CN103304602B - Dabigatran etcxilate glucuronate salt and its preparation method and application - Google Patents
Dabigatran etcxilate glucuronate salt and its preparation method and application Download PDFInfo
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Abstract
The invention provides the following dabigatran etcxilate glucuronate salt of a kind of formula, its hydrate and/or solvate:
Description
Technical field
The present invention relates to the acid-addition salts of a kind of dabigatran etcxilate, be specifically related to a kind of dabigatran etcxilate glucuronate salt
And its preparation method and application.
Background technology
Dabigatran (Dabigatran) is the anticoagulant of a kind of innovation, and thin blood medicine the most of new generation, in pharmacosystematics
On, belong to " direct thrombin inhibitor " (Direct Thrombin Inhibitors, DTI).Medical circle has studied card at present
Real " dabigatran " effect played in multinomial clinical indication, it likely replaces " warfarin " belonging to old-fashioned thin blood medicine
(warfarin), become in most of case for anticoagulant choice drug.
" dabigatran " enters with the form oral administration of its premedicant " dabigatran etcxilate " (dabigatran etexilate)
Enter human body." dabigatran etcxilate ", by Germany's Boehringer Ingelheim research and development, listed in Europe in 2008, trade name
" Pradaxa ", Canadian trade name " Pradax ".The Hong Kong Chinese commodity of " Pradaxa " are the most entitled " hundred reach life ", and in
The Chinese trade name in state continent and Taiwan is just in application examination & verification.At present, existing 75 countries and regions ratify its with
" Pradaxa " is trade name list marketing.FDA (Food and Drug Adminstration) (FDA) ratifies Da Bijia in JIUYUE in 2010 on the 20th
Group's ester (a kind of oral direct thrombin inhibitor) for non-valve artrial fibrillation patient (AF), with reduce its occur apoplexy and
The risk of Systemic Vascular thromboembolism.
Dabigatran etcxilate (DABIGATRAN ETEXILATE) is a kind of substituted benzimidazoles compound, chemical name 3-
[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-
Base] carbonyl] (pyridine-2-base) amino] ethyl propionate, its molecular structural formula is as follows:
Molecular formula: C34H41N7O5, molecular weight: 627.74.
Dabigatran etcxilate dissolubility in water is less, and under the impact of pharmaceutic adjuvant and preventing, it is in pharmaceutical preparation
It is not easy to dissolution, makes the preparation of pharmaceutical preparation be subject to many limitations.It addition, the dabigatran etcxilate mesylate listed (please
See Chinese patent CN1675193A) there is the defects such as less stable, bioavailability are low, it is therefore desirable to find and be more suitable for medicine
The compound of dabigatran etcxilate, to meet market and the demand of relevant disease preventing and controlling.
Summary of the invention
Therefore, it is an object of the invention to overcome dabigatran etcxilate and the poor stability of existing compound, biological utilisation
Spend the defects such as low, it is provided that a kind of stability is more preferable, water solublity is bigger, bioavailability higher dabigatran etcxilate glucuronic acid
Salt and hydrate thereof and/or solvate, and their preparation method and application.
Term as used herein " solvate ", refer to periodic three-dimensional arrange in comprise one or more organic
The crystal form of solvent molecule.
Phrase used herein " pharmaceutically acceptable ", refer to rational medicine judge in the range of be applicable to
The contact tissue of the mankind or animal does not has excessive toxicity, zest, anaphylaxis or other problem or complication simultaneously and has
There are the compound of rational benefit/risk ratio, material, compositions and/or dosage form.
The invention provides the following dabigatran etcxilate glucuronate salt of a kind of formula, its hydrate and/or solvation
Thing:
Wherein, n is 1,2 or 3.
Dabigatran etcxilate glucuronate salt, its hydrate and/or solvate according to the present invention, wherein, per molecule
Can be containing the water of 0.5～10 molecules in the hydrate of described dabigatran etcxilate glucuronate salt, it may be preferred to for containing 0.5
～2 water of molecule.Can be containing 0.5～10 molecules in the solvate of dabigatran etcxilate glucuronate salt described in per molecule
Solvent, it may be preferred to for the solvent containing 0.5～2 molecules.
Such as, the hydrate of the dabigatran etcxilate glucuronate salt of the present invention can be semihydrate, monohydrate, one
Times semihydrate, 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, eight
Times semihydrate, nonahydrate, nine times of semihydrates or decahydrate.The most such as, the dabigatran etcxilate glucal of per molecule
The solvate of hydrochlorate can contain 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 solvents of molecule.
It should be noted that the hydrate of the dabigatran etcxilate glucuronate salt of the above-mentioned present invention enumerated or solvate,
A kind of existence form that mainly the dabigatran etcxilate glucuronate salt of the present invention produces in crystallization or purge process, its institute
The water of crystallization contained or crystallization organic solvent typically can control or remove, such as can be by heating calcination or calcining etc.
Mode makes water of crystallization or crystallization organic solvent removing.Therefore, the hydrate of the dabigatran etcxilate glucuronate salt of the present invention and
Solvate still falls within the content of technical scheme content and scope of patent protection.
Dabigatran etcxilate glucuronate salt, its hydrate and/or solvate according to the present invention, wherein, described molten
Agent compound can be alcohol solvent compound, Methanol Solvate, acetone solvate, acetonitrile solvate, ethyl acetate solvent
One or more in compound, tetrahydrofuran solvate and ether solvent compound.
Dabigatran etcxilate glucuronate salt, its hydrate and/or solvate according to the present invention, wherein, described
In hydrate, dabigatran etcxilate glucuronate salt can account for more than 95wt%, it may be preferred to for more than 98wt%, can be more excellent
Elect more than 99wt% as.In described solvate, dabigatran etcxilate glucuronate salt can account for more than 95wt%, Ke Yiyou
Elect more than 98wt% as, more than 99wt% can be more preferably.
Present invention also offers the preparation dabigatran etcxilate glucuronate salt of the present invention, its hydrate and/or solvation
The method of thing, the method may include that and in water or the first organic solvent, dabigatran etcxilate and glucuronic acid are mixed into salt
And crystallize, through filtering, washing, after drying, use water or the second organic solvent to carry out recrystallization, prepare described dabigatran etcxilate Portugal
Grape glycuronate, its hydrate or solvate.Those skilled in the art can as required, by conventional means, as reduced
Crystallization temperature or partial solvent etc. is evaporated off, to accelerate the formation of crystallization.
The method according to the invention, wherein, described in be mixed into the step of salt can be at 0 DEG C to water or the first organic solvent
Carry out under reflux temperature, it may be preferred to for carrying out at 0～30 DEG C.As preferably, the step of described crystallize can in room temperature or
Carry out less than under conditions of room temperature, it may be preferred to for carrying out at 0～20 DEG C.Described first organic solvent and the second organic solvent
Identical or different, ethanol, methanol, propanol, isopropanol, butanol, Ethyl formate, ethyl acetate, isopropyl acetate, second can be selected from
Acid butyl ester, ether, diisopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, oxolane, petroleum ether, acetonitrile, dichloromethane
Alkane, chloroform, normal hexane, hexamethylene, acetone, butanone, pentanone, toluene, dimethyl acetylamide or dimethylbenzene.
The method according to the invention, wherein, described dabigatran etcxilate can be 10 with the mol ratio of described glucuronic acid:
1～1: 10.This mol ratio can be preferably 3: 1～1: 3.
Present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises the dabigatran etcxilate glucose of the present invention
Aldehydic acid salt, its hydrate and/or solvate, or comprise the dabigatran etcxilate glucuronic acid prepared according to the method for the present invention
Salt, its hydrate and/or solvate, and pharmaceutically acceptable adjuvant.
Described pharmaceutical composition can comprise the dabigatran etcxilate glucuronate salt of the present invention as active matter therein
Matter, it is also possible to simultaneously comprise other material with pharmaceutical active, is used for combining and controls forming the pharmaceutical composition of a kind of compound recipe
Treat.
When the dabigatran etcxilate glucuronate salt of the present invention is used for treating as active component, the most directly suffer from
The chemicals that person is simple, is the most all to occur with the form of the pharmaceutical composition containing pharmaceutically acceptable adjuvant.The present invention
Dabigatran etcxilate glucuronate salt can also be generally oral or parenteral way by the administration of any appropriate
Footpath, so, those skilled in the art can also pharmaceutically may be used according to what required form of medication selection pharmaceutical composition comprised
The adjuvant accepted.
Should be appreciated that, according to method well known in the art, pharmaceutically acceptable adjuvant can be to maintain pharmaceutical dosage form
Substrate or adjuvant, select generally according to different medicaments or be applied in combination, and optionally includes that excipient, such as crystallite are fine
Dimension element, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, mannitol, sorbitol, glucose, really
One or more in sugar, water, Polyethylene Glycol, propylene glycol, glycerol, cyclodextrin, cyclodextrin derivative etc.；Can also include gluing
Mixture, such as polyvidone (polyvinylpyrrolidone), methylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl
One or more in cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum etc.；Also include lubricant, the most firmly
One or more in fatty acid magnesium, stearic acid, Pulvis Talci, stearyl fumarate, sodium lauryl sulfate etc.；Can also include
Disintegrating agent, such as carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospolyvinylpyrrolidone,
One or more in cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, pregelatinized Starch, etc.；Also include surface
Activating agent, such as one or more of sodium lauryl sulphate, Tween-80, etc.；Can also include pH value regulator or
Buffer agent, such as phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide
One or more, etc.；Can also include preservative, such as sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, to hydroxyl
One or more in yl benzoic acid propyl ester, etc.；Stabilizer and antioxidant, such as calcium disodium edetate, sulfurous can also be included
One or more in acid sodium, vitamin C, etc.；Can also include taste regulator, such as maltose alcohol, fructose, sucrose,
One or more in saccharin sodium, Fructus Citri tangerinae essence, strawberry essence, etc.；It can in addition contain include other routines, appropriate adding
Add agent.
Additionally, when pharmaceutical dosage form is tablet or capsule, pharmaceutically acceptable adjuvant can also comprise film coating.With
In the material of film coating, including the coating materials being suitable for, such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose phthalate, etc.；Plasticizer, such as Polyethylene Glycol, triethyl citrate can also be comprised, etc.
Deng；Also include appropriate solubilizers, such as Tween-80；Suitable pigment can also be included, as titanium dioxide, various ferrum oxide,
Pink pigment, etc..
According to the pharmaceutical composition of the present invention, described pharmaceutical composition can be tablet, hard capsule, soft capsule, drip
Pill, granule, pellet or oral fluid agent.
The pharmaceutical composition of the present invention can be prepared as acceptable any pharmaceutical dosage form on pharmaceutics as required, such as mouth
Formulation, ejection preparation, parenteral liquid preparation, etc.；As oral tablet, capsule, granule, oral solution,
Powder agent, pill, sublingual administration agent, etc.；And for example injection, including powder ampoule agent for injection and injection, etc., the most non-mouth
The eye drop of clothes, nasal drop, [Dan, the emulsion of Transdermal absorption, etc..Can also be the rapid release of any of the above dosage form, slow release,
The dosage forms such as controlled release, such as oral dispersible tablet, slow releasing tablet, chewable tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet,
Special-shaped sheet, effervescent granule, etc..Especially, prepare by means known in the art, be preferred for preparing sheet edible on pharmaceutics
Agent (including dispersible tablet, slow releasing tablet, chewable tablet, enteric coatel tablets, oral cavity disintegration tablet, Special-shaped sheet), capsule (include gastric solubleness, enteric, delay
Release capsule), granule, oral solution, injection (including powder ampoule agent for injection and injection) etc., to meet on Clinical practice
Various needs.
According to the pharmaceutical composition of the present invention, wherein, in described pharmaceutical composition, described dabigatran etcxilate glucal
Hydrochlorate can be 1: 1～5 with the weight ratio of described pharmaceutically acceptable adjuvant, it may be preferred to is 1: 1～2.Dabigatran etcxilate
Glucuronate salt content in pharmaceutical composition can be 0.1～100mg, can be such as 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..
Present invention also offers the dabigatran etcxilate glucuronate salt of the present invention, its hydrate and/or solvate, or
Dabigatran etcxilate glucuronate salt, its hydrate and/or the solvate prepared according to the method for the present invention, is used in preparation
Application in the medicine for the treatment of or prevention cardiovascular disease.Can be preferably in preparation for treating or prevent phlebothrombosis or urgency
Application in the medicine of property coronary syndrome.
Dabigatran etcxilate glucuronate salt provided by the present invention, its hydrate and/or solvate have higher
Degree of dissociation so that it is water solublity obtains and greatly improves.On the one hand this can make course of dissolution more rapid, on the other hand can also subtract
The amount of few required aqueous solvent.It addition, the dabigatran etcxilate glucuronate salt of the present invention and hydrate and solvate thereof also have
There are higher stability and bioavailability.
When being prepared as pharmaceutically active substances or preparation, storing and apply galenical, changing of above biochemical property
Kind is highly important, and this can ensure that the quality of galenical is higher, and its high stability also makes what the later stage processed to add work step
The most simpler, reduce production cost.Further, its high crystalline can use point analysis methods such as such as X-ray diffraction to it
The release of hydrate or solvate carries out simple and clear analysis, in order to carry out suitable selection.These factors are for activity
For the quality of material and the galenical in time preparing, store and be administered, it is all critically important.Additionally, due to galenic
Active component in preparation is more stable, thus can avoid the preparation of complexity.
Use physical-chemical operates, as being dried, sieve, grind and the galenic such as medicament figuration processing, including mixed processing,
Granulation, spray-drying, tabletting etc., can make active substance absorb or loss moisture.This also by the temperature in its local environment and
The impact of relative humidity.When preparing some preparations, free water and combine water can be introduced into together with excipient or because of
Preparation process associative operation and in handled material add water.Therefore, under different temperatures and relative humidity, pharmacy is lived
Property material can contact within considerably long period with free water.In the case, the dabigatran etcxilate glucose of the present invention
Aldehydic acid salt does not show measurable moisture absorption or loss, and the most this stability is conducive to the last of its chemical preparation
In the stage, the processing stage of being also beneficial to the galenic of different dosage form, and its stable lasting effectiveness also benefits to patient.
Meanwhile, the dabigatran etcxilate glucuronate salt of the present invention also has more preferable dissolubility or a compressibility, thus more
Be suitable to be directly compressible into corresponding tablet formulation or capsule.
Additionally, the dabigatran etcxilate glucuronate salt of the present invention also has more preferably chemical stability, due to Da Bijia
Containing fatty amine structure in group's ester molecular structure, it is oxidized easily, the stability of dabigatran etcxilate after becoming salt, can be increased.This salt is also
It is likely to be of the advantage avoiding or reducing other active ingredient degradation.
Compared with compound well known in the prior art, described salt also has more effectively, toxicity is lower, action time more
Length, field of activity are wider, effect is higher, side effect is less, be more easy to advantage or other useful pharmacological property of absorption.
More specifically, the dabigatran etcxilate glucuronate salt of the present invention and hydrate and/or solvate thereof also have
But it is not limited to following beneficial effect:
1) relative to dabigatran etcxilate mesylate, dabigatran etcxilate glucuronate salt provided by the present invention has good
Good stability.Such as, dabigatran etcxilate mesylate was degraded to about 50% at 10 days under super-humid conditions, and dabigatran etcxilate
Glucuronate salt is almost without changes of contents.
2) the dabigatran etcxilate glucuronate salt of the present invention has preferable water solublity, is experimentally verified that, it is in water
Dissolubility up to 2.1mg/ml H2O (temperature 25 DEG C), and dabigatran etcxilate is the most insoluble when pH value is more than 4, dabigatran
Ester mesylate is 1.8mg/ml.Thus, the dabigatran etcxilate glucuronate salt of the present invention has relatively dabigatran etcxilate first sulphur
Hydrochlorate is more preferably or the most suitable bioavailability.
3) the dabigatran etcxilate glucuronate salt of the application also has preferable mobility and compressibility.Inventor is respectively
Dabigatran etcxilate glucuronate salt and dabigatran etcxilate mesylate to the present invention carry out mobility and compressibility measures, its
Result see table 1.
Table 1 dabigatran etcxilate glucuronate salt and the mobility of dabigatran etcxilate mesylate and compressibility measure
Wherein, the mobility of powder body is typically main to weigh angle of repose, and angle of repose is the least, and mobility is preferable.Conventional θ≤
30 ° of good fluidities, θ≤40 ° can meet production needs.Bulk density refer to powder quality divided by volume of a container shared by this powder body,
The density tried to achieve.Its volume used cumulative volume including space between the hole and particle of particle itself.Bulk density
Big for heavy, bulk density little for lightweight, with molding, bulk density is big just can show that compressibility is good with less pressure.Gu it is close
Degree be after certain speed and time tap vibrations powder quality divided by volume of a container shared by this powder body, the density tried to achieve.Gu
Density value shows greatly good fluidity.The least compressibility of compression ratio is the best, and generally less than 0.2 can meet production needs.Data above
Showing, the dabigatran etcxilate glucuronate salt of the present invention all shows on indices relative to dabigatran etcxilate mesylate
Go out more preferable mobility and compressibility, thus be more suitable for the large-scale production of medicine.
Detailed description of the invention
The present invention is further illustrated below by specific embodiment, it should be understood, however, that, these embodiments are only
It is used for specifically describing in more detail, and is not to be construed as limiting in any form the present invention.
This part to the present invention test used in material and test method carry out general description.Although it is
Realize many materials that the object of the invention used and operational approach is to it is known in the art that but the present invention still uses up at this
May describe in detail.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour
It is well known in the art as method.
If no special instructions, the mass spectrograph used in following example is Agientl 100 type level Four bar liquid matter connection
With instrument, the nuclear magnetic resonance analyser used is Bruker ARX-400NMR type nuclear magnetic resonance analyser.
Embodiment 1
The present embodiment is for illustrating the preparation of the dabigatran etcxilate glucuronate salt of the present invention.
The dabigatran etcxilate of 0.8mmol and the glucuronic acid of 0.8mmol are joined at 20 DEG C the anhydrous second of 20ml
In alcohol, mix and blend becomes salt, then crystallize at 20 DEG C in 6 hours, filters, and uses ethyl acetate washing, after drying, adds first
Alcohol carries out recrystallization, obtains the Methanol Solvate of the dabigatran etcxilate glucuronate salt of 0.300g.Record ESI-MS (EFI
Mist ionization-mass spectrometry) (m/z): 854 [M+H]+。
Above-mentioned Methanol Solvate is dried, obtains the dabigatran etcxilate glucuronate salt of white solid
0.289g, is computed, and in above-mentioned Methanol Solvate, the content of dabigatran etcxilate glucuronate salt is 96.2wt%.Often
This Methanol Solvate of molecule contains the methanol of 1 molecule.
Above-mentioned dabigatran etcxilate glucuronate salt is measured:
ESI-MS (m/z): 822 [M+H]+
1H NMR(DMAO-d6, 400MHz) and δ: 0.88 (t, J=9.0Hz, 3H, CH3), 1.13 (t, J=8.4Hz, 3H,
CH3), 1.27-1.37 (m, 6H, CH2CH2CH2), 1.57-1.61 (m, 2H, CH2), 2.68 (t, J=14.4Hz, 2H, CH2),
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,
CH3), 3.95-4.01 (m, 4H, 2CH2), 4.22 (t, J=14.4Hz, 2H, CH2), 4.32-4.33 (m, 1H), 4.34-4.35
(m, 1H), 4.61 (d, J=5.6Hz, 2H, CH2), 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, NH2)。
Fusing point: 134-135 DEG C
Elementary analysis:
C34H41N7O5(627.74)·1/nC6H10O7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate glucuronate salt is:
Embodiment 2
The present embodiment is for illustrating the preparation of the dabigatran etcxilate glucuronate salt of the present invention.
The dabigatran etcxilate of 1.6mmol and the glucuronic acid of 0.8mmol are joined in 20ml water at 30 DEG C, mixing
Stir 6 hours and become salt, then crystallize at 30 DEG C, filter, use ethyl acetate washing, after drying, add water and heavily tie
Crystalline substance, obtains the hydrate of the dabigatran etcxilate glucuronate salt of 0.200g.Record ESI-MS (m/z): 761 [M+H]+.
Above-mentioned hydrate is dried, obtains the dabigatran etcxilate glucuronate salt 0.191g of white solid, through meter
Calculating, in above-mentioned hydrate, the content of dabigatran etcxilate glucuronate salt is 95.3wt%.Containing 2 in this hydrate of per molecule
The water of molecule, i.e. dihydrate.
Above-mentioned dabigatran etcxilate glucuronate salt is measured:
ESI-MS (m/z): 725 [M+H]-
1H NMR(DMAO-d6, 400MHz) and δ: 0.88 (t, J=9.0Hz, 3H, CH3), 1.13 (t, J=8.4Hz, 3H,
CH3), 1.27-1.37 (m, 6H, CH2CH2CH2), 1.57-1.61 (m, 2H, CH2), 2.68 (t, J=14.4Hz, 2H, CH2),
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, CH3), 3.95-4.01 (m, 4H, 2CH2), 4.22 (t, J=14.4Hz, 2H, CH2), 4.32-4.33 (m, 0.5H),
4.34-4.35 (m, 0.5H), 4.61 (d, J=5.6Hz, 1H, CH2), 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, NH2)。
Fusing point: 128-129 DEG C
Elementary analysis:
C34H41N7O5(627.74)·1/n C6H10O7
Discovery value: C 61.31 N 13.53 H 6.40 O 18.76
Calculate: n=2
The molecular structural formula of therefore obtained dabigatran etcxilate glucuronate salt is:
Embodiment 3
The present embodiment is for illustrating the preparation of the dabigatran etcxilate glucuronate salt of the present invention.
The dabigatran etcxilate of 2.4mmol and the glucuronic acid of 0.8mmol are joined 20ml dehydrated alcohol at 0 DEG C
In, mix and blend becomes salt, then crystallize at 0 DEG C in 6 hours, filters, and uses ethyl acetate washing, after drying, adds second two
Diethylene glycol dimethyl ether carries out recrystallization, obtains the dabigatran etcxilate glucuronate salt 0.200g of white solid.
Above-mentioned dabigatran etcxilate glucuronate salt is measured:
ESI-MS (m/z): 693 [M+H]
1H NMR(DMAO-d6, 400MHz) and δ: 0.88 (t, J=9.0Hz, 3H, CH3), 1.13 (t, J=8.4Hz, 3H,
CH3), 1.27-1.37 (m, 6H, CH2CH2CH2), 1.57-1.61 (m, 2H, CH2), 2.68 (t, J=14.4Hz, 2H, CH2),
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, CH3), 3.95-4.01 (m, 4H, 2CH2), 4.22 (t, J=14.4Hz, 2H, CH2), 4.32-4.33 (m, 0.3H),
4.34-4.35 (m, 0.3H), 4.61 (d, J=5.6Hz, 7H, CH2), 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, NH2)。
Fusing point: 126-127 DEG C
Elementary analysis:
C34H41N7O5(627.74)·1/n C6H10O7
Discovery value: C 62.44 N 14.16 H 6.45 O 16.94
Calculate: n=3
The molecular structural formula of therefore obtained dabigatran etcxilate glucuronate salt is:
Embodiment 4
The present embodiment is for illustrating the preparation of the dabigatran etcxilate glucuronate salt of the present invention.
The dabigatran etcxilate of 0.8mmol and the glucuronic acid of 2.4mmol are joined 20ml absolute methanol at 30 DEG C
In, mix and blend becomes salt, then crystallize at 10 DEG C in 6 hours, filters, and uses ether washing, after drying, adds oxolane
Carry out recrystallization, obtain the tetrahydrofuran solvate of the dabigatran etcxilate glucuronate salt of 0.320g.Record its ESI-MS
(m/z): 858 [M+H]+。
Above-mentioned tetrahydrofuran solvate is dried, obtains the dabigatran etcxilate glucuronate salt of white solid
0.306g, is computed, and in above-mentioned solvate, the content of dabigatran etcxilate glucuronate salt is 95.8wt%.Per molecule this four
Hydrogen THF solvent compound contains the oxolane of 0.5 molecule.
Above-mentioned dabigatran etcxilate glucuronate salt is measured:
ESI-MS (m/z): 822 [M+H]+。
Fusing point: 134-136 DEG C
Elementary analysis:
C34H41N7O5(627.74)·1/n C6H10O7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate glucuronate salt is:
Embodiment 5
The present embodiment is for illustrating the preparation of the dabigatran etcxilate glucuronate salt of the present invention.
The dabigatran etcxilate of 0.8mmol and the glucuronic acid of 1.6mmol are joined in 20ml acetone at 10 DEG C, mixed
Close stirring and become salt, then crystallize at 10 DEG C in 6 hours, filter, use ether washing, after drying, add dehydrated alcohol and carry out
Recrystallization, obtains the alcohol solvent compound of the dabigatran etcxilate glucuronate salt of 0.250g.Record its ESI-MS (m/z): 868
[M+H]+。
Above-mentioned alcohol solvent compound is dried, obtains the dabigatran etcxilate glucuronate salt of white solid
0.237g, is computed, and in above-mentioned solvate, the content of dabigatran etcxilate glucuronate salt is 95wt%.This second of per molecule
Solvate contains the ethanol of 1 molecule.
Dabigatran etcxilate glucuronate salt is measured:
ESI-MS (m/z): 822 [M+H]
Fusing point: 133-135 DEG C
Elementary analysis:
C34H41N7O5(627.74)·1/n C6H10O7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate glucuronate salt is:
Embodiment 6
The present embodiment is for illustrating the preparation of the dabigatran etcxilate glucuronate salt of the present invention.
The dabigatran etcxilate of 0.8mmol and the glucuronic acid of 8mmol are joined in 20ml chloroform at 30 DEG C,
Mix and blend becomes salt, then crystallize at 20 DEG C in 6 hours, filters, and uses ether washing, after drying, adds water and heavily tie
Crystalline substance, obtains the hydrate of the dabigatran etcxilate glucuronate salt of 0.270g.Record its ESI-MS (m/z): 831 [M+H]+。
Above-mentioned hydrate is dried, obtains the dabigatran etcxilate glucuronate salt 0.267g of white solid, through meter
Calculating, in above-mentioned hydrate, the content of dabigatran etcxilate glucuronate salt is 99wt%.Containing 0.5 point in this hydrate of per molecule
The water of son, i.e. semihydrate.
Dabigatran etcxilate glucuronate salt is measured:
ESI-MS (m/z): 822 [M+H]+。
Fusing point: 134-135 DEG C
Elementary analysis:
C34H41N7O5(627.74)·1/n C6H10O7
Discovery value: C 58.46 N 11.93 H 6.25 O 23.36
Calculate: n=1
The molecular structural formula of therefore obtained dabigatran etcxilate glucuronate salt is:
Stability test:
Inventor to the dabigatran etcxilate glucuronate salt of embodiment 1 and dabigatran etcxilate mesylate in not equality of temperature
Carrying out observing and make assay under degree, humidity and illumination condition, data are shown in Table 2 and table 3.
Liquid-phase condition:
Chromatographic column: Agela Venusil MP C18 post (4.6mm × 250mm, 5 μm) NO:VA952505-0
Flowing phase: 0.01mol L-1Diammonium phosphate buffer-methanol (40: 60)；
Flow velocity: 1ml min-1；Detection wavelength: 250nm；Column temperature: 25 DEG C；Sample size: 20 μ l
Table 2 dabigatran etcxilate glucuronate salt and the changes of contents of dabigatran etcxilate mesylate
Table 2 is the content contrast through influence factor's result of the test of dabigatran etcxilate glucuronate salt and mesylate.
Data show, under the same conditions (high temperature, high humidity, illumination), and the former content changes over the least, belongs to evaluated error model
Enclose, and the latter was the most unstable, especially can be degraded to about 50% under super-humid conditions at 10 days, show substantially
Unstability.
Table 3 dabigatran etcxilate glucuronate salt and the cosmetic variation of dabigatran etcxilate mesylate
As shown in Table 3, under hot conditions, dabigatran etcxilate glucuronate salt is almost without change, and dabigatran etcxilate first
Sulfonate is it is observed that there is significant change in time in color.Under super-humid conditions, the former outward appearance is almost unchanged, shows more
Adding stable character, the latter's then moisture absorption is serious.
Embodiment 7
The present embodiment is for illustrating the preparation of the pharmaceutical composition of the dabigatran etcxilate glucuronate salt of the present invention.
Dabigatran etcxilate glucuronate salt is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Dabigatran etcxilate is weighed by recipe quantity
Glucuronic acid, microcrystalline Cellulose and lactose are sufficiently mixed uniformly, add 1% (weight/volume) hypromellose aqueous solution
Mixing, soft material processed, sieve, wet granular processed, it is dried in 55 DEG C.Polyvinylpolypyrrolidone and magnesium stearate are added in above-mentioned granule,
Measure intermediates content, tabletting, packaging.
Embodiment 8
The present embodiment is for illustrating the preparation of the pharmaceutical composition of the dabigatran etcxilate glucuronate salt of the present invention.
Dabigatran etcxilate glucuronate salt is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Dabigatran etcxilate is weighed by recipe quantity
Glucuronic acid, microcrystalline Cellulose, pregelatinized Starch and lactose are sufficiently mixed uniformly, add 1% (weight/volume) hydroxypropyl first fine
Dimension element aqueous solution, soft material processed, sieve, wet granular processed, it is dried in 55 DEG C.Magnesium stearate is added in above-mentioned granule, surveys
Determine intermediates content, encapsulated, packaging.
Embodiment 9
The present embodiment is for illustrating the preparation of the pharmaceutical composition of the dabigatran etcxilate glucuronate salt of the present invention.
Dabigatran etcxilate glucuronate salt is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Dabigatran etcxilate is weighed by recipe quantity
Glucuronate salt, lactose, mannitol, aspartame, essence are sufficiently mixed, and add 2% (weight/volume) hypromellose
Element aqueous solution soft material, 16 mesh sieves granulations, 55 DEG C are dried, 14 mesh sieve granulate, measure intermediates content and moisture, packaging, make altogether
Obtain 100 bags of granules.
Embodiment 10
The present embodiment is for illustrating the preparation of the pharmaceutical composition of the dabigatran etcxilate glucuronate salt of the present invention.
Dabigatran etcxilate glucuronate salt is crossed 80 mesh sieves, and 60 mesh sieves crossed by adjuvant.Dabigatran etcxilate is weighed by recipe quantity
Glucuronic acid, polyvidone, aspartame and essence elder generation mix homogeneously, then fill with mannitol, microcrystalline Cellulose and lactose successively
Divide mix homogeneously, be eventually adding magnesium stearate mix homogeneously, measure intermediates content, tabletting, packaging.
Although present invention has been a certain degree of description, it will be apparent that, without departing from the spirit and scope of the present invention
Under the conditions of, the suitable change of each condition can be carried out.It is appreciated that and the invention is not restricted to described embodiment, and be attributed to right
The scope required, it includes the equivalent of described each factor.
Claims (10)
1. a pharmaceutical composition, it is characterised in that this pharmaceutical composition comprises the dabigatran etcxilate glucal that formula is following
Hydrochlorate, and pharmaceutically acceptable adjuvant:
Wherein, n is 2 or 3；Or
This pharmaceutical composition comprises the hydrate of the dabigatran etcxilate glucuronate salt of formula above (I), wherein, in this hydration
In thing, n is 1 and contains the water of 0.5 molecule in the hydrate of dabigatran etcxilate glucuronate salt described in per molecule；Or
In this hydrate, n is 2 and contains the water of 2 molecules in the hydrate of dabigatran etcxilate glucuronate salt described in per molecule；Or
Person
This pharmaceutical composition comprises the solvate of the dabigatran etcxilate glucuronate salt of formula above (I), wherein, molten at this
In agent compound, n is the first in 1, and the solvate of dabigatran etcxilate glucuronate salt described in per molecule containing 1 molecule
Alcohol, or the solvate of dabigatran etcxilate glucuronate salt described in per molecule contain the ethanol of 1 molecule, or described in per molecule
The solvate of dabigatran etcxilate glucuronate salt contains the oxolane of 0.5 molecule.
Pharmaceutical composition the most according to claim 1, it is characterised in that described pharmaceutical composition be tablet, hard capsule,
Soft capsule, drop pill, granule, pellet or oral fluid agent.
Pharmaceutical composition the most according to claim 1, it is characterised in that in described pharmaceutical composition, described Da Bijia
Group's ester glucuronate salt is 1:1～5 with the weight ratio of described pharmaceutically acceptable adjuvant.
Pharmaceutical composition the most according to claim 3, it is characterised in that in described pharmaceutical composition, described Da Bijia
Group's ester glucuronate salt is 1:1～2 with the weight ratio of described pharmaceutically acceptable adjuvant.
5. the preparation method of the pharmaceutical composition according to any one of Claims 1-4, it is characterised in that the method includes: will
Dabigatran etcxilate and glucuronic acid are mixed into salt crystallize in water or the first organic solvent, through filtering, washing, after drying,
Use water or the second organic solvent to carry out recrystallization, prepare described dabigatran etcxilate glucuronate salt, its hydrate or solvent
Compound；And add described pharmaceutically acceptable adjuvant；Wherein, described first organic solvent and the second organic solvent is identical or
Different.
Method the most according to claim 5, it is characterised in that described in be mixed into salt at 0 DEG C to water or the first organic solvent
Reflux temperature under carry out.
7. according to the method described in claim 5 or 6, it is characterised in that described in be mixed into salt and carry out at 0～30 DEG C.
Method the most according to claim 5, it is characterised in that described first organic solvent and the second organic solvent are selected from second
Alcohol, methanol, propanol, isopropanol, butanol, Ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, ether, diisopropyl ether, just
Butyl ether, glycol dimethyl ether, methyl tert-butyl ether, oxolane, petroleum ether, acetonitrile, dichloromethane, chloroform, normal hexane, ring
Hexane, acetone, butanone, pentanone, toluene, dimethyl acetylamide or dimethylbenzene.
Method the most according to claim 5, it is characterised in that described dabigatran etcxilate and described glucuronic acid mole
Ratio is 10:1～1:10.
10. according to the method described in claim 5 or 9, it is characterised in that described dabigatran etcxilate and described glucuronic acid
Mol ratio is 3:1～1:3.
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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 |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 达比加群酯甲磺酸盐( dabigatran etexilatemesylate);张孟迪 等;《中国药物化学杂志》;20110430;第21卷(第2期);165，168 * |
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