BRPI0706729A2 - solid forms of a pyrrolopyrimidine derivative and its use as an antitumor agent - Google Patents

Abstract

SOLID FORMS OF A PYROLOPYRIMIDINE DERIVATIVE AND ITS USE AS AN ANTITUMENT AGENT The present invention relates to novel crystalline forms of {6- [4- (4-Ethi-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2 , 3-dpyrimidin-4-yl} - ((R) -1-phenylethyl) -amine, the process for the preparation of these crystalline forms of {6- [4- (4-ethylpiperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl (- (R) -1-phenyl-ethyl) -amine, compositions containing these crystalline forms of {6- [4- (4 -ethyl- and the use of these crystalline forms of {6- [4- (4-ethyl-piperazin-1-methylmethyl-phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R ) -1-phenylethyl) -amine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.

Description

Report of the Invention Patent for "FORMASSOLIDS OF A PYROLOPYRIMIDINE DERIVATIVE AND THEIR USE AS AN ANTITUMOR AGENT".

ORGANIC COMPOUNDS

The present invention relates to novel crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl] -H-pyrrole]. -phenyl-ethyl) -amine, to the process for preparing these crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl] -phenyl-yH-pyrrol] .Sc / lpyrimidin-1-yl] -1 / ?) -! (phenyl-ethyl) -amine, to compositions containing these crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (] pyrimidin-4 -yl} - ((f ') -1-phenyl-ethyl) -amine, and the use of these crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrole [2,3-dJ-pyrimidin-4-yl} - ((α) -1-phenyl-ethyl) -amine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.

The invention relates to the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine, in the process for preparation of the {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2, 3-c-lpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine, to compositions containing the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) - phenyl] -7 / - / - pyrrol [2,3-cdpyrimidin-4-yl} - ((?) -1-phenylethyl) -amine, and the use of the amorphous form of {6- [4- ( 4-Ethyl-piperazin-1-ylmethyl-phenin-TH-pyrrol-2 (pyrimidin-1-yl-Cyclo) -! -phenyl-ethyl) -amine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.

Background of the Invention

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((f ') -1-phenyl -ethyl) -amine is a double EGF / VEGF inhibitor and has anti-tumor behavior. In general, the preparation of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-C3 (] pyrimidin-4-yl} - (( H) -1-phenyl-ethyl) -amine is known in the art, however, it is also known that there are different crystalline forms of the same drug that may have substantial differences in some pharmaceutically important properties, so there is still a need {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1- phenylethylamine) and new preparation methods.

Summary of the Invention

According to one aspect, the invention provides a {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} -crystalline A - ((R) -1-phenyl-ethyl) -amine. Preferably, the crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) - 1-phenylethyl )amine has an X-ray diffraction pattern with a peak at a 2 theta (θ) diffraction angle of 4.4 °, 8.8 °, 9.1 °, 13.2 °, 14 , 2 °, 17.2 °, 18.2 °, 19.4 ° ± 0.2 ° as depicted in Figure 1.

In yet another aspect, the invention provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine in a solid form, wherein at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H- solid pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is its crystalline form A having an X-ray diffraction pattern with a peak at a 2θ diffraction angle of 4.4 °, 8.8 °, 9.1 °, 13.2 °, 14.2 °, 17.2 °, 18.2 °, 19.4 ° ± 0.2 ° as shown in Figure 1. Various evariant modalities are provided.

According to yet another aspect, the invention provides a pharmaceutical composition comprising the crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenylethyl) -am a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.

In yet another aspect, the invention provides a process for preparing crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin -4-yl} - ((R) -1-phenyl-ethyl) -amine, the process including:

(a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl ethyl) -amine with an alcoholic solvent to form a precipitate;

(b) resuspending the precipitate in a second alcoholic solvent; and

(c) isolate crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-aG-pyrimidin-4-yl} - (( H) -1-phenyl-ethyl) -amine.

Various embodiments and variants are provided.

In yet another aspect, the invention provides a process for preparing crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-C 3 -pyrimidin-4 -yl} - ((H) -1-phenyl-ethyl) -amine from the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2, 3-odpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine by melting the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H -pyrrol [2,3-c (lpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine in an inert gas or solvent which yields the crystalline form D of {6- [4 - (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4-yl} - ((R-phenylphenyl) -amine and / or the crystalline form {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / lpyrimidin-4-yl} - ((/ =?) - 1-phenyl-ethyl) -amine, and cool the mixture to produce {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cy] pyrimidin-4-yl (R) -1-phenylethyl) amine.

According to one aspect, the invention provides a {6- [4- (4-ethyl-iperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl formacrystalline B } - ((flu) -1-phenyl-ethyl) -amine. Preferably, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-a (] pyrimidin-4-yl} - ((f? ) -1-phenylethyl) -amine has an X-ray diffraction pattern with a peak at a 2 θ diffraction angle of 5.7 °, 6.9 °, 7.7 °, 11.7 °, 15, 6 °, 18.5 ° ± 0.2 ° as shown in Figure 5.

In yet another aspect, the invention provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c (lpyrimidin-4 -yl} - ((R) -1-phenyl-ethyl) -amine in a solid form, wherein at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl ] -7H-pyrrol [2, S-Gdpyrimidin-2HH (W) -I-phenylethyl) -amine is its crystalline form B having an X-ray diffraction pattern with a peak at a 2 θ diffraction angle of 5 , 7 °, 6.9 °, 7.7 °, 11.7 °, 15.6 °, 18.5 ° ± 0.2 ° as shown in Figure 5. Various embodiments and variants are provided.

In yet another aspect, the invention provides a pharmaceutical composition comprising the crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c]. pyrimidin-4-yl} - ((R) -1-phenylethyl) amine is a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.

According to yet another aspect, the invention provides a

process for preparing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-cy] pyrimidin-4-yl} - (B) (f) -1-phenyl-ethyl) -amine, the process including:

(a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c-pyrimidin-1-yl] -1H-phenyl-ethyl-amine with a alcoholic solvent to form a precipitate; and

(c) isolate crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c (lpyrimidin-4-yl) ((H) -1-phenyl-ethyl) -amine.

Various embodiments and variants are provided.

According to one aspect, the invention provides a {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / lpyrimidin-4] formalin C -yl} - ((flu) -1-phenylethyl) -amine. Preferably, the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-o (lpyrimidin-4-yl} - (( H) -1-phenyl-ethyl) -amine has an X-ray diffraction pattern with a peak at a 2Θ diffraction angle of 5.7 °, 6.8 °, 7.5 °, 10.2 °, 11, 6 °, 13.3 °, 15.2 °, 18.4 °, 20.8 ° ± 0.2 ° as depicted in Figure 7.

In yet another aspect, the invention provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-cdpyrimidin-4-yl } - ((?) -1-phenyl-ethyl) -amine in a solid form, wherein at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] - Solid 7H-pyrrol [2,3-c (lpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is its crystalline form having an X-ray diffraction pattern with a peak at a diffraction angle 2Θ of 5.7 °, 6.8 °, 7.5 °, 10.2 °, 11.6 °, 13.3 °, 15.2 °, 18.4 °, 20.8 ° ± 0.2 ° as shown in Figure 7. Various embodiments and variants are provided.

According to yet another aspect, the invention provides a pharmaceutical composition comprising the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-TH-pyrrole] -Sc4-pyrimidin-1-yl]. (1/1?) -! phenylethylamine is a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.

According to yet another aspect, the invention provides a process for preparing the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / 1-pyriniclin]. -4-yl} - ((f) -1-phenyl-ethyl) -amine, the process including:

(a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1- phenylethylamine with an alcoholic solvent to form a precipitate; and

(b) isolating the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl-γH-pyrrol-β-cdpyrimidin-yl] -1H-phenyl-ethyl-amine.

Various embodiments and variants are provided.

In yet another aspect, the invention provides a process for the preparation of an amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3] -GI] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine by spray drying a solution containing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl) -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenylethyl) -amine.

Pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4 -yl} - ((R) -1-phenyl-ethyl) -amine produced by the process described, and one or more pharmaceutically acceptable excipients are also provided.

Brief Description of the Drawings

Figure 1 shows the X-ray powder diffraction diagram of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidine 4-yl} - ((R) -1-phenyl-ethyl) -amine.

Figure 2 is a characteristic infrared spectrum of formacrystalline A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / lpyrimidin-A- WH (R) -I-phenyl-ethyl) -amine.

Figure 3 shows the DSC of crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-y-pyrrole] -S-c / lpyrimidin-1-yl] -C1-; Figure 4 shows the Raman spectrum of crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3- Gpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine.

Figure 5 shows the X-ray powder diffraction diagram of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cdpjrimidin-1-yl) B-crystalline form B N-1-phenyl-ethyl-amine.

Figure 6 shows the DSC of crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-1 H -pyrrole] -S-cpyrimidin-1-yl] -H = -); -phenyl-etii) -amine.

Figure 7 shows the X-ray powder diffraction diagram of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine.

Figure 8 is a characteristic infrared spectrum of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-Q (] pyrimidin-4-yl) formacrystaline C - ((R) -1-phenyl-ethyl) -amine.

Figure 9 shows the DSC of the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-1 H -pyrrole] -S-G-pyrimidin-1-yl] -1- (R). (phenyl-ethyl) -amine.

Figure 10 shows the Raman spectrum of the crystalline form Cde {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-H-pyrrole] -S-c / lpyrimidin-1-yl] -1 H). (phenyl-ethyl) -amine.

Figure 11 shows the amorphous form X-ray powder diffraction diagram of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-cpyrimidin-2-one]. 4-yl} - ((R) -1-phenyl-ethyl) -amine.

Detailed Description of the Invention

Unless otherwise defined, all technical and scientific terms used herein in this patent application have the same meaning as commonly understood by one ordinarily skilled in the art to which this invention belongs. While any methods and materials similar or equivalent to those described herein, in this patent application may be used in the practice or experimentation of the present invention, preferred methods and materials are described.

For the purposes of the present invention, the following terms are defined below. The crystalline compound, referred to herein, in this patent application, as "crystalline form A" and referred to in the following as crystalline form A of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is a {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7W-pyrrol [2,3-c /] pyrimidin-4-yl} - ((R) -1- phenylethyl) amine. It is characterized by X-ray powder diffraction, DSC, Raman Spectrode and / or infrared spectroscopy. It is further described below.

The crystalline compound, referred to herein as "crystalline form B" and referred to in the following parts as {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] crystalline form B ] -7 / - / - pyrrol [2,3-G (| pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is a new crystalline form of {6- [4- ( 4-ethyl-piperazin-1-ylmethyl) -phenyl] -7- [pyrrolo [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine. It is characterized by X-ray powder and / or DSC diffraction and is further described below.

The crystalline compound, referred to herein as "crystalline form C" and referred to in the following parts as {6- [4- (4-ethyl-piperazin-1-ylmethyl) phenyl] C-form ] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is a new crystalline form of {6- [4- (4- ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine. It is characterized by X-ray powder diffraction, DSC, Raman Spectrode and / or infrared spectroscopy. It is further described below.

"Pharmaceutically acceptable" means being useful for preparing a pharmaceutical composition which is generally non-toxic and not biologically undesirable and includes that which is acceptable for veterinary use and / or human pharmaceutical use.

An "anti-solvent" is a solvent which when added to an existing solution of a substance has reduced the solubility of the substance.

The term "composition" includes, but is not limited to, a powder, solution, suspension, gel, ointment, emulsion and / or mixtures thereof. The term composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts. A "composition" may contain a single crystalline form or a mixture of crystalline forms of the active ingredient. A "compound" is a chemical that includes molecules of the same chemical structure.

The term "pharmaceutical composition" is intended to encompass a product comprising one or more active ingredients, pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or depletion. or aggregating any two or more of the ingredients, or disassociating one or more of the ingredients, or other reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing the active ingredient, one or more additional active ingredients and pharmaceutically acceptable excipients.

The term "excipient" means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent and vehicle. Excipients which are useful for preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary as well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more of said excipient.

"Therapeutically effective amount" means the amount of a compound which, when administered to treat or prevent a disease, is sufficient to effect said treatment or prevention for the disease. The "therapeutically effective amount" will vary depending upon the compound, the disease and its condition. severity and age, weight, etc., of the patient being treated.

In referring to a chemical reaction, the terms "treat", "contact" and "react" are used interchangeably herein, in this dependent application, and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated product and / or desired. It should be recognized that the reaction which produces the indicated and / or desired product may not necessarily result directly from the combination of two reagents which were initially added, that is, there may be one or more intermediates which are produced in the mixture which is essential. leads to the formation of the indicated and / or desired product.

The term "essentially free of" in reference to a composition as used herein in this patent application means that the substance form of which the composition is free cannot be detected by methods known to those skilled in the art.

The term "essentially pure" is understood in the context of the present invention meaning especially that at least 90%, preferably at least 95% by weight of the crystals of an acid addition salt of formula (I) are present in the form of crystal according to the invention.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) Amine has the following chemical structure:

<formula> formula see original document page 10 </formula>

The invention relates especially to particular crystalline forms, preferably those, which are referred to in the following parts as crystalline form A of a {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -amide. 7H-pyrrol [2,3-cpyrimidin-4-yl} - ((R) -1-phenylethyl) amine of the compound of formula (I) described above; {6- [4- (4-Ethyl-piperazin-1-ylmethyl-phenyl-1 H -pyrrole] -Sc / lpyrimidin-1-yl-1-phenyl-ethyl-amine B-crystalline form B; {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7/- [pyrrolo [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl -ethyl) -amine.

Particularly solid forms of the same drug substance may have different properties, including characteristics, which have functional implications with respect to their use as a drug substance and may have substantial differences in the pharmaceutically important properties referred to as indices. of dissolution and bioavailability. Also, different crystalline forms may have different processing properties, such as hygroscopicity, flowability and the like, which may affect their suitability as active pharmaceuticals for commercial production.

The X-ray diffraction pattern shown in Figure 1 for crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-af] pyrimidin-4 -yl} - ((f) -1-phenyl-ethyl) -amine is summarized in Table 1. X-ray powder diffraction patterns were measured on a Scintag INC X 1 with CuK alpha radiation source (λ = 1.5406 THE).

Table 1. X-ray Powder Diffraction Peaks for Crystalline Form Ade {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-a (] pyrimidin-2-one) 4-yl} - ((R) -1-phenylethylamine

<table> table see original document page 11 </column> </row> <table>

It should be borne in mind that slight variations in the observed 2Θ angles or spacing values d are expected based on the specific diffractometer employed, the analyst, and the technique of sample preparation. More variation is expected for relative intensity peaks. Identification of the exact crystalline form of a compound should be based primarily on the 2Θ angles observed with lesser importance attributed to relative intensity peaks. Some margin of error is present in each of the 2Θ angle assignments reported herein in this patent application. . The error margin is, in a preferred embodiment, the crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-G-pyrimidin-4 -yl} - ((R) -1-phenyl-ethyl) -amine is approximately ± 0.2 ° for each of the assignment peaks.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c (] pyrimidin-4-yl} - ((/ ?) -1-phenyl-ethyl) -amine may also be characterized by infrared spectroscopy.Crystalline form A shows a standard absorption characteristic in infrared (IR) spectroscopic analysis as depicted in Figure 2. IR spectroscopic analysis was performed. in a Bruker IFS-55. Crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c /] pinmiclin-4-yl } - ((H) -1-phenyl-ethyl) -amine has characteristic absorptions which can be differentiated from those of other polymorphs in about 695, 802, 836, 923, 934, 1013, 1095, 1146, 1165,1207, 1229, 1292, 1300, 1310, 1348, 1358, 1507, 1546, 1595, and 3269 cm -1 in IR spectroscopic analysis. Some margin of error is present in any of the characteristic absorptions reported herein in this application. The margin of error attributed in the characteristic absorptions is approximately 2 cm "1 in the range from 1900 to 800 cm" 1.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-dpyrimidin-4-yl} - ((R) -1-phenyl-2-yl) crystalline form A ethyl) -amine may also be characterized by Differential Scanning Calorimeter (DSC). Crystalline form A presents a characteristic pattern in DSC analysis as shown in Figure 3. DSC analysis was measured on a Perkin Elmer Pyris 1. Crystalline form A of {6- [4- (4-ethyl-piperazin-1- ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine has a characteristic melting peak with an onset temperature above 240 ° C, preferably above 250 ° C. Fusion is associated with decomposition. The onset temperature therefore varies with the warming index and the instrumental conditions used for analysis.

Crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol-4'-pyrimidin-1'-yl-1'-phenyl-ethyl-amine may also be characterized by Raman Spectrum. Crystalline form A has a characteristic Raman Spectrum pattern as depicted in Figure 4. Raman Spectrum analysis was measured on a Bruker RFS100 instrument. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol-4Sc / pyrimidin-4-yl] -1H-phenyl-ethyl-amine crystalline form A has absorptions. which can be differentiated from those of other polymorphs at about 158, 183, 920, 935, 1002, 1159, 1178, 1308, 1405, 1422, 1446, 1496,1544, 1618 and 3060 cm-1 in the analysis. Some margin of error of ± 3 cm-1 in the range from 2000 to 500 cm-1 is present in each of the characteristic absorptions reported herein in this patent application.

One or more of the physical properties and / or spectroscopic properties may be the basis for characterizing the crystalline or polymorphic forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H- pyrrol [2,3-c / pyrimidin-4-yl} - ((flu) -1-phenyl-ethyl) -amine.

The invention also provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl] -1H-pyrrol-2-pyrimidin-1-yl] -H-1 - (R). solid -phenyl-ethyl) -amine, which is at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2 Pyridin-4-yl} - ((R) -1-phenyl-ethyl) -aminasolid in the composition, its crystalline form A. The preferred detachment form is {6- [4- ( 4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-pyrimidin-4-yl} - ((N-1-phenyl-ethyl) -amine suitable for use as an ingredient in the formulation of pharmaceuticals The remainder of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c /] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -aminasolid in the composition, i.e. 20% or less of the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] - 7H-pyrrol [2,3-c-pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amin may be, for example, other crystalline forms of {6- [4- (4- piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c (lpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine In a specific embodiment , the composition contains at least 90% of the crystalline form A of {6- [4- ( 4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / lpyrimidin-4-yl} - ((flu) -1-phenyl-ethyl) -amine with respect to {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-2-yl) solid) ethylamine in the composition. In another specific embodiment, the composition contains at least 95% of crystalline form A with respect to the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2 , 3-d] pinmidin-4-yl} - ((R) -1-phenylethyl) -aminasolid in the composition.

A process for the preparation of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-M} - (( R) -1-phenylethyl) -amine involves:

(a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl ethyl) -amine with an alcoholic solvent to form a precipitate;

(b) resuspending the precipitate in a second alcoholic solvent; and

(c) isolate crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R ) -1-phenyl-ethyl) -amine.

Various embodiments and variants are provided.

In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cdpyrimidin-4-yl} - ((R) -1-phenyl-ethyl ) -amine is contacted with methanol at an elevated temperature so that no remaining crystals are visible. The solution is placed in an ice bath and stirred. The precipitate is collected over a filter. The precipitate is then resuspended with isopropanol at an elevated temperature before the solution is filtered off and dried to yield {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2] , 3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine.

The above conditions for the selective preparation of the individual decrystalline forms are not conclusive. In general, for example, parameters such as the weight ratio of the compound of formula (I) to the solvent and anti-solvent may be varied. The X-ray diffraction pattern shown in Figure 5 for crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is summarized in Table 4. X-ray powder diffraction patterns were measured on a ScintagINC X1 with CuK alpha radiation source (λ = 1.5406 Î ±). Table 4. X-ray Powder Diffraction Peaks for Crystalline Form Bde {6- [4- (4-Ethyl-piperazin-1-methylmethyl) -phenyl] -7H-pyrrol [2, 3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine

<table> table see original document page 15 </column> </row> <table>

It should be borne in mind that slight variations in the observed 2Θ angles or spacing values d are expected based on the specific diffractometer employed, the analyst, and the technique of sample preparation. More variation is expected for relative intensity peaks. Identification of the exact crystalline form of a compound should be based primarily on the 2Θ angles observed with lesser importance attributed to relative intensity peaks.

Some margin of error is present in each of the 2Θ angle assignments reported herein in this patent application. The margin of error is in one preferred embodiment the crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cpyrimidin-4 -yl} - ((-phenyl-ethyl) -amine is approximately ± 0.02 for each of the assignment peaks.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl-1H-1-phenyl-ethyl-amine crystalline form B It can also be characterized by DSC. Crystalline form B shows a characteristic peak in DSC analysis as depicted in Figure 6. DSC analysis was measured on a Perkin Elmer Pyris 1. Crystalline form B of {6- [4- (4- ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine exhibits a characteristic endothermic transition in about 94 ° C followed by an exothermic event at about 138 ° C and an endothermic peak at about 255 ° C.

One or more of the physical properties and / or spectroscopic properties may be the basis for characterizing crystal forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2 1,3-c] pyrimidin-4-yl} - ((R) -1-phenylethyl) amine.

The invention also provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-1 H -pyrrole] -S-4-pyrimidin-1-yl] - (R) -. solid (phenyl-ethyl) -amine, which is at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-yH-pyrrol] -S-G-pyrimidin-1-yl). ^ -IR) -! -phenylethyl) -aminasolid in the composition, its crystalline form Β. The preferred form of decomposition is {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / J-pyrimidin-4-yl} - (( (1) - 1-phenyl-ethyl) -amine suitable for use as an active ingredient in the formulation of pharmaceuticals. The remainder of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrroI [2,3-c3 (] pyrimidin-4-yl} - ((/ 7) -1-phenylethyl) -aminasolid in the composition, ie 20% or less of the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2, 3-C-pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amin may be, for example, other crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl] ) -phenyl] -7H-pyrrol [2,3-c / lpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine In a specific embodiment, the composition contains at least 90% of the cris form 6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl3-7H-pyrrol [2,3-c / lpyrimidin-4-yl} - ((A) -I-phenyl-2-yl) ethyl) -amine with respect to the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c /) pyrimidin-4-yl} - ( Solid (H) -1-phenyl-ethyl) -amine in the composition. In another specific embodiment, the composition contains at least 95% of crystalline form B with respect to the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2 Solid 3-C (1β-pyrimidin-4-yl) - ((R) -1-phenyl-ethyl) -amine in the composition.

A process for the preparation of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / lpyrimidin-4-yl} - (( f) -1-phenyl-ethyl) -amine involves:

(a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-af] pyrimidin-4-yl} - ((ph) -1-phenyl ethyl) -amine with an alcoholic solvent to form a precipitate; and (c) isolating crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-gpyrimidin-4-yl} - ( (R) -1-phenyl-ethyl) -amine.

Various embodiments and variants are provided.

In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenN] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((F ') -1 (phenyl-ethyl) -amine is contacted with methanol at an elevated temperature, so that no remaining crystals are visible. The solution is placed in an ice bath and stirred. The precipitate is collected on a dry filter to give crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3- (pyrimidin-2-yl) 4-yl} - ((R) -1-phenethyl) -amine.

In one embodiment, {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7Î ± -pyrrol-C-pyrimidin-1-yl] -1H-1-phenyl-ethyl-amine is contacted with ethanol at an elevated temperature, so that no remaining crystals are visible. The solution is placed in an ice bath and stirred. The precipitate is collected on a dry filter to give crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-C5 (lpyrimidin-2-yl). 4-yl} - ((R) -1-phenyl-ethyl) -amine.

The X-ray diffraction pattern shown in Figure 7 for the crystalline C form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c /] pyrimidin-2-one. 4-yl} - ((/ :?) - 1-phenyl-ethyl) -amine is summarized in Table 5. X-ray powder diffraction patterns were measured on a Scintag INC X1 with CuK alpha radiation source (λ = 1, 5406 Á).

Table 5. X-ray Powder Diffraction Peaks for Crystalline Form Cde {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / lpinmidin-4 -yl} - ((/ =?) -1-phenylethyl) -amine

<table> table see original document page 17 </column> </row> <table> <table> table see original document page 18 </column> </row> <table>

It should be borne in mind that slight variations in the observed 2Θ angles or spacing values d are expected based on the specific diffractometer employed, the analyst, and the technique of sample preparation. More variation is expected for relative intensity peaks. Identification of the exact crystalline form of a compound should be based primarily on the 2Θ angles observed with lesser importance attributed to relative intensity peaks.

Some margin of error is present in each of the 2Θ angle assignments reported herein in this patent application. The margin of error is, in a preferred embodiment, the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (]) pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is approximately ± 0.02 for each of the assignment peaks.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (lpyrimidin-4-yl) - ((R) -1- phenylethylamine can also be characterized by infrared spectroscopy.Crystalline form C has a characteristic absorption pattern in IR spectroscopic analysis as shown in Figure 7. IR spectroscopic analysis was measured on a Bruker IFS-55.Crystalline form C {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / lpyrimidin-4-yl} - ((f ') -1-phenyl-ethyl ) -amine has characteristic absorptions which may be differentiated from those of other crystalline forms by about 701, 764, 842, 932, 1013, 1110, 1127, 1147, 1164, 1121,1300, 1312, 1347. , 1544, 1597, 3130 and 3429 cm-1 in IR spectroscopic analysis. Some error margin is present in each of the characteristic absorptions reported herein in this patent application. The error margin attributed in the characteristic absorptions is approximately 2 cm-1in. range 1 900 to 800 cm -1.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c /] pyrimiclin-4-yl} - ((f) -1) crystalline form C (phenyl-ethyl) -amine may also be characterized by DSC. Crystalline form C shows a characteristic peak in DSC analysis as depicted in Figure 9. DSC analysis was measured on a Perkin Elmer Pyris 1. Crystalline form C of {6- [4- (4-ethyl -piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-a (] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine exhibits a characteristic endothermic transition at about 99 ° C ° C followed by an exothermic event at about 139 ° C and an endothermic peak about 253 ° C.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c /] pyrimidin-4-yl} - ((f) -1) crystalline form C (phenyl-ethyl) -amine may also be characterized by Raman Spectrum. Crystalline form C shows a characteristic Raman Spectrum pattern as depicted in Figure 4. Raman Spectrum analysis was measured on a Bruker RFS 100 instrument. Crystalline form C of {6- [4- (4- Piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cdpyrimidin-1-yl] -1-phenyl-ethyl-amine has characteristic absorption, which can be differentiated from that of other polymorphs by about 179.254, 776, 803, 844, 933, 1000, 1024, 1166, 1309, 1405, 1450, 1497, 1543,1570, 1618 and 3059 cm -1 in the Raman Spectrum analysis. Some error margin of ± 3 cm -1 in the range of 200 to 500 cm -1 is present in each of the characteristic absorptions reported herein in this patent application.

One or more of the physical properties and / or spectroscopic properties may be the basis for characterizing the crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2, 3-C (1-pinmiclin-4-yl} - ((R) -1-phenyl-ethyl) -amine.

The invention also provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4-yl} - ((R) - Solid 1-phenylethyl) amine, which is at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-methylmethyl) -phen] -7 / - / - pyrrol [2J3 -c (1-pyrimidin-4-yl) - (((:?) -1-phenyl-ethyl) -aminasolid in the composition, its crystalline form C. The preferred detachment form is {6- [4- (4-ethyl) -piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / pyrimidin-4-yl} - ((F ') -1-phenyl-ethyl) -amine suitable for use as an ingredient in the formulation of pharmaceutical products. The remainder of {6- [4- (4-ethyl-piperazin-1-ylmethyl] -phenyl-βH-pyrrol-β-β-pyrimidinyl-yl] -1H-1-phenyl-ethyl) -aminasolid in the composition, that is, 20% or less of the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-G (] pyrinriidin-4-yl} ((R) -1-phenyl-ethyl) -amin may be, for example, other crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-irrol [2,3 -c (] pyrimidin-4-yl} - ((f) -1-phenyl-ethyl) -amine In a specific embodiment, the composition contains at least 90% of the {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c] pyrimidin-4-yl} - ((F ') -1-phenyl-ethyl) -amine with respect to the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (lpyrimidin-4-yl} - ((R)) -1 solid (phenyl-ethyl) -amine In another specific embodiment, the composition contains at least 95% of crystalline form C with respect to the total weight of {6- [4- (4-ethyl-piperazin-1-ylmetM ) -phenyl] -7H-pyrrol [2,3-c / 1piNmidin-4-yl} - ((R) -1-phen (ethyl) aminesolid in the composition.

A process for the preparation of {6- [4- (4-Ethyl-piperazin-1-ylmethyl-phenyl-1 H -pyrrol-4-yl] -pyrimidin-1-yl] -1-C-crystalline form C; -phenylethyl) -amine involves:

(a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-d] pyrimidin-4-yl} ((R) -1 phenyl ethyl amine with an alcoholic solvent to form a precipitate;

(b) isolate the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - (( (f) -1-phenylethyl) -amine.

In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-aG-pyrimidin-4-yl} - ((f ') -1-phenyl- ethyl) -amine is dissolved in methanol at an elevated temperature; the solution is cooled to about 0 ° C; and {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((/ =?) -1-phenyl-ethyl) -amine is obtained. This process is highly reproducible and the resulting crystalline product has good filtration properties.

The above conditions for the selective preparation of the individual crystal forms are not conclusive. In general, for example, it is possible to vary parameters such as the weight ratio of the compound of formula (I) to the solvent and anti-solvent. Figure 11 shows the X-ray powder diffractogram of the {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / lpyrimidin-4-yl} - ((F ') -1-phenyl-ethyl) -amine on a Scintag INC X1 with alpha CuC radiation source (λ = 1.5406 Á). As is apparent from Figure 11, the dust obtained by the inventors is amorphous.

The invention also provides a composition containing {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cppiNrnidin-4-yl} - ((F ') -1 solid (phenyl-ethyl) -amine, which is at least 80% by weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amide in the composition, its amorphous form. The preferred form of this composition is {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (] pyrimidin-4-yl} - ( (f) - 1-phenyl-ethyl) -amine solid suitable for use as an activone ingredient in the pharmaceutical formulation The remainder of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c / pyrimidin-4-yl} - ((?) -1-phenylethyl) aminesolid in the composition, ie 20% or less of the total weight of { 6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl ) -amin may be, for example, crystalline forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-cdpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine In a specific embodiment, the composition contains at least 90% of the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) - phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine with respect to the total weight of {6- [4- (4-ethyl- piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-et (1) -a solid mine in the composition. In another specific embodiment, the composition contains at least 95% of the amorphous form with respect to the total weight of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3- cflpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine in the composition. In yet another embodiment, the composition is essentially free of any forms of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2, S-Gppyrimidin-1 H (R) - I-phenyl-ethyl) -amines different in their form to -morph.

Also provided are pharmaceutical compositions containing one of crystalline forms A, B, C or the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [ 2,3-c / lpyrimidin-4-yl} - ((R) -1-phenylethyl) -aminated present invention and a pharmaceutically acceptable carrier. In addition to the active compound, the pharmaceutical composition includes one or more pharmaceutically acceptable carriers, also known as excipients, which ordinarily lack pharmaceutical activity, but have a number of useful properties which may, for example, enhance stability, sterility. , bioavailability and ease of formulation of a pharmaceutical composition. These carriers are pharmaceutically acceptable, meaning they are not harmful to humans or animals when properly taken and are compatible with other ingredients in a given formulation. The carriers may be solid, semi-solid or liquid, and may be formulated with the compound in bulk, but essentially in the form of a unit dosage formulation, that is, a physically distinct one until it contains a specific amount of active ingredient as such. tablet or capsule. Pharmaceutical compositions may include, in addition to a compound of this invention, one or more pharmaceutical compounds.

The pharmaceutical compositions of the present invention comprising the crystalline forms of the present invention may be in the form of suspensions, solutions, elixirs, aerosols or solid dosage forms.

Pharmaceutical compositions are contemplated in various formulations suitable for various modes of administration including, but not limited to, inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), implantable and transdermal administration. The most appropriate route of administration in a given case depends on the duration of the subject's condition, the desired treatment duration, the nature and severity of the condition being treated, and the particular formulation being used. The formulations may be in bulk or in unit dosage form, and may be prepared by methods known in the art for a given formulation.

The amount of active ingredient included in a unit dosage form depends on the type of formulation in which the active ingredient is presented. A pharmaceutical composition will generally contain from about 0.1 wt% to about 99 wt% of the active ingredient, preferably about 1 wt% to 50 wt% for oral administration and about 0.2 wt% to about 20% by weight for parenteral administration.

Formulations suitable for oral administration include capsules (hard and soft), capsules, lozenges, syrups, suppositories and tablets, each containing a predetermined amount of the active compound, such as a powder or granules, as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Said formulations may be prepared by any suitable pharmacy method which includes the step of bringing into association the active compound and a suitable vehicle or vehicles. The amount of active ingredient per dosage unit of solid formulations may be as described in the prior art for {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol preparations [2,3-d] pyridin-4-yl} - ((R) -1-phenyl-ethyl) -amine.

In another aspect, the invention also provides methods of treatment using the compounds and pharmaceutical compositions of this invention. By subject is meant a human or an animal, preferably a human being. Animals contemplated by this invention include any animal safely treatable by the compounds of this invention. Most notably, the crystalline forms A, B, C or the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-TH-pyrrol]. ) -! Phenyl-ethyl) -amine of the present invention exhibit high antiproliferative and anti-tumor activity as a result of double EGF and VEGF inhibition, which can be extremely useful for cancer treatment. In addition, its highly selective and potent inhibition of the double inhibitor EGF and VEGF may lead to superior clinical outcomes for the patient, ie delaying or suppressing disease progression with equally tolerable regimens. Potential applications include a variety of solid tumors and more specifically, for example, breast cancer, colon cancer, ovarian cancer and leukemia.

In addition, several other indications that may be affected by dual activity EGF and VEGF can be effectively treated by these compositions, including multidrug resistance (MDR), one of the major problems in currently used cancer chemotherapy and inflammatory diseases. in general.

The present invention relates especially to the crystalline forms A, B, C or the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3- d] -pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine described herein in this patent application for the treatment of one of the aforementioned diseases or in the preparation of a pharmacological agent for the treatment the same.

The invention also relates to a method for treating warm-blooded animals suffering from said diseases, especially a tumor disease, wherein an amount of the crystalline forms A, B, C or the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine which is effective against the disease in question, especially an antiproliferative and especially tumor-inhibiting amount, is administered to warm-blooded animals in need of such treatment. The invention further relates to the use of crystalline forms A, B, C or the amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d ] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amin for the inhibition of the above or for the preparation of pharmaceutical compositions for use in the treatment of the human or animal body, especially for treating a variety of solid tumors and more specifically, for example breast cancer, colon cancer, deovarian cancer, and leukemia. Depending on the species, age, individual condition, method of administration and clinical presentation, effective doses, for example, daily doses of about 1 to 2500 mg, preferably 1 to 1000 mg, especially 5 to 500 mg, are administered to warm-blooded animals of about 70 kg in body weight.

The invention also relates to pharmaceutical preparations which contain an effective amount, especially an effective amount for preventing or treating one of the aforementioned diseases, the crystalline forms A, B, C or the amorphous form of {6- [4- (4-ethyl-2 piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine of formula (I), together with pharmaceutically acceptable carriers which are suitable for topical administration; enteral, e.g. oral or rectal; or parenteral and may be inorganic or organic and solid or liquid. Especially tablets or gelatin capsules containing the active substance together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerin; and / or lubricants, for example silica, talc, stearic acid or salts thereof, typically magnesium or calcium stearate; and / or PEG, are used for oral administration. Tablets may also contain binders, for example magnesium aluminum silicate, starches, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; and, if desired, disintegrants, for example starches, agar, alginic acid or a salt thereof, typically sodium alginate; and / or effervescent or adsorbent mixtures, coloring agents, flavorings and sweetening agents. The pharmacologically active compounds of the present invention may further be used in the form of preparations for parenteral administration or infusion solutions. Said solutions are preferably isotonic aqueous solutions or suspensions, possibly being prepared prior to use, for example by lyophilized preparations containing the active substance either alone or together with a vehicle, for example, mannitol. Pharmaceutical substances may be sterilized and / or may contain excipients, for example preservatives, stabilizers, wetting agents and / or emulsifiers; solubilizers; salts for regulating osmotic pressure; and / or tampons. The present pharmaceutical preparations which, if desired, may contain additional pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, for example by conventional mixing, granulating, coating, dissolving or lyophilizing processes. , and contain from about 1 to 100%, especially from about 1% to about 20%, of the substance or substances.

The invention is further defined by reference to the following examples describing in detail the preparation of the compound and the compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention. The following examples are not intended to limit the scope of the invention as defined above or as claimed below.

EXAMPLES

Example 1 - Preparation of Crystalline Form A of (6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl1-7 / - / - pyrroir2,3-c / lpyrimidin-4-yl) - ((/ :?) -1-phenyl-ethyl) -amine using methanol and isopropanol

A reactor is charged with {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / pyrimidin-4-yl} - ((R) -1- crude phenylethylamine and methanol. The solution is cured at about 50 to 60 ° C. The solution is cooled to about 0 ° C. Before the precipitate is isolated by filtration. The precipitate is resuspended in isopropanol for at least 24 hours before being placed in a water bath at about 25 ° C. The solution is isolated by filtration to yield crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine.

Example 2 - Preparation of Crystalline Form B of (6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolf2,3-c / pyrimidin-4-yl) [1-] phenylethylamine using methanol

A reactor is charged with {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c /] pyrimidin-4-yl} - ((f Β) -1-crude phenylethylamine and methanol. The suspension is cured to about 50 to 60 ° C, then cooled to about 0 ° C before crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] - 7H-pyrrol [2,3-C 3 -pyrimidin-4-yl} - ((R) -1-phenylethyl) -amine is isolated by filtration.

Example 3 - Preparation of Crystalline Form B of {6- (4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl-7β- / pyrrolf2.3-c / lpyrimidin-4-yl) - ((? ) -1-phenyl-ethyl) -amine using methanol

A reactor is charged with {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2, S-Odpyrimidin-1 H (R) -I-phenyl-ethyl ) crude amine and ethanol. The suspension is cured to about 50 to 60 ° C, then cooled to about 0 ° C. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] - Pyrrolo [2,3-G (] pyrimidin-4-yl} - ((R) -1-phenylethyl) amine is isolated by filtration.

Example 4 - Preparation of C-1-4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl-7- [pyrrolo [2,3-c / lpyrimidin-4-yl) - ((F ) -1-phenyl-ethyl) -amine using methanol

A reactor is charged with {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c /] pyrimidin-4-yl} - ((/ Crude 1-phenyl-ethyl) -amine and methanol. The suspension is cured to about 50 to 60 ° C, then cooled to about 0 ° C before {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] - Pyrrolo [2, S-Odpyrimidin-1 H (H) -1-phenylethyl) amine is isolated by filtration.

Example 5 - Preparation of the amorphous form of (6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl-7H-pyrroir2,3-c / lpyrimidin-4-yl) - ((R)? 1-phenyl-ethyl) -amine

About 100 mg of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (] pyrimidin-4-yl} - ((R) -1 (phenyl-ethyl) -amine is suspended in about 5mL of a 1: 1 mixture of acetone / n-hexane (v / v) .The suspension is equilibrated for about 15 minutes in an ultrasonic bath in at room temperature and then filtered using a 0.2 pm cellulose filter Clear solution is allowed to evaporate under vacuum for about 15 to 20 minutes The solid residue is characterized by X-ray powder diffraction using a Bruker D8 Diffractrometer Advance with CuKa radiation (λ = 1.5406 Á) The X-ray powder pattern is shown in Figure 11 and characterized by a wide halo effect.

Claims (61)

1. A compound which is a crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} ((R) -1-phenylethyl) -amine. A compound according to claim 1 which shows X-ray Nadifration a peak at a 2 theta diffraction angle (Θ) of 4.4 ° ± 0.2 degrees (°). A compound according to claim 1 having an X-ray diffraction pattern, expressed in terms of 2Θ angles, including five or more peaks selected from the group consisting of about 4.4 °, -8.8 °, 9.1 °, 13.2 °, 14.2 °, 17.2 °, 18.2 °, 19.4 ° ± 0.2 °. A compound according to claim 1 having essentially the same X-ray diffraction pattern as shown in Figure 1. A compound according to claim 1, having an infrared absorption spectrum with absorption bands at about 695, -802, 836, 923, 934, 1013, 1095, 1146, 1165, 1207, 1229, 1292, 1300, 1310, -1348, 1358, 1507, 1546, 1595 and 3269 ± 2 cm -1. A composition comprising {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-αGpinmidin-4-yl} - ((f ') -1-phenyl- ethyl) -amine as a solid, wherein at least 80% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c (] pyrimidin-4-yl} - ((R) -1-phenylethyl) -amine is solid formacrystalline A. The composition of claim 6, wherein at least 90% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [ Solid 2,2-C-pyrimidin-1 H (H) -1-phenyl-ethyl) -amine is crystalline form A. A composition according to claim 6, wherein at least 95% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2, S Solid (pyrimidin-1 H (1H) -1-phenylethyl) amine is crystalline form A. A pharmaceutical composition comprising: (a) the compound as defined in claim 1; and (b) a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition according to claim 9, further comprising one or more pharmaceutically acceptable excipients. Pharmaceutical composition according to claim 9, which is a dosage form suitable for oral administration. The pharmaceutical composition of claim 11, wherein said dosage form is selected from a tablet, capsule or solution. 13. Use of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [213-cdpyrimidin-4-yl} - ((?)) Crystalline form A -1-phenyl-ethyl) -amine as defined in any one of claims 1 to 5 for the preparation of a pharmacological agent for the treatment of a tumor disease. 14. Process for the preparation of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-aG-pyrimidin-4-yl} - ((/ =?) -1-phenyl-ethyl) -amine comprising: (a) contacting {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-cdpyrimidin-2-one} (b) resuspending the precipitate with a second solvent to form a second precipitate; and (c) isolating the second precipitate. The process according to claim 14, wherein the solvent is methanol. The process according to claim 14, wherein the second solvent is isopropanol. The process according to claim 14, further comprising drying the isolated precipitate. 18. Compound which is crystalline form A of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c / lpyrirriidin-4-yl} - ( (R) -1-phenyl-ethyl) -amine produced by the process as defined in claim 14. 19. Compound which is crystalline form B of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c] pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine. A compound according to claim 19 which shows X-ray diffraction a peak at a 2Θ diffraction angle of 5.7 ° ± 0.2 °. A compound according to claim 19 having an X-ray diffraction pattern, expressed in terms of angles of 20, including three or more peaks selected from the group consisting of about 5.7 °, 6.9 °, 7.7 °, 11.7 °, 15.6 °, 18.5 ° ± 0.2 °. A compound according to claim 19 having essentially the same X-ray diffraction pattern as shown in Figure 5. 23. Composition comprising {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl (ethyl) -aminacomide as a solid, wherein at least 80% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-2-one Solid 4-yl} - ((R) -1-phenylethyl) -amine is formacristaline B. The composition of claim 23, wherein at least 90% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] Solid pyrimidin-4-yl} ((R) -1-phenyl-ethyl) -amine is crystalline form B. The composition of claim 23, wherein at least 95% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-G ( | pyrimidin-4-yl} - ((R) -1-phenylethyl) -amine is the crystalline form B. A pharmaceutical composition comprising: (a) the compound as defined in claim 19; and (b) a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition of claim 26, further comprising one or more pharmaceutically acceptable excipients. Pharmaceutical composition according to claim 26, which is a dosage form suitable for oral administration. The pharmaceutical composition of claim 28, wherein said dosage form is selected from a tablet, capsule or solution. 30. Use of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R)) crystalline form B -1-phenylethyl) -amine as defined in any one of claims 19 to 22 for the preparation of a pharmacological agent for the treatment of a tumor disease. 31. Process for the preparation of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-ptrrol [2,3-c-pyrimidin-4-yl} - (B) (R) -phenyl-ethyl) -amine comprising: (a) contact {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-cpyrimidin -4-yl} - ((R) -1-phenyl-ethyl) -amine in a solvent to form a precipitate; and (c) isolating the second precipitate. The process according to claim 31, wherein the solvent is methanol. The process of claim 31 further comprising drying the isolated precipitate. 34. Compound which is crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-a (] pyrimidin-4- yl} - ((R) -1-phenylethyl) amine. A compound according to claim 34 which shows X-ray diffraction a peak at a 2Ѳ diffraction angle of 7.5 ° ± 0.2 °. A compound according to claim 34 having an X-ray diffraction pattern, expressed in terms of 2Ѳ angles, which includes five or more peaks selected from the group consisting of about 5.7 °, 6.8 °. 7.5 °, 10.2 °, 11.6 °, 13.3 °, 15.2 °, 18.4 °, 20.8 ° ± 0.2 °. A compound according to claim 34, essentially having the same X-ray diffraction pattern as shown in Fig. 7. A compound according to claim 34, having an infrared absorption spectrum with absorption bands at about 701, 764, 842, 932, 1013, 1110, 1127, 1147, 1164, 1121, 1300, 1312, 1347, 1544, 1597, 3130 and 3429 cm -1 ± 2 cm -1. 39. Composition comprising {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c (] pyrimidin-4-yl} - ((/: ?) -1-phenyl-ethyl) -amine as a solid, wherein at least 80% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - Solid pyrrol [2,3-cdpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is formacristaline C. The composition of claim 39, wherein at least 90% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7Î ± -pyrrole. Solid cdpyrimidin-1 H-1 H -1-phenyl-ethyl-amine is crystalline form C. A composition according to claim 40, wherein at least 95% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol2. Solid N-1-phenyl-ethyl-amine is the crystalline form C. A pharmaceutical composition comprising: (a) the compound as defined in claim 34; and (b) a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition according to claim 42, further comprising one or more pharmaceutically acceptable excipients. The pharmaceutical composition of claim 42, which is a dosage form suitable for oral administration. The pharmaceutical composition of claim 44, wherein said dosage form is selected from a tablet, capsule or solution. 46. Use of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-c /] pyrimidin-4-yl} - crystalline form C ((R) -1-phenyl-ethyl) -amine as defined in any one of claims 34 to 38 for the preparation of a pharmacological agent for the treatment of a tumor disease. 47. Process for the preparation of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c-pyrimidin-4-yl} - (C) (R) -1-phenyl-ethyl) -amine comprising: (a) contacting {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-a-pyrimidin-2-one 4-yl} - ((R) -1-phenyl-ethyl) -amine in a solvent to form a precipitate; and (b) isolating the precipitate. A process according to claim 47, wherein the solvent is methanol. A process according to claim 47 further comprising drying the isolated precipitate. 50. A compound which is the crystalline form C of {6- [4- (4-ethyl-piperazin-1-ylmethyl-phenyl-1 H -pyrrole] -S-c / pyrimidin-4-yl) -6- (R). (phenyl-ethyl) -amine produced by the process as defined in claim 47. 51. Compound which is {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7- - / - pyrrol [2,3-c-pyrimidin-4-yl} - ((R) - Amorphous 1-phenyl) -amine. A compound according to claim 51, essentially having the same X-ray diffraction pattern as shown in Fig. 11. 53. Composition comprising {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-c (] pyrimidin-4-yl} - ((R) -1 -phenyl-ethyl) -amine as a solid, wherein at least 80% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2, Solid 3-c (lpyrimidin-4-yl} - ((R) -1-phenylethyl) amine is amorphous. A composition according to claim 53, wherein at least 90% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol-C / pyrimidin Solid N-phenyl-1-phenyl-ethyl-amine is amorphous. The composition of claim 53, wherein at least 95% by weight of said {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3 Solid -cdpyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine is amorphous. The composition of claim 53, wherein essentially all {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7 / - / - pyrrol [2,3-cpyrimidin Solid -4-yl} - ((flu) -1-phenylethyl) -amine is amorphous. A pharmaceutical composition comprising: (a) the compound as defined in claim 51; and (b) a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition of claim 57, further comprising one or more pharmaceutically acceptable excipients. Pharmaceutical composition according to claim 57, is in a dosage form suitable for oral administration. A pharmaceutical composition according to claim 51, wherein the dosage form is selected from a tablet, capsule or solution. 61. Use of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrol [2,3-d] pyrimidin-4-yl} - ((R) -1-phenyl Amorphous ethyl) -amine as defined in any one of claims 51 to 60 for the preparation of a pharmacological agent for the treatment of a tumor disease.