CN102993175B - Dabigatran derivatives, and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and specifically relates to a preparation method of a benzimidazole derivative represented by a general formula I. R1 and R2 are respectively as defined in the specifications. The invention relates to Dabigatran derivatives represented by a general formula I, nontoxic and pharmaceutically acceptable salts thereof, medicine compositions containing the compounds as active components, and applications of the compounds and medicine compositions as thrombin inhibitors. The general formula I is shown in the specification.

Description

Ester derivative of dabigatran and its production and use

Technical field

The invention belongs to medical technical field, relate to particularly 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 (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.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 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 having rhythm abnormality (atrial fibrillation) patient.

Zymoplasm is extracellular Insulin-Like serine protease, has vital role in coagulation process, 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 in vivo activated dabigatran, and dabigatran is brought into play 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 needs 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 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 ₁for H or C ₁-C ₅alkyl, R ₂for 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 ₁for H or C ₁-C ₂alkyl, R ₂for 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 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 formula I, and the ester derivative that comprises the dabigatran shown in 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 to be 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, 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 ofNovel 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:

General formula I

R ₁=H ,-CH ₃,-CH ₂cH ₃; R ₂=C ₁-C ₈alkyl or the alkyl of replacement.

3-nitro-4-chloro-benzoic acid of take is starting raw material, reacts and obtains 3-nitro-4-methyl amino-phenylformic acid, then react with sulfur oxychloride with aqueous methylamine solution, becomes acyl chlorides (intermediate 5); PA reacts with ethyl propenoate and obtains N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 2), and intermediate 2 reacts and obtains intermediate 6 with intermediate 5; Intermediate 6 is reduced and obtains intermediate 7 under the catalysis of palladium carbon, then obtain intermediate 8 through amidation, condensation; Intermediate 8 is reacted with sodium hydroxide and reacts with chloroparaffin and obtain intermediate 9, and intermediate 9 reacts and obtains intermediate 10 with acidic alcohol and ammonia ethanolic soln, and intermediate 10 reacts from the Acibenzolar of different replacements the ester derivative (I that obtains dabigatran _1-16).

embodiment 1

3-(2-(((4-(N '-(((4-((methoxycarbonyl) amino) phenyl) oxygen base) carbonyl) 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) synthetic

Under nitrogen protection, in compound PA (11.2g, 0.12mol), add ethyl propenoate (13.8g, 0.14mol), stirring and refluxing 24h at 10 ℃, elimination precipitate, remaining concentrated rear column chromatography purification obtains white solid 10g.

2) 4-amine methyl-3-nitro-phenylformic acid (4) is synthetic

In the chloro-3-nitrobenzoic acid of 4-(10.0g, 0.05mol), add 33% aqueous methylamine solution 50mL, system is reacted 6 hours at 110 ℃.Add glacial acetic acid that pH value is adjusted to 4.Standing over night, separates out a large amount of yellow solids, and elimination solution obtains yellow solid 7.1g.

3) 4-amine methyl-3-nitro-Benzoyl chloride (5) is synthetic

Compound 4 (5.8g, 0.03mol) is dissolved in 70mol thionyl chloride, refluxes 2 hours, concentrating under reduced pressure, resistates adds the methylene dichloride of 30mL, and it is dissolved, and directly carries 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 methylene dichloride of 15mL and the triethylamine of 15mL to the little dichloromethane solution that slowly adds compound 6 of room temperature.Mixed system is at room temperature reacted 12 hours, 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 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.In ice-water bath, stir 35min, 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), with saturated brine (5mLx3), wash, after anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry, ice acetic acid in residuum (45ml), reflux 2h, is evaporated to dry, in residuum, add strong aqua (15ml), stirring at room 30min boils off solvent, adds methylene dichloride (25ml) in residuum, through saturated brine (5mLx3), washs, after anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry, and residuum, through column chromatography purifying, obtains amorphous yellow solid 3.1g.

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 200mL ethanol, adds the sodium hydroxide solution 10mL of 1N, under room temperature, stirring reaction is complete to hydrolysis, evaporate to dryness, dissolves with 20mLDMF, adds 1.76g methyl iodide, stirring at room 24 hours, concentrated, 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 100mL ethanol, be cooled to 0 ℃, pass into dry hydrogen chloride gas to saturated, stirred overnight at room temperature, in solvent evaporated resistates, add 100mL ethanol, under cooling conditions, slowly add ammonia ethanolic soln, and at room temperature stir 12 hours, solvent evaporated, column chromatography purification obtains white solid 2.5g.

9) 3-(2-(((4-(N '-(((4-((methoxycarbonyl) amino) phenyl) oxygen base) carbonyl) amidino) phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I ₁) synthetic

Upper step product (10a) is dissolved in tetrahydrofuran (THF) (50ml), add methyl (4-((((4-nitrophenyl) carbonyl) oxygen base) methyl) phenyl) carbamate (2.0g) and DIEA (3ml), stirred overnight at room temperature, evaporate to dryness, column chromatography purification obtains white target product 1.8g. ¹H NMR(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)，6.76(d，J＝8.8Hz，2H，ArH)，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)，7.82(d，J＝8.6Hz，2H，ArH)，8.40(dq，J＝4.8Hz，J＝1.6Hz，1H，ArH)，8.50-9.30(br s，1H，NH)，8.50-9.30(br s，2H，NH ₂)，ESI-MS：m/z 693[M+H] ⁺。

embodiment 2-16

With reference to the operation of embodiment 1, difference is to select different carboxylicesterss to react from different Acibenzolar side chains, obtains the compound of following formula I.

embodiment 17

The mensuration of anticoagulating active evaluation-activated partial thromboplastin time (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, by the dosage of 10mg/Kg (amounting to into dabigatran calculates) gastric infusion, after half an hour, pass through heart puncturing extracting blood, 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 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	21.2±4.5
Dabigatran etcxilate	75.3±2.1
		I 3	112.3±4.0
I 4	105.8±3.2
		I 5	165.1±4.8
I 10	147.5±3.7
		I 12	135.8±3.1
I 13	77.0±2.9
		I 14	68.4±3.8

Claims (3)

1. the ester derivative of the dabigatran shown in formula 1 or its pharmacy acceptable salt:

Wherein, R ₁and R ₂be defined as follows respectively:

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 ₁₀: R ₁for-CH ₂cH ₃, R ₂for-CH ₂cH ₃;

I ₁₂: R ₁for-CH ₂cH ₃, R ₂for-CH ₂cH ₂cH ₂cH ₃.

2. pharmaceutical composition, it comprises ester derivative or its pharmacologically acceptable salt of at least one dabigatran claimed in claim 1, and one or more pharmaceutically acceptable carrier or vehicle.

3. the ester derivative of dabigatran claimed in claim 1 or its pharmacologically acceptable salt are being prepared the purposes of thrombin inhibitors.