CN109053732A - A kind of pair of fluorine replaces spiral shell [indolizine-pyrazoline] derivative and the preparation method and application thereof of the structure containing pyridazinone - Google Patents
A kind of pair of fluorine replaces spiral shell [indolizine-pyrazoline] derivative and the preparation method and application thereof of the structure containing pyridazinone Download PDFInfo
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Abstract
The invention discloses spiral shell [indolizine-pyrazoline] derivatives and the preparation method and application thereof that a kind of pair of fluorine replaces the structure containing pyridazinone, with 1,3- dipole-diople interaction method is in (E) -7- to fluorobenzylidene -6, pyrazole ring is introduced in 7- indoline piperazine -8 (5H) -one structure, to synthesize spiral shell [indolizine-pyrazoline] derivative that a kind of pair of fluorine replaces the structure containing pyridazinone.Spiral shell [indolizine-pyrazoline] derivative prepared by the present invention for replacing the structure containing pyridazinone to fluorine, has stronger inhibiting tumour cells effect, provides the foundation for its further field of medicaments application.
Description
Technical field
The invention belongs to the spiral shell [indolizines-that pharmaceutical technology field more particularly to a kind of pair of fluorine replace the structure containing pyridazinone
Pyrazoline] derivative and the preparation method and application thereof.
Background technique
(E) for -7- to fluorobenzylidene -6,7- indoline piperazine -8 (5H) -one, chemical structural formula is as follows:
Wherein, Ar=-FC6H4。
1,3- Dipolar Cycloaddition becomes synthesis five member ring heterocyclic compound with its good region and main selectivity
More active a kind of reaction in most important method and heterocyclic drug chemical research.In recent years, due to pyridazinone
Closing object becomes the hot spot of materia medica circle research because of its distinctive physiological activity, has very strong inhibition cancer cell diffusion, antibacterial, resists
The effects of virus, reducing blood lipid and good hypoglycemic, promotion are metabolized.So either from pharmacology still from synthetic degree of angle
Consider, this heterocyclic compounds has very high synthesis to be worth.
Pyrazole derivatives as a kind of useful intermediate and themselves shown a variety of pharmaceutical activity come out and
It gets more and more people's extensive concerning.Indolizine skeleton is structural unit very common in bioactivity alkaloid, is had significant anti-thin
The mitotic characteristic of born of the same parents or treatment cardiovascular disease and antihypertensive effect.Therefore, different heterocycles are studied in same molecule
Assemble on influence caused by pharmacological activity, has great importance.
Summary of the invention
The object of the present invention is to provide spiral shell [indolizine-pyrazoline] derivatives that a kind of pair of fluorine replaces the structure containing pyridazinone
And the preparation method and application thereof, prepare spiral shell [indolizine-pyrazoline] derivative that a kind of pair of fluorine replaces the structure containing pyridazinone.
To achieve the goals above, technical solution of the present invention is as follows:
A kind of pair of fluorine replaces spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone, described to replace fluorine containing pyridazine
Spiral shell [indolizine-pyrazoline] derivatives chemical structural formula of ketone structure is as follows:
Wherein, Ar=-FC6H4。
The invention also provides a kind of pair of fluorine to replace the preparation of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone
Method, comprising:
Step 1, the chromone aldehyde hydazone derivative for synthesizing the structure containing pyridazinone；
Step 2, the chromone aldehyde hydazone derivative for synthesizing alpha-chloro pyridazinone structure；
(E) -7- is added to -8 (5H) -one of fluorobenzylidene -6,7- indoline piperazine and α-in step 3 in methylene chloride
The chromone aldehyde hydazone derivative of chloro-pyridazine ketone structure, the mixed liquor that triethylamine and methylene chloride is added dropwise with constant pressure funnel are supreme
It states in solution, drop continues stirring at normal temperature 20~30 hours after finishing, and TLC tracking, revolving removes solvent after complete reaction, will rotate
After remaining residue dissolution, with the isolated spiral shell [indolizine-pyrazoles for replacing the structure containing pyridazinone to fluorine of silica gel column chromatography
Quinoline] derivative.
Further, the chromone aldehyde hydazone derivative Yu (E) -7- of the alpha-chloro pyridazinone structure be to fluorobenzylidene -6,
The ratio between amount of substance of 7- indoline piperazine -8 (5H) -one is 1.6:1~2:1.
Further, the mixed liquor of the triethylamine and methylene chloride, wherein the ratio between triethylamine and methylene chloride volume are as follows:
1:10~1:20.
Further, the spreading agent used when the silica gel column chromatography separates is V(ethyl acetate):V(petroleum ether)=1:5.
The invention also provides a kind of pair of fluorine to replace spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone anti-swollen
Application in terms of tumor medicine.
A kind of pair of fluorine proposed by the present invention replaces spiral shell [indolizine-pyrazoline] derivative and its preparation of the structure containing pyridazinone
Method and application, with 1,3- dipole-diople interaction method in (E) -7- to fluorobenzylidene -6,7- indoline piperazine -8 (5H) -one
Pyrazole ring is introduced in structure, to synthesize spiral shell [indolizine-pyrazoline] derivative that a kind of pair of fluorine replaces the structure containing pyridazinone.This
Spiral shell [indolizine-pyrazoline] derivative for replacing the structure containing pyridazinone to fluorine of invention preparation has the suppression of stronger tumour cell
Effect processed provides the foundation for its further field of medicaments application.
Detailed description of the invention
Fig. 1 is the compound 1 of the structure containing pyridazinone of the invention and the preparation method flow chart of compound 2；
Fig. 2 is that the compounds of this invention 4 prepares chemical structural formula schematic diagram.
Specific embodiment
Technical solution of the present invention is described in further details with reference to the accompanying drawings and examples, following embodiment is not constituted
Limitation of the invention.
In recent years, become the heat of materia medica circle research because of its distinctive physiological activity due to pyridazinone compound
Point has the effects of very strong inhibition cancer cell diffusion, antibacterial, antiviral, reducing blood lipid and good hypoglycemic, promotion are metabolized.
Pyrazole derivatives are as a kind of useful intermediate and themselves shown a variety of pharmaceutical activity come out and by people
Extensive concern.Indolizine skeleton is structural unit very common in bioactivity alkaloid, has significant anti-cell to have silk point
The characteristic or treatment cardiovascular disease split and antihypertensive effect.
The technical program is assembled and to caused by pharmacological activity to preferably study different heterocycles in same molecule
It influences, the spiral shell [indolizine-pyrazoline] that a kind of pair of fluorine replaces the structure containing pyridazinone has been synthesized by 1,3- Dipolar Cycloaddition
Derivative.
A kind of embodiment of the invention provides the spiral shell [indolizine-pyrazoline] that a kind of pair of fluorine replaces the structure containing pyridazinone
Derivative, chemical structural formula are as follows:
Wherein: Ar=-FC6H4, Br is bromine.
Another embodiment of the invention proposes the spiral shell [indolizine-pyrazoles that a kind of pair of fluorine replaces the structure containing pyridazinone
Quinoline] derivative preparation method, comprising the following steps:
Step 1, the chromone aldehyde hydazone derivative for synthesizing the structure containing pyridazinone.
The 6- bromo chromone and 6- oxygen -1,6- dihydrogen dazin -3- carbonic acid hydrazine that the present invention has carboxaldehyde radicals to replace with 3 are dehydrated anti-
The method that schiff bases should be generated, to synthesize the chromone aldehyde hydazone derivative of the structure containing pyridazinone.Below by the color of the structure containing pyridazinone
Keto-aldehyde hydazone derivative is also referred to as compound 1.
Embodiment 1: taking 6- oxygen -1,6- dihydrogen dazin -3- carbonic acid hydrazine of 2mmol to be added in the flask for filling 15mL ethyl alcohol,
Then the 6- bromo chromone for having carboxaldehyde radicals to replace dissolved with 2 mmol 3 into 20mL is slowly added dropwise to dissolving in boiling water bath return stirring
Ethanol solution, continue boiling water bath return stirring 1 hour, be added dropwise 10 drop hydrochloric acid, have pale yellow precipitate appearance.Continuous boiling water
Bath return stirring 5 hours stops water-bath, and people's 20mL distilled water is added to stir, and pale yellow precipitate darkens, and filters to obtain yellowish red color
Needle-shaped product.It is rinsed repeatedly with anhydrous ether, ethyl alcohol recrystallization is simultaneously dried in vacuo to obtain compound 1: the chromone of the structure containing pyridazinone
Aldehyde hydazone derivative.
Step 2, the chromone aldehyde hydazone derivative for synthesizing alpha-chloro pyridazinone structure.
Embodiment 2: being added compound 1 (10.0mmol) in 12.5mL DMF, makes it completely dissolved under stirring at normal temperature, will
Reaction controlling at 35 DEG C hereinafter, 15.0mmol NCS is added portionwise points for 5~10 times, TLC tracking, during fully reacting is fallen back,
It being extracted 3 times with ether, solution extracted is dry with anhydrous magnesium sulfate, and revolving uses chloroform/petroleum ether recrystallization after removing ether,
The chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure is obtained, below by the chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure
Referred to as compound 2.
It should be noted that the synthesis about compound 1,2, has had many methods to carry out it in the art
Research, specific embodiment used by the present embodiment only enumerates in the lab, those skilled in the art can also use it
Other party method prepare compound 1,2.
(E) -7- is added to -8 (5H) -one of fluorobenzylidene -6,7- indoline piperazine and α-in step 3 in methylene chloride
The chromone aldehyde hydazone derivative of chloro-pyridazine ketone structure, the mixed liquor that triethylamine and methylene chloride is added dropwise with constant pressure funnel are supreme
It states in solution, drop continues stirring at normal temperature 20~30 hours after finishing, and TLC tracking, revolving removes solvent after complete reaction, will rotate
After remaining residue dissolution, with the isolated spiral shell [indolizine-pyrazoles for replacing the structure containing pyridazinone to fluorine of silica gel column chromatography
Quinoline] derivative.
Embodiment 3: ((E) -7- is to fluorobenzylidene -6,7- indoline for addition compound 3 in 20mL methylene chloride
Piperazine -8 (5H) -one) 1mmol and compound 2 (the chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure) 1.6mmol, are dripped with constant pressure
The mixed liquor of triethylamine 0.5mL and methylene chloride 5mL is added dropwise into above-mentioned solution in liquid funnel, and drop continues stirring at normal temperature 24 after finishing
Hour, TLC tracking rotates away solvent after complete reaction, takes the dissolution of 3mL ethyl acetate stand-by, finally uses V(ethyl acetate):
V(petroleum ether)The isolated compound 4 of=1:5 silica gel column chromatography.
It should be noted that above-mentioned methylene chloride is reaction dissolvent, for compound 2 and 3 to be dissolved, the present invention is not limited to
Specific methylene chloride.
In this step, the chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure and (E) -7- are to fluorobenzylidene -6,7-
The ratio between amount of substance of indoline piperazine -8 (5H) -one is 1.6:1~2:1.Three second in the mixed liquor of triethylamine and methylene chloride
The ratio between amine and methylene chloride volume are as follows: 1:10~1:20.
Embodiment 4: ((E) -7- is to fluorobenzylidene -6,7- indoline for addition compound 3 in 20mL methylene chloride
Piperazine -8 (5H) -one) 1mmol and compound 2 (the chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure) 2mmol, use constant pressure addition
The mixed liquor of triethylamine 0.5mL and methylene chloride 10mL is added dropwise into above-mentioned solution in funnel, and it is small that drop continues stirring at normal temperature 24 after finishing
When, TLC tracking rotates away solvent after complete reaction, takes the dissolution of 3mL ethyl acetate stand-by, finally uses V(ethyl acetate):
V(petroleum ether)The isolated compound 4 of=1:5 silica gel column chromatography.
In embodiment 3,4, ethyl acetate convenient for being transferred out of, and is easy for that will rotate remaining residue dissolution
It is added to the top of chromatographic column.It is easily understood that residue is dissolved using solvent, be not have to ethyl acetate, example
Ethyl alcohol, acetone can also such as be used.
Preferably, the spreading agent that the silica gel column chromatography uses when separating is V to the present invention(ethyl acetate):V(petroleum ether)=1:5.When
The spreading agent of other right ratios also can be practical, such as V(ethyl acetate):V(petroleum ether)=1:6.
Experimental data is as follows: a kind of pair of fluorine replaces spiral shell [indolizine-pyrazoline] derivative (compound of the structure containing pyridazinone
4), pale yellow powder, yield 37.4%, fusing point: 215-216 DEG C, nucleus magnetic hydrogen spectrum data and Elemental analysis data are as follows:
1H NMR(DMSO-d6) δ: 10.17 (s, 1H, NHN), 7.32-7.19 (m, 9H, Ar-H), 6.88 (t, J=8.0,
1H), 6.58 (s, 1H), 6.50 (s, 1H, C=C-H), 6.32 (d, J=4.0,1H), 4.53 (t, J=12.5,1H), 4.47
(s, 1H, C=C-H), 4.05 (d, J=12.5,1H), 2.43 (t, J=14.0,1H), 1.69 (d, J=14.5,1H),
IR(KBr)v/cm-13429 (N-C=O), 3103 (ArH), 1770 (C=O, pyridazinone), 1664 (C=
), O 1617,1582,1464 (C=N, C=C), 1255 (C-O-C), 1610 (chromone-ring), 655 (C-F)
M/e:627 (100.0%)
Anal.calcd.for C30H19BrFN5O5: C, 57.33；H,3.07；N,11.12.
The present embodiment replaces fluorine and is contained pyridazinone using the In-vitro Inhibitory Effect of 4 pairs of compound different tumor strains of mtt assay measurement
The antitumor cytolytic activity result of spiral shell [indolizine-pyrazoline] derivative of structure is as follows:
Compound 4 is dissolved with DMSO, dilute, tumour cell KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell),
HL-60 (leukaemia cell), Bel-7402 (human liver cancer cell), HO8901 (ovarian cancer cell), ECA109 (colon-cancer cell) exist
It is planted on 96 orifice plates into 4000/200 holes μ L/, every hole is added 2 μ L of compound, and final concentration of 12.0 μM, 6.0 μM, 3.0 μM, 1.5
μM, jointly in 37 DEG C, 5%CO2It is incubated for 72 hours in cell incubator, with DMSO (1%) for blank control.After 72 hours, add
The MTT for entering final concentration of 0.25mg/mL is placed in 37 DEG C, 5%CO24 hours in cell incubator, solvent, every hole are blotted later
100 μ l DMSO are added, are measured at 570nm with enzyme linked immunological instrument absorbance (OD value), the data obtained is for calculating IC50Value.It chooses
The compound that inhibitory activity is high is selected, measures the compound effects time difference under various concentration to human tumor cells period and apoptosis
Influence.
The test-compound of various concentration carries out scalping with 96 orifice plates, according to resulting inhibiting rate, calculates IC50Value, as a result
It see the table below.
Table 1
In table 1, there is shown replace spiral shell [indolizine-pyrazoline] derivative (compound of the structure containing pyridazinone to fluorine
4) to the IC of six kinds of tumor cell lines50Value, illustrates compound to KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HL-60
(leukaemia cell), Bel-7402 (human liver cancer cell) have stronger inhibiting tumour cells effect, are its further medicine neck
Domain application provides the foundation.
The above embodiments are merely illustrative of the technical solutions of the present invention rather than is limited, without departing substantially from essence of the invention
In the case where mind and its essence, those skilled in the art make various corresponding changes and change in accordance with the present invention
Shape, but these corresponding changes and modifications all should fall within the scope of protection of the appended claims of the present invention.
Claims (6)
1. spiral shell [indolizine-pyrazoline] derivative that a kind of pair of fluorine replaces the structure containing pyridazinone, which is characterized in that described to be taken to fluorine
Generation spiral shell [indolizine-pyrazoline] derivatives chemical structural formula of the structure containing pyridazinone is as follows:
Wherein, Ar=-FC6H4。
2. the preparation method that a kind of pair of fluorine replaces spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone, which is characterized in that
The preparation method of described spiral shell [indolizine-pyrazoline] derivative for replacing the structure containing pyridazinone to fluorine, comprising:
Step 1, the chromone aldehyde hydazone derivative for synthesizing the structure containing pyridazinone；
Step 2, the chromone aldehyde hydazone derivative for synthesizing alpha-chloro pyridazinone structure；
(E) -7- is added to -8 (5H) -one of fluorobenzylidene -6,7- indoline piperazine and alpha-chloro in step 3 in methylene chloride
The mixed liquor of triethylamine and methylene chloride is added dropwise to above-mentioned molten with constant pressure funnel in the chromone aldehyde hydazone derivative of pyridazinone structure
In liquid, drop continues stirring at normal temperature 20~30 hours after finishing, and TLC tracking, revolving removes solvent after complete reaction, and revolving is remaining
Residue dissolution after, with silica gel column chromatography it is isolated to fluorine replace the structure containing pyridazinone spiral shell [indolizine-pyrazoline] spread out
Biology.
3. replacing the preparation side of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone to fluorine as claimed in claim 2
Method, which is characterized in that the chromone aldehyde hydazone derivative and (E) -7- of the alpha-chloro pyridazinone structure are to fluorobenzylidene -6,7- bis-
The ratio between amount of substance of hydrogen indoles piperazine -8 (5H) -one is 1.6:1~2:1.
4. replacing the preparation side of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone to fluorine as claimed in claim 2
Method, which is characterized in that the mixed liquor of the triethylamine and methylene chloride, wherein the ratio between triethylamine and methylene chloride volume are as follows: 1:
10~1:20.
5. replacing the preparation side of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone to fluorine as claimed in claim 2
Method, which is characterized in that the spreading agent that the silica gel column chromatography uses when separating is V(ethyl acetate):V(petroleum ether)=1:5.
6. spiral shell [indolizine-pyrazoline] derivative the answering in terms of anti-tumor drug that a kind of pair of fluorine replaces the structure containing pyridazinone
With.
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| CN107674083A (en) * | 2017-11-07 | 2018-02-09 | 绍兴文理学院 | A kind of preparation method and applications of the L leucine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
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