CN105061317A - Indazole salt compound and preparing method and application thereof - Google Patents

Indazole salt compound and preparing method and application thereof Download PDF

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Publication number
CN105061317A
CN105061317A CN201510527995.1A CN201510527995A CN105061317A CN 105061317 A CN105061317 A CN 105061317A CN 201510527995 A CN201510527995 A CN 201510527995A CN 105061317 A CN105061317 A CN 105061317A
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indazole
salt compound
methyl
acid
piperazinyl
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CN105061317B (en
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张辰
韩峰
杜永忠
王再红
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Zhejiang Daguo Biological Pharmaceutical Co Ltd
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Zhejiang Daguo Biological Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides an indazole salt compound (II). A preparing method of the indazole salt compound includes the steps that 3-{2-[4N-(2-methyl-3-chlorphenyl)-1N-piperazinyl] ethyl}-5,6-dimethoxy-1H-indazole and acid of the same mole number as the 3-{2-[4N-(2-methyl-3-chlorphenyl)-1N-piperazinyl] ethyl}-5,6-dimethoxy-1H-indazole are added to an organic solvent such as methyl alcohol to be heated, the obtained matter is cooled after a reaction is completely finished to be filtered, solid is separated out, and the indazole salt compound is obtained. The preparing method is simple, low in production cost and facilitates industrialized production; the indazole salt compound has good water solubility; the solubility in water of the salt compound is obviously improved compared with that of other hydrochloride, injection liquid is prepared easily, and the indazole salt compound has higher clinical medication practicability; the indazole salt compound has the biological activity of inhibiting human breast carcinoma cell lines and can be applied to preparation of medicine for inhibiting the biological activity of breast cancer cells. Please see the molecular formula in the specification.

Description

One class indazole salt compounds and its preparation method and application
Technical field
The invention belongs to medical art, relate to a kind of indazole compounds composition, relate generally to 3-{2-[4 n-(2-methyl-3-chloro-phenyl-)-1 n-piperazinyl] ethyl }-5,6-dimethoxys-1 h-indazole salt and preparation method thereof, and the purposes in preparation treatment breast cancer medicines.
Background technology
Cancer is serious harm human life and healthy common disease, frequently-occurring disease.Have the feature that sickness rate is high, mortality ratio is high and recurrence rate is high in recent years, society and economical load increase the weight of increasingly.
3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl had been introduced in document in recent years }-5, 6-dimethoxy-1H-indazole hydrochloride (I) can regulate and control the homeostasis (LuYM of Calmodulin-Dependent kinases in myocardial hypertrophy pathologic process and Starch phosphorylase, ShiodaN, HanF, MoriguchiS, KasaharaJ, ShirasakiY, QinZH, FukunagaK.ImbalancebetweenCaMkinaseIIandcalcineurinactiv itiesimpairscaffeine-inducedcalciumreleaseinhypertrophic cardiomyocytes.BiochemPharmacol.200715, 74 (12): 1727-37).But this compound water does not dissolve, and is difficult to make preparation and plays drug effect, and have not yet to see the report of this material for antitumor drug.
Summary of the invention
An object of the present invention is to provide a class indazole salt compounds, relate to water-soluble 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole salt compounds, its chemical general formula (II) is as follows:
Described acid group selects the one in oxalate, sulfate radical or nitrate radical.
Another object of the present invention is to provide 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl } preparation method of-5,6-dimethoxy-1H-indazole salt compounds, realized by following steps:
By 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole and acid are reacted in organic solvent, recrystallization obtains target compound 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole salt.
Reaction formula:
Described acid comprises oxalic acid, sulfuric acid, nitric acid, Citric Acid etc.
Described organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, butyl alcohol-tert, 2-butanols, Pentyl alcohol, primary isoamyl alcohol, toluene, acetone, 2-butanone, acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) etc.
Described heating temperature range is at 60 ~ 120 degree.
Another object of the present invention is to provide the application of above-mentioned indazole salt compounds (II) in preparation treatment breast cancer medicines.Prove through pharmacodynamic experiment, described indazole salt compounds (II) has the biological activity suppressing Breast cancer lines.
Feature of the present invention is that the preparation technology of (1) described indazole salt compounds is simple, and production cost is low, is convenient to suitability for industrialized production; (2) described indazole compounds composition has water-soluble preferably, this salt compounds compared with its hydrochloride in water solubleness significantly improve, be easy to prepare injection liquid, there is higher clinical application accessibility; (3) salt compounds described in has the biological activity suppressing Breast cancer lines, can apply in for the preparation of the bioactive medicine of inhibition tumor cell.
Embodiment
The present invention is described further in conjunction with the embodiments, but does not therefore limit the present invention within described scope of embodiments.
The preparation of embodiment 1 indazole compounds salt
In 50 ml methanol, add 3-{2-[4 n-(2-methyl-3-chloro-phenyl-)-1 n-piperazinyl] ethyl-5,6-dimethoxy-1H-indazole 0.415 gram (1 mmole), oxalic acid 0.09 gram (1 mmole), mixture refluxes 1 hour.Thin-layer chromatography (TLC) detection reaction is complete, revolves steaming and flings to excessive methanol, gained solids with methanol/ether (1/10) recrystallization, obtain khaki color solid 0.505 gram.Mp：158-159℃。Product resolves confirmation for target compound 3-{2-[4 through nucleus magnetic resonance n-(2-methyl-3-chloro-phenyl-)-1 n-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole oxalate. 1HNMR(600MHz, d 6-DMSO)δ7.20(s,1H),7.07(s,1H),6.91(s,1H),3.80(s,6H),3.61-3.25(m,8H),3.20-3.05(m,4H),2.31(s,3H); 13CNMR(150MHz, d 6-DMSO)δ164.00,152.1,150.9,145.8,140.5,136.9,136.88,135.0,130.7,128.0,124.8,118.5,114.8,100.1,92.1,56.2,56.0,55.3,54.9,51.9,49.3,49.1,22.0,15.4。
Embodiment 2
Operation is with embodiment 1, and just solvent is ethanol, obtains target compound indazole oxalate 0.499 gram.
Embodiment 3
Operation is with embodiment 1, and just solvent is propyl alcohol, obtains target compound 0.45 gram.
Embodiment 4
Operation is with embodiment 1, and just solvent is Virahol, obtains target compound 0.465 gram.
Embodiment 5
Operation is with embodiment 1, and just solvent is Virahol, obtains target compound 0.465 gram.
Embodiment 6
Operation is with embodiment 1, and just solvent is propyl carbinol, obtains target compound 0.495 gram.
Embodiment 7
Operation is with embodiment 1, and just solvent is butyl alcohol-tert, obtains target compound 0.501 gram.
Embodiment 8
Operation is with embodiment 1, and just solvent is 2-butanols, obtains target compound 0.40 gram.
Embodiment 9
Operation is with embodiment 1, and just solvent is Pentyl alcohol, obtains target compound 0.45 gram.
The preparation of embodiment 10 indazole compounds composition
Operation is with embodiment 1, and just solvent is primary isoamyl alcohol, obtains target compound 0.25 gram.
Embodiment 11
Operation is with embodiment 1, and just solvent is toluene, obtains target compound 0.225 gram.
Embodiment 12
Operation is with embodiment 1, and just solvent is acetone, obtains target compound 0.499 gram.
Embodiment 13
Operation is with embodiment 1, and just solvent is 2-butanone, obtains target compound 0.35 gram.
Embodiment 14
Operation is with embodiment 1, and just solvent is acetonitrile, obtains target compound 0.485 gram.
Embodiment 15
Operation is with embodiment 1, and just solvent is dimethyl formamide (DMF), obtains target compound 0.50 gram.
Embodiment 16
Operation is with embodiment 1, and just solvent is dimethyl sulfoxide (DMSO) (DMSO), obtains target compound 0.115 gram.
Embodiment 17
Operation is with embodiment 1, and just acid used is sulfuric acid, obtains 0.510 gram, target compound vitriol.Fusing point: 216-218 DEG C, 1hNMR (600MHz, d 6-DMSO) δ 9.63 (s, 1H), 7.20 (s; 1H), 7.09 (s, 1H); 6.93 (s, 1H), 3.81 (s; 6H), 3.75-3.60 (m, 4H); 3.42-3.20 (m, 6H), 3.05-2.92 (m; 2H), 2.31 (s, 3H); 13c (150MHz, d 6-DMSO) δ 151.9,151.2,146.0,140.1,137.0,135.0,130.8,128.0,125.0,118.6,114.7,100.1,92.1,56.3,56.1,54.7,52.0,49.1,21.75,15.4.
Embodiment 18
Operation is with embodiment 1, and just acid is nitric acid, obtains 0.502 gram, target compound nitrate.Fusing point: 140-141.0 DEG C, 1hNMR (600MHz, d 6-DMSO) δ 9.72 (s, 1H), 7.24 (s, 1H); 7.20 (s, 1H), 7.08 (s, 1H); 6.94 (s, 1H), 3.81 (s, 6H); 3.75-3.65 (m, 2H), 3.65-3.55 (m, 2H); 3.45-3.30 (m, 4H), 3.28-3.18 (m, 2H); 3.12-2.97 (m, 2H), 2.31 (s, 3H); 13c (150MHz, d 6-DMSO) δ 151.9,151.2,146.05,140.1,136.9,135.0,130.8,128.0,125.0,118.6,114.7,100.1,92.1,56.3,56.1,54.8,52.0,49.05,21.7,15.4.
Embodiment 19
Compound 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole oxalate and vitriol measures the Proliferation Ability of MCF-7 cell strainHJ2mm
(1) preparation of sample: each 1mg of sample thief 20 μ LDMSO dissolve, gets 2 μ L, 1000 μ L nutrient solutions and dilutes, make concentration be 100 μ g/mL, then use nutrient solution serial dilution to working concentration.
(2) cultivation of cell
1) preparation of substratum: containing 800,000 units of Penicillin in every 1000mL substratum, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum.
2) cultivation of cell: be inoculated in substratum by MCF-7 cell, puts 37 DEG C, 5%CO 2cultivate in incubator, 3 ~ 5d goes down to posterity.
(3) working sample is to the restraining effect of growth of tumour cell
By cell EDTA-trysinization liquid digestion, and be diluted to 1 × 10 with substratum 5/ mL, be added in 96 porocyte culture plates, every hole 100uL, puts 37 DEG C, 5%CO 2cultivate in incubator.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO 2cultivate in incubator, add the MTT of 5mg/mL after 72h in cell culture well, every hole 10 μ L, puts 37 DEG C and hatches 4h, add DMSO, every hole 150 μ L, and with oscillator vibrates, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.With similarity condition with containing sample, containing the culture medium culturing of same concentration DMSO cell in contrast, calculation sample is to the median lethal concentration (IC of growth of tumour cell 50).
(4) experimental result:
Adopt cis-platinum as positive control medicine in this experiment, record compound indazolium oxalate, indazole sulfuric acid salt and the control group suppression result to MCF-7 cell strain as shown in table 1.
As can be seen from Table 1, the IC of compound indazolium oxalate 50for 22.5uM, slightly lower than control group cis-platinum (IC 50for 29.2uM), to MCF-7 tumour cell, there is good restraining effect; The IC of compound indazolium vitriol 50be 11.8 μMs, be about 50% of control group cis-platinum, to MCF-7 tumour cell, there is better restraining effect.
Annex: indazole salt solubleness.

Claims (3)

1. a class indazole salt compounds, relates to water-soluble 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole salt compounds, its chemical general formula (II) is as follows:
Wherein: described acid group selects the one in oxalate, sulfate radical or nitrate radical.
2. the preparation method of a class indazole salt compounds according to claim 1, be is characterized in that, realized by following steps:
By 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole and acid are reacted in organic solvent, recrystallization obtains target compound 3-{2-[4N-(2-methyl-3-chloro-phenyl-)-1N-piperazinyl] ethyl }-5,6-dimethoxy-1H-indazole salt; Reaction formula:
Oxalic acid, sulfuric acid, nitric acid or Citric Acid are selected in wherein said acid;
Described organic solvent is the one in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, butyl alcohol-tert, 2-butanols, Pentyl alcohol, primary isoamyl alcohol, toluene, acetone, 2-butanone, acetonitrile, dimethyl formamide or dimethyl sulfoxide (DMSO);
Described heating temperature range is at 60 ~ 120 degree.
3. the application of a class indazole salt compounds according to claim 1 in preparation treatment breast cancer medicines.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407752A (en) * 2019-08-22 2019-11-05 浙江大果生物医药科技有限公司 A kind of Crystal form of oxalate of drug and preparation method thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407752A (en) * 2019-08-22 2019-11-05 浙江大果生物医药科技有限公司 A kind of Crystal form of oxalate of drug and preparation method thereof

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