CN1113909A - Chalkone acid compound and its preparation and application as medicine - Google Patents
Chalkone acid compound and its preparation and application as medicine Download PDFInfo
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- CN1113909A CN1113909A CN 94119456 CN94119456A CN1113909A CN 1113909 A CN1113909 A CN 1113909A CN 94119456 CN94119456 CN 94119456 CN 94119456 A CN94119456 A CN 94119456A CN 1113909 A CN1113909 A CN 1113909A
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Abstract
The Chalkone acid compound and its salt indicated by formula 1
R1 and R2 are identical or different in formula, represent hydrogen atom or carbon atom number as the alkyl of 1-5. The compound has excellent antitumor action and induction of differentiation.
Description
The present invention relates to be used to prevent and treat the Chalkone acid compound of malignant tumour, also relate to its preparation method and as the purposes of medicine.
Vitamin A acid and analogue thereof can be used for prevention and treatment malignant tumour, treatment acne, psoriasis and other dermatosis.But as medicine whole body or topical application administration.German Patent No.3434948 and No.3434942, European patent No.2210118 and H.Kagechika etc. are at J.Med.Chem.1988, and the aromatic carboxylic acid of replacements such as 31:2182-2192 has reported vinyl on aromatic nucleus, amido linkage, azo bond, ketenes key or carboxylic acid derivative have the effect of inducing cell differentiation and prevention or treatment dermatosis.And, European patent No.212848 and 211548 and Shudo etc. at Chem.Pharm.Bull.1986, narrated compound among the 34:121 with two-tert.-butylbenzene based structures, they have therapeutic action to asthma, anaphylactic disease and psoriasis etc.
Yet Bao Dao the compound with inducing cell Differentiation all shows the too high disease of Vitamin A so far, and toxicity is stronger, thereby has limited Clinical Application.
The purpose of this invention is to provide analogy compound in the past the better antitumor action and the new compound of induction of differentiation are arranged.
The present invention relates to have the Chalkone acid compound and its esters of formula 1 structure:
R in the formula
1And R
2Identical or different, representing hydrogen atom or carbonatoms is the alkyl of 1-5.
Alkyl among the present invention can be alkyl straight chain or side chain, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group etc.In addition, the salt of The compounds of this invention means acceptable salt on the pharmacology, organic alkali salts such as for example inorganic base salts such as potassium, sodium, magnesium, ammonium, and triethylamine.
Compound of the present invention is to be prepared through condensation reaction in the presence of sodium hydroxide by the benzoylformic acid derivative of formula 2 expressions and the formyl radical benzoic acid derivative shown in the formula 3:
R in the formula
1And R
2Definition ditto described.
The route of administration of compound of the present invention for example can non-per os medication or per os medication.The formulation of non-per os medication can be an injection, and peroral administration formulation for example is a kind of formulation in tablet, granule, capsule, syrup, the suspension agent etc.Used formulation can be selected according to patient's symptom, age and therapeutic purpose.Vehicle commonly used for example has crystalline cellulose, starch, lactose, mannitol etc.; Wedding agent for example has hydroxypropylcellulose, polyvinylpyrrolidone etc.; Lubricant for example has Magnesium Stearate, talcum powder etc.; Disintegrating agent for example has calcium carboxymethylcellulose etc.These preparations can prepare with general conventional method.
Be 0.1-500mg dosage scope every day of adult, can once or divide three administrations.Dosage can be done suitable increase and decrease according to patient's age, body weight and symptom.
Brief description of drawings is as follows:
Fig. 1 is the effect to mouse HL-60 cell and medullary cell (CFU-GM) of all-trans-retinoic acid and chalcone compounds of the present invention.
Fig. 2 is that all-trans-retinoic acid and chalcone compounds of the present invention are respectively to the influence of people's liver cancer Bel-7402 cell alpha-fetoprotein secretory volume.
Fig. 3 is that all-trans-retinoic acid and chalcone compounds of the present invention are respectively to the influence of people's liver cancer Bel-7402 cell albumin secretion amount.
Fig. 4 is that all-trans-retinoic acid and chalcone compounds of the present invention are respectively to people's liver cancer Bel-7402 cell γ-active influence of paddy ammonia transpeptidase.
The present invention is described in further detail below in conjunction with embodiment.
Among the following embodiment, used chemical reagent is all available from Beijing chemical reagent factory, Aldrich and Fluka company, the pharmacological experiment of all uses uses reagent available from SIGMA and GIDCO company, molecular biology with carrier except that the PST72 carrier available from the PROMAGA company, all the other are French professor Chambon and give.The model of used cell flow rate photometer is a PATAX II type, and nuclear magnetic resonance analyser is a JEOL FX-90Q type, and mass spectrograph is the ZAB-2F type.
Embodiment 1
4-[3-(3, the 5-di-tert-butyl-hydroxy phenyl)-3-oxo-1-propenyl] benzoic preparation
3,5-di-tert-butyl-hydroxy phenyl ethyl ketone 4.5g(18.3mmol) and 4-acyl radical methyl benzoate 3.0g(18.3mmol) be dissolved among the anhydrous methanol 100ml, adding exsiccant powdered sodium hydroxide 6.0g, stirring heating refluxed 10 hours.After the reaction solution cooling, add sodium hydroxide 2.0g in the solution of 20ml water, stirring heating refluxed 2 hours.Reaction solution is regulated pH5-6 with hydrochloric acid after cooling off, and removes methyl alcohol under reduced pressure, adds water 100ml in the residuum, stirred 10 minutes, and filter collection solid, dry back alcohol crystal gets this title compound 4.5g, is faint yellow crystallization, mp.222-224 ℃.
Ultimate analysis C
24H
28O
4=380.46
Calculated value (%): C 75.75, and H 7.42
Measured value (%): C 75.73, and H 7.38
1H-NMR（DMSO-d6） δppm：
1.42（s，18H，t-Bu），
7.52-8.00（m，Ar-H）
MS m/e：
380（M
+，30），365（M
+-CH
3，100），233（6）
IR （KBr）ν（cm
-1）：
3620，2969，1780，1755，1605，1570，
1420，1320，1290，1210，845，780
4-[3-(3,5-di-t-butyl-4-p-methoxy-phenyl)-3-oxo-1-propenyl] benzoic preparation
3,5-di-t-butyl-4-p-methoxy-phenyl ethyl ketone 3.0g(11.0mmol) and 4-acyl radical methyl benzoate 1.88g(11.0mmol) be dissolved among the anhydrous methanol 40ml, adding 20% aqueous sodium hydroxide solution 5ml, stirring at room is after 4 hours, and placement is spent the night.Add entry 10ml in the reaction solution, stirred overnight at room temperature is regulated pH7 with hydrochloric acid, removes most of methyl alcohol under reduced pressure, and add hydrochloric acid again and make pH2-3, the solid that the filter collection is separated out, dry back alcohol crystal gets this title compound 3.8g, mp.192-194 ℃.
Ultimate analysis C
25H
30NO
4=394.49
Calculated value (%): C 76.11, and H 7.67
Measured value (%): C 75.75, and H 7.59
MS m/e：
394（M
+，10），378（12），261（50），247（100），149（99）
Embodiment 3
2-[3-(3, the 5-di-tert-butyl-hydroxy phenyl)-3-oxo-1-propenyl] benzoic preparation
3; 5-di-tert-butyl-hydroxy phenyl ethyl ketone 0.65g(2.62mmol) and 2-acyl radical methyl benzoate 0.43g(2.62mmol) according to getting the thick product 0.89g of this title compound with embodiment 1 similar methods; alcohol crystal gets yellow crystal 0.72g, mp.105-106 ℃.
Ultimate analysis C
24H
28O
4=380.46
Calculated value (%): C 75.75, and H 7.42
Measured value (%): C 75.60, and H 6.93
1H-NMR（DMSO-d6） δppm：
1.40（s，18H，t-Bu），
5.38，6.06（m，2H，CH＝CH）
7.68（m，6H，Ar-H）
MS m/e：
380（M
+，67），233（100）
IR （KBr）ν（cm
-1）：
3590，2960，2910，1760，1660，1585，
1420，1350，1230，880，780，745
Inhibited proliferation to human cancer cell
The cell of logarithmic phase is inoculated in 96 orifice plates by 12000/milliliter, abandon substratum next day, change the compound of embodiment 2 preparations that contain different concns and the substratum of coordinative solvent contrast, every group of parallel 3-6 hole, after 37 ℃ of continuation are cultivated 4-5 days, abandon supernatant.Every group adds freshly prepared 0.2mg/ml of containing of 200 μ l and MTT serum free medium, continues to cultivate 4hr.Abandon supernatant gently, add 200 μ l DMSO dissolving MTT first hairpin precipitation, with miniature ultrasonic vibrator vibration mixing.On MR700 type microplate reader, measure the optical density value at 570nm place.Be calculated as follows cell survival rate, and calculate IC
50The results are shown in Table 1.
Tumour cell survival rate=(experimental port measured value)/(control wells measured value) * 100%
Table 1
IC
50mol/L×10
-6
Human ovarian cancer A2780 5.57
People's liver cancer Bel-7402 5.79
Human esophagus cancer CaEs-17 2.42
Human cytomegalovirus lung cancer PLA-801 4.29
Human cytomegalovirus lung cancer PLA-801D 3.94
Human oral cancer KB 4.40
Human colon carcinoma HCT-8 6.45
The human oral cancer KB/VAR200* of anti-vincristine(VCR) the 4.36
The human colon carcinoma HCT-8/VCR2000* of anti-vincristine(VCR) the 1.05
* multidrug resistance cell
To the chondrosarcomatous restraining effect of rat
Get well-grown tumour under the aseptic condition, shred, by dilution in 1: 3, with the 16# needle inoculation in 60-80g Wistar rat oxter, 0.3ml/ only, next day random packet, every group 10, the next day 1 gastric infusion (compounds of embodiment 2 preparations), be administered four times altogether.Put to death animal after 45 days, weigh, knurl is heavy, the result estimates with tumour inhibiting rate.The results are shown in Table 2.
Tumour inhibiting rate=(control group knurl weight-experimental group knurl is heavy)/(the control group knurl is heavy) * 100%
Table 2
Dosage (mg/Kg) tumour inhibiting rate (%)
0.6×4 95.5***
1.2×4 99.3***
＊＊＊P＜0.01
Restraining effect to murine sarcoma S180
Get well-grown tumour under the aseptic condition, shred,, be inoculated in ICR mouse oxter by dilution in 1: 3,0.2ml/ only, next day random packet, 10 every group, the next day 1 gastric infusion, (compounds of embodiment 2 preparations) altogether are administered three times.Put to death animal after ten days, weigh, knurl is heavy, the result estimates with tumour inhibiting rate.The results are shown in Table 3.
Table 3
Dosage (mg/Kg) tumour inhibiting rate (%)
11.8×3 36.5***
5.9×3 32.6***
Embodiment 7
Restraining effect to murine melanoma B16
Get well-grown tumour under the aseptic condition, shred,, be inoculated in C57BL/6 mouse oxter by dilution in 1: 3,0.2ml/ only, next day random packet, 10 every group, gastric infusion (compounds of embodiment 2 preparations), the next day once, be administered three times altogether.Put to death animal after ten days, weigh, knurl is heavy, the result estimates with tumour inhibiting rate.The results are shown in Table 4.
Table 4
Dosage (mg/Kg) tumour inhibiting rate (%)
1×3 20.9*
5×3 58.9**
＊P＞0.05;＊＊P＜0.01
Restraining effect to Mice Bearing Lewis Lung Cancer
Get well-grown tumour under the aseptic condition, shred, by dilution in 1: 3, be inoculated in C57BL/6 mouse oxter, 0.2ml/ only.Next day random packet, 10 every group, gastric infusion (embodiment 2 preparation compounds), the next day once.Put to death animal after ten days, weigh, knurl is heavy, the result estimates with tumour inhibiting rate.The results are shown in Table 5.
Table 5
Dosage (mg/Kg) tumour inhibiting rate (%)
2×3 25.5*
4×3 51***
6×3 65***
Embodiment 9
Selectively acting is observed
HL-60 cell clone rate of formation: adopt double-deck soft agar culture method.In the 31mm plate, behind medicine of adding different concns (being respectively the compound of all-trans-retinoic acid and embodiment 2 preparations) and the coordinative solvent, add the RPNI1640 bottom substratum that contains 0.5% agar and 20% calf serum.The upper strata adds the RPNI1640 substratum that contains 0.3% agar and 1000 viable cell.Put 37 ℃, 5%CO
2And cultivated 10-14 days in the incubator of certain humidity.Counting colony number under 16 * anatomical lens, every group of parallel three wares.
Bone marrow cells in mice CFU-GM measures: get mouse femur under the aseptic condition, take out marrow and make individual cells, in respect of the karyocyte number.In containing the Fischer's substratum of 35% horse serum, add 1%L-glutamin and make reinforcement Fischer's liquid.After 31mm plate bottom adds different concns and is subjected to reagent thing (being respectively the compound of all-trans-retinoic acid and embodiment 2 preparations) and coordinative solvent, add the reinforcement Fischer's liquid that contains 0.5% agar, 1% conditioned medium, make the bottom substratum.The upper strata adds and contains 0.3% agar and 6.6 * 10
4The reinforcement Fischer's liquid of karyocyte, put 37 ℃, 5%CO
2And cultivated 10-14 days in the cultivation box of saturated humidity.Counting colony number under 16 * anatomical lens, every group of parallel three wares.See Fig. 1.
Differentiation-inducing action to the HL-60 cell
Cell and cellular control unit with all-trans-retinoic acid and medicine of the present invention (compounds of embodiment 2 preparations) effect certain hour, the centrifugal 5min of 1000rpm under 4 ℃ of conditions, abandon supernatant, every pipe adds the physiological saline 0.5ml that contains 0.1%NBT, 200ng/ml TPA, puts in 37 ℃ of water-baths and is incubated 1hr.The centrifugal 5hr of 1000rpm gets the cell precipitation smear.Every slide is observed 200 cells under Wright-Giemsa dyeing, the oily mirror, calculates NBT positive cells number.
The result: the differentiation-inducing action and the all-trans-retinoic acid of medicine of the present invention are similar, and 10
-6Mol/L effect 6 days can make the NBT positive rate reach about 90% EC
505.8 * 10
-9Mol/L.
Embodiment 11
Differentiation-inducing action to the NB4 cell
Cell and cellular control unit with medicine (being respectively the compound of all-trans-retinoic acid and embodiment 2 preparations) effect certain hour, the centrifugal 5min of 1000rpm under 4 ℃ of conditions, abandon supernatant, every pipe adds the physiological saline 0.5ml that contains 0.1%NBT, 200ng/ml TPA, puts in 37 ℃ of water-baths and is incubated 1hr.The centrifugal 5hr of 1000rpm gets the cell precipitation smear.Every slide is observed 200 cells under Wright-Giemsa dyeing, the oily mirror, calculates NBT positive cells number.
Result: the EC of The compounds of this invention
50Be 3.9 * 10
-9Mol/L, all-trans-retinoic acid are 2.8 * 10
-9Mol/L.
Embodiment 12
Cancer differentiation-inducing action to people's liver cancer Bel-7402
The mensuration of alpha-fetoprotein (AFP) and albumin (ALB) secretory volume: the liver cancer cell in the vegetative period of taking the logarithm, counting makes 1 * 10
8/ ml is inoculated in the 20ml culturing bottle, dosing next day (being respectively the compound of all-trans-retinoic acid and embodiment 2 preparations), and control group adds coordinative solvent.After continuing to cultivate certain hour, collect supernatant liquor.After the lyophilize, be dissolved among the PBS.Adopt radioimmunology, press the content that AFP and ALB kit method are measured AFP and ALB.Cell with 0.1% trysinization after, expect blue method of exclusion living cell counting number by tire.AFP and ABL result are scaled ng/10
7The results are shown in Figure 2,3.
Gamma glutamyl transpeptidase (γ-GT) determination of activity: will handle the cell and the control cells of certain hour to medicine (being respectively the compound of all-trans-retinoic acid and embodiment 2 preparations), wash twice with PBS after, scrape with Policeman again.After centrifugal,, make homogenate with cell ultrasonication in 0.05M Tris.HCl damping fluid.The centrifugal 8min of 1000 * g gets supernatant and surveys γ-GT vigor.γ-GT vitality test: get 0.25ml matrix damping fluid (10 μ mol/ml, γ glutamy-α that the cell conditioned medium 50 μ l that make join 37 ℃ of preheatings
Amine borate buffer pH9.0), 37 ℃ of temperature are bathed 1hr, add 50 μ l diazo reagents (0.29 aniline sulfonic acid, 0.1% Sodium Nitrite 24: 1) mixing.Control tube adds 50 μ l cell conditioned mediums, diazo reagent, matrix damping fluid 0.25ml mixing.Room temperature was placed after 10 minutes, and photometry density value under the 520nm wavelength returns to zero with control tube.According to α
The amine typical curve is surveyed α
The amine burst size.The result per hour be scaled every mg albumen discharge α-
The nmol number of amine.The results are shown in Figure 4.
Claims (6)
1, Chalkone acid compound and the salt of representing by formula 1 thereof
R in the formula
1And R
2Identical or different, representing hydrogen atom or carbonatoms is the alkyl of 1-5.
2, compound as claimed in claim 1 and salt thereof is characterized in that described compound is 4-[3-(3, the 5-di-tert-butyl-hydroxy phenyl)-3-oxo-1-propenyl] phenylformic acid.
3, compound as claimed in claim 1 and salt thereof is characterized in that described compound is 4-[3-(3,5-di-t-butyl-4-p-methoxy-phenyl)-3-oxo-1-propenyl] phenylformic acid.
4, compound as claimed in claim 1 and salt thereof is characterized in that described compound is 2-[3-(3, the 5-di-tert-butyl-hydroxy phenyl)-3-oxo-1-propenyl] phenylformic acid.
5, a kind of method for preparing chalcone compounds as claimed in claim 1 and salt thereof comprises: will be by the benzoylformic acid derivative of formula 2 expression and the condensation reaction of formyl radical benzoic acid derivative in the presence of sodium hydroxide by formula 3 expressions:
In the formula, R
1, R
2Has definition as hereinbefore.
6, Chalkone acid compound as claimed in claim 1 and salt thereof the application in preparing the medicine that tumour cell is had induction of differentiation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94119456 CN1113909A (en) | 1994-12-16 | 1994-12-16 | Chalkone acid compound and its preparation and application as medicine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94119456 CN1113909A (en) | 1994-12-16 | 1994-12-16 | Chalkone acid compound and its preparation and application as medicine |
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|---|---|
| CN1113909A true CN1113909A (en) | 1995-12-27 |
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ID=5039245
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|---|---|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101485651B (en) * | 2009-03-04 | 2011-01-19 | 中国人民解放军第二军医大学 | Dihydrochalcone derivates and use thereof |
| CN101228872B (en) * | 2008-02-28 | 2011-06-15 | 四川大学 | Uses of chalcone synthesis on agricultural chemical |
| CN104945281A (en) * | 2014-03-31 | 2015-09-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Flavone acetate derivatives, and pharmaceutical composition, preparation method and application thereof |
| CN105017056A (en) * | 2014-04-30 | 2015-11-04 | 中国医学科学院药物研究所 | Phenyl acrylketone derivative and preparation method, drug composition and application thereof |
-
1994
- 1994-12-16 CN CN 94119456 patent/CN1113909A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101228872B (en) * | 2008-02-28 | 2011-06-15 | 四川大学 | Uses of chalcone synthesis on agricultural chemical |
| CN101485651B (en) * | 2009-03-04 | 2011-01-19 | 中国人民解放军第二军医大学 | Dihydrochalcone derivates and use thereof |
| CN104945281A (en) * | 2014-03-31 | 2015-09-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Flavone acetate derivatives, and pharmaceutical composition, preparation method and application thereof |
| CN105017056A (en) * | 2014-04-30 | 2015-11-04 | 中国医学科学院药物研究所 | Phenyl acrylketone derivative and preparation method, drug composition and application thereof |
| CN105017056B (en) * | 2014-04-30 | 2019-02-01 | 中国医学科学院药物研究所 | Phenylpropen ketone derivatives and its preparation method and pharmaceutical composition and purposes |
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