CN101723935B - 1,5-diaryl-substituted 2,4-dienone derivative as well as preparation method and application thereof - Google Patents
1,5-diaryl-substituted 2,4-dienone derivative as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1,5-diaryl-substituted 2,4-dienone derivative as well as a preparation method and application thereof. A chemical formula of the derivative is shown as a formula (I). The derivative has strong interaction with guanine-enriched telomere DNA and proto-oncogene c-myc, c-kit1 and c-kit2 DNA, better suppressive activity to telomere/telomerase in cancer cells, stronger inhibition effect to the expression of proto-oncogene c-myc, better anti-tumor activity and lower toxic and side effects, simple preparation method, low-price raw materials and prospect for developing into a novel anti-cancer medicine.
Description
Technical field
The present invention relates to the new drug compound technical, be specifically related to a kind ofly 1, the two aryl of 5-replace 2,4-dienone derivative and preparation method thereof and application.
Background technology
Cancer is one of principal disease that threatens human health and life security.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Seek efficient, highly selective, cancer therapy drug that toxic side effect is little is one of important directions of drug development research.
The synthetic cancer therapy drug take DNA as shot design for the special higher structure design synthesized micromolecule inhibitor of the telomeric dna with important physiological significance and proto-oncogene DNA, is the important method of Development of Novel cancer therapy drug particularly.
With telomeric dna, and proto-oncogene such as c-myc, the interactional micromolecular compound of c-kit DNA have some common constitutional featuress: the almost plane aromatic ring structure with three or more; Article one, or several under physiological condition with the side chain of lotus on schedule.Their mechanism of anticancer action mainly is by interacting with telomeric dna or proto-oncogene c-myc, c-kit DNA, the telomerase activation of anticancer, or the expression of c-myc, c-kit gene, thereby the propagation of anticancer.
Summary of the invention
The object of the present invention is to provide a kind of be rich in telomeric dna and the proto-oncogene c-myc of guanine, c-kit1, c-kit2 DNA have strong interaction very, have 1 of antitumour activity, the two aryl of 5-replace 2,4-dienone derivative.
It is above-mentioned 1 that another object of the present invention is to provide, and the two aryl of 5-replace the preparation method of 2,4-dienone derivative.
It is above-mentioned 1 that another object of the present invention is to provide, and the two aryl of 5-replace the application of 2,4-dienone derivative in the preparation cancer therapy drug.
Above-mentioned purpose of the present invention is achieved by following scheme:
The present invention is according to some and telomeric dna or c-myc, c-kit1, c-kit2 DNA has the constitutional features curcumine of antitumour activity (as have) of interactional micromolecular compound, design is synthetic to obtain of the present invention 1, the two aryl of 5-replace 2,4-dienone derivative, this derivative also possesses and telomeric dna and proto-oncogene c-myc, c-kit1, c-kit2 DNA has the very characteristics of strong interaction, and is of the present invention 1, and the two aryl of 5-replace 2,4-dienone derivative, its chemical formula is suc as formula shown in (I):
In the above-mentioned formula (I),
X is-(CH
2)
n-, wherein, n takes from 0～4;
Perhaps X is-CH
2NHCH
2-,-CH
2NH (CH
3) CH
2-,-CH
2NH
+(CH
3)
2CH
2-,-CH
2NH (CH
2CH
3) CH
2,-CH
2NH
+(CH
2CH
3)
2CH
2
Y is compound shown in compound shown in compound, the formula (IV) shown in compound shown in the formula (II), the formula (III) or the formula (V):
Wherein,
R
1Take from C
1-6Alkyl, preferable methyl or ethyl;
R
2Take from H, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, benzyl, nitro or ester group, preferred electron withdrawing group is such as halogen, nitro or ester group;
R
3Take from halogen, C
1-3Halogen-containing alkyl chain or C
2-8Nitrogenous alkyl group side chain, preferred
R
4Take from H, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, benzyl, nitro or C
1-3Ester group, preferred electron withdrawing group is such as halogen, nitro or C
1-3Ester group;
R
5Take from C
1-6Alkyl, preferable methyl or ethyl;
R
6Take from H, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, benzyl, nitro or C
1-3Ester group, preferred electron withdrawing group is such as halogen, nitro or C
1-3Ester group;
Z is O, NH or NR
7
Wherein, R
7Can be C
1-6Alkyl or C
2-8Nitrogenous alkyl group side chain, preferred
The present invention 1, and the two aryl of 5-replace the preparation method of 2,4-dienone derivative, and different according to Z in the formula (I) and Y can be divided into three kinds of preparation methods, specific as follows shown in:
1. Z is O in formula (I), and when Y was compound shown in compound shown in the formula (III) or the formula (IV), the method comprised the steps:
Aromatic aldehyde and alicyclic ketone (or acetone) are carried out two aldol reactions, obtain shown in the formula (I) 1, the two aryl of 5-replace 2,4-dienone derivative.
In the above-mentioned steps (1), the molar ratio of aromatic aldehyde and alicyclic ketone (or acetone) is (2～5): 1, and preferred 2: 1.
In the above-mentioned steps (1), reaction solvent adopts alcohols in two aldol reactions, and preferred volume per-cent is 95% ethanol.
In the above-mentioned steps (1), catalyzer adopts sodium hydroxide solution in two aldol reactions, and preferred mass percentage ratio is 10% sodium hydroxide solution.
In the above-mentioned steps (1), the temperature of reaction of two aldol reactions is selected room temperature, perhaps between room temperature and the follow-up reflux temperature all can, reflux temperature is different and difference according to solvent.
In the above-mentioned steps (1), the reaction times of two aldol reactions can be specifically slightly variant according to the active height of aromatic aldehyde, generally selected 5～30 minutes all can realize the present invention.
In the above-mentioned steps (1), the consumption of the catalyzer sodium hydroxide solution of two aldol reactions, and the reaction times, it is comparatively crucial factor, must strict consumption and the reaction times of controlling NaOH, the quantity not sufficient of alkali or excessive and long yield and the aftertreatment that all can the affect reaction reaction times.
2. Z is O in formula (I), and when Y was compound shown in compound shown in the formula (II) or the formula (V), the method comprised the steps:
(1) aromatic aldehyde and alicyclic ketone (or acetone) are carried out two aldol reactions, obtain suc as formula compound shown in (VI);
(2) with compound shown in the formula (VI) in tetramethylene sulfone after the heating for dissolving, add excess iodine methane, methylation reaction occurs under the reflux state, prepare shown in the formula (I) 1, the two aryl of 5-replace 2,4-dienone derivative.
In the above-mentioned steps (1), the molar ratio of aromatic aldehyde and alicyclic ketone (or acetone) is (2～5): 1, and preferred 2: 1.
In the above-mentioned steps (1), reaction solvent adopts alcohols in two aldol reactions, and preferred volume per-cent is 95% ethanol.
In the above-mentioned steps (1), catalyzer adopts sodium hydroxide solution in two aldol reactions, and the preferred mass mark is 10% sodium hydroxide solution.
In the above-mentioned steps (1), the temperature of reaction of two aldol reactions is selected room temperature, perhaps between room temperature and the follow-up reflux temperature all can, reflux temperature is different and difference according to solvent.
In the above-mentioned steps (1), the reaction times of two aldol reactions can be specifically slightly variant according to the active height of aromatic aldehyde, generally selected 5～30 minutes all can realize the present invention.
In the above-mentioned steps (1), the consumption of the catalyzer sodium hydroxide solution of two aldol reactions, and the reaction times, it is comparatively crucial factor, must strict consumption and the reaction times of controlling NaOH, the quantity not sufficient of alkali or excessive and long yield and the aftertreatment that all can the affect reaction reaction times.
In the above-mentioned steps (2), with the elder generation of compound shown in the formula (VI) heating for dissolving in reaction solvent, then compound and methyl iodide carry out methylation reaction shown in the formula (VI) under reflux state, the molar ratio of compound and iodomethane reaction is 1 shown in the formula (VI): (2～10), preferred 1: 10.
In the above-mentioned steps (2), the reaction solvent of methylation reaction can be selected tetramethylene sulfone or methyl iodide, preferred tetramethylene sulfone, and the consumption of tetramethylene sulfone is 1～5 times of molar equivalent of compound shown in the formula (VI).
In the above-mentioned steps (2), the reaction times of methylation reaction is 1～5 hour.
In this preparation method, can also be only by aromatic aldehyde and alicyclic ketone are carried out two aldol reactions, just can prepare required 1, the two aryl replacement of 5-2,4-dienone derivative.
3. Z is NH or NR in formula (I)
7The time, the method comprises the steps:
(1) aromatic aldehyde and alicyclic ketone (or acetone) are carried out two aldol reactions, obtain suc as formula compound shown in (VI);
(2) reaction of compound shown in the formula (VI) and amine is generated azomethine, obtain shown in the formula (I) 1, the two aryl of 5-replace 2,4-dienone derivative.
In the above-mentioned steps (1), the molar ratio of aromatic aldehyde and alicyclic ketone (or acetone) is (2～5): 1, and preferred 2: 1.
In the above-mentioned steps (1), reaction solvent adopts alcohols in two aldol reactions, and preferred volume per-cent is 95% ethanol.
In the above-mentioned steps (1), catalyzer adopts sodium hydroxide solution in two aldol reactions, and the preferred mass mark is 10% sodium hydroxide solution.
In the above-mentioned steps (1), the temperature of reaction of two aldol reactions is selected room temperature, perhaps between room temperature and the follow-up reflux temperature all can, reflux temperature is different and difference according to solvent.
In the above-mentioned steps (1), the reaction times of two aldol reactions can be specifically slightly variant according to the active height of aromatic aldehyde, generally selected 5～30 minutes all can realize the present invention.
In the above-mentioned steps (1), the consumption of the catalyzer sodium hydroxide solution of two aldol reactions, and the reaction times, it is comparatively crucial factor, must strict consumption and the reaction times of controlling NaOH, the quantity not sufficient of alkali or excessive and long yield and the aftertreatment that all can the affect reaction reaction times.
In the above-mentioned steps (2), the molar ratio of the reaction of compound and amine shown in the formula (VI) is 1: (1.2～3), preferred 1: 1.2.
In the above-mentioned steps (2), the reaction of compound and amine shown in the formula (VI) generates azomethine, needs strong dewatering agent in the reaction process, can select titanium tetrachloride solution as dewatering agent, promotes the carrying out of reaction.
In the above-mentioned steps (2), compound and amine shown in the formula (VI) all need drying treatment, avoid as far as possible bringing water into reaction system, and siccative can be selected molecular sieve, calcium oxide or calcium chloride.
In the above-mentioned steps (2), compound and amine shown in the formula (VI) generate azomethine, and temperature of reaction is 0 degree, and the reaction times is 30min～3 hour.
Of the present invention 1, the two aryl of 5-replace 2,4-dienone derivative confirms through test, its be rich in the telomeric dna of guanine and proto-oncogene c-myc, c-kit1 and c-kit2 DNA and all have very strong interaction, Telomere/in the cancer cells is had good inhibition activity, therefore can be used for preparing cancer therapy drug.Of the present invention 1, the two aryl of 5-replace 2,4-dienone derivative and prepare cancer therapy drug with acceptable auxiliary combination pharmaceutically, and cancer therapy drug is tablet, pill, capsule, injection, suspension agent or emulsion etc.
Compared with prior art, the present invention has following beneficial effect:
1. of the present invention 1, the two aryl of 5-replace 2,4-dienone derivative be rich in the telomeric dna of guanine and proto-oncogene c-myc, c-kit1 and c-kit2 DNA and all have very strong interaction, it is active that Telomere/in the cancer cells is had a good inhibition, and the expression of proto-oncogene c-myc is had very strong restraining effect;
2. of the present invention 1, the two aryl of 5-replace 2,4-dienone derivative and have good anti-tumor activity and lower toxic side effect, have the prospect that develops into the new type anticancer medicine;
3. of the present invention 1, the two aryl of 5-replace 2,4-dienone derivative, and its preparation method is simple, and raw material is inexpensive, and multiple JEG-3 is had significant restraining effect, is prepared as cancer therapy drug, has the very large market space.
Embodiment
Below in conjunction with specific embodiment the present invention is done further description, but specific embodiment is not done any restriction to the present invention.
Synthesizing of embodiment 1 compound 1
6-quinoline aldehyde and the 0.005mol acetone of 0.01mol are dissolved in 8mL 95% ethanol, drip the 10%NaOH of 5ml under the room temperature, stirring had yellow mercury oxide to separate out in about 5 minutes, and it is complete to react the 10min afterreaction; Suction filtration, washing gets yellow powder, and ethyl alcohol recrystallization gets the light yellow solid powder, and namely compound 1, and its chemical formula is suc as formula shown in (VII), and the productive rate of present embodiment is 80%.
1H NMR(400MHz，DMSO)δ8.96(s，2H)，8.52-8.20(m，6H)，8.06(dd，J＝24.6，12.3，4H)，7.58(d，J＝15.9，4H).ESI-MS m/z：337.13[M+H]
+.
Synthesizing of embodiment 2 compounds 2
8-nitro 6-quinoline aldehyde and the 0.005mol acetone of 0.015mol are dissolved in 8mL 95% ethanol, drip the 15%NaOH of 5ml under the room temperature, stirring had yellow mercury oxide to separate out in about 8 minutes, and it is complete to react the 20min afterreaction; Suction filtration, washing gets yellow powder, and ethyl alcohol recrystallization gets the light yellow solid powder, and namely compound 2, and its chemical formula is suc as formula shown in (VIII), and the productive rate of present embodiment is 78%.
1H NMR(400MHz，DMSO)δ9.15(d，J＝8.2，2H)，8.46(s，2H)，8.25(s，2H)，7.95(s，1H)，7.90(s，1H)，7.80(m，2H)，7.30(m，2H).ESI-MS m/z：427.10[M+H]
+.
Synthesizing of embodiment 3 compounds 3
6-quinoline aldehyde and the 0.005mol pimelinketone of 0.02mol are dissolved in 8mL 95% propyl alcohol, drip 6ml 20%NaOH under the room temperature, stirring had yellow mercury oxide to separate out in about 15 minutes, and it is complete to react the 30min afterreaction.Suction filtration, washing gets yellow powder, and ethyl alcohol recrystallization gets the light yellow solid powder, and namely compound 3, and its chemical formula is suc as formula shown in (IX), and the productive rate of present embodiment is 72%.
1H NMR(400MHz，CDCl
3)δ8.86(dd，J＝4.1，1.3，2H)，8.11(d，J＝7.8，2H)，8.05(d，J＝8.8，2H)，7.90(s，2H)，7.83(s，2H)，7.75(dd，J＝8.8，1.7，2H)，7.36(dd，J＝8.3，4.2，2H)，3.03-2.93(m，4H)，1.85-1.74(m，2H).ESI-MS m/z：377.16[M+H]
+.
Synthesizing of embodiment 4 compounds 4
The preparation process of present embodiment comprises the steps:
(1) 3-pyridine aldehydes and the 0.005mol cyclopentanone with 0.01mol is dissolved in 8mL 95% ethanol, drip the 30%NaOH of 8ml under the room temperature, stirring had yellow mercury oxide to separate out in about 10 minutes, behind aldol addition-condensation cascade reaction 40min, react completely suction filtration, washing, get yellow powder, ethyl alcohol recrystallization, the dry light yellow solid powder that gets;
(2) above-mentioned light yellow solid powder and 0.05mol methyl iodide were refluxed 2 hours in the 2mL tetramethylene sulfone, cooling, suction filtration, the ether washing, the dry orange powder that gets, namely compound 4, and its chemical formula is suc as formula shown in (X), and the productive rate of present embodiment is 87%.
1H NMR(400MHz，D
2O)δ8.94(s，2H)，8.68(dd，J＝18.2，7.0，4H)，8.13-7.97(m，2H)，7.51(s，2H)，4.38(s，6H)，3.18(s，4H).
ESI-MS m/z：146.08[M+H]
2+.
Synthesizing of embodiment 5 compounds 5
The preparation process of present embodiment comprises the steps:
(1) 3-pyridine aldehydes and the 0.005mol pimelinketone with 0.01mol is dissolved in 8mL 60% propyl alcohol, drip the 10%NaOH of 8ml under the room temperature, stirring had yellow mercury oxide to separate out in about 25 minutes, reaction 45min afterreaction is complete, suction filtration, washing gets yellow powder, ethyl alcohol recrystallization, the dry light yellow solid powder that gets;
(2) above-mentioned light yellow solid powder and 0.025mol methyl iodide were refluxed 2 hours in the 2mL tetramethylene sulfone, cooling, suction filtration, the ether washing, the dry orange powder that gets, namely compound 5, and its chemical formula is suc as formula shown in (XI), and the productive rate of present embodiment is 87%.
1H NMR(400MHz，D
2O)δ8.83(s，2H)，8.67(s，2H)，8.51(d，J＝8.0，2H)，8.02(s，2H)，7.60(s，2H)，4.36(s，6H)，2.87(s，4H)，1.77(s，2H).ESI-MS m/z：153.04[M+H]
2+.
Synthesizing of embodiment 6 compounds 6
The preparation process of present embodiment comprises the steps:
(1) 6-chloro-3-pyridyl aldehyde and the 0.005mol pimelinketone with 0.01mol is dissolved in 8mL 95% ethanol, drips the 10%NaOH of 8ml under the room temperature, and stirring had yellow mercury oxide to separate out in about 5 minutes, and it is complete to react the 25min afterreaction; Suction filtration, washing gets yellow powder, ethyl alcohol recrystallization, the dry light yellow solid powder that gets;
(2) above-mentioned light yellow solid powder and 0.05mol methyl iodide were refluxed 2 hours in the 2mL methyl iodide, cooling, suction filtration, the ether washing, the dry orange powder that gets, namely compound 6, and its chemical formula is suc as formula shown in (XII), and the productive rate of present embodiment is 87%.
1H NMR(400MHz，D
2O)δ8.98(s，2H)，8.80(dd，J＝18.0，6.8，2H)，8.43(d，J＝8.0，2H)，7.41(s，2H)，4.39(s，6H)，3.10(s，4H).ESI-MS m/z：180.04[M+H]
2+.
Synthesizing of embodiment 7 compounds 7
With the compound 2 of embodiment 2 preparation of 0.01mol, heating for dissolving in the 3mL tetramethylene sulfone began to reflux 1.5 hours after adding the 0.1mol methyl iodide, and orange Precipitation is arranged gradually, and it is complete to react 3 hours afterreactions.Suction filtration, ether washing 3 times gets yellow powder, and namely compound 7, and its chemical formula is suc as formula shown in (XIII), and the productive rate of present embodiment is 67%.
1H NMR(400MHz，DMSO)δ9.10(d，J＝15.2，2H)，8.90(d，J＝10.9，2H)，8.16(dd，J＝23.4，7.2，2H)，8.12(s，2H)，7.93(m，4H)，7.28(s，2H)，4.42(s，6H).ESI-MS m/z：228.07[M+H]
2+.
Synthesizing of embodiment 8 compounds 8
With compound 3 heating for dissolving in the 3mL tetramethylene sulfone of embodiment 3 preparation of 0.01mol, began to reflux 2.5 hours after adding the 0.05mol methyl iodide, orange Precipitation is arranged gradually, it is complete to react 6 hours afterreactions; Suction filtration, ether washing 3 times gets yellow powder, and namely compound 8, and its chemical formula is suc as formula shown in (XIV), and the productive rate of present embodiment is 63%.
1H NMR(400MHz，DMSO)δ9.52(d，J＝5.6，2H)，9.34(d，J＝8.4，2H)，8.68(s，2H)，8.57(d，J＝9.2，2H)，8.44(d，J＝9.0，2H)，8.22(dd，J＝8.3，5.8，2H)，7.91(s，2H)，4.66(s，6H)，3.09(d，J＝5.3，4H)，1.94-1.74(m，2H).ESI-MS m/z：203.10[M+H]
2+.
Synthesizing of embodiment 9 compounds 9
The preparation process of present embodiment comprises the steps:
(1) 6-quinoline aldehyde and the 0.005mol 1-methyl-4-piperidone with 0.01mol is dissolved in 8mL 95% ethanol, drips the 10%NaOH of 8ml under the room temperature, and stirring had yellow mercury oxide to separate out in about 20 minutes, and it is complete to react the 45min afterreaction; Suction filtration, washing gets yellow powder, ethyl alcohol recrystallization, the dry light yellow solid powder that gets;
(2) above-mentioned light yellow solid powder and 0.05mol methyl iodide were refluxed 2 hours in the 2mL tetramethylene sulfone, cooling, suction filtration, the ether washing, the dry orange powder that gets, namely compound 9, and its chemical formula is suc as formula shown in (XV), and the productive rate of present embodiment is 71%.
1H NMR(400MHz，D
2O)δ9.15(d，J＝5.6，2H)，9.05(d，J＝8.4，2H)，8.41-8.33(m，4H)，8.25(s，2H)，8.13(d，J＝9.2，2H)，7.96(dd，J＝8.4，5.8，2H)，4.90(s，4H)，4.55(s，6H)，3.11(s，6H).ESI-MS m/z：218.12[M+H]
2+.
Synthesizing of embodiment 10 compounds 10
2-chloro-N-(4-aldehyde radical phenyl) ethanamide and the 0.005mol pimelinketone of 0.012mol are dissolved in the 8mL95% ethanol, and room temperature drips 5ml 10%NaOH, and stirring had yellow mercury oxide to separate out in about 10 minutes under the reflux conditions, and reaction 30min afterreaction is complete; Suction filtration, washing gets yellow powder, and ethyl alcohol recrystallization gets the light yellow solid powder, and namely compound 10, and its chemical formula is suc as formula shown in (XVI), and the productive rate of present embodiment is 65%.
1H NMR(400MHz，DMSO)δ10.80(s，2H)，7.82(dd，J＝28.9，15.6Hz，6H)，7.56(d，J＝8.7Hz，4H)，4.65(s，4H)，4.33(d，J＝8.0Hz，4H)，2.99(d，J＝12.9Hz，4H).ESI-MS m/z：457.09[M+H]
+.
Synthesizing of embodiment 11 compounds 11
3-chloro-N-(4-aldehyde radical phenyl) propionic acid amide and the 0.005mol pimelinketone of 0.01mol are dissolved in the 8mL95% ethanol, drip 5ml 10%NaOH under the room temperature, return stirring had yellow mercury oxide to separate out about 25 minutes, and reaction 50min afterreaction is complete; Suction filtration, washing gets yellow powder, and ethyl alcohol recrystallization gets the light yellow solid powder, and namely compound 11, and its chemical formula is suc as formula shown in (XVII), and the productive rate of present embodiment is 69%.
1H NMR(400MHz，DMSO)δ10.52(s，2H)，7.79(d，J＝8.6，6H)，7.53(d，J＝8.6，4H)，4.60(s，4H)，3.90(t，J＝6.2，4H)，2.98(d，J＝9.1，3H)，2.89(t，J＝6.2，4H).ESI-MS m/z：500.32[M+H]
+.
Synthesizing of embodiment 12 compounds 12
The preparation process of present embodiment comprises the steps:
(1) 3-pyridine aldehydes and the 0.005mol pimelinketone with 0.018mol is dissolved in 8mL 95% propyl alcohol, drips the 10%NaOH of 8ml under the room temperature, and stirring had yellow mercury oxide to separate out in about 20 minutes, and it is complete to react the 35min afterreaction; Suction filtration, washing gets yellow powder, ethyl alcohol recrystallization, the dry light yellow solid powder that gets;
(2) with above-mentioned light yellow solid powder and 0.012mol N, N-dimethyl-1, ice bath stirs in the 3-propylene diamine, adds the TiCl of 2mL triethylamine (utilizing the generation of the alkalescence promotion reaction of triethylamine) and catalytic amount
4, 0 ℃ is reacted half an hour, rises to room temperature, solvent evaporated, and chloroform/methanol (90/10) column chromatography purification, drying obtains pale yellow powder, and namely compound 12, and its chemical formula is suc as formula shown in (XVIII), and the productive rate of present embodiment is 42%.
1H NMR(400MHz，CDCl
3)δ 8.89(s，2H)，8.38(d，J＝15.6Hz，2H)，7.82(d，J＝8.7Hz，2H)，7.54(d，J＝8.0Hz，2H)，6.44(s，2H)，2.90(d，J＝12.9Hz，4H)，2.56(d，J＝8.0Hz，2H)，2.26(s，6H)，1.65(m，4H).ESI-MS m/z：347.45[M+H]
+.
Embodiment 13 1, and the two aryl of 5-replace 2,4-dienone derivative to the restraining effect of growth of tumour cell
Present embodiment selects HL-60 (human leukemia cell line), K562 (human leukemia cell line) and three kinds of tumor cell lines of CA-46 (human lymphoma cell's strain) as subjects, to embodiment 1～12 prepare 1, the two aryl of 5-replace the test that 2,4-dienone derivative carries out the inhibition tumor cell growth.
Adopting mtt assay to carry out the cell in vitro poison measures: the logarithmic phase cell adds 1 of different concns, and the two aryl of 5-replace 2,4-dienone derivative, act on after 48 hours, measure its absorbancy.Compound concentration when calculating respectively cell growth inhibiting and reaching 50% is with IC
50Value representation, the result is as shown in table 1:
Table 11, the two aryl replacement of 5-2,4-dienone derivative is grown to tumor cell line
Restraining effect (IC
50/ μ M)
| The two aryl of 1,5-replace 2,4-dienone derivative | Compound 1 | Compound 2 | Compound 3 | Compound 4 | Compound 5 | Compound 6 | Compound 7 | Compound 8 | Compound 9 | Compound 10 | Compound 11 | Compound 12 |
| HL-60 | 50 | 7 | 50 | 12 | 10 | 10 | 9 | 12 | 16 | 48 | 19 | 29 |
| K562 | 50 | 5 | 8 | 16 | 20 | 8 | 5 | 7 | 18 | 50 | 31 | 34 |
| CA-46 | 50 | 6 | 50 | 50 | 50 | 13 | 10 | 9 | 20 | 50 | 27 | 42 |
As can be seen from Table 1: 12 kinds of compounds of embodiment 1～12 preparation gained all have stronger restraining effect external to three kinds of tumor cell lines, illustrate of the present inventionly 1, and the two aryl of 5-replace 2,4-dienone derivative and can be used for preparing anticancer medicine.
Claims (10)
1. the two aryl of 5-replace 2,4-dienone derivative, and its chemical formula is suc as formula shown in (I):
Wherein,
X is-(CH
2)
n-,-CH
2NHCH
2-,-CH
2N (CH
3) CH
2-,-CH
2N
+(CH
3)
2CH
2-,-CH
2N (CH
2CH
3) CH
2-or-CH
2N
+(CH
2CH
3)
2CH
2-;
Y is compound shown in compound shown in compound, the formula (IV) shown in compound shown in the formula (II), the formula (III) or the formula (V):
Z is O, NH or NR
7
N is 1～4;
R
1Take from C
1-6Alkyl;
R
2Take from H, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, benzyl, nitro or ester group;
R
3Take from halogen, C
1-3Halogen-containing alkyl chain or C
2-8Nitrogenous alkyl group side chain;
R
4Take from H, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, benzyl, nitro or C
1-3Ester group;
R
5Take from C
1-6Alkyl;
R
6Take from H, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, benzyl, nitro or C
1-3Ester group;
R
7Take from C
1-6Alkyl or C
2-8Nitrogenous alkyl group side chain.
2. a claim 1 is described 1, and the two aryl of 5-replace the preparation method of 2,4-dienone derivative, it is characterized in that when formula (I)
Middle Z is O, and Y is formula (III)
Shown in compound or formula (IV)
Shown in during compound, the method comprises the steps:
Aromatic aldehyde and alicyclic ketone or acetone are carried out two aldol reactions, obtain shown in the formula (I) 1, the two aryl of 5-replace 2,4-dienone derivative.
3. a claim 1 is described 1, and the two aryl of 5-replace the preparation method of 2,4-dienone derivative, it is characterized in that when formula (I)
Middle Z is O, and Y is formula (II)
Shown in compound or formula (V)
Shown in during compound, the method comprises the steps:
(1) aromatic aldehyde and alicyclic ketone or acetone are carried out two aldol reactions, obtain suc as formula compound shown in (VI);
(2) with compound shown in the formula (VI) in tetramethylene sulfone after the heating for dissolving, add excess iodine methane, methylation reaction occurs under the reflux state, prepare shown in the formula (I) 1, the two aryl of 5-replace 2,4-dienone derivative.
4. a claim 1 or 3 described 1, the two aryl of 5-replace the preparation method of 2,4-dienone derivative, it is characterized in that when formula (I)
Middle Z is NH or NR
7The time, the method comprises the steps:
(1) aromatic aldehyde and alicyclic ketone or acetone are carried out two aldol reactions, obtain suc as formula (VI)
Shown in compound;
(2) reaction of compound shown in the formula (VI) and amine is generated azomethine, obtain shown in the formula (I) 1, the two aryl of 5-replace 2,4-dienone derivative.
5. according to claim 2,3 or 4 described preparation methods, the molar ratio that it is characterized in that described aromatic aldehyde and alicyclic ketone or acetone is 2～5: 1.
6. according to claim 2,3 or 4 described preparation methods, it is characterized in that in the described pair of aldol reaction adopting mass percent is that 10% sodium hydroxide solution is as catalyzer.
7. according to claim 2,3 or 4 described preparation methods, the reaction times that it is characterized in that described pair of aldol reaction is 5～30 minutes.
8. described preparation method according to claim 3 is characterized in that the molar ratio of compound shown in the described formula (VI) and iodomethane reaction is 1: 2～10.
9. described preparation method according to claim 4 is characterized in that the molar ratio of compound shown in the described formula (VI) and amine reaction is 1: 1.2～3.
10. claim 1 is described 1, and the two aryl of 5-replace the application of 2,4-dienone derivative in the preparation cancer therapy drug.
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