CN103936771B - Adamantyl pyridinecarboxylic amine complex, intermediate and its preparation method and application - Google Patents
Adamantyl pyridinecarboxylic amine complex, intermediate and its preparation method and application Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- -1 Adamantyl pyridinecarboxylic amine Chemical class 0.000 title claims abstract description 36
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 claims abstract description 15
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims abstract description 13
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical group [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 3
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- 239000000243 solution Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 7
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- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 5
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- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LYCIRRKDZZREHU-UHFFFAOYSA-N 2-(1-adamantyl)pyridine Chemical compound C1C(C2)CC(C3)CC1CC23C1=CC=CC=N1 LYCIRRKDZZREHU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 229960003805 amantadine Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 150000004699 copper complex Chemical class 0.000 description 2
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- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
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- 241001500351 Influenzavirus A Species 0.000 description 1
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- SANBFZGNRVMYPL-UHFFFAOYSA-N O=C(C1(CC(C2)C3)CC3CC2C1)NCc1ncccc1 Chemical compound O=C(C1(CC(C2)C3)CC3CC2C1)NCc1ncccc1 SANBFZGNRVMYPL-UHFFFAOYSA-N 0.000 description 1
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- 238000002835 absorbance Methods 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical group C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N alpha-methylpyridine Natural products CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
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- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
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- 238000002484 cyclic voltammetry Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
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- KBLZDCFTQSIIOH-UHFFFAOYSA-M tetrabutylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC KBLZDCFTQSIIOH-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Pyridine Compounds (AREA)
Abstract
The present invention discloses a kind of adamantyl pyridinecarboxylic amine complex, intermediate and its preparation method and application, the structure of described title complex is as shown in the formula (I), formula (I), n is 1-3, M is divalent metal, and N3 is selected from perchlorate, hexafluorophosphoricacid acid ions or tetrafluoroborate ion; Title complex provided by the invention or the title complex prepared according to method provided by the invention have the activity of excellent catalysis superoxide anion disproportionation.
Description
Technical field
The present invention relates to a kind of adamantyl pyridinecarboxylic amine complex, prepare the preparation method and application of the intermediate of this adamantyl pyridinecarboxylic amine complex, this adamantyl pyridinecarboxylic amine complex and this intermediate.
Background technology
Medical circle generally thinks that free radical is the major cause that human senility and nerve degenerative diseases produce. Modern medicine confirms, the excessive Superoxide anion free radical (O produced in biological oxidation process2��-) disease such as human senility and cancer, cardiovascular and cerebrovascular diseases and amyotrophic lateral sclerosis can be caused. Superoxide-dismutase (SOD) removes O in body2��-Specificity enzyme, be called as " human body street cleaner ", clinical medicine be used for the treatment of the multiple disease such as Alzheimer's disease and tumour, also extensively for skin care product and healthcare products. But natural SOD have extract difficulty, cost height, transformation period short, easily by protease hydrolysis, be difficult to the shortcoming such as permeate through cell membranes and allogenicity, be restricted on clinical treatment is applied.
Therefore, carrying out the research of SOD chemical simulation, O is removed in exploitation2��-Exogenous chemical medicine, be a kind of effective way of the disease that prevention and therapy causes because of SOD inactivation.
Summary of the invention
It is an object of the invention to, in order to overcome the natural SOD of superoxide-dismutase natural in prior art, there is extraction difficulty, cost height, easily by protease hydrolysis, it is difficult to the shortcoming such as permeate through cell membranes and allogenicity, provide a kind of easily preparation, cost is low, efficiently with the SOD analogue enztme with diamantane and pyridinecarboxylic amine structure being easy to permeate through cell membranes, i.e. adamantyl pyridinecarboxylic amine complex, provide the preparation method and application of adamantyl pyridinecarboxylic amine complex simultaneously, additionally provide the intermediate and its preparation method of preparing adamantyl pyridinecarboxylic amine complex.
In order to realize above-mentioned purpose, the present invention provides a kind of adamantyl pyridinecarboxylic amine complex, wherein, the structure of described title complex as shown in the formula (I),
Formula (I), n is 1-3, M is divalent metal, and N3 is selected from perchlorate, hexafluorophosphoricacid acid ions or tetrafluoroborate ion.
Preferably, in formula (I), n is 1-3, M is Cu2+Or Zn2+, N3 is perchlorate; More preferably, the title complex of structure shown in formula (I) is the title complex of structure shown in formula (II).
Present invention also offers the intermediate of the adamantyl pyridinecarboxylic amine complex of structure shown in a kind of preparation formula (I), wherein, the structure of described intermediate such as formula shown in (L1),
In formula (L1), n is 1-3;
Preferably, the compound of structure shown in formula (L1) is the compound of structure shown in formula (L2).
Present invention also offers the preparation method of the intermediate of the adamantyl pyridinecarboxylic amine complex of structure shown in a kind of preparation formula (L1), wherein, under the existence of carbonate, compound by structure shown in 1-diamantane acyl chlorides and formula (C1) carries out contact reacts in organic solvent;
In formula (C1), n is 1-3, it may be preferred that n is 1;
More preferably, described carbonate is salt of wormwood or sodium carbonate, and described organic solvent is acetonitrile or toluene;
Further preferably, described carbonate is salt of wormwood, and described organic solvent is toluene.
Present invention also offers the preparation method of the adamantyl pyridinecarboxylic amine complex of structure shown in a kind of preparation formula (I), wherein, in presence of organic solvent, by the intermediate of structure shown in formula (L1) and [M (N3)2]��6H2O carries out complex reaction;
In formula (L1), n is 1-3, it may be preferred that n is 1;
In above-mentioned formula, M is divalent metal, and N3 is selected from perchlorate, hexafluorophosphoricacid acid ions or tetrafluoroborate ion;
Preferably, M is Cu2+Or Zn2+, N3 is perchlorate;
More preferably, described [M (N3)2]��6H2O is Cu(ClO4)2��6H2O��
Present invention also offers above-mentioned adamantyl pyridinecarboxylic amine complex or adamantyl pyridinecarboxylic amine complex prepared by above-mentioned method in the application eliminated in Superoxide radical anion.
Protein engineering research shows that the SOD active centre of ox red corpuscle has and coordinates, by the copper of divalence or zinc cation, the structure formed with nitrogen-atoms, thus inferring that the adamantyl pyridinecarboxylic amine complex of structure shown in formula provided by the invention (II) may have the activity eliminating Superoxide radical anion, the adamantyl pyridinecarboxylic amine complex of structure shown in same up-to-date style (II) has diamantane and pyridine structure. Diamantane a kind of contains 10 carbon atoms and the cage compound of 16 hydrogen atom three volution saturated alkanes, there is attach structure symmetry, good stability, relatively strong parent's fat cross the feature such as film and bio-compatibility. Amantadine and derivative thereof can suppress influenza A virus to wear into suction suction tract epithelial cell, and the nucleic acid of adventitia and releasing virus that stripping removes virus enters host cell; Dopaminergic terminals release Dopamine HCL (DA) in striatum can also be promoted, strengthen the DA of central nervous system and the effect of catecholamine, increase neuronic DA content. Amantadine and derivative thereof as clinical medicine, extensively for treatment and the prevention of the diseases such as influenza virus A type infectious diseases and Parkinson's disease. Pyridine derivatives, the title complex that easy and metal ion assembling is formed has various structure and unique physicochemical property. Thus inferring, title complex provided by the invention may have excellently stability, relatively strong parent's fat and cross film, bio-compatibility so that this title complex likely has the drug effects such as anti-malarial, antitumor, sterilization, anti-inflammatory, hypertension; Pyridine structure makes the method for the adamantyl pyridinecarboxylic amine complex of structure shown in preparation formula (II) comparatively simple simultaneously, and raw material is easy to get.
Other features and advantages of the present invention are described in detail in embodiment part subsequently.
Accompanying drawing explanation
Accompanying drawing is used to provide a further understanding of the present invention, and forms a part for specification sheets, is used from explanation the present invention with embodiment one below, but is not construed as limiting the invention. In the accompanying drawings:
Fig. 1 is that riboflavin-methionine(Met) luminescence method measures complex-catalyzed superoxide anion O2��-The schematic diagram of disproportionation activity;
Fig. 2 is the adamantyl pyridine carboxamide complex monocrystal diffractogram of structure shown in formula (II);
Fig. 3 is the adamantyl pyridinecarboxylic amine complex of structure shown in formula (II) and the test result figure of the activity of BeSOD catalysis superoxide anion disproportionation;
Fig. 4 is the test result figure of the electrochemical properties of the adamantyl pyridinecarboxylic amine complex of structure shown in formula (II); And
Fig. 5 is the mechanism figure of the complex-catalyzed superoxide anion disproportionation of adamantyl pyridine carboxamide of structure shown in formula (II).
Embodiment
Hereinafter the specific embodiment of the present invention is described in detail. Should be understood that, embodiment described herein, only for instruction and explanation of the present invention, is not limited to the present invention.
The present invention provides a kind of adamantyl pyridinecarboxylic amine complex, wherein, the structure of described title complex as shown in the formula (I),
Formula (I), n is 1-3, M is divalent metal, and N3 is selected from perchlorate, hexafluorophosphoricacid acid ions or tetrafluoroborate ion;
Preferably, in formula (I), n is 1-3, M is Cu2+Or Zn2+, N3 is perchlorate;
More preferably, the title complex of structure shown in formula (I) is the title complex of structure shown in formula (II).
The present invention also carries the intermediate of the adamantyl pyridinecarboxylic amine complex having encircleed structure shown in a kind of preparation formula (I), wherein, the structure of described intermediate such as formula shown in (L1),
In formula (L1), n is 1-3, it may be preferred that the compound of structure shown in formula (L1) is the compound of structure shown in formula (L2).
Present invention also offers the preparation method of the intermediate of the adamantyl pyridinecarboxylic amine complex of structure shown in a kind of preparation formula (L1), wherein, under the existence of carbonate, compound by structure shown in 1-diamantane acyl chlorides and formula (C1) carries out contact reacts in organic solvent;
In formula (C1), n is 1-3, it may be preferred that n is 1.
According to the present invention, if described organic solvent can solubilizing reaction raw material and with reaction solvent reaction organic solvent. Acetonitrile, N can be enumerated, one or more in dinethylformamide, methyl-sulphoxide and toluene as such reaction solvent. It is preferably toluene. More preferably above-mentioned organic solvent is anhydrous solvent (namely water-content is less than 50ppm).
1-diamantane acyl chlorides can be commercially available product in the present invention, it is also possible to be existing synthesis now use, in order to ensure the receipts rate of contact reacts, it is preferable that 1-diamantane acyl chlorides now synthesizes existing use.
According to the present invention, the carbonate (namely can be dissolved in above-mentioned organic solvent) that described carbonate preferably can be dissolved in reaction system. One or more in sodium carbonate, salt of wormwood and cesium carbonate can be enumerated as such carbonate. It is preferably sodium carbonate or salt of wormwood, it is more preferable to be salt of wormwood.
According to the present invention, being within the scope of suitable pH to ensure the receipts rate of contact reacts to control described contact reacts, relative to 1-diamantane acyl chlorides 1mmol, the consumption of described carbonate is 1-4mmol.
According to the present invention, the consumption of described Compound C 1 and the consumption of organic solvent can change in wide scope. But in order to improve receipts rate, it is preferable that relative to 1-adamantanamine hydrochloride 1mmol, the consumption of described Compound C 1 is 1-3mmol, and the consumption of described organic solvent is 2-20ml.
In the preparation method of above-mentioned intermediate, in order to improve the receipts rate of contact reacts, it is preferable that described contact reacts carries out below 0 DEG C, and the temperature of reaction of described contact reacts is-10-0 DEG C, it is preferable to-3-0 DEG C;
According to the present invention, in order to described contact reacts can be enable fully to carry out, the reaction times of described contact reacts is 3-20h, it is preferable that 10-15h.
Present invention also offers the preparation method of the adamantyl pyridinecarboxylic amine complex of structure shown in a kind of preparation formula (I), wherein, in presence of organic solvent, by the intermediate of structure shown in formula (L1) and [M (N3)2]��6H2O carries out complex reaction;
In formula (L1), n is 1-3, it may be preferred that n is 1;
In above-mentioned formula, M is divalent metal, and N3 is selected from perchlorate, hexafluorophosphoricacid acid ions or tetrafluoroborate ion;
Preferably, M is Cu2+Or Zn2+, N3 is perchlorate;
More preferably, described [M (N3)2]��6H2O is Cu (ClO4)2��6H2O��
According to the present invention, if described organic solvent can solubilizing reaction raw material and with reaction solvent reaction organic solvent. Acetonitrile, N can be enumerated, one or more in the alcohol of dinethylformamide, C1-C3 and methyl-sulphoxide as such reaction solvent. It is preferably the alcohol of C1-C3, it is more preferable to be ethanol. Further preferred above-mentioned organic solvent is anhydrous solvent (namely water-content is less than 50ppm).
According to the present invention, described [M (N3)2]��6H2The consumption of O can change in wide region. But in order to improve receipts rate, relative to intermediate described in 1mmol, described [M (N3)2]��6H2The consumption of O is 0.5-2mmol; In order to improve receipts rate further, it is more preferable to ground, relative to intermediate described in 1mmol, described [M (N3)2]��6H2The consumption of O is 0.5-1mmol.
According to the present invention, the consumption of described organic solvent can change in wide scope. But in order to improve receipts rate, it is preferable that, relative to intermediate described in 1mmol, the consumption of described organic solvent is 20-400ml; In order to improve receipts rate further, relative to intermediate described in 1mmol, the consumption of described organic solvent is 40-250ml.
According to the present invention, in order to improve the speed of response of complex reaction, it may be preferred that described complex reaction carries out under heating, it is preferable that the temperature of reaction of described complex reaction is 40-100 DEG C, it is more preferable to be 40-80 DEG C.
According to the present invention, in order to described complex reaction can be enable fully to carry out, it is preferable that the reaction times of described complex reaction is 1-6h, it is more preferable to be 2-3h.
Adamantyl pyridinecarboxylic amine complex prepared by the method described in above-mentioned adamantyl pyridinecarboxylic amine complex or upper item that present invention also offers is in the application eliminated in Superoxide radical anion.
Hereinafter will be described the present invention by embodiment, but the present invention is not limited in following embodiment.
The medicine used in following examples, test case and solvent: riboflavin and methionine(Met) are purchased from my fourth reagent (China) company limited; Nitro blue tetrazolium (NBT) is purchased from Sa grace chemical technology (Shanghai) company limited; Other reagent is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.
Testing method in following examples and test case is: ultimate analysis carries out with the use of Germany elemental analyser VarioELIIICHNanalyzer, examination of infrared spectrum carries out with the use of Japan Shimadzu Fourier transformation infrared spectrometer IRPrestige-21, single crystal diffraction test is undertaken by Germany BrukerAXS single crystal diffractometer Smol/LARTAPEX II, visible-ultraviolet test is undertaken by Japan's Shimadzu ultraviolet-visible pectrophotometer UV-2450 photometer, electrochemical properties test is undertaken by CHI-440a type electrochemical workstation, core magnetic tester is undertaken by Germany's BrukerAV300 nuclear magnetic resonance analyser.
Preparation example 1
The preparation of 1-diamantane acyl chlorides:
In 250mL round-bottomed flask, add 1-adamantanecarboxylic acid solid 10.0mmol and dry toluene solvent 60mL successively, magnetic agitation is slowly dripped after dissolving and is added thionyl chloride 20mL, back flow reaction 8 hours at 80 DEG C, being cooled to 20 DEG C, rotary evaporation is except desolventizing, then repeats 3 times and add 10mL dry toluene, rotary evaporation, except desolventizing and excessive thionyl chloride, obtains faint yellow crystalline powder.
Embodiment 1-1
The preparation of the intermediate of structure shown in formula (L2):
In 100mL round-bottomed flask, under 0 DEG C of condition, add 1-diamantane acyl chlorides 5.0mmol and 25mL dry toluene successively, after magnetic agitation is dissolved, add 10mmol Anhydrous potassium carbonate, slower dripping adds 2-methylamino pyridine 6.3mmol, reacts 12 hours under condition of ice bath, filtering, decompression rotates distilled and obtains light yellow thick product 1.154g except after desolventizing. Thick product carries out recrystallization with ethyl acetate and ether mixed solvent, obtains white powder. At ethyl acetate and sherwood oil mixed solvent (v/v=1:3) recrystallization, obtaining white powder 1.050g, receipts rate is 76%. Its detection data are as follows.
White powder is carried out ultimate analysis, and result is C17H22N2O:C, 75.36%; N, 10.18%; H, 8.47%; Calculated value: C, 75.52%; N, 10.36%; H, 8.20%, illustrate that detected value and calculated value match;1HNMR(CDCl3,300MHz):��(ppm):8.53(m,1H,NH),7.65(s,1H,Py),7.22-7.25(m,2H,Py),6.98(s,1H,Py),4.52(d,2H,Py-CH2),2.05(d,3H,CH),1.91(d,6H,CH2),1.70(m,6H,CH2); IR (KBrdisc, cm-1):3441,2900,2845,1628,1588,1532,1350,747,671��
Embodiment 1-2
The preparation of the intermediate of structure shown in formula (L2):
Carrying out according to the method for embodiment 1-1, institute is 10mmol the difference is that 2-methylamino pyridine, obtains white powder, and receipts rate is 76%. Its detection data are as follows.
White powder is carried out ultimate analysis, and result is C17H22N2O:C, 75.36%; N, 10.18%; H, 8.47%; Calculated value: C, 75.52%; N, 10.36%; H, 8.20%, illustrate that detected value and calculated value match;1HNMR(CDCl3,300MHz):��(ppm):8.53(m,1H,NH),7.65(s,1H,Py),7.22-7.25(m,2H,Py),6.98(s,1H,Py),4.52(d,2H,Py-CH2),2.05(d,3H,CH),1.91(d,6H,CH2),1.70(m,6H,CH2); IR (KBrdisc, cm-1):3441,2900,2845, 1628,1588,1532,1350,747,671��
Embodiment 1-3
The preparation of the intermediate of structure shown in formula (L2):
Carrying out according to the method for embodiment 1-1, institute is 15mmol the difference is that 2-methylamino pyridine, obtains white powder, and receipts rate is 76%. Its detection data are as follows.
White powder is carried out ultimate analysis, and result is C17H22N2O:C, 75.36%; N, 10.18%; H, 8.47%; Calculated value: C, 75.52%; N, 10.36%; H, 8.20%, illustrate that detected value and calculated value match;1HNMR(CDCl3,300MHz):��(ppm):8.53(m,1H,NH),7.65(s,1H,Py),7.22-7.25(m,2H,Py),6.98(s,1H,Py),4.52(d,2H,Py-CH2),2.05(d,3H,CH),1.91(d,6H,CH2),1.70(m,6H,CH2); IR (KBrdisc, cm-1):3441,2900,2845,1628,1588,1532,1350,747,671��
Embodiment 1-4
The preparation of the intermediate of structure shown in formula (L2):
Carrying out according to the method for embodiment 1-1, institute is 5mmol the difference is that salt of wormwood, obtains white powder, and receipts rate is 75%. Its detection data are as follows.
White powder is carried out ultimate analysis, and result is C17H22N2O:C, 75.36%; N, 10.18%; H, 8.47%; Calculated value: C, 75.52%; N, 10.36%; H, 8.20%, illustrate that detected value and calculated value match;1HNMR(CDCl3,300MHz):��(ppm):8.53(m,1H,NH),7.65(s,1H,Py),7.22-7.25(m,2H,Py),6.98(s,1H,Py),4.52(d,2H,Py-CH2),2.05(d,3H,CH),1.91(d,6H,CH2),1.70(m,6H,CH2); IR (KBrdisc, cm-1):3441,2900,2845,1628,1588,1532,1350,747,671��
Embodiment 1-5
The preparation of the intermediate of structure shown in formula (L2):
Carrying out according to the method for embodiment 1-1, institute is 18mmol the difference is that salt of wormwood, obtains white powder, and receipts rate is 74%. Its detection data are as follows.
White powder is carried out ultimate analysis, and result is C17H22N2O:C, 75.36%; N, 10.18%; H, 8.47%; Calculated value: C, 75.52%; N, 10.36%; H, 8.20%, illustrate that detected value and calculated value match;1HNMR(CDCl3,300MHz):��(ppm):8.53(m,1H,NH),7.65(s,1H,Py),7.22-7.25(m,2H,Py),6.98(s,1H,Py),4.52(d,2H,Py-CH2),2.05(d,3H,CH),1.91(d,6H,CH2),1.70(m,6H,CH2); IR (KBrdisc, cm-1):3441,2900,2845,1628,1588,1532,1350,747,671��
Embodiment 2
The preparation of title complex shown in formula (II):
In the round-bottomed flask of 100ml, add 0.037gCu (ClO successively4)2��6H2O (0.1mmol), (2-picoline)-1-diamantane acid amides 0.054g (0.2mmol) and 15mL methyl alcohol, after 20 DEG C of lower magnetic force stirring and dissolving, back flow reaction 2 hours at 50 DEG C, obtain deep green settled solution, it is cooled to 20 DEG C, after filtering, filtrate is volatilized naturally, obtains deep green bulk crystals after one week, and receipts rate is 46%. Its detection data are as follows.
Above-mentioned deep green bulk crystals is carried out ultimate analysis, and result is C34H46N4O11Cl2Cu:C, 49.56%; N, 6.67%; H, 5.89%; Calculated value: C, 49.73%; N, 6.82%; H, 5.65%, illustrate that detected value and calculated value match; IR (KBrdisc, cm-1):2900,2851,1588,1539,1353,1100,780,617��
Title complex II is carried out single crystal diffraction, and as shown in Figure 2, as shown in Figure 2, title complex II is mononuclear copper complex to result, bivalent cupric ion and two N, H2O on the upper carbonyl of 1 of O and two diamantane in O carries out coordinating the title complex being formed and having 5 coordinate bonds, and two adamantane structures distribute axisymmetricly about the central shaft of title complex II simultaneously.
Test case 1
Riboflavin-methionine(Met) luminescence method measures complex-catalyzed superoxide anion O2��-The principle of disproportionation activity as shown in Figure 1, when there are not the stand-in of SOD or SOD in the solution, O2The Superoxide radical anion O that under existing, riboflavin and methionine(Met) produce2��-, main O2��-Can react with nitro blue tetrazolium NBT and generate blue compound (in ultraviolet-visible spectrophotometer ��maxCan be detected under=560nm). When solution having SOD or stand-in exist, O2��-Will part catalyzed generation H2O2And O2, the amount generating compound of wearing in one's hair by the blue first moon with NBT reaction just reduces, and therefore can be measured SOD and stand-in catalysis O over time by ��=560nm place absorbancy2��-The activity of disproportionation. Specific experiment method is as follows:
Prepare, with redistilled water, the 0.05mol/L phosphate buffer soln that pH is 7.8, and it is that solvent prepares 8.25 �� 10 respectively taking phosphate buffer soln-5Mol/L riboflavin, the methionine(Met) of 0.25mol/L, 1.15 �� 10-3The NBT of mol/L. In the SOD or stand-in determination of activity of various different concns, get above riboflavin successively, methionine(Met) and each 1mL of NBT solution, mix with the SOD of different concns or stand-in, being diluted to 25mL with phosphate buffered saline buffer, the thermostatic bath lucifuge that then mixed solution puts into 25 �� 0.1 DEG C is put into thermostat container after being incubated 10 minutes and is carried out illumination. 3.5 took out the absorbance A that 3mL solution Japan Shimadzu ultraviolet-visible pectrophotometer UV-2450 photometer (doing blank with phosphate buffer soln) measures solution under 560nm wavelength in minute every 0.5 minute. Under measuring, by riboflavin-methionine(Met) method, the title complex different concns obtained, absorbancy is over time, data linear regression fit absorbancy under finite concentration changed in time obtains a straight line, gained straight slope, i.e. the changing value �� A/ �� t of unit time absorbancy. When SOD in solution or stand-in concentration are zero, the �� A/ �� t obtained is (�� A/ �� t) 0, measuring, when the concentration of SOD in solution or stand-in is mol/L, the �� A/ �� t that obtains is (�� A/ �� t) m, obtains SOD or the stand-in inhibiting rate percentage ratio under this concentration by following formula.
Taking title complex concentration as X-coordinate, inhibiting rate is ordinate zou, obtains the concentration that inhibiting rate is 50% title complex, namely draws the SOD reactivity parameter IC of title complex II50, i.e. the concentration of an activity unit. The IC of stand-in50It is worth more little, represents that activity is more high.
Measure natural ox erythrocyte superoxide dismutase (BeSOD) and the activity of title complex II catalysis Superoxide radical anion disproportionation according to the method described above. As shown in Figure 3, it is possible to from the change curve of inhibiting rate with Different Complex concentration, the concentration of title complex, i.e. IC when showing that inhibiting rate is 50%50Value. By comparing IC50Value judges the activity of title complex, IC50It is worth more little then expression title complex activity more high.
The IC of BeSOD50It is 0.04 ��m of ol/L, the IC of title complex II50It is 0.12 ��m of ol/L. As shown in Figure 5, in title complex II structure, two diamantane groups are positioned at same side and have constructed hydrophobic channel thus concerted catalysis, amide nitrogen atom protonization is positively charged simultaneously, can identify Superoxide radical anion in catalytic process, so that title complex II has excellent IC50, therefore, title complex II has the activity of higher catalysis Superoxide radical anion disproportionation.
Test case 2
The redox-potential of title complex II utilizes cyclic voltammetry to measure at CHI-440a type electrochemical workstation, it may also be useful to three-electrode system, and platinum wire electrode is as supporting electrode, and glass-carbon electrode is as working electrode, and silver/silver chloride electrode is as reference electrode. Title complex II N, N '-dimethyl methane amide makes solvent, and concentration is that the tetrabutylammonium perchlorate of 0.1mol/L is as supporting electrolyte. All tests carry out in room temperature all under nitrogen protection, and sweep velocity is 100mVS-1. The Electrochemical results of title complex II is as shown in Figure 4: Epc is 0.240V and Epa is 0.390V, and its half-wave potential is 0.315V. The half-wave potential of title complex II is in catalysis superoxide anion disproportionation-0.36V-0.69V(vsAg/AgCl) in potential range, so chemically the known copper complex II in thermodynamics aspect has the activity of catalysis superoxide anion disproportionation.
Below the preferred embodiment of the present invention is described in detail; but, the detail that the present invention is not limited in above-mentioned enforcement mode, within the scope of the technical conceive of the present invention; the technical scheme of the present invention can being carried out multiple simple variant, these simple variant all belong to protection scope of the present invention. It should be noted that in addition, each concrete technology feature described in above-mentioned embodiment, when not contradiction, it is possible to combined by any suitable mode, in order to avoid unnecessary repetition, various possible array mode is illustrated by the present invention no longer separately.
In addition, can also carrying out arbitrary combination between the various different enforcement mode of the present invention, as long as it does not run counter to the thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (13)
1. an adamantyl pyridinecarboxylic amine complex, it is characterised in that, the structure of described title complex such as formula shown in (I),
Formula (I), n is 1, M is Cu2+, N3 is selected from perchlorate.
2. the preparation method of the intermediate of the adamantyl pyridinecarboxylic amine complex of structure shown in a formula (L1), it is characterized in that, under the existence of carbonate, compound by structure shown in 1-diamantane acyl chlorides and formula (C1) carries out contact reacts in organic solvent;
In upper formula, n is 1; Described carbonate is salt of wormwood, and described organic solvent is toluene.
3. preparation method according to claim 2, wherein, relative to 1-diamantane acyl chlorides 1mmol, the consumption of described Compound C 1 is 1-3mmol, and the consumption of described organic solvent is 2-20ml, and the consumption of described carbonate is 1-4mmol.
4. preparation method according to Claims 2 or 3, wherein, the temperature of reaction of described contact reacts is-10-0 DEG C; The reaction times of described contact reacts is 3-20h.
5. preparation method according to claim 4, wherein, the temperature of reaction of described contact reacts is-3-0 DEG C; The reaction times of described contact reacts is 10-15h.
6. the preparation method of the adamantyl pyridinecarboxylic amine complex of structure shown in a formula as claimed in claim 1 (I), it is characterized in that, in presence of organic solvent, by the intermediate of structure shown in formula (L1) and [M (N3)2]��6H2O carries out complex reaction;
In formula (L1), n is 1, and in above-mentioned formula, M is Cu2+, N3 is selected from perchlorate; Described organic solvent is methyl alcohol.
7. preparation method according to claim 6, wherein, relative to intermediate described in 1mmol, described [M (N3)2]��6H2The consumption of O is 0.5-2mmol, and the consumption that described organic solvent is is 20-400ml.
8. preparation method according to claim 7, wherein, relative to intermediate described in 1mmol, described [M (N3)2]��6H2The consumption of O is 0.5-1mmol, and the consumption of described organic solvent is 40-250ml.
9., according to preparation method described in any one in claim 6-8, wherein, the temperature of reaction of described complex reaction is 40-100 DEG C.
10. preparation method according to claim 9, wherein, the temperature of reaction of described complex reaction is 40-80 DEG C.
11. according to preparation method described in any one in claim 6-8, and wherein, the reaction times of described complex reaction is 1-6h.
12. preparation methods according to claim 11, wherein, the reaction times of described complex reaction is 2-3h.
The application of 13. adamantyl pyridinecarboxylic amine complexes according to claim 1 in the preparation of the medicine for eliminating Superoxide radical anion.
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| CN1230111A (en) * | 1996-07-08 | 1999-09-29 | 盖尔德马研究及发展公司 | Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents |
| JP2004284994A (en) * | 2003-03-24 | 2004-10-14 | Sumitomo Chem Co Ltd | New copper complex containing adamantane structure |
| CN102105437A (en) * | 2008-07-25 | 2011-06-22 | H.隆德贝克有限公司 | Adamantyl diamide derivatives and uses of same |
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| CN1230111A (en) * | 1996-07-08 | 1999-09-29 | 盖尔德马研究及发展公司 | Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents |
| JP2004284994A (en) * | 2003-03-24 | 2004-10-14 | Sumitomo Chem Co Ltd | New copper complex containing adamantane structure |
| CN102105437A (en) * | 2008-07-25 | 2011-06-22 | H.隆德贝克有限公司 | Adamantyl diamide derivatives and uses of same |
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| Nitrophenol Resins for Facile Amide and Sulfonamide Library Synthesis;J W Lee et al.;《J.Comb.Chem.》;20030125;第5卷(第3期);第330-335页 * |
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