CN107334767B - A kind of application of pyridazinone compound in oncotherapy - Google Patents
A kind of application of pyridazinone compound in oncotherapy Download PDFInfo
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- CN107334767B CN107334767B CN201710429186.6A CN201710429186A CN107334767B CN 107334767 B CN107334767 B CN 107334767B CN 201710429186 A CN201710429186 A CN 201710429186A CN 107334767 B CN107334767 B CN 107334767B
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- compound
- pyridazinone compound
- tumor
- pyridazinone
- imb5036
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
Abstract
The present invention relates to a kind of application of pyridazinone compound in oncotherapy, pyridazinone compound of the present invention, its mechanism of action is by causing DNA damage to DNA of tumor cell double-strand break, experiment in vitro shows stronger inhibited proliferation to kinds of tumor cells, it is tested in vivo for treating mouse bearing liver cancer, moderate tumor killing effect can be obtained.Pyridazinone compound of the invention, structural formula are as follows:The compound is a kind of brand new compound by causing DNA of tumor cell double-strand damage, is the prospect of anti-tumor drug with good development.
Description
Technical field:
The invention belongs to pharmaceutical technology fields.More particularly it relates to which a kind of pyridazinone compound is controlled in tumour
Application in treatment.
Background technique:
Malignant tumour is to seriously threaten the common disease of human health and life.The poison of the anti-tumor drug of clinical application at present
Property be puzzlement chemotherapy of tumors the problem of, find new anti-tumor drug be anti-tumor drug research a big task.The present invention relates to
And compound be pyridazinone compound.Pyridazinone compound is that one kind has the active heterocyclic compound of good biological,
It is occupied an important position in the research fields such as pesticide medicine.Pyridazinone compound can be used as calcium sensitizer for treating heart function
Can obstacle and heart failure cardiotonic drug, in addition platelet aggregation-against, decompression and anti-inflammatory, Hemorrhagic shock, in terms of
There is certain curative effect.Certain Pyridazinones Derivatives also have good activity in antitumor action, such as:
Chinese patent 200880017969.2 discloses a kind of pyridazinone derivative, has anti-tumor activity.
Chinese patent 200910127196.X discloses a kind of 6- (3- (trifluoromethyl) phenyl) pyridazine -3 (2H) -one
Parent nucleus has the purposes of pyridazinone compound in the preparation of antitumor drugs shown in following structural formula I, especially anti-liver
Purposes in cancer drug.
Chinese patent 201410018618.0 discloses a series of Pyridazinones Derivatives and its antineoplastic action.
Chinese patent 201310306863.7 discloses pyridazinone compound as tyrosine kinase inhibitor, especially
Purposes in c-Met inhibitor.
Compound IMB5036 and IMB5043 are the compound of the known structure in existing compound library, can be from the market
It is commercially available, can also synthesize to obtain according to corresponding chemical synthesis process, two compounds of the invention are bought from ENAMINE
Ltd company.Its anti-tumor activity so far and there are no any report.Although two compounds belong to pyridazinone compound,
But in structure and the prior art has significant difference, and the present inventor is found surprisingly that during antitumor medicine screening
Both compounds have lethal effect to kinds of tumors.
Summary of the invention:
The present invention provides a kind of pyridazinone compound, structural formula is as follows:
Wherein, R1, R2 are simultaneously halogen, are preferably simultaneously Cl, or are simultaneously Br；R3 is O, and R4 is selected from such as flowering structure:
It is preferred that following two pyridazinone compound:
Compound I is named as IMB5036, and No. CAS is 1090393-42-2.
Compound ii is named as IMB5043, and No. CAS is 1089995-96-9.
Present inventors studied the pharmaceutical activity of both compounds, it is found that it is good IMB5036 and IMB5043 has
Anti-tumor activity, it is especially best to liver cancer treatment effect.Being further discovered that can be by causing DNA double chain fracture that DNA is caused to damage
Wound is to play antitumor action.
For this purpose, it includes IMB5036 and IMB5043 anti-swollen in preparation that the present invention, which provides a kind of above-mentioned pyridazinone compound,
Application in tumor medicine.
Tumour of the present invention is selected from: liver cancer, colorectal cancer, cancer of pancreas, the cancer of the esophagus, lung cancer, oophoroma, breast cancer,
The tumour that fibrosarcoma and other treatments are resisted or be resistant to.
The present invention further provides the pharmaceutical composition containing pyridazinone compound, the pyridazinone compound structure
As described above.
Illustrate beneficial effects of the present invention below by way of experimental data.
Test example 1: cytotoxicity of the compound to culture cell.
MTT (Methyl thiazoly tetrazolium assay salt) method detection compound IMB5036 and IMB5043 makees the cell toxicant of culture cell
With.Cell is used containing 10% fetal calf serum (Giboco BRL Inc.), 2mM glutamine, 100 μ g/ml streptomysins and 100U/mL
The RPMI-1640 culture medium (Giboco BRL Inc.) of penicillin contains 5%CO at 37 DEG C2Incubator in cultivate.
The tumor cell line used is usual cell strain, this room saves, also commercially such as ATCC cell bank
(Rockville, MD, USA), National Laboratory cellular resources shared platform etc. are bought.The cell dissociation of logarithmic growth phase counts,
96 orifice plates are laid on by 4000 cells/wells, after culture 24 hours, the drug of various concentration are added, each drug concentration sets 3 and puts down
Row hole.After continuing culture 48 hours, every hole is added with the 20 μ L of MTT (Amresco, Ohio, USA) of the PBS 5mg/mL dissolved,
It after 37 DEG C are continued culture 4 hours, inhales and abandons supernatant, 150 μ L dimethyl sulfoxides are added, shaking table shakes 15 minutes at room temperature, microplate reader
The absorbance value A of 570nm is measured on (Thermo Labsystems, Multiskan MK3).Experiment is all provided with no medicine control every time
Hole and each 3 hole of cell-free blank well.By formula: inhibiting rate %=(A control group-A administration group)/(A control group-A blank group) ×
100% calculates drug to the proliferation inhibition rate and calculation of half inhibitory concentration (IC of cell50).The results are shown in Table 1, two kinds of chemical combination
Object has preferable lethal effect to the tumour cell of separate sources, and IMB5036 makees the killing of human liver cancer cells Hep G2
With most strong, IC50It is 1.85 μM；IMB5043 is also most strong to the lethal effect of SMMC-7721, IC50It is 3.56 μM.And Human embryo
Liver cell L02 is then insensitive to two compounds.
Cytotoxic activity of the table 1.IMB5036 and IMB5043 to tumour cell and normal cell L02
Test example 2: indirect immunofluorescence detects influence of the IMB5036 and IMB5043 to DNA damage.
The SMMC-7721 cell inoculation of logarithmic growth phase adds after 24 hours respectively in six orifice plates for being covered with coverslip
Enter 1 μM of IMB5036 and 2 μM of IMB5046, while control wells are set, after drug-treated 24 hours, takes out coverslip and successively use
PBS is washed 3 times, fixes 15 minutes with 4% paraformaldehyde, the penetrating processing of 0.1%TritonX-100 15 minutes, 1%BSA room temperature
Closing 30 minutes；AF488 label γ-H2AX antibody (EMD Millipore) is added to be incubated for 1 hour at 37 DEG C of temperature, fluorescence
It observes and takes pictures under microscope (Olympus IX81).As the result is shown IMB5036 and with IMB5043 processing neoplastic cell nuclei with it is right
It is compared according to group, the pH2AX foci of formation significantly increases (Fig. 1).
The animal experiment therapeutic scheme of test example 3:IMB5036 and IMB5043.
With the interior curative effect of human liver cancer SMMC-7721 xenograft tumor models evaluation compound.Take SMMC-7721 thin
Born of the same parents press 1 × 107It is subcutaneous that/0.2mL/ is only inoculated in NIH nu/nu mouse armpit, takes tumor mass to cut into physiological saline after two weeks
2mm3Fritter, it is subcutaneous that tumor mass is transplanted to nude mice armpit with trochar.7th day by nude mice press tumor mass size packets, every group 7
Only, make the tumor mass size average value of every group of animal close.Compound is dissolved in dimethyl sulfoxide (Sigma)/polyoxyethylene caster
In oily (Cremophor EL) (Sigma)/physiological saline (1:2:17) mixed liquor, intraperitoneal administration, dosage be 12.5 or
25mg/kg, 5 times/week, 0.2mL/, successive administration two weeks.Every 2-3 days tumour major diameter a of measurement and therewith during experiment
Vertical minor axis b, and record the weight of animals.With formula V=1/2ab2Calculate knurl product and inhibiting rate (control group knurl product-examination
Test a group knurl product)/control group knurl product × 100%.When knurl product reaches 1000mm3When de- neck put to death animal.
The experimental results showed that IMB5036 can significantly inhibit the growth of tumour, the IMB5036 of 12.5 and 25mg/kg passes through
Intraperitoneal administration, the 28th day tumour inhibiting rate is respectively 30.6% and 66.2% (Fig. 2) after administration, and the animal of all processing groups does not have
Apparent weight loss or the exception (Fig. 3) of behavior, illustrate that mouse can preferably be resistant to the drug of this dose.IMB5043 is aobvious
Moderate tumor killing effect is shown, the IMB5043 of 12.5 and 25mg/kg is by intraperitoneal administration, the 28th day tumor suppression after administration
Rate is respectively 28.6% and 58.8% (Fig. 4), and the animal of all processing groups does not have apparent weight loss or the exception of behavior (figure
5), illustrate that mouse can preferably be resistant to the drug of this dose.
The present invention further comprises the compounds of this invention or its pharmaceutically acceptable salt, the pharmaceutically acceptable salt
Selected from inorganic acid or organic acid formation salt, such as with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, lemon
The salt that acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid are formed,
Their alkali metal salt, alkali salt, silver salt, barium salt etc. can be prepared according to a conventional method.
The present invention also provides the pharmaceutical compositions containing compounds of the invention or their medicinal salts.Pharmaceutical composition is to be suitble to medicine
Dosage form exists.Medicinal preparation is selected from tablet, capsule, granule, oral solution, injection etc..
Pharmaceutical composition of the invention, as dosage form, the effective quantity of the invention compound contained in every dose is 0.1~
1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, also can refer to each taking agent
Amount, such as each taking 100mg.
Solid can be used when being prepared into the solid pharmaceutical preparation of tablet, Capsule form in pharmaceutical composition of the invention
Carrier.Workable solid carrier is preferably selected from diluent, flavoring agent, solubilizer, lubricant, suspending agent, adhesive, expansion
One of agent etc. or many kinds of substance, or can be encapsulating substance.Suitable solid carrier includes magnesium carbonate, magnesium stearate, talcum
Powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter etc..Due to them
It is easy to be administered, tablet and the best oral solid formulation of Capsules representative.
The weight ratio of the compounds of this invention that described pharmaceutical composition contains in the composition is 0.1~99.9%, drug
The weight ratio of acceptable carrier in the composition is 0.1~99.9%.
It is uniform for ease of administration and dosage, said medicine preparation is configured to dosage unit form and is particularly advantageous.
The dosage unit form of preparation refers to the physical separation unit for being suitable for single dose, and each unit, which contains, generates desired control
The active constituent for the predetermined amount of therapeutic effect calculated.This dosage unit form can be packaged form, such as tablet, capsule.
Although the amount of contained active constituent can change in dosage unit form, generally according to selected active constituent
Effect is adjusted within the scope of 1~800mg.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is lower than the optimal dose of active constituent, dosage is then gradually increased, until reaching optimum therapeuticing effect.It rises for convenience
See, total daily dose can be divided into several parts, be administered in several times.
The present invention is compared with pyridazinone compound in the prior art, and anti-tumor activity is higher, and toxic side effect is smaller, this
Invention pyridazinone compound LD50 numerical value is much higher than the pyridazinone compound of the prior art, is suitable as oral antineoplastic
Object uses.
Detailed description of the invention:
Fig. 1 IMB5036 and IMB5043 can cause human liver cancer cells Hep G2 nucleus γ-H2AX foci shape
At increasing (Fig. 1).
Fig. 2 IMB5036 can significantly inhibit the growth of tumour, and the IMB5036 of 12.5 and 25mg/kg passes through intraperitoneal administration,
The 28th day tumour inhibiting rate is respectively 30.6% and 66.2% (Fig. 2) after administration.
The animal of all IMB5036 processing groups of Fig. 3 does not have apparent weight loss or the exception of behavior (Fig. 3).
The tumor killing effect that Fig. 4 IMB5043 is shown, the IMB5043 of 12.5 and 25mg/kg is by intraperitoneal administration, after administration
28th day tumour inhibiting rate is respectively 28.6% and 58.8% (Fig. 4).
The animal of all IMB5043 processing groups of Fig. 5 does not have apparent weight loss or the exception of behavior (Fig. 5).
Specific embodiment
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
The preparation of tablet
Any one compound of IMB5036 and IMB5043 0.5g, starch 4.5g, Icing Sugar 0.9g and distilled water 1ml are taken, on
State component after mixing, pelletize, whole grain is dry, be added a small amount of lubricant tabletting packing to get.
Embodiment 2
The preparation of capsule
Any one compound of IMB5036 and IMB5043 0.5g, starch 4.5g, Icing Sugar 0.9g and distilled water 1ml are taken, on
State component after mixing, pelletize, whole grain is dry, dispense capsule to get.
Embodiment 3
The preparation of granule
Any one compound of IMB5036 and IMB5043 0.5g, starch 4.5g, Icing Sugar 0.9g and distilled water 1ml are taken, on
State component after mixing, pelletize, whole grain is dry, packing to get.
Claims (3)
1. a kind of pyridazinone compound application in preparation of anti-tumor drugs, the pyridazinone compound structure is as follows:
Wherein the tumour is selected from: liver cancer, colorectal cancer, cancer of pancreas.
2. application according to claim 1, wherein the drug is selected from tablet, capsule, granule, oral solution, injection
Agent.
3. a kind of with inhibition liver cancer, colorectal cancer, the pharmaceutical composition of cancer of pancreas, which is characterized in that the pharmaceutical composition contains
There is pyridazinone compound, the pyridazinone compound structure is as follows:
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Cited By (1)
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| WO2022258992A1 (en) * | 2021-06-10 | 2022-12-15 | Universitetet I Oslo | Pyridazinones for the treatment or prevention of hypertension |
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| CN109620829B (en) * | 2018-12-29 | 2021-04-06 | 温州医科大学附属第一医院 | Pharmaceutical composition for treating acute respiratory distress syndrome and preparation method thereof |
| CN111297870B (en) * | 2020-03-20 | 2021-03-26 | 中国医学科学院医药生物技术研究所 | Application of nitrobenzoic acid compounds in preparation of drugs for treating tumors |
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| CN1277605A (en) * | 1997-08-22 | 2000-12-20 | 艾博特公司 | Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| CN1342149A (en) * | 1998-10-27 | 2002-03-27 | 艾博特公司 | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| CN1583727A (en) * | 2003-12-30 | 2005-02-23 | 浙江工业大学 | Synthesis of fluoropyridazinone |
| WO2005111019A1 (en) * | 2004-05-18 | 2005-11-24 | Aventis Pharma S.A. | Novel pyridazinone derivatives as inhibitors of cdk2 |
| CN101326167A (en) * | 2005-12-05 | 2008-12-17 | 默克专利有限公司 | Pyridiazinone derivatives for tumour treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101537006B (en) * | 2008-03-18 | 2012-06-06 | 中国科学院上海药物研究所 | Application of pyridazinone compounds in preparing antitumor drugs |
| CN103893178B (en) * | 2014-03-19 | 2016-06-01 | 中山大学 | Benzene-sulfamide compound is in the application prepared in anti-HIV-1 virus drugs |
| CN106467495A (en) * | 2015-08-19 | 2017-03-01 | 中国科学院上海药物研究所 | Pyridazinone compound, its preparation method, pharmaceutical composition and purposes |
| CN107964007B (en) * | 2016-10-20 | 2021-02-12 | 沈阳中化农药化工研发有限公司 | Pyridazinone compound and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1277605A (en) * | 1997-08-22 | 2000-12-20 | 艾博特公司 | Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| CN1342149A (en) * | 1998-10-27 | 2002-03-27 | 艾博特公司 | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| CN1583727A (en) * | 2003-12-30 | 2005-02-23 | 浙江工业大学 | Synthesis of fluoropyridazinone |
| WO2005111019A1 (en) * | 2004-05-18 | 2005-11-24 | Aventis Pharma S.A. | Novel pyridazinone derivatives as inhibitors of cdk2 |
| CN101326167A (en) * | 2005-12-05 | 2008-12-17 | 默克专利有限公司 | Pyridiazinone derivatives for tumour treatment |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022258992A1 (en) * | 2021-06-10 | 2022-12-15 | Universitetet I Oslo | Pyridazinones for the treatment or prevention of hypertension |
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