JP2009523768A - Solid forms of pyrrolopyrimidine derivatives and their use as antitumor agents - Google Patents

Abstract

  The present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl -Ethyl) -amine, a new crystalline form, {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( A process for the preparation of these crystalline forms of (R) -1-phenyl-ethyl) -amine, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d ] Compositions containing these crystalline forms of pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine, and {6- [4- (4-ethyl-piperazin-1-ylmethyl)- These crystalline forms of phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine Relates to the use in the diagnostic or therapeutic treatment of warm-blooded animals, especially humans.

Description

  The present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl -Ethyl) -amine, a new crystalline form, {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( R) -1-Phenyl-ethyl) -amines in a process for preparing these crystal forms, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine, and their crystalline forms of {6- [4- (4-ethyl-piperazine- 1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine For use in the diagnostic or therapeutic treatment of warm-blooded animals, especially humans.

  The present invention relates to amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)- 1-phenyl-ethyl) -amine, the amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- Process for the preparation of ((R) -1-phenyl-ethyl) -amine, the amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d ] Pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine and the amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] ] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine warm-blooded animals, especially It relates to use in human diagnostics or therapeutic treatments.

BACKGROUND OF THE INVENTION {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 as a drug -Phenyl-ethyl) -amine is a dual EGF / VEGF inhibitor and exhibits anti-tumor behavior. Generally, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl ) -Amine production methods are known in the art. However, it is also known that different crystal forms of the same drug substance can make substantial differences in certain pharmaceutically important properties. Thus, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl There is still a need for new solid forms and new processes for the preparation of) -amines.

SUMMARY OF THE INVENTION According to one aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- Crystalline form A of ((R) -1-phenyl-ethyl) -amine is provided. Preferably, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- The crystalline form A of ethyl) -amine is 4.4, 8.8, 9.1, 13.2, 13.2, 17.2, 18.2 as described in FIG. It has an X-ray diffraction pattern having a peak at a diffraction angle of 2 theta (θ) of 19.4 ° ± 0.2 °.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( R) -1-phenyl-ethyl) -amine in solid form, wherein the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3 -D] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is at least 80% by weight, as shown in FIG. 1, 4.4 °, 8.8 °, 9.1 °. , 13.2 °, 14.2 °, 17.2 °, 18.2 °, 19.4 ° ± 0.2 °, with an X-ray diffraction pattern having peaks at diffraction angles 2θ. . Various aspects and variations are provided.

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

According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( A process for the preparation of crystalline form A of R) -1-phenyl-ethyl) -amine comprising:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine and an alcohol solvent are contacted to form a precipitate;
(b) resuspending the precipitate in a second alcohol solvent;
(c) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- A method is provided comprising isolating crystalline form A of ethyl) -amine.
Various aspects and variations are provided.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( The crystalline form A of R) -1-phenyl-ethyl) -amine is converted to {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine- From the crystalline form C of 4-yl}-((R) -1-phenyl-ethyl) -amine, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is melted in an inert gas or solvent, whereby {6- [ 4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1- Enyl-ethyl) -amine and / or crystalline form E {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -((R) -1-phenyl-ethyl) -amine was formed and the mixture was then cooled to give {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H- A process is provided that is prepared by forming crystalline form A of pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine.

According to one aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R ) -1-Phenyl-ethyl) -amine crystal form B is provided. Preferably, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- The crystalline form B of ethyl) -amine is 5.7 °, 6.9 °, 7.7 °, 11.7 °, 15.6 °, 18.5 ° ± 0.2, as described in FIG. It has an X-ray diffraction pattern having a peak at a diffraction angle 2θ of °.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( R) -1-phenyl-ethyl) -amine in solid form, wherein the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3 -D] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is at least 80% by weight, as described in FIG. 5, 5.7 °, 6.9 °, 7.7 A composition is provided that is its crystalline form B having an X-ray diffraction pattern with peaks at diffraction angles 2θ of °, 11.7 °, 15.6 °, 18.5 ° ± 0.2 °. Various aspects and variations are provided.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( There is provided a pharmaceutical composition comprising crystalline form B of R) -1-phenyl-ethyl) -amine and a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.

According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( A process for the preparation of crystalline form B of R) -1-phenyl-ethyl) -amine comprising:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine in contact with an alcohol solvent to form a precipitate; and
(c) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- A method is provided comprising isolating crystalline form B of ethyl) -amine.
Various aspects and variations are provided.

According to one aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R Crystalline form C of) -1-phenyl-ethyl) -amine is provided. Preferably, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- The crystalline form C of ethyl) -amine is 5.7 °, 6.8 °, 7.5 °, 10.2 °, 11.6 °, 13.3 °, 15.2 as described in FIG. It has peaks at diffraction angles 2θ of °, 18.4 °, 20.8 ° ± 0.2 °.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( R) -1-phenyl-ethyl) -amine in solid form, wherein the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3 -D] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is at least 80% by weight, as described in FIG. 7, 5.7 °, 6.8 °, 7.5 Its crystal form C has peaks at diffraction angles 2θ of °, 10.2 °, 11.6 °, 13.3 °, 15.2 °, 18.4 °, 20.8 ° ± 0.2 °. A composition is provided. Various aspects and variations are provided.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( There is provided a pharmaceutical composition comprising crystalline form C of R) -1-phenyl-ethyl) -amine and a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.

According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( A process for the preparation of crystalline form C of R) -1-phenyl-ethyl) -amine, comprising:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine in contact with an alcohol solvent to form a precipitate; and
(b) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- A method is provided comprising isolating crystalline form C of ethyl) -amine.
Various aspects and variations are provided.

  According to yet another aspect, the present invention relates to {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-(( (6) Amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [, comprising spray drying a solution containing R) -1-phenyl-ethyl) -amine. A process for the preparation of 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is provided.

  Amorphous {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} prepared by the method described herein Also provided are pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of-((R) -1-phenyl-ethyl) -amine and one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R 2 shows an X-ray powder diffraction diagram of crystalline form A of) -1-phenyl-ethyl) -amine.

  FIG. 2 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl 2 is a characteristic infrared spectrum of crystalline form A of (ethyl) -amine.

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

  FIG. 4 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl Fig. 3 shows the Raman spectrum of crystalline form A of -ethyl) -amine.

  FIG. 5 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl -X-ray powder diffraction diagram of crystalline form B of -ethyl) -amine.

  FIG. 6 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl. -DS) of crystalline form B of -ethyl) -amine.

  FIG. 7 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl -X-ray powder diffraction diagram of crystalline form C of -ethyl) -amine.

  FIG. 8 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl 2 is a characteristic infrared spectrum of crystalline form C of (ethyl) -amine.

  FIG. 9 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl -DS) of crystalline form C of ethyl) -amine.

  FIG. 10 shows {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl. 1 shows the Raman spectrum of crystalline form C of (ethyl) -amine.

  FIG. 11 shows amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)- 1 shows an X-ray powder diffraction diagram of 1-phenyl-ethyl) -amine.

DETAILED DESCRIPTION OF THE INVENTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

For purposes of the present invention, the following terms are defined below.
Here, it is named “Crystal Form A” and hereinafter {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} The crystalline compound referred to as crystalline form A of-((R) -1-phenyl-ethyl) -amine is {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is a novel crystalline form. It is characterized via X-ray powder diffraction, DSC, Raman spectrum and / or infrared spectroscopy. Further details will be described later.

  Here, it is named “Crystal Form B” and hereinafter {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} The crystalline compound referred to as crystalline form B of-((R) -1-phenyl-ethyl) -amine is {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is a novel crystalline form. It is characterized via X-ray powder diffraction and / or DSC. Further details will be described later.

  Here, it is named “Crystal Form C” and hereinafter {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} The crystalline compound referred to as crystalline form C of-((R) -1-phenyl-ethyl) -amine is {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is a novel crystalline form. It is characterized via X-ray powder diffraction, DSC, Raman spectrum and / or infrared spectroscopy. Further details will be described later.

“Pharmaceutically acceptable” means generally useful for the manufacture of pharmaceutical compositions that are non-toxic and not biologically undesirable, and / or veterinary use and / or Including those that are acceptable for human pharmaceutical use.
A “poor solvent” is a solvent that reduces the solubility of a substance when added to a solution of the substance present.

  The term “composition” includes, but is not limited to, powders, solutions, suspensions, gels, ointments, emulsions and / or mixtures thereof. The term composition is intended to encompass products that contain a particular component in a particular amount, as well as products that are produced, directly or indirectly, by a combination of a particular component in a particular amount. A “composition” may comprise a single crystal form or a mixture of crystal forms of the active ingredient. A “compound” is a chemical substance that contains molecules of the same chemical structure.

  The term “pharmaceutical composition” refers to an active ingredient (s), a product comprising a pharmaceutically acceptable excipient that constitutes a carrier, and a combination or combination of two or more ingredients, either directly or indirectly. It is intended to encompass products that are brought about by crystallization or aggregation, or by the dissociation of one or more components, or by other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass all compositions made by admixing the active ingredient, additional active ingredient (s) and pharmaceutically acceptable excipients.

  The term “excipient” means a component of a pharmaceutical product that is not an active ingredient, such as bulking agents, diluents and carriers. Excipients useful in the manufacture of pharmaceutical compositions are preferably generally safe, non-toxic, biologically or otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and more than one such excipient.

  “Therapeutically effective amount” means the amount of a compound that, when administered for the treatment or prevention of a disease, is sufficient to effect such treatment or prevention of the disease. “Therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.

  When referring to a chemical reaction, the terms “treatment”, “contact” and “reaction” are used interchangeably herein to indicate two or more reagents, and / or suitable conditions for producing the desired product. It means to add or mix under. The reaction to produce the product shown and / or desired is not necessarily directly derived from the combination of the two reagents initially added, i.e. produced in a mixture and finally shown and / or desired product. It should be recognized that there may be one or more intermediates leading to the formation of

  As used herein, the term “substantially free” for a composition means that a material that is free of the composition 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 in particular that at least 90%, preferably at least 95% by weight of the crystals of the acid addition salt of formula (I) are present in the crystalline form according to the invention. .

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

  The present invention especially relates to a specific crystalline form, preferably {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2] of the compound of formula (I) above. , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine crystal form A; {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine crystal form B and {6- [4- (4-ethyl-piperazine-1) -Ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine.

  Different solids of the same medicament can differ in properties, including features that have functional relevance for their use as pharmaceutical substances, and have considerable differences in pharmaceutically important properties such as dissolution rate and bioavailability. obtain. Similarly, different crystalline forms may have different processing characteristics such as hygroscopicity, flowability, etc. that may affect the stability of commercial products as active pharmaceuticals.

  {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Table 1 summarizes the X-ray diffraction pattern described in FIG. The X-ray powder diffraction pattern was measured with a Scintag INC X 1 using a CuK alpha source (λ = 1.5406Å).

  It should be noted that the observed 2θ angle or d-spacing value is expected to vary slightly based on the particular diffractometer, analyst and sample preparation technique used. Larger changes are predicted for the relative peak intensity. The identification of the exact crystal form of the compound should be based on the 2θ angle observed first, with less importance on the relative peak intensity.

  There are some errors in each of the 2θ angle assignment values reported here. Preferred variant, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- The assigned error limit for crystalline form A of ethyl) -amine is about ± 0.2 ° for each peak assigned value.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Amine crystal form A can also be characterized by infrared spectroscopy. Crystal form A exhibits a characteristic pattern in infrared (IR) spectroscopy as described in FIG. IR spectroscopy was measured with Bruker IFS-55. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystal form A of amine is about 695, 802, 836, 923, 934, 1013, 1095, 1146, 1165, 1207, 1229, 1292, 1300, 1310, 1348, 1358, 1507, 1546, 1595 and It has a characteristic absorption at 3269 cm ⁻¹ that distinguishes it from other polymorphisms. There is some margin of error for each characteristic absorption reported here. Margin of error allocated in the characteristic absorption is approximately 2 cm ^-1 in the range of 1900-800cm ^-1.

  {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Amine crystal form A can also be characterized by differential scanning calorimetry (DSC). Crystal form A shows a characteristic pattern in DSC analysis as shown in FIG. DSC analysis was measured with a Perkin Elmer Pyris 1. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The amine crystal form A has a characteristic melting peak starting at 240 ° C. or higher, preferably 250 ° C. or higher. Melting is also accompanied by degradation. Thus, the starting temperature will vary depending on the heating rate and the equipment conditions used for the analysis.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystalline form A of the amine can also be characterized by a Raman spectrum. Crystal form A shows a characteristic pattern in the Raman spectrum as shown in FIG. Raman spectral analysis was measured with a Bruker RFS 100 instrument. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystalline form A of the amine is found in Raman spectral analysis at about 158, 183, 920, 935, 1002, 1159, 1178, 1308, 1405, 1422, 1446, 1496, 1544, 1618 and 3060 cm ⁻¹ with other polymorphs. It has a characteristic absorption that can distinguish it. Each of the characteristic absorptions reported herein, there are some of the margin of error of ± 3 cm ^-1 in the range of 2000-500cm ^-1.

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

  The present invention also provides solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 -Phenyl-ethyl) -amine comprising a solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ At least 80% of the total weight of 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is its crystalline form A. A preferred form of this composition is {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3] suitable for use as an active ingredient in pharmaceutical product formulations. -D] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine powder. The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 in the composition -Phenyl-ethyl) -amine residue, ie {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- 20% or less of the total weight of ((R) -1-phenyl-ethyl) -amine is, for example, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. In one specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] in the composition. At least 90% of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl]-, based on the total weight of pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine Crystalline form A of 7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is included. In another specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in the composition. Contain at least 95% of crystalline Form A, based on the total weight of -4-yl}-((R) -1-phenyl-ethyl) -amine.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The process for preparing amine crystal form A is:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine and an alcohol solvent are contacted to form a precipitate;
(b) resuspending the precipitate in a second alcohol solvent;
(c) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Isolating crystalline form A of ethyl) -amine.
Various aspects and variations are provided.

  In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1- Phenyl-ethyl) -amine is contacted with methanol at high temperature so that no visible crystals remain. Place the solution in an ice bath and stir. Collect the precipitate on a filter. The precipitate is then resuspended in isopropanol, then the solution is filtered and dried to give {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d The crystal form A of pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is prepared.

  The above conditions for the selective production of individual crystal forms are not critical. In general, it is possible to vary parameters such as, for example, the weight ratio of the compound of formula (I) to solvent and antisolvent. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The X-ray diffraction pattern set forth in FIG. 5 for amine crystal form B is summarized in Table 4. The X-ray powder diffraction pattern was measured with a Scintag INC X 1 using a CuK alpha source (λ = 1.5406Å).

  It should be noted that the observed 2θ angle or d-spacing value is expected to vary slightly based on the particular diffractometer, analyst and sample preparation technique used. Larger changes are predicted for the relative peak intensity. The identification of the exact crystal form of the compound should be based on the 2θ angle observed first, with less importance on the relative peak intensity.

  There are some errors in each of the 2θ angle assignment values reported here. Preferred variant, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- The assigned error limit for crystalline form B of ethyl) -amine is about ± 0.02 for each peak assigned value.

  {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The amine crystal form B can also be characterized by DSC. Crystal form B shows a characteristic peak in DSC analysis as shown in FIG. DSC analysis was measured with a Perkin Elmer Pyris 1. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Amine crystal form B exhibits a characteristic endothermic transition at 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 and / or spectroscopic properties are {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} It may be the basis for the characterization of the crystalline form of-((R) -1-phenyl-ethyl) -amine.

  The present invention also provides solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 -Phenyl-ethyl) -amine comprising a solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ At least 80% of the total weight of 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is its crystalline form B. A preferred form of this composition is {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3] suitable for use as an active ingredient in pharmaceutical product formulations. -D] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine powder. The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 in the composition -Phenyl-ethyl) -amine residue, ie {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- 20% or less of the total weight of ((R) -1-phenyl-ethyl) -amine is, for example, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. In one specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] in the composition. At least 90% of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl]-, based on the total weight of pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine Includes crystal form B of 7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. In another specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in the composition. Contain at least 95% of crystalline form B with respect to the total weight of -4-yl}-((R) -1-phenyl-ethyl) -amine.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The process for producing amine crystal form B is:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine in contact with an alcohol solvent to form a precipitate; and
(c) is replaced with {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl -Isolating crystalline form B of -ethyl) -amine.
Various aspects and variations are provided.

  In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1- Phenyl-ethyl) -amine is contacted with methanol at high temperature so that no visible crystals remain. Place the solution in an ice bath and stir. The precipitate was collected on a filter and dried to give {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- Crystalline form B of ((R) -1-phenyl-ethyl) -amine is prepared.

  In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1- Phenyl-ethyl) -amine is contacted with ethanol at high temperature so that no visible crystals remain. Place the solution in an ice bath and stir. The precipitate was collected on a filter and dried to give {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- Crystalline form B of ((R) -1-phenyl-ethyl) -amine is prepared.

  {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The X-ray diffraction pattern set forth in FIG. 7 for amine crystal form C is summarized in Table 5. The X-ray powder diffraction pattern was measured with a Scintag INC X 1 using a CuK alpha source (λ = 1.5406Å).

  It should be noted that the observed 2θ angle or d-spacing value is expected to vary slightly based on the particular diffractometer, analyst and sample preparation technique used. Larger changes are predicted for the relative peak intensity. The identification of the exact crystal form of the compound should be based on the 2θ angle observed first, with less importance on the relative peak intensity.

  There are some errors in each of the 2θ angle assignment values reported here. Preferred variant, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- The assigned error limit for crystalline form C of ethyl) -amine is about ± 0.02 for each peak assigned value.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystalline form C of the amine can also be characterized by infrared spectroscopy. Crystal form C shows a characteristic absorption pattern in IR spectroscopy as described in FIG. IR spectroscopy was measured with Bruker IFS-55. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystal form C of the amine is about 701, 764, 842, 932, 1013, 1110, 1127, 1147, 1164, 1121, 1300, 1312, 1347, 1544, 1597, 3130 and 3429 cm ⁻¹ in IR spectroscopy. It has a characteristic absorption that can distinguish it from other polymorphisms. There is some margin of error for each characteristic absorption reported here. Margin of error allocated in the characteristic absorption is approximately 2 cm ^-1 in the range of 1900-800cm ^-1.

  {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Amine crystal form C can also be characterized by DSC. Crystal form C shows a characteristic peak in DSC analysis as shown in FIG. DSC analysis was measured with a Perkin Elmer Pyris 1. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Crystalline form C of amine exhibits a characteristic endothermic transition at about 99 ° C, followed by an exothermic event at about 139 ° C, and an endothermic peak at about 253 ° C.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystalline form C of the amine can also be characterized by a Raman spectrum. Crystal form C shows a characteristic pattern in the Raman spectrum as shown in FIG. Raman spectral analysis was measured with a Bruker RFS 100 instrument. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The crystalline form C of the amine is about 179, 254, 776, 803, 844, 933, 1000, 1024, 1166, 1309, 1405, 1450, 1497, 1543, 1570, 1618 and 3059 cm ⁻¹ in Raman spectral analysis, etc. It has a characteristic absorption that can distinguish it from the polymorphism of. Each of the characteristic absorptions reported herein, there are some of the margin of error of ± 3 cm ^-1 in the range 200-500cm ^-1.

  One or more of the physical and / or spectroscopic properties are {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} It may be the basis for the characterization of the crystalline form of-((R) -1-phenyl-ethyl) -amine.

  The present invention also provides solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 -Phenyl-ethyl) -amine comprising a solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ At least 80% of the total weight of 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is its crystalline form C. A preferred form of this composition is {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3] suitable for use as an active ingredient in pharmaceutical product formulations. -D] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine powder. The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 in the composition -Phenyl-ethyl) -amine residue, ie {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- 20% or less of the total weight of ((R) -1-phenyl-ethyl) -amine is, for example, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. In one specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] in the composition. At least 90% of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl]-, based on the total weight of pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine Crystalline form C of 7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is included. In another specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in the composition. It contains at least 95% of crystalline form C, based on the total weight of -4-yl}-((R) -1-phenyl-ethyl) -amine.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- The process for preparing the amine crystal form C is:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine in contact with an alcohol solvent to form a precipitate; and
(b) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Isolating crystalline form C of ethyl) -amine.

  In one embodiment, {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1- Dissolve phenyl-ethyl) -amine in methanol at high temperature; cool the solution to about 0 ° C .; and {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine crystal form C. This method is very reproducible and the resulting crystal product has good filtration properties.

  The above conditions for the selective production of individual crystal forms are not critical. In general, it is possible to vary parameters such as, for example, the weight ratio of the compound of formula (I) to solvent and antisolvent.

  FIG. 11 shows amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] measured with a Scintag INC X 1 using a CuK alpha source (λ = 1.5406Å). FIG. 4 shows an X-ray powder diffractogram of -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. As is clear from FIG. 11, the powder obtained by the present inventors is in an amorphous form.

  The present invention also provides solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 -Phenyl-ethyl) -amine comprising a solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [ At least 80% of the total weight of 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is in its amorphous form. A preferred form of this composition is {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,2], suitable for use as an active ingredient in solid pharmaceutical product formulations. 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine powder. The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 in the composition -Phenyl-ethyl) -amine residue, ie {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- 20% or less of the total weight of ((R) -1-phenyl-ethyl) -amine is, for example, the crystalline form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H— It may be pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. In one specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] in the composition. At least 90% of amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl)-, based on the total weight of pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine Phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. In another specific embodiment, the composition comprises the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in the composition. It contains at least 95% amorphous form with respect to the total weight of -4-yl}-((R) -1-phenyl-ethyl) -amine. In yet another embodiment, the composition comprises {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine-4 other than its amorphous form. Substantially free of all forms of -yl}-((R) -1-phenyl-ethyl) -amine.

  Crystalline Form A, B, C or Amorphous {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl of the present invention Also provided is a pharmaceutical composition comprising}-((R) -1-phenyl-ethyl) -amine and a pharmaceutically acceptable carrier. In addition to the active compound, the pharmaceutical composition does not have normal pharmaceutical activity, but has various useful properties that can be, for example, stability, sterility, increased bioavailability, and simple pharmaceutical composition formulation Including one or more pharmaceutically acceptable carriers, also known as excipients. These carriers are pharmaceutically acceptable, meaning that they are not dangerous to humans or animals when properly ingested and are compatible with the other ingredients in a given formulation. The carrier can be a solid, semi-solid, or liquid and can be formulated in large quantities with the compound, but ultimately is a unit dosage formulation, ie, physically until it contains a certain amount of active ingredient such as a tablet or capsule. To separate. The pharmaceutical composition may contain one or more active pharmaceutical compounds in addition to the compound of the present invention.

  The pharmaceutical composition of the invention comprising the crystalline form of the invention may be in the form of a suspension, solution, elixir, aerosol or solid dosage form.

  The pharmaceutical composition contemplates various formulations suitable for various modes of administration, including inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), implants and transdermal administration. . The most suitable route of administration in some cases will depend on the condition of the subject, the duration of treatment desired, the nature and severity of the condition being treated, and the particular formulation used. The formulations are in large quantities or dosage forms and can be prepared by methods known in the art for certain formulations.

  The amount of active ingredient contained in the unit dosage form depends on the type of formulation in which the active ingredient is present. The pharmaceutical compositions are generally about 0.1% to about 99%, preferably about 1% to 50% by weight of active ingredient for oral administration, and about 0.2% by weight for parenteral administration. To about 20% by weight of the active ingredient.

  Formulations suitable for oral administration include capsules (hard and soft), cachets, lozenges, syrups, suppositories and tablets, each with a predetermined amount of the compound as a powder or granule, in solution in an aqueous or non-aqueous liquid or As a suspension; or as an oil-in-water or water-in-oil emulsion. Such formulations can be prepared by any suitable formulation method including the step of bringing into association the active compound with one or more suitable carriers. The amount of active ingredient per unit dose of the solid formulation is {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl. The formulation of}-((R) -1-phenyl-ethyl) -amine can be as described in the prior art.

  In other aspects, the present invention also provides methods of treatment using the compounds and pharmaceutical compositions of the present invention. A subject means a human or animal, preferably a human. Animals contemplated by the present invention include all animals that can be safely treated with the compounds of the present invention. Most notably, crystalline forms A, B, C or amorphous forms of the present invention {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] Pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine exhibits high antiproliferative and antitumor activity as a result of dual EGF and VEGF inhibition, which is very useful for cancer treatment. Can be useful. Furthermore, their highly selective and potent dual EGF and VEGF inhibition can lead to superior clinical outcomes for patients, ie, delay or suppression of disease progression, with equally tolerated regimens. Possible applications include various solid tumors and more specifically, for example, breast cancer, colon cancer, ovarian cancer and leukemia. In addition, various other applications in which dual EGF and VEGF activity can affect can be effectively treated with these compositions, and are one of the major problems in currently used cancer chemotherapy and in general inflammatory diseases Includes some multi-drug resistance (MDR).

  The present invention provides, inter alia, for the non-vaginal treatment of the disease or in the manufacture of a medicament for their treatment, the crystalline forms A, B, C or amorphous forms of {6- [4- (4 -Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine.

  The present invention also provides a method of treating a warm-blooded animal having the disease, especially a tumor disease, in an effective amount against the intended disease, in particular an antiproliferative and especially tumor-inhibiting effective amount of crystalline form A, B, C or amorphous form of {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)- It also relates to a method comprising administering 1-phenyl-ethyl) -amine to an animal in need of such treatment. The invention further relates to the treatment of various solid tumors and more particularly, for example, breast cancer, colon cancer, ovarian cancer and leukemia, for the above inhibition or for use in the treatment of humans or animals. Crystalline Form A, B, C or Amorphous {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2, It relates to the use of 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. Depending on the species, age, individual condition, mode of administration and the clinical increase concerned, an effective amount, for example a daily dose of about 1-2500 mg, preferably 1-1000 mg, especially 5-500 mg, of about 70 kg body weight Administer to warm-blooded animals.

  The present invention relates to an effective amount of crystalline form A, B, C or amorphous form of formula (I) {6- [4- (4-ethyl-piperazine-), especially for the prevention or treatment of the disease. 1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine; topical; enteral, eg oral or rectal; Or a pharmaceutical formulation suitable for specific enteral administration and comprising a pharmaceutically acceptable carrier that can be inorganic or organic, solid or liquid. In particular, the active substance may be a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerine; and / or a lubricant such as silica, talc, stearic acid or salts thereof, typically magnesium stearate or Tablets or gelatin capsules containing calcium stearate; and / or PEG are used for oral administration. Tablets may likewise be combined with binders such as aluminum silicate magnesium, starch, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; and, if desired, disintegrants, For example, starch, agar, alginic acid or a salt thereof, typically sodium alginate; and / or an effervescent mixture, or adsorbents, colorants, flavors and sweeteners may be included. The pharmacologically active compounds according to the invention can furthermore be used in the form of parenteral preparations or infusions. Such solutions are preferably isotonic aqueous solutions or suspensions, which should be prepared before use, for example in the case of lyophilized preparations which contain the active substance alone or together with a carrier, for example mannitol. Is possible. The pharmaceutical substance may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting agents and / or emulsifiers; solubilizers; osmotic pressure adjusting salts; and / or buffers. Pharmaceutical formulations which can contain further pharmacologically active substances such as antibiotics if desired are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, About 1-100%, especially about 1% to about 20% of one or more active substances.

  The invention is further defined with reference to the following examples describing details for the preparation of the compounds and compositions of the invention and their utility. It will be apparent to those skilled in the art that many modifications, both in materials and methods, can be made without departing from the objects and advantages of the invention. The following examples are not intended to limit the scope of the invention as defined above and in the appended claims.

Example 1 {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R ) Preparation of crystalline form A of 1-phenyl-ethyl) -amine Crude {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d in a reaction vessel ] Add pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine and methanol. The solution is aged at about 50-60 ° C. The solution is cooled to about 0 ° C., after which the precipitate is isolated by filtration. The precipitate is also resuspended in isopropanol for at least 24 hours and then placed in a water bath at about 25 ° C. The solution was isolated by filtration and {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)- Crystalline form A of 1-phenyl-ethyl) -amine is prepared.

Example 2 {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)-using methanol Preparation of crystalline form B of 1-phenyl-ethyl) -amine Crude {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in a reaction vessel Charge -4-yl}-((R) -1-phenyl-ethyl) -amine and methanol. The suspension is aged at about 50-60 ° C. and then cooled to about 0 ° C., after which {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3 The crystalline form B of -d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is isolated by filtration.

Example 3 {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)-using methanol Preparation of crystalline form B of 1-phenyl-ethyl) -amine Crude {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in a reaction vessel Add -4-yl}-((R) -1-phenyl-ethyl) -amine and ethanol. The suspension is aged at about 50-60 ° C. and then cooled to about 0 ° C., after which {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3 The crystalline form B of -d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is isolated by filtration.

Example 4 {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R)-using methanol Preparation of crystalline form C of 1-phenyl-ethyl) -amine Crude {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine in a reaction vessel Charge -4-yl}-((R) -1-phenyl-ethyl) -amine and methanol. The suspension is aged at about 50-60 ° C. and then cooled to about 0 ° C., after which {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3 The crystalline form C of -d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine is isolated by filtration.

Example 5 Amorphous {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 -Phenyl-ethyl) -amine preparation About 100 mg of {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}- ((R) -1-phenyl-ethyl) -amine is suspended in about 5 mL of acetone / n-hexane (v / v) 1: 1 mixture. The suspension is allowed to equilibrate for about 15 minutes in an ultrasonic bath at room temperature and then filtered using a 0.2 μm cellulose filter. The clear solution is evaporated under vacuum for about 15-20 minutes. The solid residue is characterized by X-ray powder diffraction using a Bruker D8 Advance diffractometer using CuKα irradiation (λ = 1.5406 Å). The X-ray powder pattern is shown in FIG. 11 and is characterized by a wide halo effect.

{6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows an X-ray powder diffraction diagram of amine crystal form A. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 is a characteristic infrared spectrum of crystal form A of amine. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows the DSC of amine crystal form A. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows the Raman spectrum of amine crystal form A. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows an X-ray powder diffraction diagram of amine crystal form B. FIG. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows a DSC of amine crystal Form B. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows an X-ray powder diffraction diagram of amine crystal form C. FIG. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 is a characteristic infrared spectrum of crystal form C of amine. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows a DSC of crystal form C of amine. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- 2 shows the Raman spectrum of crystal form C of amine. Amorphous {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- 2 shows an X-ray powder diffraction diagram of (ethyl) -amine.

Claims (61)

  {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- A compound which is crystal form A of an amine.   The compound according to claim 1, which exhibits a peak at a diffraction angle of 2 theta (θ) of 4.4 ° ± 0.2 ° (°) in X-ray diffraction.   Expressed in terms of 2θ angle, approximately 4.4 °, 8.8 °, 9.1 °, 13.2 °, 14.2 °, 17.2 °, 18.2 °, 19.4 ° ± 0.2 2. The compound of claim 1 having an X-ray diffraction pattern comprising 5 or more peaks selected from the group consisting of [deg.].   The compound of claim 1 having substantially the same X-ray diffraction pattern as shown in FIG. 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 The compound of claim 1 having an infrared absorption spectrum.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Containing the amine as a solid, where the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-( A composition wherein at least 80% by weight of (R) -1-phenyl-ethyl) -amine is in crystalline form A.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl A composition according to claim 6, wherein at least 90% by weight of the) -amine is in crystalline form A.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl A composition according to claim 6, wherein at least 95% by weight of the) -amine is in crystalline form A. (a) the compound of claim 1; and
(b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.   10. The pharmaceutical composition according to claim 9, further comprising one or more pharmaceutically acceptable excipients.   The pharmaceutical composition according to claim 9, which is a dosage form suitable for oral administration.   12. The pharmaceutical composition according to claim 11, wherein the dosage form is selected from tablets, capsules or solutions.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,6] for the manufacture of a medicament for the treatment of tumor diseases. Use of crystalline form A of 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- A process for the preparation of amine crystal form A comprising:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine is contacted with a solvent to form a precipitate;
(b) resuspending the precipitate in a second solvent to form a second precipitate; and
(c) isolating the second precipitate.   15. A process according to claim 14, wherein the solvent is methanol.   15. A method according to claim 14, wherein the second solvent is isopropanol.   15. The method of claim 14, further comprising drying the isolated precipitate.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-produced by the method of claim 14 A compound which is crystal form A of ((R) -1-phenyl-ethyl) -amine.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- A compound which is crystal form B of an amine.   The compound according to claim 19, which shows a peak at a diffraction angle 2θ of 5.7 ° ± 0.2 ° in X-ray diffraction.   Three selected from the group consisting of approximately 5.7 °, 6.9 °, 7.7 °, 11.7 °, 15.6 °, 18.5 ° ± 0.2 ° expressed in terms of 2θ angle. 20. A compound according to claim 19 having an X-ray diffraction pattern comprising or more peaks.   20. A compound according to claim 19 having substantially the same X-ray diffraction pattern as shown in FIG.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Containing the amine as a solid, where the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-( A composition wherein at least 80% by weight of (R) -1-phenyl-ethyl) -amine is crystalline Form B.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl 24) The composition of claim 23, wherein at least 90% by weight of the amine is in crystalline form B.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl 24. The compound of claim 23, wherein at least 95% by weight of the) -amine is in crystalline form B. (a) a compound according to claim 19; and
(b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.   27. The pharmaceutical composition according to claim 26, further comprising one or more pharmaceutically acceptable excipients.   27. A pharmaceutical composition according to claim 26, which is in a dosage form suitable for oral administration.   29. A pharmaceutical composition according to claim 28, wherein the dosage form is selected from tablets, capsules or solutions.   23. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,2] according to any of claims 19 to 22 for the manufacture of a medicament for the treatment of tumor diseases. Use of crystalline form B of 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- A process for the preparation of amine crystal form B comprising:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine is contacted with a solvent to form a precipitate; and
(c) isolating the second precipitate.   32. The method of claim 31, wherein the solvent is methanol.   32. The method of claim 31, further comprising drying the isolated precipitate.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- A compound which is the crystalline form C of the amine.   The compound according to claim 34, which shows a peak at a diffraction angle 2θ of 7.5 ° ± 0.2 ° in X-ray diffraction.   About 5.7 °, 6.8 °, 7.5 °, 10.2 °, 11.6 °, 13.3 °, 15.2 °, 18.4 °, 20.8 ° ± 0.2 ° 35. The compound of claim 34, having an X-ray diffraction pattern comprising 5 or more peaks selected from the group consisting of:   35. The compound of claim 34, having substantially the same X-ray diffraction pattern as shown in FIG. Infrared absorption spectra 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. 35. The compound of claim 34 having   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Containing the amine as a solid, where the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-( A composition wherein at least 80% by weight of (R) -1-phenyl-ethyl) -amine is in crystalline form C.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl 40. The composition of claim 39, wherein at least 90% by weight of the amine is crystalline form C.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl 41. The composition of claim 40, wherein at least 95% by weight of the) -amine is in crystalline form C. (a) a compound according to claim 34; and
(b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.   43. The pharmaceutical composition according to claim 42, further comprising one or more pharmaceutically acceptable excipients.   43. The pharmaceutical composition according to claim 42, which is in a dosage form suitable for oral administration.   45. The pharmaceutical composition according to claim 44, wherein the dosage form is selected from a tablet, capsule or solution.   39. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,40] according to any of claims 34 to 38 for the manufacture of a medicament for the treatment of tumor diseases. Use of crystalline form C of 3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- A process for preparing an amine crystal form C comprising:
(a) {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl- Ethyl) -amine is contacted with a solvent to form a precipitate; and
(b) A method comprising isolating the precipitate.   48. The method of claim 47, wherein the solvent is methanol.   48. The method of claim 47, further comprising drying the isolated precipitate.   47. {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-produced by the method of claim 46 A compound which is crystal form C of ((R) -1-phenyl-ethyl) -amine.   Amorphous {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl ) —A compound that is an amine.   52. The compound of claim 51, having substantially the same X-ray diffraction pattern as shown in FIG.   {6- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl)- Containing the amine as a solid, where the solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-( A composition wherein at least 80% by weight of (R) -1-phenyl-ethyl) -amine is in amorphous form.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl 54. The composition of claim 53, wherein at least 90% by weight of the amine is amorphous.   The solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl 54. The composition of claim 53, wherein at least 95% by weight of the) -amine is in amorphous form.   Virtually all solid {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl}-((R) -1 54. The composition of claim 53, wherein the -phenyl-ethyl) -amine is in amorphous form. (a) the compound of claim 51; and
(b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.   58. The pharmaceutical composition according to claim 57, further comprising one or more pharmaceutically acceptable excipients.   58. The pharmaceutical composition according to claim 57, which is in a dosage form suitable for oral administration.   58. The pharmaceutical composition according to claim 57, wherein the dosage form is selected from a tablet, capsule or solution.   61. Amorphous {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo according to any of claims 51 to 60 for the manufacture of a medicament for the treatment of tumor diseases Use of 2,3-d] pyrimidin-4-yl}-((R) -1-phenyl-ethyl) -amine.

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