CN108066341A - Purposes of the compound in anticancer drug is prepared - Google Patents
Purposes of the compound in anticancer drug is prepared Download PDFInfo
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- CN108066341A CN108066341A CN201610997766.0A CN201610997766A CN108066341A CN 108066341 A CN108066341 A CN 108066341A CN 201610997766 A CN201610997766 A CN 201610997766A CN 108066341 A CN108066341 A CN 108066341A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
The invention discloses the purposes of formula (1) compound represented or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt in medicine preparation, and the drug is for treating cancer and prevention cancer return.
Description
Technical field
The present invention relates to field of medicaments, and in particular, to purposes of the compound in anticancer drug is prepared.
Background technology
Tetra- serobilas of G- are that the single stranded DNA rich in guanine (G) in people's telomerase and gene promoter area or RNA sequence are formed
Four chain structures.Tetra- serobilas of G- are found in tumour cell high expression, and therefore, the tetra- serobila ligands of G- of high specific may
According to there is antitumor activity.Our research finds that imidazole salt macrocyclic compound is that preferable tetra- serobilas of G- of a kind of selectivity are matched somebody with somebody
Body has good stabilization to G- tetra-.The purposes of the macrocyclic compound of tetra- serobilas of G- in medicine preparation can be stablized to need
Further research.
The content of the invention
It is contemplated that at least solve one of technical problem in the prior art.For this purpose, one object of the present invention
It is proposition formula (1) compound represented or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable
The purposes of salt in medicine preparation, drug have good G- tetra- for treating cancer and prevention cancer return, such compound
The stability of serobila not only itself has antitumor activity, but also has synergistic effect with other antitumor drugs.
According to an aspect of the present invention, the present invention provides formula (1) compound represented or its stereoisomer, geometry
The purposes of isomers, tautomer, pharmaceutically acceptable salt in medicine preparation, the drug is for treating cancer and in advance
Anti-cancer recurs,
Wherein：
Ar1And Ar2Independently selected from following group：
Each X independently is O, S and N,
Each R1And R2It independently is hydroxyl, halogen, amino, cyano, C1-6Alkyl, C2-6Alkenyl.
According to an embodiment of the invention, Ar1For
According to an embodiment of the invention, Ar1For
According to an embodiment of the invention, Ar2For
According to an embodiment of the invention, Ar2For
According to an embodiment of the invention, the compound has the structure of one of：
Or its stereoisomer, geometric isomer, tautomer,
Pharmaceutically acceptable salt
According to an embodiment of the invention, the pharmaceutically acceptable salt is inorganic acid salt or acylate.
According to an embodiment of the invention, the inorganic acid salt is at least one selected from hydrochloric acid, sulfuric acid and phosphoric acid.
According to an embodiment of the invention, the acylate is selected from acetic acid, trifluoroacetic acid, malonic acid, citric acid and right
At least one of toluenesulfonic acid.
According to an embodiment of the invention, the cancer be selected from the cancer of the brain, cutaneum carcinoma, kidney, osteocarcinoma, sarcoma, prostate cancer,
Uterine cancer, black cancer, colon cancer, lymph cancer, leukaemia, cancer of pancreas, cell carcinoma, breast cancer, liver cancer, lung cancer, stomach cancer
With at least one of oophoroma.
According to an embodiment of the invention, the drug further comprises other antineoplastics.
According to an embodiment of the invention, other antineoplastics are selected from cyclophosphamide, phosphinothioylidynetrisaziridine, Semustine, salt
Sour mustargen, busulfan, Chlorambucil, n-formyl sarcolysine Carmustine, hemel, lomustine, melphalan, Nitrocaphane,
Ifosfamide, dibromannitol, cytarabine, fluorouracil, methotrexate (MTX), hydroxycarbamide, Tegafur, Meisoindigotin, mercaptopurine,
Actinomycin D, mitomycin, doxorubicin hydrochloride, bleomycin A5 hydrochloride, epirubicin hydrochloride, NSC 654509, hydrochloric acid are soft red
Mycin, homoharringtonine, vincristine sulphate, Hydroxycamptothecin, Etoposide, vindesine sulfate, vinblastine sulfate, weight wine
Stone acid Vinorelbine, taxol, aminoglutethimide, tamoxifen, Flutamide, Gonadorelin, leuprorelin acetate, Letrozole, card
Platinum, procarbazine hydrochloride, amsacrine, citric acid Dacarbazine, L-Asparaginasum, at least the one of cis-platinum and mitoxantrone hydrochloride
Kind.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
It obtains substantially or is recognized by the practice of the present invention.
Description of the drawings
The above-mentioned and/or additional aspect and advantage of the present invention will become in the description from combination accompanying drawings below to embodiment
Substantially and it is readily appreciated that, wherein：
Fig. 1 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 1-1 according to an embodiment of the invention；
Fig. 2 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 1-2 according to an embodiment of the invention；
Fig. 3 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 1-4 according to an embodiment of the invention；
Fig. 4 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 1-4 according to an embodiment of the invention；
Fig. 5 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 2-1 according to an embodiment of the invention；
Fig. 6 shows the close-up schematic view of the H-NMR collection of illustrative plates of compound 2-1 according to an embodiment of the invention；
Fig. 7 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 3-1 according to an embodiment of the invention；
Fig. 8 shows the close-up schematic view of the H-NMR collection of illustrative plates of compound 3-1 according to an embodiment of the invention；
Fig. 9 shows the schematic diagram of the H-NMR collection of illustrative plates of compound 4-1 according to an embodiment of the invention；
Figure 10 shows the close-up schematic view of the H-NMR collection of illustrative plates of compound 4-1 according to an embodiment of the invention.
Specific embodiment
The embodiment of the present invention is described below in detail, the example of the embodiment is shown in the drawings, wherein from beginning to end
Same or similar label represents same or similar element or has the function of same or like element.Below with reference to attached
The embodiment of figure description is exemplary, and is only used for explaining the present invention, and is not considered as limiting the invention.
According to an aspect of the present invention, the present invention provides formula (1) compound represented or its stereoisomer, geometry
The purposes of isomers, tautomer, pharmaceutically acceptable salt in medicine preparation, the drug is for treating cancer and in advance
Anti-cancer recurs,
Wherein：
Ar1And Ar2Independently selected from following group：
Each X independently is O, S and N,
Each R1And R2It independently is hydroxyl, halogen, amino, cyano, C1-6Alkyl, C2-6Alkenyl.
Formula (1) compound represented according to an embodiment of the invention has the stability of good tetra- serobilas of G-, G- tetra-
Serobila is widely present in human body telomerase, gene promoter area, the high expression especially in tumour cell.Tetra- chains of G- in cancer cell
The formation of body can inhibit telomerase activation, cause the immortality of cell.Accordingly, it is capable to the compound for stablizing tetra- serobilas of G- is possible to
With good antitumous effect.Formula (1) compound represented of the embodiment of the present invention not only itself has antitumor activity, and
And there is synergistic effect with other antitumor drugs.
Unless otherwise indicated, structural formula described in the invention includes all isomeric forms, (such as mapping is different
Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism))：Such as R, S configuration containing asymmetric center, (Z) of double bond,
(E) isomers and (Z), the rotamer of (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right
Reflect isomers, the mixture of diastereoisomer or geometric isomer (or rotamer) belongs to the scope of the present invention.
In addition, it is necessary to explanation, unless otherwise explicitly pointing out, the description side used in the whole text herein
Formula " each ... independently to be ", " ... it independently is " and " ... it is each independently " it can exchange, it should all be interpreted broadly, both
It can refer in different groups, not influence mutually, can also be represented between expressed specific option between same-sign
In identical group, do not influenced mutually between expressed specific option between same-sign, with R1Exemplified by, structural formulaAnd structural formulaR between the two1Specific option from each other from shadow
It rings.
Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention
Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals
The enriched isotope of son.
Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with
Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) includes passing through proton transfer
Change, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) tautomer includes
Recombinate the change of bonding electrons.
Term " pharmaceutically acceptable salt " used in the present invention refers to the organic salt of the compound of the present invention and inorganic
Salt.Pharmaceutically acceptable salt is known to us in fields, such as document：S.M.Berge et al.,
Recorded in J.Pharmaceutical Sciences, 66,1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed
Include, but is not limited to, the inorganic acid salt to be formed reacted with amino group, as hydrochloride, hydrobromate, phosphate, sulfate,
Perchlorate and acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two
Hydrochlorate obtains these salt by other methods such as ion-exchange recorded on books document.Other can pharmaceutically connect
The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boron
Hydrochlorate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second sulphur
Hydrochlorate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, oneself
Hydrochlorate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malic acid
Salt, malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectic acid
Salt, persulfate, 3- phenylpropionic acids salt, picrate, pivalate, propionate, stearate, rhodanate, to toluene sulphur
Hydrochlorate, undecylate, valerate etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkane
Base)4Salt.
According to an embodiment of the invention, Ar1For
According to an embodiment of the invention, Ar1For
According to an embodiment of the invention, Ar2For
According to an embodiment of the invention, Ar2For
According to an embodiment of the invention, the compound has the structure of one of：
Or its stereoisomer, geometric isomer, tautomer,
Pharmaceutically acceptable salt.
The compound of the present invention (herein, form of presentation " formula (I) compound and its stereoisomer, geometrical isomerism
Body, tautomer and pharmaceutically acceptable salt and prodrug " may be collectively referred to as " the compound of the present invention "), it can be used for giving birth to
Medical product treating cancer is produced, it is described in the invention including those.Further, the compound of the present invention can be used for producing
Anticancer product.The compound of the present invention can be used for producing a kind of pharmaceuticals for mitigating, preventing, controlling or treating cancer as a result,
Disease.The compound of the present invention may be used as the active ingredient of pharmaceutical composition as a result, which can include formula (I)
Representative compound can also further include at least one pharmaceutically acceptable carrier, assistant agent or diluent.
According to an embodiment of the invention, pharmaceutically acceptable salt is inorganic acid salt or acylate.
According to an embodiment of the invention, which is at least one selected from hydrochloric acid, sulfuric acid and phosphoric acid.
According to an embodiment of the invention, which is selected from acetic acid, trifluoroacetic acid, malonic acid, citric acid and to first
At least one of benzene sulfonic acid.
The salt of the compound of the present invention can also include the intermediate or formula that are used to prepare or purify compound shown in formula (I)
(I) salt of the separated enantiomter of compound shown in, but it is not necessarily pharmaceutically acceptable salt.
According to an embodiment of the invention, which can be selected from the cancer of the brain, cutaneum carcinoma, kidney, osteocarcinoma, sarcoma, prostate
Cancer, uterine cancer, black cancer, colon cancer, lymph cancer, leukaemia, cancer of pancreas, cell carcinoma, breast cancer, liver cancer, lung cancer, stomach
At least one of cancer and oophoroma.
According to an embodiment of the invention, which may further include other antineoplastics.The foregoing chemical combination of the present invention
Object can generate synergistic effect with other antitumor drugs, significantly improve the tumor killing effect of other antineoplastics.
According to an embodiment of the invention, the species of other antineoplastics is not particularly limited, as long as inhibiting tumour
Growth, other antineoplastics include but not limited to cyclophosphamide, phosphinothioylidynetrisaziridine, Semustine, mustine hydrochlcride, busulfan, benzene
Butyric acid mustargen, n-formyl sarcolysine Carmustine, hemel, lomustine, melphalan, Nitrocaphane, ifosfamide, dibromo are sweet
It is mould to reveal alcohol, cytarabine, fluorouracil, methotrexate (MTX), hydroxycarbamide, Tegafur, Meisoindigotin, mercaptopurine, actinomycin D, mitogen
Element, doxorubicin hydrochloride, bleomycin A5 hydrochloride, epirubicin hydrochloride, NSC 654509, daunorubicin hydrochloride, high cepehalotaxus fortunei ester
Alkali, vincristine sulphate, Hydroxycamptothecin, Etoposide, vindesine sulfate, vinblastine sulfate, liquor epinephrinae bitartratis ophthalmicus Vinorelbine, purple
China fir alcohol, aminoglutethimide, tamoxifen, Flutamide, Gonadorelin, leuprorelin acetate, Letrozole, carboplatin, procarbazine hydrochloride,
Amsacrine, citric acid Dacarbazine, L-Asparaginasum, at least one of cis-platinum and mitoxantrone hydrochloride.
Below with reference to specific embodiment, the present invention will be described, it is necessary to which explanation, these embodiments are only explanation
Property, and be not considered as limiting the invention.
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it is carried out according to the described technology of document in the art or condition or according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available, such as can purchase from Sigma companies.
Embodiment 1
Synthetic route：
1) under Ar gas shieldeds, 2,6-diaminopyridine (2.18g, 20mmol) is put into successively in 250ml there-necked flasks, 2,6-
Dibromo pyridine (14.22g, 60mmol) and potassium tert-butoxide (22.4g, 200mmol).After being vigorously stirred 0.5h, it is rapidly added
The THF of 180ml dryings, obtains a dark green solution.The reaction was continued 1.5h.Then, system is warming up to 60-70 DEG C, slowly dripped
Add CH3THF solution (11.36g, the 80mmol CH of I3I is dissolved in 20ml THF), the reaction was continued about 1.5h.After reaction, revolve
Solvent is evaporated off, residual residue is dissolved in 500ml ethyl acetate, and organic layer extracts (3*150ml) with saturated salt solution, is associated with
Machine layer is simultaneously dried with anhydrous magnesium sulfate.Tan solid product 1-1 (N are obtained after column chromatography2,N6-bis(6-bromopyridin-
2-yl)-N2,N6- dimethylpyridine-2,6-diamine, N2,N6- two (6- bromopyridine -2- bases)-N2,N6- dimethyl pyrazole
Pyridine -2,6- diamines has the nuclear-magnetism of the compound or mass spectrum also please to provide together as crossed) 7.54g, yield 84%, compound 1-1
H-NMR collection of illustrative plates as shown in Figure 1, for subsequent reactions.
2) in 250ml three neck round bottom flask, sequentially add chemical combination 1-1 (30g, 0.6mol), 1H- imidazoles (9.43g,
0.14mol), CuI (1.63g, 8.5mmol), L-Proline (1.97g, 0.017mmol) and DMSO (80ml).Room temperature condition
Under be stirred to react 30min after, be warming up to 120 DEG C.It after reacting 12h, is cooled to room temperature, vacuum distillation removes DMSO, residual solid
It is dissolved in the mixed liquor of dichloromethane and water, pH is adjusted to neutrality with 6mol/L HCl.After dichloromethane aqueous phase extracted, it is associated with
Machine phase is simultaneously dried with anhydrous sodium sulfate.Product 1-2 (N are obtained after dichloromethane/n-hexane recrystallization2,N6-bis(6-(1H-
imidazol-1-yl)pyridin-2-yl)-N2,N6- dimethylpyridine-2,6-diamine, N2,N6- two (6- (1H-
- 1 base of imidazoles) pyridine -2- bases)-N2,N6- lutidines -2,6- diamines asks inventor to provide Chinese, has the change as crossed
The nuclear-magnetism or mass spectrum for closing object also please provide together) 24.4g, yield 96%, the H-NMR collection of illustrative plates of compound 1-2 is as shown in Figure 2.
3) 9,10-, bis- bromomethyl anthracenes (3.64g10mmol) are taken, are dissolved in respectively with compound 1-2 (4.23g, 10mmol)
It in 750ml acetonitriles, is instilled dropwise in 100ml acetonitriles under reflux state, the reaction was continued under reflux state 48h.Then, add in
NH4PF6(16.3g, 100mmol), the reaction was continued for 24 hours.After reaction, revolving removes acetonitrile, after residual solid is washed with water,
Remaining solid is dissolved with acetonitrile, and is filtered with diatomite.Filtrate is recrystallized after being spin-dried for acetonitrile/Isosorbide-5-Nitrae-dioxane, obtains Huang
Color powdery product 1-4, i.e. ring (N2,N6- two (6- (- 1 base of 1H- imidazoles) pyridine -2- bases)-N2,N6- lutidines -2,6-
Diamines) [1] (9,10- dimethylanthracene) two hexafluorophosphates, 5.1g, yield 56%, H-NMR collection of illustrative plates such as Fig. 3 of compound 1-4
Shown in 4, wherein Fig. 4 is the partial enlarged view of Fig. 3.
Embodiment 2
Synthetic route
Take compound 1-2 (4.23g, 10mmol) points to xylylene bromide (2.64g, 10mmol), obtained with embodiment 1
It is not dissolved in 750ml acetonitriles, is instilled dropwise in 100ml acetonitriles under reflux state, the reaction was continued under reflux state 48h.Then, add
Enter NH4PF6(16.3g, 100mmol), the reaction was continued for 24 hours.After reaction, revolving removes acetonitrile, and residual solid is washed with water
Afterwards, remaining solid is dissolved with acetonitrile, and is filtered with diatomite.Filtrate is recrystallized after being spin-dried for acetonitrile/Isosorbide-5-Nitrae-dioxane, is obtained
It is light yellow to white powder product 2-1, i.e. ring (N2,N6- two (6- (- 1 base of 1H- imidazoles) pyridine -2- bases)-N2,N6- dimethyl
Pyridine-2,6-diamines) (Isosorbide-5-Nitrae-dimethyl benzene) two hexafluorophosphate 4.7g, yield 58%, the H-NMR collection of illustrative plates of compound 2-1
As it can be seen in figures 5 and 6, wherein Fig. 6 is the partial enlarged view of Fig. 5.
Embodiment 3
Synthetic route
An xylylene bromide (2.64g, 10mmol) is taken, is dissolved in 750ml second respectively with compound 1-2 (4.23g, 10mmol)
It in nitrile, is instilled dropwise in 100ml acetonitriles under reflux state, the reaction was continued under reflux state 48h.Then, NH is added in4PF6
(16.3g, 100mmol), the reaction was continued for 24 hours.After reaction, revolving removes acetonitrile, after residual solid is washed with water, uses acetonitrile
Remaining solid is dissolved, and is filtered with diatomite.Filtrate is recrystallized after being spin-dried for acetonitrile/Isosorbide-5-Nitrae-dioxane, obtain it is light yellow extremely
White powder product 3-1, i.e. ring (N2,N6- two (6- (- 1 base of 1H- imidazoles) pyridine -2- bases)-N2,N6- lutidines -2,
6- diamines) [1] (1,3- dimethyl benzene) two hexafluorophosphates, 4.3g, yield 52%, the H-NMR collection of illustrative plates of compound 3-1 is as schemed
Shown in 7 and 8, wherein Fig. 8 is the partial enlarged view of Fig. 7.
Embodiment 4
Synthetic route
Adjacent xylylene bromide (2.64g, 10mmol) is taken, is dissolved in 750ml second respectively with compound 1-2 (4.23g, 10mmol)
It in nitrile, is instilled dropwise in 100ml acetonitriles under reflux state, the reaction was continued under reflux state 48h.Then, NH is added in4PF6
(16.3g, 100mmol), the reaction was continued for 24 hours.After reaction, revolving removes acetonitrile, after residual solid is washed with water, uses acetonitrile
Remaining solid is dissolved, and is filtered with diatomite.Filtrate is recrystallized after being spin-dried for acetonitrile/Isosorbide-5-Nitrae-dioxane, obtain it is light yellow extremely
White powder product 4-1, that is, ring (N2,N6- two (6- (- 1 base of 1H- imidazoles) pyridine -2- bases)-N2,N6- lutidines -2,6-
Diamines) [1] (1,2- dimethyl benzene) two hexafluorophosphates, 4.7g, yield 43%, H-NMR collection of illustrative plates such as Fig. 9 of compound 4-1 and
Shown in 10, wherein Figure 10 is the partial enlarged view of Fig. 9.
Embodiment 5
In the present embodiment, research embodiment 1 obtains the external tumor-inhibiting action of compound 1-4 (abbreviation MAC), specific as follows：
It takes multiplication good and is in the cell suspension that 5*104/ml is made in the HT1080 cells of exponential phase, be inoculated in
In 96 orifice plates, 200 μ L/ holes.After being incubated overnight, the complete culture solution for the drug that 200 μ L contain various concentration is added in per hole, is continued
Cultivate 72 it is small when, the MTT solution of 5g/l is then added in per hole, after 4h, incline each hole supernatant, and DMSO200 μ L are added in per hole, quiet
Put 20min；The OD value in each hole of 96 orifice plates, each measured concentration are measured under 490 wavelength with 550 type instruments of BIORAD
4 parallel holes are set, are repeated 3-4 times.
Calculating Road inhibitory rate of cell growth according to the following equation, growth of tumour cell inhibiting rate (%) inhibiting rate=【1-
(ODSample/ODControl)】* 100%
Experimental result：The experimental results are shown inthe following table, and MAC has certain tumor-inhibiting action in itself, furthermore, it is possible to significantly carry
The tumor killing effect of high PTX, as shown in table 2, after MAC is added in, the PTX of 30 μ g/ml carries the inhibiting rate of HT1080 by 43.2%
Height is to 81.0%, and as shown in table 3, with the increase of the concentration of MAC, MAC also dramatically increases the tumor-inhibiting action promotion of PTX, is in
Dose dependent.It is thin to show that there is imidazole salts macrocyclic compound MAC apparent auxiliary PTX to inhibit human fibrosarcoma for experiment as a result,
The ability of born of the same parents' multiplication.
Table 1
Table 2
Table 3
Embodiment 6
Using the method for embodiment 6, research embodiment 1 obtains the external tumor-inhibiting action of compound MAC, simply that tumour is thin
Born of the same parents become A549-r, and other conditions are constant, and experimental result is as follows：
The experimental results are shown inthe following table, and as shown in table 4, MAC has certain tumor-inhibiting action in itself, furthermore, it is possible to significantly
The tumor killing effect of PTX is improved, as shown in table 5, after MAC is added in, after MAC is added in, the inhibition of the PTX of 50 μ g/l to MCF-7
Rate is increased to 69.1% by 12.4%, it is shown that there is imidazole salts macrocyclic compound the anti-human lung carcinoma cells of apparent auxiliary PTX to increase
The ability grown.When imidazole salts macrocyclic compound (MAC) concentration of itself is 5 μM, the inhibiting rate to MCF-7 is 18.2%, when
When PTX concentration itself is 50 μ g/l, the inhibiting rate of MCF-7 can be significantly improved for 12.4%, MAC (5 μM)+PTX50 μ g/l
The inhibiting rate of MCF-7 is 35.4%.The PTX of 50 μ g/l is 12.4% to the inhibiting rate of MCF-7, with imidazole salts macrocyclic compound
The raising (0 μM -10 μM) of concentration, PTX can significantly improve the inhibiting rate of MC2F-7, in dose dependent.Table is tested as a result,
Bright imidazole salts macrocyclic compound MAC has the ability that apparent auxiliary PTX inhibits breast cancer tumor cells multiplication.
Table 4
Table 5
Embodiment 7
Using the method for embodiment 6, research embodiment 1 obtains the external tumor-inhibiting action of compound MAC, simply that tumour is thin
Born of the same parents become A549-r, and other conditions are constant, and experimental result is as follows：
The experimental results are shown inthe following table, and as shown in table 6, MAC has certain tumor-inhibiting action in itself, furthermore, it is possible to significantly
The tumor killing effect of PTX is improved, as shown in table 7, when the concentration of MAC in itself is 5 μM, the inhibiting rate to A549-r is 9.3%, when
It is -24.3% to the inhibiting rate of A549-r when PTX concentration itself is 250mg/l, and can be with during MAC (5 μM)+PTX250mg/l
The inhibiting rate for significantly improving A549-r is 25.6%.The PTX of 250mg/ml is -24.3% to the inhibiting rate of A549-r, with miaow
The raising (0 μM -10 μM) of azoles salt macrocyclic compound concentration, PTX can significantly improve the inhibiting rate of A549-r.
Table 6
Table 7
Embodiment 8
Using the method for embodiment 5, research embodiment 2 obtains compound 2-1, the compound 3-1 that embodiment 3 obtains and reality
The external tumor-inhibiting action for the compound 4-1 that example 4 obtains is applied, tumour cell is simply become into SW480, DU145, A375, BGC-823
With Hela cells, and 5 FU 5 fluorouracil is set other conditions are constant, and experimental result is as follows for positive controls：
The experimental results are shown inthe following table, and as shown in table 8, compound 2-1,3-1 and 4-1 are respectively provided with certain tumor-inhibiting action,
But different tumours are different to the dose dependent of different compounds, and the same compound to the inhibiting rates of different tumours not yet
Together, the dosage of the same race of the same compound also differs greatly to the inhibiting rate of different tumours.
Table 8
Embodiment 8
Using the method for embodiment 5, influence of the different salt of compound coupling to the compound tumor-inhibiting action, tool are studied
Body, compare the influence embodiment 2 of hydrochloride and dihydric phosphate to compound tumor-inhibiting action and obtain compound 2-1, embodiment 3
The external tumor-inhibiting action for the compound 4-1 that obtained compound 3-1 and embodiment 4 is obtained, simply becomes tumour cell
SW480, DU145, A375, BGC-823 and Hela cell, other conditions are constant, and experimental result is as follows：
Experimental result is as shown in table 9, wherein, hydrochloride is represented with " Cl ", and dihydric phosphate is represented with " P ", such as 2-1-
Cl represents the hydrochloride of compound 2-1, the results showed that different salts has a certain impact to the tumor-inhibiting action of compound, and
And influence of the different salts of same compound to the inhibitory action of different tumours is different.
Table 9
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description
Point is contained at least one embodiment of the present invention or example.In the present specification, schematic expression of the above terms is not
Centainly refer to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
One or more embodiments or example in combine in an appropriate manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：Not
In the case of departing from the principle of the present invention and objective a variety of change, modification, replacement and modification can be carried out to these embodiments, this
The scope of invention is limited by claim and its equivalent.
Claims (10)
1. formula (1) compound represented or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt
Purposes in medicine preparation, the drug is for treating cancer and prevents cancer return,
Wherein：
Ar1And Ar2Independently selected from following group：
Each X independently is O, S and N,
Each R1And R2It independently is hydroxyl, halogen, amino, cyano, C1-6Alkyl, C2-6Alkenyl.
2. purposes according to claim 1, which is characterized in that Ar1For
3. purposes according to claim 2, which is characterized in that Ar1For
4. purposes according to claim 1, which is characterized in that Ar2For
5. purposes according to claim 4, which is characterized in that Ar2For
6. purposes according to claim 1, which is characterized in that the compound has the structure of one of：
Or its stereoisomer, geometric isomer, tautomer,
Pharmaceutically acceptable salt.
7. purposes according to claim 1, which is characterized in that the pharmaceutically acceptable salt is inorganic acid salt or organic
Hydrochlorate,
Optionally, the inorganic acid salt is at least one selected from hydrochloric acid, sulfuric acid and phosphoric acid.
Optionally, the acylate is at least one selected from acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-methyl benzenesulfonic acid
Kind.
8. purposes according to claim 1, which is characterized in that the cancer is the cancer of the brain, cutaneum carcinoma, kidney, osteocarcinoma, meat
Knurl, prostate cancer, uterine cancer, black cancer, colon cancer, lymph cancer, leukaemia, cancer of pancreas, cell carcinoma, breast cancer, liver
Cancer, lung cancer, at least one of stomach cancer and oophoroma.
9. purposes according to claim 1, which is characterized in that the drug further comprises other antineoplastics.
10. purposes according to claim 9, which is characterized in that other antineoplastics are to be replaced selected from cyclophosphamide, plug
Group, Semustine, mustine hydrochlcride, busulfan, Chlorambucil, n-formyl sarcolysine Carmustine, hemel, lomustine, phenylpropyl alcohol ammonia
Sour mustargen, Nitrocaphane, ifosfamide, dibromannitol, cytarabine, fluorouracil, methotrexate (MTX), hydroxycarbamide, Tegafur,
Meisoindigotin, mercaptopurine, actinomycin D, mitomycin, doxorubicin hydrochloride, bleomycin A5 hydrochloride, epirubicin hydrochloride, hydrochloric acid pyrrole
It is soft than star, daunorubicin hydrochloride, homoharringtonine, vincristine sulphate, Hydroxycamptothecin, Etoposide, vindesine sulfate,
Vinblastine sulfate, liquor epinephrinae bitartratis ophthalmicus Vinorelbine, taxol, aminoglutethimide, tamoxifen, Flutamide, Gonadorelin, acetic acid bright third
Rayleigh, Letrozole, carboplatin, procarbazine hydrochloride, amsacrine, citric acid Dacarbazine, L-Asparaginasum, cis-platinum and hydrochloric acid rice support
At least one of anthraquinone.
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