CN103420984A - Dabigatran derivative used as prodrug, and preparation method and application thereof - Google Patents
Dabigatran derivative used as prodrug, and preparation method and application thereof Download PDFInfo
- Publication number
- CN103420984A CN103420984A CN2012101647217A CN201210164721A CN103420984A CN 103420984 A CN103420984 A CN 103420984A CN 2012101647217 A CN2012101647217 A CN 2012101647217A CN 201210164721 A CN201210164721 A CN 201210164721A CN 103420984 A CN103420984 A CN 103420984A
- Authority
- CN
- China
- Prior art keywords
- dabigatran
- formula
- ester derivative
- alkyl
- salt
- 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.)
- Granted
Links
- 0 C[n]1c(ccc(C(N(CCC(O*)=C)c2ncccc2)=C)c2)c2nc1*Nc(cc1)cc(C(N)=NC(*)=O)c1F Chemical compound C[n]1c(ccc(C(N(CCC(O*)=C)c2ncccc2)=C)c2)c2nc1*Nc(cc1)cc(C(N)=NC(*)=O)c1F 0.000 description 1
Abstract
The invention relates to a preparation method of a benzimidazole derivative shown as a general formula I, wherein R1, R2 and R3 are defined as in the specification. The invention relates to a Dabigatran derivative shown as the general formula I and non-toxic pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing these compounds as active components, and application of the compounds and the pharmaceutical composition as thrombin inhibitors.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to ester derivative of dabigatran and preparation method thereof, the pharmaceutical composition that contains these derivatives and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Background technology
Dabigatran etcxilate is a kind of novel synthetic direct thrombin inhibitor, is the prodrug of dabigatran, belongs to the thrombin inhibitors of non-peptide class, by the research and development of German Boehringer Ingelheim company.In April, 2008, at first, in Germany and Britain's listing, commodity are called Pradaxa, for preventing and treating Acute Venous thrombus (VTE).This is the oral new drug of the anticoagulation of first listing over 50 years after warfarin, have potent, without characteristics such as special medication monitoring, drug interaction are few.External, in vivo test and clinical every research all point out this product to have good curative effect and pharmaco-kinetic properties, are landmark breakthroughs in anticoagulation therapy field and potential lethality thrombus prevention field.U.S. food and Drug Administration approval Pradaxa capsule on October 19th, 2010 (dabigatran etcxilate) is preventing apoplectic and blood coagulation in rhythm abnormality (atrial fibrillation) patient is arranged.
In coagulation process, zymoplasm has important effect, and it is extracellular Insulin-Like serine protease, and on the one hand, it can make the Fibrinogen cracking become scleroproein, and the latter participates in forming the hard clot suppository matrix; On the other hand, it can activate and assemble by induced platelet, and then causes the reaction of series of secondary coagulation cascade.Dabigatran etcxilate is prodrug, is converted in vivo activated dabigatran, and dabigatran is brought into play the anticoagulation effect by direct Trombin inhibiting.Oral after stomach and intestine absorb, be converted in vivo the dabigatran with direct anticoagulant active.Medicine is incorporated into the scleroproein specific combination site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thereby has blocked final step and the thrombosis of blood coagulation waterfall network.
But the oral administration biaavailability of dabigatran etcxilate lower (<6.5%), therefore remain further to be improved.
Summary of the invention
The present invention relates to ester derivative and non-toxicity pharmacy acceptable salt thereof by the dabigatran shown in the structural formula I, and contain the pharmaceutical composition of these compounds as activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Therefore first aspect of the present invention provides ester derivative and the pharmacologically acceptable salt thereof of the dabigatran of formula I representative:
Wherein,
R
1Represent H or C
1-C
5Alkyl or the alkyl of replacement; R
2Represent H or C
1-C
3Alkyl or the alkyl of replacement; R
3Represent C
1-C
6Alkyl or the alkyl of replacement.
Preferably, the invention provides ester derivative or its pharmacologically acceptable salt, the wherein R of the dabigatran of formula I representative
1Represent H, methyl or ethyl, R
2Represent H or CH
3, R
3Represent methylidene, ethyl, propyl group, butyl, amyl group or n-hexyl.
More preferably, the invention provides the ester derivative of dabigatran of formula I representative or the compound that its pharmacologically acceptable salt is selected from following structural formula representative:
Each substituting group of objectives compound is defined as follows respectively:
I
1: R
1For-CH
3, R
2For-H, R
3For-CH
3
I
2: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
3
I
3: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
3
I
4: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
2CH
3
I
5: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
2CH
2CH
3
I
6: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
2CH
2CH
2CH
3
I
7: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
3
I
8: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
3
I
9: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
3
I
10: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
2CH
3
I
11: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
2CH
2CH
3
I
12: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
2CH
2CH
2CH
3
I
13: R
1For-CH
3, R
2For-CH
3, R
3For-CH
3
I
14: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
3
I
15: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
3
I
16: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
2CH
3
I
17: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
2CH
2CH
3
I
18: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
2CH
2CH
2CH
3
I
19: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
3
I
20: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
3
I
21: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
3
I
22: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
2CH
3
I
23: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
2CH
2CH
3
I
24: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
2CH
2CH
2CH
3
Second aspect of the present invention relates to pharmaceutical composition, and it comprises ester derivative or its pharmacologically acceptable salt of the dabigatran of at least one formula I representative, and one or more pharmaceutically acceptable carrier or vehicle.
Second aspect of the present invention relates to ester derivative and the non-toxicity pharmacy acceptable salt thereof of the dabigatran shown in the formula I, and the ester derivative that comprises the dabigatran shown in the formula I and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents as anticoagulant purposes.
The compound of formula I representative can form pharmaceutical salts with mineral acid, for example vitriol, phosphoric acid salt, hydrochloride, hydrobromate; Also can form pharmaceutical salts with organic acid, such as acetate, oxalate, Citrate trianion, succinate, gluconate, tartrate, tosilate, benzene sulfonate, mesylate, benzoate, lactic acid salt, maleate etc.Selecting and preparing suitable salt is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable dosage forms according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they are conducive to active compound is processed into to the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can be prepared according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.The compounds of this invention also can be prepared for administered parenterally or transdermal administration or mucosal, or adopts the mode administration of suppository or implants.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
At first reference (Hauel NH, Nar H, Priepke H, et al.Structure-Based Design of Novel Potent NopePtide Thrombin Inhibitors. J.Med. Chem.2002; 45:1757-1766) the ester derivative of the dabigatran shown in the synthetic dabigatran etcxilate of method and formula I:
R
1=H ,-CH
3,-CH
2CH
3R
2=H, CH
3, R
3=C
1-C
6Alkyl or the alkyl of replacement.
Take compound 1 as starting raw material, through amidation, condensation, obtain intermediate 2; Intermediate 2 is reacted with sodium hydroxide and reacts with chloroparaffin and obtain intermediate 3, and intermediate 3 reacts and obtains intermediate 4 with acidic alcohol and ammonia ethanolic soln, and intermediate 4 reacts from the Acibenzolar of different replacements the ester derivative (I that obtains dabigatran
1-32)
Embodiment 1 (suitable) 3-(2-(((the fluoro-3-of 4-(N'-(methoxycarbonyl) amidino) phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
1) preparation
1) 3-(2-(((3-cyano group-4-fluorophenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) ethyl propionate (2A) is synthetic
2-((3-cyano group-4-fluorophenyl) amino) acetic acid (1.93 g, 0.0l mo1), EDC1 (1.9 g, 0.01 mo1), I-hydroxybenzotriazole (1.3 5 g, 0.01 mo1) is dissolved in THF (35 mL) and DMF (5 mL) mixed solution.Stir 35 min in ice-water bath, rise to room temperature, slowly drip THF (15 mL) solution of 1 (3.1 g, 0.009 mo1).Finish and stir 6 h.Boil off solvent, add methylene dichloride (30 mL), with saturated brine (5 mL x 3), wash, after anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry, ice acetic acid in residuum (45 mL), reflux 2 h, be evaporated to dry, add strong aqua (15 mL) in residuum, stirring at room 30 min boil off solvent, add methylene dichloride (25 mL) in residuum, through saturated brine (5 mL x 3), wash, after anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry, and residuum, through the column chromatography purifying, obtains amorphous yellow solid 3.1 g.
2) 3-(2-(((3-cyano group-4-fluorophenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (3Aa) is synthetic
5.0 g intermediate 2A are dissolved in 200 mL ethanol, add sodium hydroxide solution 10 mL of 1N, under room temperature, stirring reaction is complete to hydrolysis, evaporate to dryness, dissolve with 20 mLDMF, adds 1.76 g methyl iodide, stirring at room 24 hours, concentrated, the post separation obtains 4.0 g target intermediates.
3) 3-(2-(((3-amidino-4-fluorophenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (4 Aa) is synthetic
4.0g intermediate 3Aa is dissolved in 100 mL ethanol, be cooled to 0 ℃, pass into dry hydrogen chloride gas to saturated, stirred overnight at room temperature, add 100 mL ethanol in the solvent evaporated resistates, slowly add the ammonia ethanolic soln under cooling conditions, and at room temperature stir 12 hours, solvent evaporated, column chromatography purification obtains white solid 2.5 g.
4) (suitable) 3-(2-(((the fluoro-3-of 4-(N'-(methoxycarbonyl) amidino) phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
1) synthetic
Upper step product (4 Aa) is dissolved in tetrahydrofuran (THF) (50 mL), adds methyl-chloroformate (0.516 g) and DIEA (3 mL), stirred overnight at room temperature, evaporate to dryness, column chromatography purification obtains white target product 1.8 g.
1H?NMR(DMSO-d
6,400?MHz)δ:?2.69(t,?J=7.1Hz,?2H,?CH
2),?3.68(s,?3H,?CH
3),?3.72(s,?3H,?CH
3),?4.22(t,?J=7.1?Hz,?2H,?CH
2),?3.?8(s,?3H,?CH
3),?5.49(d,?J=5.6,?2H,?CH
2),?6.34(br?t,?1H,?NH),?6.83~6.95(m,?2H,?ArH?),?6.9~7.05(m,?2H,?ArH),?7.06~7.18(m,?2H,?ArH),?7.38(d,?J=8.4,?1H,?ArH),?7.44(s,?1H,?ArH),?7.67(d,?J=8.4,?1H,?ArH),?8.38(m,?1H),?8.50-9.30(br?s,?2H,?NH
2),?ESI-MS:?m/z?562?[M+H]
+。
Embodiment 2-24
With reference to the operation of embodiment 1, difference is to select different phenoxy acetic acids, and different carboxylicesterss reacts from different Acibenzolar side chains, obtains the compound of following formula I.
The mensuration of embodiment 25 anticoagulating active evaluation-activated partial thromboplastin times (aPPT)
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/mL, dosage (amounting to into dabigatran calculates) gastric infusion by 10mg/Kg, pass through heart puncturing extracting blood after half an hour, add 4% matrimony vine acid sodium solution to 0.4% final concentration anti-freezing, centrifugal 5 minutes of 12000r/min, get blood plasma 0.1mL, add aPPT reagent 0.1mL, 37 ℃ of pre-temperature are after 3 minutes, the calcium chloride solution 0.1mL that adds 37 ℃ of pre-temperature, by platelet aggregation thrombin analysis-e/or determining setting time, be the aPPT value.The results are shown in Table 1.
The measurement result of table 1 activated partial thromboplastin time (aPPT)
Compound | aPPT(sec) |
Physiological saline | 21.3±4.4 |
Dabigatran etcxilate | 75.4±2.0 |
Ⅰ 3 | 165.1±2.9 |
Ⅰ 4 | 127.6±3.3 |
Ⅰ 5 | 68.5±3.7 |
Ⅰ 10 | 147.6±3.6 |
Ⅰ 12 | 135.9±3.0 |
Ⅰ 13 | 77.1±2.8 |
Ⅰ 14 | 165.2±4.7 |
Ⅰ 16 | 102.4±3.0 |
Ⅰ 17 | 95.9±3.2 |
Ⅰ 18 | 145.2±4.5 |
Ⅰ 22 | 105.9±3.1 |
Ⅰ 23 | 80.9±3.6 |
Ⅰ 24 | 112.4±3.9 |
Claims (7)
2. ester derivative or its pharmacy acceptable salt with dabigatran of formula I structure according to claim 1:
Wherein,
R
1For H, methyl or ethyl; R
2For H or CH
3R
3For methyl, ethyl, propyl group, butyl, amyl group or n-hexyl.
3. according to described ester derivative or its pharmacologically acceptable salt with dabigatran of formula I structure of claim 1-2 any one, be selected from the compound of following structural formula representative:
Wherein, R
1, R
2And R
3Be defined as follows respectively:
I
1: R
1For-CH
3, R
2For-H, R
3For-CH
3
I
2: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
3
I
3: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
3
I
4: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
2CH
3
I
5: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
2CH
2CH
3
I
6: R
1For-CH
3, R
2For-H, R
3For-CH
2CH
2CH
2CH
2CH
2CH
3
I
7: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
3
I
8: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
3
I
9: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
3
I
10: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
2CH
3
I
11: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
2CH
2CH
3
I
12: R
1For-CH
2CH
3, R
2For-H, R
3For R
3-CH
2CH
2CH
2CH
2CH
2CH
3
I
13: R
1For-CH
3, R
2For-CH
3, R
3For-CH
3
I
14: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
3
I
15: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
3
I
16: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
2CH
3
I
17: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
2CH
2CH
3
I
18: R
1For-CH
3, R
2For-CH
3, R
3For-CH
2CH
2CH
2CH
2CH
2CH
3
I
19: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
3
I
20: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
3
I
21: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
3
I
22: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
2CH
3
I
23: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
2CH
2CH
3
I
24: R
1For-CH
2CH
3, R
2For-CH
3, R
3For R
3-CH
2CH
2CH
2CH
2CH
2CH
3.
4. according to described ester derivative or its pharmacy acceptable salt with dabigatran of formula I structure of claim 1-3 any one, the salt that the ester derivative of the dabigatran that described salt is formula I structure becomes with organic acid or mineral acid.
5. ester derivative or its pharmacy acceptable salt with dabigatran of formula I structure according to claim 4, described salt can be vitriol, phosphoric acid salt, hydrochloride, hydrobromate, acetate, oxalate, Citrate trianion, succinate, gluconate, tartrate, tosilate, benzene sulfonate, mesylate, benzoate, lactic acid salt, maleate.
6. a pharmaceutical composition, it is characterized in that, comprise at least one ester derivative or its pharmaceutically acceptable medicine with dabigatran of formula I structure as described as claim 1-3 any one, and one or more pharmaceutically acceptable carrier or vehicle.
7. according to described ester derivative or the purposes of its pharmacy acceptable salt in preparing thrombin inhibitors with dabigatran of formula I structure of claim 1-3 any one.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210164721.7A CN103420984B (en) | 2012-05-24 | 2012-05-24 | Dabigatran derivative used as prodrug, and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210164721.7A CN103420984B (en) | 2012-05-24 | 2012-05-24 | Dabigatran derivative used as prodrug, and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103420984A true CN103420984A (en) | 2013-12-04 |
CN103420984B CN103420984B (en) | 2015-07-08 |
Family
ID=49646408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210164721.7A Expired - Fee Related CN103420984B (en) | 2012-05-24 | 2012-05-24 | Dabigatran derivative used as prodrug, and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103420984B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103694224A (en) * | 2013-12-17 | 2014-04-02 | 上海应用技术学院 | Dabigatran etexilate analog centered by fluorine-containing-group-modified benzene ring and synthesis method thereof |
CN109897028A (en) * | 2017-12-11 | 2019-06-18 | 上海美悦生物科技发展有限公司 | Dabigatran ester derivant and its pharmaceutical use |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101980697A (en) * | 2008-03-28 | 2011-02-23 | 贝林格尔.英格海姆国际有限公司 | Process for preparing orally administered dabigatran formulations |
WO2011061080A1 (en) * | 2009-11-18 | 2011-05-26 | Boehringer Ingelheim International Gmbh | Method for producing dabigatran etexilate |
CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
-
2012
- 2012-05-24 CN CN201210164721.7A patent/CN103420984B/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101980697A (en) * | 2008-03-28 | 2011-02-23 | 贝林格尔.英格海姆国际有限公司 | Process for preparing orally administered dabigatran formulations |
CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
WO2011061080A1 (en) * | 2009-11-18 | 2011-05-26 | Boehringer Ingelheim International Gmbh | Method for producing dabigatran etexilate |
CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103694224A (en) * | 2013-12-17 | 2014-04-02 | 上海应用技术学院 | Dabigatran etexilate analog centered by fluorine-containing-group-modified benzene ring and synthesis method thereof |
CN109897028A (en) * | 2017-12-11 | 2019-06-18 | 上海美悦生物科技发展有限公司 | Dabigatran ester derivant and its pharmaceutical use |
CN109897028B (en) * | 2017-12-11 | 2021-05-28 | 上海美悦生物科技发展有限公司 | Dabigatran etexilate derivative and pharmaceutical application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN103420984B (en) | 2015-07-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102875529B (en) | Dabigatran derivatives and preparation method thereof | |
CN102050815B (en) | Dabigatran ester derivatives as prodrug | |
CN102050814B (en) | Ester derivatives of dabigatran | |
US6642224B1 (en) | Diazepan derivatives or salts thereof | |
WO2016007046A1 (en) | Substituted 2-thioxo-imidazolidin-4-ones and spiro analogues thereof, active anti-cancer ingredient, pharmaceutical composition, medicinal preparation, method for treating prostate cancer | |
WO2024040768A1 (en) | 5-pyridine-1h-indazole compound, pharmaceutical composition, and use | |
CN106831556A (en) | Sulfamide compound and preparation method thereof and the purposes as lithate transporter inhibitors class medicine | |
CN109503548B (en) | Butylphthalide derivative and preparation method and application thereof | |
CN103420980A (en) | Dabigatran derivatives | |
CN103420985B (en) | As the dabigatran ester derivative and its production and use of prodrug | |
CN103420984B (en) | Dabigatran derivative used as prodrug, and preparation method and application thereof | |
CN103420983B (en) | Dabigatran derivative, and preparation method and application thereof | |
CN105646531B (en) | Dabigatran cyclic derivatives and its production and use | |
CN103420982B (en) | Dabigatran derivative, and preparation method and application thereof | |
CN103420994B (en) | As the dabigatran ester derivative and its production and use of prodrug | |
SK281017B6 (en) | 3,4-dihydroisoquinoline derivates, method of their preparation, pharmaceuticals them containing and their use | |
CN102993175B (en) | Dabigatran derivatives, and preparation method and application thereof | |
JP6695361B2 (en) | Deuterated thienopiperidine derivative, preparation method and use thereof | |
CZ2003835A3 (en) | Method for efficient preparation of Xa factor inhibitor | |
CN103554087A (en) | Dabigatran derivative, as well as preparation method and antithrombus application thereof | |
CN102250099A (en) | Non-peptide thrombin inhibitors as well as preparation method and medical application thereof | |
CN107141268B (en) | A kind of Paeonol phenylacetic acid compound, preparation method and medical usage | |
CN102993174A (en) | Dabigatran etexilate derivative as a prodrug | |
CN104628714A (en) | Ester derivative of dabigatran as well as preparation method and application thereof | |
CN112010774A (en) | FXIa coagulation factor inhibitor, and pharmaceutical composition and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150708 Termination date: 20210524 |