POLYMORPHS
The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.
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This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION1. Field of the Invention
The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.
2. Description of the Prior Art
The enzyme DPP-IV, also known by the name CD26, is a serine protease which promotes the cleaving of dipeptides in proteins with a proline or alanine group at the N-terminal end. DPP-IV inhibitors thereby influence the plasma level of bioactive peptides including the peptide GLP-1. Compounds of this type are useful for the prevention or treatment of illnesses or conditions which are associated with an increased DPP-IV activity or which can be prevented or alleviated by reducing the DPP-IV activity, particularly type I or type II diabetes mellitus, prediabetes, or reduced glucose tolerance.
WO 2004/018468 describes DPP-IV inhibitors with valuable pharmacological properties. One example of the inhibitors disclosed therein is 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.
Within the scope of the present invention it has been found that 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine may take on various polymorphous crystal modifications and that the compound prepared in WO 2004/018468 is present at ambient temperature as a mixture of two enantiotropic polymorphs. The temperature at which the two polymorphs transform into one another is 25±15° C. (see
The pure high temperature form (polymorph A), which can be obtained by heating the mixture to temperatures >40° C., melts at 206±3° C. In the X-ray powder diagram (see
Anhydrous polymorph A may be prepared by
- (a) refluxing 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in absolute ethanol and optionally filtering the mixture,
- (b) cooling the hot solution or the hot filtrate until crystallisation sets in,
- (c) diluting with a solvent such as tert.-butylmethylether,
- (d) suction filtering the solvent mixture and
- (e) drying the polymorph A at 45° C. in vacuo.
The low temperature form (polymorph B) is obtained by cooling to temperatures <10° C. In the X-ray powder diagram (see
Anhydrous polymorph B may be prepared by
- (a) dissolving 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in absolute ethanol and refluxing and optionally filtering the mixture,
- (b) cooling the hot solution or the hot filtrate for crystallisation to a temperature below 10° C.,
- (c) diluting with a solvent such as tert.-butylmethylether,
- (d) suction filtering the solvent mixture and
- (e) drying the polymorph at a temperature below 10° C. in vacuo.
Another polymorph (polymorph C) shows characteristic reflexes in the X-ray powder diagram (see
Polymorph C is obtained if
- (a) 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is dissolved in methanol and refluxed and optionally filtered in the presence of activated charcoal,
- (b) the methanolic solution is cooled to a temperature of 40-60° C.,
- (c) a solvent such as tert.-butylmethylether or diisopropylether is added,
- (d) the resulting suspension is first of all cooled slowly to 15-25° C. and then later to 0-5° C.,
- (e) the crystals formed are suction filtered and washed again with tert.-butylmethylether or diisopropylether and
- (f) the crystals thus obtained are dried at a temperature of 70° C. in the vacuum dryer.
Another polymorph (polymorph D) melts at 150±3° C. This polymorph is obtained if polymorph C is heated to a temperature of 30-100° C. or dried at this temperature.
Finally, there is also polymorph E, which melts at a temperature of 175±3° C. Anhydrous polymorph E is formed if polymorph D is melted. On further heating, polymorph E crystallises out of the melt.
The polymorphs thus obtained may be used in the same way as the mixture of the two polymorphs A and B described in WO 2004/018468 for preparing a pharmaceutical composition which is suitable for treating patients with type I and type II diabetes mellitus, prediabetes or reduced glucose tolerance, with rheumatoid arthritis, obesity, or calcitonin-induced osteoporosis, as well as patients in whom an allograft transplant has been carried out. These medicaments contain in addition to one or more inert carriers at least 0.1% to 0.5%, preferably at least 0.5% to 1.5% and particularly preferably at least 1% to 3% of one of the polymorphs A, B, or C.
The following Examples are intended to illustrate the invention in more detail.
Example 1 Crystallisation of Polymorph ACrude 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is refluxed with 5 times as much absolute ethanol and the hot solution is filtered clear through activated charcoal. After the filtrate has been cooled to 20° C. and crystallisation has set in, the solution is diluted to double the volume with tert.-butylmethylether. Then the suspension is cooled to 2° C., stirred for 2 hours, suction filtered and dried in the vacuum dryer at 45° C.
Plymorph A melts at 206±3° C. In the DSC diagram another slightly endothermic signal can be seen at approx. 25° C. This is a fully reversible solid-solid phase transition between the two enantiotropic crystal modifications A and B. The form A is the thermodynamically stable modification above this transformation temperature, w| form B is the thermodynamically stable modification below this transformation temperature.
Polymorph B is obtained by cooling form A from Example 1 to temperatures <10° C.
Crude 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (26 kg) is refluxed with 157 l methanol, combined with 1.3 kg of activated charcoal and after 30 minutes' stirring the mixture is filtered and rinsed with 26 l methanol. 122 l of methanol are distilled off from the filtrate, then the residue is cooled to 45-55° C. 52 l of tert.-butylmethylether are added to the residue over 30 minutes. Then the mixture is stirred for another 60 minutes at 45-55° C. Crystallisation takes place within this time. A further 78 l tert. butylmethylether are added to the suspension over 30 minutes and then it is stirred again for a further 60 minutes at 45-55° C. It is diluted to four times the volume. The suspension is slowly cooled to 15-25° C. and stirred overnight at this temperature. After the suspension has been cooled to 0-5° C. the crystals are suction filtered, washed with 2 batches tert.-butylmethylether and dried at 70° C. in the vacuum dryer.
Polymorph D is obtained if polymorph C from Example 3 is heated to a temperature of 30-100° C. or dried at this temperature.
Example 5 Crystallisation of Polymorph EAnhydrous polymorph E is obtained if polymorph D is melted. On further heating, polymorph E crystallises out of the melt.
In the DSC diagram of form C a whole range of signals can be observed. The strongest signal is the melting point of the anhydrous form A at approx. 206° C., which is produced in the DSC experiment. Before the melting point a number of other endothermic and exothermic signals can be observed. Thus, for example, a very broad and weak endothermic signal can be seen between 30 and 100° C., which correlates with the main loss of weight in thermogravimetry (TR). A TG/IR coupling experiment provides the information that only water escapes from the sample in this temperature range.
An X-ray powder diagram taken of a sample maintained at a temperature of 100° C. shows different X-ray reflexes from the starting material, suggesting that form C is a hydrate phase with stoichiometry somewhere in the region of a hemihydrate or monohydrate. The temperature-controlled sample is another anhydrous modification D, which only stable under anhydrous conditions. The D form melts at approx. 150° C. Another anhydrous crystal modification E crystallises from the melt, and when heated further melts at approx. 175° C. Finally, form A crystallises from the melt of form E. Form E is also a metastable crystal modification which occurs only at high temperatures.
Claims
1. An isolated form of an anhydrous polymorph A of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that it melts at 206±3° C., and further characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47.
2. (canceled)
3. An isolated form of an anhydrous polymorph B of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å.
4-13. (canceled)
14. The isolated form of polymorph A of claim 1, further characterised in that the reflex at 11.59 Å in the X-ray powder diagram has a relative intensity of 100% and further characterized in that the X-ray powder diagram exhibits no reflexes having a relative intensity of 1% or more at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, and 6.98 Å.
15. The isolated form of polymorph B of claim 3, further characterised in that the reflex at 11.3 Å in the X-ray powder diagram has a relative intensity of 100% and further characterized in that the X-ray powder diagram exhibits no reflexes having a relative intensity of 1% or more at the following d values: 11.59 Å, 7.60 Å, and 7.15 Å.
16. An isolated form of an anhydrous polymorph B of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to claim 3, further characterised in that at a temperature of 10-40° C. it transforms reversibly into the polymorph A, said polymorph A characterised in that it melts at 206±3° C., and further characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47.
17. Anhydrous polymorph A of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, said polymorph A characterised in that it melts at 206±3° C., and further characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47, unmixed with polymorph B, said polymorph B characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å.
18. Anhydrous polymorph B of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, said polymorph B characterised in that at a temperature of 10-40° C. it transforms reversibly into the polymorph A, and further characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å, unmixed with polymorph A, said polymorph A characterised in that it exhibits an X-ray powder diagram having inter alia characteristic reflexes at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47.
19. An isolated form of an anhydrous polymorph A of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised by its lattice metrics: Symmetry: monocline spatial group: P a: 16.16(2) Å b: 17.02(1) Å c: 18.18(2) Å β: 100.95(6)° cell volume: 4907(11) Å3
20. An isolated form of an anhydrous polymorph B of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised by its lattice metrics: Symmetry: monocline spatial group: P21/c (# 14) a: 15.23(1) Å b: 16.94(1) Å c: 18.79(1) Å β: 95.6(2)° cell volume: 4823(3) Å3
Type: Application
Filed: Aug 1, 2012
Publication Date: Nov 22, 2012
Applicant: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG (Ingelheim am Rhein)
Inventors: Peter SIEGER (Mittelbiberach), Dirk KEMMER (Guldental), Peter KOHLBAUER (Biberach an der Riss), Thomas NICOLA (Ingelheim am Rhein), Martin RENZ (Eberhardzell-Dietenwengen)
Application Number: 13/563,767
International Classification: C07D 473/04 (20060101);