CN107446001A - Using 1- pyridine -6- methoxy-p-carbolines as nickel chloride (II) chelate of part and its synthetic method and application - Google Patents
Using 1- pyridine -6- methoxy-p-carbolines as nickel chloride (II) chelate of part and its synthetic method and application Download PDFInfo
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- CN107446001A CN107446001A CN201610377085.4A CN201610377085A CN107446001A CN 107446001 A CN107446001 A CN 107446001A CN 201610377085 A CN201610377085 A CN 201610377085A CN 107446001 A CN107446001 A CN 107446001A
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 24
- 239000013522 chelant Substances 0.000 title abstract description 30
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 title abstract description 17
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 title abstract description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 239000002798 polar solvent Substances 0.000 claims abstract description 18
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims abstract description 15
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 9
- 238000010668 complexation reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 239000000376 reactant Substances 0.000 claims description 12
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- JTEJPPKMYBDEMY-UHFFFAOYSA-N 5-methoxytryptamine Chemical class COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 3
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- RQLKZZBMSWQOQJ-UHFFFAOYSA-N 1-methoxy-9h-pyrido[3,4-b]indole Chemical compound C12=CC=CC=C2NC2=C1C=CN=C2OC RQLKZZBMSWQOQJ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000013078 crystal Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- 239000000047 product Substances 0.000 description 13
- 229910006148 NiII Inorganic materials 0.000 description 12
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- 238000000034 method Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 239000003446 ligand Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
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- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 240000005523 Peganum harmala Species 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002050 diffraction method Methods 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 235000005126 Peganum harmala Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
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- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
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- 229940088597 hormone Drugs 0.000 description 1
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- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
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- 239000011572 manganese Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
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- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
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- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
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- 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
- 229960001756 oxaliplatin Drugs 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/04—Nickel compounds
- C07F15/045—Nickel compounds without a metal-carbon linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of using the methoxy-beta carboline of 1 pyridine 6 as nickel chloride (II) chelate of part and its synthetic method and application.Shown in the structural formula such as following formula (I) of nickel chloride (II) chelate, its preparation method is:Compound and Nickel dichloride hexahydrate as shown in following formula (II) are taken, is dissolved in polar solvent, complexation reaction is carried out, that is, obtains target product.Nickel chloride (II) chelate of the present invention shows the antitumor activity more stronger than its part, has preferable potential medical value, is expected to be used for the preparation of various antineoplastics.Structure shown in formula (I) and formula (II) is as follows:
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of using 1- pyridine -6- methoxy-p-carbolines as nickel chloride (II) chelate of part and its synthetic method and application.
Background technology
Cancer (also known as malignant tumour) is that one of death rate highest disease, serious threat the health of the mankind in the world at present.In recent years, as the clinical practice of the medicines such as cis-platinum, Metal Substrate chelate antineoplastic have been increasingly becoming study hotspot.The build-in attribute of metal and the combination of biologically active ligand molecule, for some efficient, low toxicities, spectrum is wide and provides wide space for the new drug development of target activity.
Beta-carboline alkaloid is a kind of active component separated from Xinjiang medicinal plant harmel (Peganum harmala).Pharmacological activity with wide spectrum, such as antianxiety, antidepression, anti-spasm and antitumor, anti-malarial, anti parasitic, anti-AIDS.It is long-standing come treating cancer with seed of peganum harmala in Chinese herbal medicine formula.The structural modification of beta-carboline alkaloid enjoys the concern of researcher always.It is generally believed that the planar conjugate structure and different substituents group (such as benzyl (- C of most of beta-carboline alkaloids6H5), methoxyl group (- OCH3)) presence and its antitumor activity there is significant relation.Research to beta-carboline alkaloid at present mainly includes the following aspects:Found in the plant of never equal category first, being studied based on natural product chemistry and carry out separating-purifying;Second, it is fully synthetic or semi-synthetic to beta-carboline alkaloid progress by methodology of organic synthesis, its structure is modified.It is other then be to its pharmacological activity (such as antitumor activity) carry out molecular mechanism research.DNA is such as inserted, suppresses topoisomerase, suppress CDK etc..But from the point of view of current progress, content of the beta-carboline alkaloid in natural plants is general all than relatively low, and extraction is relatively complicated, it is unfavorable for furtheing investigate it, though and organic semisynthesis on yield with certain advantage, but limited by cost is produced, therefore the expansion research at present to beta-carboline alkaloid is still inadequate.
On the other hand, the effect played with platinum series antineoplastic medicament (cis-platinum, carboplatin, oxaliplatin etc.) in the treatment of disease is increasing, and inorganic drug research turns into worldwide focus.Because platinum series antineoplastic medicament has the shortcomings of strong poorly water-soluble, drug resistance and nerve, kidney toxic side effect, their use range is limited.Preclinical and clinical trial shows:The development of non-platinum medicine has broad prospects.By the effort of nearly 30 years, chemist had found some transition metal chelates, and these transition metals are generally positioned in the periodic table of elements period 4 and are micro elements needed by human mostly.Such as manganese, iron, cobalt, nickel, copper, zinc and the tin of IV A races.The micro presence in human body or organism of these elements is widely distributed, and they form the large biological molecules such as enzyme, hormone or vitamin, play important physiological action in vivo by being chelated with protein or the coordination of some organic groups.Such as Zn (II) is the required composition of tens kinds of enzymes of archaeal dna polymerase;Fe (II) is present in hemoglobin and myoglobins the delivery and release for participating in oxygen;Mn (II) can promote mitochondria metabolism and energy conversion, and its presence can activate a variety of enzymatic activitys;Cu (II) is one of teleorganic element, and in life entity, it forms chelate with organic ligand and is widely present.But the chemical research at present using 1- pyridine -6- methoxy-p-carbolines as nickel chloride (II) chelate of part still belongs to blank.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of new nickel chloride (II) chelate, i.e., nickel chloride (II) chelate using 1- pyridine -6- methoxy-p-carbolines as part, and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt:
The synthetic method of compound is shown in above-mentioned formula (I):Compound and Nickel dichloride hexahydrate as shown in following formula (II) are taken, is dissolved in polar solvent, complexation reaction is carried out, that is, obtains target product;
The synthetic route of above-mentioned synthetic method is as follows:
Compound shown in the raw material formula (II) being related in above-mentioned synthetic method participates in reacting as part, and its chemical name is 1- pyridine -6- methoxy-p-carbolines (1-Pyridine-6-Methoxy- β-Carboline), abbreviation LKL.Compound shown in the formula (II) can designed, designed synthetic route prepared, preferably prepared as follows:Using 5- methoxytryptamines and pyridine-2-formaldehyde as raw material, add acidic materials and carry out cyclization (i.e. Pictet-Spengler condensation reactions), products therefrom with Pd/C oxidative dehydrogenations, produces again.Specific synthetic route is as follows:
Reagent:(a) tetrahydrofuran or dichloromethane;(b) dimethylbenzene or methyl phenyl ethers anisole.
The more specifically synthetic method of compound shown in above-mentioned formula (II), comprises the following steps:
1. taking 5- methoxytryptamines to be dissolved in tetrahydrofuran or dichloromethane, pyridine-2-formaldehyde is then added, after mixing, partially acidic material, stirring reaction is added dropwise;After reaction terminates, reactant is adjusted to neutral or alkalescence, is extracted with ethyl acetate or chloroform, is collected organic phase, solvent is evaporated off, obtains yellow oily solid i.e. compound 1;
2. compound 1 is dissolved in dimethylbenzene or methyl phenyl ethers anisole, Pd/C is added, is reacted under heating condition, gained reactant filtering, washed filter cake, collect filtrate, be spin-dried for, that is, obtain the crude product (i.e. compound 2) of compound shown in formula (II).
Shown in above-mentioned formula (II) the step of compound synthesis method 1. in, the ratio between amount of material of raw material 5- methoxytryptamines and pyridine-2-formaldehyde be usually 1:1.5 or 1:1, the preferably mole of pyridine-2-formaldehyde is carried out slightly larger than the amount of the material of 5- methoxytryptamines with reacting fully.The pH value of filtrate is adjusted using alkali lye, and described alkali lye can be ammoniacal liquor, or in sodium acetate, sodium carbonate, sodium phosphate, sodium acid carbonate and potassium carbonate any one or more alkaline matters the aqueous solution.Preferably use the sodium bicarbonate solution or ammonia spirit of saturation.Reactant is preferably transferred to pH value as 7~9.
Shown in above-mentioned formula (II) the step of compound synthesis method 1. in, acidic materials used can be trifluoroacetic acid, acetic acid, hydrochloric acid or sulfuric acid.The dosage of hydrochloric acid and trifluoroacetic acid is usually 4~5 times of pyridine-2-formaldehyde volume, and if acetic acid, then addition is 6~7 times of pyridine-2-formaldehyde volume, and if sulfuric acid, then addition is 2~3 times of pyridine-2-formaldehyde volume, preferred trifluoroacetic acid in the application.The reaction added after acidic materials is preferably carried out at normal temperatures.
Shown in above-mentioned formula (II) the step of compound synthesis method 1. in, with pyridine-2-formaldehyde aldimine condensation reaction occurs under acid catalysis for raw material 5- methoxytryptamines, intermediate schiff bases is formed, schiff bases occurs ring closure reaction and forms compound 1 under the action of an acid.Because trifluoroacetic acid is smoke strong acid in synthetic method, therefore reaction is preferably carried out under condition of ice bath.Whether reaction can use thin-layer chromatography (TLC) tracing detection completely, generally control the reaction time appropriate for 1~2h.After the completion of reaction, it must be depressurized in 30~45 DEG C of temperature ranges and be spin-dried for solvent, occurred to prevent side reaction.Solvents tetrahydrofurane or the dosage of dichloromethane are advisable with that can dissolve the raw material of participation reaction, it is generally the case that are calculated by 1mmol 5- methoxytryptamines on the basis of 0.5~1mL tetrahydrofurans or the dissolving of 0.4~1mL dichloromethane.
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, Pd/C addition is usually 1~2 times of the amount of the material of compound 1, and described Pd/C can be 5%Pd/C or 10%Pd/C, and 10%Pd/C is preferably used in this synthetic method;In the step, reaction condition is preferably carried out under the conditions of 140~160 DEG C, carries out back flow reaction under the conditions of 140~160 DEG C more preferably in reflux.Whether reaction is complete, can use TLC tracing detections, generally controls the reaction time appropriate for 12~24h.
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, generally use methanol, chloroform and ethyl acetate washing filter cake it is multiple, preferably 5~10 times;To its washing sequence and no requirement (NR), preferably methanol at first, chloroform take second place, ethyl acetate it is last.
What the above method was prepared is the crude product of compound shown in formula (II), in order to further improve the purity of compound shown in formula (II), it is more beneficial for the progress of subsequent reactions, preferably above-mentioned gained crude product is purified, is used further to after operation in the synthetic method of target product of the present invention.Described purification process is same as the prior art, can be specifically to be purified crude product using fast liquid chromatography, to obtain pure compounds shown in formula (II);Reagent used is to press 3 by ethyl acetate and n-hexane in purge process:7~3:The mixed solvent of 9 volume ratio composition, or press 3 by ethyl acetate and petroleum ether:7~3:The mixed solvent of 9 volume ratio composition.
In the synthetic method of compound shown in formula (I) of the present invention, described polar solvent is ethanol and one kind in water, acetone, chloroform, dimethyl sulfoxide (DMSO), DMF and acetonitrile or any two or more combination.Preferable ethanol ratio shared in polar solvent is 80~85v/v%.When in polar solvent containing any two or more selection in water, acetone, chloroform, dimethyl sulfoxide (DMSO), DMF and acetonitrile, under precondition of their total amount without departing from 20%, their proportioning can be any proportioning.The dosage of the polar solvent can be determined as needed, it is generally the case that compound shown in 2mmol Nickel dichloride hexahydrate and 1mmol formulas (II) is dissolved with 35~40mL polar solvent.In specific dissolving step, additive polarity solvent again after typically compound shown in Nickel dichloride hexahydrate and formula (II) is mixed;Also compound shown in six directions nickel chloride and formula (II) can be dissolved with polar solvent respectively, remixes and react together.
In the synthetic method of compound shown in formula (I) of the present invention, the mol ratio of compound is stoichiometric proportion shown in the Nickel dichloride hexahydrate and formula (II), usually 2:1.
Compound shown in formula (I) of the present invention specifically in synthesis, can use normal pressure solwution method or the hot method of high pressure solvent to be synthesized.
When using normal pressure solwution method, its synthetic method includes:Compound shown in formula (II) and Nickel dichloride hexahydrate are taken, is dissolved in polar solvent, gained mixed liquor reacts under heating condition, and reactant removes partial solvent, stands, and separates out, isolates solid, produce target product.
In above-mentioned normal pressure solwution method, reaction preferably uses back flow reaction, and reaction is preferably carried out in 45 DEG C to polar solvent of reflow temperature range, more preferably reacted under the conditions of 65~80 DEG C.Whether reaction can use thin-layer chromatography tracing detection completely, and under above-mentioned qualifications, reaction time control is more suitable in 24~48h.Reactant removes partial solvent by the way of concentration, and typically concentration removes the 80~90% of polar solvent addition.
When the hot method of high pressure solvent, its synthetic method includes:Compound shown in formula (II) and Nickel dichloride hexahydrate are taken, is dissolved in polar solvent, gained mixed liquor is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, sealing, is then reacted under heating condition, is obtained target product.
In the above-mentioned hot method of high pressure solvent, described container is usually heavy wall borosilicate glass tube, and reaction is generally carried out under the conditions of 45~80 DEG C, and under this temperature conditions, the time of reaction is preferably controlled in 48~72h, also can extend to more than 72h according to actual conditions.
Present invention additionally comprises the application of compound or its pharmaceutically acceptable salt in antineoplastic is prepared shown in above-mentioned formula (I).
Present invention additionally comprises the antineoplastic prepared using compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) as active component.
Compared with prior art, the invention provides a kind of new nickel chloride (II) chelate, i.e., nickel chloride (II) chelate using 1- pyridine -6- methoxy-p-carbolines as part, and its synthetic method and application.Applicant is by investigating its inhibitory action to various tumor cell strains, as a result show that 1- pyridines -6- methoxy-p-carbolines nickel chloride (II) chelate shows the antitumor activity more stronger than its part, with preferable potential medical value, the preparation of various antineoplastics is expected to be used for.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of final product made from the embodiment of the present invention 1;
Fig. 2 is the carbon-13 nmr spectra figure of final product made from the embodiment of the present invention 1;
Fig. 3 is the electrospray ionization mass spectrum spectrogram of final product made from the embodiment of the present invention 1;
Fig. 4 is the x-ray crystal structure figure of final product made from the embodiment of the present invention 1;
Fig. 5 is the x-ray crystal structure figure of final product made from the embodiment of the present invention 4.
Fig. 6 is the electrospray ionization mass spectrum spectrogram of final product made from the embodiment of the present invention 4.
Embodiment
With reference to specific embodiment, the present invention is described in further detail, and to more fully understand present disclosure, but the present invention is not limited to following examples.
Embodiment 1:Compound shown in formula (II) is the synthesis of 1- pyridine -6- methoxy-p-carbolines (LKL)
1) 50mg 5- methoxytryptamines are taken, are dissolved in 20mL tetrahydrofurans, stirs and 25 μ L pyridine-2-formaldehydes is added dropwise, ice bath stirring 20min, then add the μ L of trifluoroacetic acid 110, remove ice bath after reacting about 1h, normal temperature continues to react about 1h;Reaction terminates rear gained reactant and adjusted with enough ammoniacal liquor to neutrality, and separates organic phase with ethyl acetate, and decompression is spin-dried for, and obtains yellow oily liquid, and this step does not purify to be directly used in reacts in next step;
2) yellow oily liquid is added in 50mL dimethylbenzene, then adds 100mg 10%Pd/C, be warming up to 140 DEG C, it is back flow reaction, overnight;After reaction terminates, reactant is filtered, filter cake is washed 10 times with methanol, chloroform, ethyl acetate successively, collects filtrate, filtrate decompression is spin-dried for, obtains crude product, and upper fast liquid chromatography is purified (V afterwardsEthyl acetate:VN-hexane=3:7) yellow crystals, are obtained (yield is about 70%).
It is as follows that gained yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum and single crystal diffraction analysis, specific spectral characteristic:
(1) proton nmr spectra and carbon spectrum, their spectrogram difference is as illustrated in fig. 1 and 2.
1H NMR(500MHz,CDCl3)δ:11.22 (s, 1H), 8.82~8.74 (m, 2H), 8.53 (d, J=5.1Hz, 1H), 7.98 (d, J=5.1Hz, 1H), 7.90 (td, J=7.8,1.8Hz, 1H), 7.60 (d, J=2.4Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 7.37-7.32 (m, 1H), 7.25 (dd, J=8.8,2.5Hz, 1H), 3.96 (s, J=4.0Hz, 3H).
13C NMR(126MHz,CDCl3)δ:157.87,154.08,148.25,138.09,137.44, 136.83,135.68,135.30,130.36,122.92,121.41,121.35,118.51,115.36,112.67,103.57,77.30,77.25,77.04,76.79,56.02。
(2) electrospray ionization mass spectrum, as shown in figure 3, ESI-MS m/z:276.11[M+H]+.
(3) X ray single crystal diffraction is analyzed, and determines that its mono-crystalline structures is as shown in Figure 4.
Accordingly, it can be determined that above-mentioned yellow solid product is 1- pyridine -6- methoxy-p-carbolines, shown in its chemical structural formula such as following formula (II):
Embodiment 2:Ligand L KL synthesis
1) 50mg 5- methoxytryptamines are taken, are dissolved in 30mL dichloromethane, stirs and 30 μ L pyridine-2-formaldehydes is added dropwise, after uniform stirring 10min, add acetic acid 180 μ L, normal-temperature reaction about 2h;After reaction terminates, gained reactant is adjusted to neutrality with enough ammoniacal liquor, and organic phase is separated with chloroform, decompression is spin-dried for, and obtains yellow oily liquid, and this step does not purify to be directly used in reacts in next step;
2) yellow oily liquid is added in 40mL methyl phenyl ethers anisoles, then adds 50mg 10%Pd/C, be warming up to 160 DEG C, back flow reaction 20h;After reaction terminates, reactant is filtered, washed 5 times with chloroform, methanol, ethyl acetate successively, collected filtrate, filtrate decompression is spin-dried for, obtains crude product, upper fast liquid chromatography is purified (V afterwardsEthyl acetate:VPetroleum ether=3:9) yellow crystals, are obtained (yield is about 55%).
Gained yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum and single crystal diffraction analysis, is defined as target product 1- pyridine -6- methoxy-p-carbolines.
Embodiment 3:Ligand L KL synthesis
1) 50mg 5- methoxytryptamines are taken, are dissolved in 30mL tetrahydrofurans, stirs and 20 μ L pyridine-2-formaldehydes is added dropwise, ice bath stirring 15min, then add the μ L of sulfuric acid 60, remove ice bath after reacting about 1h, normal temperature continues to react about 0.5h;Reaction terminates rear gained reactant and adjusted with enough ammoniacal liquor to alkalescence, and separates organic phase with ethyl acetate, and decompression is spin-dried for, and obtains yellow oily liquid, and this step does not purify to be directly used in reacts in next step;
2) yellow oily liquid is added in 40mL methyl phenyl ethers anisoles, then adds 120mg 5%Pd/C, be warming up to 150 DEG C, back flow reaction 24h;After reaction terminates, reactant is filtered, filter cake is washed 8 times successively with methanol, chloroform, ethyl acetate successively, collects filtrate, filtrate decompression is spin-dried for, obtains crude product, and upper fast liquid chromatography is purified (V afterwardsEthyl acetate:VPetroleum ether=3:8) yellow crystals, are obtained (yield is about 45%).
Gained yellow crystals are carried out with proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum and single crystal diffraction analysis, is defined as target product 1- pyridine -6- methoxy-p-carbolines.
Embodiment 4:Chelate [NiII(LKL)Cl(μ2-Cl)]2Synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.2mmol Nickel dichloride hexahydrates and 0.1mmol ligand L KL are directly added into, adding the mixed solvent that 0.5mL is made up of ethanol and dimethyl sulfoxide (DMSO), (volume ratio of ethanol and dimethyl sulfoxide (DMSO) is 5:1);Vacuum is evacuated to after liquid nitrogen frozen, openend is sealed, then the fully reaction 48h under the conditions of 80 DEG C;After reaction terminates, cool 5 DEG C per hour, until dropping to room temperature, that is, there is red sheet crystalline solids product to separate out.
By above-mentioned gained red product through electrospray ionization mass spectrum (as shown in Figure 6) and X ray single crystal diffraction analytical structure measure (as shown in Figure 5), it is defined as nickel chloride (II) chelate using 1- pyridine -6- methoxy-p-carbolines as part, i.e. target chelate [NiII(LKL)Cl(μ2-Cl)]2, its structural formula is for example following shown:
Embodiment 5:Chelate [NiII(LKL)Cl(μ2-Cl)]2Synthesis
Embodiment 4 is repeated, unlike:
Reaction temperature is changed to 45 DEG C, reaction time 72h, after reaction terminates, and directly cools down.
Separate out red powder and carry out structure determination through electrospray ionization mass spectrum and the analysis of X ray single crystal diffraction, be defined as target chelate [NiII(LKL)Cl(μ2-Cl)]2(yield 80%).
Embodiment 6:Chelate [NiII(LKL)Cl(μ2-Cl)]2Synthesis
Embodiment 4 is repeated, unlike:
(volume ratio of ethanol and chloroform is 15 to the mixed solvent that polar solvent is changed to be made up of ethanol and chloroform:2), reaction temperature is still 80 DEG C, reaction time 48h, after reaction terminates, is directly cooled down.
Separate out product and carry out structure determination through electrospray ionization mass spectrum and the analysis of X ray single crystal diffraction, be defined as target chelate [NiII(LKL)Cl(μ2-Cl)]2(yield 89%).
Embodiment 7:Chelate [NiII(LKL)Cl(μ2-Cl)]2Synthesis
Ligand L KL 1mmol, Nickel dichloride hexahydrate 2mmol are weighed respectively;Ligand L KL is dissolved in 20mL ethanol, Nickel dichloride hexahydrate is dissolved in 10mL DMF, uniformly mixes two kinds of solution, 24h is reacted at 80 DEG C, it is concentrated under reduced pressure after removing most of solvent (the 80% of solvent adding amount), is cooled to room temperature, stands, separate out red solid, solid is isolated, is washed with water, dries, obtain red solid product.
Products therefrom carries out structure determination by the analysis of electrospray ionization mass spectrum combination X ray single crystal diffraction, is defined as target chelate [NiII(LKL)Cl(μ2-Cl)]2(yield 80%).
Embodiment 8:Chelate [NiII(LKL)Cl(μ2-Cl)]2Synthesis
Embodiment 7 is repeated, unlike:
DMF in polar solvent makes acetone into, and the volume ratio of ethanol and acetone is 10:1, reaction temperature is 75 DEG C, reaction time 48h.
Separate out product and carry out structure determination through infrared spectrum, elementary analysis, electrospray ionization mass spectrum, the analysis of X ray single crystal diffraction, be defined as target chelate [NiII(LKL)Cl(μ2-Cl)]2(yield 78%).
Embodiment 9:Chelate [NiII(LKL)Cl(μ2-Cl)]2Synthesis
Ligand L KL 1mmol, Nickel dichloride hexahydrate 2mmol are weighed respectively;Ligand L KL and Nickel dichloride hexahydrate are dissolved in the in the mixed solvent being made up of 10mL ethanol and 10mL acetonitriles, 48h is reacted at 45 DEG C, it is concentrated under reduced pressure after removing most of solvent (the 90% of solvent adding amount), it is cooled to room temperature, stand, separate out red solid, isolate solid, it is washed with water, dries, obtains red solid product.
Products therefrom carries out structure determination by the analysis of electrospray ionization mass spectrum combination X ray single crystal diffraction, is defined as target chelate [NiII(LKL)Cl(μ2-Cl)]2(yield 75%).
Of the present invention antitumor activity experiment is carried out to the chelate and its ligand L KL using purposes of the 1- pyridine -6- methoxy-p-carbolines as nickel chloride (II) chelate of part in pharmacy, applicant to absolutely prove.
Experimental example 1:Nickel chloride (II) chelate (being made by the method for embodiment 4) and ligand L KL (being made by the method for embodiment 1) using 1- pyridine -6- methoxy-p-carbolines as part carry out external inhibitory activity experiment to a variety of human tumor strains
1st, cell line and cell culture
This experiment is from T24 (human bladder cancer cell), OS-RC-2 (human renal carcinoma cell), NCI-H-460 (human large cell lung cancer), SK-OV-3 (strain of people's ovary adenocarcinoma cells), Hep G2 (human liver cancer cell), MGC803 (gastric carcinoma cells) etc..
All cell lines cultivate the tire of ox containing 10%FBS serum, 1% mycillin mixed liquor DMEM nutrient solutions in, put 37 DEG C of 5%CO containing volumetric concentration2Cultivated in incubator.OS-RC-2 cell lines are the RPMI-1640 nutrient solutions in the tire of ox containing 10%FBS serum, 1% mycillin mixed liquor, and other conditions are consistent.
2nd, primary dcreening operation
Serum-free DMEM, OS-RC-2 are changed after 96 orifice plates of each strain cell kind are adherent and changes RPMI-1640, dosing after 12 to 18 hours.This experiment compound (purity is >=95%), is configured to 200 μm of ol/L intermediate concentrations by compound, takes 20 μ L intermediate concentration compound solutions, add in 96 orifice plates of existing 180 μ L cell liquid, final compound concentration is 20 μm of ol/L.DMSO final concentration≤1%, test the inhibition level that compound on tumor cell grows under the concentration.Every inhibiting rate is more than 50%, and meet the metamorphosis (such as cell shrinkage, crushing, floating etc.) of cell under light microscopic suppressed (or impaired), then it is determined as that primary dcreening operation is effective, it is table 1 to try to achieve inhibiting rate result.
3rd, cell growth inhibition test (mtt assay)
After test-compound to be measured is dissolved with DMSO, serum free medium dilution intermediate concentration is 200 μm of ol/L, 100 μm of ol/L, 50 μm of ol/L, 25 μm of ol/L, 12.5 μm of ol/L, it is degerming with the filtering with microporous membrane of d=0.22 μm of diameter again, it is placed at 4 DEG C and preserves.
The panel of tumor cell line in exponential phase is inoculated in 96 orifice plates respectively with every μ L of hole 180 respectively, edge hole adds 200 μ L PBS (phosphoric acid buffer salt powder prepares solution), and cell concentration is about 1 × 104/ hole, cultivate 12 hours, after cell attachment, change serum-free DMEM, OS-RC-2 changes RPMI-1640, and 12 to 18 hours compound intermediate concentration liquid, each concentration of compound is parallel to set 5 multiple holes, wherein DMSO final concentration≤1%, corresponding negative control group (there was only cell and equivalent DMSO, no medicine in nutrient solution) and blank control group (there was only the medicine of equivalent in nutrient solution, acellular) are set simultaneously, each group is also parallel to set 5 multiple holes, drug treating time 48h.Culture terminates to add 10 μ L MTT (5mg/mL PBS) per hole in first 4 hours, continue after cultivating 4h, incline nutrient solution, the μ L/ holes of DMSO 100 are added, plate shaker vibration 7min, crystal is fully dissolved, blank control group returns to zero, absorbance (A) value after removing background absorbance value is determined with 570nm/630nm dual wavelengths with ELIASA, measures inhibiting rate, IC50, its test result is as shown in the following Table 2:
Table 1:
Table 2:
Claims (10)
1. compound or its pharmaceutically acceptable salt shown in lower formula (I):
2. the synthetic method of compound described in claim 1, it is characterised in that:Take such as following formula (II) institute
Show compound and Nickel dichloride hexahydrate, be dissolved in polar solvent, carry out complexation reaction, that is, obtain target
Product;
3. synthetic method according to claim 2, it is characterised in that:Described polar solvent
For ethanol and it is selected from water, acetone, chloroform, dimethyl sulfoxide (DMSO), DMF and acetonitrile
In one kind or any two or more combination.
4. the synthetic method according to Claims 2 or 3, it is characterised in that:Take shown in formula (II)
Compound and Nickel dichloride hexahydrate, are dissolved in polar solvent, and gained mixed liquor reacts under heating condition,
Reactant removes partial solvent, stands, and separates out, isolates solid, produce target product.
5. synthetic method according to claim 4, it is characterised in that:React at 45 DEG C extremely
Property solvent reflow temperature range in carry out.
6. the synthetic method according to Claims 2 or 3, it is characterised in that:Take shown in formula (II)
Compound and Nickel dichloride hexahydrate, are dissolved in polar solvent, and gained mixed liquor is placed in container, through liquid
Vacuum is evacuated to after chilled nitrogen, is sealed, is then reacted under heating condition, obtain target product.
7. synthetic method according to claim 6, it is characterised in that:Reaction is at 45~80 DEG C
Under the conditions of carry out.
8. the synthetic method according to Claims 2 or 3, it is characterised in that:Formula (II) institute
Show that compound is prepared as follows:Using 5- methoxytryptamines and pyridine-2-formaldehyde as raw material, add
Enter trifluoroacetic acid and carry out cyclization, products therefrom with Pd/C oxidative dehydrogenations, produces again.
9. compound described in claim 1 or its pharmaceutically acceptable salt are preparing antineoplastic
In application.
10. prepared using compound described in claim 1 or its pharmaceutically acceptable salt as active component
Antineoplastic.
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