CN103772474A - Salts of conessine derivative - Google Patents
Salts of conessine derivative Download PDFInfo
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- CN103772474A CN103772474A CN201210403273.1A CN201210403273A CN103772474A CN 103772474 A CN103772474 A CN 103772474A CN 201210403273 A CN201210403273 A CN 201210403273A CN 103772474 A CN103772474 A CN 103772474A
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- compound
- conessine
- pharmaceutically acceptable
- formula iii
- derivative
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Abstract
The invention relates to fumarate or pharmaceutically acceptable solvates of a conessine derivative and application of fumarate or the pharmaceutically acceptable solvates to prepare acetylcholinesterase inhibitor medicaments.
Description
Invention field
The present invention relates to pharmaceutical chemistry field, particularly, the present invention relates to organic acid salt and the pharmacy application thereof of conessine derivative.
Background technology
For now, although acetylcholinesterase depressant is existing a variety of, existing these medicines easily cause many and heavy untoward reaction, the easy generation resistance having, 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 of CN 102153614A, to have described some and have the compound of inhibiting activity of acetylcholinesterase.
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 the activity that its acetylcholinesterase suppresses is higher because of synergy between the two.
Surprising and the significant stability of these compounds, the activity that water-soluble, enzyme suppresses 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:
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.
Formula I compound can be prepared by the method for describing in the patent specification of CN 102153614A 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 acetylcholinesterase depressant.
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 producing acetylcholinesterase depressant.
Provide embodiments of the invention below for further illustrating and describe in more detail the present invention.
Embodiment 1
Conessine fumarate
Compound conessine 3.57 grams (0.01mol) and fumaric acid 1.17 grams (0.01mol) are dissolved in 90 milliliters of the ethanol 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 conessine fumarate crystal, leach conessine fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 4.72 grams of products.
Embodiment 2
Conessine fumarate
1.17 grams of 3.57 grams of compound conessine fumarates and fumaric acid are stirred to solid in 90 milliliters of ethanol 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 conessine fumarate crystal, leach conessine fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 4.71 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. conessine (I) fumaric acid (II) salt (III);
2. the application of the compound of claim 1 in the medicine of preparing acetylcholinesterase depressant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210403273.1A CN103772474A (en) | 2012-10-22 | 2012-10-22 | Salts of conessine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210403273.1A CN103772474A (en) | 2012-10-22 | 2012-10-22 | Salts of conessine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103772474A true CN103772474A (en) | 2014-05-07 |
Family
ID=50565288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210403273.1A Pending CN103772474A (en) | 2012-10-22 | 2012-10-22 | Salts of conessine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103772474A (en) |
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2012
- 2012-10-22 CN CN201210403273.1A patent/CN103772474A/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: 20140507 |