CN101659663A - Indolizine derivative as well as preparation method and application thereof - Google Patents
Indolizine derivative as well as preparation method and application thereof Download PDFInfo
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- CN101659663A CN101659663A CN200910153147A CN200910153147A CN101659663A CN 101659663 A CN101659663 A CN 101659663A CN 200910153147 A CN200910153147 A CN 200910153147A CN 200910153147 A CN200910153147 A CN 200910153147A CN 101659663 A CN101659663 A CN 101659663A
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Abstract
The invention discloses an indolizine derivative as well as a preparation method and an application thereof, which belongs to the technical field of medicinal chemistry. The preparation method of theindolizine derivative is characterized by comprising the steps of: dissolving 10mmol of onium salt in 40mL of DMF; adding 2mL of triethylamine, 40mmol of acrylontitrile, and 4g of TPCD; reacting for 4to 15 hours at the temperature of 70 to 120 DEG C; cooling; pouring the reactant into 100mlL of 5 percent hydrochloric acid liquid; separating out sediment; filtering to obtain a crude product; and chromatographing through silicagel column to obtain the product. The invention creatively designs to induce a cyclopropyl group with unique bioactivity into an indolizine system and the compounded indolizine derivatives have good activity for resisting the increment of liver cancer cell strain (Hep-G2); and the indolizine derivatives can be further modified to serve as new anti-liver cancer medicine.
Description
Technical field:
The present invention relates to a kind of compound, specifically relate to the application of indolizine derivative that a kind of cyclopropyl replaces and preparation method thereof antitumour activity, belong to the pharmaceutical chemistry technical field.
Background technology:
The cyclopropanes compound is the broad-spectrum organic synthesis intermediate of a class, and the cyclopropane structure is present in many important natural product molecules and has in the medicine of physiologically active.All contain cyclopropyl in many quinolone medicines, structure activity study shows, if N-replaces the position cycloaliphatic ring when replacing, in cyclopropyl, cyclobutyl, cyclopentyl, what its anti-microbial effect was best is cyclopropyl.Research finds that also some xacin-series medicine has certain restraining effect to the topoisomerase II of prokaryotic cell prokaryocyte, and cyclopropyl can be strengthened this activity, for example Ciprofloxacin, baloxacin etc.Cyclopropane amino acid has a lot of unique biological activity, and for example, cleomycin is a kind of microbiotic with anti-tumor activity.
(hepatocellular carcinoma is the most common histological type in the primary hepatocarcinoma HCC) to hepatocellular carcinoma, is one of worldwide cancer the most occurred frequently, and is also very common in China's liver cancer.The searching toxic side effect is light, can effectively suppress tumour cell again and increase, and becomes the important directions of research.
Summary of the invention:
The objective of the invention is to by to a kind of activity research, the application of indolizine derivative that a kind of cyclopropyl replaces and preparation method thereof and medicines resistant to liver cancer is provided cyclopropyl.
Main purpose of the present invention provides a kind of indolizine derivative, and its structure is shown in general formula 4:
In the formula: R is selected from H, C
1-6Alkyl, C
1-6Alkoxyl group, amino, nitro, halogen, n are 1-3, preferably from H, 5-CH
3, 7-CH
3, 5-Br, 8-Br; R
1Be selected from H, C
1-6Alkoxy-C O-is preferably from H, CH
3O-CO-, C
2H
5O-CO-; R
2Be selected from H, CN, C
1-6Alkoxy-C O-is preferably from H, CH
3O-CO-, C
2H
5O-CO-.
Below be the structural formula of indolizine derivative of the present invention under the different substituents:
Secondary objective of the present invention provides a kind of preparation method of above-mentioned indolizine derivative, may further comprise the steps: 10mmol salt 2 is dissolved among the 40mL DMF, add the 2mL triethylamine, 40mmol vinyl cyanide, 4g TPCD, behind reaction 4～15h under 70～120 ℃, cooling, reactant is poured in 100mL 5% hydrochloric acid soln, separates out precipitation, filter crude product, through silica gel column chromatography [developping agent is: V (sherwood oil): V (ethyl acetate)=5: 1] pure product.Adopt this method can make 4a, 4b, 4e, 4f and 4l-p in the above-claimed cpd.
Another kind of preparation method is: 10mmol salt 2 is dissolved among the 40mL DMF, adds the 2mL triethylamine, the 40mmol diethyl maleate, 4g TPCD, behind reaction 4～15h under 70～120 ℃, cooling, reactant is poured in 100mL 5% hydrochloric acid soln, ether (2 * 100mL) extractions 2 times, merge organic layer, (2 * 50mL) wash water, anhydrous magnesium sulfate drying, steaming desolventize crude product, through silica gel column chromatography [developping agent is: V (sherwood oil): V (ethyl acetate)=5: 1] pure product.Adopt this method can make 4c and 4g-k in the above-claimed cpd.
Another kind of preparation method is: 10mmol salt 2 is dissolved among the 40mL DMF, add the 2mL triethylamine, the 10mmol N-phenylmaleimide, 4g TPCD, behind reaction 4～15h under 70～120 ℃, cooling, reactant is poured in the 100mL5% hydrochloric acid soln, separate out precipitation, filter crude product, through silica gel column chromatography [developping agent is: V (sherwood oil): V (ethyl acetate)=5: 1] pure product.Adopt this method can make 4d in the above-claimed cpd.
The temperature of above-mentioned reaction is selected 70～120 ℃, and 90 ℃ is best, the selection of time 4～15h of reaction, best results under 5h or the 10h.
Reaction equation of the present invention is as follows:
Another aspect of the present invention provides the application of a kind of above-mentioned indolizine derivative in the preparation medicines resistant to liver cancer.
Beneficial effect of the present invention is as follows:
The biological activity of indolizine is very extensive, mainly contain antitumor, antibiotic, antiviral, kill acarid, anti-inflammatory, anti-arrhythmia, hypertension etc.By to the active research of cyclopropyl group unique biological, we design with innovating will have in the middle of unique bioactive cyclopropyl group introducing indolizine system, synthetic indolizine analog derivative, it is active to have good resistance hepatoma cell strain (Hep-G2) increment, and this class indolizine derivative is further modified and be can be used as new medicines resistant to liver cancer.
The invention will be further described below in conjunction with the drawings and specific embodiments.
Description of drawings:
(400MHz, the CDCl of Fig. 1 indolizine derivative of the present invention (4a)
3) nucleus magnetic resonance figure;
(400MHz, the CDCl of Fig. 2 indolizine derivative of the present invention (4b)
3) nucleus magnetic resonance figure.
Embodiment:
Embodiment 1:
10mmol salt 2 is dissolved among the 40mL DMF, add the 2mL triethylamine, the 40mmol vinyl cyanide, 4g TPCD, behind reaction 5-10h under 90 ℃, cooling, reactant is poured in 100mL 5% hydrochloric acid soln, separate out precipitation, filter crude product, through silica gel column chromatography [developping agent is: V (sherwood oil): V (ethyl acetate)=5: 1] pure product.
3-Cyclopropylcarbonyl-1-indolizinecarbonitrile?(4a).whitepowder?m.p.163-164℃.
1H?NMR(CDCl
3，400MHz)：δ1.04(s，2H)，1.25(s，2H)，2.51(s，1H)，7.06(s，1H)，7.42(s，1H)，7.79(s，1H)，7.94(s，1H)，9.90(s，1H).
Embodiment 2:
10mmol salt 2 is dissolved among the 40mL DMF, add the 2mL triethylamine, the 40mmol methyl acrylate, 4g TPCD, behind reaction 5-10h under 90 ℃, cooling, reactant is poured in 100mL 5% hydrochloric acid soln, separate out precipitation, filter crude product, through silica gel column chromatography [developping agent is: V (sherwood oil): V (ethyl acetate)=5: 1] pure product.
Methyl?3-cyclopropylcarbonylindolizine-1-carboxylate(4b).Yellow?powder?m.p.135-136℃.
1H?NMR(CDCl
3，400MHz)：δ0.97-1.02(m，2H)，1.21-1.25(m，2H)，2.56-2.62(m，1H)，3.94(s，3H)，6.99(t，1H，J＝7.0Hz)，7.38(t，1H，J＝7.8Hz)，8.17(s，1H)，8.34(d，1H，J＝9.2Hz)，9.90(d，1H，J＝6.8Hz).
Embodiment 3:
4-Cyclopropylcarbonyl-2-methyl-1，3-dioxo-1H-pyrrolo[3，4-a]indolizine?Yellow?powder(4d).m.p.211-212℃.
1H?NMR(CDCl
3，400MHz)：δ1.10-1.15(m，2H)，1.26-1.30(m，2H)，3.81-3.87(m，1H)，7.10-7.13(m，1H)，7.39-7.46(m，3H)，7.47-7.53(m，3H)，8.00(d，1H，J＝8.8Hz)，10.05(d，1H，J＝7.2Hz).
Table 1, compound tabulation:
The antiproliferative activity test
Get one bottle in the cell that just grows up to complete individual layer, collecting cell behind the tryptic digestion, with transfer pipet piping and druming evenly, get two cell suspension trypan blues (Trypan Blue) dyeing, in microscopically living cell counting number (the dead cell number must not surpass 5%), adjust cell number to 1 * 10 with complete culture solution
5Individual cell/mL.Every hole adds 100 μ L cell suspensions in 96 porocyte culture plates, and culture plate is placed CO
2Cultivate 12h in the incubator, in every hole, add the solution that 11 μ L contain the different concns sample after taking out culture plate, make the medicine final concentration be respectively 40.0,20.0,10.0,5.0,1.0 and 0.1 μ g/mL, each concentration is established 3 parallel holes, and other establishes 3 porocytes and does not add tested medicine and do the normal control hole.Add behind the medicine culture plate mixing that on the microwell plate vibrator, vibrates, place CO
2Continue to cultivate 48h in the incubator.Take out culture plate, every hole adds the MTT liquid of 25 μ L4mg/mL, and the vibration mixing continues to cultivate 6h.Add every hole 100 μ L SDS lysates (90mL tri-distilled water+10g SDS+5mL Virahol+2mL concentrated hydrochloric acid) back and cultivate 12h.Measure each hole photoabsorption (OD value) in microplate reader, measure wavelength 570nm, reference wavelength 630nm.Calculate the inhibiting rate of medicine on cell proliferation according to each hole OD value.
Each hole photoabsorption (OD value) of measuring by microplate reader in the experiment, the inhibiting rate of calculating medicine on cell proliferation:
Inhibiting rate=[1-(specimen OD value-blank OD value)/(negative control OD value-blank OD value)] * 100
Be calculated as follows the IC of sample
50Value (Kou Shifa):
lgIC
50＝Xm-I[P-(3-Pm-Pn)/4]
Xm wherein: the logarithmic value of the peak concentration of design; I: maximal dose is than the logarithmic value of facing dosage mutually; P: positive reaction rate sum; Pm: maximum positive reaction rate; The minimum positive reaction rate of Pn, statistics is as shown in table 2:
The pharmaceutical activity data of table 2, compound
| ??Compd. | ??IC 50(μg/mL) | ??Compd. | ??IC 50(μg/mL) |
| ??4a | ??0.32±0.9 | ??4i | ??2.5±0.5 |
| ??4b | ??6.6±16 | ??4j | ??0.20±0.09 |
| ??4c | ??32±0.9 | ??4k | ??1.1±0.6 |
| ??4d | ??0.48±0.05 | ??4l | ??2.1±0.9 |
| ??4d’ | ??0.56±0.07 | ??4m | ??4.6±16 |
| ??4e | ??21±0.6 | ??4n | ??4.3±1.9 |
| ??4f | ??25±0.7 | ??4o | ??9.3±1.3 |
| ??4g | ??0.29±0.9 | ??4p | ??27±0.9 |
| ??4h | ??1.8±0.6 |
Claims (8)
1, a kind of indolizine derivative, its structure is shown in general formula 4:
Formula 4
In the formula:
R is selected from H, C
1-6Alkyl, C
1-6Alkoxyl group, amino, nitro or halogen, n are 1～3;
R
1Be selected from H or C
1-6Alkoxy-C O-;
R
2Be selected from H, CN or C
1-6Alkoxy-C O-.
2, a kind of indolizine derivative according to claim 1, it is characterized in that: R is H, 5-CH
3, 7-CH
3, 5-Br or 8-Br.
3, a kind of indolizine derivative according to claim 1 is characterized in that: R
1Be H, CH
3O-CO-or C
2H
5O-CO-.
4, a kind of indolizine derivative according to claim 1 is characterized in that: R
2Be H, CH
3O-CO-or C
2H
5O-CO-.
5, a kind of preparation method of indolizine derivative, may further comprise the steps: 10mmol salt is dissolved among the 40mL DMF, add the 2mL triethylamine, 40mmol vinyl cyanide, 4g TPCD, behind reaction 4～15h under 70～120 ℃, cooling, reactant is poured in 100mL 5% hydrochloric acid soln, separates out precipitation, filter crude product, get product through silica gel column chromatography.
6, a kind of preparation method who prepares the described indolizine derivative of claim 1 may further comprise the steps: 10mmol salt is dissolved among the 40mL DMF, adds the 2mL triethylamine, the 40mmol diethyl maleate, 4g TPCD is behind reaction 4～15h under 70～120 ℃, cooling, reactant is poured in 100mL 5% hydrochloric acid soln, and extracted with diethyl ether 2 times merges organic layer, washing, anhydrous magnesium sulfate drying, steam desolventize crude product, get product through silica gel column chromatography.
7, a kind of preparation method who prepares the described indolizine derivative of claim 1, may further comprise the steps: 10mmol salt is dissolved among the 40mL DMF, add the 2mL triethylamine, 10mmolN-phenyl maleimide, 4g TPCD, behind reaction 4～15h under 70～120 ℃, cooling, reactant is poured in the 100mL5% hydrochloric acid soln, separates out precipitation, filter crude product, get product through silica gel column chromatography.
8, according to the application of the described indolizine derivative of claim 1～4 in the preparation medicines resistant to liver cancer.
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| CN2009101531473A CN101659663B (en) | 2009-09-24 | 2009-09-24 | Indolizine derivative as well as preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801576A (en) * | 2016-04-12 | 2016-07-27 | 湖北科技学院 | Synthetic method of indolizine compounds |
| CN108530442A (en) * | 2018-04-04 | 2018-09-14 | 安徽师范大学 | 1,2,3- tri- replaces Indoli zine derivatives and preparation method thereof |
| CN114276343A (en) * | 2020-09-27 | 2022-04-05 | 中石化南京化工研究院有限公司 | Preparation method of fluorescent probe for detecting trace iron ions in chlorobenzene |
-
2009
- 2009-09-24 CN CN2009101531473A patent/CN101659663B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801576A (en) * | 2016-04-12 | 2016-07-27 | 湖北科技学院 | Synthetic method of indolizine compounds |
| CN108530442A (en) * | 2018-04-04 | 2018-09-14 | 安徽师范大学 | 1,2,3- tri- replaces Indoli zine derivatives and preparation method thereof |
| CN114276343A (en) * | 2020-09-27 | 2022-04-05 | 中石化南京化工研究院有限公司 | Preparation method of fluorescent probe for detecting trace iron ions in chlorobenzene |
| CN114276343B (en) * | 2020-09-27 | 2023-07-07 | 中国石油化工股份有限公司 | Preparation method of fluorescent probe for detecting trace iron ions in chlorobenzene |
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Granted publication date: 20110608 Termination date: 20130924 |