CN104710422A - Cytisine derivative - Google Patents
Cytisine derivative Download PDFInfo
- Publication number
- CN104710422A CN104710422A CN201310684148.7A CN201310684148A CN104710422A CN 104710422 A CN104710422 A CN 104710422A CN 201310684148 A CN201310684148 A CN 201310684148A CN 104710422 A CN104710422 A CN 104710422A
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- derivative
- acid
- tocosamine
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
Abstract
The invention relates to a cytisine derivative maleate or its pharmaceutically acceptable solvate and an application of the cytisine derivative maleate or its pharmaceutically acceptable solvate in preparation of medicines for treating tumors.
Description
Invention field
The present invention relates to medicinal chemistry art, specifically, the present invention relates to Tocosamine derivative organic acid salt and pharmacy application thereof.
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 the easy generation resistance had, the result for the treatment of of existing medicine is still not ideal enough.Chinese invention patent application publication No. is describe the active compound that some have Therapeutic cancer in the patent documentation of CN102952134A.
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 antineoplastic activity in surprise because of synergy between the two compared with corresponding free alkali.
Surprising and the significant stability of these compounds, water-soluble, antineoplastic 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
ˉ;
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, toxilic acid, fumaric acid, particularly toxilic acid.
Preferred counter ion are maleate ions.
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, fumaric acid, particularly toxilic acid.
Preferred source of counter ions is toxilic 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 documentation of CN 102952134A according to Chinese invention patent application publication No..
Suitable source of counter ions knownly can easily to obtain through commercial sources, such as toxilic 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 maleate represented is stable especially in aqueous.More surprisingly wherein II
--the formula III compound of the maleate 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 Tumor suppression 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 the application on the medicine of production for treating and/or Tumor suppression of 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
Tocosamine derivative maleate
Compound Tocosamine derivative 0.32 gram (1mmol) and toxilic acid 0.12 gram (1mmol) are dissolved in the ethanol 10 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 Tocosamine derivative maleic acid salt, leach Tocosamine derivative maleic acid salt, dry with cold washing with alcohol and under 50 DEG C of vacuum conditions, obtain 0.43 gram of product.
Embodiment 2
Tocosamine derivative maleate
Compound Tocosamine derivative maleate 0.32 gram and toxilic acid 0.12 gram are stirred to solid in the ethanol 10 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 Tocosamine derivative maleic acid salt, leach Tocosamine derivative maleic acid salt, dry under 50 DEG C of vacuum conditions with cold washing with alcohol, obtain 0.42 gram of product.
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. Tocosamine derivative (I) toxilic acid (II) salt (III);
2. the compound of claim 1 is in the application preparing treatment and/or slow down in the medicine of tumour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310684148.7A CN104710422A (en) | 2013-12-13 | 2013-12-13 | Cytisine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310684148.7A CN104710422A (en) | 2013-12-13 | 2013-12-13 | Cytisine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104710422A true CN104710422A (en) | 2015-06-17 |
Family
ID=53410204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310684148.7A Pending CN104710422A (en) | 2013-12-13 | 2013-12-13 | Cytisine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104710422A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2550241A (en) * | 2016-02-05 | 2017-11-15 | Achieve Pharma Uk Ltd | Salt |
| CN109172569A (en) * | 2018-09-13 | 2019-01-11 | 淮安亿泰生物科技有限公司 | A kind of alkaloid compound for preventing and treating patients with lung cancer cisplatin-resistant |
-
2013
- 2013-12-13 CN CN201310684148.7A patent/CN104710422A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2550241A (en) * | 2016-02-05 | 2017-11-15 | Achieve Pharma Uk Ltd | Salt |
| GB2550241B (en) * | 2016-02-05 | 2018-04-25 | Achieve Pharma Uk Ltd | Cytisine succinate salts |
| US10300050B2 (en) | 2016-02-05 | 2019-05-28 | Achieve Pharma Uk Limited | Succinate salt of cytisine and use thereof |
| AU2017215300B2 (en) * | 2016-02-05 | 2022-03-03 | Achieve Pharma Uk Limited | Succinate salt of cytisine and use thereof |
| CN109172569A (en) * | 2018-09-13 | 2019-01-11 | 淮安亿泰生物科技有限公司 | A kind of alkaloid compound for preventing and treating patients with lung cancer cisplatin-resistant |
| CN109172569B (en) * | 2018-09-13 | 2020-12-22 | 浙江亚瑟医药有限公司 | Alkaloid compound for preventing and treating cisplatin resistance of lung cancer patient |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150617 |