CN103374007A - Salt of dihydrochelerythrine derivative - Google Patents
Salt of dihydrochelerythrine derivative Download PDFInfo
- Publication number
- CN103374007A CN103374007A CN201210111547XA CN201210111547A CN103374007A CN 103374007 A CN103374007 A CN 103374007A CN 201210111547X A CN201210111547X A CN 201210111547XA CN 201210111547 A CN201210111547 A CN 201210111547A CN 103374007 A CN103374007 A CN 103374007A
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- Prior art keywords
- compound
- dihydrochelerythrine
- pharmaceutically acceptable
- formula
- iii
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- 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.)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to fumarate or pharmacological acceptable solvates of dihydrochelerythrine and derivatives of the dihydrochelerythrine as well as an application of the fumarate or pharmacological acceptable solvates to the preparation of drugs for treating hepatitis B.
Description
Invention field
The present invention relates to the pharmaceutical chemistry field, particularly, the present invention relates to dihydrochelerythrine organic acid salt and pharmacy thereof and use.
Background technology
For now, although the hepatitis b virus infected medicine for the treatment of 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 CN101084906A to have the active compound for the treatment of hepatitis B.
Summary of the invention
The invention discloses some novel 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-soluble 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.
Effective preparation and a large amount of advantages that provide of using are provided surprising and significant stable, water-soluble, the antiviral activity of these compounds.
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 fumaric acid.
Preferred counter ion are fumarate ions.
Formula (III) compound is salt.
Suitable pharmaceutically acceptable solvate is hydrate.
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 after this if necessary, prepares its pharmaceutically acceptable solvate again.
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 fumaric acid.
Preferred source of counter ions is fumaric 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
-In the situation in source with formula (I) compound and counter ion II
-The source is mixed then crystallization 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 101084906A 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 fumaric acid perhaps can prepare according to known method required source of counter ions.
The stable available conventional quantitative analysis method of the compounds of this invention is measured; For example the stability of solid chemical compound can be measured with the stability test of accelerating, 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 like this stability of the compounds of this invention in the aqueous solution be included in 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 fumaric acid radical of expression is stable especially in the aqueous solution.More surprised is II wherein
-Formula (III) compound of the fumaric acid radical of expression is unusual stablizing in the aqueous solution.
Described test compound quantitative analysis test can ordinary method, usually uses chromatography, 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 treatment and/or suppress hepatitis b virus infected formula (III) compound and/or pharmaceutically acceptable solvate.
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 compound, composition and the component to people and animal doctor's use, and for example, term " pharmaceutically acceptable salt " comprises the upper acceptable salt of animal doctor.
Suitable pharmaceutical 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 hepatitis B virus.
The below provides embodiments of the invention and is used for further specifying and describing in more detail the present invention.
Embodiment 1
The dihydrochelerythrine fumarate
Compound dihydrochelerythrine 3.51 gram (0.01mol) and fumaric acid 1.17 are restrained in 80 milliliters of the ethanol that (0.01mol) be dissolved in boiling.This hot solution is through diatomite filtration, then Slow cooling under mild stirring, in 0-5 ℃ temperature environment, leave standstill a few hours, separate out dihydrochelerythrine fumarate crystal, leach dihydrochelerythrine fumarate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 4.65 gram products.
Embodiment 2
The dihydrochelerythrine fumarate
Compound dihydrochelerythrine fumarate 3.51 gram and fumaric acid 1.17 grams are stirred to solid in 80 milliliters of the ethanol of backflow all dissolve.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 dihydrochelerythrine fumarate crystal, leach dihydrochelerythrine fumarate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 4.63 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. dihydrochelerythrine (I) fumaric acid (II) salt (III);
2. the compound of claim 1 is in preparation treatment hepatitis B and/or slow down application in the hepatitis B virus infective medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210111547XA CN103374007A (en) | 2012-04-16 | 2012-04-16 | Salt of dihydrochelerythrine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210111547XA CN103374007A (en) | 2012-04-16 | 2012-04-16 | Salt of dihydrochelerythrine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103374007A true CN103374007A (en) | 2013-10-30 |
Family
ID=49459892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210111547XA Pending CN103374007A (en) | 2012-04-16 | 2012-04-16 | Salt of dihydrochelerythrine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103374007A (en) |
-
2012
- 2012-04-16 CN CN201210111547XA patent/CN103374007A/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: 20131030 |