WO2013124749A1 - Nouveau polymorphe d'étéxilate de dabigatran - Google Patents
Nouveau polymorphe d'étéxilate de dabigatran Download PDFInfo
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- WO2013124749A1 WO2013124749A1 PCT/IB2013/050657 IB2013050657W WO2013124749A1 WO 2013124749 A1 WO2013124749 A1 WO 2013124749A1 IB 2013050657 W IB2013050657 W IB 2013050657W WO 2013124749 A1 WO2013124749 A1 WO 2013124749A1
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- methyl
- carbonyl
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- amino
- phenylamino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the invention relates to new polymorphs of the active substance Dabigatran etexilate, processes for the preparation thereof and the use thereof as pharmaceutical compositions.
- This active substance with the chemical formula I
- the compound of formula I is only converted into the actual effective compound, namely the compound of formula II, in the body.
- the main fields of application of the compound of chemical formula I are the post-operative prophylaxis of deep vein thrombosis and the prevention of stroke.
- Dabigatran etexilate was first described in WO 199837075 by Hauel et al.
- dabigatran etexilate of the formula II is prepared in an analogous manner to the process described in Example 90 by reacting l-methyl-2- [N-(4-amidino-pheny])-aminomethyl]-5-benzirnidazol-carbonate-N-(2-pyridyl)-A)-[2- (ethoxy- carbonyl)-ethyl]-amid hydrochloride and hexyl chloroformate.
- the thus-formed base is characterized by thin layer chomatography and mass spectrometry. No information is provided in the description relating to the crystallographic properties of the dabigatran etexilate base.
- salts of dabigatran etexilate are described, such as the hydrochloride, citrate, tartarate, malonate, maleate and salicilate salts. These salts are not characterized by powder X-ray diffraction patterns, only by differential scanning calorimetry curves. The melting points ranked in order are as follows: 135°C, 170°C, 160°C, 100°C, 120°C, and 155 °C.
- WO20061314913 polymorphic forms of the dabigatran etexilate base are described.
- the polymorphic forms obtained by crystallization are characterized by X-ray powder diffraction patterns, differential scanning calorimetry curves and thermogravimetric measurements data.
- WO 2008043759 further dabigatran etexilate salts and polymorphic forms thereof are described, such as two polymorph (I and II) of the salt formed with phosphoric acid, two polymorph (III and IV) of the salt formed with fumaric acid, three polymorph (I, II and V) of the salt formed with oxalic acid, three polymorph (II, V and VI) of the salt formed with hydrogen chloride and four polymorph (I, V, VI and VII) of the salt formed with p- toluenesulfonic acid.
- the polymorphic forms are characterized by X-ray powder diffraction pattern.
- Form IV of the salt formed with fumaric acid and four Forms (I, V, VI and VII) of the salt formed with p-toluenesulfonic acid are characterized by differential scanning calorimetry curves, too.
- WO2008059029 two further anhydrous forms and three solvates of the dabigatran etexilate base are described.
- the anhydrous forms III and IV, the monohydrate forms I and II and the nitrobenzene solvate form I are characterized by X-ray powder diffraction pattern and differential scanning calorimetry curves.
- the aim of the invention is to provide new polymorphs of the compound of formula I having advantageous properties for pharmaceutical use.
- examples of these parameters are the stability of effect of the starting substance under different ambient conditions, stability in the course of the preparation of the pharmaceutical formulation and stability in the final compositions of the pharmaceutical preparation.
- the pharmaceutical active substance used to prepare the pharmaceutical compositions should therefore have high stability, which should also be guaranteed even under different environmental conditions. This is absolutely essential to prevent the use of pharmaceutical compositions which contain, in addition to the active substance itself, breakdown products thereof, for example. In such cases the content of active substance found in the pharmaceutical formulations might be less than specified.
- the absorption of moisture reduces the content of pharmaceutically active substance as a result of the increased weight caused by the uptake of water.
- Pharmaceutical compositions with a tendency to absorb moisture have to be protected from moisture during storage, e.g.
- a pharmaceutically active substance should be only slightly hygroscopic.
- the problem of the present invention is to provide a pharmaceutically active substance which not only is characterised by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.
- the object of the present invention to provide novel polymorph of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate) referred to as form A.
- Another object of the present invention to provide process for the preparation of novel polymorph of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate) referred to as form A
- the present invention to provide novel polymorph of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ - 1 -methyl- 1H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate) referred to as form A.
- the present invention relates to the above-mentioned polymorphic form of the active substance 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino] - methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] - propionic acid ethyl ester, in crystalline form, referred to as form A characterised by XRD.
- the present invention relates to the above-mentioned polymorphic form of the active substance 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino] - methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] - propionic acid ethyl ester, in crystalline form, referred to as form A characterised by TGA.
- the present invention relates to the above-mentioned polymorphic form of the active substance 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino] - methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] - propionic acid ethyl ester, in crystalline form, referred to as form A characterised by XRD, DSC, TGA Fig.
- Fig. 1 shows the X-ray powder diffraction pattern of new polymorph Form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate).
- Fig. 1 shows the X-ray powder diffraction pattern of new polymorph Form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate).
- Fig. 3 shows the TGA of new polymorph Form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-phenylamino] - methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin- 2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate).
- crystallizing means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.
- treating refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.
- the term "triturating” as used hereinabove refers to suspending product in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.
- the first embodiment, of the present invention relates to the novel polymorph of new polymorph Form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] -propionic acid ethyl ester compound of formula I (dabigatran etexilate).
- the present invention relates to a novel polymorph Form A of 3- [(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino] - methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate) characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2 ⁇ at about 4.9, 8.8, 9.2, 9.7, 10.4, 12.7, 13.3, 13.8, 14.7, 15.5, 18.0, 18.9, 20.1 , 20.8, 21.6, 22.3, 22.7, 23.3, 23.8, 24.2, 24.7, 26.8, 27.4, 28.2, 28.7, 29.5, and 36.6
- the present invention relates to novel polymorph Form A of 3- [(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino] - methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester compound of formula I (dabigatran etexilate), characterised by TGA characterized is depicted in Fig. 3.
- the present invention relates to novel polymorph Form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] -propionic acid ethyl ester compound of formula I (dabigatran etexilate), characterised by XRD, DSC, TGA which is depicted in Fig. 1 to 3.
- the invention also relates to the methods of selectively producing the polymorphic form as well as the modifications which may be obtained by these methods.
- the present invention relates to process for preparation of the form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -1 - methyl- lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] -propionic acid ethyl ester compound of formula I (dabigatran etexilate) is obtained by
- the present invention provides a process for the preparation of form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -!- methyl- lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] -propionic acid ethyl ester compound of formula I (dabigatran etexilate) which comprising step of
- the present invention provides a process for the preparation of form A of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -1 - methyl- lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] -propionic acid ethyl ester compound of formula I (dabigatran etexilate) which comprising step of :
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Abstract
L'invention concerne un nouveau polymorphe d'ester éthylique d'acide 3-[(2-{[4-(hexyloxycarbonylaminoimino-méthyl)-phénylamino]-méthyl}-1-méthyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionique.
Applications Claiming Priority (2)
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IN513/MUM/2012 | 2012-02-20 | ||
IN513MU2012 | 2012-02-20 |
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WO2013124749A1 true WO2013124749A1 (fr) | 2013-08-29 |
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PCT/IB2013/050657 WO2013124749A1 (fr) | 2012-02-20 | 2013-01-25 | Nouveau polymorphe d'étéxilate de dabigatran |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014020546A3 (fr) * | 2012-07-31 | 2014-03-27 | Ranbaxy Laboratories Limited | Formes cristallines d'étexilate de dabigatran et leur procédé de préparation |
WO2015033353A3 (fr) * | 2013-09-03 | 2015-06-04 | Laurus Labs Private Limited | Nouveaux sels d'addition d'acide d'étéxilate de dabigatran et procédé pour la préparation de ceux-ci |
WO2015124764A1 (fr) | 2014-02-24 | 2015-08-27 | Erregierre S.P.A. | Procédé de synthèse de dabigatran étexilate mésylate, intermédiaires de ce procédé et nouveau polymorphe de dabigatran étexilate |
WO2017151042A1 (fr) * | 2016-03-02 | 2017-09-08 | Marvel Pharma Consulting | Compositions pharmaceutiques pour thérapie anticoagulante à la demande |
WO2023174090A1 (fr) * | 2022-03-15 | 2023-09-21 | 青岛华麒医药科技创新发展有限公司 | Cocristal d'étexilate de dabigatran et son procédé de préparation |
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WO2008059029A2 (fr) * | 2006-11-16 | 2008-05-22 | Boehringer Ingelheim International Gmbh | Nouveaux polymorphes d'éthyle 3-[(2-{[4- (hexyloxycarbonylamino-imino-méthyl)-phénylamino]-méthyl}-1-méthyl-1h- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate |
CN101189224A (zh) * | 2005-06-04 | 2008-05-28 | 贝林格尔·英格海姆国际有限公司 | 3-[(2-{[4-(己氧基羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯的多晶型 |
-
2013
- 2013-01-25 WO PCT/IB2013/050657 patent/WO2013124749A1/fr active Application Filing
Patent Citations (2)
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CN101189224A (zh) * | 2005-06-04 | 2008-05-28 | 贝林格尔·英格海姆国际有限公司 | 3-[(2-{[4-(己氧基羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯的多晶型 |
WO2008059029A2 (fr) * | 2006-11-16 | 2008-05-22 | Boehringer Ingelheim International Gmbh | Nouveaux polymorphes d'éthyle 3-[(2-{[4- (hexyloxycarbonylamino-imino-méthyl)-phénylamino]-méthyl}-1-méthyl-1h- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate |
Non-Patent Citations (2)
Title |
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DATABASE IP.COM PRIOR ART DATABASE 14 February 2011 (2011-02-14), "Disclosed Anonymously, Polymorphic forms of Dabigatran etexilate", retrieved from http://priorarldatabase.ocmJIPCOM/000204135 accession no. PCOM000204135D. * |
HAUEL N. H. ET AL.: "Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors", J. MED. CHEM., vol. 45, 2002, pages 1757 - 1766, XP001098844 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014020546A3 (fr) * | 2012-07-31 | 2014-03-27 | Ranbaxy Laboratories Limited | Formes cristallines d'étexilate de dabigatran et leur procédé de préparation |
WO2015033353A3 (fr) * | 2013-09-03 | 2015-06-04 | Laurus Labs Private Limited | Nouveaux sels d'addition d'acide d'étéxilate de dabigatran et procédé pour la préparation de ceux-ci |
WO2015124764A1 (fr) | 2014-02-24 | 2015-08-27 | Erregierre S.P.A. | Procédé de synthèse de dabigatran étexilate mésylate, intermédiaires de ce procédé et nouveau polymorphe de dabigatran étexilate |
WO2017151042A1 (fr) * | 2016-03-02 | 2017-09-08 | Marvel Pharma Consulting | Compositions pharmaceutiques pour thérapie anticoagulante à la demande |
WO2023174090A1 (fr) * | 2022-03-15 | 2023-09-21 | 青岛华麒医药科技创新发展有限公司 | Cocristal d'étexilate de dabigatran et son procédé de préparation |
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