CN103086994A - Salts of isoxazole derivatives - Google Patents
Salts of isoxazole derivatives Download PDFInfo
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- CN103086994A CN103086994A CN2011103377858A CN201110337785A CN103086994A CN 103086994 A CN103086994 A CN 103086994A CN 2011103377858 A CN2011103377858 A CN 2011103377858A CN 201110337785 A CN201110337785 A CN 201110337785A CN 103086994 A CN103086994 A CN 103086994A
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Abstract
The invention relates to applications of fumarates of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholine-4-yl-methyl-phenyl)-isoxazole-3-ethylformamide and derivatives thereof, or pharmaceutically acceptable solvates in the preparation of medicines for treating cancers.
Description
Invention field
The present invention relates to the pharmaceutical chemistry field, particularly, the organic acid salt and the pharmacy thereof that the present invention relates to 5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine are used.
Background technology
For now, although the medicine for the treatment of cancer is existing a variety of, existing these medicines easily cause many and heavy untoward reaction, and the result for the treatment of of some medicines is still not ideal enough.Chinese invention patent Granted publication number has the active compound for the treatment of cancer for having described some in the patent of CN 1771235B.
Summary of the invention
The invention discloses some novel compound, the preparation method of these compounds contains the pharmaceutical composition of these compounds and the pharmacy of these compounds and composition and uses.
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 its anticancer activity is higher because of between the two synergy.
Effective preparation and a large amount of advantages that provide of using are provided surprising with significant stable, water-soluble, the anticancer activity of these compounds.
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
-The expression counter ion.
Suitable counter ion II
-The ion that is 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:
Counter ion II with above-mentioned definition
-The source reaction after this if necessary, then prepares its pharmaceutically acceptable solvate.
Suitable counter ion II
-The 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 the source is normally carried out under conventional salt-forming condition, for example, in solvent, be generally C1---C4 alkanol solvent such as ethanol, can provide under the arbitrary temp that generates required suitable speed, usually in the temperature that raises for example at the temperature of solvent refluxing, be conveniently with the molar weight that approximately waits but the slightly excessive counter ion II of preferred use
-In the situation in source with formula (I) compound and counter ion II
-The source is mixed then crystallization and is gone out required product (III).
The pharmaceutically acceptable solvate of formula (III) compound can prepare with the chemical process of routine.
Formula (I) compound can prepare for the method described in the patent of CN 1771235B according to Chinese invention patent Granted publication number.
Suitable source of counter ions is knownly can easily obtain through the business approach, and for example fumaric acid, perhaps can prepare according to known method required source of counter ions.
The stable available conventional quantitative analysis method of the compounds of this invention is measured; 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 the 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 be settled out the degree of parent free alkali in the aqueous solution of mensuration by test compound, we demonstrate good aqueous stability by discoverable type (III) compound.II wherein particularly
-Formula (III) compound of the fumaric acid radical of expression is stable especially in the aqueous solution.More surprised is II wherein
-Formula (III) compound of the fumaric acid radical of expression is abnormal stablizing in the aqueous solution.
Described test compound quantitative analysis test can ordinary method, usually 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 pharmaceutically acceptable solvate as therapeutic active substance.
Like this, the invention provides as formula (III) compound and/or the pharmaceutically acceptable solvate for the treatment of and/or suppress cancer.
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 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 to be configured to unit dosage.
Usually, activeconstituents can the 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 production for treating and/or inhibition cancer.
The below provides embodiments of the invention and is used for further illustrating and describing in more detail the present invention.
Embodiment 1
5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate
5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine 46.6 grams (0.1mol) and fumaric acid 11.7 (0.1mol) gram are dissolved in 1000 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 5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate crystal, leach 5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 52.9 gram products.
Embodiment 2
5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate
5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate 45.9 grams and fumaric acid 11.7 grams are stirred to solid in 1000 milliliters of ethanol that refluxes all dissolve.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 5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate crystal, leach 5-(2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine fumarate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 53.6 gram 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 be thought can not limit the present invention to explanation of the present invention.
Claims (2)
- (1.5-2,4-dihydroxyl-5-sec.-propyl-phenyl)-4-(4-morpholine-4-ylmethyl-phenyl)-isoxazoles-3-formyl ethamine (I) fumaric acid (II) salt (III).
- 2. the application of the compound of claim 1 in the medicine of preparation treatment cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103377858A CN103086994A (en) | 2011-10-31 | 2011-10-31 | Salts of isoxazole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103377858A CN103086994A (en) | 2011-10-31 | 2011-10-31 | Salts of isoxazole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103086994A true CN103086994A (en) | 2013-05-08 |
Family
ID=48200178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011103377858A Pending CN103086994A (en) | 2011-10-31 | 2011-10-31 | Salts of isoxazole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103086994A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771235A (en) * | 2003-02-11 | 2006-05-10 | 弗奈利斯(剑桥)有限公司 | Isoxazole compounds |
-
2011
- 2011-10-31 CN CN2011103377858A patent/CN103086994A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771235A (en) * | 2003-02-11 | 2006-05-10 | 弗奈利斯(剑桥)有限公司 | Isoxazole compounds |
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| PB01 | Publication | ||
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130508 |