[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN107334767A - A kind of application of pyridazinone compound in oncotherapy - Google Patents

A kind of application of pyridazinone compound in oncotherapy Download PDF

Info

Publication number
CN107334767A
CN107334767A CN201710429186.6A CN201710429186A CN107334767A CN 107334767 A CN107334767 A CN 107334767A CN 201710429186 A CN201710429186 A CN 201710429186A CN 107334767 A CN107334767 A CN 107334767A
Authority
CN
China
Prior art keywords
compound
pyridazinone
imb5036
follows
pyridazinone compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710429186.6A
Other languages
Chinese (zh)
Other versions
CN107334767B (en
Inventor
弓建华
郑艳波
甄永苏
李毅
刘秀均
司书毅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Medicinal Biotechnology of CAMS
Original Assignee
Institute of Medicinal Biotechnology of CAMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Medicinal Biotechnology of CAMS filed Critical Institute of Medicinal Biotechnology of CAMS
Priority to CN201710429186.6A priority Critical patent/CN107334767B/en
Publication of CN107334767A publication Critical patent/CN107334767A/en
Application granted granted Critical
Publication of CN107334767B publication Critical patent/CN107334767B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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, test in vivo for treating mouse bearing liver cancer, moderate tumor killing effect can be obtained.The pyridazinone compound of the present invention, its structural formula are as follows：The compound is a kind of brand new compound by causing DNA of tumor cell double-strand damage, has the good prospect for developing into antineoplastic.

Description

A kind of application of pyridazinone compound in oncotherapy
Technical field：
The invention belongs to pharmaceutical technology field.More particularly it relates to a kind of pyridazinone compound is controlled in tumour Application in treatment.
Background technology：
Malignant tumour is serious threat human health and the common disease of life.The poison of the antineoplastic of clinical practice at present Property be puzzlement chemotherapy of tumors the problem of, find new antineoplastic be antineoplastic research a big task.The present invention relates to And compound be pyridazinone compound.Pyridazinone compound is a kind of heterocyclic compound with good biological activity, Occupy critical role in the research fields such as agricultural chemicals medicine.Pyridazinone compound can be used as calcium sensitizer to be used to treat heart work( Energy obstacle and the cardiotonic drug of heart failure, in addition in platelet aggregation-against, decompression and anti-inflammatory, Hemorrhagic shock, anticonvulsion etc. There is certain curative effect.Some Pyridazinones Derivatives also have good activity in antitumor action, such as：
Chinese patent 200880017969.2 discloses a kind of pyridazinone derivative, has antitumor activity.
Chinese patent 200910127196.X discloses a kind of 6- (3- (trifluoromethyl) phenyl) pyridazine -3 (2H) -one Purposes of the pyridazinone compound in antineoplastic is prepared having shown in following structural formula I of parent nucleus, 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, is particularly 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 synthesizes to obtain according to corresponding chemical synthesis process, of the invention two compounds is bought from ENAMINE Ltd companies.Its antitumor activity so far and there are no any report.Although two compounds belong to pyridazinone compound, But in structure and 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.
The content of the invention：
The invention provides a kind of pyridazinone compound, its structural formula are as follows：
Wherein, R1, R2 are simultaneously halogen, are preferably simultaneously Cl, or be Br simultaneously；R3 is O, and R4 is selected from following structure：
It is preferred that following two pyridazinone compounds：
Compound I, is named as IMB5036, and its No. CAS is 1090393-42-2.
Compound ii, IMB5043 is named as, its No. CAS is 1089995-96-9.
Present inventors studied the pharmaceutical activity of both compounds, it is found that IMB5036 and IMB5043 has well Antitumor activity, it is particularly best to liver cancer treatment effect.Being further discovered that can be by causing DNA double chain fracture to cause DNA to damage Hinder to play antitumor action.
Therefore, a kind of above-mentioned pyridazinone compound of present invention offer is anti-swollen in preparation including IMB5036 and IMB5043 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, Fibrosarcoma and the tumour of other treatment resistances or tolerance.
The present invention further provides the pharmaceutical composition containing pyridazinone compound, the pyridazinone compound structure It is as described above.
Illustrate beneficial effects of the present invention below by way of experimental data.
Test example 1：CDCC of the compound to culture cell.
MTT (Methyl thiazoly tetrazolium assay salt) method detection compound IMB5036 and IMB5043 makees to the cell toxicant for cultivating cell With.Cell, which is used, contains 10% hyclone (Giboco BRL Inc.), 2mM glutamine, 100 μ g/ml streptomysins and 100U/mL The RPMI-1640 culture mediums (Giboco BRL Inc.) of penicillin contain 5%CO at 37 DEG C2Incubator in cultivate.
The tumor cell line used is usual cell strain, and this room preserves, also commercially such as ATCC cell banks (Rockville, MD, USA), National Laboratory cellular resources shared platform etc. are bought.Take the logarithm growth period cell dissociation count, 96 orifice plates are laid on by 4000 cells/wells, after cultivating 24 hours, add the medicine of various concentrations, each drug concentration sets 3 and put down Row hole.After continuing culture 48 hours, added per hole with the 5mg/mL of the PBS dissolvings μ L of MTT (Amresco, Ohio, USA) 20, After 37 DEG C are continued culture 4 hours, supernatant is abandoned in suction, adds 150 μ L dimethyl sulfoxide (DMSO)s, and shaking table shakes 15 minutes at room temperature, ELIASA 570nm absorbance value A is determined on (Thermo Labsystems, Multiskan MK3).Experiment is all provided with no medicine control every time Hole and each 3 hole of acellular blank well.By formula:Inhibiting rate %=(A control group-A administration groups)/(A control group-A blank groups) × 100% calculates proliferation inhibition rate and calculation of half inhibitory concentration (IC of the medicine to cell50).As a result as shown in table 1, two kinds of chemical combination Thing has preferable lethal effect to the tumour cell of separate sources, and killings of the IMB5036 to human liver cancer cells Hep G2 is made With most strong, IC50For 1.85 μM；IMB5043 is also most strong to SMMC-7721 lethal effect, IC50For 3.56 μM.And Human embryo Liver cell L02 is then insensitive to two compounds.
Table 1.IMB5036 and IMB5043 is to tumour cell and normal cell L02 cytotoxic activity
Test example 2：IIF detects influences of the IMB5036 and IMB5043 to DNA damage.
The SMMC-7721 cells in growth period of taking the logarithm are inoculated in six orifice plates for being covered with cover glass, after 24 hours respectively plus Enter 1 μM of IMB5036 and 2 μM of IMB5046, while control wells are set, drug-treated is taken out cover glass and used successively after 24 hours PBS is washed 3 times, and 15 minutes are fixed with 4% paraformaldehyde, the penetrating processing of 0.1%TritonX-100 15 minutes, 1%BSA room temperatures Closing 30 minutes；Add AF488 mark γ-H2AX antibody (EMD Millipore) to be incubated 1 hour at 37 DEG C of temperature, fluorescence Observe and take pictures under microscope (Olympus IX81).As a result show IMB5036 and with IMB5043 processing neoplastic cell nuclei with it is right Compared according to group, the pH2AX foci of formation significantly increases (Fig. 1).
Test example 3：IMB5036 and IMB5043 animal experiment therapeutic scheme.
With curative effect inside 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 armpits, takes tumor mass to be cut into physiological saline after two weeks 2mm3Fritter, it is subcutaneous that tumor mass is transplanted to nude mice armpit with trochar.Nude mice was pressed into tumor mass size packets in 7th day, every group 7 Only, approach the tumor mass size average value of every group of animal.Compound is dissolved in dimethyl sulfoxide (DMSO) (Sigma)/polyoxyethylene caster Oily (Cremophor EL) (Sigma)/physiological saline (1:2:17) in mixed liquor, intraperitoneal administration, dosage be 12.5 or 25mg/kg, 5 times/week, 0.2mL/, successive administration two weeks.During experiment per 2-3 days measurement tumour major diameter a and therewith Vertical minor axis b, and record the weight of animals.With formula V=1/2ab2Calculate knurl volume and inhibiting rate (control group knurl volume-examination Test a group knurl volume)/control group knurl volume × 100%.When knurl volume reaches 1000mm3When de- neck put to death animal.
Test result indicates that IMB5036 can significantly inhibit the growth of tumour, 12.5 and 25mg/kg IMB5036 passes through Intraperitoneal administration, the tumour inhibiting rate of the 28th day is respectively 30.6% and 66.2% (Fig. 2) after administration, and the animal of all treatment groups does not have Obvious Body weight loss or the exception (Fig. 3) of behavior, illustrate that mouse can preferably be resistant to the medicine of this dose.IMB5043 shows Moderate tumor killing effect is shown, 12.5 and 25mg/kg IMB5043 is by intraperitoneal administration, the tumor suppression of the 28th day after administration Rate is respectively 28.6% and 58.8% (Fig. 4), and the animal of all treatment groups does not have obvious Body weight loss or the exception of behavior (figure 5), illustrate that mouse can preferably be resistant to the medicine 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, butanedioic 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 composition containing the compounds of this invention or its pharmaceutical salts.Pharmaceutical composition is with suitable medicine Dosage form is present.Medicinal preparation is selected from tablet, capsule, granule, oral liquid, injection etc..
The pharmaceutical composition of the present invention, as dosage form, the effective dose of the invention compound contained in every dose for 0.1~ 1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, can also refer to each taking agent Amount, such as each taking 100mg.
Solid can be used when preparing the solid pharmaceutical preparation of piece agent, Capsule form in the pharmaceutical composition of the present invention Carrier.Workable solid carrier is preferably selected from diluent, flavor enhancement, solubilizer, lubricant, suspending agent, adhesive, expansion One or more materials in agent etc., 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%, medicine The weight ratio of acceptable carrier in the composition is 0.1~99.9%.
Homogeneous for ease of administration and dosage, it is particularly advantageous that said medicine preparation is configured into dosage unit form. The dosage unit form of preparation refers to the physical separation unit for being adapted as single dose, and each unit, which contains, produces desired control The active component of the scheduled volume calculated of therapeutic effect.This dosage unit form can be packaged form, such as tablet, capsule.
Although the amount of contained active component can change in dosage unit form, the general active component selected by Effect, adjust in the range of 1~800mg.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Typically, treatment is started Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active component.Rise for convenience See, total daily dose can be divided into several parts, fraction time administration.
Of the invention to be compared with pyridazinone compound of the prior art, antitumor activity is higher, and toxic side effect is smaller, this Invention pyridazinone compound LD50 numerical value is far above the pyridazinone compound of prior art, is suitable as oral antineoplastic Thing uses.
Brief description of the drawings：
Fig. 1 IMB5036 and IMB5043 can cause human liver cancer cells Hep G2 nucleus γ-H2AX foci shapes Into increasing (Fig. 1).
Fig. 2 IMB5036 can significantly inhibit the growth of tumour, 12.5 and 25mg/kg IMB5036 by intraperitoneal administration, The tumour inhibiting rate of the 28th day is respectively 30.6% and 66.2% (Fig. 2) after administration.
The animal of all IMB5036 treatment groups of Fig. 3 does not have obvious Body weight loss or the exception of behavior (Fig. 3).
The tumor killing effect that Fig. 4 IMB5043 are shown, 12.5 and 25mg/kg IMB5043 is by intraperitoneal administration, after administration The tumour inhibiting rate of the 28th day is respectively 28.6% and 58.8% (Fig. 4).
The animal of all IMB5043 treatment groups of Fig. 5 does not have obvious Body weight loss or the exception of behavior (Fig. 5).
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 it is well mixed after, granulation, whole grain, dry, add a small amount of lubricant tabletting packing, produce.
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 it is well mixed after, granulation, whole grain, dry, dispense capsule, produce.
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 it is well mixed after, granulation, whole grain, dry, packing, produce.

Claims (10)

1. a kind of application of pyridazinone compound in antineoplastic is prepared, the pyridazinone compound structure is as follows：
Wherein, R1, R2 are halogen simultaneously, and R3 O, R4 are selected from following structure：
Or
2. application according to claim 1, wherein R1 in the compound, R2 are simultaneously Cl, or it is Br simultaneously.
3. application according to claim 1, wherein the compound is selected from compound I, it is named as IMB5036, structural formula It is as follows：
4. application according to claim 1, wherein the compound, is compound ii, is named as IMB5043, structural formula It is as follows：
5. application according to claim 1, wherein the tumour is selected from：Liver cancer, colorectal cancer, cancer of pancreas, the cancer of the esophagus, lung Cancer, oophoroma, breast cancer, fibrosarcoma and the tumour of other treatment resistances or tolerance.
6. application according to claim 1, wherein the medicine is selected from tablet, capsule, granule, oral liquid, injection Agent.
7. the pharmaceutical composition containing pyridazinone compound, the pyridazinone compound structure is as follows：
Wherein, R1, R2 are halogen simultaneously, and R3 O, R4 are selected from following structure：
Or
8. pharmaceutical composition according to claim 7, wherein R1 in the compound, R2 are simultaneously Cl, or it is Br simultaneously.
9. pharmaceutical composition according to claim 7, wherein the compound is selected from compound I, IMB5036 is named as, Structural formula is as follows：
10. pharmaceutical composition according to claim 7, wherein the compound, is compound ii, is named as IMB5043, Structural formula is as follows：
CN201710429186.6A 2017-06-08 2017-06-08 A kind of application of pyridazinone compound in oncotherapy Expired - Fee Related CN107334767B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710429186.6A CN107334767B (en) 2017-06-08 2017-06-08 A kind of application of pyridazinone compound in oncotherapy

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710429186.6A CN107334767B (en) 2017-06-08 2017-06-08 A kind of application of pyridazinone compound in oncotherapy

Publications (2)

Publication Number Publication Date
CN107334767A true CN107334767A (en) 2017-11-10
CN107334767B CN107334767B (en) 2019-03-05

Family

ID=60220582

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710429186.6A Expired - Fee Related CN107334767B (en) 2017-06-08 2017-06-08 A kind of application of pyridazinone compound in oncotherapy

Country Status (1)

Country Link
CN (1) CN107334767B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109620829A (en) * 2018-12-29 2019-04-16 温州医科大学附属第医院 A kind of pharmaceutical composition and preparation method thereof for treating acute respiratory distress syndrome
CN111297870A (en) * 2020-03-20 2020-06-19 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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB202108303D0 (en) * 2021-06-10 2021-07-28 Univ Oslo Therapy

Citations (9)

* Cited by examiner, † Cited by third party
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
CN101537006A (en) * 2008-03-18 2009-09-23 中国科学院上海药物研究所 Application of pyridazinone compounds in preparing antitumor drugs
CN103893178A (en) * 2014-03-19 2014-07-02 中山大学 Application of benzene-sulfamide compounds in preparing anti-HIV-1(human immunodeficiency virus-1) drug
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
CN107964007A (en) * 2016-10-20 2018-04-27 沈阳中化农药化工研发有限公司 Pyridazinone compound and its application

Patent Citations (9)

* Cited by examiner, † Cited by third party
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
CN101537006A (en) * 2008-03-18 2009-09-23 中国科学院上海药物研究所 Application of pyridazinone compounds in preparing antitumor drugs
CN103893178A (en) * 2014-03-19 2014-07-02 中山大学 Application of benzene-sulfamide compounds in preparing anti-HIV-1(human immunodeficiency virus-1) drug
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
CN107964007A (en) * 2016-10-20 2018-04-27 沈阳中化农药化工研发有限公司 Pyridazinone compound and its application

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109620829A (en) * 2018-12-29 2019-04-16 温州医科大学附属第医院 A kind of pharmaceutical composition and preparation method thereof for treating acute respiratory distress syndrome
CN111297870A (en) * 2020-03-20 2020-06-19 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
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

Also Published As

Publication number Publication date
CN107334767B (en) 2019-03-05

Similar Documents

Publication Publication Date Title
CN105377299B (en) For treat prostate cancer comprising dihydro pyrazine simultaneously-combination treatments of pyrazine compound and androgen receptor antagonists
CN107257786A (en) The method of Bei Evil thiazines sample compound processed
CN107334767B (en) A kind of application of pyridazinone compound in oncotherapy
CN108503650A (en) Dioxane and quinazoline compounds or its pharmaceutical salts or its hydrate and its application as tyrosine kinase inhibitor
US9562046B2 (en) Means and method for treating solid tumors
CN101429201A (en) Lemon acid berbamine salt, preparation method and application thereof
CN106146372B (en) For preventing and treating the organic selenium compounds of cancer
CN106349228B (en) Substituted quianzolinones and its preparation method and application
PT1549329E (en) Extract with anti-tumor and anti-poisonous activity
CN110279866B (en) Combination product comprising limonoids and thiazolidinediones
US11999709B2 (en) Processes for preparing oxathiazin-like compounds
CN112494490B (en) Application of pimavanserin tartrate in preparation of drug for treating glioma
CN111821303B (en) Application of vortioxetine and salts thereof in preparation of antitumor drugs
CN108623560A (en) A kind of Quinolone acid analog derivative and its preparation method and application
CN101423519A (en) Tetrandrine organic acid salt as well as preparation method and application
CN101233125A (en) Antitumoral compounds
CN115990162B (en) Application of 4-hydroxy-2-pyridone alkaloid in preparation of medicines for treating gastric cancer
CN108623591A (en) A kind of purposes of piperazine Nino peace compound
US11958835B1 (en) 6-(6-bromo-2-oxo-2H-chromen-3-yl)-4-(4-chlorophenyl)-2-alkoxynicotinonitrile as antimicrobial agents
CN113164483A (en) Pharmaceutical composition for preventing or treating cancer comprising PLK1 activation inhibitor as active ingredient
CN102786517B (en) The pyrimidine thiazole amines derivative of GK and PPAR double excitation activity
CN102276625B (en) Thiadiazole derivative
RU2430724C2 (en) Coformulated antituberculous drug
US4619928A (en) Compositions for treating tumors
JP2010500387A5 (en)

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20190305