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PROCESSES FOR THE PREPARATION OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-[(4-PYRININ-3-YL)PYRIMIDIN-2-YLOAMINO]PHENYL]BENZAMIDE MESYLATE

IP.com Disclosure Number: IPCOM000171337D
Publication Date: 2008-Jun-05
Document File: 8 page(s) / 268K

Publishing Venue

The IP.com Prior Art Database

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Page 1 of 8

PROCESSES FOR THE PREPARATION OF

-

4

(

-

4

-

METHYLPIPERAZIN

-

1

)

YLMETHYL

-

-

N

[

-

METHYL

-

4

-

3

[(

-

4

-

PYRININ

-

3

)

YL

PYRIMIDIN

-

-

2

]

]

PHENYL

BENZAMIDE

MESYLATE

YLOAMINO

    4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyrinin-3-yl)pyrimidin-2- yloamino]phenyl]benzamide mesylate("IMBM"), a compound having the chemical structure,

N

O

H3C

N H

CH3

NH

N N

N

H3C SO3H

N

is a protein-tyrosine kinase inhibitor, especially useful in the treatment of various types of cancer and can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus it can also be used for the treatment of non-maligant diseases. 4-(4- methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyrinin-3-yl)pyrimidin-2- yloamino]phenyl]benzamide("IMB") is usually administered orally in the form of a suitable salt, e.g., IMBM.

    Herein is described processes to prepare crystalline IMBM designated form beta. As used herein the term form beta refers to crystalline IMBM characterized by data selected from the group consisting of PXRD pattern having at least five peaks selected from the list consisting of peaks at about 9.7, 13.9, 14.7, 17.5, 18.2, 20.0, 20.6, 21.1, 22.1,
22.7, 23.8, 29.8 and 30.8 ± 0.2 degrees two theta, a powder XRD pattern depicted in Figure 1, and combination thereof.

Figure 1: Powder X-ray diffraction pattern for IMBM form beta.

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    Form beta of IMBM can be prepared by a process comprising suspending form IV of IMBM in a solvent selected from the group consisting of: a ketone, cyclic ether, an ester or mixtures thereof.

    As used herein the term form IV refers to crystalline IMBM characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 8.1, 9.7,
17.0, 20.1, and 21.5 ± 0.2 degrees two-theta; a powder XRD pattern with peaks at about
8.1, 9.7, 13.2, 16.2, and 17.0± 0.2 degrees two-theta; a powder XRD pattern having peaks at about 8.1, 9.7, 16.2, 17.0 and 21.5± 0.2 degrees two-theta; a PXRD pattern having at least five peaks selected from the list consisting of peaks at about 8.1, 9.7, 13.2, 14.3,
16.2, 17.0, 24.1, 24.8, 25.8, 26.6, 28.9, 30.3 ± 0.2 degrees two-theta; a powder XRD pattern depicted in Figure 2; a solid-state 13C NMR spectrum with signals at about 162.3, 160.9, 157.1 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 56.1, 54.7 and 50.9 ± 0.1 ppm, a 13C

NMR spectrum depicted in Figures 3, and a and a solid-state 13C NMR spectrum depicted in Figure 4; wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is typically at about 106.2± 1ppm.

Figure 2: Powder X-ray diffraction pattern for IMBM form IV.

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