CN100363370C - Prosome compound water soluble salicylamide ammonium phosphate of CA4 and synthetic method - Google Patents
Prosome compound water soluble salicylamide ammonium phosphate of CA4 and synthetic method Download PDFInfo
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- CN100363370C CN100363370C CNB2005100154903A CN200510015490A CN100363370C CN 100363370 C CN100363370 C CN 100363370C CN B2005100154903 A CNB2005100154903 A CN B2005100154903A CN 200510015490 A CN200510015490 A CN 200510015490A CN 100363370 C CN100363370 C CN 100363370C
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Abstract
The present invention discloses a water-soluble salicylamide ammonium phosphate of a precursor compound of a CA4 and a synthesis method for the salicylamide ammonium phosphate, which belongs to the technical field of the preparation of CA4 derivatives. The structure of the compound is shown in formula I, and the synthesis method comprises that: the cis-CA4 and 2-chloro-5, 6-benzo-1, 3, 2-dioxaphosphorinane-2, 4-dione are added into benzene or toluene according to a molar ratio, and pyridine is dripped into the benzene or the toluene by stirring; silica gel column chromatography is carried out on reaction solution which is concentrated, and 2-{2-methoxyl-5-[(Z)-2-(3, 4, 5-trimethoxyphenyl) vinyl]phenoxyl}-5, 6-benzo-1, 3, 2-dioxaphosphorinane-2, 4-dione is obtained after the reaction solution is dried; after that the compound is dissolved by using the toluene, etc., and is filled with ammonia at room temperature to react, and a precipitate is precipitated out, and is filtered so as to obtain the compound shown in formula I. The present invention has the advantages that preparation process is relatively simple, and the prepared compound has favorable dissolubility; meanwhile, salicylamide which has an analgesic effect and has no toxic and side effect is generated when the compound is decomposed. The compound exists in the forms of a tablet shape, a capsule shape, a pill shape and an injection, and has a great prospect of medicine development.
Description
Technical field
The present invention relates to precursor compound water soluble salicylamide ammonium phosphate salt and the synthetic method of CA4, belong to the derivative technology of preparing of CA4.
Background technology
Cancer has become common frequently-occurring disease in the world, and annual new cases estimate at 6,350,000, and the whole world year death toll is up to 6,000,000, and sickness rate still presents the trend of rising.In China, relevant statistics shows, recent years, the cancer mortality people several years has become one of human main diseases cause of the death up to 1,000,000 examples.This shows that cancer is greatly endangering human existence health, capture cancer and be the whole world faces a difficult problem and urgent task.
Pharmacological agent is one of three big therapies of cancer therapy.In recent years, all kinds of cancer therapy drugs competitively come out, and make cancer therapy obtain certain change clinically, but still are faced with formidable challenges.Scientific research finds that growth of tumor is that blood vessel is dependent.Seek novel growth inhibitor for tumor vessels, become the new way of current tumor research and searching medicine.
Have now found that diphenylethylene compounds CombretastatinA4 (CA4) (United States Patent (USP), Feb, 22,1988 of extraction separation in the Combretum caffrum trunk of South Africa; 4,996,237) have anti-tumor activity, it directly acts on endotheliocyte, induces the endothelial cell apoptosis of propagation, thereby suppresses tumor vascular generation.But,, its clinical application is very restricted because this compound water soluble is very poor.Therefore,, seek and a kind ofly can improve that it is water-soluble, do not reduce its active derivative again and seem particularly urgent by a series of structure of modification.CA4 is found so far, and its multiple derivative occurs in succession.Typically for example, CA4 phosphate derivative CA4P (United States Patent (USP), Jul, 23,1993; 5,561,122), CA4P is rapid in vivo, and dephosphorylation generates CA4, and be 30min plasma half-life, and its anti-tumor in vivo activity improves greatly.By studies confirm that, CA4P can suppress to provide for cancer cells the growth of the vascular tissue of nutrient, but it can not destroy normal blood vessels.The CA4P not only research aspect tumour obtains the progress of application, the also progress of making a breakthrough property aspect the abnormal vascular formation under the various ophthalmic diseases situations of treatment, the newtype drug .OXiGENE that might become the treatment proliferative retinopathy has finished CA4P in the II at US and European three centers phase clinical study.But discover that there is side effect in it is to cause having an intense pain of patient's lump.
The phosphatic patent of similar CA4 (Chinese patent 01803140) is also arranged at home.In addition, domestic patent application also reported CA4 Phosphorylcholine class a series of prodrugs (application number 03135840.3) though. their greatest drawback of existing of solubility problem that all these effort have solved natural CA4 are lump pain violent can not alleviate cancer and send out the time.
Summary of the invention
The invention provides precursor compound water soluble salicylamide ammonium phosphate salt and the synthetic method of a kind of CA4, the precursor compound of this CA4 has improved the solvability of natural CA4 greatly, and its preparation process is simple relatively.
The present invention realizes by following technical proposals, and the precursor compound water soluble salicylamide ammonium phosphate salt of a kind of CA4 is characterized in that structure is shown in the formula I:
The synthetic method of the compound of said structure is characterized in that comprising following process:
1. with compound (2-chloro-5 shown in cis-CA4 and the II formula, the 6-phendioxin, 3,2-dioxy phospha hexamethylene-2, the 4-diketone) be 1: 1～5 to join in anhydrous benzene or the toluene in molar ratio, stir down at-5～25 ℃, drip and 2-chloro-5 the 6-phendioxin, 3,2-dioxy phosphorus heterocycle-2, the equimolar anhydrous pyridine of 4-diketone reacted 2～10 hours.Reaction solution is that 3: 2 eluent carries out silica gel column chromatography with anhydrous sherwood oil and ethyl acetate volume ratio, concentrate, obtain (the 2-{2-methoxy-5-[(Z)-2-(3 of the compound shown in the III formula after the drying, 4, the 5-trimethoxyphenyl) vinyl] phenoxy group }-5,6-phendioxin, 3,2-dioxy phospha hexamethylene-2, the 4-diketone).
2. use toluene, acetone, ether or methylene dichloride with compound dissolution shown in the III formula, after at room temperature logical exsiccant ammonia made it fully reaction in 1～10 minute, there is precipitation to separate out, filter, (the O-(2-carboxamide phenyl)-O '-{ 2-methoxy-5-[(Z)-2-(3 of compound shown in the I formula, 4, the 5-trimethoxyphenyl) vinyl] phenyl } ammonium phosphate).
The present invention compared with prior art has following advantage: preparation process is simple relatively, and prepared compound has good solubility, produces the salicylic amide that has pain relieving and have no side effect simultaneously when decomposing, and salicylic amide is the anodyne of including on the pharmacopeia.Just because of this compound has above characteristics, so, compound shown in the I formula of the present invention (O-(2-carboxamide phenyl)-O '-the 2-methoxy-5-[(Z)-2-(3,4, the 5-trimethoxyphenyl) vinyl] phenyl } ammonium phosphate) have great drug development prospect, this compound exists with the form of its sheet, capsule, ball shape, injection injection.
Embodiment
Embodiment one
1.III compound shown in the formula is synthetic: with 1.00g cis-CA4, compound shown in the 1.04g II formula and 15ml dry-out benzene place the exsiccant reaction flask, stir in ice-water bath, drip the 0.38ml anhydrous pyridine, after 2 hours, reaction is finished.With anhydrous sherwood oil and ethyl acetate volume ratio is that 3: 2 eluent carries out silica gel column chromatography, concentrate, after the drying compound 1.18g shown in the III formula, productive rate is 74.6%.Its corresponding spectral data is as follows: IR (KBr, cm
-1): 3030,2925,2853,1780,1577,1459,1116,991,953;
1HNMR (CDCl
3, ppm): 3.72 (s, 9H), 3.84 (s, 3H), 6.47 (m, 4H), 6.79 (d, J=9.0,1H), 7.11 (d, J=9.0,1H), 7.23 (m, 2H), 7.38 (m, 1H), 7.75 (t, 1H), 8.12 (d, J=2.0,1H).
2.I compound shown in the formula is synthetic: compound shown in the 1.00g III formula and 10ml dry toluene are placed the exsiccant reaction flask, and logical exsiccant ammonia reacted after 5 minutes, separated out precipitation, filtered, and got Compound I 1.05g, productive rate 98.3% after the drying.Its corresponding spectral data is as follows: IR (KBr, cm
-1): 3176,2960,2839,1662,1609,1580,1510,1455,1296,1238,1124,1096,904;
1HNMR (DMSO-d
6, ppm): 3.61 (s, 6H), 3.62 (s, 3H), 3.67 (s, 3H), 6.39 (d, J=12.5,1H), 6.45 (d, J=12.5,1H), 6.53 (s, 2H), 6.87～7.78 (m, 8H).
Embodiment two
1.III compound shown in the formula is synthetic: with 1.00g cis-CA4, compound shown in the 1.73g II formula and 15ml dry-out benzene place the exsiccant reaction flask, stirring at room drips the 0.63ml anhydrous pyridine, and after 1.5 hours, reaction is finished.With anhydrous sherwood oil and ethyl acetate volume ratio is that 3: 2 eluent carries out silica gel column chromatography, concentrate, after the drying compound 1.20g shown in the III formula, productive rate is 75.9%.Corresponding spectral data is with shown in the embodiment one.
2.I compound shown in the formula is synthetic: compound shown in the 1.00g III formula and 10ml dry toluene are placed the exsiccant reaction flask, and logical exsiccant ammonia reacted after 5 minutes, separated out precipitation, filtered, and drying gets Compound I 1.052g, productive rate 99.0%.Corresponding spectral data is with shown in the embodiment one.
Embodiment three
1.III compound shown in the formula is synthetic: with 1.00g cis-CA4, compound shown in the 2.08g II formula and 15ml dry toluene place the exsiccant reaction flask, stir in ice-water bath, drip the 0.75ml anhydrous pyridine, after 1.5 hours, reaction is finished.With anhydrous sherwood oil and ethyl acetate volume ratio is that 3: 2 eluent carries out silica gel column chromatography, concentrate, after the drying compound 1.21g shown in the III formula, productive rate is 76.5.%.Corresponding spectral data is with shown in the embodiment one.
2.I compound shown in the formula is synthetic: compound shown in the 1.00g III formula and 10ml anhydrous methylene chloride are placed the exsiccant reaction flask, and logical exsiccant ammonia reacted after 5 minutes, separated out precipitation, filtered, and got Compound I 1.04g, productive rate 97.4% after the drying.Corresponding spectral data is with shown in the embodiment one.
Embodiment four
1.III compound shown in the formula is synthetic: with 1.00g cis-CA4, compound shown in the 1.38g II formula and 15ml dry toluene place the exsiccant reaction flask, stirring at room drips the 0.50ml anhydrous pyridine, and after 1.5 hours, reaction is finished.With anhydrous sherwood oil and ethyl acetate volume ratio is that 3: 2 eluent carries out silica gel column chromatography, concentrate, after the drying compound 1.22g shown in the III formula, productive rate is 77.2%.Corresponding spectral data is with shown in the embodiment one.
2.I compound shown in the formula is synthetic: compound shown in the 1.00g III formula and 10ml anhydrous methylene chloride are placed the exsiccant reaction flask, and logical exsiccant ammonia reacted after 5 minutes, separated out precipitation, filtered, and got Compound I 1.04g, productive rate 97.4% after the drying.Corresponding spectral data is with shown in the embodiment one.
Embodiment five
1.III compound shown in the formula is synthetic: with 1.00g cis-CA4, compound shown in the 1.38g II formula and 15ml dry-out benzene place the exsiccant reaction flask, stir in ice-water bath, drip the 0.50ml anhydrous pyridine, after 2 hours, reaction is finished.With anhydrous sherwood oil and ethyl acetate volume ratio is that 3: 2 eluent carries out silica gel column chromatography, concentrate, after the drying compound 1.17g shown in the III formula, productive rate is 74.0%.Corresponding spectral data is with shown in the embodiment one.
2.I compound shown in the formula is synthetic: compound shown in the 1.00g III formula and 10ml anhydrous diethyl ether are placed the exsiccant reaction flask, and logical exsiccant ammonia reacted after 5 minutes, separated out precipitation, filtered, and drying gets Compound I 1.03g, productive rate 96.4%.Corresponding spectral data is with shown in the embodiment one.
Embodiment six
1.III compound shown in the formula is synthetic: with 1.00g cis-CA4, compound shown in the 1.38g II formula and 15ml dry-out benzene place the exsiccant reaction flask, stirring at room drips the 0.50ml anhydrous pyridine, and after 2 hours, reaction is finished.With anhydrous sherwood oil and ethyl acetate volume ratio is that 3: 2 eluent carries out silica gel column chromatography, concentrate, after the drying compound 1.18g shown in the III formula, productive rate is 75.6%.Corresponding spectral data is with shown in the embodiment one.
2.I compound shown in the formula is synthetic: compound shown in the 1.00g III formula and 10ml anhydrous propanone are placed the exsiccant reaction flask, and logical exsiccant ammonia reacted after 5 minutes, separated out precipitation, filtered, and drying gets Compound I 1.02g, productive rate 95.5%.Corresponding spectral data is with shown in the embodiment one.
Claims (2)
1. the precursor compound water soluble salicylamide ammonium phosphate salt of a CA4 is characterized in that structure is shown in the formula I:
Me represents methyl in the formula.
2. synthetic method by the described compound of claim 1 is characterized in that comprising following process:
1). with cis-CA4 and 2-chloro-5,6-phendioxin, 3,2-dioxy phospha hexamethylene-2, the 4-diketone is 1: 1～5 to join in anhydrous benzene or the toluene in molar ratio, stirs down at-5～25 ℃, drips and 2-chloro-5, the 6-phendioxin, 3,2-dioxy phospha hexamethylene-2, the equimolar anhydrous pyridine of 4-diketone, reacted 2～10 hours, reaction solution is that 3: 2 eluent carries out silica gel column chromatography with anhydrous sherwood oil and ethyl acetate volume ratio, concentrates, and obtains 2-{2-methoxy-5-[(Z)-2-(3 after the drying, 4, the 5-trimethoxyphenyl) vinyl] phenoxy group }-5,6-phendioxin, 3,2-dioxy phospha hexamethylene-2, the 4-diketone;
2). with toluene, acetone, ether or methylene dichloride with 2-{2-methoxy-5-[(Z)-2-(3,4, the 5-trimethoxyphenyl) vinyl] phenoxy group-5, the 6-phendioxin, 3,2-dioxy phospha hexamethylene-2, the dissolving of 4-diketone, after at room temperature logical exsiccant ammonia made it fully reaction in 1～10 minute, the precipitation precipitate filtered, get compound shown in the I formula, be O-(2-carboxamide phenyl)-O '-{ 2-methoxy-5-[(Z)-2-(3,4, the 5-trimethoxyphenyl) vinyl] phenyl } ammonium phosphate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996237A (en) * | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
-
2005
- 2005-10-18 CN CNB2005100154903A patent/CN100363370C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996237A (en) * | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
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