CN103304602A - Dabigatran etexilate gluconate, and preparation method and application thereof - Google Patents
Dabigatran etexilate gluconate, and preparation method and application thereof Download PDFInfo
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- CN103304602A CN103304602A CN2012100579570A CN201210057957A CN103304602A CN 103304602 A CN103304602 A CN 103304602A CN 2012100579570 A CN2012100579570 A CN 2012100579570A CN 201210057957 A CN201210057957 A CN 201210057957A CN 103304602 A CN103304602 A CN 103304602A
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Abstract
The invention provides a dabigatran etexilate gluconaten having a general formula shown in the specification, and a hydrate and/or solvate thereof. In the formula, n is 1, 2 or 3. The invention also provides a preparation method of the dabigatran etexilate gluconaten, the hydrate and/or solvate thereof, and an application in the preparation of medicines for treating or preventing cardiovascular diseases.
Description
Technical field
The present invention relates to a kind of acid salt of dabigatran etcxilate, be specifically related to a kind of dabigatran etcxilate glucuronate and its preparation method and application.
Background technology
Dabigatran (Dabigatran) is a kind of anti-coagulant of innovation, and namely thin blood medicine of new generation on pharmacosystematics, belongs to " direct thrombin inhibitor " (Direct Thrombin Inhibitors, DTI).At present medical circle studies confirm that the effect that " dabigatran " brought into play in multinomial clinical indication, it might replace belong to old-fashioned thin blood medicine " warfarin " (warfarin), become and be used for anticoagulant choice drug in most of cases.
" dabigatran " enters human body with the form oral administration of its premedicant " dabigatran etcxilate " (dabigatran etexilate)." dabigatran etcxilate " researched and developed by German Boehringer Ingelheim, goes on the market in Europe in 2008, and commodity are called " Pradaxa ", and Canadian commodity are called " Pradax ".The Hong Kong Chinese commodity of " Pradaxa " are " hundred reach life " by name then, and the Chinese trade name in China's Mainland and Taiwan is just in the application audit.At present, it is ratified take " Pradaxa " as the trade(brand)name list marketing in existing 75 countries and regions.Approval was used for non-valvular Patients With Atrial Fibrillation (AF) with dabigatran etcxilate (a kind of oral direct thrombin inhibitor), the risk that palsy and general blood vessel embolism occurs to reduce it on September 20th, 2010 in FDA (Food and Drug Adminstration) (FDA).
Dabigatran etcxilate (DABIGATRAN ETEXILATE) is a kind of benzimidazoles compound of replacement, chemical name 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, its molecular structural formula is as follows:
Molecular formula: C
34H
41N
7O
5, molecular weight: 627.74.
The solubleness of dabigatran etcxilate in water is less, and in the impact of pharmaceutical excipient with prevent down, it is not easy to stripping in pharmaceutical preparation, the preparation of pharmaceutical preparation is subject to many limitations.In addition, the dabigatran etcxilate mesylate that has gone on the market (seeing also Chinese patent CN1675193A) has the defectives such as less stable, bioavailability be low, therefore need to seek the compound that is more suitable for medicinal dabigatran etcxilate, with the demand of satisfying the market and relative disease preventing and controlling.
Summary of the invention
Therefore, the object of the invention is to overcome the defective such as poor stability, the bioavailability of dabigatran etcxilate and existing compound thereof be low, provide a kind of stability better, water-soluble larger, dabigatran etcxilate glucuronate and hydrate and/or solvate that bioavailability is higher, and their preparation method and application.
Term as used herein " solvate " refers to the crystallized form that comprises one or more organic solvent molecules in the periodicity three-dimensional arrangement.
The employed phrase of this paper " pharmaceutically acceptable " refers to and be applicable to contact with the tissue of the mankind or animal compound, material, composition and/or the formulation that does not have simultaneously excessive toxicity, pungency, anaphylaxis or other problem or complication and have rational benefit/risk ratio in the scope that rational medicine is judged.
The invention provides the following dabigatran etcxilate glucuronate of a kind of general formula, its hydrate and/or solvate:
Wherein, n is 1,2 or 3.
According to dabigatran etcxilate glucuronate of the present invention, its hydrate and/or solvate, wherein, can contain the water of 0.5～10 molecule in the hydrate of the described dabigatran etcxilate glucuronate of per molecule, can be preferably the water that contains 0.5～2 molecule.The solvent of 0.5～10 molecule can be contained in the solvate of the described dabigatran etcxilate glucuronate of per molecule, the solvent that contains 0.5～2 molecule can be preferably.
For example, the hydrate of dabigatran etcxilate glucuronate of the present invention can be semihydrate, monohydrate, sesqui hydrate, dihydrate, two times of semihydrates, trihydrate, three times of semihydrates, tetrahydrate, four times of semihydrates, pentahydrate, five times of semihydrates, hexahydrate, six times of semihydrates, heptahydrate, seven times of semihydrates, eight hydrates, octuple semihydrate, nonahydrate, nine times of semihydrates or decahydrate.Again for example, the solvate of the dabigatran etcxilate glucuronate of per molecule can contain the solvent of half molecule, 1 molecule, 1.5 molecules, 2 molecules, 2.5 molecules, 3 molecules, 3.5 molecules, 4 molecules, 4.5 molecules, 5 molecules, 5.5 molecules, 6 molecules, 6.5 molecules, 7 molecules, 7.5 molecules, 8 molecules, 8.5 molecules, 9 molecules, 9.5 molecules or 10 molecules.
Should illustrate, hydrate or the solvate of the above-mentioned dabigatran etcxilate glucuronate of the present invention of enumerating, it mainly is a kind of existence form that dabigatran etcxilate glucuronate of the present invention produces in crystallization or purge process, the crystal water that it is contained or crystallization organic solvent normally can be controlled or remove, such as can crystal water or crystallization organic solvent being removed by modes such as heating calcination or calcinings.Therefore, the hydrate of dabigatran etcxilate glucuronate of the present invention and solvate still belong to the content of technical scheme content of the present invention and scope of patent protection.
According to dabigatran etcxilate glucuronate of the present invention, its hydrate and/or solvate, wherein, described solvate can be in alcohol solvent compound, methanol solvate compound, acetone solvate, acetonitrile solvate, ethyl acetate solvent compound, tetrahydrofuran solvate and the ether solvent compound one or more.
According to dabigatran etcxilate glucuronate of the present invention, its hydrate and/or solvate, wherein, in described hydrate, the dabigatran etcxilate glucuronate can account for more than the 95wt%, can be preferably more than the 98wt%, more preferably more than the 99wt%.In described solvate, the dabigatran etcxilate glucuronate can account for more than the 95wt%, can be preferably more than the 98wt%, more preferably more than the 99wt%.
The present invention also provides the method for preparing dabigatran etcxilate glucuronate of the present invention, its hydrate and/or solvate, the method can comprise: dabigatran etcxilate and glucuronic acid are mixed salify and crystallization in water or the first organic solvent, after after filtration, washing, the drying, make water or the second organic solvent carry out recrystallization, make described dabigatran etcxilate glucuronate, its hydrate or solvate.Those skilled in the art can as required, by conventional means, remove partial solvent etc. such as reduction Tc or steaming, to accelerate the formation of crystallization.
The method according to this invention, wherein, the step of described mixing salify can be carried out to the reflux temperature of water or the first organic solvent at 0 ℃, can be preferably under 0～30 ℃ and carry out.As preferably, the step of described crystallization can or be lower than under the condition of room temperature in room temperature carries out, and can be preferably under 0～20 ℃ and carry out.Described the first organic solvent and the second organic solvent are identical or different, can be selected from ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethyl formate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), sherwood oil, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, toluene, N,N-DIMETHYLACETAMIDE or dimethylbenzene.
The method according to this invention, wherein, the mol ratio of described dabigatran etcxilate and described glucuronic acid can be 10: 1～1: 10.This mol ratio can be preferably 3: 1～1: 3.
The present invention also provides a kind of pharmaceutical composition, this pharmaceutical composition comprises dabigatran etcxilate glucuronate of the present invention, its hydrate and/or solvate, or comprise dabigatran etcxilate glucuronate, its hydrate and/or the solvate that makes according to method of the present invention, and pharmaceutically acceptable auxiliary material.
Described pharmaceutical composition can comprise dabigatran etcxilate glucuronate conduct of the present invention active substance wherein, can also comprise simultaneously the material that other has pharmaceutical active, is used for combination therapy with the pharmaceutical composition that forms a kind of compound.
When dabigatran etcxilate glucuronate of the present invention is used for the treatment of as activeconstituents, generally directly not giving the patient simple chemical, all is that the form that contains the pharmaceutical composition of pharmaceutically acceptable auxiliary material occurs usually.Dabigatran etcxilate glucuronate of the present invention also can be by the administration of any appropriate, usually can be oral or parenteral route, so, the pharmaceutically acceptable auxiliary material that those skilled in the art also can comprise according to required form of medication selection pharmaceutical composition.
Be to be understood that, according to method well known in the art, pharmaceutically acceptable auxiliary material can be matrix or the auxiliary material that keeps pharmaceutical dosage form, usually select or be used in combination according to different medicaments, optionally comprise vehicle, for example one or more in Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin, the cyclodextrin derivative etc.; Can also comprise tackiness agent, for example one or more in polyvidone (polyvinylpyrrolidone), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, the xanthan gum etc.; Also comprise lubricant, for example one or more in Magnesium Stearate, stearic acid, talcum powder, stearyl fumarate, the Sodium Lauryl Sulphate BP/USP etc.; Can also comprise disintegrating agent, one or more in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, croscarmellose sodium, crosslinked carboxymethyl fecula sodium, the pregelatinized Starch for example, etc.; Also comprise tensio-active agent, one or more of sodium lauryl sulphate, Tween-80 for example, etc.; Can also comprise pH value conditioning agent or buffer reagent, one or more of phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, yellow soda ash, sodium hydroxide for example, etc.; Can also comprise sanitas, one or more in Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, the propylparaben for example, etc.; Can also comprise stablizer and oxidation inhibitor, one or more in Calcium Disodium Edetate, S-WAT, the vitamins C for example, etc.; Can also comprise the taste conditioning agent, one or more in maltose alcohol, fructose, sucrose, soluble saccharin, orange essence, the strawberry flavour for example, etc.; Can also comprise in addition additive other routines, appropriate.
In addition, when pharmaceutical dosage form was tablet or capsule, pharmaceutically acceptable auxiliary material can also comprise the film dressing.Be used for the material of film dressing, comprise suitable Drug coating, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, etc.; Can also comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, etc.; Also comprise suitable solubilizing agent, such as Tween-80; Can also comprise suitable pigment, such as titanium dioxide, various ferric oxide, pink pigment, etc.
According to pharmaceutical composition of the present invention, described pharmaceutical composition can be tablet, hard capsule, soft capsule, pill, granule, pellet or oral fluid agent.
Pharmaceutical composition of the present invention can be prepared as acceptable any pharmaceutical dosage form on the pharmaceutics as required, such as oral preparations, injection formulations, non-oral liquid preparation, etc.; Such as oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent, etc.; And for example injection comprises powder ampoule agent for injection and injection liquid, etc., for another example emulsion of non-oral eye drop, nasal drops, [Dan, Transdermal absorption, etc.Also can be the formulation such as quick-release, slowly-releasing, controlled release of above various formulations, for example oral dispersible tablet, slow releasing tablet, chewable tablet, slow releasing capsule, enteric coated tablet, effervescent tablet, orally disintegrating tablet, Special-shaped sheet, effervescent granule, etc.Especially, by the means known in the art preparation, be preferred for preparing on the pharmaceutics edible tablet (comprising dispersible tablet, slow releasing tablet, chewable tablet, enteric coated tablet, orally disintegrating tablet, Special-shaped sheet), capsule (comprise that stomach is molten, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc., to satisfy the various needs in the clinical use.
According to pharmaceutical composition of the present invention, wherein, in described pharmaceutical composition, the weight ratio of described dabigatran etcxilate glucuronate and described pharmaceutically acceptable auxiliary material can be 1: 1～5, can be preferably 1: 1～and 2.The content of dabigatran etcxilate glucuronate in pharmaceutical composition can be 0.1～100mg, for example can be 0.1mg, 0.5mg, 1mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg or 150mg, etc.
The present invention also provides dabigatran etcxilate glucuronate of the present invention, its hydrate and/or solvate, or the dabigatran etcxilate glucuronate, its hydrate and/or the solvate that make according to method of the present invention, for the preparation of the application in the medicine for the treatment of or preventing cardiovascular disease.Can be preferably for the preparation of the application in the medicine for the treatment of or prevention phlebothrombosis or acute coronary syndrome.
Dabigatran etcxilate glucuronate provided by the present invention, its hydrate and/or solvate have higher liberation degree, and its water-soluble acquisition is greatly improved.This can make dissolution process rapider on the one hand, also can reduce on the other hand the amount of required aqueous solvent.In addition, dabigatran etcxilate glucuronate of the present invention and hydrate thereof and solvate also have higher stability and bioavailability.
When being prepared as pharmaceutically active substances or preparation, storage and application galenical, the improvement of above biochemical property is very important, this quality that can guarantee galenical is higher, and its high stability also so that the procedure of processing of post-processed is simpler, has reduced production cost.And its high crystalline can use such as analytical procedures such as X-ray diffractions simple and clear analysis is carried out in the release of its hydrate or solvate, in order to carry out appropriate selection.For the galenical of these factors during for the quality of active substance and for preparation, storage and administration, all be very important.In addition, because the activeconstituents in the galenical is more stable, thereby can avoid complicated preparation work.
The operation of use physical-chemical is processed such as galenics such as drying, screening, grinding and medicament figurations, comprises combination treatment, granulation, spray-drying, compressing tablet etc., active substance is absorbed or loss moisture.This also is subject to temperature in its environment of living in and the impact of relative humidity.Under the situation of some preparations of preparation, free-water and can in handled material, add entry with the relating operation that vehicle is introduced into or processes because of preparation in conjunction with water.Therefore, under differing temps and relative humidity, pharmaceutically active substances can contact within quite long period with free-water.In the case, dabigatran etcxilate glucuronate of the present invention does not show measurable moisture absorption or loss, therefore this stability is conducive to the final stage of its chemical preparation, the treatment stage of also being conducive to the galenic of different dosage form, and its stable lasting validity is of value to the patient equally.
Simultaneously, dabigatran etcxilate glucuronate of the present invention also has better solvability or compressibility, thereby is more suitable for directly being compressed into corresponding tablet formulation or capsule.
In addition, dabigatran etcxilate glucuronate of the present invention also has better chemical stability, contains the aliphatic amide structure owing in the dabigatran ester molecular structure, and is easily oxidized, can increase the stability of dabigatran etcxilate behind the salify.This salt also may have advantages of avoiding or reduce other activeconstituents degraded.
With Compound Phase ratio well known in the prior art, that described salt also has is more effective, toxicity is lower, action time is longer, field of activity is wider, it is higher to render a service, side effect still less, the advantage or other the useful pharmacological property that more easily absorb.
More specifically, dabigatran etcxilate glucuronate of the present invention and hydrate thereof and/or solvate also have but are not limited to following beneficial effect:
1) with respect to the dabigatran etcxilate mesylate, dabigatran etcxilate glucuronate provided by the present invention has satisfactory stability.For example, the dabigatran etcxilate mesylate was degraded to about 50% under the super-humid conditions at 10 days, and the dabigatran etcxilate glucuronate is almost without content.
2) dabigatran etcxilate glucuronate of the present invention has water-solublely preferably, confirms through test, and its solubleness in water can reach 2.1mg/ml H
2O (25 ℃ of temperature), and dabigatran etcxilate is almost insoluble greater than 4 o'clock in the pH value, the dabigatran etcxilate mesylate is 1.8mg/ml.Thereby dabigatran etcxilate glucuronate of the present invention has the bioavailability better or suitable at least than the dabigatran etcxilate mesylate.
3) the application's dabigatran etcxilate glucuronate also has preferably flowability and compressibility.The contriver carries out flowability and compressibility mensuration to dabigatran etcxilate glucuronate of the present invention and dabigatran etcxilate mesylate respectively, and it the results are shown in following table 1.
The flowability of table 1 dabigatran etcxilate glucuronate and dabigatran etcxilate mesylate and compressibility are measured
Wherein, the mobile general main of powder weighed with the slope of repose, and the slope of repose is less, and is better mobile.Conventional θ≤30 ° of good fluidities, need of production ° can be satisfied in θ≤40.Loose density refers to that powder quality is divided by the shared volume of a container of this powder, the density of trying to achieve.Its used volume comprises the cumulative volume in space between the hole of particle itself and the particle.What loose density was large is heavy, and what loose density was little is lightweight, and the less pressure of the large usefulness of loose density just can moulding, shows that compressibility is good.Gu density be after certain speed and time are knocked vibrations powder quality divided by the shared volume of a container of this powder, the density of trying to achieve.Gu density value shows greatly good fluidity.The less compressibility of compression ratio is better, is generally less than 0.2 and can satisfies need of production.Above data show, dabigatran etcxilate glucuronate of the present invention all shows better flowability and compressibility with respect to the dabigatran etcxilate mesylate on indices, thereby is more suitable for the scale operation of medicine.
Embodiment
Further specify the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the usefulness that specifically describes more in detail, and should not be construed as for limiting in any form the present invention.
General description is carried out to the material and the test method that use in the present invention's test in this part.Although for realizing that the employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that in context, if do not specify, material therefor of the present invention and working method are well known in the art.
If no special instructions, the employed mass spectrograph in following examples is Agientl 100 type level Four bar LC-MS instrument, and employed nuclear magnetic resonance analyser is Bruker ARX-400NMR type nuclear magnetic resonance analyser.
Embodiment 1
The present embodiment is used for illustrating the preparation of dabigatran etcxilate glucuronate of the present invention.
Under 20 ℃, join the dabigatran etcxilate of 0.8mmol and the glucuronic acid of 0.8mmol in the dehydrated alcohol of 20ml, 6 hours salifies of mix and blend, then at 20 ℃ of lower crystallizatioies, filter, the washing of use ethyl acetate, after drying, add methyl alcohol and carry out recrystallization, obtain the methanol solvate compound of the dabigatran etcxilate glucuronate of 0.300g.Record ESI-MS (electron spray ionisation-mass spectrum) (m/z): 854[M+H]
+
Above-mentioned methanol solvate compound is carried out drying, obtain the dabigatran etcxilate glucuronate 0.289g of white solid, as calculated, in above-mentioned methanol solvate compound, the content of dabigatran etcxilate glucuronate is 96.2wt%.The methyl alcohol that contains 1 molecule in this methanol solvate compound of per molecule.
Above-mentioned dabigatran etcxilate glucuronate is measured:
ESI-MS(m/z)：822[M+H]
+
1H?NMR(DMAO-d
6，400MHz)δ：0.88(t，J＝9.0Hz，3H，CH
3)，1.13(t，J＝8.4Hz，3H，CH
3)，1.27-1.37(m，6H，CH
2CH
2CH
2)，1.57-1.61(m，2H，CH
2)，2.68(t，J＝14.4Hz，2H，CH
2)，2.91-2.95(m，1H)，3.12-3.16(m，1H)，3.35-3.41(m，1H)，3.55-3.57(m，1H)，3.77(s，3H，CH
3)，3.95-4.01(m，4H，2CH
2)，4.22(t，J＝14.4Hz，2H，CH
2)，4.32-4.33(m，1H)，4.34-4.35(m，1H)，4.61(d，J＝5.6Hz，2H，CH
2)，4.75-4.85(m，1H)，4.91-4.94(m，2H)，6.45-6.46(m，2H)，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)，7.42(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(brs，2H，NH
2)。
Fusing point: 134-135 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
6H
10O
7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate glucuronate is:
Embodiment 2
The present embodiment is used for illustrating the preparation of dabigatran etcxilate glucuronate of the present invention.
Under 30 ℃, join the dabigatran etcxilate of 1.6mmol and the glucuronic acid of 0.8mmol in the 20ml water, 6 hours salifies of mix and blend, then at 30 ℃ of lower crystallizatioies, filter, the washing of use ethyl acetate, after drying, add entry and carry out recrystallization, obtain the hydrate of the dabigatran etcxilate glucuronate of 0.200g.Record ESI-MS (m/z): 761[M+H]+.
Above-mentioned hydrate is carried out drying, obtain the dabigatran etcxilate glucuronate 0.191g of white solid, as calculated, in the above-mentioned hydrate, the content of dabigatran etcxilate glucuronate is 95.3wt%.The water that contains 2 molecules in this hydrate of per molecule, i.e. dihydrate.
Above-mentioned dabigatran etcxilate glucuronate is measured:
ESI-MS(m/z)：725[M+H]
-
1H?NMR(DMAO-d
6，400MHz)δ：0.88(t，J＝9.0Hz，3H，CH
3)，1.13(t，J＝8.4Hz，3H，CH
3)，1.27-1.37(m，6H，CH
2CH
2CH
2)，1.57-1.61(m，2H，CH
2)，2.68(t，J＝14.4Hz，2H，CH
2)，2.91-2.95(m，0.5H)，3.12-3.16(m，0.5H)，3.35-3.41(m，0.5H)，3.55-3.57(m，0.5H)，3.77(s，3H，CH
3)，3.95-4.01(m，4H，2CH
2)，4.22(t，J＝14.4Hz，2H，CH
2)，4.32-4.33(m，0.5H)，4.34-4.35(m，0.5H)，4.61(d，J＝5.6Hz，1H，CH
2)，4.75-4.85(m，0.5H)，4.91-4.94(m，1H)，6.45-6.46(m，2H)，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)，7.42(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(brs，2H，NH
2)。
Fusing point: 128-129 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/n?C
6H
10O
7
Discovery value: C 61.31 N 13.53 H 6.40 O 18.76
Calculate: n=2
Therefore the molecular structural formula of prepared dabigatran etcxilate glucuronate is:
Embodiment 3
The present embodiment is used for illustrating the preparation of dabigatran etcxilate glucuronate of the present invention.
Under 0 ℃, join the dabigatran etcxilate of 2.4mmol and the glucuronic acid of 0.8mmol in the 20ml dehydrated alcohol, 6 hours salifies of mix and blend, then at 0 ℃ of lower crystallization, filter, the washing of use ethyl acetate, after drying, add glycol dimethyl ether and carry out recrystallization, obtain the dabigatran etcxilate glucuronate 0.200g of white solid.
Above-mentioned dabigatran etcxilate glucuronate is measured:
ESI-MS(m/z)：693[M+H]
1H?NMR(DMAO-d
6，400MHz)δ：0.88(t，J＝9.0Hz，3H，CH
3)，1.13(t，J＝8.4Hz，3H，CH
3)，1.27-1.37(m，6H，CH
2CH
2CH
2)，1.57-1.61(m，2H，CH
2)，2.68(t，J＝14.4Hz，2H，CH
2)，2.91-2.95(m，0.3H)，3.12-3.16(m，0.3H)，3.35-3.41(m，0.3H)，3.55-3.57(m，0.3H)，3.77(s，3H，CH
3)，3.95-4.01(m，4H，2CH
2)，4.22(t，J＝14.4Hz，2H，CH
2)，4.32-4.33(m，0.3H)，4.34-4.35(m，0.3H)，4.61(d，J＝5.6Hz，7H，CH
2)，4.75-4.85(m，0.3H)，4.91-4.94(m，7H)，6.45-6.46(m，2H)，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)，7.42(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，2H，NH
2)。
Fusing point: 126-127 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/n?C
6H
10O
7
Discovery value: C 62.44 N 14.16 H 6.45 O 16.94
Calculate: n=3
Therefore the molecular structural formula of prepared dabigatran etcxilate glucuronate is:
Embodiment 4
The present embodiment is used for illustrating the preparation of dabigatran etcxilate glucuronate of the present invention.
Under 30 ℃, join the dabigatran etcxilate of 0.8mmol and the glucuronic acid of 2.4mmol in the 20ml anhydrous methanol, 6 hours salifies of mix and blend, then at 10 ℃ of lower crystallizatioies, filter, the washing of use ether, after drying, add tetrahydrofuran (THF) and carry out recrystallization, obtain the tetrahydrofuran solvate of the dabigatran etcxilate glucuronate of 0.320g.Record its ESI-MS (m/z): 858[M+H]
+
Above-mentioned tetrahydrofuran solvate is carried out drying, obtain the dabigatran etcxilate glucuronate 0.306g of white solid, as calculated, the content of dabigatran etcxilate glucuronate is 95.8wt% in the above-mentioned solvate.The tetrahydrofuran (THF) that contains 0.5 molecule in this tetrahydrofuran solvate of per molecule.
Above-mentioned dabigatran etcxilate glucuronate is measured:
ESI-MS(m/z)：822[M+H]
+。
Fusing point: 134-136 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/n?C
6H
10O
7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate glucuronate is:
Embodiment 5
The present embodiment is used for illustrating the preparation of dabigatran etcxilate glucuronate of the present invention.
Under 10 ℃, join the dabigatran etcxilate of 0.8mmol and the glucuronic acid of 1.6mmol in the 20ml acetone, 6 hours salifies of mix and blend, then at 10 ℃ of lower crystallizatioies, filter, the washing of use ether, after drying, add dehydrated alcohol and carry out recrystallization, obtain the alcohol solvent compound of the dabigatran etcxilate glucuronate of 0.250g.Record its ESI-MS (m/z): 868[M+H]
+
Above-mentioned alcohol solvent compound is carried out drying, obtain the dabigatran etcxilate glucuronate 0.237g of white solid, as calculated, in the above-mentioned solvate, the content of dabigatran etcxilate glucuronate is 95wt%.The ethanol that contains 1 molecule in this alcohol solvent compound of per molecule.
The dabigatran etcxilate glucuronate is measured:
ESI-MS(m/z)：822[M+H]
Fusing point: 133-135 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/n?C
6H
10O
7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate glucuronate is:
Embodiment 6
The present embodiment is used for illustrating the preparation of dabigatran etcxilate glucuronate of the present invention.
Under 30 ℃, join the dabigatran etcxilate of 0.8mmol and the glucuronic acid of 8mmol in the 20ml trichloromethane, 6 hours salifies of mix and blend, then at 20 ℃ of lower crystallizatioies, filter, the washing of use ether, after drying, add entry and carry out recrystallization, obtain the hydrate of the dabigatran etcxilate glucuronate of 0.270g.Record its ESI-MS (m/z): 831[M+H]
+
Above-mentioned hydrate is carried out drying, obtain the dabigatran etcxilate glucuronate 0.267g of white solid, as calculated, the content of dabigatran etcxilate glucuronate is 99wt% in the above-mentioned hydrate.The water that contains 0.5 molecule in this hydrate of per molecule, i.e. semihydrate.
The dabigatran etcxilate glucuronate is measured:
ESI-MS(m/z)：822[M+H]
+。
Fusing point: 134-135 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/n?C
6H
10O
7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate glucuronate is:
Stability test:
The contriver observes and does assay to dabigatran etcxilate glucuronate and the dabigatran etcxilate mesylate of embodiment 1 under differing temps, humidity and illumination condition, data see Table 2 and table 3.
Liquid-phase condition:
Chromatographic column: Agela Venusil MP C18 post (4.6mm * 250mm, 5 μ m) NO:VA952505-0
Moving phase: 0.01molL
-1Secondary ammonium phosphate damping fluid-methyl alcohol (40: 60);
Flow velocity: 1mlmin
-1Detect wavelength: 250nm; Column temperature: 25 ℃; Sample size: 20 μ l
The content of table 2 dabigatran etcxilate glucuronate and dabigatran etcxilate mesylate
Table 2 is that the content of dabigatran etcxilate glucuronate and mesylate is through the contrast of influence factor test-results.Data show, under the same conditions (high temperature, high humidity, illumination), and the former content temporal evolution is very little, belong to the error at measurment scope, and the latter is very unstable under super-humid conditions, especially can be degraded to about 50% under the super-humid conditions at 10 days, shows obvious unstable.
The appearance change of table 3 dabigatran etcxilate glucuronate and dabigatran etcxilate mesylate
As shown in Table 3, under the hot conditions, the dabigatran etcxilate glucuronate is almost unchanged, and the dabigatran etcxilate mesylate can be observed color considerable change occurs in time.Under the super-humid conditions, the former outward appearance is almost constant, shows more stable character, and the latter then moisture absorption is serious.
Embodiment 7
The present embodiment is for the preparation of the pharmaceutical composition that dabigatran etcxilate glucuronate of the present invention is described.
The dabigatran etcxilate glucuronate is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.Take by weighing dabigatran etcxilate glucuronic acid, Microcrystalline Cellulose and lactose by recipe quantity and fully mix, add 1% (weight/volume) hypromellose aqueous solution, softwood processed sieves, and wet granular processed is in 55 ℃ of dryings.Polyvinylpolypyrrolidone and Magnesium Stearate are added in the above-mentioned particle, measure intermediate content, compressing tablet, packing.
Embodiment 8
The present embodiment is for the preparation of the pharmaceutical composition that dabigatran etcxilate glucuronate of the present invention is described.
The dabigatran etcxilate glucuronate is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.Take by weighing dabigatran etcxilate glucuronic acid, Microcrystalline Cellulose, pregelatinized Starch and lactose by recipe quantity and fully mix, add 1% (weight/volume) hypromellose aqueous solution, softwood processed sieves, and wet granular processed is in 55 ℃ of dryings.Magnesium Stearate is added in the above-mentioned particle, measures intermediate content, encapsulated, packing.
Embodiment 9
The present embodiment is for the preparation of the pharmaceutical composition that dabigatran etcxilate glucuronate of the present invention is described.
The dabigatran etcxilate glucuronate is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.Taking by weighing dabigatran etcxilate glucuronate, lactose, N.F,USP MANNITOL, aspartame, essence by recipe quantity fully mixes, add again 2% (weight/volume) hypromellose aqueous solution softwood processed, 16 mesh sieves are granulated, 55 ℃ of dryings, the whole grain of 14 mesh sieves, measure intermediate content and moisture, packing makes 100 bags of granules altogether.
Embodiment 10
The present embodiment is for the preparation of the pharmaceutical composition that dabigatran etcxilate glucuronate of the present invention is described.
The dabigatran etcxilate glucuronate is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.Taking by weighing dabigatran etcxilate glucuronic acid, polyvidone, aspartame and essence by recipe quantity mixes first, fully mix with N.F,USP MANNITOL, Microcrystalline Cellulose and lactose successively again, add at last Magnesium Stearate and mix, measure intermediate content, compressing tablet, packing.
Although the present invention has carried out description to a certain degree, significantly, under the condition that does not break away from the spirit and scope of the present invention, can the suitable variation of each condition of carrying out.Be appreciated that to the invention is not restricted to described embodiment, and be attributed to the scope of claim, it comprises the replacement that is equal to of described each factor.
Claims (11)
1. dabigatran etcxilate glucuronate, its hydrate and/or solvate that general formula is following:
Wherein, n is 1,2 or 3.
2. dabigatran etcxilate glucuronate according to claim 1, its hydrate and/or solvate, it is characterized in that, contain the water of 0.5～10 molecule in the hydrate of the described dabigatran etcxilate glucuronate of per molecule, be preferably the water that contains 0.5～2 molecule; Contain the solvent of 0.5～10 molecule in the solvate of the described dabigatran etcxilate glucuronate of per molecule, be preferably the solvent that contains 0.5～2 molecule.
3. dabigatran etcxilate glucuronate according to claim 1 and 2, its hydrate and/or solvate, it is characterized in that, described solvate is one or more in alcohol solvent compound, methanol solvate compound, acetone solvate, acetonitrile solvate, ethyl acetate solvent compound, tetrahydrofuran solvate and the ether solvent compound.
4. according to claim 1 each described dabigatran etcxilate glucuronate, its hydrate and/or solvate in 3, it is characterized in that, in described hydrate, the dabigatran etcxilate glucuronate accounts for more than the 95wt%, be preferably more than the 98wt%, more preferably more than the 99wt%; In described solvate, the dabigatran etcxilate glucuronate accounts for more than the 95wt%, is preferably more than the 98wt%, more preferably more than the 99wt%.
5. the preparation method of each described dabigatran etcxilate glucuronate, its hydrate and/or solvate in the claim 1 to 4, it is characterized in that, the method comprises: dabigatran etcxilate and glucuronic acid are mixed salify and crystallization in water or the first organic solvent, after after filtration, washing, the drying, make water or the second organic solvent carry out recrystallization, make described dabigatran etcxilate glucuronate, its hydrate or solvate.
6. method according to claim 5 is characterized in that, described mixing salify carries out to the reflux temperature of water or the first organic solvent at 0 ℃, is preferably under 0～30 ℃ and carries out; Preferably, described crystallization is in room temperature or be lower than under the condition of room temperature and carry out, and is preferably under 0～20 ℃ and carries out; Described the first organic solvent and the second organic solvent are identical or different, are selected from ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethyl formate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), sherwood oil, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, toluene, N,N-DIMETHYLACETAMIDE or dimethylbenzene.
7. according to claim 5 or 6 described methods, it is characterized in that, the mol ratio of described dabigatran etcxilate and described glucuronic acid is 10: 1～1: 10, is preferably 3: 1～1: 3.
8. pharmaceutical composition, it is characterized in that, this pharmaceutical composition comprises each described dabigatran etcxilate glucuronate, its hydrate and/or solvate in the claim 1 to 4, or the dabigatran etcxilate glucuronate, its hydrate and/or the solvate that make according to each described method in the claim 5 to 7, and pharmaceutically acceptable auxiliary material.
9. pharmaceutical composition according to claim 8 is characterized in that, described pharmaceutical composition is tablet, hard capsule, soft capsule, pill, granule, pellet or oral fluid agent.
10. according to claim 8 or the pharmaceutical composition described in 9, it is characterized in that, in described pharmaceutical composition, the weight ratio of described dabigatran etcxilate glucuronate and described pharmaceutically acceptable auxiliary material is 1: 1～5, be preferably 1: 1～and 2.
11. each described dabigatran etcxilate glucuronate, its hydrate and/or solvate in the claim 1 to 4, or the dabigatran etcxilate glucuronate, its hydrate and/or the solvate that make according to each described method in the claim 5 to 7, for the preparation of the application in treatment or the medicine of preventing cardiovascular disease, be preferably for the preparation of the application in the medicine for the treatment of or prevention phlebothrombosis or acute coronary syndrome.
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| WO2008043759A1 (en) * | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| CN101489819A (en) * | 2006-07-14 | 2009-07-22 | 约翰逊控制器汽车电子有限责任公司 | Display device for a motor vehicle comprising a substantially parallel light beam |
| 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 |
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| CN101489819A (en) * | 2006-07-14 | 2009-07-22 | 约翰逊控制器汽车电子有限责任公司 | Display device for a motor vehicle comprising a substantially parallel light beam |
| WO2008043759A1 (en) * | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
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| WO2016009405A1 (en) * | 2014-07-18 | 2016-01-21 | Sifavitor S.R.L. | Crystalline compounds of dabigatran etexilate |
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