CN103087052A - Thiophene derivatives and medicinal use thereof - Google Patents
Thiophene derivatives and medicinal use thereof Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- methyl
- compound
- hydroxyl
- pharmaceutically acceptable
- cyclohexyl
- 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.)
- Pending
Links
- 150000003577 thiophenes Chemical class 0.000 title 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 12
- 239000001530 fumaric acid Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 4
- 241000711549 Hepacivirus C Species 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012453 solvate Substances 0.000 abstract description 12
- -1 (S)tetrahydrofuran-3-oxy Chemical group 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 208000010710 hepatitis C virus infection Diseases 0.000 abstract description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 abstract 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract 1
- 150000002500 ions Chemical class 0.000 description 12
- 238000012360 testing method Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WVWYKLFOYGDSLI-WLHGVMLRSA-N OC(/C=C/C(O)=O)=O.OC(C1=CC=CS1)=O Chemical compound OC(/C=C/C(O)=O)=O.OC(C1=CC=CS1)=O WVWYKLFOYGDSLI-WLHGVMLRSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 238000003860 storage Methods 0.000 description 5
- 239000003513 alkali Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 3
- 238000004445 quantitative analysis Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 2
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 2
- 229960001661 ursodiol Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103087052A true CN103087052A (en) | 2013-05-08 |
Family
ID=48200232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011103378009A Pending CN103087052A (en) | 2011-10-31 | 2011-10-31 | Thiophene derivatives and medicinal use thereof |
Country Status (1)
| Country | Link |
|---|---|
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103570626A (en) | Salt of dihydropyrimidine derivative | |
| CN103450184A (en) | Salt of scoulerine derivatives | |
| CN103833757A (en) | Salt of methoxy-canthin-6-tone derivative | |
| CN103626773A (en) | Salt of vasicine derivative | |
| CN103087052A (en) | Thiophene derivatives and medicinal use thereof | |
| CN103626700A (en) | Salt of cyclopropane dicarboxamide derivative | |
| CN103058994A (en) | Urea derivative and medicinal application thereof | |
| CN103121993A (en) | Salt of 2,6-dichloro-3-fluorophenyl derivative | |
| CN103450185A (en) | Salts of dehydrocheilanthifoline derivatives | |
| CN103374008A (en) | Salt of chelerythrine derivative | |
| CN103374010A (en) | Salt of methoxy dihydronitidine derivate | |
| CN103121968A (en) | Salt of quinoline derivative | |
| CN103772475A (en) | Conimine derivative salts | |
| CN103833758A (en) | Salt of hydroxyl canthin-6-one derivative | |
| CN103242241A (en) | Salt of cyclopropane-carboxylic acid amide derivative | |
| CN103910677A (en) | Salt of corydine derivative | |
| CN103086994A (en) | Salts of isoxazole derivatives | |
| CN103121994A (en) | Salt of pyrrole derivative | |
| CN103059022A (en) | Purine derivative and pharmaceutical application thereof | |
| CN103012303A (en) | Isoxazole derivative and drug use thereof | |
| CN103086982A (en) | Pyrimidine derivative salts | |
| CN103121971A (en) | Salt for aryl urea derivant | |
| CN103058937A (en) | Pyrimidine derivative and medicinal application thereof | |
| CN103012166A (en) | Cyclohexanol derivative and pharmaceutical application thereof | |
| CN103374007A (en) | Salt of dihydrochelerythrine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130508 |