CN103242278A - Salt of dimethoxy indolone derivative - Google Patents
Salt of dimethoxy indolone derivative Download PDFInfo
- Publication number
- CN103242278A CN103242278A CN2012100333566A CN201210033356A CN103242278A CN 103242278 A CN103242278 A CN 103242278A CN 2012100333566 A CN2012100333566 A CN 2012100333566A CN 201210033356 A CN201210033356 A CN 201210033356A CN 103242278 A CN103242278 A CN 103242278A
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- Prior art keywords
- compound
- dimethoxy
- pharmaceutically acceptable
- salt
- iii
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Abstract
The invention relates to (E)-1,3-dihydro -5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-2H-indol-2-one and a derivative fumarate or a pharmaceutically acceptable solvate thereof, and an application thereof in preparation of medicines for treating cancers.
Description
Invention field
The present invention relates to the pharmaceutical chemistry field, particularly, the present invention relates to (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one organic acid salt and pharmacy application thereof.
Background technology
For now, though the medicine for the treatment of cancer is existing a variety of, existing these medicines easily cause many and heavy untoward reaction, the generation resistance that has, and the result for the treatment of of existing medicine is still not ideal enough.The Chinese invention patent application publication number is to have described some in the patent application of CN 1668298 A to have the active compound for the treatment of cancer.
Summary of the invention
The invention discloses some new compound, the preparation method of these compounds contains the pharmaceutical composition of these compounds and the pharmacy of these compounds and composition and uses.
These compound exhibits good water-solubility stability and solid form stability.The special good stability of some compound exhibits of these compounds.These compounds are compared with corresponding free alkali, and it has very high solvability in water.
These compounds are compared with corresponding free alkali and are shown that in surprise its anticancer activity is higher because of between the two synergy.
These compounds surprising with remarkable stability, water-soluble, anticancer activity be effectively preparation and a large amount of advantages that provide of using.
Therefore, the invention provides a kind of formula (III) compound:
{(I)H}+II
-；
Wherein the chemical structure of I is as follows:
Wherein the chemical structure of II is as follows:
And/or pharmaceutically acceptable solvate, wherein:
II
-The expression counter ion.
Suitable counter ion II
-The ion that is provided by pharmaceutically acceptable organic acid is provided.
The preferred acceptable organic acid of medicine comprises cholic acid, Chenodiol, ursodesoxycholic acid, Deoxycholic Acid, tartrate, toxilic acid, fumaric acid, particularly toxilic acid.
Preferred counter ion are maleate ions.
Formula (III) compound is salt.
The acceptable solvent thing is hydrate on the appropriate drug.
In addition, the present invention also provides the preparation method of formula (III) and/or pharmaceutically acceptable solvate.This method comprises formula (I) compound:
Counter ion II with above-mentioned definition
-The source reaction, if after this needs are arranged, its pharmaceutically acceptable solvate of refabrication.
Suitable counter ion II
-The source is pharmaceutically acceptable organic acid.
The preferred acceptable organic acid of medicine comprises cholic acid, Chenodiol, ursodesoxycholic acid, Deoxycholic Acid, tartrate, toxilic acid, fumaric acid, particularly toxilic acid.
Preferred source of counter ions is toxilic acid.
Formula (I) compound and counter ion II
-Reaction between the source is normally carried out under conventional salt-forming condition, for example, in solvent, be generally C1---C4 alkanol solvent such as ethanol, can provide under the arbitrary temp that generates required suitable speed, usually in the temperature that raises for example under the temperature of solvent refluxing, conveniently be with the molar weight that waits approximately but the slightly excessive counter ion II of preferred usefulness
-Under the situation in source with formula (I) compound and counter ion II
-The source is mixed crystallization then and is gone out required product (III).
The pharmaceutically acceptable solvate of formula (III) compound can prepare with the chemical process of routine.
Formula (I) compound can be that the method for describing in the patent application of CN 1668298 A prepares according to the Chinese invention patent application publication number.
Suitable source of counter ions is knownly can easily obtain through commercial approach, and for example toxilic acid perhaps can prepare required source of counter ions according to known method.
The stable available conventional quantitative analysis method of The compounds of this invention is measured; For example the stability test of the stable available acceleration of solid chemical compound is measured, for example dsc (DSC), thermo-gravimetric analysis (TGA) and the test of the thermoisopleth in intensification.This test comprises the room temperature storage test.(in wherein during known under temperature and humidity control condition storage test compound).The quantitative analysis of test compound is before storage period, in storage period or after storage period.Stability with respect to suitable reference standard determination test compound.
As mentioned above, compound of the present invention is compared with corresponding free alkali, and it has significantly high solvability in water.The ordinary method of measuring the stability of The compounds of this invention in the aqueous solution like this be included in the known temperature condition and known during in be settled out the degree of parent free alkali in the aqueous solution of mensuration by test compound, we go out good aqueous stability at discoverable type (III) compound exhibits.II wherein particularly
-Formula (III) compound of the maleate of expression is stable especially in the aqueous solution.More surprised is II wherein
-Formula (III) compound of the maleate of expression is unusual stablizing in the aqueous solution.
Described test compound quantitative analysis test can ordinary method, uses chromatography usually, and for example high pressure lipuid chromatography (HPLC) is carried out.
As mentioned above, compound of the present invention has practical therapeutic activity.
Therefore, the invention provides formula (III) compound and/or pharmaceutically acceptable solvate as therapeutic active substance.
Like this, the invention provides as formula (III) compound and/or the pharmaceutically acceptable solvate for the treatment of and/or suppress cancer.
Formula (III) compound and/or pharmaceutically acceptable solvate can himself form be used, and the form that preferably also can contain the pharmaceutical composition of pharmaceutically acceptable carrier is used.
Therefore, the present invention also provides a kind of pharmaceutical composition that contains formula (III) compound and/or pharmaceutically acceptable solvate and pharmaceutically acceptable carrier.
Term used herein " pharmaceutically acceptable " comprises the compound to people and animal doctor's use. composition and component, for example, term " pharmaceutically acceptable salt " comprises that the animal doctor goes up acceptable salt.
The appropriate drug composition is the composition of unit dosage, for example oral liquid, tablet, capsule, injection liquid, sprays.
Optimum pharmaceutical composition is oral liquid, sprays.
According to the convention on the medicine of routine, carrier can comprise thinner, weighting agent, disintegrating agent, wetting agent, lubricant, tinting material, seasonings or other conventional additives.
Optimum composition is to be configured to unit dosage.
Usually, activeconstituents can the aforementioned pharmaceutical compositions form be used.
The present invention also provides a kind of contain formula (III) compound and/or the application of pharmaceutically acceptable solvate on the medicine of production for treating and/or inhibition cancer.
Provide embodiments of the invention below and be used for further specifying and describing in more detail the present invention.
Embodiment 1
(E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate
With compound (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one 2.97 grams (0.01mol) and toxilic acid 1.17 restrain in 80 milliliters of the ethanol that (0.01mol) be dissolved in boiling.This hot solution is through diatomite filtration, slowly cooling under mild stirring then, in 0-5 ℃ temperature environment, leave standstill a few hours, separate out (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate crystal, leach (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 4.12 gram products.
Embodiment 2
(E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate
With compound (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate 2.97 grams and toxilic acid 1.17 grams are stirred to solid and all dissolve in 80 milliliters of the ethanol of backflow.Add gac, this hot solution through diatomite filtration, is cooled to room temperature in the stirring.In 0-5 ℃ temperature environment, leave standstill a few hours, separate out (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate crystal, leach (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one maleate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 4.11 gram products.
The present invention can summarize with other the specific form without prejudice to spirit of the present invention or principal character.Therefore, no matter from which point, above-mentioned embodiment of the present invention all can only be thought can not limit the present invention to explanation of the present invention.
Claims (2)
1. (E)-1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene radical]-2H-indol-2-one (I) toxilic acid (II) salt (III).
{(I)H}+II
-
(III)
2. the application of the compound of claim 1 in the medicine of preparation treatment cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100333566A CN103242278A (en) | 2012-02-14 | 2012-02-14 | Salt of dimethoxy indolone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100333566A CN103242278A (en) | 2012-02-14 | 2012-02-14 | Salt of dimethoxy indolone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103242278A true CN103242278A (en) | 2013-08-14 |
Family
ID=48922183
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100333566A Pending CN103242278A (en) | 2012-02-14 | 2012-02-14 | Salt of dimethoxy indolone derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103242278A (en) |
-
2012
- 2012-02-14 CN CN2012100333566A patent/CN103242278A/en active Pending
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130814 |