CN102993174A - Dabigatran etexilate derivative as a prodrug - Google Patents
Dabigatran etexilate derivative as a prodrug Download PDFInfo
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- CN102993174A CN102993174A CN201110265002XA CN201110265002A CN102993174A CN 102993174 A CN102993174 A CN 102993174A CN 201110265002X A CN201110265002X A CN 201110265002XA CN 201110265002 A CN201110265002 A CN 201110265002A CN 102993174 A CN102993174 A CN 102993174A
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- dabigatran
- formula
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- KSGXQBZTULBEEQ-UHFFFAOYSA-N CCCCCCOC(/N=C(/c(cc1)ccc1NCc1nc2cc(C(N(CCC(OCC)=O)c3ccccn3)=O)ccc2[n]1C)\N)=O Chemical compound CCCCCCOC(/N=C(/c(cc1)ccc1NCc1nc2cc(C(N(CCC(OCC)=O)c3ccccn3)=O)ccc2[n]1C)\N)=O KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 1
- YBSJFWOBGCMAKL-UHFFFAOYSA-N C[n](c(CNc(cc1)ccc1C(N)=N)nc1c2)c1ccc2C(N(CCC(O)=O)c1ccccn1)=O Chemical compound C[n](c(CNc(cc1)ccc1C(N)=N)nc1c2)c1ccc2C(N(CCC(O)=O)c1ccccn1)=O YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 1
- 0 C[n](c(CNc(cc1)ccc1C(N)=NCOC(O*)=O)nc1c2)c1ccc2C(N(CCC(O*)=O)c1ccccn1)=O Chemical compound C[n](c(CNc(cc1)ccc1C(N)=NCOC(O*)=O)nc1c2)c1ccc2C(N(CCC(O*)=O)c1ccccn1)=O 0.000 description 1
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Abstract
The invention relates to a preparation method of a benzimidazole derivative represented by the general formula I, wherein R1 and R2 are respectively defined in the specifications. The invention relates to a dabigatran etexilate derivative represented by the general formula I, a non-toxic pharmaceutically acceptable salt thereof, medicine compositions comprising the compounds as active components, and applications of the compounds and the medicine compositions as thrombin inhibitors. The general formula I is represented below.
Description
Technical field
The invention belongs to medical technical field, be specifically related to ester derivative of dabigatran and preparation method thereof, contain the pharmaceutical composition of these derivatives and described compound and pharmaceutical composition as the purposes of thrombin inhibitors.
Background technology
Dabigatran etcxilate (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.In April, 2008, at first in Germany and Britain's listing, commodity are called Pradaxa, are used for control Acute Venous thrombus (VTE).This is the oral new drug of the anticoagulation of first listing over 50 years after warfarin, is another milestone 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.
Zymoplasm is extracellular Insulin-Like serine protease, has vital role in coagulation process, and on the one hand, it can make the Fibrinogen cracking become scleroproein, and the latter participates in consisting of the hard clot suppository matrix; On the other hand, it can activate and gathering 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.Dabigatran etcxilate is a kind of novel synthetic direct thrombin inhibitor, is for oral prodrug, belongs to the thrombin inhibitors of non-peptide class.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 remains 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 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 of formula I representative:
General formula I
Wherein,
R
1Be H or C
1-C
5Alkyl, R
2Be C
1-C
8Alkyl 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
1Be H or C
1-C
2Alkyl, R
2Be C
1-C
8Alkyl.
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:
General formula I
Each substituting group of objectives compound is defined as follows respectively:
I
1: R
1For-CH
3, R
2For-CH
3
I
2: R
1For-CH
3, R
2For-CH
2CH
3
I
3: R
1For-CH
3, R
2For-CH
2CH
2CH
3
I
4: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
3
I
5: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
3
I
6: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
3
I
7: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
3
I
8: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
2CH
3
I
9: R
1For-CH
2CH
3, R
2For-CH
3
I
10: R
1For-CH
2CH
3, R
2For-CH
2CH
3
I
11: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
3
I
12: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
3
I
13: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
3
I
14: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
3
I
15: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
3
I
16: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
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 a formula I representative, and one or more pharmaceutically acceptable carrier or vehicle.
The 3rd 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 comprise the ester derivative of 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 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, perhaps 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.
Reference (Hauel NH, Nar H, Priepke H, et al.Structure-Based Design ofNovel Potent NopePtide Thrombin Inhibitors.J.Med.Chem.2002 at first; 45:1757-1766) the ester derivative of the dabigatran shown in the synthetic dabigatran etcxilate of method and the formula I:
General formula I
R
1=H ,-CH
3,-CH
2CH
3R
2=C
1-C
8Alkyl or the alkyl of replacement.
Take 3-nitro-4-chloro-benzoic acid as starting raw material, obtain 3-nitro-4-methyl amino-phenylformic acid with the aqueous methylamine solution reaction, with the sulfur oxychloride reaction, become acyl chlorides (intermediate 5) again; PA and ethyl propenoate reaction obtain N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 2), and intermediate 2 obtains intermediate 6 with intermediate 5 reactions; Intermediate 6 reduced under the catalysis of palladium carbon obtain intermediate 7, obtain intermediate 8 through amidation, condensation again; Intermediate 8 and sodium hydroxide reaction are obtained intermediate 9 with the chloroparaffin reaction again, and intermediate 9 obtains intermediate 10 with acidic alcohol and the reaction of ammonia ethanolic soln, and intermediate 10 reacts the ester derivative (I that obtains dabigatran from the Acibenzolar of different replacements
1-16)
Embodiment 1
3-(2-(((4-(N '-(((methoxycarbonyl) oxygen base) methyl) amidino) phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
1) preparation
1) 3-(pyridine-2-imines)-ethyl propionate (2) is synthetic
Under the nitrogen protection, in compound PA (11.2g, 0.12mol), add ethyl propenoate (13.8g, 0.14mol), at 10 ℃ of lower stirring and refluxing 24h, the elimination precipitate, remaining concentrated rear column chromatography purification obtains white solid 10g.
2) 4-amine methyl-3-nitro-phenylformic acid (4) is synthetic
The aqueous methylamine solution 50mL of adding 33% in 4-chloro-3-nitrobenzoic acid (10.0g, 0.05mol) makes system 110 ℃ of lower reactions 6 hours.Add glacial acetic acid the pH value is transferred to 4.Hold over night is separated out a large amount of yellow solids, and elimination solution gets yellow solid 7.1g.
3) 4-amine methyl-3-nitro-Benzoyl chloride (5) is synthetic
Compound 4 (5.8g, 0.03mol) is dissolved in the 70mol thionyl chloride, refluxed 2 hours, concentrating under reduced pressure, resistates add the methylene dichloride of 30mL, make its dissolving, directly carry out next step reaction.
4) 3-[(4-amine methyl-3-nitro-benzoyl)-pyridine-2-imines]-ethyl propionate (6) synthetic
Compound 2 (5.8g, 0.03mol) is dissolved in the triethylamine of the methylene dichloride of 15mL and 15mL the dichloromethane solution of the little slow adding compound 6 of room temperature.Mixed system was at room temperature reacted 12 hours, the elimination precipitate, resistates obtains amorphous yellow solid 10.5g through column chromatography purification.
5) 3-[(3-amino-4-amine methyl-benzoyl)-pyridine-2-imines]-ethyl propionate (7) synthetic
Compound 6 (10.5g, 0.03mol) is dissolved in the 120mL dehydrated alcohol, adds 1.0g 10% palladium carbon, reaction is spent the night, and filters, the concentrated compound 9.2g that obtains.
6) 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate (8) synthetic
1-(4-cyano group-benzene imines)-acetic acid (1.8g, 0.01mol), EDC1 (1.9g, 0.01mol), I-hydroxybenzotriazole (1.35g, 0.01mol) are dissolved in THF (35ml) and DMF (5ml) mixed solution.Stir 35min in the ice-water bath, rise to room temperature, slowly drip THF (15ml) solution of 7 (3.1g, 0.009mol).Finish and stir 6h.Boil off solvent, add methylene dichloride (30ml), wash with saturated brine (5mLx3), behind anhydrous sodium sulfate drying, filter, filtrate is concentrated into dried, ice acetic acid in the residuum (45ml), reflux 2h is evaporated to dried, add strong aqua (15ml) in the residuum, stirring at room 30min boils off solvent, adds methylene dichloride (25ml) in the residuum, washs through saturated brine (5mLx3), filter behind the anhydrous sodium sulfate drying, filtrate is concentrated into dried, and residuum gets amorphous yellow solid 3.1g through the column chromatography purifying.
7) N-[[2-(((4-cyano group-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl)-carbonyl]-N-(pyridine-2-yl)-Beta-alanine methyl esters (9a) synthetic
5.0g intermediate 8 is dissolved in the 200mL ethanol, adds the sodium hydroxide solution 10mL of 1N, stirring reaction is complete to hydrolysis under the room temperature, evaporate to dryness with the 20mLDMF dissolving, adds the 1.76g methyl iodide, stirring at room 24 hours, concentrated, the post separation obtains 4.0g target intermediate.
8) N-[[2-(((4-carbamimido-phenyl)-amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl)-carbonyl]-N-(pyridine-2-yl)-Beta-alanine methyl esters (10a) synthetic
4.0g intermediate 9a is dissolved in the 100mL ethanol, be cooled to 0 ℃, pass into dry hydrogen chloride gas to saturated, stirred overnight at room temperature, add 100mL ethanol in the solvent evaporated resistates, under cooling conditions, slowly add the ammonia ethanolic soln, and at room temperature stirred 12 hours, solvent evaporated, column chromatography purification obtain white solid 2.5g.
9) 3-(2-(((4-(N '-(((methoxycarbonyl) oxygen base) methyl) amidino) phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
1) synthetic
Product of upper step (10a) is dissolved among the DMF (50ml), adds chloromethylchloroformate (2.0g) and DIEA (3ml), stirred overnight at room temperature, evaporate to dryness, column chromatography purification obtain the target product 1.8g of white.
1HNMR(DMAO-d
6，400MHz)δ：1.13(t，J＝8.4Hz，3H，CH
3)，1.45(d，J＝8.4Hz，3H，CH
3)，2.68(t，J＝14.4Hz，2H，CH
2)，3.77(s，3H，CH
3)，3.95-4.01(m，2H，CH
2)，3.95-4.01(m，2H，CH
2)，4.61(d，J＝5.6Hz，2H，CH
2)，6.89(d，J＝7.6Hz，1H，ArH)，6.96(t，1H，NH)，7.10-7.14(m，1H，ArH)，7.16(dd，J＝8.8Hz，J＝1.6Hz，1H，ArH)，7.20-7.24(m，4H，ArH)，7.42(d，J＝8.6Hz，1H，ArH)，7.47(d，J＝1.6Hz，1H，ArH)，7.52(dt，J＝10.4Hz，J＝1.6Hz，1H，ArH)，8.40(dq，J＝4.8Hz，J＝1.6Hz，1H，ArH)，8.50-9.30(br s，2H，NH
2)，ESI-MS：m/z 574[M+H]
+。
Embodiment 2-16
With reference to the operation of embodiment 1, difference is to select different carboxylicesterss to react with different Acibenzolar side chain, obtains the compound of following formula I.
Embodiment 17
The mensuration of anticoagulating active evaluation-activated partial thromboplastin time (aPPT)
With the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate and target compound to be measured 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 with platelet aggregation thrombin analysis-e/or determining setting time, is 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 | 20.2±4.4 |
| Dabigatran etcxilate | 69.4±2.1 |
| I 1 | 89.3±2.0 |
| I 6 | 45.8±3.2 |
| I 7 | 105.1±1.8 |
| I 8 | 77.5±2.7 |
| I 9 | 65.8±2.1 |
| I 11 | 97.0±2.4 |
| I 16 | 98.4±3.6 |
Claims (5)
1. the ester derivative or its pharmacy acceptable salt that have the dabigatran of formula I structure:
General formula I
Wherein,
R
1Be H or C
1-C
5Alkyl; R
2Be C
1-C
8Alkyl or the alkyl of replacement.
2. ester derivative or its pharmacy acceptable salt, the wherein R with dabigatran of formula I structure according to claim 1
1Be H or C
1-C
2Alkyl, R
2Be C
1-C
8Alkyl.
3. each described ester derivative or its pharmacy acceptable salt with dabigatran of formula I structure according to claim 1-2, described derivative is selected from the compound of following structural formula representative:
General formula I
Wherein, R
1And R
2Be defined as follows respectively:
I
1: R
1For-CH
3, R
2For-CH
3
I
2: R
1For-CH
3, R
2For-CH
2CH
3
I
3: R
1For-CH
3, R
2For-CH
2CH
2CH
3
I
4: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
3
I
5: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
3
I
6: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
3
I
7: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
3
I
8: R
1For-CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
2CH
3
I
9: R
1For-CH
2CH
3, R
2For-CH
3
I
10: R
1For-CH
2CH
3, R
2For-CH
2CH
3
I
11: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
3
I
12: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
3
I
13: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
3
I
14: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
3
I
15: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
3
I
16: R
1For-CH
2CH
3, R
2For-CH
2CH
2CH
2CH
2CH
2CH
2CH
2CH
3
4. pharmaceutical composition, it comprises at least a such as each described ester derivative or its pharmacy acceptable salt with dabigatran of formula I structure of claim 1-3, and one or more pharmaceutically acceptable carrier or vehicle.
5. each described ester derivative or its pharmacy acceptable salt with dabigatran of formula I structure of claim 1-4 is in the purposes aspect the thrombin inhibitors medicine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110265002XA CN102993174A (en) | 2011-09-08 | 2011-09-08 | Dabigatran etexilate derivative as a prodrug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110265002XA CN102993174A (en) | 2011-09-08 | 2011-09-08 | Dabigatran etexilate derivative as a prodrug |
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| Publication Number | Publication Date |
|---|---|
| CN102993174A true CN102993174A (en) | 2013-03-27 |
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ID=47922345
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|---|---|---|---|
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1088702C (en) * | 1997-02-18 | 2002-08-07 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| US20030130265A1 (en) * | 2001-09-08 | 2003-07-10 | Boehringer Ingelheim Pharma Kg | Benzimidazole derivatives, a process for their manufacture and use as a medicine |
| CN102050814A (en) * | 2009-11-06 | 2011-05-11 | 北京美倍他药物研究有限公司 | Ester derivatives of dabigatran |
| CN102050815A (en) * | 2009-11-06 | 2011-05-11 | 北京美倍他药物研究有限公司 | Dabigatran ester derivatives as prodrug |
-
2011
- 2011-09-08 CN CN201110265002XA patent/CN102993174A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1088702C (en) * | 1997-02-18 | 2002-08-07 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| US20030130265A1 (en) * | 2001-09-08 | 2003-07-10 | Boehringer Ingelheim Pharma Kg | Benzimidazole derivatives, a process for their manufacture and use as a medicine |
| CN102050814A (en) * | 2009-11-06 | 2011-05-11 | 北京美倍他药物研究有限公司 | Ester derivatives of dabigatran |
| CN102050815A (en) * | 2009-11-06 | 2011-05-11 | 北京美倍他药物研究有限公司 | Dabigatran ester derivatives as prodrug |
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Application publication date: 20130327 |