AU2013203622B2 - Polymorphs - Google Patents

Abstract

Doumn -i/4/2013 The invention relates to polymorphic crystal modifications of 1-((4-methyl-quinazolin-2 yl)methvl)-3,7-(2-butyn-lvl)-8-(3-(R)-aminopiperidin-1I -yl)xanthine, their production and their use for the preparation of a drug.

Description

POLYMORPHS This application is a divisional of Australian Patent Application No. 2007247190, the entire content of which is incorporated herein by reference. The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 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-Wr 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-I!V 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-yl)methyl]-3 methyl-7-(2-butyn- I -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-yI)-8-(3-(R)-amino-piperidin-1-yil)-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±1 5'C (see Figures 1 and 2). 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 Figure 3) this form shows characteristic reflexes at the following d values: 11.49 A. 7.60 A, 7.15 A, 3.86 A, 3.54 A and 3.47 A (cf. also Table I and 2).

-2 Anhydrous polymorph A may be prepared by (a) refluxing -[4-methyl-quinazoln-2-yi)methyl]-3-methyi-7-(2-butyn-1-yi) 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 polymorphh B) is obtained by cooling to temperatures <10 'C. In the X-ray powder diagram (see Figure 4) this form shows characteristic reflexes at the following d values: 11.25 A, 9.32 A, 7.46 A, 6.98 A and 3.77 A (cf. also Table 3 and 4). Anhydrous polymorph B may be prepared by (a) dissolving 1-[( 4-methyl-quinazolin-2-yl)methyi] -3-methyl-7-(2-butyn-1-yl) 8-(3-( R)-amino-piperidi-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 polymorphh C) shows characteristic reflexes in the X-ray powder diagram (see Figure 5) at the following d values: 12.90 A, 11.10 A. 6.44 A, 3.93 A and 3.74 A (cf. also Table 5). Polymorph C is obtained if (a) 1-[(4 -methyli-quinazolin-2-yl)methyi] -3 -methyl-7-(2-bu tyn-1-yl)-8-(3-(R) amino-piperidin- 1-yi)-xanthine is dissolved in methanol and refluxed and H:\rbr\lntrovn\NRPortbl\DCC\RBR\9502303_I.docx- 1/02/2016 -3 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. In one embodiment, the invention provides a medicament containing 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, wherein said medicament contains 0.1% to 0.5%, or 0.5% to 1.5% , or 1% to 3% of anhydrous polymorph A in addition to one or more inert carriers, wherein anhydrous polymorph A is characterised in that it melts at 206±3 'C.

H:\rbr\Intrwovn\NRPortbl\DCC\RBR\9502303_I.docx-1 1/02/2016 - 3a In one embodiment, the invention provides a medicament containing 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, wherein said medicament contains 0.1% to 0.5%, or 0.5% to 1.5% , or 1% to 3% of anhydrous polymorph B in addition to one or more inert carriers, wherein anhydrous polymorph B is characterised in that at a temperature of 10-40'C it transforms reversibly into the polymorph A of the preceding embodiment. In one embodiment, the invention provides use of the medicament according to any one of the preceding embodiments for the treatment of patients with type II diabetes mellitus. In one embodiment, the invention provides a method of preparing a medicament according to any of the preceding embodiments, characterized in that polymorph A or B as defined in any of the preceding embodiments is combined with one or more inert carriers. The following Examples are intended to illustrate the invention in more detail. Example 1 Crystallisation of polymorph A Crude 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 -4 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 45CC. Polymorph A melts at 206 ± YC. 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, while form B is the thermodynamically stable modification below this transformation temperature. Figure 2 shows a cyclic DSC diagram, in which the phase transition from -40 'C to 120 'C and vice versa has been run through a total of 3 times. During heating, the phase transition is observed as an endothermic signal and, correspondingly, during cooling it is observed as an exothermic signal. During the first heating cycle the phase transition may also be observed as an endothermic double signal or as a very broad signal while in all the other cycles the signal occurs as a very sharp endothermic or exothermic signal, depending on whether heating or cooling is taking place. Table 1: Labelled X-ray reflexes up to 30 2 0 with intensities (standardised) for the anhydrous polymorph A 2 0 intensity dl labellhng dP [H I/L (%1 f A) ____k_____A] 5.56 1 15.89 1 0 0 -0.008 7.18 32 12.31 0 1 1 0.005 7.62 100 11.59 1 1 0 0.007 8.49 20 10.41 -1 1 1 0.002 9.91 24 8.92 0 0 2 0.003 10.41 18 8.49 0 2 0 0.024 11.18 24 7.91 2 0 0 0.038 11.63 41 7.60 -1 1 2 0.003 2 O intensity dh _____ labelling d ca | 1 I %) I Al h ___k__ IA] 12.37 59 7.15 -1 2 1 -0.003 13.19 6 6.71 1 2 1 -0.014 13.45 3 6.58 -2 0) 2 0.007 14.05 6 6.30 2 1 1 0.011 14.38 6 6.16 0 22 0.003 14.71 10) 6.02 -1 2 2 -0.008 15.26 13 5.80 2 2 0 0.001 15.76 10) 5.62 -1 1 3 0.008 16.09 1 5.51 1 2 2 -0.010 16.32 1 5.43 2 0 2 0.035 16.69 4 5.31 2 2 1 -0.007 17.03 3 5.20 -1 3 1 0.026 17.63 6 5.03 1 3 1 0.006 18.17 5 4.88 -1 2 3 -0.004 18.78 7 4.72 -1 3 2 -0.014 1 9.30) 1 4.60 -2 3 1 -0.019 19.61 24.52 -3 2 1 0.036 19.86 20 4.47 -2 2 3 0.0)40 20.29 10 4.37 2 0 3 0.019 20.57 4 4...31 0 1 4 0.006 21.12 1 4.20 3 0 2 0.0)48 21.57 12 4.12 -2 1 4 0.028 22.46 10 3.96 1 4 1 0.035 23.03 35 3.86 4 1 0 0.0)22 23.39 21 3.80 -1 4 2 0.019 24.08 2 3.69 -3 1 4 -0.006 24.51 1 3.63 -. 4 0 3 0.0)36 24.91 10 3.57 -2 4 2 0.003 25.14 39 3.54 3 1 3 0.043 25.69 36 3.47 -3 3 3 0.041 26.68 3 3.34 0 5 1 0.035 26.90 2 3.31 3 4 0 0.027 2 8 intensity dh ______ labelling d pca "H /I (% I fAl h _ _k _ JAI 27.10 2 3.19 0 2 5 0.030 27.42 3 3.25 4 3 0 0.006 28.19 2 3.16 -1 5 2 -0.035 8.54 2 3.12 3 0 4 0.047 28.94 11 3.08 0 4 4 -0.036 29.18 5 3.06 -4 3 3 0.017 29.50 4 3.03 -1 0 6 0.041 30.18 2.96 -1 5 3 -0.042 Table 2 Lattice metrics of the anhydrous form A Symmetry: monocline spatial group: P a: 16.16(2) A b: 17.02(1)A c: 18.18(2) A P3: 100.95(6) cell volume: 4907(11) A Example 2 Crystallisation of polymorph B Polymorph B is obtained by cooling form A from Example I to temperatures <10 'C. Table 3: Labelled X-ray reflexes up to 30 2 0 with intensities (standardised) for the anhydrous form 13 2 0 intensity dA labelling d 1' 1 1/1 [% [Al b k I JAI 5.82 3 15.17 1 0 0 -0.007 7.04 33 12.55 0 1 1 0.001 2 0 intensity d labellingd [[A] k I 7.82 100 11.3 I i 0 -0.004 8.84 11 10 -1 1 1 0.001 9.44 40 9.36 1 1 1 0.011 10.62 14 8.32 -1 0 2 0.013 10.79 24 8.19 0 1 2 -0.005 11.82 39 7.48 -1 1 2 -0.003 12.64 53 7 -1 1 -0.009 13.07 11 6.77 1 2 1 -0.006 13.24 6 6.68 -2 1 1 0.004 14.04 16 6.3 2 1 1 0.003 15.23 17 5.81 -2 1 2 0.003 15.70 22 5.64 2 2 0 0.016 16.38 2 5.41 0 3 1 -0.010 16.73 6 5.3 2 2 1 0.008 17.67 8 5.02 0 2 3 0.014 18.16 3 4.88 -1 2 3 0.005 18.33 9 4.84 3 1 0 0.016 18.48 10 4.8 -3 1 1 -0.003 18.97 15 4.68 0 0 4 -0.001 19.56 6 4.54 1 3 2 0.013 20.00 17 4.44 2 1 3 0.000 20.42 9 4.35 1 0 4 0.009 20.76 4 4 27 3 0 2 -0.014 20.97 4 4.23 0 4 0 0.010 21.07 5 4.21 1 1 4 -0.009 2.22 1 4.18 0 3 3 0.001 21.40 7 4.15 3 1 0.004 21.66 4 4.1 -1 3 3 0.018 21.98 7 4.04 2 2 3 -0.003 2 0 intensity d labellingd [[A] k I 22.16 10 4.01 -3 i 3 0.008 22.97 3 3.87 1 2 4 -0.006 23.58 43 3.77 -2 3 3 -0.003 23.78 15 3.74 2 2 4 -0.004 24.05 6 3.7 4 1 0 -0.002 24.29 8 3.66 -2 4 1 -0.008 24.4 6 5 3.64 3 3 1 0.018 24.71 7 3.6 0 3 4 0.001 24.96 23 3.56 2 3 3 -0.001 25.45 12 3.5 -2 4 2 -0.010 25.75 35 3.46 4 2 0 0.011 25.99 4 3.43 3 2 3 0.014 2 6.15 6 3.41 3 3 2 0.010 26.57 12 3.35 -2 3 4 -0.001 26.82 4 3.32 -3 2 4 0.011 27.20 6 3.8 1 2 5 -0.010 27.43 4 3.25 -2 4 3 -0.003 27.60 3 3.23 -2 2 5 -0.005 28.19 4 3.16 3 4 1 0.010 28.40 15 3.14 0 4 4 -0.013 28.64 12 3.11 0 0 6 0.016 29.18 6 3.06 -4 3 2 0.004 2 9.4 2 3.03 1 4 4 0.002 29.99 10 2.98 0 5 3 -0.008 30.77 3 2.9 -4 3 3 0.018 Table 4: Lattice metrics of the anhydrous form B Symmetry: monocline spatial group: P2 1 /c (# 14) a: 15.23(1) A b: 16.94(1) A c: 18.79(1) A B: 95.6(2) cell volume: 4823(3) A Example 3 Crystallisation of polymorph C Crude 1-[(4-methyl.-quinazolin-2-yl)methyl]-3-methyl-7--(2-butyn-1-yl)-8-(3-(R)-amino piperidin-1-yl)-xanthine (26 kg) is refluxed with 157 1 methanol. combined with 1.3 kg of activated charcoal and after 30 minutes' stirring the mixture is filtered and rinsed with 26 1 methanol. 122 1 of methanol are distilled off from the filtrate, then the residue is cooled to 45-55'C. 52 1 of tert.-butylmethylether are added to the residue over 30 minutes. Then the mixture is stirred for another 60 minutes at 45-55 0 C. Crystallisation takes place within this time. A further 78 1 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.-butyinethylether and dried at 70'C in the vacuum dryer. Table 5: X-ray reflexes up to 30 2 0 with intensities (standardised) for the anhydrous form C 2 6 de intensity .2 6 dbk intensity 2 0 dhk intensity [ ' [Al I/I [ I " [Al I/l %] [A I/lo [% 3.38 26.16 4 7.52 11.74 14 11.11 7.96 2 6.85 12.90 100 7.96 11.10 36 11.581 7.64 7.18 112.31 11 9.80 9.02 3 12.30 7.19 5 2~ 10 -F 2 e dho intensity 2 &e dbtd intensity 2 e dag intensity H [A.1 I/1 [%)] [O1 [Al I/I, [* A 1/1; 14 I%1 13.30 6.65 16 18.33 4.83 6 24.68 3.60 6 13.75 6.44 26 18.75 4.73 15 25.01 3.56 7 14.38 6.16 17 20.51 4.33 8 25.57 3.48 4 14.74 6.01 11 20.77 4.27 8 25.96 3.43 4 14.95 5.92 10 21.47 4.14 3 26.93 3.31 18 15.63 5.66 6 21.96 4.05 4 27.22 3.27 13 16.28 5.44 5 22.59 3.93 26 27.92 3.19 10 17.81 4.98 10 23.76 3.74 29 Example 4 Crystallisation of polymorph ) Polymorph C 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 E Anhydrous poliymoriph 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 [3cumen-il/04/2013 -11 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. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Trhe reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (10)

1. A medicament containing 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, wherein said medicament contains 0.1% to 0.5%, or 0.5% to 1.5% , or 1% to 3% of anhydrous polymorph A in addition to one or more inert carriers, wherein anhydrous polymorph A is characterised in that it melts at 206±3 'C.

2. Medicament according claim 1, wherein polymorph A is characterised in that in the X ray powder diagram it has inter alia characteristic reflexes at the following d values: 11.59 ,

7.60 A, 7.15 A, 3.86 A, 3.54 A and 3.47 A. 3. A medicament containing 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, wherein said medicament contains 0.1% to 0.5%, or 0.5% to 1.5% , or 1% to 3% of anhydrous polymorph B in addition to one or more inert carriers, wherein anhydrous polymorph B is characterised in that at a temperature of 10-40'C it transforms reversibly into the polymorph A of claim 1. 4. Medicament according to claim 3, wherein polymorph B is characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 11.25 A, 9.32 A, 7.46 A, 6.98 A and 3.77 A. 5. Use of the medicament according to any one of claims 1 to 4 for the treatment of patients with type II diabetes mellitus. 6. The medicament according to claim 1 or 2, wherein polymorph A is characterised by its lattice metrics: Symmetry: monocline spatial group: P a: 16.16(2) A H:\rbr\Intrwovn\NRPortbl\DCC\RBR\9502303_I.docx- 1/02/2016 - 13 b: 17.02(1)A c: 18.18(2) A B: 100.95(6) cell volume: 4907(11) A3 7. The medicament according to claim 3 or 4, wherein polymorph B is characterised by its lattice metrics: Symmetry: monocline spatial group: P2 1 /c (# 14) a: 15.23(1) A b: 16.94(1) A c: 18.79(1) A B: 95.6(2) cell volume: 4823(3) A 3

8. The medicament according to claim 1, 2 or 6, wherein the X-ray powder diagram of polymorph A is substantially as shown in Figure 3.

9. The medicament according to claim 3, 4 or 7, wherein the X-ray powder diagram of polymorph B is substantially as shown in Figure 4.

10. The medicament according to claim 1, 2, 6 or 8, wherein the X-ray powder diagram of polymorph A is substantially free of the characteristic reflexes of polymorph B according to claim 4.

11. The medicament according to claim 3, 4, 7 or 9, wherein the X-ray powder diagram of polymorph B is substantially free of the characteristic reflexes of polymorph A according to claim 2. H:\rbr\Intrwovn\NRPortbl\DCC\RBR\9502303_I.docx- 1/02/2016 - 14 12. The medicament according to any of the claims 1 to 11, wherein said medicament contains 0.1% to 0.5% of polymorph A or B in addition to one or more inert carriers.

13. The medicament according to any of the claims 1 to 11, wherein said medicament contains 0.5% to 1.5% of polymorph A or B in addition to one or more inert carriers.

14. The medicament according to any of the claims 1 to 11, wherein said medicament contains 1% to 3% of polymorph A or B in addition to one or more inert carriers.

15. A method of preparing a medicament according to any of the preceding claims, characterized in that polymorph A or B as defined in any of the preceding claims is combined with one or more inert carriers.