CN104447552A - Pharmaceutical use of corydine derivative - Google Patents
Pharmaceutical use of corydine derivative Download PDFInfo
- Publication number
- CN104447552A CN104447552A CN201410766854.0A CN201410766854A CN104447552A CN 104447552 A CN104447552 A CN 104447552A CN 201410766854 A CN201410766854 A CN 201410766854A CN 104447552 A CN104447552 A CN 104447552A
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- malate
- dibenzo
- trimethoxy
- 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.)
- Pending
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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
Abstract
The invention relates to corydine malate or a pharmaceutically acceptable solvate and an application thereof in preparation of medicaments for preventing and/or treating cervical cancer. The formula is as shown in the specification.
Description
Invention field
The present invention relates to medicinal chemistry art, specifically, the present invention relates to malate and the pharmaceutical applications thereof of (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g derivative.
Background technology
For now, although the existing many kinds of the medicine preventing and/or treating cervical cancer, these medicines existing easily cause many and heavy untoward reaction, and the generation resistance had, the result for the treatment of of existing medicine still cannot be satisfactory.Chinese invention patent Authorization Notice No. is describe some in the patent documentation of CN102302496 B to have the active compound preventing and/or treating cervical cancer.
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}+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-represent counter ion.
The suitable counter ion II-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:
React with counter ion II-source defined above, after this if necessary, then prepare 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, oxysuccinic acid, particularly oxysuccinic acid.
Preferred source of counter ions is oxysuccinic acid.
Reaction between formula I compound and counter ion II-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, when being conveniently the counter ion II-source with the molar weight about waited but preferably by the amount of skipping over, formula I compound is mixed then crystallization with counter ion II-source and go 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 documentation of CN 102302496B 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 the formula III compound of the malate of wherein II-expression is stable especially in aqueous.The more surprisingly wherein II-formula III compound of malate that represents 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 as preventing and/or treating the formula III compound of cervical 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 application prevented and/or treated on the medicine of cervical cancer in production containing formula III compound and/or pharmaceutically acceptable solvate.
Provide embodiments of the invention below for further illustrating and describing the present invention in more detail.
Embodiment 1
(6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate
Compound (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g 3.41 grams (0.01mol) and oxysuccinic acid 1.34 grams (0.01mol) are dissolved in the ethanol 100 milliliters of boiling.This hot solution is through diatomite filtration, and then Slow cooling under mild agitation, leaves standstill a few hours in the temperature environment of 0-5 DEG C, separate out (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate crystal, leach (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate crystal, dry with washing with alcohol and under 50 DEG C of vacuum conditions, obtain 4.62 grams of products.
Embodiment 2
(6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate
Compound (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate 3.41 grams and oxysuccinic acid 1.34 grams are stirred to solid in the ethanol 100 milliliters of backflow 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 (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate crystal, leach (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g malate crystal, dry under 50 DEG C of vacuum conditions with washing with alcohol, obtain 4.61 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. (6aS)-2,10,11-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g (I) oxysuccinic acid (II) salt (III);
2. the compound of claim 1 is preparing the application prevented and/or treated in the medicine of cervical cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410766854.0A CN104447552A (en) | 2014-12-11 | 2014-12-11 | Pharmaceutical use of corydine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410766854.0A CN104447552A (en) | 2014-12-11 | 2014-12-11 | Pharmaceutical use of corydine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104447552A true CN104447552A (en) | 2015-03-25 |
Family
ID=52894382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410766854.0A Pending CN104447552A (en) | 2014-12-11 | 2014-12-11 | Pharmaceutical use of corydine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447552A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302496A (en) * | 2011-08-01 | 2012-01-04 | 王芳 | Applications of isoquinoline-type alkaloid and derivatives thereof in preparing medicaments for preventing or treating cervical cancer |
| CN103910677A (en) * | 2013-01-04 | 2014-07-09 | 上海壹志医药科技有限公司 | Salt of corydine derivative |
-
2014
- 2014-12-11 CN CN201410766854.0A patent/CN104447552A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302496A (en) * | 2011-08-01 | 2012-01-04 | 王芳 | Applications of isoquinoline-type alkaloid and derivatives thereof in preparing medicaments for preventing or treating cervical cancer |
| CN103910677A (en) * | 2013-01-04 | 2014-07-09 | 上海壹志医药科技有限公司 | Salt of corydine derivative |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 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: 20150325 |