CN103626773A - Salt of vasicine derivative - Google Patents
Salt of vasicine derivative Download PDFInfo
- Publication number
- CN103626773A CN103626773A CN201210306937.2A CN201210306937A CN103626773A CN 103626773 A CN103626773 A CN 103626773A CN 201210306937 A CN201210306937 A CN 201210306937A CN 103626773 A CN103626773 A CN 103626773A
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- CN
- China
- Prior art keywords
- compound
- vasicine
- formula
- pharmaceutically acceptable
- iii
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to fumarate of vasicine (formula I), a preparation method thereof or a pharmaceutically acceptable solvate thereof, and application of the fumarate of vasicine (formula I) to preparation of 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 vasicine 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 number is in CN 101433565A, to have described some to 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 of its acetylcholinesterase inhibition 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 of using.
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 in the temperature raising for example at the temperature of solvent refluxing, 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 specification sheets of CN 101433565A according to Chinese invention patent application publication number.
Suitable source of counter ions is knownly through commercial sources, can easily obtain, fumaric acid for example, 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; For example the stability of solid chemical compound can be measured with the stability test of accelerating, for example dsc (DSC), thermo-gravimetric analysis (TGA) and the test of 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.Stability with respect to 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 mensuration in the aqueous solution of test compound, be settled out the degree of parent free alkali, we demonstrate good aqueous stability by discoverable type (III) compound.Particularly wherein the formula of the fumaric acid radical of II-expression (III) compound is stable especially in the aqueous solution.More surprised is formula (III) compound abnormal stablizing in the aqueous solution of the wherein fumaric acid radical of 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
Vasicine fumarate
Compound vasicine 1.88 grams (0.01mol) and fumaric acid 1.17 grams (0.01mol) are dissolved in 60 milliliters of the ethanol of boiling.This hot solution is through diatomite filtration, Slow cooling under mild stirring then, standing a few hours in the temperature environment of 0-5 ℃, separate out vasicine fumarate crystal, leach vasicine fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 3.04 grams of products.
Embodiment 2
Vasicine fumarate
1.17 grams of 1.88 grams of compound vasicine fumarates and fumaric acid are stirred to solid in 60 milliliters of ethanol refluxing all to be dissolved.Add gac, this hot solution, through diatomite filtration, is cooled to room temperature in stirring.Standing a few hours in the temperature environment of 0-5 ℃, separate out vasicine fumarate crystal, leach vasicine fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 3.04 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. vasicine (I) fumaric acid (II) salt (III);
2. the application of the compound of claim 1 in preparing the medicine of acetylcholinesterase depressant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210306937.2A CN103626773A (en) | 2012-08-25 | 2012-08-25 | Salt of vasicine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210306937.2A CN103626773A (en) | 2012-08-25 | 2012-08-25 | Salt of vasicine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103626773A true CN103626773A (en) | 2014-03-12 |
Family
ID=50208254
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210306937.2A Pending CN103626773A (en) | 2012-08-25 | 2012-08-25 | Salt of vasicine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103626773A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356138A (en) * | 2014-10-27 | 2015-02-18 | 上海中医药大学 | Vasicine R-type optical isomer as well as preparation method and application thereof |
| CN109316481A (en) * | 2018-12-03 | 2019-02-12 | 泰州职业技术学院 | A kind of medicine for relieving pain and application thereof |
-
2012
- 2012-08-25 CN CN201210306937.2A patent/CN103626773A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356138A (en) * | 2014-10-27 | 2015-02-18 | 上海中医药大学 | Vasicine R-type optical isomer as well as preparation method and application thereof |
| CN109316481A (en) * | 2018-12-03 | 2019-02-12 | 泰州职业技术学院 | A kind of medicine for relieving pain and application thereof |
| CN109316481B (en) * | 2018-12-03 | 2021-02-23 | 泰州职业技术学院 | Medicine for relieving pain and application thereof |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | 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: 20140312 |