CN110317216A - A kind of application of triazolopyridazine derivates in field of medicaments - Google Patents
A kind of application of triazolopyridazine derivates in field of medicaments Download PDFInfo
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- CN110317216A CN110317216A CN201810261922.6A CN201810261922A CN110317216A CN 110317216 A CN110317216 A CN 110317216A CN 201810261922 A CN201810261922 A CN 201810261922A CN 110317216 A CN110317216 A CN 110317216A
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- acid
- compound
- triazol
- pyridazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention discloses a kind of Triazolopyridazine compound 3- (4- (benzos [d] [1,3] two cyclopentadienyl -5- ylmethyl is disliked) -1- piperazinyl) -3'- phenyl -6,6'- bis- [1,2,4] triazol [4,3-b] pyridazine, preparation method and its application in preparation inhibition tumor promotion drug.Specifically, compound 3- (4- (benzo [d] [1 in the present invention, 3] two cyclopentadienyl -5- ylmethyl is disliked) -1- piperazinyl) -3'- phenyl -6,6'- bis- [1,2,4] triazol [4,3-b] pyridazine or its drug that pharmaceutically prepared by acceptable salt have the function of inhibiting tumor promotion, can be used for preparing relevant anti-tumor drug.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are specifically related to a kind of medical applications field of small molecule compound.
Background technique
Cancer has become the big killer of the mankind.Michael etc. describes thiazolamine class breast cancer medicines
(Bioorg&Med.Chem.2004,12,1029)；Chinese patent (CN200910226728.5) describe 4- tert-butyl -5- (1,
2,4- triazol-1-yl) -2- benzyl imino thiazole anti-tumor activity；Hu Aixi etc. describes 5- benzyl -4- tert-butyl -2- benzyl
The anti-tumor activity [CN200910226774.5, CN101781269] of imino thiazole.Hu Aixi etc. describes 4- (benzo furan
Mutter -5- base) preparation of -2- benzyl imino thiazole and its anti-tumor activity [CN201010533786.5].Triazole class compounds tool
There are very high sterilization, weeding, desinsection and plant growth regulating activity, because of the double action that it has sterilization, control long, becoming most has
One of pesticide of future [the Recent Advances pesticide of external fungicide, 1989,28 (1): 48] Liu Aiping [Chinese patent
CN98112665.0；Central China Normal University's journal (natural science edition), 2004,38 (1): 66-68] describe following 4 kinds of 3,3-
The preparation of dimethyl -1- (1,2,4- triazol-1-yl) diacetylmonoxime benzylic ether and its under 100mg/L dosage to Pyricularia oryzae, rice
Sheath blight fungus, Sclerotinia sclerotiorum, cotton rhizoctonia solani and fusarium graminearum mycelia there is bactericidal effect, the present invention will be small
The compound application and field of antineoplastic medicaments containing triazole type of molecule.
Summary of the invention
Technical problem to be solved by the present invention lies in the present invention provides a kind of small molecule compounds --- compound 3-
Two [1,2,4] triazol [4,3- of (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- phenyl -6,6'-
B] pyridazine or its officinal salt in preparation for treat and the purposes in the drug of antitumor relevant Cancerous disease, test table
Bright, which has significant inhibiting effect to Partial tumors cell, can be used as the active constituent for preparing anti-tumor drug.
Wherein, compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- the piperazinyl) -3'- phenyl -
The structural formula of 6,6'- bis- [1,2,4] triazol [4,3-b] pyridazine is as follows:
Formulas I
The application of compound of formula I or its pharmaceutically acceptable salt in preparation inhibition tumor promotion drug.
Triazolopyridazine compound according to claim 1, which is characterized in that preparation method includes:
(1) by 5- (iodomethyl) benzo [d] [1,3] two dislike the bromo- 3- of cyclopentadienyl 2mol and 6- (1- piperazinyl)-[1,2,4] triazol [4,
3-b] pyridazine reacted, obtain midbody compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazine
Base) bromo- [1,2,4] triazol [4,3-b] pyridazine of -6-；
(2) by the midbody compound 3- of above-mentioned preparation (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -
Bromo- [1,2,4] triazol [4,3-b] pyridazine of 6- and (3- phenyl-[1,2,4] triazol [4,3-b] pyridazine -6- base) boric acid carry out
Reaction obtains target compound compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- benzene
Base -6,6'- two [1,2,4] triazol [4,3-b] pyridazine.
Pharmaceutically acceptable salt of the present invention is compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1-
Piperazinyl) -3'- phenyl -6,6'- two [1,2,4] triazol [4,3-b] pyridazine and one or both of inorganic acid or organic acid
Pharmaceutically acceptable salt formed above, the salt are acid-addition salts.
Inorganic acid of the present invention is preferably hydrochloric acid, phosphoric acid and sulfuric acid.
Organic acid of the present invention is preferably acetic acid, maleic acid, citric acid, benzene sulfonic acid, toluenesulfonic acid, fumaric acid and wine
Stone acid.
The present invention also provides a kind of drug, by compound 3-, ((benzo [d] [1,3] two dislikes cyclopentadienyl -5- Ji Jia to 4- to the drug
Base) -1- piperazinyl) -3'- phenyl -6,6'- two [1,2,4] triazol [4,3-b] pyridazine or its pharmaceutically acceptable salt and one kind
Or a variety of pharmaceutically acceptable carriers, diluent and excipient composition, the carrier include pharmaceutical field routine diluent,
Excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, surfactant, absorption carrier, lubricant etc..This
The diversified forms such as injection, tablet, pulvis, granule, capsule, oral solution, paste, creme can be made in invention drug, above-mentioned
The drug of various dosage forms can be prepared according to the conventional method of pharmaceutical field.
Drug of the present invention preparation inhibit tumor promotion drug can by injection, injection, collunarium, eye drip, infiltration,
The method absorb, physically or chemically mediated imports body such as muscle, intradermal, subcutaneous, vein, mucosal tissue；Or by other objects
Body is imported after matter mixing or package.
Preparation provided by the invention inhibits tumor promotion drug, and the drug is a variety of by inhibiting tumor promotion to treat or prevent
Tumour.The tumour includes prognosis of squamous cell lung cancer, cancer of pancreas, liver cancer, uterine cancer, cholangiocarcinoma, cancer of pancreas, gastric cancer and the cancer of the esophagus.
The tumour is preferred, tumor cells of hepatocellular carcinoma (HCC), human liver cancer cell (Bel7402 cell), colon cancer cell (HT-
And breast cancer cell (MCF-7) 29).
Drug of the present invention also has treatment or prevention, the proliferation of tumour cell relevant to anti-tumor activity and anti-withers
The effect died.
Drug of the present invention also have by inhibit tumor promotion treat or prevent cirrhosis and or virus hepatitis
Effect.
Small molecule compound compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazine in the present invention
Base) -3'- phenyl -6,6'- bis- [1,2,4] triazol [4,3-b] pyridazine has the function of antitumor inhibitor, it can be used as system
The active constituent of standby anti-tumor drug, be used to prepare to antitumor relevant anti-tumor drug, can be used for preparing antitumor
Related liver cirrhosis and or virus hepatitis drug.
Specific embodiment
Further description is made to the present invention below in conjunction with specific embodiment.
1 compound 3- of embodiment (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- phenyl -
The preparation of 6,6'- bis- [1,2,4] triazol [4,3-b] pyridazine:
Chloro- [1,2,4] triazol [4,3-b] pyridazine of the bromo- 6- of 3- and piperazine obtain the chloro- 3- of intermediate 6- (1- piperazinyl)-[1,2,
4] triazol [4,3-b] pyridazine, continues and 5- (iodomethyl) benzo [d] [1,3] two dislikes cyclopentadienyl reaction and obtains intermediate 3- (4- (benzene
And cyclopentadienyl -5- ylmethyl is disliked in [d] [1,3] two) -1- piperazinyl) chloro- [1,2,4] triazol [4, the 3-b] pyridazine of -6-, continues and intermediate
Body (3- phenyl-[1,2,4] triazol [4,3-b] -6- pyridazinyl) acid reaction obtains target compound.
200ml toluene and 0.21g palladium acetate are added in the there-necked flask of 300ml, adds condenser pipe, nitrogen is replaced 3 times, is added
Tri-tert Phosphine ligands are stirred at room temperature 5 ~ 10 minutes.Then 5- (iodomethyl) benzo [d] [1,3] two is added and dislikes cyclopentadienyl 2mol and 6-
Bromo- 3- (1- piperazinyl)-[1,2,4] triazol [4,3-b] pyridazine 2.2mol and sodium tert-butoxide.Oil bath heating is warming up to 120
℃.After 20 hours, there-necked flask is lifted from oil bath, is cooled to room temperature under nitrogen protection.Extracted with ether, saturated salt solution
It takes, separates organic phase, be dried to obtain intermediate 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl)-with anhydrous magnesium sulfate
1- piperazinyl) bromo- [1,2,4] triazol [4,3-b] pyridazine of -6-.
Intermediate 3- (4- (benzo [d] [1,3] two dislike cyclopentadienyl -5- ylmethyl) piperazine -1- base of above-mentioned preparation) -6- it is bromo- [1,
2,4] triazol [4,3-b] pyridazine and (3- phenyl-[1,2,4] triazol [4,3-b] pyridazine -6- base) boric acid, according to above-mentioned system
Preparation Method, same molar ratio, target compound compound 3- is prepared, and ((benzo [d] [1,3] two dislikes cyclopentadienyl -5- Ji Jia to 4-
Base) -1- piperazinyl) -3'- phenyl -6,6'- bis- [1,2,4] triazol [4,3-b] pyridazine, yield 62%, mass spectrum is theoretical value:
522.21 measured value: 532.29.
It is tested through nuclear-magnetism, H spectrum is1HNMR(500MHz, Chloroform)δ8.94(s,2H),8.30(s,2H),
8.21(s,2H),
7.62(s,2H),7.50(s,1H),6.98(s,1H),6.83(d,J=25.0Hz,2H),5.97(s,2H),3.66(s,
2H),3.41(s,4H),2.62(s,4H)；13CNMR (125MHz)δ157.48(s),151.71(s),148.73 (d,J=
131.8Hz),146.39 (d,J=91.1Hz),142.98(d,
J=38.9Hz),131.13(s),130.19(s),129.33(s),128.95-128.17(m),120.27(d,J=
41.8Hz),109.72(d,
J=93.4Hz),101.95(s),63.79 (s),51.07(s),48.16(s)。
2 compound 3- of embodiment (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- phenyl -6,6'-
The anti-tumor activity of two [1,2,4] triazol [4,3-b] pyridazines
1. anti-tumor activity principle
Mtt assay biological activity test is also known as MTT colorimetric method, is a kind of method for detecting cell survival and growth.MTT analytic approach with
Based on living cells metabolin reducing agent thiazolyl blue [MTT], MTT is a kind of dyestuff that can receive hydrogen atom.Living cells mitochondria
In dehydrogenase relevant to NADP the MTT of yellow can be converted to the first a ceremonial jade-ladle, used in libation of insoluble bluish violet in the cell
(formazon), and dead cell is then without this function.After dissolving first a ceremonial jade-ladle, used in libation (formazon) with dimethyl sulfoxide (DMSO), microplate reader is used
Its absorbance value is measured at 570nm wavelength, can reflect the quantity of survivaling cell indirectly, and sample is observed according to the variation of OD value
Inhibiting effect of the product to tumour cell.In a certain range, it is directly proportional to cell survivaling number to crystallize the amount to be formed by MTT.
2. anti-tumor activity is tested
Sample:
Compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- phenyl -6,6'- two [1,2,4]
Triazol [4,3-b] pyridazine.
Cell line:
Tumor cells of hepatocellular carcinoma (HCC), human liver cancer cell (Bel7402 cell), colon cancer cell (HT-29) and breast cancer cell
(MCF-7) it is purchased from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences's cell centre.
Reagent:
Thiazolyl blue (MTT is purchased from Sigma-ALdrich company), RPMI1640 culture solution, newborn bovine serum, antibiotic (U.S.'s English
Outstanding Life Technologies, Inc.)；Pancreatin (AMRESCO company, the U.S.)；96 well culture plates (Jiangsu, which is converged, reaches Medical Devices Co., Ltd.)；Two
Methyl sulfoxide (Sigma Co., USA).
Instrument:
XMZ-S236 type superclean bench (Shimadzu group (Hong Kong) Co., Ltd), HF151UV type CO2 incubator (Shanghai power Shen
Scientific instrument Co., Ltd)；DYS-809 inverted biologic microscope (Shanghai point answers optical instrument)；MultiskanMK3 type enzyme mark
Instrument (Thermo company, the U.S.)；Smart Plus series ultrapure water machine (power health biologic medical science and technology Pty Ltd).
Experimental implementation:
Test of the sample for cell HCC, cell Bel7402, cell HT-29 and cell MCF-7, the experimental implementation of every kind of cell
Process is identical, and in an experimentation, 5 concentration gradients (0.025 μm of ol/mL, 0.05 μm of ol/mL, 0.1 μ are arranged in per sample (p.s.)
Mol/mL, 0.25 μm of ol/mL and 0.5 μm of ol/mL), four parallel samples of each concentration, every group of experiment is 3 times parallel, and passes through sky
White group of control is drawn a conclusion, and microplate reader detects each hole OD value, Detection wavelength 570nm.
3. antitumor activity evaluation
Sample solution concentration logarithm and cell inhibitory rate linear regression calculate sample using GraphPad software and press down to the half of cell
Concentration IC50 value processed, compound is 0.095 μm of ol/mL for the IC50 of tumor cells of hepatocellular carcinoma (HCC), to tumor cells of hepatocellular carcinoma
(Bcl-7402) IC50 is 0.082 μm of ol/mL, and the IC50 to colon cancer cell (HT-29) is 0.094 μm of ol/mL, to mammary gland
The IC50 of cancer cell (MCF-7) is 0.089 μm of ol/mL.Test result shows that compound 3- ((dislike 4- by benzo [d] [1,3] two
Cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- phenyl -6,6'- two [1,2,4] triazol [4,3-b] pyridazine is thin for hepatic carcinoma
Born of the same parents (HCC), human liver cancer cell (Bel7402 cell) and colon cancer cell (HT-29) and breast cancer cell (MCF-7) have good
Inhibitory activity, can be used for preparing anti-tumor drug.
Claims (10)
1. a kind of Triazolopyridazine compound, which is characterized in that the compound is 1 compound of formula, its chemical name is: change
Close two [1,2,4] triazol of object 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- phenyl -6,6'-
[4,3-b] pyridazine,
Formula 1.
2. Triazolopyridazine compound according to claim 1, which is characterized in that preparation method includes:
(1) by 5- (iodomethyl) benzo [d] [1,3] two dislike the bromo- 3- of cyclopentadienyl 2mol and 6- (1- piperazinyl)-[1,2,4] triazol [4,
3-b] pyridazine reacted, obtain midbody compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazine
Base) bromo- [1,2,4] triazol [4,3-b] pyridazine of -6-；
(2) by the midbody compound 3- of above-mentioned preparation (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -
Bromo- [1,2,4] triazol [4,3-b] pyridazine of 6- and (3- phenyl-[1,2,4] triazol [4,3-b] pyridazine -6- base) boric acid carry out
Reaction obtains target compound compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- benzene
Base -6,6'- two [1,2,4] triazol [4,3-b] pyridazine.
3. Triazolopyridazine compound according to claim 1, which is characterized in that by the compound or its pharmaceutically may be used
The salt of receiving inhibits the application in tumor promotion drug in preparation.
4. the application of a kind of Triazolopyridazine compound according to claim 3 or its pharmaceutically acceptable salt,
It is characterized in that, the pharmaceutically acceptable salt is compound 3- (4- (benzo [d] [1,3] two dislikes cyclopentadienyl -5- ylmethyl) -1- piperazine
Piperazine base) -3'- phenyl -6,6'- two [1,2,4] triazol [4,3-b] pyridazine and one or both of inorganic acid or organic acid with
The pharmaceutically acceptable salt of upper formation, the salt are acid-addition salts.
5. the application of compound according to claim 3 or its pharmaceutically acceptable salt, which is characterized in that the nothing
Machine acid includes hydrochloric acid, phosphoric acid and sulfuric acid.
6. the application of compound according to claim 3 or its pharmaceutically acceptable salt, which is characterized in that described to have
Machine acid includes acetic acid, maleic acid, citric acid, benzene sulfonic acid, toluenesulfonic acid, fumaric acid and tartaric acid.
7. the application of compound according to claim 3 or its pharmaceutically acceptable salt, which is characterized in that it is prepared
Inhibition tumor promotion drug by compound 3- (4- (benzo [d] [1,3] two dislike cyclopentadienyl -5- ylmethyl) -1- piperazinyl) -3'- benzene
Base -6,6'- two [1,2,4] triazol [4,3-b] pyridazine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable
Carrier, diluent and excipient composition.
8. the application of compound according to claim 3 or its pharmaceutically acceptable salt, which is characterized in that preparing
Anti-human liver cancer tumour medicine, human colon carcinoma drug, the application in human breast carcinoma drug.
9. the application of compound according to claim 3 or its pharmaceutically acceptable salt, which is characterized in that it is prepared
Drug also there are treatment or prevention, the effect of the proliferation and anti-apoptotic of tumour cell relevant to anti-tumor activity.
10. the application of compound according to claim 3 or its pharmaceutically acceptable salt, which is characterized in that it is made
Standby drug also have the function of by inhibit tumor promotion treat or prevent cirrhosis and or virus hepatitis.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801973A (en) * | 2007-08-09 | 2010-08-11 | 赛诺菲-安万特 | Novel 6-triazolopyridazinesulfanyl benzothiazole and benzimidazole derivatives, method for production thereof and application as medicaments and pharmaceutical compositions and novel use as met inhibitors |
| CN106536524A (en) * | 2014-07-28 | 2017-03-22 | 阿斯利康(瑞典)有限公司 | [1,2,4]triazolo[4,3-b]pyridazines for use in the treatment of proliferative diseases |
| CN107375292A (en) * | 2017-07-28 | 2017-11-24 | 江苏理工学院 | A kind of new application of Triazolopyridazine compound |
-
2018
- 2018-03-28 CN CN201810261922.6A patent/CN110317216A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801973A (en) * | 2007-08-09 | 2010-08-11 | 赛诺菲-安万特 | Novel 6-triazolopyridazinesulfanyl benzothiazole and benzimidazole derivatives, method for production thereof and application as medicaments and pharmaceutical compositions and novel use as met inhibitors |
| CN106536524A (en) * | 2014-07-28 | 2017-03-22 | 阿斯利康(瑞典)有限公司 | [1,2,4]triazolo[4,3-b]pyridazines for use in the treatment of proliferative diseases |
| CN107375292A (en) * | 2017-07-28 | 2017-11-24 | 江苏理工学院 | A kind of new application of Triazolopyridazine compound |
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Application publication date: 20191011 |