CN104387381A - Drug application of hydroxyl phenanthroquinolizidine derivatives - Google Patents
Drug application of hydroxyl phenanthroquinolizidine derivatives Download PDFInfo
- Publication number
- CN104387381A CN104387381A CN201410766602.8A CN201410766602A CN104387381A CN 104387381 A CN104387381 A CN 104387381A CN 201410766602 A CN201410766602 A CN 201410766602A CN 104387381 A CN104387381 A CN 104387381A
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- CN
- China
- Prior art keywords
- hydroxyl
- compound
- pharmaceutically acceptable
- phenanthroquinolizidine
- malate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to hydroxyl phenanthroquinolizidine malate or pharmaceutically acceptable solvate of hydroxyl phenanthroquinolizidine malate and application of hydroxyl phenanthroquinolizidine malate to preparation of tumor drugs.
Description
Invention field
The present invention relates to medicinal chemistry art, specifically, the present invention relates to hydroxyl phenanthro-quinoline Li Xiding organic acid salt and pharmacy application.
Background technology
For now, although the medicine of Therapeutic cancer is existing a variety of, these medicines existing easily cause many and heavy untoward reaction, and some generation resistances, the result for the treatment of of existing medicine is still not ideal enough.Chinese invention patent Authorization Notice No. is describe the active compound that some have Therapeutic cancer in the patent application of CN 1233642 C.
Summary of the invention
The invention discloses the compound that some is new, the preparation method of these compounds, the pharmacy application of the pharmaceutical composition containing these compounds and these compounds and composition.
These compounds show good water-soluble stability and solid form stability.Some compound of these compounds shows special good stability.It has very high solvability to these compounds in water compared with corresponding free alkali.
It is higher that these compounds show its anticancer activity in surprise because of synergy between the two compared with corresponding free alkali.
Surprising and the significant stability of these compounds, water-soluble, anticancer activity are that effective preparation provides advantage with a large amount of use.
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
-represent counter ion.
Suitable counter ion II
-the ion provided by pharmaceutically acceptable organic acid is provided.
The acceptable organic acid of preferred medicine comprises cholic acid, Chenodiol, ursodesoxycholic acid, Deoxycholic Acid, tartrate, oxysuccinic acid, particularly oxysuccinic acid.
Preferred counter ion are malate ion.
Formula III compound is salt.
Suitable pharmaceutically acceptable solvate is hydrate.
In addition, present invention also offers the preparation method of formula III and/or pharmaceutically acceptable solvate.This method comprises formula I compound:
With counter ion II defined above
-source is reacted, and after this if necessary, then prepares its pharmaceutically acceptable solvate.
Suitable counter ion II
-source is pharmaceutically acceptable organic acid.
The acceptable organic acid of preferred medicine comprises cholic acid, Chenodiol, ursodesoxycholic acid, Deoxycholic Acid, tartrate, toxilic acid, oxysuccinic acid, particularly oxysuccinic acid.
Preferred source of counter ions is oxysuccinic acid.
Formula I compound and counter ion II
-reaction between source is normally carried out under conventional salt formation condition, such as, in a solvent, be generally C1---C4 alkanol solvent as ethanol, can provide under the arbitrary temp generating required suitable rate, usually, at the temperature of the temperature such as solvent refluxing raised, be conveniently with the molar weight about waited but preferably with the counter ion II of the amount of skipping over
-by formula I compound and counter ion II when source
-source mixes then crystallization and goes out required product (III).
The pharmaceutically acceptable solvate of formula III compound can be prepared by the chemical process of routine.
Formula I compound can be prepared by the method described in the patent specification of CN1233642C according to Chinese invention patent Authorization Notice No..
Suitable source of counter ions knownly can easily to obtain through commercial sources, such as oxysuccinic acid, or can source of counter ions needed for the preparation of known method.
The stability of the compounds of this invention can measure by normal quantitative analysis method; The stability of such as solid chemical compound can measure with the stability test accelerated, and such as dsc (DSC), thermo-gravimetric analysis (TGA) is tested with the thermoisopleth in intensification.This test comprises room temperature storage test.(wherein within known period 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.Relative to the stability of suitable reference standard determination test compound.
As mentioned above, it has significantly high solvability to compound of the present invention in water compared with corresponding free alkali.The ordinary method of such mensuration the compounds of this invention stability be in aqueous included in known temperature condition and known during in measure by the degree being settled out parent free alkali in the aqueous solution of test compound, we find that formula III compound demonstrates good aqueous stability.Particularly wherein II
-the formula III compound of the malate represented is stable especially in aqueous.More surprisingly wherein II
-the formula III compound of the malate represented is abnormal stable in aqueous.
Described test compound quantitative analysis test in conventional manner, can use chromatography usually, and such as high pressure lipuid chromatography (HPLC) is carried out.
As mentioned above, compound of the present invention has practical therapeutic activity.
Therefore, the invention provides the formula III compound as therapeutic active substance and/or pharmaceutically acceptable solvate.
Like this, the invention provides the formula III compound being used as treatment and/or suppression cancer and/or pharmaceutically acceptable solvate.
Formula III compound and/or pharmaceutically acceptable solvate can himself form be used, and preferably also can the form of pharmaceutical composition containing pharmaceutically acceptable carrier use.
Therefore, present invention also offers a kind of pharmaceutical composition containing formula III compound and/or pharmaceutically acceptable solvate and pharmaceutically acceptable carrier.
Term used herein " pharmaceutically acceptable " comprises the compound, composition and the component that use people and animal doctor, and such as, term " pharmaceutically acceptable salt " comprises the upper acceptable salt of animal doctor.
Suitable pharmaceutical composition is the composition of unit dosage, such as 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 configured to unit dosage.
Usually, activeconstituents can aforementioned pharmaceutical compositions form be used.
Present invention also offers a kind of containing formula III compound and/or pharmaceutically acceptable solvate at production for treating and/or suppress on the medicine of cancer application.
Provide embodiments of the invention below for further illustrating and describing the present invention in more detail.
Embodiment 1
Hydroxyl phenanthro-quinoline Li Xiding malate
By compound hydroxyl phenanthro-quinoline in west fixed 3.63 grams (0.01mol) and oxysuccinic acid 1.34 grams (0.01mol) be dissolved in the ethanol 100 milliliters of boiling.This hot solution is through diatomite filtration, then Slow cooling under mild agitation, a few hours are left standstill in the temperature environment of 0-5 DEG C, separate out hydroxyl phenanthro-quinoline Li Xiding malate crystal, leach hydroxyl phenanthro-quinoline Li Xiding malate crystal, dry with washing with alcohol and under 50 DEG C of vacuum conditions, obtain 4.86 grams of products.
Embodiment 2
Hydroxyl phenanthro-quinoline Li Xiding malate
By compound hydroxyl phenanthro-quinoline Li Xiding malate 3.63 grams and oxysuccinic acid 1.34 grams in the ethanol 100 milliliters of backflow, be stirred to solid all dissolve.Add gac, by this hot solution through diatomite filtration, in stirring, be cooled to room temperature.In the temperature environment of 0-5 DEG C, leave standstill a few hours, separate out hydroxyl phenanthro-quinoline Li Xiding malate crystal, leach hydroxyl phenanthro-quinoline Li Xiding malate crystal, dry under 50 DEG C of vacuum conditions with washing with alcohol, obtain 4.82 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 be thought explanation of the present invention and can not limit the present invention.
Claims (2)
1. hydroxyl phenanthro-quinoline Li Xiding (I) oxysuccinic acid (II) salt (III);
2. the compound of claim 1 is preparing the application in antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410766602.8A CN104387381A (en) | 2014-12-11 | 2014-12-11 | Drug application of hydroxyl phenanthroquinolizidine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410766602.8A CN104387381A (en) | 2014-12-11 | 2014-12-11 | Drug application of hydroxyl phenanthroquinolizidine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104387381A true CN104387381A (en) | 2015-03-04 |
Family
ID=52605356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410766602.8A Pending CN104387381A (en) | 2014-12-11 | 2014-12-11 | Drug application of hydroxyl phenanthroquinolizidine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104387381A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1463973A (en) * | 2002-06-18 | 2003-12-31 | 中国科学院成都生物研究所 | Novel anticancer plants extract, process of extraction and analogue thereof |
| CN101189968A (en) * | 2006-11-23 | 2008-06-04 | 南开大学 | Phenanthroindolizidine and phenanthroquinolizidine derivatives and applications of salts in pesticides |
| WO2014000586A1 (en) * | 2012-06-25 | 2014-01-03 | 南开大学 | Phenanthroindolizidine alkaloid derivates and salt thereof as well as preparation, plant-virus resisting activity, and anti-cancer activity of phenanthroindolizidine alkaloid derivates and salt thereof |
-
2014
- 2014-12-11 CN CN201410766602.8A patent/CN104387381A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1463973A (en) * | 2002-06-18 | 2003-12-31 | 中国科学院成都生物研究所 | Novel anticancer plants extract, process of extraction and analogue thereof |
| CN101189968A (en) * | 2006-11-23 | 2008-06-04 | 南开大学 | Phenanthroindolizidine and phenanthroquinolizidine derivatives and applications of salts in pesticides |
| WO2014000586A1 (en) * | 2012-06-25 | 2014-01-03 | 南开大学 | Phenanthroindolizidine alkaloid derivates and salt thereof as well as preparation, plant-virus resisting activity, and anti-cancer activity of phenanthroindolizidine alkaloid derivates and salt thereof |
Non-Patent Citations (1)
| Title |
|---|
| CUI MINGBO ET AL.: ""Total Synthesis of Phenanthro-Quinolizidine Alkaloids: (±)-Cryptopleurine, (±)-Boehmeriasin A, (±)-Boehmeriasin B and (±)-Hydroxycryptopleurine"", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
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|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150304 |