# Patent

## Title
Polymorphs

## Abstract

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.

## Background
This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
1. 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-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the thermoanalysis of the anhydrous form A/B.
FIG. 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.
FIG. 3 shows an X-ray powder diagram of the anhydrous form A.
FIG. 4 shows an X-ray powder diagram of the anhydrous form B.
FIG. 5 shows an X-ray powder diagram of polymorph C.
FIG. 6 shows the thermoanalysis of form C.



DETAILED DESCRIPTION OF THE INVENTION
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 FIGS. 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 FIG. 3) this form shows characteristic reflections at the following d values: 11.49 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47 Å (cf. also Table 1 and 2).
Anhydrous polymorph A may be prepared by

    (a) refluxing 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 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 FIG. 4) this form shows characteristic reflections at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å (cf. also Table 3 and 4).
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 reflections in the X-ray powder diagram (see FIG. 5) at the following d values: 12.90 Å, 11.10 Å, 6.44 Å, 3.93 Å and 3.74 Å (cf. also Table 5).
Polymorph C is obtained if

    (a) 1-[(4-methyl-quinazolin-2-yl)methyl]-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 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 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.
FIG. 1 shows the thermoanalysis of the anhydrous form A/B.
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.
FIG. 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.
FIG. 3 shows an X-ray powder diagram of the anhydrous form A







TABLE 1







Labelled X-ray reflexes up to 30 ° 2 ⊖ with intensities (standardised) for


the anhydrous polymorph A











2 Θ
intensity
dhkl
labelling
dexp-calc













[°]
I/Io [%]
[Å]
h
k
l
[Å]
















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


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
2
2
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


19.30
1
4.60
−2
3
1
−0.019


19.61
2
4.52
−3
2
1
0.036


19.86
20
4.47
−2
2
3
0.040


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
0.048


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
0.022


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
0.036


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


27.10
2
3.29
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


28.54
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
7
2.96
−1
5
3
−0.042
















TABLE 2





Lattice metrics of the anhydrous form A


















Symmetry:
monocline



space 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









Example 2
Crystallisation of Polymorph B
Polymorph B is obtained by cooling form A from Example 1 to temperatures <10° C.
FIG. 4 shows an X-ray powder diagram of the anhydrous form B







TABLE 3







Labelled X-ray reflexes up to 30 ° 2 ⊖ with intensities (standardised) for


the anhydrous form B











2 Θ
intensity
dhkl
labelling
dexp-calc













[°]
I/Io [%]
[Å]
h
k
l
[Å]
















5.82
3
15.17
1
0
0
−0.007


7.04
33
12.55
0
1
1
0.001


7.82
100
11.3
1
1
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
2
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


21.22
12
4.18
0
3
3
0.001


21.40
7
4.15
3
2
1
0.004


21.66
4
4.1
−1
3
3
0.018


21.98
7
4.04
2
2
3
−0.003


22.16
10
4.01
−3
1
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


24.46
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


26.15
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
3.28
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


29.42
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



space 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









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 I methanol, combined with 1.3 kg of activated charcoal and after 30 minutes' stirring the mixture is filtered and rinsed with 26 I methanol. 122 I of methanol are distilled off from the filtrate, then the residue is cooled to 45-55° C. 52 I 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 I 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.
FIG. 5 shows an X-ray powder diagram of polymorph C







TABLE 5







X-ray reflexes up to 30° 2 Θ with intensities


(standardised) for the anhydrous form C









2 Θ
dhkl
intensity


[°]
[Å]
I/Io [%]












3.38
26.16
4


6.85
12.90
100


7.18
12.31
11


7.52
11.74
14


7.96
11.10
36


9.80
9.02
3


11.11
7.96
2


11.58
7.64
3


12.30
7.19
5


13.30
6.65
16


13.75
6.44
26


14.38
6.16
17


14.74
6.01
11


14.95
5.92
10


15.63
5.66
6


16.28
5.44
5


17.81
4.98
10


18.33
4.83
6


18.75
4.73
15


20.51
4.33
8


20.77
4.27
8


21.47
4.14
3


21.96
4.05
4


22.59
3.93
26


23.76
3.74
29


24.68
3.60
6


25.01
3.56
7


25.57
3.48
4


25.96
3.43
4


26.93
3.31
18


27.22
3.27
13


27.92
3.19
10









Example 4
Crystallisation of Polymorph D
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 E
Anhydrous polymorph E is obtained if polymorph D is melted. On further heating, polymorph E crystallises out of the melt.
FIG. 6 shows a thermoanalysis of form C
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 reflections 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. A method of preparing 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, the method comprising:
(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 to provide a solution;
(b) refluxing the solution to provide a hot solution and, optionally filtering the hot solution to provide a hot filtrate,
(c) cooling the hot solution or the hot filtrate until crystallisation sets in,
(d) diluting the cooled solution or the cooled filtrate with a solvent to provide a solvent mixture,
(e) suction filtering the solvent mixture, and
(f) drying the solids collected by filtration at 45° C. in vacuo to provide said anhydrous polymorph A; wherein
said anhydrous polymorph A melts at 206±3° C., and
said anhydrous polymorph A exhibits an X-ray powder diagram having characteristic reflections at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47 Å.

2. The method of claim 1, wherein the solvent used in Step (d) is tertiary-butylmethylether.

3. The method according to claim 1, wherein anhydrous polymorph A has an X-ray powder diagram as shown in FIG. 3.

4. The method of claim 1, further characterized in that the reflection 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 reflections having a relative intensity of 1% or more at the following d values: 11.3 Å, 9.36 Å, 7.48 Å, and 7 Å.

5. The method according to claim 1, wherein polymorph A is characterised by its lattice metrics:















Symmetry:
monoclinic



space 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.

6. A method of preparing 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, the method comprising:
(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 to provide a solution,
(b) refluxing the solution to provide a hot solution and, optionally filtering the hot solution to provide a hot filtrate,
c) cooling the hot solution or the hot filtrate for crystallisation to a temperature below 10° C. to provide a cold solution or cold filtrate,
(d) diluting the cold solution or cold filtrate with a solvent to provide a solvent mixture,
(e) suction filtering the solvent mixture, and
(f) drying the collected solids at a temperature below 10° C. in vacuo to provide anhydrous polymorph B;
or
cooling polymorph A or a mixture of polymorphs A and B to temperatures <10° C.; wherein
said anhydrous polymorph B transforms reversibly into the polymorph A of claim 1 at temperature of 10-40° C., and
said anhydrous polymorph B exhibits an X-ray powder diagram having characteristic reflections at the following d values: 11.3 Å, 9.36 Å, 7.48 Å, 7 Å and 3.77 Å.

7. The method of claim 6, wherein the solvent in Step (d) is tertiary-butylmethylether.

8. The method according to claim 6 wherein anhydrous polymorph B has an X-ray powder diagram as shown in FIG. 4.

9. The method of claim 6, further characterized in that the reflection 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 reflections having a relative intensity of 1% or more at the following d values: 11.59 Å, 7.60 Å, and 7.15 Å.

10. The method according to claim 6, wherein polymorph B is characterised by its lattice metrics:















Symmetry:
monoclinic



space 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.

11. A method of preparing a medicament, the method comprising
i) preparing the anhydrous polymorph A by the method of claim 1, and
ii) combining the anhydrous polymorph A with one or more inert carriers to provide a medicament containing 0.1% to 0.5%, or 0.5% to 1.5%, or 1% to 3% of the anhydrous polymorph A based on the total weight of the polymorph A and the one or more inert carriers.

12. A method of preparing a medicament, the method comprising
i) preparing the anhydrous polymorph B by the method of claim 6, and
ii) combining the anhydrous polymorph B with one or more inert carriers to provide a medicament containing 0.1% to 0.5%, or 0.5% to 1.5%, or 1% to 3% of the anhydrous polymorph B based on the total weight of the polymorph B and the one or more inert carriers.