US 8,710,058 B2 · Polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof

Abstract

Compounds of the present invention concern 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 compound, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, has the following structural formula: The hydrochloride solvates and crystalline modifications thereof according to the invention are useful for treatment of physiological and/or pathophysiological conditions, such as cancer, that 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, especially Met-kinase. The present invention further relates to processes of manufacturing these crystalline modifications.

Claims31

Dependent claims

A compound in crystalline form wherein said compound is a hydrochloride solvate of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile,

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 in the form of a polymorph characterized by the following XRD data:
°2θ (Cu-Kα1 radiation)
Peak No.
d/Å
±0.1°
(h, k, 1)
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).

63 more elements

A process for manufacturing a polymorph of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, said process comprising:

(a) dispersing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base) or one or more salts thereof in a solvent or a solvent mixture, optionally under stirring, and optionally heating up the resulting dispersion to 30° C. to 95° C., optionally under stirring,
(b) converting 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base) or one or more salts thereof into the corresponding hydrochloride salt by addition of aqueous hydrochloric acid solution, optionally under stirring, optionally heating up the resulting dispersion to 30° C. to 95° C., for one or more minutes or hours, optionally under stirring, and optionally adding further solvent or solvent mixture, optionally under stirring,
(c) cooling down the dispersion of (b) to room temperature, optionally under stirring, and incubating the dispersion at room temperature for one or more hours or days, optionally under stirring, to precipitate 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, and
(d) isolating precipitated 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate by solid-liquid separation, optionally washing with a solvent or a solvent mixture, and optionally subsequent drying, optionally at 30° C. to 95° C.,
wherein the polymorph is characterized by the following XRD data:
°2θ (Cu-Kα radiation)
Peak No.
d/Å
±0.1°
(h, k, 1)
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).

67 more elements

(a) dispersing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base) or one or more salts thereof in a solvent or a solvent mixture, optionally under stirring,
(b) converting 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base) or one or more salts thereof into the corresponding hydrochloride salt by addition of aqueous hydrochloric acid solution, optionally under stirring, to yield a dispersion, heating up the resulting dispersion to 30° C. to 100° C., optionally under stirring, and optionally subjecting the dispersion to solid-liquid separating, to obtain a solution,
(c) heating up the resulting solution of (b) to 30° C. to 100° C., optionally under stirring, and subsequently cooling the solution down over one or more hours or days, optionally under stirring, and optionally cooling the solution further down, optionally under stirring, to yield precipitated 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, and
(d) isolating precipitated 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate by solid-liquid separation, optionally washing 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate with a solvent or a solvent mixture, and optionally subsequent drying 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, optionally at 30° C. to 95° C.,
wherein said polymorph is characterized by the following XRD data:
Form H2:
°2θ (Cu-Kα radiation)
Peak No.
d/Å
±0.1°
(h, k, 1)
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).

68 more elements

Dependencies are inferred from the claim text.

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

Life of this patent

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

Life of this patent

Abstract

Claims31