CN103539779A - Hydroxyl substituted benzene sulfonate of dabigatran etexilate and preparation method and usage thereof - Google Patents
Hydroxyl substituted benzene sulfonate of dabigatran etexilate and preparation method and usage thereof Download PDFInfo
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- CN103539779A CN103539779A CN201210242230.XA CN201210242230A CN103539779A CN 103539779 A CN103539779 A CN 103539779A CN 201210242230 A CN201210242230 A CN 201210242230A CN 103539779 A CN103539779 A CN 103539779A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a hydroxyl substituted benzene sulfonate of dabigatran etexilate and a preparation method and a usage thereof. The preparation method comprises: respectively adding dabigatran etexilate and hydroxyl substituted benzenesulfonic acid into an organic solvent, stirring and dissolving to obtain a clear solution; and reacting under a certain temperature, concentrating, stewing, separating out crystals, and filtering to obtain the hydroxyl substituted benzene sulfonate of dabigatran etexilate. The hydroxyl substituted benzene sulfonate of dabigatran etexilate provided by the invention has good stability; the provided preparation method is simple, convenient, feasible, stable and reliable, and a crystal form suitable for medicinal can be obtained; and the obtained product is good in quality and high in yield.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of hydroxyl-substituted sulfonate with the dabigatran etcxilate (dabigatran etexilate) of blood coagulation resisting function, its preparation method and the pharmaceutical composition that this compound is activeconstituents of take, and they are in the prevention of the disease causing for the preparation of thrombus or embolism or the purposes in medicine.
Background technology
In recent years, cardiovascular and cerebrovascular diseases sickness rate is in rising trend, serious harm human health, and wherein, the relative disease that thrombus or embolism cause is current cause disabled and dead primary factor.The control of thrombus and complication thereof has become the important topic that world medical circle faces.The cardiovascular and cerebrovascular diseases that anticoagulation medicine can effectively improve and pre-preventing thrombosis causes, reduce mortality ratio, thereby the research and development of related drugs has become the focus for the treatment of cardiovascular disease.
For more than half a century, anticoagulation medicine is mainly comprised of vitamin K antagon and heparin class material.Wherein warfarin (Warfarin) is a unique orally active vitamin K antagon and a unique anticoagulation medicine of getting permission prolonged application clinically.Although warfarin is effective, also can bring the serious even bleeding risk of lethality.Meanwhile, because the individual difference of pharmacokinetics is large, drug interaction is complicated, and is vulnerable to the impact of diet, is difficult to clinically correctly, determines easily and must frequently carry out coagulation function monitoring by dosage, and compliance is poor.Its onset is slow, treatment window is narrower.And heparin class material is because needing drug administration by injection, therefore often limited the use of in inpatient or short-term prevention venous thromboembolism.During the clinical application of heparin, need to carry out coagulation function detection equally, its side effect comprises brings out thrombopenia and osteoporosis etc.Therefore the oral anticoagulant medicine that, urgent clinical needs are new, safer, medication is easier.
Dabigatran etcxilate (dabigatran etexilate, likes I), chemistry 3-[[[2-[[[4-[[[(hexyloxy by name) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, it is the novel anticoagulation medicine by the exploitation of German Boehringer Ingelheim company, the salt type that its listing adopts is mesylate, and commodity are called Pradaxa.Dabigatran etcxilate is the oral new drug of the anticoagulation of first listing over 50 years after warfarin, is described as another milestone in anticoagulation therapy field and potential lethality thrombus prevention field.Dabigatran etcxilate is bi precursor medicine, is converted in vivo activated dabigatran (dabigatran, formula II), and the latter brings into play anticoagulation effect by direct Trombin inhibiting.Dabigatran etcxilate is oral administration, have potent, without features such as special medication monitoring, drug interaction are few.Potential applicability in clinical practice is optimistic, to prevention of deep vein thrombosis and prevent that from there is significant effect the aspects such as palsy.It successfully goes on the market and indicates the important breakthrough of anticoagulation medicine research field.But similar with anticoagulation medicines such as warfarins, also there is the untoward reaction that easily causes hemorrhage (particularly gastrointestinal hemorrhage) in dabigatran etcxilate.
The preparation of dabigatran etcxilate is disclosed in patent DE19706229A1, WO9837075, EP0966454B1 and CN1088702C first and the purposes at field of medicaments as thrombin inhibitors.Above-mentioned patent has also been protected the physiologically acceptable salt of dabigatran etcxilate, but related embodiment is not clearly provided.
Patent WO2005028468 discloses three kinds of crystal formations of dabigatran etcxilate mesylate, comprises crystal formation I, crystal form II and semihydrate crystal formation.Adopt X-ray powder diffraction (XRPD) and means of differential scanning calorimetry (DSC) method to characterize above-mentioned crystal formation.
Patent WO2006114415 discloses the acid salt of 6 kinds of new dabigatran etcxilates, comprise hydrochloride, Citrate trianion, tartrate, malonate, maleate, salicylate, these salt do not adopt X-ray powder diffraction method to characterize, and only adopt DSC method to characterize.
Patent WO2006131491 discloses the crystal formation of 3 kinds of dabigatran etcxilate free alkalis, and these polymorphic systems obtain with crystallization mode, and this patent has adopted the methods such as X-ray powder diffraction, DSC and TG to characterize each crystal formation.
Patent WO2008043759 further discloses acid salt and the polymorphic thereof of multiple dabigatran etcxilate, comprise two kinds of phosphatic crystal formations (crystal formation I, II), the crystal formation of two kinds of fumarates (crystalline form III, IV), the crystal formation of three kinds of oxalate (crystal formation I, II, V), the crystal formation of three kinds of hydrochlorides (crystal form II, V, VI), the crystal formation of four kinds of tosilate (crystal formation I, V, VI, VII).This patent has adopted X-ray powder diffraction and DSC method to characterize each crystal formation.
Patent WO2008059029 discloses two kinds of anhydrides of dabigatran etcxilate and the crystal formation of three kinds of solvates, comprises anhydride crystal formation (II, IV), monohydrate crystal formation (I, II) and oil of mirbane solvate (crystal formation I).
Patent WO2011110876A1 discloses a plurality of new dabigatran etcxilate acid salt and polymorphics thereof, comprises phosphoric acid salt (crystalline form III), fumarate (crystal form V), vitriol (crystal formation I), vitriol dihydrate (crystal formation I), vitriol monohydrate (crystal formation I), maleate (crystal form II), oxalate (crystal formation VI), hydrochloride (VII, VIII, IX, X), tosilate (crystal formation VIII, IX), mesylate (crystalline form IV).This patent has adopted X-ray powder diffraction and DSC method to characterize each crystal formation.
Patent CN102050815A discloses multiple alkyl derivative and non-toxicity pharmacy acceptable salt (vitriol, the hydrochloride of dabigatran, hydrobromate, phosphoric acid salt, acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc.), the multiple alkyl derivative hydrochloride of disclosed dabigatran wherein, and carried out anticoagulating active evaluation.
Quite important to the clinical application of medicine in view of having the acid salt of Good Pharmacy character, the pharmaceutically acceptable dabigatran etcxilate acid salt that therefore continues to find novel type is very necessary.
Summary of the invention
The object of the invention is to improve the water-soluble and relevant pharmaceutical properties of dabigatran etcxilate, provide a kind of acid salt of new dabigatran etcxilate, i.e. the hydroxyl-substituted sulfonate of dabigatran etcxilate.
Another object of the present invention is to provide a kind of preparation method of hydroxyl-substituted sulfonate of above-mentioned dabigatran etcxilate.
Another object of the present invention is to provide more than one pharmaceutical compositions that hydroxyl-substituted sulfonate of stating dabigatran etcxilate is activeconstituents.
The hydroxyl-substituted sulfonate that a further object of the present invention is to provide a kind of above-mentioned dabigatran etcxilate is in the prevention of the disease causing for the preparation of thrombus or embolism or the purposes in medicine.
Object of the present invention realizes by following proposal:
The hydroxyl-substituted sulfonate of a kind of dabigatran etcxilate provided by the invention, has following formula (III) structure:
Wherein, R
1, R
2, R
3, R
4and R
5can be H or OH, and have one at least for OH.
The hydroxyl-substituted sulfonate of described dabigatran, it is characterized in that described compound is 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 2,5-dihydroxy benzenes sulfonic acid salt.
The preparation method of the hydroxyl-substituted sulfonate of dabigatran etcxilate of the present invention, comprises the steps:
1) in organic agent, add dabigatran etcxilate, hydroxyl-substituted sulfonic acid respectively, stir, dissolve, reaction, obtains settled solution at a certain temperature;
2) above-mentioned reaction solution is concentrated, cooling, standing, crystallization, suction filtration, it is as follows that the hydroxyl that obtains dabigatran etcxilate replaces reaction process of the present invention:
In step 1, described temperature of reaction is 0-100 ℃, is preferably 30 ℃.
In step 1, described organic solvent needs only energy solubilizing reaction thing and does not hinder reaction, can be one or more of chloroform, methylene dichloride, ethyl acetate, acetone, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, acetonitrile, propionitrile, propyl alcohol, propyl carbinol, the trimethyl carbinol, ethanol, methyl alcohol, be preferably ethyl acetate.
In step 1, described dabigatran etcxilate and the mol ratio of hydroxyl-substituted sulfonic acid are 1:1-2, are preferably 1:1.2.
Described 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 2, the crystal formation of 5-dihydroxy benzenes sulfonic acid salt, it is characterized in that, reflection angle 2 θ of its powder X-ray-diffractogram have located charateristic avsorption band at 5.47 ± 0.2,10.85 ± 0.2,13.54 ± 0.2,18.13 ± 0.2,22.32 ± 0.2,24.85 ± 0.2,27.05 ± 0.2 °.
Described 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] crystal form A of ethyl propionate p-hydroxybenzenyl sulfonate salt, it is characterized in that, reflection angle 2 θ of its powder X-ray-diffractogram have located charateristic avsorption band at 7.02 ± 0.2,11.73 ± 0.2,15.46 ± 0.2,17.62 ± 0.2,19.92 ± 0.2,20.97 ± 0.2,23.64 ± 0.2,25.26 ± 0.2 °.
Formula of the present invention (III) compound can per os or oral administration not.During oral administration administration, can adopt conventional preparation technique, these chemicals and conventional pharmaceutically acceptable carrier are mixed and made into conventional solid preparation, as granule, capsule, tablet, powder or syrup etc.; During non-oral administration administration, can adopt conventional preparation technique to be made into preparation capable of permeating skin, injection liquid, infusion solution or suppository etc.Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, as vehicle, disintegrating agent, tackiness agent, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent.
Pharmaceutical composition of the present invention contains the above-mentioned formula of activeconstituents (III) compound for the treatment of significant quantity, and contains one or more pharmaceutically acceptable carriers.The various formulations of this pharmaceutical composition can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, are then made into required formulation.
These preparations can be manufactured by following additives by currently known methods: the vehicle (as: sugar derivatives such as lactose, white sugar, glucose, N.F,USP MANNITOL, sorbyl alcohol; The starch derivative such as W-Gum, yam starch, Alpha-starch, dextrin; Crystalline cellulose derivative; Sudan Gum-arabic; Dextran; The organic excipients such as Propiram; And the silicate derivative such as light silicon anhydride, synthetic aluminium silicate, Calucium Silicate powder, magnesium aluminum silicate; The phosphoric acid salt such as secondary calcium phosphate; The carbonate such as calcium carbonate; The inorganic excipients of the vitriol such as calcium sulfate etc.), the lubricant (as: Metallic stearates such as stearic acid, calcium stearate, Magnesium Stearate; Ethylene glycol; FUMARIC ACID TECH GRADE; Sodium Benzoate; DL-leucine; The dodecyl sulfate such as sodium lauryl sulphate, Stepanol MG; The silicic acid such as silicic anhydride, hydrate of silicic acid class; And above-mentioned starch derivative), tackiness agent (as: hydroxypropylcellulose, HPMC, polyvinylpyrrolidone, polyoxyethylene glycol and open the same compound of agent with above-mentioned tax), disintegrating agent (as: low-substituted hydroxypropyl cellulose derivative; Carboxymethyl starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone etc. are through starch or the cellulose family of chemical modification; Above-mentioned starch derivative), the emulsifying agent (as: colloidal clay such as wilkinite, V word glue; The metal hydroxides such as magnesium hydroxide, aluminium hydroxide; The anion surfactant such as sodium lauryl sulphate, calcium stearate; The cats products such as benzalkonium chloride; And the nonionogenic tenside such as Voranol EP 2001, polyoxyethylene dehydration sorbitol fatty acid ester, sucrose-fatty), the stablizer (as: parabens such as para methyl paraben, propylparaben; The alcohols such as trichloro-butyl alcohol, phenylcarbinol, phenylethyl alcohol; The phenols such as benzalkonium chloride, phenol, cresols; Thimerosal; Dehydroacetic acid (DHA); And Sorbic Acid), correctives (as: normally used sweetening material, acid flavoring, spices), thinner etc.
Formula of the present invention (III) compound and aforementioned pharmaceutical compositions can be used for the medicine that preparation has Trombin inhibiting effect, the disease that prevention or treatment thrombus or embolism cause.
The amount of application of formula of the present invention (III) compound can be taked different consumptions according to variations such as route of administration, patient's age, body weight, the disease for the treatment of and severity.
Sometimes, the hydroxyl-substituted sulfonate of dabigatran etcxilate of the present invention is placed in air or by recrystallize, will absorb moisture and produce planar water formation hydrate, and the acid salt that therefore contains moisture is also contained in the present invention.
Sometimes, the crystallization or in put procedure, will form solvate in organic solvent in organic solvent of the hydroxyl-substituted sulfonate of dabigatran etcxilate of the present invention, therefore corresponding solvate is also contained in the present invention.
Tool of the present invention has the following advantages and effect:
1) the hydroxyl-substituted sulfonate of dabigatran etcxilate provided by the invention, has satisfactory stability;
2) preparation method of the present invention is simple and easy to do, reliable and stable, and products obtained therefrom quality is good, and yield is high.
Embodiment
Below in conjunction with embodiment, the present invention is done to further detailed description, but embodiments of the present invention are not limited to this.
Embodiment 1: dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt synthetic
By dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g, 0.054mol) adds in the reaction flask that ethyl acetate (300ml) is housed respectively, and temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.This crystal is suspended in water (300ml), and temperature control, at 30 ℃, stirs 4 hours.Filter 40 ℃ of vacuum-dryings of filter cake.Weight: 33.8g, yield: 92%.The corresponding crystal formation called after of this product crystal form A.
Be below dabigatran etcxilate 2, the structural characterization data of 5-dihydroxy benzenes sulfonic acid salt:
m.p.163.5-164.5℃.
IR(KBr)
v:3280(N-H),3174(O-H),2980(-CH
3),2933(-CH
2-),2856(-CH
3),1759,1734,(-CO
2-),1647(-CON-),1608(-O-CO-NH-),1207,1072(SO
3 -).
ESI-MS(positive)：m/z=628,[M+H]
+;m/z=650,[M+Na]
+.
ESI-MS(negtive)：m/z=189,[M-H]
-.
1H?NMR(DMSO-d
6,δ/ppm)：0.8654-0.8789(d,3H,-CH
3);1.0797-1.1385(m,3H,-CH
3);1.3056-1.3753(m,4H,-CH
2-);1.6390-1.6906(m,2H,-CH
2-);2.6668-2.7013(t,2H,-CH
2-);3.7742(s,3H,-CH
3);3.9467-3.9997(m,2H,-CH
2-);4.2078-4.2634(m,4H,-CH
2-);4.6945(s,2H,-CH
2-);6.5511-6.6255(m,2H,-ArH);6.8569-6.9105(m,4H,-ArH);7.1047-7.1759(m,2H,-ArH);7.4093-7.4303(d,2H,-ArH);7.4748,(s,1H,-NH-);7.5326-7.5914(m,2H,-ArH);7.6425-7.6641(d,2H,-ArH);8.3835-8.3908(d,1H,-ArH);8.8095(s,1H,-NH-);9.8412(s,1H,-NH-);9.9997(s,1H,-OH);10.5749(br.,1H,-OH);11.8550-11.8644(br.,1H,-SO
3H).
Above data acknowledgement products therefrom is dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt.
Embodiment 2: dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt synthetic
By dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g, 0.054mol) adds in the reaction flask that ethyl acetate (500ml) is housed respectively, and temperature control, at 10 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.This crystal is suspended in water (300ml), and temperature control, at 30 ℃, stirs 4 hours.Filter 40 ℃ of vacuum-dryings of filter cake.Weight: 30.1g, yield: 82%.
The characterization result of product is with embodiment 1.
Embodiment 3: dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt synthetic
By dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g, 0.054mol) adds in the reaction flask that ethyl ester ethyl ester (200ml) is housed respectively, is heated to 60 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.This crystal is suspended in water (300ml), and temperature control, at 30 ℃, stirs 4 hours.Filter 40 ℃ of vacuum-dryings of filter cake.Weight: 31.3g, yield: 85%.
The characterization result of product is with embodiment 1.
Embodiment 4: dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt synthetic
By dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (17.1g, 0.09mol) adds in the reaction flask that ethyl acetate (300ml) is housed respectively, and temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.This crystal is suspended in water (300ml), and temperature control, at 30 ℃, stirs 4 hours.Filter 40 ℃ of vacuum-dryings of filter cake.Weight: 29.8g, yield: 81%.
The characterization result of product is with embodiment 1.
Embodiment 5: dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt synthetic
By dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g, 0.054mol) adds in the reaction flask that acetone (200ml) is housed respectively, and temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.This crystal is suspended in water (300ml), and temperature control, at 30 ℃, stirs 4 hours.Filter 40 ℃ of vacuum-dryings of filter cake.Weight: 33.1g, yield: 90%.
The characterization result of product is with embodiment 1.
Embodiment 6: dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt synthetic
By dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g, 0.054mol) adds in the reaction flask that methylene dichloride (400ml) is housed respectively, and temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.This crystal is suspended in water (300ml), and temperature control, at 30 ℃, stirs 4 hours.Filter 40 ℃ of vacuum-dryings of filter cake.Weight: 29.4g, yield: 80%.
The characterization result of product is with embodiment 1.
Embodiment 7: dabigatran etcxilate p-hydroxybenzenyl sulfonate salt synthetic
Respectively dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g, 0.054mol) are added in the reaction flask that ethyl acetate (300ml) is housed, temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, weight: 33.9g, yield: 94%.
Be below the structural characterization data of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt:
m.p.:174.0-176.0℃.
IR(KBr)
v:3300(N-H),3200(O-H),2956(-CH
3),2933(-CH
2-),2860(-CH
3),1731,(-CO
2-),1654(-CON-),1608(-O-CO-NH-),1197,1031(SO
3 -).
ESI-MS(positive)：m/z=628,[M+H]
+;m/z=650,[M+Na]
+.
ESI-MS(negtive)：m/z=173,[M-H]
-.
1H?NMR(DMSO-d
6,δ/ppm)：1.1009-1.1364(t,3H,-CH
3);1.2905-1.3743(m,4H,-CH
2-);1.6384-1.7062(m,2H,-CH
2-);2.6628-2.6976(m,2H,-CH
2-);3.7747(s,1H,-CH
3);3.9424-3.9957(m,2H,-CH
2-);4.2026-4.2665(m,4H,-CH
2O-);4.6971(s,1H,-ArH);6.6419-6.6627(d,2H,-ArH);6.8536-6.9091(m,3H,-ArH);7.1047-7.1705(m,2H,-CH2);7.3807-7.4366(m,3H,-ArH);7.4694(s,1H,-NH-);7.5305-7.5694(m,1H,-ArH);7.6329-7.6540(m,3H,-ArH);8.3815-8.3909(d,1H,-ArH);9.5051(s,1H,-NH-);10.0226(s,1H,-NH-);10.6241(s,1H,-OH),11.8763(s,1H,-SO
3H).
Above data acknowledgement products therefrom is dabigatran etcxilate p-hydroxybenzenyl sulfonate salt.
Embodiment 8: dabigatran etcxilate p-hydroxybenzenyl sulfonate salt synthetic
Respectively dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g, 0.054mol) are added in the reaction flask that ethyl acetate (500ml) is housed, temperature control, at 10 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, weight: 30.3g, yield: 84%.
The characterization result of product is with embodiment 7.
Embodiment 9: dabigatran etcxilate p-hydroxybenzenyl sulfonate salt synthetic
Respectively dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g, 0.054mol) are added in the reaction flask that ethyl acetate (200ml) is housed, be heated to 60 ℃, stir it is dissolved, obtain settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, weight: 31.4g, yield: 87%.
The characterization result of product is with embodiment 7.
Embodiment 10: dabigatran etcxilate p-hydroxybenzenyl sulfonate salt synthetic
Respectively dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (15.7g, 0.09mol) are added in the reaction flask that ethyl acetate (300ml) is housed, temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, weight: 29.6g, yield: 82%.
The characterization result of product is with embodiment 7.
Embodiment 11: dabigatran etcxilate p-hydroxybenzenyl sulfonate salt synthetic
Respectively dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g, 0.054mol) are added in the reaction flask that acetone (200ml) is housed, temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, weight: 32.8g, yield: 91%.
The characterization result of product is with embodiment 7.
Embodiment 12: dabigatran etcxilate p-hydroxybenzenyl sulfonate salt synthetic
Respectively dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g, 0.054mol) are added in the reaction flask that methylene dichloride (500ml) is housed, temperature control, at 30 ℃, stirs it is dissolved, and obtains settled solution.Concentration of reaction solution to 1/2 volume, standing, cooling, crystallization, is the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, weight: 29.9g, yield: 83%.
The characterization result of product is with embodiment 7.
Embodiment 13: containing the tablet of 60 milligrams of active substances
Composition:
Preparation: by (1), mix (2) and (3), with (4) aqueous solution granulation.(5) are added in dry granules material.By this mixture compacting in flakes, two-sided, two faces are all carved characters, and one side has separated time.
Tablet diameters: 9 millimeters
Embodiment 14: containing the tablet of 350 milligrams of active substances
Composition:
Preparation: by (1), mix (2) and (3), with (4) aqueous solution granulation.(5) are added in dry granules material.By this mixture compacting in flakes, two-sided, two faces are all carved characters, and one side has separated time.
Tablet diameters: 12 millimeters
Embodiment 15: containing the capsule of 350 milligrams of active substances
Composition:
Preparation: (1) is ground with (3).Abrasive material is joined in the mixture of (2) and (4) under violent stirring.This powdered mixture is packed in No. 3 hard gelatin capsules with capsule packing machine.
Embodiment 16: containing the capsule of 60 milligrams of active substances
Composition:
Preparation: (1) is ground with (3).Abrasive material is joined in the mixture of (2) and (4) under violent stirring.This powdered mixture is packed in No. 3 hard gelatin capsules with capsule packing machine.
Test case 1: the stability study of dabigatran etcxilate and dabigatran etcxilate salt
Get and reach than adding ester group four hydration free alkalis, dabigatran etcxilate mesylate (commercially available product) and dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt (the embodiment 1 gained) test that accelerates the failure under high temperature, high humidity, high light condition respectively, after 10 days, carry out Liquid Detection, result is as follows:
The stability study of table 1. dabigatran etcxilate and dabigatran etcxilate salt (0 day content is set as to 100%)
From table 1, under super-humid conditions 2,5-dihydroxy benzenes sulfonic acid salt and four hydration free alkali stability differences are less, and apparently higher than mesylate, under high temperature and high light condition, 2,5-dihydroxy benzenes sulfonic acid salt-stable is obviously better than mesylate and free alkali hydrate, so the bright dabigatran etcxilate 2 of above data sheet, 5-dihydroxy benzenes sulfonic acid salt has better stability.
Test case 2: activated partial thromboplastin time (APTT) is measured
By the kunming mice random packet of quality 18-20 gram, 10 every group, overnight fasting.By dabigatran etcxilate, dabigatran etcxilate 2, 5-dihydroxy benzenes sulfonic acid salt (embodiment 1 gained), dabigatran etcxilate p-hydroxybenzenyl sulfonate salt (embodiment 7 gained) and blank suspend or are 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 etcxilate) gastric infusion, 30min is by heart puncturing extracting blood, plasma sample is after certain hour is heated, add partial thromboplastin reagent, adopt the rayed sample that wavelength is 660nm, in coagulation process, the turbidity of blood is measured by measuring the change of scattered light intensity, by Percentage Detection method, try to achieve the clotting time, be APTT value.Instrument model: Sysmex CA-1500 automatic blood blood coagulation analyzer.The results are shown in Table 2.
Table 2. dabigatran etcxilate and dabigatran etcxilate salt activated partial thromboplastin time (APTT) are measured (n=10)
Accompanying drawing explanation
Fig. 1 dabigatran etcxilate 2, and the X-ray powder diffraction collection of illustrative plates of 5-dihydroxy benzenes sulfonic acid salt (X ' Pert PRO MPD X-ray diffractometer; Co/K-alpha1 source of radiation,
)
Fig. 2 dabigatran etcxilate 2, the X-ray powder diffraction data report (page 1) of 5-dihydroxy benzenes sulfonic acid salt
Fig. 3 dabigatran etcxilate 2, the X-ray powder diffraction data report (page 2) of 5-dihydroxy benzenes sulfonic acid salt
Fig. 4 dabigatran etcxilate 2, the DSC collection of illustrative plates of 5-dihydroxy benzenes sulfonic acid salt
Fig. 5 dabigatran etcxilate 2, the TGA collection of illustrative plates of 5-dihydroxy benzenes sulfonic acid salt
The powder diffraction spectrum of Fig. 6 dabigatran etcxilate p-hydroxybenzenyl sulfonate salt (X ' Pert PRO MPD X-ray diffractometer; Cu/K-alpha1 source of radiation,
)
The X-ray powder diffraction data report (page 1) of Fig. 7 dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
The X-ray powder diffraction data report (page 2) of Fig. 8 dabigatran etcxilate p-hydroxybenzenyl sulfonate salt.
Claims (10)
1. a hydroxyl-substituted sulfonate for dabigatran etcxilate, has following structural formula:
Wherein, R
1, R
2, R
3, R
4and R
5can be H or OH, and have one at least for OH.
2. the hydroxyl-substituted sulfonate of dabigatran according to claim 1, it is characterized in that described compound is 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 2,5-dihydroxy benzenes sulfonic acid salt.
3. a preparation method for the hydroxyl-substituted sulfonate of dabigatran etcxilate claimed in claim 1, is characterized in that comprising the steps:
1) in organic agent, add dabigatran etcxilate and hydroxyl-substituted sulfonic acid respectively, stir, dissolve, reaction, obtains settled solution at a certain temperature;
2) above-mentioned reaction solution is concentrated, standing, crystallization, suction filtration, obtains the hydroxyl-substituted sulfonate of dabigatran etcxilate.
4. the preparation method of the hydroxyl-substituted sulfonate of dabigatran etcxilate according to claim 3, is characterized in that, in step 1, described temperature of reaction is 0-100 ℃, is preferably 30 ℃.
5. the preparation method of the hydroxyl-substituted sulfonate of dabigatran etcxilate according to claim 3, it is characterized in that, in step 1, described organic solvent is one or more of chloroform, methylene dichloride, ethyl acetate, acetone, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, acetonitrile, propionitrile, propyl alcohol, propyl carbinol, the trimethyl carbinol, ethanol, methyl alcohol, is preferably ethyl acetate.
6. the preparation method of the hydroxyl-substituted sulfonate of dabigatran etcxilate according to claim 3, is characterized in that, in step 1, described dabigatran etcxilate and the mol ratio of hydroxyl-substituted sulfonic acid are 1:1-2, are preferably 1:1.2.
7. the 3-[[[2-[[[4-[[[(hexyloxy described in) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate 2, the crystal form A of 5-dihydroxy benzenes sulfonic acid salt, it is characterized in that, reflection angle 2 θ of its powder X-ray-diffractogram 5.47 ± 0.2,10.85 ± 0.2,13.54 ± 0.2,18.13 ± 0.2,22.32 ± 0.2,24.85 ± 0.2, there is charateristic avsorption band at 27.05 ± 0.2o place.
8. the 3-[[[2-[[[4-[[[(hexyloxy described in) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] crystal form A of ethyl propionate p-hydroxybenzenyl sulfonate salt, it is characterized in that, reflection angle 2 θ of its powder X-ray-diffractogram 7.02 ± 0.2,11.73 ± 0.2,15.46 ± 0.2,17.62 ± 0.2,19.92 ± 0.2,20.97 ± 0.2,23.64 ± 0.2, there is charateristic avsorption band at 25.26 ± 0.2o place.
9. a pharmaceutical composition with the disease that blood coagulation resisting function and prevention or treatment thrombus or embolism cause, the hydroxyl-substituted sulfonate of the dabigatran etcxilate claimed in claim 1 that it is characterized in that containing effective therapeutic dose.
10. the hydroxyl-substituted sulfonate of dabigatran etcxilate according to claim 1 is in the prevention of disease or the purposes of medicine preparing anticoagulation medicine and cause for thrombus or embolism.
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| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| WO2011110876A1 (en) * | 2010-02-02 | 2011-09-15 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Novel salts for the manufacture of pharmaceutical compositions |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
| WO2012077136A2 (en) * | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN102558153A (en) * | 2012-02-08 | 2012-07-11 | 北京阜康仁生物制药科技有限公司 | Novel pharmaceutical salt of dabigatran etexilate and preparation method thereof |
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| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| WO2011110876A1 (en) * | 2010-02-02 | 2011-09-15 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Novel salts for the manufacture of pharmaceutical compositions |
| WO2012077136A2 (en) * | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
| CN102558153A (en) * | 2012-02-08 | 2012-07-11 | 北京阜康仁生物制药科技有限公司 | Novel pharmaceutical salt of dabigatran etexilate and preparation method thereof |
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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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