CN103420984B - 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
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- CN103420984B CN103420984B CN201210164721.7A CN201210164721A CN103420984B CN 103420984 B CN103420984 B CN 103420984B CN 201210164721 A CN201210164721 A CN 201210164721A CN 103420984 B CN103420984 B CN 103420984B
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- formula
- dabigatran
- ester derivative
- salt
- dabigatran ester
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- 0 CCC(CC1)C(*Nc(cc2)cc(C(N)=NC([O+])=O)c2F)=Nc2c1ccc(C(N(CCC(O*)=O)c1ncccc1)=O)c2 Chemical compound CCC(CC1)C(*Nc(cc2)cc(C(N)=NC([O+])=O)c2F)=Nc2c1ccc(C(N(CCC(O*)=O)c1ncccc1)=O)c2 0.000 description 1
Abstract
The invention relates to a preparation method of a benzimidazole derivative of a general formula I, wherein R1, R2 and R3 are defined in the specification. The invention relates to a Dabigatran derivative of 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 pharmaceutical synthesis field, ester derivative being specifically related to dabigatran and preparation method thereof, the pharmaceutical composition containing these derivatives and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Background technology
Dabigatran etcxilate is a kind of direct thrombin inhibitor of novel synthesis, is the prodrug of dabigatran, belongs to the thrombin inhibitors of non-peptide class, is researched and developed by German Boehringer Ingelheim company.In April, 2008, 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 anticoagulation of first listing over 50 years after warfarin, have potent, without the need to features such as special Medication monitor, 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's approval Pradaxa capsule on October 19th, 2010 (dabigatran etcxilate) are for there to be preventing apoplectic and blood coagulation in rhythm abnormality (atrial fibrillation) patient.
In coagulation process, zymoplasm has important effect, and it is extracellular Insulin-Like serine protease, and on the one hand, it can make Fibrinogen cracking become scleroproein, and the latter participates in forming 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 into activated dabigatran in vivo, and dabigatran plays anticoagulation effect by direct Trombin inhibiting.Oral after gastrointestinal absorption, be converted into the dabigatran with direct anticoagulant active in vivo.Medicine is incorporated into the scleroproein specific binding site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thus has blocked final step and the thrombosis of blood coagulation waterfall network.
But the oral administration biaavailability of dabigatran etcxilate lower (<6.5%), therefore needs to be improved further.
Summary of the invention
The present invention relates to by the ester derivative of the dabigatran shown in structural formula I and non-toxic pharmacy acceptable salt thereof, and containing these compounds as the pharmaceutical composition of 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 representated by formula I:
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 representated by formula I
1represent H, methyl or ethyl, R
2represent H or CH
3, R
3represent methyl, ethyl, propyl group, butyl, amyl group or n-hexyl.
More preferably, the invention provides the ester derivative of the dabigatran representated by formula I or its pharmacologically acceptable salt and be selected from compound representated by following structural formula:
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 representated by least one formula I, and one or more pharmaceutically acceptable carrier or vehicle.
Second aspect of the present invention relates to ester derivative and the non-toxic pharmacy acceptable salt thereof of the dabigatran shown in formula I, and the ester derivative of the dabigatran shown in contained I and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents as anticoagulant purposes.
Compound representated by formula I can form pharmaceutical salts with mineral acid, such as vitriol, phosphoric acid salt, hydrochloride, hydrobromate; Also pharmaceutical salts can be formed 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 separately or with the form administrations 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 being processed into 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-bowel or topical, preferred oral and injection form administration.Capsule and tablet etc. can be comprised 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.
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 method synthesis dabigatran etcxilate and the dabigatran shown in formula I:
R
1=H ,-CH
3,-CH
2cH
3; R
2=H, CH
3, R
3=C
1-C
6alkyl or the alkyl of replacement.
With compound 1 for starting raw material, obtain intermediate 2 through amidation, condensation; Intermediate 2 and sodium hydroxide are reacted and be obtained by reacting intermediate 3 with chloroparaffin again, intermediate 3 is obtained by reacting intermediate 4 with acidic alcohol and ammonia ethanolic soln, and intermediate 4 and the Acibenzolar of different replacement are obtained by reacting the ester derivative (I of dabigatran
1-32)
Embodiment 1 (suitable) 3-(2-(((the fluoro-3-of 4-(N'-(methoxycarbonyl) amidino) phenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
1) preparation
1) synthesis of 3-(2-(((3-cyano group-4-fluorophenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate (2A)
2-((3-cyano group-4-fluorophenyl) is 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 stirring 6 h.Boil off solvent, add methylene dichloride (30 mL), wash with saturated brine (5 mL x 3), filter after anhydrous sodium sulfate drying, filtrate is concentrated into dry, ice acetic acid (45 mL) in residuum, reflux 2 h, be evaporated to dry, strong aqua (15 mL) is added in residuum, stirring at room temperature 30 min boils off solvent, methylene dichloride (25 mL) is added in residuum, wash through saturated brine (5 mL x 3), filter after anhydrous sodium sulfate drying, filtrate is concentrated into dry, residuum is through purification by column chromatography, obtain amorphous yellow solid 3.1 g.
2) synthesis of 3-(2-(((3-cyano group-4-fluorophenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (3Aa)
Be dissolved in 200 mL ethanol by 5.0 g intermediate 2A, add sodium hydroxide solution 10 mL of 1N, stirred at ambient temperature reaction is complete to hydrolysis, evaporate to dryness, dissolves with 20 mLDMF, adds 1.76g methyl iodide, stirring at room temperature 24 hours, concentrated, post is separated and obtains 4.0 g title intermediate.
3) synthesis of 3-(2-(((3-amidino-4-fluorophenyl) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (4 Aa)
4.0g intermediate 3Aa is dissolved in 100 mL ethanol, be cooled to 0 DEG C, pass into dry hydrogen chloride gas to saturated, stirred overnight at room temperature, add 100 mL ethanol in solvent evaporated resistates, slowly add ammonia ethanolic soln in the cooling condition, 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) is amino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
1) synthesis
Be dissolved in tetrahydrofuran (THF) (50 mL) by upper step product (4 Aa), (0.516 g) and DIEA (3 mL), stirred overnight at room temperature, evaporate to dryness, and column chromatography purification obtains target product 1.8 g of white to add methyl-chloroformate.
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 time (aPPT)
By the kunming mice of quality 18-20g, random packet, often organizes 10, overnight fasting.Dabigatran etcxilate and target compound to be measured are suspended or be dissolved in the aqueous solution of Xylo-Mucine of 1%, be made into the concentration of 1mg/mL, by dosage (amounting to into the dabigatran to calculate) gastric infusion of 10mg/Kg, heart puncturing extracting blood is passed through 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 DEG C of pre-temperature are after 3 minutes, add the calcium chloride solution 0.1mL of 37 DEG C of pre-temperature, by platelet aggregation thrombin analysis-e/or determining setting time, be 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 (5)
1. there is dabigatran ester derivative or its pharmacologically acceptable salt of formula I structure, be selected from the compound representated by following structural formula:
Wherein, R
1, R
2and R
3be defined as follows respectively:
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
10: R
1for-CH
2cH
3, R
2for-H, R
3for-CH
2cH
2cH
2cH
3;
I
12: R
1for-CH
2cH
3, R
2for-H, R
3for-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
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
22: R
1for-CH
2cH
3, R
2for-CH
3, R
3for-CH
2cH
2cH
2cH
3;
I
23: R
1for-CH
2cH
3, R
2for-CH
3, R
3for-CH
2cH
2cH
2cH
2cH
3;
I
24: R
1for-CH
2cH
3, R
2for-CH
3, R
3for-CH
2cH
2cH
2cH
2cH
2cH
3.
2. dabigatran ester derivative or its pharmacy acceptable salt with formula I structure according to claim 1, salt formed by the dabigatran ester derivative that described salt is formula I structure and organic acid or mineral acid.
3. dabigatran ester derivative or its pharmacy acceptable salt with formula I structure according to claim 2, 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.
4. a pharmaceutical composition, it is characterized in that, comprise the dabigatran ester derivative with formula I structure of at least one as described in any one of claim 1-3 or its pharmaceutically acceptable medicine, and one or more pharmaceutically acceptable carrier or vehicle.
5. the dabigatran ester derivative with formula I structure according to any one of claim 1-3 or its pharmacy acceptable salt are preparing the purposes in thrombin inhibitors.
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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 |
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 |
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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 |
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 |
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