CN109180738A - Organic iridium complex and preparation method thereof and application in preparation of anti-tumor drugs - Google Patents
Organic iridium complex and preparation method thereof and application in preparation of anti-tumor drugs Download PDFInfo
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- CN109180738A CN109180738A CN201810961839.XA CN201810961839A CN109180738A CN 109180738 A CN109180738 A CN 109180738A CN 201810961839 A CN201810961839 A CN 201810961839A CN 109180738 A CN109180738 A CN 109180738A
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- iridium complex
- organic iridium
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- phenylbenzimidazol
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- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 47
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000010668 complexation reaction Methods 0.000 title abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 title description 7
- 229940041181 antineoplastic drug Drugs 0.000 title description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 33
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 22
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 18
- AZRBPNMWQFEAJW-UHFFFAOYSA-N 2-(4-iodophenyl)-1-phenylbenzimidazole Chemical compound C1=CC(I)=CC=C1C1=NC2=CC=CC=C2N1C1=CC=CC=C1 AZRBPNMWQFEAJW-UHFFFAOYSA-N 0.000 claims abstract description 16
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 16
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 201000007270 liver cancer Diseases 0.000 claims abstract description 12
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 230000036571 hydration Effects 0.000 claims abstract description 11
- 238000006703 hydration reaction Methods 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 11
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims abstract description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 206010020772 Hypertension Diseases 0.000 claims abstract description 6
- 229910021638 Iridium(III) chloride Inorganic materials 0.000 claims abstract description 6
- 238000006392 deoxygenation reaction Methods 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 6
- DANYXEHCMQHDNX-UHFFFAOYSA-K trichloroiridium Chemical compound Cl[Ir](Cl)Cl DANYXEHCMQHDNX-UHFFFAOYSA-K 0.000 claims abstract description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims abstract description 5
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 5
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 5
- HRDCVMSNCBAMAM-UHFFFAOYSA-N 3-prop-2-ynoxyprop-1-yne Chemical class C#CCOCC#C HRDCVMSNCBAMAM-UHFFFAOYSA-N 0.000 claims abstract description 3
- CKDZUORTXOCQNI-UHFFFAOYSA-N 3-methoxy-1h-indole Chemical class C1=CC=C2C(OC)=CNC2=C1 CKDZUORTXOCQNI-UHFFFAOYSA-N 0.000 claims abstract 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 abstract description 20
- -1 stirring Chemical compound 0.000 abstract description 7
- 238000012827 research and development Methods 0.000 abstract description 3
- 239000012327 Ruthenium complex Substances 0.000 abstract 1
- 239000002547 new drug Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229910052697 platinum Inorganic materials 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 230000031700 light absorption Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 3
- IKCZUPRWPVLSLF-UHFFFAOYSA-N 2-methoxy-1h-indole Chemical class C1=CC=C2NC(OC)=CC2=C1 IKCZUPRWPVLSLF-UHFFFAOYSA-N 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
- 229910052792 caesium Inorganic materials 0.000 description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0033—Iridium compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses organic iridium complex and preparation method thereof, the following steps are included: hydrated iridium trichloride and pentamethylcyclopentadiene base is taken to be dissolved in dehydrated alcohol, return stirring, obtain chemical compounds I, 2- (4- iodophenyl) -1- phenylbenzimidazol and 3- methoxy indoles is taken to be added in carbon tetrachloride, it is heated to reflux temperature, add N- bromo-succinimide, back flow reaction, remove carbon tetrachloride, chemical compounds I is added thereto, one hydration p-methyl benzenesulfonic acid, toluene, stirring, ethylenediamine is added dropwise simultaneously, cesium carbonate, the mixed liquor of triethylamine, logical nitrogen deoxygenation, add bis- (2-propynyl) ethers of diethylene glycol, tetrakis triphenylphosphine palladium, cupric iodide, 80 DEG C of reactions, hydrochloric acid is added dropwise to neutrality, brown solid is precipitated, the as described organic iridium complex.The invention also discloses application of organic ruthenium complex in preparation treatment gastric cancer medicament, liver-cancer medicine, hypertension drug, prepare new drug for research and development and provide experimental basis.
Description
Technical field
The present invention relates to organic iridium complex fields.It is more particularly related to a kind of organic iridium complex and its
Preparation method and application in preparation of anti-tumor drugs.
Background technique
Chemotherapy is one of main means for the treatment of of cancer, and 1978, Barnett Rosenberg had found cis-platinum antineoplastic
Characteristic, cis-platinum has become one of most common anti-tumor drug.The discovery of cis-platinum excites numerous scientific workers couple
In the research of platinum metals drug, the several generations platinum complex such as carboplatin, oxaliplatin is synthesized and is applied to clinic, but these
Drug inevitably still has the similar disadvantage of cis-platinum, and serious toxicity is lower to certain activity of tumor cells, structure
On similitude drug resistance or cross resistance are become limit such clinical drug application, and be currently employed for clinicalization
The tens of kinds of anti-tumor drugs treated or assisted only have preferable curative effect to the treatment of Partial tumors.Therefore, it prepares new
Metal complex is applied to prepare anti-tumor drug, provides more selections for the treatment of tumor disease, it has also become current grinds
Study carefully hot spot.
Summary of the invention
It is an object of the invention to solve at least the above problems, and provide the advantages of at least will be described later.
It is a still further object of the present invention to provide a kind of organic iridium complex and preparation method thereof and preparing antineoplastic
Application in object increases the type of preparation treatment hypertension drug to increase the type for preparing treatment gastric cancer and liver-cancer medicine.
In order to realize these purposes and other advantages according to the present invention, a kind of organic iridium complex is provided, this is organic
The structural formula of complex of iridium are as follows:
The preparation method of organic iridium complex, comprising the following steps:
Step 1: it is anhydrous to take hydrated iridium trichloride and pentamethylcyclopentadiene base to be dissolved in for 1:1.05~1.08 in molar ratio
In ethyl alcohol, 6~8h of return stirring obtains chemical compounds I；
Step 2: counting by molar, 1 molar part 2- (4- iodophenyl) -1- phenylbenzimidazol and 1.02~1.05 is taken to rub
You are added in carbon tetrachloride part 3- methoxy indoles, are heated to reflux temperature, add N- bromo-succinimide, flow back
Reaction 22~for 24 hours, remove carbon tetrachloride, thereto be added 1.02~1.04 molar part chemical compounds Is, one hydration p-methyl benzenesulfonic acid,
Toluene, stirring, while the mixed liquor of ethylenediamine, cesium carbonate, triethylamine is added dropwise, lead to nitrogen deoxygenation, adds 1.02~1.05 and rub
Bis- (2-propynyl) ethers of your part diethylene glycol, tetrakis triphenylphosphine palladium, cupric iodide, 80 DEG C of reactions 22~for 24 hours, hydrochloric acid is added dropwise into
Property, brown solid, the as described organic iridium complex is precipitated.
Preferably, in step 2 2- (4- iodophenyl) -1- phenylbenzimidazol and N- bromo-succinimide ratio
For 1mol:6~10g.
Preferably, in step 2 2- (4- iodophenyl) -1- phenylbenzimidazol and one hydration p-methyl benzenesulfonic acid ratio
It is 1
Mol:10~12g.
Preferably, the ratio of 2- (4- iodophenyl) -1- phenylbenzimidazol and ethylenediamine is 1mol:1g in step 2,
Ethylenediamine in mixed liquor, cesium carbonate, triethylamine weight ratio be 1:5:15
Preferably, the ratio of 2- (4- iodophenyl) -1- phenylbenzimidazol and tetrakis triphenylphosphine palladium is in step 2
1mol:15g, the weight ratio of tetrakis triphenylphosphine palladium and cupric iodide is 15:2 in step 2.
Application of the organic iridium complex in the drug of preparation treatment gastric cancer and liver cancer.
Application of the organic iridium complex in preparation treatment hypertension drug.
The present invention is include at least the following beneficial effects: preparation method of the present invention is simple, and reaction pilot process is mentioned without separation
Pure operation, preparation cost is low, and benzimidazole and indoles heterocycle are contained in obtained organic iridium complex, there is big conjugated system, point
Son is more stable, while having ethylene glycol structure, enhances its hydrophobic effect, is conducive to penetrate cancer cell film, and it is anti-swollen to enhance it
Tumor activity, organic iridium complex of the invention have preferably the growth of SGC-7901 cell, liver cancer BEL-7404 cell
Inhibitory activity, the drug for research and development preparation new treatment gastric cancer and liver cancer provides data basis, to angiotensin converting enzyme
There is preferable inhibitory activity, the drug for the new treatment hypertension of research and development preparation provides data basis.
Further advantage, target and feature of the invention will be partially reflected by the following instructions, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Specific embodiment
The present invention will be further described in detail below with reference to the embodiments, to enable those skilled in the art referring to specification
Text can be implemented accordingly.
It should be noted that experimental method described in following embodiments is unless otherwise specified conventional method, institute
Reagent and material are stated, unless otherwise specified, is commercially obtained.
<embodiment 1>
The preparation method of organic iridium complex, comprising the following steps:
Step 1: taking hydrated iridium trichloride and pentamethylcyclopentadiene base to be dissolved in dehydrated alcohol for 1:1.05 in molar ratio
In, return stirring 6h obtains chemical compounds I；
Step 2: counting by molar, 1 molar part 2- (4- iodophenyl) -1- phenylbenzimidazol and 1.02 molar part 3- are taken
Methoxy indoles is added in carbon tetrachloride, is heated to reflux temperature, adds N- bromo-succinimide, 2- (4- iodobenzene
Base) ratio of -1- phenylbenzimidazol and N- bromo-succinimide is 1mol:6g, back flow reaction 22h, carbon tetrachloride is removed,
1.02 molar part chemical compounds Is, hydration a p-methyl benzenesulfonic acid, solvent toluene, 2- (4- iodophenyl) -1- phenyl benzo are added thereto
The ratio of imidazoles and a hydration p-methyl benzenesulfonic acid is 1mol:10g, stirring, at the same be added dropwise ethylenediamine, cesium carbonate, triethylamine it is mixed
The ratio of conjunction liquid, 2- (4- iodophenyl) -1- phenylbenzimidazol and ethylenediamine is 1mol:1g, ethylenediamine, carbonic acid in mixed liquor
Caesium, triethylamine weight ratio be 1:5:15, lead to nitrogen deoxygenation, it is bis- (2-propynyl) to add 1.02 molar part diethylene glycols
The ratio of ether, tetrakis triphenylphosphine palladium, cupric iodide, 2- (4- iodophenyl) -1- phenylbenzimidazol and tetrakis triphenylphosphine palladium is
The weight ratio of 1mol:15g, tetrakis triphenylphosphine palladium and cupric iodide is 15:2,80 DEG C of reaction 22h, and hydrochloric acid is added dropwise to neutrality, analysis
Brown solid out, as product organic iridium complex.
<embodiment 2>
The preparation method of organic iridium complex, comprising the following steps:
Step 1: taking hydrated iridium trichloride and pentamethylcyclopentadiene base to be dissolved in dehydrated alcohol for 1:1.08 in molar ratio
In, return stirring 8h obtains chemical compounds I；
Step 2: counting by molar, 1 molar part 2- (4- iodophenyl) -1- phenylbenzimidazol and 1.05 molar part 3- are taken
Methoxy indoles is added in carbon tetrachloride, is heated to reflux temperature, adds N- bromo-succinimide, 2- (4- iodobenzene
Base) ratio of -1- phenylbenzimidazol and N- bromo-succinimide is 1mol:10g, back flow reaction for 24 hours, removes four chlorinations
1.04 molar part chemical compounds Is, hydration a p-methyl benzenesulfonic acid, solvent toluene, 2- (4- iodophenyl) -1- phenyl is added in carbon thereto
The ratio of benzimidazole and a hydration p-methyl benzenesulfonic acid is 1mol:12g, is stirred, while ethylenediamine, cesium carbonate, triethylamine is added dropwise
Mixed liquor, the ratio of 2- (4- iodophenyl) -1- phenylbenzimidazol and ethylenediamine is 1mol:1g, ethylenediamine, carbon in mixed liquor
Sour caesium, triethylamine weight ratio be 1:5:15, lead to nitrogen deoxygenation, it is bis- (2-propynyl) to add 1.05 molar part diethylene glycols
The ratio of ether, tetrakis triphenylphosphine palladium, cupric iodide, 2- (4- iodophenyl) -1- phenylbenzimidazol and tetrakis triphenylphosphine palladium is
The weight ratio of 1mol:15g, tetrakis triphenylphosphine palladium and cupric iodide is 15:2, and for 24 hours, hydrochloric acid is added dropwise to neutrality, analysis in 80 DEG C of reactions
Brown solid out, as product organic iridium complex.
<embodiment 3>
The preparation method of organic iridium complex, comprising the following steps:
Step 1: taking hydrated iridium trichloride and pentamethylcyclopentadiene base to be dissolved in dehydrated alcohol for 1:1.06 in molar ratio
In, return stirring 7h obtains chemical compounds I；
Step 2: counting by molar, 1 molar part 2- (4- iodophenyl) -1- phenylbenzimidazol and 1.03 molar part 3- are taken
Methoxy indoles is added in carbon tetrachloride, is heated to reflux temperature, adds N- bromo-succinimide, 2- (4- iodobenzene
Base) ratio of -1- phenylbenzimidazol and N- bromo-succinimide is 1mol:8g, back flow reaction 23h, carbon tetrachloride is removed,
1.03 molar part chemical compounds Is, hydration a p-methyl benzenesulfonic acid, solvent toluene, 2- (4- iodophenyl) -1- phenyl benzo are added thereto
The ratio of imidazoles and a hydration p-methyl benzenesulfonic acid is 1mol:11g, stirring, at the same be added dropwise ethylenediamine, cesium carbonate, triethylamine it is mixed
The ratio of conjunction liquid, 2- (4- iodophenyl) -1- phenylbenzimidazol and ethylenediamine is 1mol:1g, ethylenediamine, carbonic acid in mixed liquor
Caesium, triethylamine weight ratio be 1:5:15, lead to nitrogen deoxygenation, it is bis- (2-propynyl) to add 1.03 molar part diethylene glycols
The ratio of ether, tetrakis triphenylphosphine palladium, cupric iodide, 2- (4- iodophenyl) -1- phenylbenzimidazol and tetrakis triphenylphosphine palladium is
The weight ratio of 1mol:15g, tetrakis triphenylphosphine palladium and cupric iodide is 15:2,80 DEG C of reaction 23h, and hydrochloric acid is added dropwise to neutrality, analysis
Brown solid out, as product organic iridium complex.
The chemical structural formula of the resulting organic iridium complex of above-described embodiment 1~3 are as follows:
The physicochemical property of the resulting organic iridium complex of above-described embodiment 1~3: brown crystal, it is soluble easily in water and organic molten
Agent,1H NMR(CDCl3, 400MHZ), δ (ppm): 8.36 (dd, 1H, J=7.5,1.4Hz), 8.08-8.01 (m, 3H), 7.95
(d, 2H, J=7.5Hz), 7.81 (dd, 2H, J=7.5,1.5Hz), 7.68-7.50 (m, 7H), 7.39 (t, 1H), 7.05 (td,
1H, J=7.5,1.4Hz), 5.02 (s, 2H), 4.66 (s, 2H), 4.51 (d, 2H, J=2.9Hz), 3.99 (t, 2H, J=
7.0Hz,),3.81-3.61(m,8H),2.89(t,1H),1.70(s,15H)。
The chemical equation of the resulting organic iridium complex of above-described embodiment 1~3 is as follows:
<anti tumor activity in vitro experiment>
SGC-7901 cell culture: SGC-7901 cell is added to the RPMI- of the calf serum containing 100mL/L
It in 1640 culture medium, cultivates in 37 DEG C, the incubator of 5% carbon dioxide, with 2.5g/L pancreatin, EDTA had digestive transfer culture, takes pair
The cell of number growth is tested.
Mtt assay measures organic iridium complex to the inhibitory activity of SGC-7901 cell strain: test sets blank control group
And experimental group, the SGC-7901 cell of logarithmic growth phase, 96 orifice plates are added, 100 μ L cell suspensions are added in every hole, successively
Embodiment 3 resulting organic iridium complex is added and forms 0.10,0.20,0.40,0.80,1.60,3.20,6.40umol/mL
Concentration, 8 multiple holes of each concentration, while using physiological saline as blank control group, 20 μ L are added containing tetramethyl after 72h after dosing
The phosphate buffer of base azo azoles salt (MTT) 2g/L, 37 DEG C, the incubator of 5% carbon dioxide be incubated for 4h, discard supernatant liquid,
200 μ L of dimethyl sulfoxide is added in every hole, with the value at microplate reader measurement 490nm, reflects survivaling cell quantity, calculates organic iridium cooperation
Object is to the half-inhibitory concentration of SGC-7901 cell strain, and the results are shown in Table 1.
Half-inhibitory concentration of 1 organic iridium complex of table to tumour cell
| Cell strain | SGC-7901 |
| IC50(umol/mL) | 1.2±0.80 |
Liver cancer BEL-7404 cell culture: liver cancer BEL-7404 cell is added to the RPMI- of the calf serum containing 100mL/L
It in 1640 culture medium, cultivates in 37 DEG C, the incubator of 5% carbon dioxide, with 2.5g/L pancreatin, EDTA had digestive transfer culture, takes pair
The cell of number growth is tested.
Mtt assay measures organic iridium complex to the inhibitory activity of liver cancer BEL-7404 cell: test set blank control group and
96 orifice plates are added in experimental group, the liver cancer BEL-7404 cell of logarithmic growth phase, and 100 μ L cell suspensions are added in every hole, successively plus
Enter the resulting organic iridium complex of embodiment 3 formed 0.05,0.10,0.20,0.40,0.80,1.60,3.20umol/mL it is dense
Degree, 8 multiple holes of each concentration, while using physiological saline as blank control group, 20 μ L are added containing MTT after 72h after dosing
The phosphate buffer of 2g/L, 37 DEG C, the incubator of 5% carbon dioxide be incubated for 4h, discard supernatant liquid, dimethyl sulfoxide is added in every hole
200 μ L reflect survivaling cell quantity with the value at microplate reader measurement 490nm, calculate organic iridium complex to liver cancer BEL-7404
The half-inhibitory concentration of cell, the results are shown in Table 2.
Half-inhibitory concentration of 2 organic iridium complex of table to tumour cell
| Cell strain | BEL-7404 |
| IC50(umol/mL) | 0.33±0.21 |
The result of experiment one and experiment two can be seen that the organic iridium complex to SGC-7901 cell, liver cancer
BEL-7404 cell has inhibitory effect, and the anti-tumor drug to research and develop new provides experimental basis.
<angiotensin converting enzyme (ACE) inhibitory activity>
Hippuric acid-histidine-Leucine is dissolved in the borate buffer solution of the 0.1mol/L of the NaCl containing 0.2mol/L
In, the pH of buffer is 8.3, is configured to take the 100 above-mentioned horses of μ L containing hippuric acid-histidine-Leucine 5.0mmol/L solution
Uric acid-histidine-Leucine solution is mixed with the aqueous solution of 100 μ L organic iridium complex containing 0.1g/L, adds 150 μ L
250 μ L 1.0mol/L hydrochloric acid are added in 37 DEG C of reaction 60min in 0.1U/mL angiotensin converting enzyme solution, terminate reaction,
Ethyl acetate 1.5mL is added afterwards to be extracted, intense oscillations 1min is centrifuged 5min under the revolving speed of 3000r/min, takes acetic acid second
The diaminobenzidine color developing agent that 1.0mL acetic anhydride and 2.0mL mass fraction are 0.5%, 40 DEG C of colour developings are added in ester layer 0.5mL
30min measures its light absorption value at 459nm.Inhibiting rate is calculated according to the following formula:
Inhibiting rate=[(A-S)/(A-C)] × 100%
Wherein A is the light absorption value for replacing inhibitor to be measured with water, and the light absorption value that S is measured for addition inhibitor, C is to add
The reference light absorption value of ethyl acetate, acetic anhydride and color developing agent.
Inhibiting rate of 3 organic iridium complex of table to ACE
| Inhibitor | ACE inhibiting rate (%) |
| Organic iridium complex | 88.6 |
Table 3 shows that organic iridium complex has preferable inhibitory activity to ACE in the present invention, to research and develop new treatment
Hypertension drug provides experimental basis.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily
Realize other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and embodiment shown and described herein.
Claims (8)
1. organic iridium complex, which is characterized in that the structural formula of the organic iridium complex are as follows:
。
2. the preparation method of organic iridium complex as described in claim 1, which comprises the following steps:
Step 1: taking hydrated iridium trichloride and pentamethylcyclopentadiene base to be dissolved in dehydrated alcohol for 1:1.05~1.08 in molar ratio
In, 6~8h of return stirring obtains chemical compounds I；
Step 2: counting by molar, 1 molar part 2- (4- iodophenyl) -1- phenylbenzimidazol and 1.02~1.05 molar parts are taken
3- methoxy indoles is added in carbon tetrachloride, is heated to reflux temperature, adds N- bromo-succinimide, back flow reaction
22~for 24 hours, carbon tetrachloride is removed, 1.02~1.04 molar part chemical compounds Is, hydration a p-methyl benzenesulfonic acid, toluene are added thereto,
Stirring, while the mixed liquor of ethylenediamine, cesium carbonate, triethylamine is added dropwise, lead to nitrogen deoxygenation, adds 1.02~1.05 molar parts two
Bis- (2-propynyl) ethers of ethylene glycol, tetrakis triphenylphosphine palladium, cupric iodide, 80 DEG C of reactions 22~for 24 hours, hydrochloric acid is added dropwise to neutrality, analysis
Brown solid out, the as described organic iridium complex.
3. the preparation method of organic iridium complex as claimed in claim 2, which is characterized in that 2- (4- iodobenzene in step 2
Base) ratio of -1- phenylbenzimidazol and N- bromo-succinimide is 1mol:6~10g.
4. the preparation method of organic iridium complex as claimed in claim 2, which is characterized in that 2- (4- iodobenzene in step 2
Base) -1- phenylbenzimidazol and one hydration p-methyl benzenesulfonic acid ratio be 1mol:10~12g.
5. the preparation method of organic iridium complex as claimed in claim 2, which is characterized in that 2- (4- iodobenzene in step 2
Base) ratio of -1- phenylbenzimidazol and ethylenediamine is 1mol:1g, the weight of ethylenediamine, cesium carbonate, triethylamine in mixed liquor
Ratio is 1:5:15.
6. the preparation method of organic iridium complex as claimed in claim 2, which is characterized in that 2- (4- iodobenzene in step 2
Base) ratio of -1- phenylbenzimidazol and tetrakis triphenylphosphine palladium is 1mol:15g, tetrakis triphenylphosphine palladium and iodine in step 2
The weight ratio for changing copper is 15:2.
7. organic iridium complex as described in claim 1 is in the application of the drug of preparation treatment gastric cancer and liver cancer.
8. application of the organic iridium complex as described in claim 1 in preparation treatment hypertension drug.
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