CN103508951A - Salts of 2-hydroxy-1-methoxyaporphine derivative - Google Patents
Salts of 2-hydroxy-1-methoxyaporphine derivative Download PDFInfo
- Publication number
- CN103508951A CN103508951A CN201210209251.1A CN201210209251A CN103508951A CN 103508951 A CN103508951 A CN 103508951A CN 201210209251 A CN201210209251 A CN 201210209251A CN 103508951 A CN103508951 A CN 103508951A
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- CN
- China
- Prior art keywords
- compound
- hydroxy
- pharmaceutically acceptable
- methoxyaporphine
- aporphine
- 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.)
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to fumarates of 2-hydroxy-1-methoxyaporphine and 2-hydroxy-1-methoxyaporphine derivatives or pharmaceutically acceptable solvates thereof, and an application of the fumarates or the solvates in preparation of acetylcholinesterase inhibitor drugs.
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 2-hydroxy-1-methoxy-aporphine.
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.In the patent that Chinese invention patent Granted publication number is CN 101712649B, describe some and there is 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｝+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 being provided by pharmaceutically acceptable organic acid is provided.
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:
With counter ion II defined above
--source reaction, after this if necessary, then prepares 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.
Formula I compound and counter ion II
--reaction between source is normally 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 by slightly excessive counter ion II
--in the situation in source by formula I compound and counter ion II
--source is mixed then crystallization and is gone 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 101712649B according to Chinese invention patent Granted 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 find that formula III compound demonstrates good aqueous stability.II wherein particularly
--the formula III compound of the fumaric acid radical representing is stable especially in the aqueous solution.II wherein that more surprised is
--the formula III compound of the fumaric acid radical representing is abnormal stablizing in the aqueous solution.
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
2-hydroxy-1-methoxy-aporphine fumarate
Compound 2-hydroxy-1-methoxy-aporphine 2.81 grams (0.01mol) and fumaric acid 1.17 grams (0.01mol) are dissolved in 80 milliliters of the ethanol of boiling.This hot solution is through diatomite filtration, then Slow cooling under mild stirring, standing a few hours in the temperature environment of 0-5 ℃, separate out 2-hydroxy-1-methoxy-aporphine fumarate crystal, leach 2-hydroxy-1-methoxy-aporphine fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 3.93 grams of products.
Embodiment 2
2-hydroxy-1-methoxy-aporphine fumarate
1.17 grams of 2.81 grams of compound 2-hydroxy-1-methoxy-aporphine fumarates and fumaric acid are stirred to solid in 80 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 2-hydroxy-1-methoxy-aporphine fumarate crystal, leach 2-hydroxy-1-methoxy-aporphine fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 3.91 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)
1.2-hydroxyl-1-methoxy aporphine (I) fumaric acid (II) salt (III);
｛（Ⅰ）H｝+Ⅱ
ˉ
（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 |
|---|---|---|---|
| CN201210209251.1A CN103508951A (en) | 2012-06-24 | 2012-06-24 | Salts of 2-hydroxy-1-methoxyaporphine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210209251.1A CN103508951A (en) | 2012-06-24 | 2012-06-24 | Salts of 2-hydroxy-1-methoxyaporphine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103508951A true CN103508951A (en) | 2014-01-15 |
Family
ID=49892436
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210209251.1A Pending CN103508951A (en) | 2012-06-24 | 2012-06-24 | Salts of 2-hydroxy-1-methoxyaporphine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103508951A (en) |
-
2012
- 2012-06-24 CN CN201210209251.1A patent/CN103508951A/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: 20140115 |