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Publication numberUS20070259900 A1
Publication typeApplication
Application numberUS 11/744,700
Publication dateNov 8, 2007
Filing dateMay 4, 2007
Priority dateMay 4, 2006
Also published asCA2651089A1, CA2810295A1, CA2810522A1, CA2810839A1, CN101437823A, CN102838599A, EP2016079A1, EP2540725A1, US20120296091, WO2007128721A1
Publication number11744700, 744700, US 2007/0259900 A1, US 2007/259900 A1, US 20070259900 A1, US 20070259900A1, US 2007259900 A1, US 2007259900A1, US-A1-20070259900, US-A1-2007259900, US2007/0259900A1, US2007/259900A1, US20070259900 A1, US20070259900A1, US2007259900 A1, US2007259900A1
InventorsPeter Sieger, Dirk Kemmer, Peter Kohlbauer, Thomas Nicola, Martin Renz
Original AssigneePeter Sieger, Dirk Kemmer, Peter Kohlbauer, Thomas Nicola, Martin Renz
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Polymorphs
US 20070259900 A1
Abstract
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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Claims(12)
1. 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.
2. Polymorph A according to claim 1, characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 11.49 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47.
3. 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 at a temperature of 10-40° C. it transforms reversibly into the polymorph A of claim 1.
4. Polymorph B according to claim 3, characterised in that in the X-ray powder diagram it has 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.
5. Polymorph C 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 loses water at a temperature of 30-100° C. and in the DSC diagram it exhibits further thermal effects at approx. 150° C. and 175° C.
6. Polymorph C according to claim 5, characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 12.90 Å, 11.10 Å, 6.44 Å, 3.93 Å and 3.74 Å.
7. Anhydrous polymorph D 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 150±3° C.
8. Anhydrous polymorph E 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 175±3° C.
9. Method of preparing the polymorph C according to claim 5, characterised in that
(a) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is refluxed in methanol,
(b) the methanolic solution is cooled to a temperature of 40-60° C.,
(c) a solvent such as tert.-butylmethylether is added,
(d) the resulting suspension is cooled first of all to 15-25° C. and then to 0-5° C.,
(e) the crystals are suction filtered and
(f) dried in vacuo at a temperature of 70° C.
10. Method according to claim 9, characterised in that after step (a) the hot solution is filtered.
12. A method for the treatment of patients with type I and type II diabetes mellitus, prediabetes or reduced glucose tolerance, rheumatoid arthritis, obesity, or calcitonin-induced osteoporosis, as well as patients in whom an allograft transplant has been carried out, the method comprising the step of administering a pharmaceutical composition comprising at least one of the polymorphs A, B, and C, and one or more inert carriers, diluents, or carriers and diluents.
13. A pharmaceutical composition comprising at least one of the polymorphs A, B, and C, and one or more inert carriers, diluents, or carriers and diluents.
Description
BACKGROUND OF THE INVENTION

This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in its entirety.

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 reflexes 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 reflexes 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 reflexes 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 Θ 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
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

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 Θ 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
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

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 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.

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 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.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US7470716Jun 24, 2005Dec 30, 2008Boehringer Ingelheim International GmbhImidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US7495002Sep 1, 2005Feb 24, 2009Boehringer Ingelheim International Gmbhe.g. 1-[(3-methyl-isoquinolin- 1 -yl)methyl]-3-methyl-7-(2-butyn- 1 -yl)-8-[(2-amino-ethyl) -methylamino]-xanthine; dipeptidyl-peptidase-IV (DPP-IV) inhibitor; antidiabetic, diuretic, antihypertensive agent; insulin resistance, obesity; irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis
US7495003 *Sep 1, 2005Feb 24, 2009Boehringer Ingelheim International Gmbhe.g. 1-(naphthyl-1-ylmethyl)-3-(methoxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine; dipeptidyl-peptidase-IV (DPP-IV) inhibitor; antidiabetic, diuretic, antihypertensive agent; insulin resistance, obesity; irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis
US7495005Aug 7, 2003Feb 24, 2009Boehringer Ingelheim Pharma Gmbh & Co. KgAntidiabetic agents; antiarthritic agents; obesity; graft verses host disease; osteoporosis
US7560450Nov 18, 2003Jul 14, 2009Boehringer Ingelheim Pharma Gmbh & Co., KgXanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7645763Feb 22, 2005Jan 12, 2010Boehringer Ingelheim Pharma Gmbh & Co. Kgdipeptidylpeptidase-IV inhibitors; antidiabetic agents, antiarthritic agents, obesity, allograft transplantation, and osteoporosis caused by calcitonin; 1,3-disubstituted-7-(2-butyn-1-yl)-8-(3-aminopiperidin-1-yl)-xanthine compounds
US7667035Sep 10, 2008Feb 23, 2010Boehringer Ingelheim International Gmbh(R)-2-(-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one; inhibitors of dipeptidylpeptidase IV (DPP IV)
US7696212Dec 10, 2008Apr 13, 2010Boehringer Ingelheim Pharma Gmbh And Co. Kg1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine; antiarthritic agents; obesity; antidiabetic agents; osteoporosis; dipeptidylpeptidase-IV (DPP-IV) inhibitors
US7838529Jan 16, 2009Nov 23, 2010Boehringer Ingelheim International Gmbhtype II diabetes mellitus and obesity; dipeptidylpeptidase-IV (DPP-IV) inhibitor; 1-[2-(2-formylaminophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-aminopiperidin-1-yl)xanthine (xanthine=3,7-dihydro-purine-2,6-dione)
US7906539Aug 15, 2008Mar 15, 2011Boehringer Ingelheim International GmbhImidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US8071583Aug 7, 2007Dec 6, 2011Boehringer Ingelheim International GmbhPyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus
WO2010086411A1 *Jan 29, 2010Aug 5, 2010Boehringer Ingelheim International GmbhDpp-iv inhibitors for treatment of diabetes in paediatric patients
WO2011113947A1 *Mar 18, 2011Sep 22, 2011Boehringer Ingelheim International GmbhCombination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
WO2014064215A1Oct 24, 2013May 1, 2014INSERM (Institut National de la Santé et de la Recherche Médicale)TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL
Classifications
U.S. Classification514/266.2, 544/284
International ClassificationA61K31/517, C07D405/14
Cooperative ClassificationC07D473/04
European ClassificationC07D473/04
Legal Events
DateCodeEventDescription
Jul 13, 2010ASAssignment
Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH,GERMANY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SIEGER, PETER;KEMMER, DIRK;KOHLBAUER, PETER AND OTHERS;SIGNED BETWEEN 20070606 AND 20070618;REEL/FRAME:24670/697
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SIEGER, PETER;KEMMER, DIRK;KOHLBAUER, PETER;AND OTHERS;SIGNING DATES FROM 20070606 TO 20070618;REEL/FRAME:024670/0697
Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY