Polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyrdazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof

Patent metadata

Field	Value
Publication number	US-9308205-B2
Application number	US-201514609137-A
Country	US
Kind code	B2
Filing date	Jan 29, 2015
Priority date	Jan 8, 2009
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The present invention relates to 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride solvates and crystalline modifications thereof. The present invention further relates to processes of manufacturing these crystalline modifications as well as their use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by the inhibition, regulation and/or modulation of signal transduction of kinases, in particular by the inhibition of tyrosine kinases, e.g. pathophysiological conditions such as cancer.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising a therapeutically effective amount of a 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride solvate excluding 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate crystalline modification H2:
Form H2:

°2θ (Cu—Kα 1

Peak No.
d/Å
radiation) ± 0.1°
(h, k, l)

1
8.71
10.1
(1, 0, 0)

2
8.22
10.8
(−1, 1, 1)

3
7.59
11.6
(1, 2, 0)

4
6.78
13.0
(0, 3, 1)

5
6.58
13.5
(−1, 3, 1)

6
5.73
15.4
(−1, 4, 1)

7
4.98
17.8
(−1, 1, 2)

8
4.84
18.3
(−2, 1, 1)

9
4.68
19.0
(−2, 2, 1)

10
4.43
20.0
(−2, 3, 1)

11
4.35
20.4
(2, 0, 0)

12
3.73
23.9
(−2, 4, 2)

13
3.64
24.5
(0, 5, 2)

14
3.39
26.3
(0, 6, 2)

15
3.13
28.5
(−3, 2, 2)

and
a therapeutically effective amount of at least one additional pharmaceutically active substance selected from C225 and Erlotinib.

2. The pharmaceutical composition of claim 1 , wherein the 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride solvate is crystalline.

3. The pharmaceutical composition according to any of claim 1 , wherein the 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride solvate is 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate excluding 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate crystalline modification H2.

4. The pharmaceutical composition according to claim 1 , wherein the compound 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is in its crystalline modification H1, which is characterized by XRD peaks comprising 5.9°, 16.0° and 23.4° (in °2θ using Cu—Kα 1 radiation, ±0.1°).

5. The pharmaceutical composition according to claim 4 , wherein the 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate in its crystalline modification H1 is characterized by the following XRD data:
Form H1:

°2θ (Cu—Kα 1

Peak No.
d/Å
radiation) ± 0.1°

1
14.88
5.9

2
9.99
8.8

3
7.83
11.3

4
7.25
12.2

5
6.10
14.5

6
5.84
15.2

7
5.52
16.0

8
5.38
16.5

9
4.92
18.0

10
4.12
21.6

11
3.80
23.4

12
3.57
24.9

13
3.49
25.5

14
3.30
27.0

15
2.95
30.3.

6. The pharmaceutical composition according to claim 3 , wherein the compound 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin

Assignees

• Merck Patent Gmbh

Inventors

• Becker Axel
• Kuehn Clemens
• Saal Christoph
• Schadt Oliver
• Dorsch Dieter
• Bokel Heinz-Hermann
• Stieber Frank
• Donini Cristina

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title