CN103864687A - Dicranostigma leptopodum berberrubine salt derivative - Google Patents
Dicranostigma leptopodum berberrubine salt derivative Download PDFInfo
- Publication number
- CN103864687A CN103864687A CN201210546862.5A CN201210546862A CN103864687A CN 103864687 A CN103864687 A CN 103864687A CN 201210546862 A CN201210546862 A CN 201210546862A CN 103864687 A CN103864687 A CN 103864687A
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- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- berberrubine
- alkali
- favus
- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to dicranostigma leptopodum berberrubine, a dicranostigma leptopodum berberrubine fumarate derivative, pharmaceutically acceptable solvates of the fumarate derivative, and applications of the solvates and the fumarate derivative for preparation of medicines treating cancer.
Description
Invention field
The present invention relates to pharmaceutical chemistry field, particularly, the present invention relates to favus of the scalp premium alkali organic acid salt and pharmacy application thereof.
Background technology
For now, although the medicine for the treatment of cancer is existing a variety of, existing these medicines easily cause many and heavy untoward reaction, some generation resistances, and the result for the treatment of of existing medicine is still not ideal enough.Chinese invention patent application publication No. is in the patent application of CN 102464617A, to have described some and 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, the pharmacy application of the pharmaceutical composition that contains these compounds and these compounds and composition.
These compounds have shown good water-soluble stability and solid form stability.Some compound of these compounds shows special good stability.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 synergy between the two.
Surprising and the significant stability of these compounds, water-soluble, anticancer activity are effective preparation and a large amount of advantages that provide that use.
Therefore, the invention provides a kind of formula III compound:
｛（Ⅰ）H｝+Ⅱˉ；
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-expression counter ion.
Suitable counter ion II-the comprise ion being provided by 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 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:
React with counter ion defined above II-source, after this if necessary, then prepare its pharmaceutically acceptable solvate.
Suitable counter ion II-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.
Reacting normally between formula I compound and counter ion II-source carried out under conventional salt-forming condition, for example, in solvent, be generally C1---C4 alkanol solvent as ethanol, can provide under the arbitrary temp that generates required suitable speed, conventionally at the temperature of for example solvent refluxing of temperature raising, be conveniently molar weight approximately to wait but preferably formula I compound mixed to then crystallization with counter ion II-source in the situation with slightly excessive counter ion II-source and go out required product (III).
The pharmaceutically acceptable solvate of formula III compound can be prepared by conventional chemical process.
Prepared by the method that formula I compound is described in can the patent application that be CN102464617A according to Chinese invention patent application publication No..
Suitable source of counter ions is knownly can easily obtain through commercial sources, for example fumaric acid, or can prepare required source of counter ions according to known method.
The stability of the compounds of this invention can be measured with conventional quantitative analysis method; The stability of for example solid chemical compound can be measured with the stability test of accelerating, for example dsc (DSC), and thermo-gravimetric analysis (TGA) is tested with the thermoisopleth in intensification.This test comprises 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.With respect to the stability of 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 find that formula III compound demonstrates good aqueous stability.Particularly wherein the formula III compound of the fumaric acid radical of II-expression is stable especially in the aqueous solution.More surprised is formula III compound abnormal stablizing in the aqueous solution of the fumaric acid radical of wherein II-expression.
Described test compound quantitative analysis test can ordinary method, conventionally 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 the pharmaceutically acceptable solvate as therapeutic active substance.
Like this, the invention provides formula III compound and/or the pharmaceutically acceptable solvate as treatment and/or inhibition 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 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 conventional medicine, 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.
Conventionally, activeconstituents can 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 for further illustrating and describe in more detail the present invention.
Embodiment 1
Favus of the scalp premium alkali fumarate
Compound favus of the scalp premium alkali 3.54 grams (0.01mol) and fumaric acid 1.17 grams (0.01mol) are dissolved in the alcohol 95 milliliter of boiling.This hot solution is through diatomite filtration, and then Slow cooling under mild stirring leaves standstill a few hours in the temperature environment of 0-5 ℃, separate out favus of the scalp premium alkali fumarate crystal, leach favus of the scalp premium alkali fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 4.69 grams of products.
Embodiment 2
Favus of the scalp premium alkali fumarate
3.54 grams of compound favus of the scalp premium alkali fumarates are stirred to solid with 1.17 grams of fumaric acid in the alcohol 95 milliliter refluxing all to be dissolved.Add gac, this hot solution, through diatomite filtration, is cooled to room temperature in stirring.In the temperature environment of 0-5 ℃, leave standstill a few hours, separate out favus of the scalp premium alkali fumarate crystal, leach favus of the scalp premium alkali fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 4.68 grams of 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 think explanation of the present invention can not limit the present invention.
Claims (2)
1. favus of the scalp premium alkali (I) fumaric acid (II) salt (III);
2. the compound of claim 1 is treated cancer and/or slows down the application in tumour medicine in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210546862.5A CN103864687A (en) | 2012-12-16 | 2012-12-16 | Dicranostigma leptopodum berberrubine salt derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210546862.5A CN103864687A (en) | 2012-12-16 | 2012-12-16 | Dicranostigma leptopodum berberrubine salt derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103864687A true CN103864687A (en) | 2014-06-18 |
Family
ID=50903758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210546862.5A Pending CN103864687A (en) | 2012-12-16 | 2012-12-16 | Dicranostigma leptopodum berberrubine salt derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103864687A (en) |
-
2012
- 2012-12-16 CN CN201210546862.5A patent/CN103864687A/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: 20140618 |