CN104072484B - Nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic replacement) methylene imine compounds and pharmaceutically acceptable salt and its preparation method and application thereof - Google Patents
Nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic replacement) methylene imine compounds and pharmaceutically acceptable salt and its preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic) methylene imine compounds and pharmaceutically acceptable salt thereof and preparation method and application.The nitrogen of the present invention-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic) methylene imine compounds has the structure of formula I, the compound that the present invention obtains, having better anti-tumor activity and safety, in field of medicaments, treatment pulmonary carcinoma, hepatocarcinoma, breast carcinoma, colon cancer are to have very much using value.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to suppression growth of tumour cell, nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic replacement) the methylene imine compounds with antitumous effect and its preparation method and application.
Background technology
Most commonly seen in cancer is malignant tumor, is one of main " killer " of causing people dead, and within 2013, China number of cancer deaths reaches 2,500,000.Drug treatment for malignant tumor, clinical conventional antitumor drug has kind more than 100 at present, owing to antitumor drug toxic and side effects is big, such as bone marrow depression, gastrointestinal reaction, liver function injury, renal damage, cardiac toxicity etc., therefore the targeting of antitumor drug is improved, thus improving curative effect, reducing toxicity, being current cancer medication key problem in the urgent need to address.Indazole compound and nitrogen oxygen derivatives chemical characteristic thereof are known, by the bioactive further investigation to indazole derivative, report that it passes through NO release and has anticoagulant collection and vasodilatory activity and strengthen cyclic guanylic acid level, anticancer, antibacterial, parasiticide etc..Indazole compound and its nitrogen oxygen derivant have biological activity widely, have one of the focus that the medicine of indazole mother nucleus structure is antitumor research, and representative indazole series antineoplastic medicament mainly has following 4 classes:
1. VEGF (VEGFR) inhibitor
Have with the indazole kind anti-cancer drugs thing that vascular endothelial growth factor receptor inhibitors is mechanism of action: VEGF (VEGFR) the inhibitor Axitinib (axtinib) of 1 Pfizer Inc. research and development, there is potent selectivity, by suppressing VEGF to be combined with its cell surface receptor, thus realizing suppressing the effect of VEGF.Indication includes: metastatic renal cell tumor, thyroid carcinoma, cancer of pancreas etc., in January, 2012 through FDA approval listing.The pazopanib of 2 GlaxoSmithKline PLC companies of Britain research and development, has obvious inhibitory action to sarcoma, nonsmall-cell lung cancer and renal cell carcinoma；Mutiple Targets medicine ABT869 (linifanib) of 3 Abbotts of the U.S. and Genentech company joint development, can suppress VEGFR and PDGFR kinases, can effectively blocking VEGF stimulate endothelial cell proliferation.
2. the inhibitor of topological enzyme I (TopoI) and topological enzyme II (TopoII)
At present in the process for the treatment of human diseases, topological enzyme can as the important target spot of some antibiotic and antineoplastic agent effect, and these medicines can change the catalysis of topological enzyme, may result in and causes apoptosis.Topoenzyme inhibitor can be divided into by the substrate difference of its effect: Topo I inhibitor and Topo II inhibitor, and representational indazole derivative structural formula is as follows:
3. the inhibitor of surface of cell membrane epithelial growth factor receptor (EGFR) tyrosine kinase
The tyrosine kinase relevant to tumor mainly has the receptor tyrosine kinase being positioned at cell membrane and the nonreceptor tyrosine kinase being positioned at endochylema, the excessive activation of tyrosine kinase and tumorigenesis, prognosis and lapse to closely related, the major downstream signal pathway that protein tyrosine kinase activates is Ras/MAPK and PI3K/AKT signal pathway, promote cell proliferation, conversion, opposing apoptosis, to the generation of tumor, development, transfer, angiogenesis, medicine sensitivity etc. relevant.Representative indazole derivative is such as BMS-599626, and its structural formula is as follows:
4. tubulin suppresses
Micro-pipe is the key component of cytoskeleton, has the dynamics of polymerization and depolymerization.Play an important role in maintaining the processes such as cellular morphology, cell division, signal transduction and material conveying.Owing to micro-pipe has extremely important effect in cell differentiation, now become one of important target spot of antitumor drug research.The Antitubulin acting on microtubule system has also become a class effective antitumour medicine.The indazole derivative structure for representative of the Antitubulin to act on colchicine site is as follows:
Summary of the invention
It is an object of the invention to provide a kind of novel indazole compounds, have for treating proliferative disease such as cancer and the clinical practice of disease especially mediated because of VEGFR kinases dysregulation.Additionally, the compound of the present invention has more excellent antitumor usefulness.
The present invention provides nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic replacement) methylene imine compounds and pharmaceutically acceptable salt thereof that one has formula [I] structure:
Wherein: R1Selected from the monocycle benzene aromatic hydrocarbons structure containing 1,2 or 3 substituent groups；The described substituent group in monocycle benzene aromatic hydrocarbons structure is the alkyl of C1～C4, methoxyl group, nitro, carbomethoxy, formamido, dimethylamino, trifluoromethyl or mesyl.Preferred substituent group is the alkyl of C1～C4, methoxyl group or formamido.
R2Selected from aromatic heterocycle structure；Described aromatic heterocycle structure is furan, thiophene, pyridine, pyrimidine, piperazine, imidazoles, pyrazoles, pyrroles, indole, quinoline or carbazole；Preferred aromatic heterocycle structure is thiophene, pyridine, pyrazoles, pyrimidine or imidazoles.
Compound provided by the invention and pharmaceutically acceptable salt thereof are used for the purposes treating in the medicine of cancer in preparation.Specifically, these cancers are selected from: breast carcinoma, pulmonary carcinoma, bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, colon cancer, multiple myeloma, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer and carcinoma of testis.More particularly, these cancers are selected from: breast carcinoma, nonsmall-cell lung cancer, gastric cancer, colon cancer, hepatocarcinoma, ovarian cancer.
Those skilled in the art are it will be appreciated that all compounds of the present invention can both form salt.These compounds of the present invention are amine, therefore can with in many inorganic and organic acid any one reaction and form pharmaceutically acceptable acid addition salt.These pharmaceutically acceptable acid addition salts and customary preparation methods are known in the field.Referring to, for instance, P.Stahl et al., HANDBOOKOFPHARMACEUTICALSALTS:PROPERTIES, SELECTIONANDUSE, (VCHA/Wiley-VCH, 2008)；S.M.Berge et al., " PharmaceuticalSalts ", JournalofPharmaceuticalSciences, the 66th volume, the 1st phase, in January, 1977.
The invention has the beneficial effects as follows: it have been investigated that, when retaining indazole structure parent nucleus, connect heteroaromatic aldehyde at its 3 bit amino and become Schiff's base, and be bonded, with benzene sulfydryl, a series of nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic replacement) the methylene imine compounds obtained by 4 pulmonary carcinoma (H-522), hepatocarcinoma (HepG2), breast carcinoma (T-47D), colon cancer (HCT-15), ovarian cancer (PA-1) etc. are had good anti-tumor activity.The nitrogen that the present invention obtains-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic replacement) methylene imine compounds, having better anti-tumor activity and safety, in field of medicaments, treatment pulmonary carcinoma, hepatocarcinoma, breast carcinoma, colon cancer, ovarian cancer are to have very much using value.
Detailed description of the invention
Hereinafter enumerate embodiment, be for the more specifically bright present invention, but the present invention is not restricted by the embodiments.The exemplary of the present invention is described more fully below.But, these embodiments are only for illustration purpose, it is no intended to restriction is by scope of invention.The compound of the present invention can be prepared according to the explanation in following preparation method and embodiment.The name of following preparation method and embodiment adopts the Struct=Name nomenclature in Ultra10.0 to complete
The synthesis of embodiment one: N-methyl-2-((3-((pyridine-2-methyl alkene) amino)-1 hydrogen-indazole-4-base) sulfur) Benzoylamide (compound 1)
The synthesis of step 1:2-((the fluorine-based benzene of 2-cyano group-3-) sulfur)-nitrogen-methyl benzamide
Under room temperature under nitrogen protection; weigh 2; 6-difluorobenzonilyile (20.00 grams; 144 mMs); without water sodium hydroxide (11.56 grams; 289 mMs) and 80 milliliters of dimethyl sulfoxides make solvent and react in 500mL eggplant-shape bottle; 2-mercapto-N-methyl-Benzoylamide (25.38 grams it is slowly dropped under stirring; 152 mMs) 50 milliliters of DMSO solution, be warming up to 90 DEG C after dropwising, react 3 hours; reactant liquor is cooled to room temperature; pour in the ice water solution in stirring, precipitate out white crystals body 37.07 grams, productivity 90.00%.
MS:255m/z(M+H)。
1H-NMR(DMSO-d6): δ 8.29 (s, 1H), 7.79 (d, J=3.4Hz, 1H), 7.56 (d, J=3.4Hz, 1H), 7.48 (m, 2H), 7.34 (t, J=8.4Hz, 1H), 7.12 (d, J=3.6Hz, 1H), 6.88 (d, J=3.6Hz, 1H), 2.81 (s, 3H).
The synthesis of step 2:2-((3-amino-1 hydrogen-indazole-4-base) sulfur)-nitrogen-methyl benzamide
Weigh 2-((the fluorine-based benzene of 2-cyano group-3-) sulfur)-nitrogen-methyl benzamide (20.87 grams, 73 mMs), 15 milliliters of dry N-methylpyrrolidone, in 500 milliliters of eggplant-shape bottles, are warming up to 70 DEG C, instill hydrazine hydrate (98% under stirring after dissolving, 40ml, 730 mMs) react 23 hours, it is poured into the ice water solution in stirring, filters, precipitate out white solid 21.10 grams, productivity 97.00%.
1H-NMR(DMSO-d6): δ 12.40 (s, 1H), 8.34 (s, 1H), 8.08 (d, J=5.6Hz, 1H), 7.78-7.34 (m, 6H), 6.01 (s, 2H), 2.81 (s, 3H).
The synthesis of step 3:N-methyl-2-((3-((pyridine-2-methyl alkene) amino)-1 hydrogen-indazole-4-base) sulfur) Benzoylamide
500 milliliters of eggplant type bottles add 2-((3-amino-1 hydrogen-indazole-4-base) sulfur)-nitrogen-methyl benzamide 10.13 grams (34 mMs), 2-pyridine carboxaldehyde 3.75 grams (35 mMs), 10 grams of 4A molecular sieve, toluene solvant 150 milliliters, drip 10 milliliters of toluene solutions containing 1 milliliter of formic acid while stirring, room temperature reaction is stopped reaction after 21 hours, filtering molecular sieves, filtrate reduced in volume, column chromatography for separation, obtains pale yellow powder 8.82 grams (productivity 67%).
MS:388m/z(M+H)。
1H-NMR(DMSO-d6): δ 12.37 (s, 1H), 8.94 (s, 1H), 8.57 (d, J=4.2Hz, 1H), 8.35 (s, 1H), 7.77-7.34 (m, 9H), 2.89 (s, 3H).
The preparation of embodiment two: N-(4-((2-(tert-butyl group) phenyl) sulfur)-1 hydrogen-indazole-3-base)-1-(pyrimidine-2-base) methylene imine (compound 2)
The synthesis of step 1:2-((2-(tert-butyl group) phenyl) sulfur)-6-6-chlorophenyl nitrile
Under room temperature under nitrogen protection; weigh 2; 6-dichlorobenzonitrile (24.77 grams; 144 mMs); without water sodium hydroxide (11.56 grams; 289 mMs) and 80 milliliters of dimethyl sulfoxides make solvent and react in 500 milliliters of eggplant-shape bottles; 2-tert .-butylthiophenol (25.23 grams it is slowly dropped under stirring; 152 mMs) 10 milliliters of DMSO solution, be warming up to 90 DEG C after dropwising, react 2 hours; reactant liquor is cooled to room temperature; pour in the ice water solution in stirring, precipitate out white crystals body 38.27 grams, productivity 88.00%.
MS:303m/z(M+H)。
1H-NMR(DMSO-d6): δ 7.82 (d, J=3.4Hz, 1H), 7.38 (t, J=8.4Hz, 1H), 7.37-6.90 (m, 5H), 1.33 (s, 9H).
The synthesis of step 2:4-((2-(tertiary butyl) phenyl) sulfur)-3-amino-1 hydrogen indazole
Weigh 2-((2-(tert-butyl group) phenyl) sulfur)-6-6-chlorophenyl nitrile (24.16 grams, 80 mMs), 15 milliliters of dry N-methylpyrrolidone, in 500mL eggplant-shape bottle, are warming up to 70 DEG C after dissolving, instill hydrazine hydrate (98% under stirring, 40ml, 730 mMs) react 16 hours, it is poured into the ice water solution in stirring, filters, precipitate out faint yellow solid 22.57 grams, productivity 95.00%.
MS:298m/z(M+H)。
1H-NMR(DMSO-d6):δ12.58(s,1H),8.11(s,1H),7.62-6.91(m,6H),4.89(s,2H),1.32(s,9H)。
The synthesis of step 3:N-(4-((2-(tert-butyl group) phenyl) sulfur)-1 hydrogen-indazole-3-base)-1-(pyrimidine-2-base) methylene imine
500 milliliters of eggplant type bottles add 4-((2-(tertiary butyl) phenyl) sulfur)-3-amino-1 hydrogen indazole 8.91 grams (30 mMs), 2-pyrimidinecarboxaldehyde 3.78 grams (35 mMs), 10 grams of 4A molecular sieve, toluene solvant 150 milliliters, drip 10 milliliters of toluene solutions containing 1 milliliter of formic acid while stirring, room temperature reaction is stopped reaction after 21 hours, filtering molecular sieves, filtrate reduced in volume, column chromatography for separation, obtains pale yellow powder 8.38 grams (productivity 72%).
MS:388m/z(M+H)。
1H-NMR(DMSO-d6): δ 12.37 (s, 1H), 9.11 (d, J=5.6Hz, 1H), 8.17 (d, J=3.4Hz, 1H), 8.09 (s, 1H), 7.98 (t, J=9.0Hz, 1H), 7.68-6.84 (m, 7H), 1.34 (s, 9H).
The preparation of embodiment three: 1-(4 hydrogen-indazole-2-base)-nitrogen-(4-((2-methyl-5-(trifluoromethyl) phenyl) sulfur)-1 hydrogen indazole-3-base) methylene imine (compound 3)
Step 1: method, with embodiment one, substitutes 2-mercapto-N-methyl-Benzoylamide with 2-methyl-5-(trifluoromethyl) phenylmercaptan.；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2-imidazole formaldehyde.Obtain pale yellow powder shape target compound.Productivity 70%.
MS:402m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.56 (s, 1H), 8.11 (s, 1H), 8.06 (d, J=3.0Hz, 1H), 7.54-6.58 (m, 8H), 2.35 (s, 3H).
The preparation of embodiment four: 1-(furan-2-base)-nitrogen-(4-((3,4,5-trimethoxy-benzene) sulfur)-1 hydrogen indazole-3-base) methylene imine (compound 4)
Step 1: method, with embodiment one, substitutes 2-mercapto-N-methyl-Benzoylamide with 3,4,5-trimethoxy phenylmercaptan .s；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2 furan carboxyaldehyde, obtains pale yellow powder shape target compound.Productivity 79%.
MS:410m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.44 (s, 1H), 8.32 (s, 1H), 7.98 (d, J=3.4Hz, 1H), 7.88 (d, J=5.6Hz, 1H), 7.44 (t, J=9.0Hz, 1H), 7.40 (d, J=3.2Hz, 1H), 6.93-6.83 (m, 2H), 6.50 (s, 2H), 3.88 (s, 9H).
The preparation of embodiment five N-(4-((4-Nitrobenzol) sulfur)-1 hydrogen-indazole-3-base)-1-(4-hydrogen pyrazole-3-yl) methylene imine (compound 5)
Step 1: method, with embodiment one, substitutes 2-mercapto-N-methyl-Benzoylamide with p-Nitrobenzenethiol；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2-pyrazoles formaldehyde, obtains pale yellow powder shape target compound.Productivity 77%.
MS:365m/z(M+H)。
1HNMR (600MHz, CDCl3)δ:12.52(s,1H),12.47(s,1H),8.92(s,1H),8.06-6.58(m,9H)。
The preparation of embodiment six N, N-dimethyl-4-((3-((quinoline-2-methylene) amino)-1 hydrogen-indazole-4-base) sulfur) aniline (compound 6)
Step 1: method is with embodiment one, so that dimethylamino phenylmercaptan. is substituted 2-mercapto-N-methyl-Benzoylamide；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2-quinoline aldehyde, obtains pale yellow powder shape target compound.Productivity 71%.
MS:424m/z(M+H)。
1HNMR (600MHz, CDCl3)δ:12.53(s,1H),8.74(s,1H),8.33-6.55(m,13H),3.02(s,6H)。
The preparation of embodiment seven N-(4-((4-anisyl) sulfur)-1 hydrogen-indazole-3-base)-1-(thiophene-2-base) methylene imine (compound 7)
Step 1: method is with embodiment one, so that methoxybenzenethiol is substituted 2-mercapto-N-methyl-Benzoylamide；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2 thiophene carboxaldehyde, obtains pale yellow powder shape target compound.Productivity 80%.
MS:367m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.48 (s, 1H), 8.88 (s, 1H), 8.08 (d, J=3.4Hz, 1H), 7.78 (d, J=5.6Hz, 1H), 7.65 (d, J=4.8Hz, 1H), 7.46-7.16 (m, 7H), 3.85 (s, 3H).
The preparation of embodiment eight N-(4-((2-anisyl) sulfur)-1 hydrogen-indazole-3-base)-1-(pyridine-2-base) methylene imine (compound 8)
Step 1: method, with embodiment one, substitutes 2-mercapto-N-methyl-Benzoylamide with 2-methoxybenzenethiol；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2-pyridine carboxaldehyde, obtains pale yellow powder shape target compound.Productivity 69%.
MS:361m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.40 (s, 1H), 8.96 (s, 1H), 8.77 (d, J=3.6Hz, 1H), 8.11 (d, J=3.4Hz, 1H), 7.81-7.05 (m, 9H), 3.82 (s, 3H).
The preparation of embodiment nine 1-(4 hydrogen-indazole-2-base)-nitrogen-(4-((4-cumene) sulfur)-1 hydrogen-indazole-3-base) methylene imine (compound 9)
Step 1: method, with embodiment one, substitutes 2-mercapto-N-methyl-Benzoylamide with 4-isopropylbenzene thiophenol；
Step 2: method is with embodiment one.
Step 3: method, with embodiment one, substitutes 2-pyridine carboxaldehyde with 2-imidazole formaldehyde, obtains pale yellow powder shape target compound.Productivity 78%.
MS:362m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.52 (s, 1H), 9.11 (s, 1H), 8.11 (d, J=3.4Hz, 1H), 7.63 (s, 1H), 7.52-6.57 (m, 6H), 6.57 (m, 2H), 2.86 (m, 1H), 1.32 (s, 6H).
The preparation of embodiment ten N-(4-((2,6-3,5-dimethylphenyl) sulfur)-1 hydrogen-indazole-3-base)-1-(pyrimidine-2-base) methylene imine (compound 10)
Step 1: method, with embodiment two, substitutes 2-tert .-butylthiophenol with 2,6-thiophenol dimethyl benzenes；
Step 2: method is with embodiment two.
Step 3: method, with embodiment two, obtains pale yellow powder shape target compound.Productivity 68%.
MS:360m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.47 (s, 1H), 9.21 (s, 1H), 9.02 (d, J=4.2Hz, 2H), 8.07 (d, J=3.4Hz, 1H), 8.01 (t, J=9.2Hz, 1H), 7.53-7.17 (m, 5H), 2.36 (m, 6H).
The preparation of embodiment 11 N-(4-((3-((pyrimidine-2-methylene) amino)-1 hydrogen-indazole-4-base) sulfur) phenyl) acetamide (compound 11)
Step 1: method, with embodiment two, substitutes 2-tert .-butylthiophenol with 4-acetylamino phenylmercaptan.；
Step 2: method is with embodiment two.
Step 3: method, with embodiment two, obtains pale yellow powder shape target compound.Productivity 67%.
MS:389m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.58 (s, 1H), 9.80 (s, 1H), 9.08 (s, 1H), 8.98 (d, J=3.4Hz, 2H), 8.00-7.86 (m, 4H), 7.42-7.35 (m, 4H), 2.13 (s, 3H).
The preparation of embodiment 12 1-(thiazole-5-base)-nitrogen-(4-((4-(trifluoromethyl) phenyl) sulfur)-1 hydrogen-indazole-3-base) methylene imine (compound 12)
Step 1: method is with embodiment two, so that trifluoromethyl thiophenol is substituted 2-tert .-butylthiophenol；
Step 2: method is with embodiment two.
Step 3: method, with embodiment two, substitutes 2-pyrimidinecarboxaldehyde with 5-thiazole carboxaldehyde, obtains pale yellow powder shape target compound.Productivity 72%.
MS:405m/z(M+H)。
1HNMR (600MHz, CDCl3) δ: 12.44 (s, 1H), 9.33 (s, 1H), 8.97 (s, 1H), 8.22 (d, J=3.4Hz, 1H), 7.56-7.11 (m, 7H).
The pharmacodynamic experiment of embodiment 13 compound 1-12
With the embodiment 1-12 compound prepared, reference substance cyclophosphamide is that given the test agent carries out pharmacodynamic evaluation, shows nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base) good antitumor action of-1-(heteroaromatic) methylene imine compounds.
(1) for the Developing restraint activity (GI of various cancerous cell50) assay method:
Tumor cell, after trypsinization, is dispersed into individual cells, and makes it be suspended in the RPMI1640 culture medium containing penicillin (25ug/ml) and streptomycin (25ug/ml).Cell is inoculated in 96 well culture plates, at 37 DEG C, containing 5%CO2Air, after cultivating 24 hours under relative humidity 100% condition, discard culture fluid, add the culture fluid containing a series of concentration of test samples, each concentration sets parallel hole, after cultivating 24 hours, separate the culture fluid containing given the test agent, after adding the cultivation of cellar culture liquid 48 hours, discard culture fluid, then change into containing tetrazolium bromide (MTT) culture fluid, the final concentration of 0.5g/L of MTT, continuing incubation and add dmso solution liquid after 4 hours, after 1 hour, purple crystal is completely dissolved, and detects the optical density (OD) of 570nm/630mm in SK601 type microplate reader.It is calculated as follows the given the test agent half growth inhibition ratio to tumor cell:
(T-T0)/(C-C0) × 100%
Note: C represents the OD value of cellular control unit, and T represents the OD value T adding given the test agent group cell0Represent the OD value of comparison plates of cells when adding given the test agent
Given the test agent is for the inhibitory action of various cancerous cell, and result is in Table 1.
Table 1
Compound 1-12 provided by the invention, compared with control compound cyclophosphamide, it is shown that the more excellent antitumor action as shown in above-mentioned the pharmacological results.
Claims (6)
1. nitrogen-(4-(aromatic thiohydroxy)-1 hydrogen-indazole-3-base)-1-(heteroaromatic) methylene imine compounds and pharmaceutically acceptable salt thereof, it is characterised in that there is the structure of logical formula I:
Wherein, R1Selected from the monocycle benzene aromatic hydrocarbons structure containing 1,2 or 3 substituent groups；The described substituent group in the monocycle benzene aromatic hydrocarbons structure containing 1,2 or 3 substituent groups is the alkyl of C1～C4, methoxyl group, nitro, carbomethoxy, formamido group, dimethylamino, trifluoromethyl or mesyl；
R2Selected from aromatic heterocycle structure or piperazine；Described aromatic heterocycle structure is furan, thiophene, pyridine, pyrimidine, imidazoles, pyrazoles, pyrroles, indole, quinoline or carbazole.
2. compound as claimed in claim 1 and pharmaceutically acceptable salt thereof, it is characterised in that: the described substituent group in monocycle benzene aromatic hydrocarbons structure is the alkyl of C1～C4, methoxyl group or formamido group.
3. compound as claimed in claim 1 and pharmaceutically acceptable salt thereof, it is characterised in that: described aromatic heterocycle structure is the one in thiophene, pyridine, pyrazoles, pyrimidine or imidazoles.
4. compound described in any one of claim 1-3 and pharmaceutically acceptable salt application in preparation treatment antitumor drug thereof.
5. apply as claimed in claim 4, it is characterized in that, described tumor is selected from breast carcinoma, colon cancer, pulmonary carcinoma, bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, colon cancer, multiple myeloma, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer, ovarian cancer and carcinoma of testis.
6. apply as claimed in claim 5, it is characterised in that described pulmonary carcinoma is nonsmall-cell lung cancer.
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| CN1374950A (en) * | 1999-07-02 | 2002-10-16 | 阿古龙制药公司 | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| CN101044138A (en) * | 2004-11-02 | 2007-09-26 | 辉瑞有限公司 | Methods for preparing indazole compounds |
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| CN101044138A (en) * | 2004-11-02 | 2007-09-26 | 辉瑞有限公司 | Methods for preparing indazole compounds |
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