terms of alpha-amylase is suppressed.
A kind of application of azacyclo- transition metal Zn complex containing multiple coordination sites in terms of hypoglycemic medicine is prepared.
Beneficial effect of the present invention
1st, the present invention is golden using zinc as transition using 1- (BTA -1- methyl) -1- (2- ethyl imidazol(e)s) as part
Category, prepares azacyclo- transition metal Zn complex, asymmetric heterocyclic nitrogen compound is efficiently solved as part, with transition gold
Belong to the combination problem of zinc.
2nd, azacyclo- transition metal Zn complex prepared by the present invention, i.e. 1- (BTA -1- methyl) -1- (2- second
Base imidazoles) Zn complex, there is stronger inhibitory action to alpha-amylase, 1- (BTA -1- are significantly larger than used alone
Methyl) -1- (2- ethyl imidazol(e)s) or transition metal salt, to the inhibitory action of alpha-amylase, be also better than conventional hypoglycemic medicine Ah Ka
Ripple sugar.This shows that azacyclo- transition metal Zn complex of the invention has good blood sugar reducing function, can be effectively used for preparation and controls
Diabetes medicament is treated, is to treat the innovation on diabetes medicament.
3rd, preparation method of the invention is simple and convenient to operate, and production cost is low, it is easy to which technology is promoted, with good
Social and economic benefit.
Brief description of the drawings
Fig. 1 is complex [Zn (SCN)2(C12H13N5)2] construction unit figure.
Fig. 2 is complex [Zn (SCN)2(C12H13N5)2] accumulation graph.
Embodiment
The embodiment to the present invention is described in further detail with reference to embodiments.
Embodiment 1
Ligand 1 of the present invention-(BTA -1- methyl) -1- (2- ethyl imidazol(e)s) preparation method, including following step
Suddenly：
(1) 11.9g BTAs, 30ml water and 30ml formaldehyde are mixed, heating stirring makes solid dissolving, in 80 DEG C of bars
Heating water bath 1h under part, cooling, is filtrated to get product as white needles, white crystal, as hydroxyl is obtained with re-crystallizing in ethyl acetate
Methyl benzotriazazole；
(2) methylol BTA 7.4g is added in single port bottle, 25ml SOCl is added dropwise2, mixing is stirred after completion of dropwise addition
Mix 30min, 80 DEG C of backflow 3h；Excessive SOCl is boiled off with Rotary Evaporators2, obtain white crystal, as chloromethyl benzo three
Nitrogen azoles；
(3) 2- ethyl imidazol(e) 40mmol are taken, are dissolved in 20ml dimethyl sulfoxide (DMSO)s (DMSO), add what is pulverized
NaOH80mmol, is heated to 60 DEG C, adds 40mmol chloromethyl BTAs, and 60 DEG C of heating water bath 1h are cooled to room temperature,
Pour into 100g frozen water, stir, precipitate, suction filtration, precipitation is washed with water 3 times, obtains crude product；
(4) crude product is recrystallized in ethyl acetate, obtains lacteous crystal, as ligand 1-(BTA-1- methyl)-
1- (2- ethyl imidazol(e)s).
Prepared ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) constituent content is according to C12H13N5Meter
(%), theoretical value (%)：C 63.41；H 5.77；N 30.82；Experiment value (%)：C 63.21；H 5.82；N 30.97.It is infrared
Spectrum (cm-1, KBr)：3503 (s), 3236 (m), 3141 (m), 3115 (m), 3092 (w), 2976 (m), 2177 (w), 1927
(w), 1662 (m), 1614 (w), 1531 (w), 1496 (s), 1457 (s), 1431 (m), 1386 (m), 1362 (m), 1269 (s)
1237 (m), 1165 (s), 1103 (w), 1075 (s), 1009 (m), 967 (m), 923 (w), 785 (w), 746 (s), 603 (w)
538(w)。
Embodiment 2
A kind of preparation method of the azacyclo- transition metal Zn complex containing multiple coordination sites, comprises the following steps：
(1) zinc acetate [Zn (Ac) is accurately weighed2] 0.02mmol, it is dissolved in 4ml methanol, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.02mmol is accurately weighed, 4ml is dissolved in
In methanol, ligand solution is obtained；
(3) 0.02mmol KSCN accurately are weighed, is dissolved in 1ml water, obtains KSCN solution；And add KSCN solution
In zinc solution, mixed solution is obtained；
(4) ligand solution is added in mixed solution, be well mixed, filtering, filtrate adds methanol to 14ml, quiet at room temperature
Put, to colourless rectangle crystal is separated out, produce.
The experiment condition and result of the X-ray single crystal diffraction structure of complex of the present invention are as follows：
From the preferable single crystal samples of crystalline form, X-ray diffraction is carried out on Rigaku Saturn 724CCD diffractometers real
Test, using the Mo-k alpha rays position (λ=0.71073A) through graphite monochromator monochromatization as diffraction light sources, with ω -2 θ scanning sides
Formula collects point diffraction.Crystal structure is solved using direct method, and is extended with Fourier techniques, is modified by anisotropy,
Complete matrix least square method is finally used, the diffraction data and variable element according to observable are corrected, and all data are through Lp
Factor correction.Whole non-hydrogen atom coordinates are solved with direct method, hydrogen atom coordinates are obtained by difference Founcr synthetic methods, structure ginseng
Number is optimized by complete matrix least square method, in addition to hydrogen atom uses isotropic thermal parameter, and other atoms use anisotropy
Thermal parameter method, all calculating use SHELX97 programs.
The mono-crystalline structures of prepared azacyclo- transition metal Zn complex are shown in Fig. 1,2, and the complex belongs to anorthic system,
P-1 space groups, cell parameter a isB isC isα is 82.339 °, and β is 82.783 °,
γ is 70.940 °.Constituent content is according to C26H26N12S2Zn counts (%), theoretical value (%)：C 49.09；H 4.12；N 26.43；It is real
Test value (%)：C 49.37；H 4.10；N 26.70.Infrared spectrum (cm-1, KBr)：3435 (w), 3122 (m), 2981 (w),
2940 (w), 2073 (s), 1613 (w), 1547 (m), 1496 (s), 1481 (s), 1378 (m), 1347 (m), 1263 (s), 1180
(s), 1154 (s), 1081 (s), 1054 (w), 964 (m), 751 (s), 654 (w), 509 (w).
Embodiment 3
A kind of preparation method of the azacyclo- transition metal Zn complex containing multiple coordination sites, comprises the following steps：
(1) ZnSO is accurately weighed40.03mmol, is dissolved in 5ml water, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.03mmol is accurately weighed, 5ml is dissolved in
In methanol, ligand solution is obtained；
(3) 0.03mmol KSCN accurately are weighed, is dissolved in 2ml water, obtains KSCN solution；And add KSCN solution
In zinc solution, mixed solution is obtained；
(4) ligand solution is added in mixed solution, be well mixed, filtering, filtrate adds ethanol to 16ml, quiet at room temperature
Put, to colourless rectangle crystal is separated out, produce.
The mono-crystalline structures of prepared azacyclo- transition metal Zn complex are shown in Fig. 1,2, and the complex belongs to anorthic system,
P-1 space groups, cell parameter a isB isC isα is 82.339 °, and β is 82.783 °,
γ is 70.940 °.Constituent content is according to C26H26N12S2Zn counts (%), theoretical value (%)：C 49.09；H 4.12；N 26.43；It is real
Test value (%)：C 49.37；H 4.10；N 26.70.Infrared spectrum (cm-1, KBr)：3435 (w), 3122 (m), 2981 (w),
2940 (w), 2073 (s), 1613 (w), 1547 (m), 1496 (s), 1481 (s), 1378 (m), 1347 (m), 1263 (s), 1180
(s), 1154 (s), 1081 (s), 1054 (w), 964 (m), 751 (s), 654 (w), 509 (w).
Embodiment 4
A kind of preparation method of the azacyclo- transition metal Zn complex containing multiple coordination sites, comprises the following steps：
(1) ZnCl is accurately weighed20.04mmol, is dissolved in 6ml methanol, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.03mmol is accurately weighed, 6ml is dissolved in
In methanol, ligand solution is obtained；
(3) 0.03mmol KSCN accurately are weighed, is dissolved in 2ml water, obtains KSCN solution；And add KSCN solution
In zinc solution, mixed solution is obtained；
(4) ligand solution is added in mixed solution, be well mixed, filtering, filtrate adds acetonitrile to 18ml, quiet at room temperature
Put, to colourless rectangle crystal is separated out, produce.
The mono-crystalline structures of prepared azacyclo- transition metal Zn complex are shown in Fig. 1,2, and the complex belongs to anorthic system,
P-1 space groups, cell parameter a isB isC isα is 82.339 °, and β is 82.783 °,
γ is 70.940 °.Constituent content is according to C26H26N12S2Zn counts (%), theoretical value (%)：C 49.09；H 4.12；N 26.43；It is real
Test value (%)：C 49.37；H 4.10；N 26.70.Infrared spectrum (cm-1, KBr)：3435 (w), 3122 (m), 2981 (w),
2940 (w), 2073 (s), 1613 (w), 1547 (m), 1496 (s), 1481 (s), 1378 (m), 1347 (m), 1263 (s), 1180
(s), 1154 (s), 1081 (s), 1054 (w), 964 (m), 751 (s), 654 (w), 509 (w).
Experimental example
Azacyclo- transition metal Zn complex of the present invention is to the inhibitory action of alpha-amylase, its inhibiting rate assay method：
1st, the preparation of reagent
The preparation of DNS reagents weighs the dinitrosalicylic acids of 1.625g 3,5 one, adds 2mol/l sodium hydroxide solutions
81.25ml, glycerine 11.25g, shakes up, and adds water and is settled to 250ml, ultrasonic dissolution assisting, after all dissolving and clarifying, is cooled to
Room temperature, puts standby in brown reagent bottle.
The preparation of alphalise starch enzyme liquid weighs 0.06g alpha-amylases, with 0.2mol/l, pH6.5PBS buffer solution constant volume chamber
100ml, ultrasonic dissolution assisting, filtering is produced, the reagent is preferably now with the current.
2nd, 4 tool plug test tubes are taken all to sequentially add 600 μ g/ml alphalise starch enzyme liquid 1ml, 2mg/ml soluble starch solution
1ml, and add following reagent according to setting：
Test tube 1：0.25mg/ml, 0.5mg/ml or 1mg/ml acarbose 1ml
Test tube 2：The azacyclo- transition metal Zn complex 1ml of 0.25mg/ml, 0.5mg/ml or 1mg/ml present invention
Test tube 3：0.25mg/ml, 0.5mg/ml or 1mg/ml Zn (Ac)2 1ml
Test tube 4：0.25mg/ml, 0.5mg/ml or 1mg/ml 1- (BTA -1- methyl) -1- (2- ethyl imidazol(e)s)
1ml
After mixing, 37 DEG C of heating in water bath for reaction.Accurate timing 20min is often managed, to add DNS reagent 5ml terminating reactions.Boiling
(colour developing principle is for water-bath 5min colour developings：Under alpha-amylase existence condition, soluble starch and test sample are added, by determining
The activity of test sample is evaluated by the degrade amount of the reduced sugar of generation of alpha-amylase, and reduced sugar under alkaline environment can by 3,
5 one dinitrosalicylic acids are reduced, and generate the amino-compound of brownish red, there is absorption maximum at 540nm), it is cooled to after room temperature,
Absorbance is determined at 540nm.
The calculation formula of inhibiting rate is：
In formula：Emin is to replace test liquid and alpha-amylase with water, and Emax is to replace test liquid with water, background radix be with
Water replaces soluble starch solution.
The inhibitory activity of the alpha-amylase of complex of the present invention see the table below：
Inhibiting rate of the compound of various concentrations to alpha-amylase
Note：AEmin=0.134, AEmax=0.622
From the point of view of the measurement result that external hypoglycemic activity is tested, ligand 1-(BTA-1- methyl)-1- (2- ethyls
Imidazoles) there is certain inhibitory action to alpha-amylase, the suppression of azacyclo- transition metal Zn complex of the invention to alpha-amylase
Make of stronger, be better than conventional hypoglycemic medicine acarbose.And only Zn (Ac)2Suppression of the test liquid to alpha-amylase
Make of substantially weaker, 1- (BTA -1- methyl) -1- (2- ethyl imidazol(e)s) and azacyclo- transition metal zinc are not only below
Complex, will also be less than acarbose.This shows, only with regard to external hypoglycemic activity from the point of view of, the azacyclo- transition gold that the present invention is synthesized
Category Zn complex has larger superiority.Based on this, further pharmacology and physiologically active can be carried out to this complex
Research.
Claims (7)
1. a kind of azacyclo- transition metal Zn complex containing multiple coordination sites, it is characterised in that described azacyclo- transition gold
Category Zn complex is 1- (BTA -1- methyl) -1- (2- ethyl imidazol(e)s) Zn complex, and molecular formula is [Zn (SCN)2
(C12H13N5)2]；Wherein, C12H13N5For ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s), molecular structural formula
For：
2. a kind of preparation method of the azacyclo- transition metal Zn complex containing multiple coordination sites as claimed in claim 1, its
It is characterised by, comprises the following steps：
(1) transition metal zinc salt 0.02-0.04mmol accurately is weighed, is dissolved in 4-6ml solvents, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.02-0.03mmol is accurately weighed, 4- is dissolved in
In 6ml solvents, ligand solution is obtained；
(3) 0.02-0.03mmol KSCN accurately are weighed, is dissolved in 1-2ml water, obtains KSCN solution；And add KSCN solution
Enter in zinc solution, obtain mixed solution；
(4) ligand solution is added in mixed solution, is well mixed, filtering, filtrate solubilizer to 14-18ml is stood at room temperature,
To colourless rectangle crystal is separated out, produce.
3. the preparation method of the azacyclo- transition metal Zn complex according to claim 2 containing multiple coordination sites, it is special
Levy and be, described ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) preparation method comprises the following steps：
(1) 11.9g BTAs, 30ml water and 30ml formaldehyde are mixed, heating stirring makes solid dissolving, under the conditions of 80 DEG C
Heating water bath 1h, cooling, is filtrated to get product as white needles, white crystal, as methylol is obtained with re-crystallizing in ethyl acetate
BTA；
(2) methylol BTA 7.4g is added in single port bottle, 25ml SOCl is added dropwise2, mixed after completion of dropwise addition
30min, 80 DEG C of backflow 3h；Excessive SOCl is boiled off with Rotary Evaporators2, obtain white crystal, the as nitrogen of chloromethyl benzo three
Azoles；
(3) 2- ethyl imidazol(e) 40mmol are taken, are dissolved in 20ml DMSO, the NaOH 80mmol that pulverize are added, 60 DEG C are heated to, then
40mmol chloromethyl BTAs are added, 60 DEG C of heating water bath 1h are cooled to room temperature, poured into 100g frozen water, stirred, occurred
Precipitation, suction filtration, precipitation is washed with water 3 times, obtains crude product；
(4) crude product is recrystallized in ethyl acetate, obtains lacteous crystal, as ligand 1-(BTA-1- methyl)-1-
(2- ethyl imidazol(e)s).
4. the preparation method of the azacyclo- transition metal Zn complex according to claim 2 containing multiple coordination sites, it is special
Levy and be, described transition metal zinc salt is zinc sulfate, zinc acetate, zinc nitrate or zinc chloride.
5. the preparation method of the azacyclo- transition metal Zn complex according to claim 2 containing multiple coordination sites, it is special
Levy and be, the solvent of step (1), (2) and (4) is one or both of water, methanol, ethanol, dimethyl sulfoxide (DMSO), acetonitrile
Mixture.
6. the preparation method of the azacyclo- transition metal Zn complex according to claim 2 containing multiple coordination sites, it is special
Levy and be, comprise the following steps：
(1) Zn (Ac) is accurately weighed20.02mmol, is dissolved in 4ml methanol, obtains zinc solution；
(2) ligand 1-(BTA-1- methyl)-1- (2- ethyl imidazol(e)s) 0.02mmol is accurately weighed, 4ml methanol is dissolved in
In, obtain ligand solution；
(3) 0.02mmol KSCN accurately are weighed, is dissolved in 1ml water, obtains KSCN solution；And KSCN solution is added into zinc salt
In solution, mixed solution is obtained；
(4) ligand solution is added in mixed solution, be well mixed, filtering, filtrate adds methanol to 14ml, stood at room temperature, extremely
Colourless rectangle crystal is separated out, is produced.
7. a kind of azacyclo- transition metal Zn complex containing multiple coordination sites as claimed in claim 1 is preparing hypoglycemic medicine
The application of aspect.
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| CN108774252B (en) * | 2018-07-27 | 2021-01-08 | 河南中医药大学 | 1- (benzotriazole-1-methyl) -1- (2, 4-dimethyl imidazole) zinc complex and preparation method thereof |
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