CN103087052A - Thiophene derivatives and medicinal use thereof - Google Patents
Thiophene derivatives and medicinal use thereof Download PDFInfo
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- CN103087052A CN103087052A CN2011103378009A CN201110337800A CN103087052A CN 103087052 A CN103087052 A CN 103087052A CN 2011103378009 A CN2011103378009 A CN 2011103378009A CN 201110337800 A CN201110337800 A CN 201110337800A CN 103087052 A CN103087052 A CN 103087052A
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Abstract
The invention relates to fumarates of 5-(4-hydroxy-3,3-dimethyl-1-alkynyl)-3-((R)-N-((1R,4S)-4-hydroxy-4-(((S)tetrahydrofuran-3-oxy)methyl)cyclohexyl-4-methyl-cyclohexyl-3-alkenyl-formamide)thiophene-2-formic acid or derivatives, or pharmaceutically acceptable solvates thereof, and an applications of the fumarates or the solvates in the preparation of medicines for treating the hepatitis c virus infection.
Description
Invention field
The present invention relates to the pharmaceutical chemistry field, particularly, the present invention relates to 5-(4-hydroxyl-3,3-dimethyl-1-alkynyl)-3-(use by the organic acid salt of (R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid and pharmacy thereof.
Background technology
For now, although the medicine for the treatment of infection with hepatitis C virus 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.PCT International Publication number has the active compound for the treatment of infection with hepatitis C virus for having described some in the patent application of WO2011/088345A1.
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 antiviral activity is higher because of between the two synergy.
Surprising and significant stable, water-soluble, the antiviral activity of these compounds is that effectively preparation provides advantages with a large amount of uses.
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 be that the method described in the patent application of WO2011/088345A1 prepares according to the PCT application 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 formula (III) compound and/or pharmaceutically acceptable solvate as treatment and/or inhibition and/or prevention of hepatitis C infection.
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 and/or prevention of hepatitis C infection.
The below provides embodiments of the invention and is used for further illustrating and describing in more detail the present invention.
Embodiment 1
5-(4-hydroxyl-3,3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl 4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate
With 5-(4-hydroxyl-3,3-dimethyl-1-alkynyl) ((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid 56.0 grams (0.1mol) and fumaric acid 11.7 (0.1mol) gram are dissolved in 1000 milliliters of the ethanol of boiling-3-.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-(4-hydroxyl-3, 3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate crystal, leach 5-(4-hydroxyl-3, 3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 62.4 gram products.
Embodiment 2
5-(4-hydroxyl-3,3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate
With 5-(4-hydroxyl-3,3-dimethyl-1-alkynyl) ((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate 55.1 grams and fumaric acid 11.7 grams are stirred to solid and all dissolve-3-in 1000 milliliters of ethanol that refluxes.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-(4-hydroxyl-3, 3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate crystal, leach 5-(4-hydroxyl-3, 3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid fumarate crystal, with washing with alcohol and dry under 50 ℃ of vacuum conditions, get 60.4 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-(4-hydroxyl-3,3-dimethyl-1-alkynyl)-3-((R)-N-((1R, 4S)-4-hydroxyl-4-(((S) tetrahydrofuran (THF)-3-oxygen) methyl) hexanaphthene-4-methyl-cyclohexyl-3-alkene-methane amide) thiophene-2-carboxylic acid (I) fumaric acid (II) salt (III).
2. the application of the compound of claim 1 in the medicine of preparation treatment infection with hepatitis C virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103378009A CN103087052A (en) | 2011-10-31 | 2011-10-31 | Thiophene derivatives and medicinal use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103378009A CN103087052A (en) | 2011-10-31 | 2011-10-31 | Thiophene derivatives and medicinal use thereof |
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| Publication Number | Publication Date |
|---|---|
| CN103087052A true CN103087052A (en) | 2013-05-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2011103378009A Pending CN103087052A (en) | 2011-10-31 | 2011-10-31 | Thiophene derivatives and medicinal use thereof |
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| CN (1) | CN103087052A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006119646A1 (en) * | 2005-05-13 | 2006-11-16 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
| CN101568538A (en) * | 2006-11-15 | 2009-10-28 | Viro化学制药公司 | Thiophene analogues for the treatment or prevention of flavivirus infections |
| WO2011088345A1 (en) * | 2010-01-15 | 2011-07-21 | Gilead Sciences, Inc. | Inhibitors of flaviviridae viruses |
-
2011
- 2011-10-31 CN CN2011103378009A patent/CN103087052A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006119646A1 (en) * | 2005-05-13 | 2006-11-16 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
| CN101218224A (en) * | 2005-05-13 | 2008-07-09 | Viro化学制药公司 | Compounds and methods for the treatment or prevention of flavivirus infections |
| CN101568538A (en) * | 2006-11-15 | 2009-10-28 | Viro化学制药公司 | Thiophene analogues for the treatment or prevention of flavivirus infections |
| WO2011088345A1 (en) * | 2010-01-15 | 2011-07-21 | Gilead Sciences, Inc. | Inhibitors of flaviviridae viruses |
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Application publication date: 20130508 |