CN109232570A - A kind of spiral shell of the structure containing pyridazinone [indolizine-pyrazoline] derivative and the preparation method and application thereof - Google Patents
A kind of spiral shell of the structure containing pyridazinone [indolizine-pyrazoline] derivative and the preparation method and application thereof Download PDFInfo
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- CN109232570A CN109232570A CN201811172908.5A CN201811172908A CN109232570A CN 109232570 A CN109232570 A CN 109232570A CN 201811172908 A CN201811172908 A CN 201811172908A CN 109232570 A CN109232570 A CN 109232570A
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses a kind of spiral shell of structure containing pyridazinone [indolizine-pyrazoline] derivatives and the preparation method and application thereof, with 1,3- dipole-diople interaction method is in (E) -7- benzylidene -6, pyrazole ring is introduced in 7- indoline piperazine -8 (5H) -one structure, to synthesize a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone.Spiral shell [indolizine-pyrazoline] derivative of the structure prepared by the present invention containing pyridazinone 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 shells [indolizine-pyrazoline] of pharmaceutical technology field more particularly to a kind of structure containing pyridazinone to spread out
Biology and the preparation method and application thereof.
Background technique
(E) -7- benzylidene -6,7- indoline piperazine -8 (5H) -one, chemical structural formula are as follows:
Wherein, Ar=-C6H5。
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 a kind of spiral shell of structure containing pyridazinone [indolizine-pyrazoline] derivative and its preparation sides
Method and application, prepare a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone.
To achieve the goals above, technical solution of the present invention is as follows:
A kind of spiral shell of the structure containing pyridazinone [indolizine-pyrazoline] derivative, the spiral shell [indoles of the structure containing pyridazinone
Piperazine-pyrazoline] derivatives chemical structural formula is as follows:
Wherein, Ar=-C6H5。
The invention also provides the preparation method of a kind of spiral shell of structure containing pyridazinone [indolizine-pyrazoline] derivative, packets
It includes:
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；
- 8 (5H) -one of (E) -7- benzylidene -6,7- indoline piperazine and alpha-chloro is added 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 spiral shell [indolizine-pyrazoline] derivative of the isolated structure containing pyridazinone of silica gel column chromatography.
Further, the chromone aldehyde hydazone derivative of the alpha-chloro pyridazinone structure and (E) -7- benzylidene -6,7- bis-
The ratio between amount of substance of hydrogen indoles 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 spiral shell of structure containing pyridazinone [indolizine-pyrazoline] derivatives in antineoplastic object space
The application in face.
Spiral shell [indolizine-pyrazoline] derivative of a kind of structure containing pyridazinone proposed by the present invention and preparation method thereof with answer
With introducing pyrazoles in -8 (5H) -one structure of (E) -7- benzylidene -6,7- indoline piperazine with 1,3- dipole-diople interaction method
Ring, to synthesize a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone.Structure containing pyridazinone prepared by the present invention
Spiral shell [indolizine-pyrazoline] derivative, have stronger inhibiting tumour cells effect, be its further field of medicaments application
It provides the foundation.
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, a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone has been synthesized by 1,3- Dipolar Cycloaddition.
A kind of embodiment of the invention provides a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone,
Chemical structural formula is as follows:
Wherein: Ar=-C6H5, Br is bromine.
Another embodiment of the invention proposes a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone
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 2mmol 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
Shape product.It is rinsed repeatedly with anhydrous ether, ethyl alcohol recrystallization is simultaneously dried in vacuo to obtain compound 1: the chromone aldehyde of the structure containing pyridazinone
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.
- 8 (5H) -one of (E) -7- benzylidene -6,7- indoline piperazine and alpha-chloro is added 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 spiral shell [indolizine-pyrazoline] derivative of the isolated structure containing pyridazinone of silica gel column chromatography.
Embodiment 3: ((the E) -7- benzylidene -6,7- indoline piperazine -8 of compound 3 is added in 20mL methylene chloride
(5H) -one) 1mmol and compound 2 (the chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure) 1.6mmol, are leaked with constant pressure addition
The mixed liquor of triethylamine 0.5mL and methylene chloride 5mL is added dropwise into above-mentioned solution in bucket, and drop continues stirring at normal temperature 24 hours after finishing,
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- benzylidene -6,7- dihydro
The ratio between amount of substance of indolizine -8 (5H) -one is 1.6:1~2:1.In the mixed liquor of triethylamine and methylene chloride triethylamine with
The ratio between methylene chloride volume are as follows: 1:10~1:20.
Embodiment 4: ((the E) -7- benzylidene -6,7- indoline piperazine -8 of compound 3 is added in 20mL methylene chloride
(5H) -one) 1mmol and compound 2 (the chromone aldehyde hydazone derivative of alpha-chloro pyridazinone structure) 2mmol, use constant pressure funnel
The mixed liquor of triethylamine 0.5mL and methylene chloride 10mL is added dropwise into above-mentioned solution, drop continues stirring at normal temperature 24 hours after finishing,
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 spiral shell of the structure containing pyridazinone [indolizine-pyrazoline] derivative (compound 4), yellowish
Color powder, yield 57.3%, fusing point: 193-194 DEG C, nucleus magnetic hydrogen spectrum data and Elemental analysis data are as follows:
1H NMR(DMSO-d6) δ: 10.15 (s, 1H, NHN), 7.34-7.18 (m, 10H, Ar-H), 6.87 (t, J=8.0,
1H), 6.58 (s, 1H), 6.49 (s, 1H, C=C-H), 6.31 (d, J=4.0,1H), 4.51 (t, J=12.5,1H), 4.45 (s,
1H, C=C-H), 4.02 (d, J=12.5,1H), 2.44 (t, J=14.0,1H), 1.68 (d, J=14.5,1H),
IR(KBr)v/cm-13427 (N-C=O), 3105 (ArH), 1774 (C=O, pyridazinone), 1663 (C=
), O 1633,1580,1465 (C=N, C=C), 1258 (C-O-C), 1608 (chromone-ring)
M/e:609 (100.0%)
Anal.calcd.for C30H20BrN5O5: C, 59.01；H,3.34；N,11.45.
In-vitro Inhibitory Effect of the present embodiment using 4 pairs of compound different tumor strains of mtt assay measurement, the spiral shell of the structure containing pyridazinone
The antitumor cytolytic activity result of [indolizine-pyrazoline] derivative is as follows:
Compound 4 is dissolved with DMSO, is diluted, tumour cell KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HL-
60 (leukaemia cells), Bel-7402 (human liver cancer cell), HO8901 (ovarian cancer cell), ECA109 (colon-cancer cell) are in 96 holes
It is planted on plate into 4000/200 holes μ L/, 2 μ L of compound is added in every hole, final concentration of 12.0 μM, 6.0 μM, 3.0 μM, 1.5 μM, is total to
It is same as 37 DEG C, 5%CO2It is incubated for 72 hours in cell incubator, with DMSO (1%) for blank control.After 72 hours, it is added dense eventually
Degree is the MTT of 0.25mg/mL, is placed in 37 DEG C, 5%CO24 hours in cell incubator, solvent is blotted later, and 100 μ are added in every hole
L DMSO is measured at 570nm absorbance (OD value) with enzyme linked immunological instrument, and the data obtained is for calculating IC50Value.Inhibition is selected to live
Property high compound, measure influence of the compound effects time difference under various concentration to human tumor cells period and apoptosis.
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 spiral shell [indolizine-pyrazoline] derivative (compound 4) of the structure containing pyridazinone is to six kinds
The IC of tumor cell line50Value, illustrate compound to KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), (leukaemia is thin by HL-60
Born of the same parents), Bel-7402 (human liver cancer cell) have stronger inhibiting tumour cells effect, provided for its further field of medicaments application
Basis.
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. a kind of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone, which is characterized in that the structure containing pyridazinone
Spiral shell [indolizine-pyrazoline] derivatives chemical structural formula is as follows:
Wherein, Ar=-C6H5。
2. a kind of preparation method of spiral shell [indolizine-pyrazoline] derivative of structure containing pyridazinone, which is characterized in that described containing rattling away
The preparation method of spiral shell [indolizine-pyrazoline] derivative of piperazine ketone structure, 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；
- 8 (5H) -one of (E) -7- benzylidene -6,7- indoline piperazine and alpha-chloro pyridazine is added in step 3 in methylene chloride
The chromone aldehyde hydazone derivative of ketone structure, with the mixed liquor of constant pressure funnel dropwise addition triethylamine and methylene chloride to above-mentioned solution
In, drop continues stirring at normal temperature 20~30 hours after finishing, and TLC tracking, revolving removes solvent after complete reaction, will rotate remaining
After residue dissolution, with spiral shell [indolizine-pyrazoline] derivative of the isolated structure containing pyridazinone of silica gel column chromatography.
3. the preparation method of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone as claimed in claim 2, feature
It is, the chromone aldehyde hydazone derivative and (E) -7- benzylidene -6,7- indoline piperazine -8 of the alpha-chloro pyridazinone structure
The ratio between amount of substance of (5H) -one is 1.6:1~2:1.
4. the preparation method of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone as claimed in claim 2, feature
It is, 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. the preparation method of spiral shell [indolizine-pyrazoline] derivative of the structure containing pyridazinone as claimed in claim 2, feature
It is, the spreading agent that the silica gel column chromatography uses when separating is V(ethyl acetate):V(petroleum ether)=1:5.
6. a kind of application of spiral shell [indolizine-pyrazoline] derivative in terms of anti-tumor drug of structure containing pyridazinone.
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