CN102731565A - Water-soluble derivative of diphenylethene compounds, preparation method and usage thereof - Google Patents
Water-soluble derivative of diphenylethene compounds, preparation method and usage thereof Download PDFInfo
- Publication number
- CN102731565A CN102731565A CN201110086659XA CN201110086659A CN102731565A CN 102731565 A CN102731565 A CN 102731565A CN 201110086659X A CN201110086659X A CN 201110086659XA CN 201110086659 A CN201110086659 A CN 201110086659A CN 102731565 A CN102731565 A CN 102731565A
- Authority
- CN
- China
- Prior art keywords
- soluble derivative
- water
- soluble
- derivative
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention belongs to the field of antineoplastic compounds and relates to a water-soluble derivative of diphenylethene compounds, especially a water-soluble derivative of trans-4-[2-(3,5-dimethoxyphenyl)vinyl]-1,2-benzenediol as shown in the formula I, a preparation method and a usage thereof in the preparation of antitumor drugs. The water-soluble derivative of diphenylethene compounds is prepared through water-soluble reconstruction by taking the compound, trans-4-[2-(3,5- dimethoxyphenyl)vinyl]-1,2-benzenediol, as a parent nucleus. Results of in vitro antineoplastic tests show that the water-soluble derivative of diphenylethene compounds has significant effects in inhibiting brain glioma cells SF188 and U87wt, breast cancer cells MCF-7wt and large cell lung cancer cells H460. The activity of the cells decreases along with the increase of drug concentration. The derivative disclosed by the invention is an effective antitumor agent and further, the derivative can be used for preparing the antitumor drugs.
Description
Technical field
The invention belongs to the antineoplastic compound field; The soluble derivative that relates to a kind of diphenylethylene compounds; Relate in particular to trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1,2-Benzenediol soluble derivative and preparation method thereof and the purposes in the preparation antitumor drug.
Background technology
It is reported that the whole world has more than 600 ten thousand people to die from various cancers every year at present, new cases 8,000,000, these data are also increasing year by year.There is 1,000,000 New Development cancer patients every year in China, and it is about 2,000,000 to wait to treat patient, and death exceedes 1,000,000, and cancer has become first cause of the death.Therefore, research preparation antitumor drug becomes the focus of biomedicine field.
There is research from pulse family darling pea plant swainson pea (Sphaerophysa salsula (Pall.) DC.), to separate to obtain compound trans-4-that [2-(3; The 5-Dimethoxyphenyl) vinyl]-1; The 2-Benzenediol; The results showed that it has obvious antineoplastic, and (ZL 200710041994.1, ZL200710041995.6); But; Use practice to show since this compound it is water-soluble more weak, receive the restriction of the characteristic of this compound own; In drug development, application, obviously increase cost; Therefore, be necessary to research and develop verivate, be beneficial to its application in the field of medicine with water miscible this compounds.
Summary of the invention
The object of the present invention is to provide a kind of new compound with anti-tumor activity; Be specifically related to a kind of soluble derivative of diphenylethylene compounds; Relate in particular to trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1,2-Benzenediol soluble derivative.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
Another object of the present invention is to provide above-claimed cpd to exist
PreparationIn the antitumor drug
Purposes.
The invention provides a kind of soluble derivative of diphenylethylene compounds, this compound is Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1, and the soluble derivative of 2-Benzenediol has the structure of formula I:
（Ⅰ）
Wherein, R and
are water soluble group
Described water soluble group is selected from SULPHOSUCCINIC ACID ESTER sodium, ammonium salt or carboxylate salt.
On the other hand, the invention provides the preparation method of above-claimed cpd, the present invention is with compound Trans-4-[2-(3, the disubstituted basic phenyl of 5-) vinyl]-1, and the 2-Benzenediol is that parent nucleus carries out water-soluble transformation; Be example with the phosphoric acid ester sodium in one embodiment of the present of invention, it comprises step: by following synthetic route,
With trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1, the 2-Benzenediol is a raw material, prepares the phosphinylidyne dihalo-earlier, makes the soluble derivative of diphenylethylene compounds then,
1)
2)
Wherein R is: a. fatty alkyl, b. haloalkyl;
Described fatty alkyl is selected from CH
3CH
2-, (CH
3)
3C-, (CH
3)
2CH-;
Described haloalkyl is selected from CH
2ClCH
2-, (CH
3)
2CCl-etc.
The present invention carries out antitumor activity in vitro with mtt assay; The result shows; The soluble derivative of diphenylethylene compounds of the present invention has the obvious suppression effect to tumor cell line SF188 (brain glioblastoma cell), U87wt (brain glioblastoma cell), MCF-7wt (breast cancer cell), H460 (maxicell lung carcinoma cell); After the dosing, cytoactive reduces along with the increase of drug level.
Diphenylethylene compounds soluble derivative of the present invention is the effective antitumour agent.
The cell strain that the present invention's test is adopted is all available from Shanghai cell biological institute of the Chinese Academy of Sciences.
Further, compound of the present invention can be used for preparing antitumor drug.Described tumour comprises cancer of the stomach, brain tumor, lung cancer, liver cancer, mammary cancer, prostate cancer, carcinoma of the pancreas, cervical cancer or leukemia, or the like.
Compound of the present invention can combine to process antitumor drug with pharmaceutical carrier commonly used on commercially available or the pharmaceutics, is used for prevention or treats tumour and cancer.Described medicine can be processed tablet or injection.
Compound of the present invention when in treatment, using (administration), can provide different effects.Usually; Can these materials be formulated in nontoxic, inert and the pharmaceutically acceptable aqueous carrier medium, be mixed with pharmaceutical composition, wherein pH is about 5-8 usually; Preferable pH is about 6-8, although the pH value can change with being prepared Substance Properties and illness to be treated to some extent; The pharmaceutical composition for preparing can carry out administration through conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, intracutaneous or topical.
With compound of the present invention is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This type pharmaceutical composition contains compound and the pharmaceutically acceptable carrier or the vehicle of treating significant quantity.This type carrier comprises (but being not limited to): salt solution, damping fluid, glucose, water, glycerine, ethanol and combination thereof.Pharmaceutical prepn should be complementary with administering mode.Compound of the present invention can be made into the injection form, for example prepares through ordinary method with the saline water or the aqueous solution that contains glucose and other assistant agents.Pharmaceutical composition such as tablet and capsule can prepare through ordinary method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of activeconstituents is the treatment significant quantity, for example every day 1 μ g/kg body weight-Yue 2000mg/kg body weight.In addition, compound of the present invention also can use with the other treatment agent.
In the application of compound of the present invention in the preparation antitumor drug, can be injection or tablet.
When compound of the present invention is used as medicine; Can be with this compound administration of treating effective dose in Mammals; Wherein should treat effective dose usually at least about 1 microgram/kg body weight; And in most of the cases be no more than about 10 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 5 mg/kg body weight.Certainly, concrete dosage is factor such as considered route of administration, patient health situation also, and these all are within the skilled practitioners skill.
Among the present invention, utilize described compound,, can filter out with diphenylethylene compounds interactional material takes place, like acceptor, suppressor factor or antagonist etc. through various conventional screening methods.
The present invention has following advantage:
1, diphenylethylene compounds soluble derivative of the present invention can overcome the water-soluble more weak defective that prior art exists, and obviously reduces the cost in drug development, the application.
2, diphenylethylene compounds soluble derivative of the present invention has the obvious suppression effect to kinds of tumor cells, is the effective antitumour agent.
3, the present invention carries out water-soluble modification with cheap, common reagent to fat-soluble diphenylethylene compounds monomer, and the preparation method is simple and reliable, and cost is low, and efficient is high, can carry out industrialized production, helps applying.
Below content of the present invention is done further detailed explanation through concrete embodiment and accompanying drawing.But should embodiment be interpreted as limitation of the present invention.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacement means or change according to ordinary skill knowledge and conventional means are made all should be included within the present invention.
Description of drawings
Fig. 1 is Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1, the antitumor activity in vitro result of the soluble derivative of 2-Benzenediol.
Embodiment
Embodiment 1
Preparation Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1,2-Benzenediol organic phosphate disodium salt
With (uncle's O-fourth)-Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1,2-Benzenediol SULPHOSUCCINIC ACID ESTER 10 g, methyl alcohol 100 mL add in the reaction flask of 500 mL; It is an amount of to feed the exsiccant hydrogen chloride gas, is warming up to 40-50 degree reaction 24 hours, filters removal of solvent under reduced pressure; Product is used acetone recrystallization, gets the SULPHOSUCCINIC ACID ESTER of compound, filters drying; With NaOH salify in methyl alcohol of 2 M, filter, add acetone and separate out white solid, dry that product 6.1 restrains.The gained compound carries out nuclear magnetic resonance spectroscopy, and the result is as shown in table 1.
Table 1 Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1, the nuclear magnetic resonance data of 2-Benzenediol organic phosphate disodium salt
(
1H NMR 500 MHz,
13C NMR 500 MHz are at CDCl
3In)
| Sequence number | δ H | δ C |
| 1 | ? | 138.6 |
| 2 | ? | 139.7 |
| 3 | 6.70 (d，J=2.0 Hz) | 113.6 |
| 4 | ? | 129.4 |
| 5 | 6.88 (br. d，J=9.0 Hz) | 120.4 |
| 6 | 6.61 (d，J=9.0 Hz) | 117.7 |
| α | 7.04(d，J=17.0 Hz) | 127.5 |
| β | 6.91(d，J=17.0 Hz) | 126.9 |
| 1' | ? | 137.1 |
| 2' | 6.44 (2H，d，J=2.2 Hz，H-2'，6') | 102.9 |
| 3' | ? | 161.6 |
| 4' | 6.27 (t，J=2.2 Hz) | 99.6 |
| 5' | ? | 161.4 |
| 6' | ? | 102.3 |
| 2-OCH 3 | ? | ? |
| 3'，5'-OCH 3 | 3.75 (6H，s) | 55.7 |
Embodiment 2 Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1, the extracorporeal anti-tumor function test of 2-Benzenediol organic phosphate disodium salt
The take the logarithm every hole 3 * 10 of cell of phase
4Be inoculated on 96 orifice plates, behind the 12h, abandon supernatant; Click the grouping administration: normal control group and dosing group (concentration 0-100 μ M), establish 6 multiple holes, cultivate 24h for every group; Abandon supernatant, the nutrient solution 50 μ l that add band MTT cultivate 4h (0.5 mg/mL), add 100 μ l DMSO; Vibration 1h, 570 nm places survey the OD value on ELIASA.
The result shows that after the dosing, cytoactive obviously descends, and cytoactive reduces along with the increase of drug level.IC50 to SF188 (brain glioblastoma cell), HGC-27 (stomach cancer cell), MCF-7wt (breast cancer cell), H460 (maxicell lung carcinoma cell) (cell strain is all available from Shanghai cell biological institute of the Chinese Academy of Sciences) cell is respectively 0.67 μ M, 0.89 μ M, 1.17 μ M and 0.94 μ M.
Claims (8)
1. the soluble derivative of the diphenylethylene compounds of formula I structure,
（Ⅰ）
Wherein, R and
are water soluble group
Described water soluble group is selected from SULPHOSUCCINIC ACID ESTER sodium, ammonium salt or carboxylate salt.
2. by the soluble derivative of the described diphenylethylene compounds of claim 1, it is characterized in that described water soluble group is selected from phosphoric acid ester sodium.
3. by the soluble derivative of the described diphenylethylene compounds of claim 1, it is characterized in that described soluble derivative is Trans-4-[2-(3, the 5-Dimethoxyphenyl) vinyl]-1,2-Benzenediol organic phosphate disodium salt.
4. the preparation method of the soluble derivative of the diphenylethylene compounds of claim 1 is characterized in that, it comprises step: by following synthetic route; [2-(3 with trans-4-; The 5-Dimethoxyphenyl) vinyl]-1, the 2-Benzenediol is a raw material, earlier preparation phosphinylidyne dihalo-; Make the soluble derivative of diphenylethylene compounds then
1)
；
2)
Wherein R is: fatty alkyl or haloalkyl.
5. by the method for claim 4, it is characterized in that described fatty alkyl is selected from CH
3CH
2-, (CH
3)
3C-, (CH
3)
2CH-.
6. by the method for claim 4, it is characterized in that described haloalkyl is selected from CH
2ClCH
2-, (CH
3)
2CCl-.
7. the soluble derivative of the diphenylethylene compounds of claim 1 is in the purposes of preparation in the antitumor drug.
8. by the described purposes of claim 7, it is characterized in that described tumour is a cancer of the stomach, brain tumor, lung cancer, liver cancer, mammary cancer, prostate cancer, carcinoma of the pancreas, cervical cancer or leukemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110086659.XA CN102731565B (en) | 2011-04-07 | A kind of soluble derivative of diphenylethylene compounds and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110086659.XA CN102731565B (en) | 2011-04-07 | A kind of soluble derivative of diphenylethylene compounds and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102731565A true CN102731565A (en) | 2012-10-17 |
| CN102731565B CN102731565B (en) | 2016-12-14 |
Family
ID=
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214354A (en) * | 2013-04-28 | 2013-07-24 | 上海大学 | Preparation method of trans-stilbene compound and water-soluble derivative of compound |
| CN103408591A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Pterostilbene phosphate disodium salt synthesis method |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| WO1999035150A1 (en) * | 1998-01-09 | 1999-07-15 | Arizona Board Of Regents, A Body Corporate, Acting On Behalf Of Arizona State University | Synthesis of combretastatin a-4 prodrugs and trans-isomers thereo f |
| CN1526713A (en) * | 2003-09-18 | 2004-09-08 | 雍智全 | Combretastatin A-4 as phosphorylcholine precursor medicine and its synthesis and application |
| CN1737004A (en) * | 2005-04-06 | 2006-02-22 | 西南合成制药股份有限公司 | Combretastatin compound preparation method |
| CN1749261A (en) * | 2005-10-18 | 2006-03-22 | 天津大学 | Prosome compound water soluble salicylamide ammonium phosphate of CA4 and synthetic method |
| CN1807435A (en) * | 2006-02-23 | 2006-07-26 | 中国科学院广州化学研究所 | Water soluble phosphate ester salt of(Z)-3'-hydroxy-3,4',5-trimethoxydiphenyl ethylene, and its preparation method ,pharmaceutical composition and uses |
| CN101070328A (en) * | 2007-06-15 | 2007-11-14 | 中国科学院广州化学研究所 | (E)3,5-di-methoxy-diphenylene-4'-0-phosphates (salt) and its preparing method, medicine composition and use |
| CN101070274A (en) * | 2007-06-14 | 2007-11-14 | 复旦大学 | Diphenylethene compound with anti-tumor activity and preparing method |
| CN101070273A (en) * | 2007-06-14 | 2007-11-14 | 复旦大学 | Anti-tumor compound trans-4-[2-(3,5,-dimethoxyphenyl) vinyl]-1,2-xyyl alcohol and preparing method therefor |
| CN101073561A (en) * | 2007-06-22 | 2007-11-21 | 中山大学 | Use of compound with structure similia combretastatin A4 in preparation medicine for inhibiting tubulin polymerization or treating tumor |
| CN101186620A (en) * | 2007-10-19 | 2008-05-28 | 中国科学院广州化学研究所 | Method for preparing phosphate of toluylene compounds containing phenol hydroxyl group |
| CN101220054A (en) * | 2008-01-29 | 2008-07-16 | 成都恒基医药科技有限公司 | Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt |
| CN101323626A (en) * | 2007-06-12 | 2008-12-17 | 成都恒基医药科技有限公司 | Novel synthetic method of anticancer medicine |
| CN101691384A (en) * | 2008-10-08 | 2010-04-07 | 深圳海王药业有限公司 | Phosphate-containing toluylene compound, preparation method thereof and use thereof |
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| WO1999035150A1 (en) * | 1998-01-09 | 1999-07-15 | Arizona Board Of Regents, A Body Corporate, Acting On Behalf Of Arizona State University | Synthesis of combretastatin a-4 prodrugs and trans-isomers thereo f |
| CN1526713A (en) * | 2003-09-18 | 2004-09-08 | 雍智全 | Combretastatin A-4 as phosphorylcholine precursor medicine and its synthesis and application |
| CN1737004A (en) * | 2005-04-06 | 2006-02-22 | 西南合成制药股份有限公司 | Combretastatin compound preparation method |
| CN1749261A (en) * | 2005-10-18 | 2006-03-22 | 天津大学 | Prosome compound water soluble salicylamide ammonium phosphate of CA4 and synthetic method |
| CN1807435A (en) * | 2006-02-23 | 2006-07-26 | 中国科学院广州化学研究所 | Water soluble phosphate ester salt of(Z)-3'-hydroxy-3,4',5-trimethoxydiphenyl ethylene, and its preparation method ,pharmaceutical composition and uses |
| CN101323626A (en) * | 2007-06-12 | 2008-12-17 | 成都恒基医药科技有限公司 | Novel synthetic method of anticancer medicine |
| CN101070274A (en) * | 2007-06-14 | 2007-11-14 | 复旦大学 | Diphenylethene compound with anti-tumor activity and preparing method |
| CN101070273A (en) * | 2007-06-14 | 2007-11-14 | 复旦大学 | Anti-tumor compound trans-4-[2-(3,5,-dimethoxyphenyl) vinyl]-1,2-xyyl alcohol and preparing method therefor |
| CN101070328A (en) * | 2007-06-15 | 2007-11-14 | 中国科学院广州化学研究所 | (E)3,5-di-methoxy-diphenylene-4'-0-phosphates (salt) and its preparing method, medicine composition and use |
| CN101073561A (en) * | 2007-06-22 | 2007-11-21 | 中山大学 | Use of compound with structure similia combretastatin A4 in preparation medicine for inhibiting tubulin polymerization or treating tumor |
| CN101186620A (en) * | 2007-10-19 | 2008-05-28 | 中国科学院广州化学研究所 | Method for preparing phosphate of toluylene compounds containing phenol hydroxyl group |
| CN101220054A (en) * | 2008-01-29 | 2008-07-16 | 成都恒基医药科技有限公司 | Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt |
| CN101691384A (en) * | 2008-10-08 | 2010-04-07 | 深圳海王药业有限公司 | Phosphate-containing toluylene compound, preparation method thereof and use thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214354A (en) * | 2013-04-28 | 2013-07-24 | 上海大学 | Preparation method of trans-stilbene compound and water-soluble derivative of compound |
| CN103408591A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Pterostilbene phosphate disodium salt synthesis method |
| CN103408591B (en) * | 2013-07-17 | 2016-04-20 | 张家港威胜生物医药有限公司 | A kind of synthetic method of Pterostilene organic phosphate disodium salt |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102146081B (en) | Indoleacetic acid derivatives and preparation method and application thereof | |
| CN108484699B (en) | Bipyridine alkaloid, preparation method and application thereof | |
| CN102532235A (en) | Bufogenin derivative and preparation method thereof, composition containing bufogenin derivative and applications thereof | |
| CN108440583A (en) | A kind of new boronic acid derivatives and its pharmaceutical composition | |
| CN114516857A (en) | HPK1 inhibitors and uses thereof | |
| CN107001302B (en) | Water-soluble taxane derivatives and application thereof | |
| CN108836937A (en) | Cisplatin nano pharmaceutical preparation, preparation method and application | |
| US20180085344A1 (en) | Method of use of diterpenoid derivatives as anticancer agents | |
| CN110922415B (en) | Synthesis and application of novel anti-tumor active compound | |
| CN106631957A (en) | Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof | |
| CN113329745A (en) | Pharmaceutical composition for effectively resisting malignant tumor and application thereof | |
| CN104892580A (en) | Novel benzimidazole-pyrilamine derivative and application thereof | |
| WO2018058863A1 (en) | Use of polyether compounds | |
| CN102731565A (en) | Water-soluble derivative of diphenylethene compounds, preparation method and usage thereof | |
| CA2966709C (en) | Cytidine derivative dimers and applications thereof | |
| CN103242363B (en) | Florfenicol phosphodiester and salt and preparation method thereof | |
| US20160102066A1 (en) | Benzothiazole derivative and anti-tumor use thereof | |
| CN101590035B (en) | Application of dehydrogenated silybin in preparing anti-lung-cancer medicament | |
| CN102731565B (en) | A kind of soluble derivative of diphenylethylene compounds and its production and use | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN102775596B (en) | D51-7059 and its production and use | |
| CN110590778A (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and application thereof, and pharmaceutical composition | |
| GB2494595A (en) | Phenylbutyryl curcumin derivatives and uses for preparing anti-tumor drugs thereof | |
| EP2776413A1 (en) | TREATMENT OF OVARIAN CANCER WITH 2-AMINO-4H-NAPHTHO[1,2-b]PYRAN-3-CARBONITRILES | |
| CN115073481B (en) | Furana quebracho base dimer or pharmaceutically acceptable salt thereof, and preparation method and application thereof, and pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20161214 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |