CN108299473A - Complex and its application of the copper with the benzimidazoles compound containing pyridine - Google Patents
Complex and its application of the copper with the benzimidazoles compound containing pyridine Download PDFInfo
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- XMVRDBMVOLBYAS-UHFFFAOYSA-N CC1C(C)=CC(OC)=CC1 Chemical compound CC1C(C)=CC(OC)=CC1 XMVRDBMVOLBYAS-UHFFFAOYSA-N 0.000 description 1
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- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages
Abstract
The invention belongs to pharmaceutical technology fields, are related to novel copper complex --- the complex of copper and the benzimidazoles compound containing pyridine, the composition containing these complexs and its application in preparation of anti-tumor drugs.Shown in the compound of the present invention structure such as following formula (I)：Wherein, R is selected from H, C1 C6 alkoxies, halogenated C1 C6 alkoxies, hydroxyl, amino, nitro, cyano；R1Selected from H, C1 C6 alkyl, C1 C6 alkoxies, halogenated C1 C6 alkoxies, hydroxyl, amino, nitro, cyano；R2Selected from H, substituted or unsubstituted C1 C6 alkyl, C1 C6 alkoxies；The substituent group is C1 C6 alkoxies, halogenated C1 C6 alkoxies；R3Selected from H, C1 C6 alkyl, C1 C6 alkoxies.The complex of the present invention and its composition containing the complex can be used for preparing anti-tumor drug.
Description
Technical field
The present invention relates to novel copper complexes --- and the complex of copper and the benzimidazoles compound containing pyridine contains
The composition and its application in preparation of anti-tumor drugs of these complexs.
Background technology
Malignant tumour is universally acknowledged one of the disease to human health risk most serious, and harmfulness is only second to painstaking effort
Pipe disease.Therefore, reinforce the research of oncotherapy, improve the effect of existing various treatment means, reduce cancer mortality, reduce
Recurrence rate improves the quality of life of cancer patient, has important social benefit and huge economic benefit.In oncotherapy
In, chemotherapy is one of important method of current cancer therapies.In numerous chemotherapeutics, platinum group compound is a kind of antitumor work
With the drug relatively strong, Antitumor test is wider.It is antitumor to find that cis-platinum (cisplatin) has from Rosenberg in 1967 et al.
Since activity, cis-platinum is widely used in treating kinds cancer, such as carcinoma of testis, ovum as a kind of efficient antitumor drug
(Wong E, the Giandomenico CM.Current status such as nest cancer, cervix cancer, carcinoma of urinary bladder, lung cancer and head and neck cancer
of platinum-based antitumor drugs.Chem Rev,1999,99(9):2451-2466.).Then, a series of
Platinum group compound such as carboplatin (carboplatin), Nedaplatin (nedaplatin), oxaliplatin (oxaliplatin), Lobaplatin
(lobaplatin), Cycloplatin (cycloplatin) clinically successfully uses (Abu-Surrah as antitumor Metal Drugs
AS,Kettunen M.Platinum group antitumor chemistry:design and development of
new anticancer drugs complementary to cisplatin.Curr Med Chem,2006,13(11):
1337-57.), the problems such as but due to the toxicity and drug resistance of platinum group compound, it is antitumor to research and develop novel transient metal complex
Drug also increasingly causes extensive concern.
At the same time, copper is as micro- necessary to biology, is present in metalloprotein and metalloenzyme in organism
Active site participates in maintaining normal physiological function, development, bone to hemopoietic system and central nervous system in vivo
The processes such as the deposition of formation and skin pigment with connective tissue play an important roll, while in life vivo oxidation Reduction Body
There is unique catalytic action in system, DNA damage caused by aging and cancer and its associated endogenous oxidant is played
(Wang Feili, Chang Yanling pacify the progress chemical research of the non-platinum metals anticancer compounds of such as beautiful appearance and answer for key effect
With 2003,15 (5):612-616.), and toxicity of the toxicity of copper than nonessential trace element such as platinum is small, therefore copper metal is matched
Closing object is expected to keep the antitumor activity of platinum group compound to have the characteristics that hypotoxicity again simultaneously.
The present invention is on the basis of synthesizing some and containing the benzimidazoles compound of pyridine groups, as ligand, synthesis
Go out a series of complex of copper and the benzimidazoles compound containing pyridine, these complexs have significant antitumor work
Property, it is expected to become the drug candidate of new antitumoral treatment.
Invention content
Technical problem solved by the invention is to provide a kind of compound shown in formula I, its pro-drug and drug and lives
Property metabolin and its pharmaceutically acceptable salt, and provide its application in preparation of anti-tumor drugs.
Shown in the compound of the present invention structure such as following formula (I)：
Wherein,
R is selected from H, C1-C6 alkoxies, halogenated C1-C6 alkoxies, hydroxyl, amino, nitro, cyano；
R1Selected from H, C1-C6 alkyl, C1-C6 alkoxies, halogenated C1-C6 alkoxies, hydroxyl, amino, nitro, cyano；
R2Selected from H, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxies；The substituent group is C1-C6 alcoxyls
Base, halogenated C1-C6 alkoxies；
R3Selected from H, C1-C6 alkyl, C1-C6 alkoxies.
Preferably,
R is selected from H, C1-C4 alkoxies, halogenated C1-C4 alkoxies；
R1Selected from H, C1-C4 alkyl, C1-C4 alkoxies；
R2Selected from H, C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxies, the substituent group is C1-C4 alkoxies,
Halogenated C1-C4 alkoxies；
R3Selected from H, C1-C4 alkyl, C1-C4 alkoxies.
Further,
R is selected from H, methoxyl group, difluoro-methoxy；
R1Selected from H, methyl, methoxyl group；
R2Selected from H, methyl, methoxyl group, 2- methoxy ethoxies, 3- methoxy propoxies, 2,2,2- trifluoro ethoxies；
R3Selected from H, methyl, methoxyl group.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining compound of formula I, and with suitable non-toxic
The conventional acid addition salts or base addition salts that organic acid or inorganic acid or organic base or inorganic base are formed.Acid-addition salts include hydrochloric acid
Salt, hydrobromate, hydriodate, nitrate, phosphate, sulfate, perchlorate, rhodanate, disulfate, persulfuric acid
Salt, borate, formates, acetate, propionate, valerate, Pivalate, caproate, enanthate, caprylate, ethylhexanoate salt,
Undecanoate, laruate, palmitate, stearate, oleate, cyclopropionate salt, oxalates, malonate, succinic acid
Salt, maleate, fumarate, adipate, azelate, acrylates, strawberry salt, cronate, cautious chromate, clothing health
Hydrochlorate, sorbate, cinnamate, glycollate, lactate, malate, tartrate, citrate, sub- tartrate,
Mandelate, benzilate, tropate, ascorbate, gluconate, gluceptate, glucarate,
Mannose hydrochlorate, Lactobionate, benzoate, phthalate, terephthalate, furoate, nicotinate, isonicotinic acid salt, salicylate,
Acetylsalicylate, butyric acid salt, gallate, caffeiate, ferulate, picrate, camphor hydrochlorate, camphorsulfonic acid
Salt, mesylate, esilate, propane sulfonic acid salt, benzene sulfonate, tosilate, sulfanilate, sulfamic acid
Salt, taurate, 2- isethionates, glycinate, alanine salt, valine salt, leucine salt, isoleucine salt, benzene
Alanine salt, tryptophan salt, tyrosine salt, aspartate, asparagine salt, glutamate, lysine salt, glutamine
Salt, methionine salt, serine salt, threonine salt, cysteine salt, proline salt, histidine salt, arginine salt, edetic acid(EDTA)
Salt, acetonate, alpha-ketoglutarate, alginates, cyclopentane propionate, 3- phenylpropionic acids salt, 3- cyclohexylpropionic acids, 2- naphthalene first
Hydrochlorate, 2- naphthalene sulfonates, embonate, lauryl sulfate, glycerophosphate, lauryl sulfate, pectin resin acid salt etc..
Base addition salts include ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt, such as calcium and magnesium salts, the salt of organic base, example
Such as dicyclohexyl amine salt, N- methyl-D-glucamine salts etc., moreover, Basic nitrogen-containing groups can be quaternized with such reagent, such as
Chlorine, bromine and the iodide of elementary alkyl halide, such as methyl, ethyl, propyl and butyl；Dialkyl sulfate, such as dimethyl sulfate
Ester, diethylester, dibutyl ester and diamyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and
Iodide；Aralkyl halide, such as benzyl and phenethyl bromide.It is preferred for generating the acid of acid-addition salts including salt
Acid, p-methyl benzenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, p-aminobenzene sulfonic acid.
" pharmaceutically acceptable " carrier, excipient, pro-drug such as pharmaceutically acceptablely, referring to can pharmacologically connect
It is receiving and substantially non-toxic to the patient that particular compound is administered.
" pharmaceutical active metabolin " refers to the metabolite of pharmaceutically acceptable and effective compound of formula I.
The present invention also relates to its Pharmaceutical composition, the composition contains Formulas I or its stereoisomer or it is pharmaceutically applicable in
Acid-addition salts and pharmaceutically useful carrier.
Certain crystal forms of compound can exist with multicrystalline form, also be included within the present invention.In addition, some are changed
Solvate (i.e. hydrate) or ordinary organic solvents formation solvate, and such solvate can be formed with water by closing object
Also it is included within the scope of the present invention.
The present invention includes the prodrug of the compounds of this invention within its scope.Generally, such prodrug will be easy in vivo
In the compound for being converted into needs, this compound functionality derivative.Therefore, in the therapy of the present invention, term
" giving " will include to be converted into finger in vivo at it after patient with specifically disclosed compound, or with no specific disclosure of but giving
Determine the compound of compound, treats a variety of illness described.
Following reaction process summarises the preparation process for preparing the compounds of this invention.
Reaction process
The invention further relates to the complexs of copper and the benzimidazoles compound for containing pyridine to be used for as antitumor drug
Oncotherapy.
The therapy and dosage used
Various diseases to be treated and illness described herein are well known to those skilled in the art and clear.Also it should manage
Solve those skilled in the art can with the compound of therapeutically effective amount treat at present just for disease or illness and pain patient, or
Person by it is preventative treatment for disease or illness by the patient of pain to influence related disease and illness.
Terms used herein " patient " refer to the warm-blooded animal with tumour, such as mammal.It should be understood that cavy,
Dog, cat, rat, mouse horse, ox, sheep and people are the examples of the animal in this term implication scope.
Term " therapeutically effective amount " used herein refers to effectively being measured to controlling disease related with tumour and illness.Art
Language " control " is used to refer to the process of all development that can slow down, interrupt, prevent or stop disease and illness described herein,
And it is not necessarily the symptom for needing to completely eliminate whole diseases and illness.
Therapeutically effective amount can be used as those skilled in the art by curing mainly diagnostician and use conventional technique and observation
The result obtained under similar situation is readily determined.In the dose procedure for determining therapeutically effective amount, diagnostician's consideration is cured mainly
Many factors, including but not limited to：The type of mammal；Its size, age and health condition substantially；The specific disease being related to
Disease；The degree or complex situations or severity of disease；The reaction of individual patient；The specific compound of administration；Administering mode；It gives
The bioavailability characteristics of the preparation of medicine；The scheme of making up a prescription of selection；The use of adjoint drug therapy and other relevant situations.
The therapeutically effective amount of compound is estimated from about 0.001 milligram of per kilogram of body weight daily (mg/kg/ days) to about
100mg/kg/ days etc..Preferred amount can be determined by those skilled in the art.
When effective treatment suffers from the patient of above-mentioned disease and illness, such compound can be with so that compound biology can
By any form or in the way of be administered by therapeutically effective amount, including oral, sucking and parenteral path.For example, compound
Can by oral, inhalation aerosol or xeraphium, hypodermic injection, intramuscular injection, intravenous injection, cutaneous penetration, intranasal administration,
Rectally, local administration etc. mode are administered.Oral or inhalation is generally preferable for treatment respiratory disease, such as
Asthma.Those skilled in the art of preparation formula can be according to the concrete property of the compound of selection, disease or disease to be treated
The stage of the case where disease, disease or illness and other relevant situations are readily selected appropriate form of medication and mode.
The compound of the present invention can be administered alone or be combined with medicine group with pharmaceutically acceptable carrier or excipient
The form administration of object is closed, the ratio and property of carrier or excipient are by the solubility and chemical property of the compound selected, selection
Administration route and standard pharmacy criterion determine.It, can be with it pharmaceutically although the compound of the present invention is effective in itself
The form preparation formula of acceptable salt such as acid-addition salts or base addition salts and administration, this is for stabilization, facilitates crystallization, carries
The purpose of high-dissolvability etc..
The present invention provides the compounds containing therapeutically effective amount and one or more pharmaceutically acceptable carriers or tax
The pharmaceutical composition that shape agent is mixed or is otherwise in connection with.
Pharmaceutical composition is prepared by the well-known method of drug field.It can be as the carrier or medium of active constituent
Carrier or excipient can be solid, semisolid or liquid charging stock.Suitable carrier or excipient be it is well known in the art that
's.Pharmaceutical composition can be made to be suitable for, and oral, sucking, parenteral uses or local use, can be with tablet, capsule, aerosol, suction
Enter agent, suppository, solution, suspension etc. form to patient medication.
The compound of the present invention can for example with a kind of inert diluent or with a kind of edible carrier oral medication it
Can wrap in capsule or be pressed into tablet.For oral therapeutic administration, compound can be mixed with excipient, and with tablet,
Pastille, capsule, elixir, suspension, syrup, wafer, chewing gum etc. form use.These preparations should contain at least
4% the compounds of this invention, i.e. active constituent, but can be changed according to concrete form, in unit weight 4% to about
Easily change between 70%.Suitable dosage should can be obtained by being present in the amount of the compound of composition.It is currently preferred
Composition and preparation can be determined by those skilled in the art.
Tablet, pill, capsule, pastille etc. can also contain one or more following auxiliary agents：Adhesive such as crystallite
Cellulose, yellow natural gum or gelatin；Excipient such as starch or lactose, disintegrant such as alginic acid, Primogel, cornstarch
Etc.；Lubricant such as magnesium stearate or Sterotex；Glidant such as colloidal silicon dioxide；And Sweetening agents can be added such as
Sucrose or saccharin or flavoring agent such as peppermint, gaultherolin or orange flavor.When dosage unit form is capsule, in addition to containing
Have except the raw material of the above-mentioned type, liquid-carrier such as polyethylene glycol or fat oil can be contained.Other dosage unit forms
The different raw material of the others of modification dosage unit physical form can be contained, such as coating.In this way, tablet or pill can
To be coated with sugar, piece glue or other enteric coating agents syrup in addition to containing this compound, can contain sucrose as sweetener with
Certain preservative, dyes and dyestuffs and flavorant.It should be pharmacy to prepare the material that these different compositions use
It is nontoxic under pure and usage amount.
In order to which parenteral therapeutic is administered, the compound of the present invention can be added in a kind of solution or suspension.These systems
Agent should contain at least 0.1% the compounds of this invention, but can change between the 0.1 of weight of formulation and about 50%.
The amount for the compound being present in this composition should can obtain suitable dosage.Preferred composition and chaste tree processed can be by
Those skilled in the art determine.
The compound of the present invention can also be administered by sucking, such as with aerosol or xeraphium.A kind of liquefaction can be used
Or compression gas with it is a kind of distribution the compounds of this invention or its formula suitable pumping system discharge.By suckingization
Closing the formula of object administration can be conveyed with single-phase, two-phase or three-phase system.It is many for the aerosol drug delivery with compound
System is available.Dry powder formulation is by pelletizing or be milled to suitable grain size and prepare compound, or by mixing
Close prepared by having pelletized or the compound milled and suitable carrier such as lactose etc..Include by the release system of sucking
Necessary container, activator, valve, sub- container etc..It can be by preferably through the aerosol and dry powder formulation of inhalation
Those skilled in the art determine.
The compound of the present invention can cut out body with local administration, when doing so and suitably contain solution, ointment or gel
Base.Base can for example give up one or more following substances：Vaseline, lanolin, polyethylene glycol, beeswax, mineral oil, such as
The concentration of the diluent and emulsifier and stabilizer local prescriptions calcium containing compound or its pharmaceutically acceptable salt of water and alcohol
It can be from about 0.1 to about 10%w/v (weight per unit volume).
The solution or suspension can also contain one or more further auxiliaries：Sterile diluent such as water for injection,
Saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetics；Antiseptic such as benzylalcohol or hydroxyl
Methyl benzoate；Antioxidant such as vitamin C or sodium hydrogensulfite；Intercalating agent such as ethylenediamine tetra-acetic acid；Buffer example
As acetate, citrate either phosphate and adjust osmotic pressure reagent such as sodium chloride or glucose.Parenteral administration
It can be mounted in ampoule, disposable syringe or multiple dose vials made of glass or plastics.
Description of the drawings
Fig. 1 is the molecular structure of complex G-12.
Specific implementation mode
Embodiment 1：Bis- (μ-sulfate radical-O, O') bis- { 2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto-κ N] -1H-
Benzimidazole-κ N3Close two bronze medals (II) (G-11) preparation
After Salzburg vitriol 1.27g (7.97mmol) is dissolved completely in 30mL methanol, thereto be added dropwise 2- [(3,
4- dimethoxy-2-pyridinyls) methyl mercapto] -1H- benzimidazoles 2.40g (7.97mmol) 10mL methanol solutions, at room temperature instead
It should stay overnight, TLC detections after the reaction was complete, are evaporated under reduced pressure away methanol solution, and it is bis- (μ-sulfate radical) to obtain dark green solid
Bis- { 2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto] -1H- benzimidazoles-N, N "-subunits } closes two bronze medals (II) 3.67g
(3.99mmol).Yield 100.0%.m.p:>250℃；HRMS:916.965191([M-H]-)；IR:3421.0,2923.9,
1631.9,1602.3,1456.5,1339,1309.4,1276.0,1213.8,1106.5,1075,865.8,835.4。
Embodiment 2：Bis- (μ-sulfate radical-O, O') bis- { 2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto-κ N] -1H-
Benzimidazole-κ N3Close two bronze medals (II) Methanol Solvate (G-12) preparation
Take bis- { 2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto-κ the N] -1H- of 5mg or so bis- (μ-sulfate radical-O, O')
Benzimidazole-κ N3Two bronze medals (II) are closed, it is completely dissolved with 5mL methanol, different amounts of acetone is then added, while allotting difference
The methanol and acetone mixed solution of ratio.Wherein methanol is as good solvent, and acetone is as poor solvent.The different proportion that will be prepared
Mixed solution be respectively placed in before embathed with chromic acid solution it is clean and dry, in the difference fine taper bottles of inner wall smooth, bottle
After mouth is sealed with plastic packaging film, several osculums on bundle slowly volatilize convenient for bottle internal solvent.Fine taper bottle is placed in peace and quiet, is protected from light, is put down
Steady local stationary culture, obtains green crystals.Under high magnification microscope, the transparent single crystal grain of picking rule,
Its crystal diffraction data is collected on Rigaku MSC X-ray crystal diffraction instrument, SHELXL and SHELXS programs is used in combination to parse its crystalline substance
Body structure, cell parameter are shown in Table 1, and crystal structure is shown in Fig. 1.
The crystal parameters of 1. complex G-12 of table
Embodiment 3：Bis- (μ-sulfate radical-O, O') bis- { 5- difluoro-methoxies -2- [(3,4- dimethoxy-2-pyridinyls) first
Sulfenyl-κ N] -1H- benzimidazole-κ N3Close two bronze medals (II) (G-13) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:1050.919246([M-H]-)；IR:3422.7,3105.5,2949.5,2725.3,2169.5,1631.0,
1501.4,1460.7,1432.1,1356.3,1309.5,1283.1,1234.1.1303.4,1171.9,865.2,820.2。
Embodiment 4：Bis- (μ-sulfate radical-O, O') bis- { 2- { [3- methyl -4- (2,2,2- trifluoromethoxies) -2- pyridyl groups]
Methyl mercapto-κ N } -1H- benzimidazole-κ N3Close two bronze medals (II) (G-14) preparation
The preparation method of reference implementation example 1 obtains lavender chip solid, yield 100.0%.m.p:>250℃；HRMS:
1024.913695([M-H]-)；IR:3423.0,2923.6,2169.5,1696.7,1455.9,1401.7,1385.5,
1338.1,1269.6,1166.1,1113.8,1038.3,960.8,865.1,834.5。
Embodiment 5：Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- [(4- methoxyl group -3,5- dimethyl -2- pyridines
Base) methyl mercapto-κ N] -1H- benzimidazole-κ N3Close two bronze medals (II) (G-15) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:976.994612([M-H]-)；IR:3424.8,2923.2,2169.5,1696.8,1456.7,1400.8,
1385.1,1338.6,1272.7,1110.0,1053.5,1009.1,865.2,834.7。
Embodiment 6：Bis- (μ-sulfate radical-O, O') bis- { 2- [(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) methyl mercapto-κ
N] -1H- benzimidazole-κ N3Close two bronze medals (II) (G-16) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:914.973830([M-H]-)；IR:3422.8,2923.6,2169.5,1696.6,1451.4,1385.3,
1354.6,1274.1,1087.1,1039.1,995.4,865.4,835.0。
Embodiment 7：Bis- (μ-sulfate radical-O, O') bis- { 5- difluoro-methoxies -2- [(4- methoxyl group -3,5- dimethyl -2- pyrroles
Piperidinyl) methyl mercapto-κ N] -1H- benzimidazole-κ N3Close two bronze medals (II) (G-17) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:1046.958230([M-H]-)；IR:3422.4,2923.9,2169.5,1696.8,1457.0,1385.5,
1338.9,1272.7,1124.6,1039.0,1007.6,865.3,834.7。
Embodiment 8：Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- { [4- (2- methoxypropoxies) -3,5- dimethyl -
2- pyridyl groups] methyl mercapto-κ N } -1H- benzimidazole-κ N3Close two bronze medals (II) (G-18) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:1063.050545([M-H]-)；IR:3422.1,2924.0,2169.5,1696.6,1458.3,1338.2,
1273.7,1159.2,1096.0,1037.5,865.0,834.1。
Embodiment 9：Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- { [2- methyl -4- (2,2,2- trifluoromethyls) -2-
Pyridyl group] methyl mercapto-κ N } -1H- benzimidazole-κ N3Close two bronze medals (II) (G-19) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:1082.939430([M-H]-)；IR:3424.2,2924.1,2169.5,1697.0,1457.2,1418.1,
1262.5,1162.7,1036.9,963.8,863.2,834.3。
Embodiment 10：Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- [(3,4- dimethoxy-2-pyridinyls) first sulphur
Base-κ N] -1H- benzimidazole-κ N3Close two bronze medals (II) (G-20) preparation
The preparation method of reference implementation example 1 obtains bottle green band metallic luster powder, yield 100.0%.m.p:>250
℃；HRMS:978.956264([M-H]-)；IR:3423.4,2924.9,2169.5,1697.0,1499.1,1458.3,
1338.6,1308.7,1278.0,1115.5,1037.7,1003.3,865.0,835.0。
Embodiment 11：Test-compound is to human liver cancer cell HepG2, human colon cancer cell SW480 and Human normal hepatocyte
The inhibitory activity of HL7702 proliferation
(1) experiment material
Cell strain：Human liver cancer cell HepG2, human colon cancer cell SW480, the normal cancer cell HL7702 of people；10% is newborn
Cow's serum (FBS)；96 orifice plates,；The improved Eagle culture mediums (DMEM) of DulbeccoShi.
Test-compound：L-01~L-16, C-01~C-16 totally 32 compounds, with DMSO be dissolved as 50mM be stored in-
20 DEG C for use, and final concentrations of the DMSO in culture solution is less than 0.1%.
MTT experiment：It is dissolved as 5mg/mL with PBS, is stored in -20 DEG C.
(2) experimental method
Using mtt assay (Mosmann T.Rapid colorimetric assay for cellular growth and
survival:application to proliferation and cytotoxicity assays.J Immunol
Methods.1983,65(1-2):Antitumor cytolytic activity 55-63.) is carried out to test-compound.
Take HepG2 (liver cancer), SW480 (human colon carcinoma) and HL7702 (Human normal hepatocyte) in cell Eagle culture mediums
(DMEM) it is cultivated on.The culture medium is DulbeccoShi improved, including 10% calf serum (FBS), SW480 cell strains
And HepG2 cell strains.Final concentration of 50uM and 25uM, 3 parallel holes of each concentration are administered in each compound.When cell Proliferation extremely
So that it is merged the secondary culture then carried out no more than 20 generations when 80~90%, then so that them is adapted to ring before next step is disposed
Border reaches for 24 hours.These cells are placed in (8 × 10 on 96 orifice plates4/ mL), then containing 5%CO2Moist environment in cultivated
Night and temperature control are at 37 DEG C.After continuing culture for 24 hours at 37 DEG C, each hole adds people MTT (5mg/ml) solution respectively, gently shake culture
Plate is put back to and is incubated 4h in incubator again, then exhausts supernatant, in each Kong Zhongjia DMSO100 μ L, set on oscillator concussion 5~
10min makes MTT be completely dissolved, and it is a length of to measure every hole medium wave with enzyme mark photometer (TECAN SPECTRA, Wetzlar, Germany)
The light absorption value (OD values) of 490nm calculates inhibiting rate (being shown in Table 2) with following equation.
Inhibiting rate=(1- medicine groups OD values/control group OD values) × 100%
Experiment uses cis-platinum for positive control drug, cisplatin on human liver cancer cells (HepG2) and human colon cancer cell (SW480)
The IC of Proliferation Ability50Respectively 6.6 ± 1.0 μm of ol/L and 15 ± 2.7 μm of ol/L.
The experimental results showed that tested copper complex has different inhibiting effect to the proliferation of human liver cancer cell HepG2,
And dose-effect relationship is presented, only a small number of tested copper complexes have inhibiting effect to the proliferation of human colon cancer cell SW480, tested
Part copper complex be better than the proliferation to human colon cancer cell SW480 to the inhibited proliferation of human liver cancer cell HepG2
Inhibiting effect, and tested copper complex to the proliferation to Human normal hepatocyte HL7702 almost without inhibiting effect.
Inhibiting effect of 2. test-compound of table to various cell Proliferations
Pharmaceutical composition
Embodiment 13：Tablet formulation
Reactive compound 25-1000mg, starch 45mg, microcrystalline cellulose 35mg, polyvinylpyrrolidone are (water-soluble for 10%
Liquid) 4mL, sodium carboxymethylcellulose 4.5mg, magnesium stearate 0.5mg, talcum 1mg.
Embodiment 14：Suspending agent formula
Reactive compound 0.1-1000mg, sodium carboxymethylcellulose 50mg, syrup 1.25mg, sodium benzoate 0.1mg, flavoring
Appropriate agent, appropriate colorant add pure water to 5mL.
Embodiment 15：Aerosol formulations
Reactive compound 0.25mg, ethyl alcohol 25-75mL, propellant 22 (dichlorodifluoromethane) 70mg.
Embodiment 16：Suppository formulations
Reactive compound 250mg, saturated fatty acid glyceride class 2000mL.
Embodiment 17：Injectable formulation formula
Reactive compound 50mg, isotonic salting liquid 1000mL.
Embodiment 18：Ointment formula
Micronized active compounds 0.025g, atoleine 10g add soft Chinese wax to 100g.
Embodiment 19：Ointment formula
Reactive compound 0.025g, propylene glycol 5g, Arlacel-83 5g, atoleine 10g add soft Chinese wax
To 100g.
Embodiment 20：Oil-in-water creams formula
Reactive compound 0.025g, hexadecanol 5g, glycerin monostearate 5g, atoleine 10g, Ce tomacrogol
1 000 2g, citric acid 0.1g, sodium citrate 0.2g, propylene glycol 35g add water to 100g.
Embodiment 21：Oil-in-water creams formula
Micronized active compounds 0.025g, soft Chinese wax 15g, atoleine 5g, hexadecanol 5g, Sorbimacrogol
Stearate 2g, Arlacel-60 0.5g, sorbic acid 0.2g, citric acid 0.1g, sodium citrate 0.2g add water
To 100g.
Embodiment 22：Water-in-oil creams formula
Reactive compound 0.025g, soft Chinese wax 35g, atoleine 5g, the liquor-saturated sesquioleate 5g of anhydrosorbitol, sorbic acid
0.2g, citric acid 0.1g, sodium citrate 0.2g add water to 100g.
Embodiment 23：Lotion formulation
Reactive compound 0.25g, isopropanol 0.5mL, carboxyl vinyl polymer 3mg, appropriate NaOH add water to 1g.
Embodiment 24：Injection suspension formulation
Reactive compound 0.05-10mg, sodium carboxymethylcellulose 7mg, NaCl 7mg, polyoxyethylene (20) anhydro sorbitol
Monoleate 0.5mg, benzyl alcohol 8mg, adds sterile water to 1mL.
Embodiment 25：Aerosol formulations for oral cavity and nasal inhalation
Reactive compound 0.1%w/w, sorbitan trioleate 0.7%w/w, Arcton 11 24.8%w/w, two
Chloro-tetrafluoroethane 24.8%w/w, dicholorodifluoromethane 49.6%w/w.
Embodiment 26：Atomized soln formula
Reactive compound 7mg, propylene glycol 5mg, adds water to 10g.
Embodiment 27：Wp formula for sucking
Bright matter capsule is filled with the mixtures of following compositions, micronized active compounds 0.1mg, lactose 20mg, by means of
Suction apparatus sucks the powder.
Embodiment 28：Wp formula for sucking
The pulvis of nodularization is packed into multi-agent powder inhalator, and every dose contains micronized active compounds 0.1mg.
Embodiment 29：Wp formula for sucking
The pulvis of nodularization is packed into multi-agent powder inhalator, every dose contains micronized active compounds 0.1mg, micronizing breast
Sugared 1mg.
Embodiment 30：Capsule agent prescription
Reactive compound 1.0 small sugar ball 321mg, Aquacoat ECD 30 6.6mg, tributyl 2-acetylcitrate 0.5mg,
Tween-80 0.1mg, Eudragit L 100-55 17.5mg, triethyl citrate 1.8mg, talcum powder 8.8mg, antifoaming agent
MMS 0.lmg。
Embodiment 31：Capsule seedling body formula
Reactive compound 2.0mg, small sugar ball 305mg, 30 5.0mg of Aquocoat ECD, acetyl tributylcitrate
0.4mg, Tween-80 0.14mg, Eudragit NE30D 12.6mg, Eudragit S100 12.6mg, talcum powder 0.l6mg.
Embodiment 32：Enema formulation
Reactive compound 00.2mg, sodium carboxymethylcellulose 25mg, disodium ethylene diamine tetraacetate 0.5mg, para hydroxybenzene first
Sour methyl esters 0.8mg, propylparaben 0.2mg, sodium chloride 7mg, citric acid 1.8mg, Tween-80 0.01mg add pure water
To 1mL.
Embodiment 33：Formulations Formula containing liposome
A. it instils the preparation of formula
Mix the dipalmitoyl lecithin (45mg) of synthesis in a glass tube, two myristoyl lecithin (7mg),
Dipalmitoylphosphatidylglycerol (1mg) and reactive compound (5mg), all components are dissolved in chloroform, N is used2It evaporates
Most of solvent, is then depressurized, and form lipid membrane in glass pipe surface as a result, is added aqueous solution (0.9% in the lipid
NaCl), liposome is formed under the phase inversion temperature higher than lipid, it is minimum vesica to 2 μm that gained suspension, which contains magnitude range,
Liposome.
B. the preparation of sucking formula
Liposome is prepared by embodiment A, aqueous solution therein contains 10% lactose, and the ratio between lactose and lipid are 7:3.It should
Liposomal suspensions are freezed with dry ice, and are freeze-dried, and desciccate is micronized, the equal air force of matter of gained particle
It is about 2 μm to learn diameter (MMAD).
The above described is only a preferred embodiment of the present invention, being not the limitation for making other forms to the present invention, appoint
What those skilled in the art changed or be modified as possibly also with the technology contents of the disclosure above equivalent variations etc.
Imitate embodiment.It is every without departing from technical solution of the present invention content, according to the technical essence of the invention to made by above example
Any simple modification, equivalent variations and remodeling, still fall within the protection domain of technical solution of the present invention.
Claims (10)
- Formula 1. (I) compound represented, stereoisomer, pharmaceutically acceptable salt, prodrug or pharmaceutical active metabolite：Wherein,R is selected from H, C1-C6 alkoxies, halogenated C1-C6 alkoxies, hydroxyl, amino, nitro, cyano；R1Selected from H, C1-C6 alkyl, C1-C6 alkoxies, halogenated C1-C6 alkoxies, hydroxyl, amino, nitro, cyano；R2Selected from H, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxies；The substituent group is C1-C6 alkoxies, halogenated C1-C6 alkoxies；R3Selected from H, C1-C6 alkyl, C1-C6 alkoxies.
- 2. compound described in claim 1, stereoisomer, pro-drug, pharmaceutical active metabolite or can pharmaceutically connect The salt received：R is selected from H, C1-C4 alkoxies, halogenated C1-C4 alkoxies, preferably H, methoxyl group, difluoro-methoxy.
- 3. compound as claimed in claim 1 or 2, stereoisomer, pro-drug, pharmaceutical active metabolite or pharmaceutically may be used The salt of receiving：R1Selected from H, C1-C4 alkyl, C1-C4 alkoxies, preferably H, methyl, methoxyl group.
- 4. the compound described in claim 1-3 any one, stereoisomer, pro-drug, pharmaceutical active metabolite or Pharmaceutically acceptable salt：R2Selected from H, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxies, the substituent group are C1-C4 alkoxies, halogenated C1-C4 alkoxies, preferably H, methyl, methoxyl group, 2- methoxy ethoxies, 3- methoxy propoxies, 2,2,2- trifluoroethoxies Base.
- 5. the compound described in claim 1-4 any one, stereoisomer, pro-drug, pharmaceutical active metabolite or Pharmaceutically acceptable salt：R3Selected from H, C1-C4 alkyl, C1-C4 alkoxies, preferably H, methyl, methoxyl group.
- 6. compound described in claim 1, stereoisomer, pharmaceutically acceptable salt, prodrug or pharmaceutical activity metabolism Object is selected from：Bis- (μ-sulfate radical-O, O') is bis-, and { 2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto] -1H- benzimidazoles-N, N "-is sub- Base } close two bronze medals；Bis- (μ-sulfate radical-O, O') is bis-, and { 2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto] -1H- benzimidazoles-N, N "-is sub- Base } close two bronze medal Methanol Solvates；Bis- (μ-sulfate radical-O, O') bis- { 5- difluoro-methoxies -2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto] -1H- benzene And imidazoles-N, N "-subunit close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 2- { [3- methyl -4- (2,2,2- trifluoromethoxies) -2- pyridyl groups] methyl mercapto } -1H- Benzimidazole-N, N "-subunit } close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- [(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) methyl mercapto] -1H- Benzimidazole-N, N "-subunit } close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 2- [(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) methyl mercapto] -1H- benzimidazoles - N, N "-subunit } close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 5- difluoro-methoxies -2- [(4- methoxyl group -3,5- dimethyl -2- pyridyl groups) first sulphur Base] -1H- benzimidazoles-N, N "-subunit } close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- { [4- (2- methoxypropoxies) -3,5- dimethyl -2- pyridyl groups] first Sulfenyl } -1H- benzimidazoles-N, N "-subunit } close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- { [2- methyl -4- (2,2,2- trifluoromethyls) -2- pyridyl groups] first sulphur Base } -1H- benzimidazoles-N, N "-subunit } close two bronze medals；Bis- (μ-sulfate radical-O, O') bis- { 5- methoxyl groups -2- [(3,4- dimethoxy-2-pyridinyls) methyl mercapto] -1H- benzo miaows Azoles-N, N "-subunit } close two bronze medals.
- 7. compound as described in claim 1, stereoisomer, pharmaceutically acceptable salt, prodrug or pharmaceutical activity generation Thank to the preparation method of object, which is characterized in that
- 8. a kind of pharmaceutical composition, includes the compound of any one of claim 1-6 as active constituent, solid is different Structure body, pharmaceutically acceptable salt, prodrug or pharmaceutical active metabolite and pharmaceutically acceptable carrier or excipient.
- 9. the compound, its stereoisomer, pharmaceutically acceptable salt, prodrug described in claim 1-6 any one or medicine The application of object active metabolite or composition according to any one of claims 8 in preparing tumor.
- 10. application according to claim 9, it is characterised in that：The tumour is liver cancer, colon cancer or the carcinoma of the rectum.
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