CN105061440A - Coumarin pyrazole compounds containing acetylamino nitrogen heterocycles, preparation of coumarin pyrazole compounds and application of coumarin pyrazole compounds in tumor cell inhibition - Google Patents
Coumarin pyrazole compounds containing acetylamino nitrogen heterocycles, preparation of coumarin pyrazole compounds and application of coumarin pyrazole compounds in tumor cell inhibition Download PDFInfo
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- CN105061440A CN105061440A CN201510416079.0A CN201510416079A CN105061440A CN 105061440 A CN105061440 A CN 105061440A CN 201510416079 A CN201510416079 A CN 201510416079A CN 105061440 A CN105061440 A CN 105061440A
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- reaction
- coumarin
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- pyrazole compounds
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides coumarin pyrazole compounds containing acetylamino nitrogen heterocycles. The compounds have a general formula shown in the specification, wherein R is shown in the specification. Experiments prove that the coumarin pyrazole compounds containing the acetylamino nitrogen heterocycles have different levels of inhibiting effects on human colon carcinoma cell lines HCT-116, human lung cancer cell lines A549, liver cancer cells Huh7 and human spinal cord leukemia M3 cell lines HL60, so that the compounds can be possibly used for preparing anti-cancer drugs. The invention discloses a preparation method of the coumarin pyrazole compounds containing the acetylamino nitrogen heterocycles.
Description
Technical field
The present invention relates to tonka bean camphor containing kharophen nitrogen heterocyclic and pyrazole compound and preparation thereof and the application in inhibition tumor cell.
Background technology
Coumarin kind compound is extensively present in a natural quasi-aromatic compound, be distributed in many plants and spices, comprise the higher plants such as Rutaceae, umbelliferae, composite family, pulse family, thymelaeceae, Solanaceae, also existence is had in animal and microbial metabolites, be a kind of important flavor potentiator, be widely used in the industries such as perfume, makeup, stain remover.According to the difference of ring substituents and position thereof, tonka bean camphor can be divided into simple tonka bean camphor, furocoumarin(e), pyranocoumarin and other tonka bean camphors etc.Research shows, coumarin kind compound has various biological activity, as: anti-AIDS, anticancer, impact, anti-inflammatory, anticoagulation etc. on cardiovascular systems.Also there are some toxic reactions when high dosage is applied simultaneously, there is kind and locus specificity, as genetoxic, hepatotoxicity etc.Due to coumarin kind compound, to have molecular weight little, and synthesis is simple, and bioavailability is high, and pharmacological action is extensive, and the features such as toxicity is little, have become the research emphasis of much medicament research and development work in recent years.
The present invention is based on the antitumour activity of tonka bean camphor, the kharophen nitrogen heterocyclic that it introduces different substituents is modified, synthesize a series of tonka bean camphor containing kharophen nitrogen heterocyclic and pyrazole compound, and antitumour activity test is carried out to them.
Summary of the invention
The present invention relates to tonka bean camphor containing kharophen nitrogen heterocyclic and pyrazole compound and preparation thereof and the application in inhibition tumor cell.
Technical scheme of the present invention is as follows:
One class containing the tonka bean camphor of kharophen nitrogen heterocyclic and pyrazole compound, is characterized in that it has following general formula:
Wherein R is:
Prepare above-mentioned containing the tonka bean camphor of kharophen nitrogen heterocyclic and a method for pyrazole compound, it is characterized in that it is made up of the following step:
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Get bromoacetic acid 2mmol and heterocyclic amine is dissolved in the methylene dichloride of 40ml, HOBt1mmol is added under agitation condition, EDCHCl3mmol, is warming up to reflux temperature stirring reaction 6-8h, by TLC detection reaction progress, reaction is finished, reaction solution water cleans 3 times, and organic over anhydrous dried over sodium sulfate, removes solvent under reduced pressure, the product obtained, without the need to purifying, is directly used in next step reaction.
Product previous step obtained and compound 2 are respectively got 1mmol and are dissolved in dehydrated alcohol, add the sodium ethylate of 1.2mmol, heated and stirred refluxes simultaneously, after complete with TLC detection reaction, remove ethanol under reduced pressure, the resistates of gained is added in the water of about 100ml, vigorous stirring 10-15min, filter, after gained solid washed with water, drying under reduced pressure, with ethyl alcohol recrystallization, namely obtains final product.
Tonka bean camphor containing kharophen nitrogen heterocyclic of the present invention pyrazole compound has obvious restraining effect to tumour cell.Therefore tonka bean camphor containing kharophen nitrogen heterocyclic of the present invention pyrazole compound can be applied to and prepare cancer therapy drug.
Embodiment
Further describe the present invention by following examples, but scope of the present invention is not by any restriction of these embodiments.
The preparation of embodiment one: 2-(2-(4-phenylpiperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 1)
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Get bromoacetic acid 2mmol and phenylpiperazine is dissolved in the methylene dichloride of 40ml, HOBt1mmol is added under agitation condition, EDCHCl3mmol, is warming up to reflux temperature stirring reaction 6-8h, by TLC detection reaction progress, reaction is finished, reaction solution water cleans 3 times, and organic over anhydrous dried over sodium sulfate, removes solvent under reduced pressure, the product obtained, without the need to purifying, is directly used in next step reaction.
Product previous step obtained and compound 2 are respectively got 1mmol and are dissolved in dehydrated alcohol, add the sodium ethylate of 1.2mmol, heated and stirred refluxes simultaneously, after complete with TLC detection reaction, remove ethanol under reduced pressure, the resistates of gained is added in the water of about 100ml, vigorous stirring 10-15min, filter, after gained solid washed with water, drying under reduced pressure, with ethyl alcohol recrystallization, namely obtains final product.Product is white powder, productive rate 39%.Mp：213-215℃.
1HNMR(400MHz，CDCl
3)：8.34(s，1H，ArH)，8.02(dd，J
1＝7.76Hz，J
2＝1.48Hz，1H，ArH)，7.47(m，1H，ArH)，7.37(m，1H，ArH)，7.35-7.26(m，3H，ArH)，7.03(m，3H，ArH)，5.24(s，2H，-CH
2)，3.90(s，2H，-CH
2)，3.85(s，2H，-CH
2)，3.32(s，2H，-CH
2)，3.25(s，2H，-CH
2).MS(ESI)：389.34(C
22H
21N
4O
3，[M+H]
+).Anal.CalcdforC
22H
20N
4O
3：C，68.03；H，5.19；N，14.42％.Found：C，68.05；H，5.18；N，14.44％.
The preparation of embodiment two: 2-(2-(4-(2-p-methoxy-phenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 2)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 42%.Mp：243-244℃.
1HNMR(400MHz，DMSO)：8.76(s，1H，ArH)，7.98(dd，J
1＝7.72Hz，J
2＝1.36Hz，1H，ArH)，7.56(m，1H，ArH)，7.45(d，J＝7.80Hz，1H，ArH)，7.38(m，1H，ArH)，6.99(m，2H，ArH)，6.91(m，2H，ArH)，5.51(s，2H，-CH
2)，3.80(s，3H，OCH
3)，3.68(d，J＝4.64Hz，2H，-CH
2)，3.62(t，J＝4.50Hz，2H，-CH
2)，3.06(d，J＝4.16Hz，2H，-CH
2)，2.96(t，J＝4.68Hz，2H，-CH
2).MS(ESI)：419.31(C
23H
23N
4O
4，[M+H]
+).Anal.CalcdforC
23H
22N
4O
4：C，66.02；H，5.30；N，13.39％.Found：C，66.04；H，5.31；N，13.36％.
The preparation of embodiment three: 2-(2-(4-(3-p-methoxy-phenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 3)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 33%.Mp：261-263℃.
1HNMR(400MHz，DMSO)：8.75(s，1H，ArH)，7.97(d，J＝6.96Hz，1H，ArH)，7.55(t，J＝7.26Hz，1H，ArH)，7.44(d，J＝8.20Hz，1H，ArH)，7.38(t，J＝7.46Hz，1H，ArH)，7.14(t，J＝8.16Hz，1H，ArH)，6.57(d，J＝8.20Hz，1H，ArH)，6.50(s，1H，ArH)，6.41(dd，J
1＝8.08Hz，J
2＝1.56Hz，1H，ArH)，5.53(s，2H，-CH
2)，3.72(s，3H，-OCH
3)，3.68(s，2H，-CH
2)，3.62(s，2H，-CH
2)，3.26(s，2H，-CH
2)，3.16(s，2H，-CH
2).MS(ESI)：419.31(C
23H
23N
4O
4，[M+H]
+).Anal.CalcdforC
23H
22N
4O
4：C，66.02；H，5.30；N，13.39％.Found：C，66.04；H，5.31；N，13.36％.
The preparation of embodiment four: 2-(2-(4-(4-p-methoxy-phenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 4)
Preparation method is with embodiment one.Product is White crystalline solid.Productive rate 37%.Mp：256-258℃.
1HNMR(400MHz，DMSO)：8.74(s，1H，ArH)，7.97(dd，J
1＝7.72Hz，J
2＝1.24Hz，1H，ArH)，7.56(m，1H，ArH)，7.45(d，J＝7.72Hz，1H，ArH)，7.38(m，1H，ArH)，6.95(d，J＝9.04Hz，2H，ArH)，6.85(d，J＝9.04Hz，2H，ArH)，5.52(s，2H，-CH
2)，3.69(s，5H，CH
3，-CH
2)，3.62(s，2H，-CH
2)，3.12(s，2H，-CH
2)，3.02(s，2H，-CH
2).MS(ESI)：419.31(C
23H
23N
4O
4，[M+H]
+).Anal.CalcdforC
23H
22N
4O
4：C，66.02；H，5.30；N，13.39％.Found：C，66.04；H，5.31；N，13.36％.
The preparation of embodiment five: 2-(2-(4-(2-fluorophenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 5)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 35%.Mp：211-213℃.
1HNMR(400MHz，DMSO)：8.75(s，1H，ArH)，7.98(dd，J
1＝7.72Hz，J
2＝1.36Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(d，J＝7.96Hz，1H，ArH)，7.38(m，1H，ArH)，7.15(m，2H，ArH)，7.09-6.99(m，2H，ArH)，5.52(s，2H，-CH
2)，3.71(d，，J＝4.68Hz，2H，-CH
2)，3.65(t，J＝4.66Hz，2H，-CH
2)，3.13(d，J＝4.32Hz，2H，-CH
2)，3.02(t，J＝4.62Hz，2H，-CH
2).MS(ESI)：407.29(C
22H
20FN
4O
3，[M+H]
+).Anal.CalcdforC
22H
19FN
4O
3：C，65.02；H，4.71；N，13.79％.Found：C，65.04；H，4.70；N，13.81％.
The preparation of embodiment six: 2-(2-(4-(4-fluorophenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 6)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 41%.Mp：224-225℃.
1HNMR(400MHz，DMSO)：8.75(s，1H，ArH)，7.97(dd，J
1＝7.76Hz，J
2＝1.48Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(d，J＝7.84Hz，1H，ArH)，7.38(m，1H，ArH)，7.08(m，2H，ArH)，7.01(m，2H，ArH)，5.53(s，2H，-CH
2)，3.69(t，J＝4.70Hz，2H，-CH
2)，3.63(t，J＝4.86Hz，2H，-CH
2)，3.19(t，J＝4.68Hz，2H，-CH
2)，3.09(t，J＝4.92Hz，2H，-CH
2).MS(ESI)：407.29(C
22H
20FN
4O
3，[M+H]
+).Anal.CalcdforC
22H
19FN
4O
3：C，65.02；H，4.71；N，13.79％.Found：C，65.04；H，4.70；N，13.81％.
The preparation of embodiment seven: 2-(2-(4-(2-chloro-phenyl-) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 7)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 37%.Mp：197-199℃.
1HNMR(400MHz，DMSO)：8.76(s，1H，ArH)，7.98(dd，J
1＝7.80Hz，J
2＝1.36Hz，1H，ArH)，7.56(m，1H，ArH)，7.45(d，J＝7.88Hz，2H，ArH)，7.39(m，1H，ArH)，7.33(m，1H，ArH)，7.18(m，1H，ArH)，7.09(m，1H，ArH)，5.53(s，2H，-CH
2)，3.71(s，2H，-CH
2)，3.65(s，2H，-CH
2)，3.08(s，2H，-CH
2)，2.99(s，2H，-CH
2).MS(ESI)：423.67(C
22H
20ClN
4O
3，[M+H]
+).Anal.CalcdforC
22H
19ClN
4O
3：C，62.49；H，4.53；N，13.25％.Found：C，62.52；H，4.54；N，13.27％.
The preparation of embodiment eight: 2-(2-(4-(3-chloro-phenyl-) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 8)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 32%.Mp：186-189℃.
1HNMR(400MHz，DMSO)：8.74(s，1H，ArH)，7.97(dd，J
1＝7.72Hz，J
2＝1.32Hz，1H，ArH)，7.56(m，1H，ArH)，7.45(d，J＝7.92Hz，1H，ArH)，7.38(t，J＝7.48Hz，1H，ArH)，7.24(t，J＝8.12Hz，1H，ArH)，7.01(d，J＝1.88Hz，1H，ArH)，6.95(dd，J
1＝8.36Hz，J
2＝1.96Hz，1H，ArH)，6.83(dd，J
1＝7.76Hz，J
2＝1.20Hz，1H，ArH)，5.53(s，2H，-CH
2)，3.68(d，J＝4.96Hz，2H，-CH
2)，3.62(t，J＝4.82Hz，2H，-CH
2)，3.35(s，2H，-CH
2)，3.21(t，J＝4.84Hz，2H，-CH
2).MS(ESI)：423.67(C
22H
20ClN
4O
3，[M+H]
+).Anal.CalcdforC
22H
19ClN
4O
3：C，62.49；H，4.53；N，13.25％.Found：C，62.52；H，4.54；N，13.27％.
The preparation of embodiment nine: 2-(2-(4-(4-nitrophenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 9)
Preparation method is with embodiment one.Product is yellow powdery solid.Productive rate 33%.Mp：247-249℃.
1HNMR(400MHz，DMSO)：8.74(s，1H，ArH)，8.08(d，J＝9.28Hz，2H，ArH)，7.96(d，J＝7.12Hz，1H，ArH)，7.55(t，J＝7.32Hz，1H，ArH)，7.44(d，J＝8.20Hz，1H，ArH)，7.37(t，J＝7.48Hz，1H，ArH)，7.04(d，J＝9.36Hz，2H，ArH)，5.54(s，2H，-CH
2)，3.74(s，2H，-CH
2)，3.65(s，4H，-2CH
2)，3.55(s，2H，-CH
2).MS(ESI)：434.26(C
22H
20N
5O
5，[M+H]
+).Anal.CalcdforC
22H
19N
5O
5：C，60.97；H，4.42；N，16.16％.Found：C，60.99；H，4.43；N，16.18％.
The preparation of embodiment ten: 2-(2-(4-(3-(trifluoromethyl) phenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 10)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 38%.Mp：232-233℃.
1HNMR(400MHz，DMSO)：8.74(s，1H，ArH)，7.97(dd，J
1＝7.72Hz，J
2＝1.44Hz，1H，ArH)，7.56(m，1H，ArH)，7.46(t，J＝7.72Hz，2H，ArH)，7.38(t，J＝7.48Hz，1H，ArH)，7.28(d，J＝8.36Hz，1H，ArH)，7.23(s，1H，ArH)，7.12(d，J＝7.76Hz，1H，ArH)，5.54(s，2H，-CH
2)，3.71(d，J＝4.92Hz，2H，-CH
2)，3.64(t，J＝4.84Hz，2H，-CH
2)，3.39(t，J＝4.52Hz，2H，-CH
2)，3.29(t，J＝4.56Hz，2H，-CH
2).MS(ESI)：457.28(C
23H
20F
3N
4O
3，[M+H]
+).Anal.CalcdforC
23H
19F
3N
4O
3：C，60.52；H，4.20；N，12.28％.Found：C，60.54；H，4.21；N，12.27％.
The preparation of embodiment 11: 2-(2-(4-(2,4-3,5-dimethylphenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 11)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 36%.Mp：204-207℃.
1HNMR(400MHz，DMSO)：8.75(s，1H，ArH)，7.98(dd，J
1＝7.76Hz，J
2＝1.48Hz，1H，ArH)，7.56(m，1H，ArH)，7.44(d，J＝8.24Hz，1H，ArH)，7.39(t，J＝7.46Hz，1H，ArH)，7.00(s，1H，ArH)，6.94(m，2H，ArH)，5.52(s，2H，-CH
2)，3.67(d，J＝4.52Hz，2H，-CH
2)，3.62(s，2H，-CH
2)，2.88(d，J＝4.44Hz，2H，-CH
2)，2.79(t，J＝4.62Hz，2H，-CH
2)，2.25(s，3H，CH
3)，2.21(s，3H，CH
3).MS(ESI)：417.29(C
24H
25N
4O
3，[M+H]
+).Anal.CalcdforC
24H
24N
4O
3：C，69.21；H，5.81；N，13.45％.Found：C，69.24；H，5.82；N，13.43％.
The preparation of embodiment 12: 2-(2-(4-(2,3-dichlorophenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 12)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 34%.Mp：191-193℃.
1HNMR(400MHz，DMSO)：8.76(s，1H，ArH)，7.98(dd，J
1＝7.84Hz，J
2＝1.40Hz，1H，ArH)，7.56(m，1H，ArH)，7.44(d，J＝8.08Hz，1H，ArH)，7.38(t，J＝7.86Hz，1H，ArH)，7.35(d，J＝2.34Hz，2H，ArH)，7.18(m，1H，ArH)，5.54(s，2H，-CH
2)，3.72(s，2H，-CH
2)，3.65(s，2H，-CH
2)，3.09(s，2H，-CH
2)，3.00(s，2H，-CH
2).MS(ESI)：458.21(C
22H
19Cl
2N
4O
3，[M+H]
+).Anal.CalcdforC
22H
18Cl
2N
4O
3：C，57.78；H，3.97；N，12.25％.Found：C，57.79；H，3.98；N，12.23％.
The preparation of embodiment 13: 2-(2-(4-(3,4-dichlorophenyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 13)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 39%.Mp：199-202℃.
1HNMR(400MHz，DMSO)：8.74(s，1H，ArH)，7.97(dd，J
1＝7.72Hz，J
2＝1.36Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(m，2H，ArH)，7.38(m，1H，ArH)，7.19(d，J＝2.84Hz，1H，ArH)，6.98(m，1H，ArH)，5.53(s，2H，-CH
2)，3.68(d，J＝5.00Hz，2H，-CH
2)，3.61(t，J＝4.84Hz，2H，-CH
2)，3.35(s，2H，-CH
2)，3.22(t，J＝4.90Hz，2H，-CH
2).MS(ESI)：458.21(C
22H
19Cl
2N
4O
3，[M+H]
+).Anal.CalcdforC
22H
18Cl
2N
4O
3：C，57.78；H，3.97；N，12.25％.Found：C，57.79；H，3.98；N，12.23％.
The preparation of embodiment 14: 2-(2-(4-(pyridine-2-base) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 14)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 32%.Mp：213-216℃.
1HNMR(400MHz，DMSO)：8.74(s，1H，ArH)，8.14(dd，J
1＝4.80Hz，J
2＝1.48Hz，1H，ArH)，7.97(dd，J
1＝7.72Hz，J
2＝1.44Hz，1H，ArH)，7.56(m，2H，ArH)，7.44(d，J＝8.00Hz，1H，ArH)，7.38(t，J＝7.50Hz，1H，ArH)，6.88(d，J＝8.60Hz，1H，ArH)，6.68(m，1H，ArH)，5.53(s，2H，-CH
2)，3.65(s，4H，2CH
2)，3.59(t，J＝2.96Hz，2H，-CH
2)，3.54(t，J＝2.96Hz，2H，-CH
2).MS(ESI)：390.19(C
21H
20N
5O
3，[M+H]
+).Anal.CalcdforC
21H
19N
5O
3：C，64.77；H，4.92；N，17.98％.Found：C，64.79；H，4.93；N，17.96％.
The preparation of embodiment 15: 2-(2-(4-benzyl diethylenediamine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 15)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 37%.Mp：251-254℃.
1HNMR(400MHz，DMSO)：8.72(s，1H，ArH)，7.97(dd，J
1＝7.80Hz，J
2＝1.44Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(d，J＝8.24Hz，1H，ArH)，7.37(m，2H，ArH)，7.33(m，3H，ArH)，7.27(m，1H，ArH)，5.45(s，2H，-CH
2)，3.53(s，4H，2CH
2)，3.48(d，J＝4.56Hz，2H，-CH
2)，2.46(d，J＝4.68Hz，2H，-CH
2)，2.36(t，J＝4.74Hz，2H，-CH
2).MS(ESI)：403.24(C
23H
23N
4O
3，[M+H]
+).Anal.CalcdforC
23H
22N
4O
3：C，68.64；H，5.51；N，13.92％.Found：C，68.63；H，5.53；N，13.93％.
The preparation of embodiment 16: 2-(2-(4-benzhydryl piperazidine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 16)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 35%.Mp：267-268℃.
1HNMR(400MHz，DMSO)：8.71(s，1H，ArH)，7.96(t，J＝3.88Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(t，J＝6.20Hz，5H，ArH)，7.37(t，J＝7.50Hz，1H，ArH)，7.31(t，J＝7.56Hz，4H，ArH)，7.20(t，J＝7.50Hz，2H，ArH)，5.42(s，2H，-CH
2)，4.38(s，1H，-CH)，3.56(s，2H，-CH
2)，3.51(s，2H，-CH
2)，2.38(s，2H，-CH
2)，2.32(s，2H，-CH
2).MS(ESI)：479.24(C
29H
27N
4O
3，[M+H]
+).Anal.CalcdforC
29H
26N
4O
3：C，72.79；H，5.48；N，11.71％.Found：C，72.82；H，5.47；N，11.73％.
The preparation of embodiment 17: 2-(2-(4-(two (4-fluorophenyl) methyl) piperazine-1-base)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 17)
Preparation method is with embodiment one.Product is light yellow powder solid.Productive rate 33%.Mp：257-260℃.
1HNMR(400MHz，DMSO)：8.71(s，1H，ArH)，7.95(dd，J
1＝7.72Hz，J
2＝1.40Hz，1H，ArH)，7.55(m，1H，ArH)，7.46(m，5H，ArH)，7.37(m，1H，ArH)，7.15(t，J＝8.82Hz，4H，ArH)，5.42(s，2H，-CH
2)，4.48(s，1H，-CH)，3.56(s，2H，-CH
2)，3.50(s，2H，-CH
2)，2.36(s，2H，-CH
2)，2.29(s，2H，-CH
2).MS(ESI)：515.22(C
29H
25F
2N
4O
3，[M+H]
+).Anal.CalcdforC
29H
24F
2N
4O
3：C，67.70；H，4.70；N，10.89％.Found：C，67.69；H，4.72；N，10.91％.
The preparation of embodiment 18: 2-(2-(piperidin-1-yl)-2-oxoethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 18)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 29%.Mp：176-178℃.
1HNMR(400MHz，DMSO)：8.72(s，1H，ArH)，7.97(dd，J
1＝7.76Hz，J
2＝2.16Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(d，J＝7.68Hz，1H，ArH)，7.38(m，1H，ArH)，5.43(s，2H，-CH
2)，3.46(m，4H，2CH
2)，1.60(s，4H，2CH
2)，1.47(s，2H，-CH
2).MS(ESI)：312.24(C
17H
1sN
3O
3，[M+H]
+).Anal.CalcdforC
17H
17N
3O
3：C，65.58；H，5.50；N，13.50％.Found：C，65.60；H，5.51；N，13.48％.
The preparation of embodiment 19: 2-(2-morpholino-2-oxygen ethyl) chromene also [4,3-c] pyrazoles-4 (2H)-one (compound 19)
Preparation method is with embodiment one.Product is white powdery solids.Productive rate 31%.Mp：165-167℃.
1HNMR(400MHz，DMSO)：8.73(s，1H，ArH)，7.97(dd，J
1＝7.76Hz，J
2＝1.48Hz，1H，ArH)，7.55(m，1H，ArH)，7.44(d，J＝7.68Hz，1H，ArH)，7.38(m，1H，ArH)，5.47(s，2H，-CH
2)，3.67(t，J＝4.60Hz，2H，-CH
2)，3.60(t，J＝4.74Hz，2H，-CH
2)，3.55(t，J＝4.58Hz，2H，-CH
2)，3.47(t，J＝4.66Hz，2H，-CH
2).MS(ESI)：314.21(C
16H
16N
3O
4，[M+H]
+).Anal.CalcdforC
16H
15N
3O
4：C，61.34；H，4.83；N，13.41％.Found：C，61.35；H，4.85；N，13.44％.
Embodiment 20: containing the tonka bean camphor of kharophen nitrogen heterocyclic and pyrazole compound Anticancer Activities
1. experiment material and method
1.1 medicines and reagent
Adopt MTT [3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures Caffeic acids derivative to Breast cancer lines (MCF-7), the half-inhibition concentration (IC of Human Lung Cancer cell strain (A549) and mouse melanin tumor cell (B16-F10)
50).
(1) preparation of nutrient solution (often liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin Solution (200,000 U/ml) 0.5ml, after adding tri-distilled water dissolving, with the NaHCO of 5.6%
3solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO
32.00g, HEPES2.38g.
(2) preparation of PBS damping fluid (often liter): NaCl8.00g, KCl0.40g, Na
2hPO
412H
2o0.06g, KH
2pO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing PBS damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of liquid is tested: dissolved by a small amount of tri-distilled water of test sample and be made into storing solution, generally 10 times of preparation storing solutions of empirically maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 DEG C of refrigerators for subsequent use.
(5) cultivation of human colon cancer cell strain HCT-116: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(6) cultivation of human lung cancer cell A549: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(7) cultivation of liver cancer cell Huh7: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(8) cultivation of people's myeloid leukaemia M3 cell strain (HL60): be suspension growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 DEG C, 5%CO
2cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then use PBS buffer solution; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium and stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(9) cell incubation: the tumour cell in vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 10
5individual ml
-1.In 96 well culture plates, every hole adds cell suspension 100ul, puts 37 DEG C, 5%CO
224h is cultivated in incubator.After cultivating 24h, add liquid by design respectively.
(10) dosing: join in each hole by test liquid respectively according to the concentration gradient of ultimate density, each concentration establishes 6 parallel holes.Experiment is divided into drug test group (adding the test medicine of different concns respectively), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in 37 DEG C, 5%CO
248h is cultivated in incubator.The activity of positive control medicine measures according to the method for test sample.
(11) mensuration of survivaling cell: in 96 orifice plates after having cultivated 48h, every hole adds MTT40 μ l (being made into 4mg/ml with PBS damping fluid).After placing 4h at 37 DEG C, remove supernatant liquor.Every hole adds 150 μ lDMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, automatic microplate reader is utilized to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to the following formula:
Growth inhibition ratio=(1-survival rate) × 100%=[1-(OD
experiment-OD
blank)/(OD
contrast-OD
empty in vain)] × 100% (OD
experimentrepresent the average optical of testing drug group, OD
contrastrepresent the average optical of control group, OD
blankrepresent the average optical of control group).
Half-inhibition concentration (IC
50) be defined as drug level when the tumor cell survival of 50%.According to the optical density(OD) (OD value) measured, make the typical curve of inhibitory rate of cell growth, typical curve is tried to achieve the drug level of its correspondence.
The IC recorded
50be shown in Table 1.
2. experimental result
The listed tonka bean camphor containing kharophen nitrogen heterocyclic of table 1 the present invention pyrazole compound are to the suppression IC of cancer cells
50value.
Result shows: containing the tonka bean camphor of kharophen nitrogen heterocyclic and pyrazole compound to human colon cancer cell strain (HCT-116), Human Lung Cancer cell strain (A549), liver cancer cell (Huh7) and people's myeloid leukaemia M3 cell strain (HL60) have restraining effect in various degree.
Claims (3)
1. a class is containing the tonka bean camphor of kharophen nitrogen heterocyclic and pyrazole compound, it is characterized in that it has following general formula:
Wherein R is:
2. described in claim 1 containing the tonka bean camphor of kharophen nitrogen heterocyclic a method for making for pyrazole compound, it is characterized in that it is made up of following steps:
4 hydroxy coumarin 0.06mmol is dissolved in the anhydrous DMF of 46.2ml, this reaction solution is cooled to less than 0 DEG C.Below 0 DEG C under condition, slowly drip POCl while stirring
30.18mmol, treats POCl
3finish, after stirring 0.5h under reaction solution being slowly warming up to room temperature condition, be then warming up to 65-70 DEG C of stirring reaction 6h.With the reaction of TLC tracking monitor, when after completion of the reaction, reaction solution to be poured in the mixture of ice and water of 200g and vigorous stirring, have a large amount of light yellow solid 1 to separate out.By solid suction filtration, and with 5% Na
2cO
3solution washing, by gained solid drying, namely obtains intermediate.
Gained solid 1mmol in step one is dissolved in 10ml ethanol, adding stirring makes it dissolve fully, then 15-20 DEG C is cooled to, by the solution (the hydrazine hydrate 2mmol+ triethylamine 4mmol+60% ethanol 10ml of 85%) that configures under agitation, maintain the temperature at 15-20 DEG C, slowly drop in reaction solution.Drip and finish, keep temperature to be no more than 25 DEG C, stirring reaction 12h.React with TLC tracking monitor.By gained solid concentrating under reduced pressure, gained solid ethyl alcohol recrystallization, namely obtains intermediate 2.
Get bromoacetic acid 2mmol and heterocyclic amine is dissolved in the methylene dichloride of 40ml, HOBt1mmol is added under agitation condition, EDCHCl3mmol, is warming up to reflux temperature stirring reaction 6-8h, by TLC detection reaction progress, reaction is finished, reaction solution water cleans 3 times, and organic over anhydrous dried over sodium sulfate, removes solvent under reduced pressure, the product obtained, without the need to purifying, is directly used in next step reaction.
Product previous step obtained and compound 2 are respectively got 1mmol and are dissolved in dehydrated alcohol, add the sodium ethylate of 1.2mmol, heated and stirred refluxes simultaneously, after complete with TLC detection reaction, remove ethanol under reduced pressure, the resistates of gained is added in the water of about 100ml, vigorous stirring 10-15min, filter, after gained solid washed with water, drying under reduced pressure, with ethyl alcohol recrystallization, namely obtains final product.
3. tonka bean camphor containing kharophen nitrogen heterocyclic according to claim 1 pyrazole compound and preparation thereof and the application in Tumor suppression medicine.
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| CN110256390A (en) * | 2019-06-21 | 2019-09-20 | 中国人民解放军第四军医大学 | The application of coumarin kind compound, preparation method and preparation treatment cerebral apoplexy drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006088903A2 (en) * | 2005-02-15 | 2006-08-24 | Vivoquest, Inc. | Pyrazole compounds |
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2015
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|---|---|---|---|---|
| WO2006088903A2 (en) * | 2005-02-15 | 2006-08-24 | Vivoquest, Inc. | Pyrazole compounds |
Non-Patent Citations (1)
| Title |
|---|
| YONG YIN等: "Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3Kα: 2-alkylchromeno [4,3-c]pyrazol-4(2H)-one derivatives", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
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|---|---|---|---|---|
| CN110256390A (en) * | 2019-06-21 | 2019-09-20 | 中国人民解放军第四军医大学 | The application of coumarin kind compound, preparation method and preparation treatment cerebral apoplexy drug |
| CN110256390B (en) * | 2019-06-21 | 2020-11-24 | 中国人民解放军第四军医大学 | Coumarin compound, preparation method and application of coumarin compound in preparation of medicine for treating cerebral apoplexy |
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