CN103833758A - Salt of hydroxyl canthin-6-one derivative - Google Patents
Salt of hydroxyl canthin-6-one derivative Download PDFInfo
- Publication number
- CN103833758A CN103833758A CN201210485767.9A CN201210485767A CN103833758A CN 103833758 A CN103833758 A CN 103833758A CN 201210485767 A CN201210485767 A CN 201210485767A CN 103833758 A CN103833758 A CN 103833758A
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- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- salt
- hydroxyl
- canthin
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- 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
- C07D471/16—Peri-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to 4-methoxyl-5-hydroxyl canthin-6-one and a fumarate or a pharmaceutically acceptable solvate of a derivative thereof as well as an application thereof in preparation of a TNF-Alpha inhibitor medicine.
Description
Invention field
The present invention relates to pharmaceutical chemistry field, particularly, the present invention relates to 4-methoxy-5-hydroxycantin-6-one organic acid salt and pharmacy application thereof.
Background technology
For now, although existing a variety of as the medicine of TNF-alpha inhibitor, existing these medicines easily cause many and heavy untoward reaction, and the result for the treatment of of existing medicine is still not ideal enough.In the patent specification that Chinese invention patent Granted publication number is CN 101036646B, describe some and there is the active compound that TNF-α suppresses.
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 in surprise it to have TNF-α to suppress activity higher because of synergy between the two.
Surprising and the significant stability of these compounds, water-soluble, to suppress active be effectively preparation and a large amount of advantages that provide that use.
Therefore, the invention provides a kind of formula III compound:
｛（Ⅰ）H｝+Ⅱ
-;
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 at the temperature of for example solvent refluxing of temperature raising, 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 101036646B according to Chinese invention patent Granted publication number.
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 II wherein
-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 TNF-alpha inhibitor active substance.
Like this, the invention provides formula III compound and/or the pharmaceutically acceptable solvate as TNF-alpha inhibitor.
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 formula III compound and/or pharmaceutically acceptable solvate of containing to have TNF-α in production and suppress the application on active medicine.
Provide embodiments of the invention below for further illustrating and describe in more detail the present invention.
Embodiment 1
4-methoxy-5-hydroxycantin-6-one fumarate
Compound 4-methoxy-5-hydroxycantin-6-one 2.66 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, in the temperature environment of 0-5 ℃, leave standstill a few hours, separate out 4-methoxy-5-hydroxycantin-6-one fumarate crystal, leach 4-methoxy-5-hydroxycantin-6-one fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 3.82 grams of products.
Embodiment 2
4-methoxy-5-hydroxycantin-6-one fumarate
1.17 grams of 2.66 grams of compound 4-methoxy-5-hydroxycantin-6-one 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.In the temperature environment of 0-5 ℃, leave standstill a few hours, separate out 4-methoxy-5-hydroxycantin-6-one fumarate crystal, leach 4-methoxy-5-hydroxycantin-6-one fumarate crystal, with washing with alcohol dry under 50 ℃ of vacuum conditions, obtain 3.82 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)
1.4-methoxyl group-5-hydroxyl canthinone (I) fumaric acid (II) salt (III);
2. the application of the compound of claim 1 in preparation TNF-alpha inhibitor medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210485767.9A CN103833758A (en) | 2012-11-26 | 2012-11-26 | Salt of hydroxyl canthin-6-one derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210485767.9A CN103833758A (en) | 2012-11-26 | 2012-11-26 | Salt of hydroxyl canthin-6-one derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103833758A true CN103833758A (en) | 2014-06-04 |
Family
ID=50797691
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210485767.9A Pending CN103833758A (en) | 2012-11-26 | 2012-11-26 | Salt of hydroxyl canthin-6-one derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103833758A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693718A (en) * | 2016-03-14 | 2016-06-22 | 中国药科大学 | Canthin-6-ketone derivative and preparation method and application thereof |
-
2012
- 2012-11-26 CN CN201210485767.9A patent/CN103833758A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693718A (en) * | 2016-03-14 | 2016-06-22 | 中国药科大学 | Canthin-6-ketone derivative and preparation method and application thereof |
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| 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: 20140604 |