TW201336838A - Crystalline forms of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide - Google Patents

Abstract

The present invention relates to polymorphs and hydrates of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide, processes for their preparation and their use, in particular in pharmaceutical compositions.

Description

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- Crystalline type of amino)-ethyl]-guanamine

The present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- Polymorphs and hydrates of 2-yl-amino)-ethyl]-guanamine, their preparation and their use, especially in pharmaceutical compositions.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid of formula I [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) -yl-amino)-ethyl]-guanamine,

It is also abbreviated herein as "Compound I", a pharmaceutically active compound which, for example, inhibits IκB kinase (I-Kappa-B kinase, IKK) and is effective in the treatment of various diseases such as osteoarthritis or pain, for example, as WO 2004 /022553, US 7285560, WO 2004/022057 and US 7462638. However, regarding 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Data for crystalline, polymorphic or hydrates of -yl-amino)-ethyl]-guanamine are not disclosed in the prior art.

Polymorphism is the ability of a compound to have more than one crystalline or crystalline structure. Different polytypes represent different solids that share the same molecular formula, but each polytype has different physical properties. Specific compounds can cause a variety of polymorphs, each having different and unique physical properties, such as different solubility profiles, different thermodynamic stability, different crystallization characteristics, different filter properties, different melting temperatures, and/or Or different X-ray diffraction patterns. The difference in physical properties of different polymorphs is caused by the different orientations and interactions of adjacent molecules in the solid molecule. The polymorphic form of the compound can be distinguished by X-ray diffraction and by other methods such as infrared spectroscopy or Raman spectroscopy, for example. These statements are equally applicable to hydrates, i.e., solid addition compounds of compounds with water, which are solvates of a particular type and which can form when the compound is contacted with water, for example when the compound is crystallized in the presence of water.

However, the presence of different crystalline polymorphs or hydrates of the compounds cannot be foreseen as confirmed by those skilled in the art. The presence of polymorphs or hydrates or the number of polymorphs or hydrates cannot be foreseen. In addition, it is impossible to predict the crystallization to produce specific types of conditions and the characteristics of polymorphs and hydrates. Due to properties such as solubility and stability and therefore the use and storage of each polymorph and hydrate Synthesizing may vary, determining whether the presence of polymorphs and solvates such as hydrates is essential to provide a pharmaceutical with increased storage stability or a suitable solubility profile. Therefore, it is desirable to investigate all solid forms of the drug substance, including polymorphs and hydrates.

Accordingly, it is an object of the present invention to provide 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) A solid form of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, especially having a favorable property profile or a form useful for the preparation of the compound. This object is achieved by providing a compound selected from the group consisting of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(benzene) a series of polymorphs 1, polytypes 2, polymorphs 3, hydrates 1 and hydrates 2, and any mixture thereof, of phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine Achieved by a form and a hydrate having advantageous properties regarding stability, solubility, processability, hygroscopicity, fluidity, filterability or crystallization rate, for example, polytype 1, polytype The characteristics of Body 2, Polyform 3, Hydrate 1 and Hydrate 2 can be any of the data given herein. The data used to characterize the polytypes and hydrates of the invention are obtained as follows. In the context of the present invention, polymorph, polymorph, hydrate or the like refers to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S). A polymorph, polymorph or hydrate of 1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine. Terms such as "polytype", "polymorph", "phase" and "crystalline" are used interchangeably herein.

A specific example of the present invention relates to a 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-( Phenyl-pyrimidin-2-yl-amine a crystalline form of -ethyl]-guanamine, selected from the group consisting of polytype 1, polytype 2, polytype 3, and any mixture thereof, wherein polytype 1, polytype 2 And the features of polytype 3 can be any of the data given herein. A specific example of the present invention relates to a 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-( a crystalline form of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine selected from the group consisting of hydrate 1 and hydrate 2 and any mixture thereof, wherein hydrate 1 and hydrate 2 The features may be any of the data given herein.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine having an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode Characteristic reflection of the 2 sitt (2θ) angle expressed in degrees [°] at 14.9 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 20.0 ± 0.2, 22.3 ± 0.2, 25.0 ± 0.2.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine having an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode 2 expressed in degrees [°] at 10.4 ± 0.2, 14.9 ± 0.2, 17.5 ° ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 22.3 ± 0.2, 25.0 ± 0.2 Characteristic reflection of the West Tower (2θ) angle.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has a characteristic reflection imparted in the context in an X-ray powder diffraction pattern using CuK _α1 radiation in a reflective mode Any one or more of them.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine having X-rays as shown in Figure 1 substantially obtained as CuK _α1 radiation that has been used in a reflective mode The powder diffraction pattern, in which the exact relative intensity of the reflection shown in Figure 1 is not a prerequisite, and may vary and represent another specific example of the invention.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The polymorph 1 of the amino)-ethyl]-guanamine can also be characterized by its melting properties, such as its use in differential scanning calorimetry (DSC) using a starting temperature of 253 ± 1 ° C and / or 257 ± 1 ° C The melting point of the peak temperature (heating rate 10 ° C / min) was measured.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- Polymorph 1 of the amino)-ethyl]-guanamine is 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine A thermodynamically most stable polymorph of methotyryl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine at temperatures above about 20 ° C, for example in phase inversion experiments Confirmed in the middle. Therefore, the polytype 1 is particularly suitable when high stability is required compared to other polytypes. Polymorph 1 is further characterized by a low hygroscopicity of about 0.9% water at 80% high relative humidity. Due to its stability and low hygroscopicity, polytype 1 is particularly suitable for 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1 - Storage of amine mesyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine. Polymorph 1 is further characterized by low solubility in water by casting Appropriate pharmaceutical formulation containing solid polytype 1 for 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine formazan The depot effect of the pharmacological activity of benzyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine is easier to achieve. Therefore, the polytype 1 is particularly suitable for use in a pharmaceutical composition or drug designed to have a long acting period.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine having an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode Characteristic reflection of the 2 sitt (2θ) angle expressed in degrees [°] at 5.8 ± 0.2, 6.7 ± 0.2, 9.3 ± 0.2, 11.2 ± 0.2, 19.4 ± 0.2, 22.1 ± 0.2.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine having an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode 2 sita (2θ) angle expressed in degrees [°] at 5.8 ± 0.2, 6.7 ± 0.2, 9.3 ± 0.2, 9.9 ± 0.2, 11.2 ± 0.2, 16.5 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 22.1 ± 0.2 Characteristic reflection.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has a characteristic reflection imparted in the context in an X-ray powder diffraction pattern using CuK _α1 radiation in a reflective mode Any one or more of them.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine having X-rays as shown in Figure 2 substantially obtained as CuK _α1 radiation having been used in a reflection mode The powder diffraction pattern, wherein the exact relative intensity of the reflections shown in Figure 2, is not a requirement and may vary and represent another specific embodiment of the invention.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The polymorph 2 of the amino)-ethyl]-guanamine can also be characterized by its properties in the differential scanning calorimetry (DSC), which results in a starting temperature of 222 ± 1 ° C and / or 225 ± 1 The endothermic peak at the peak temperature of °C, followed by the end temperature of 248 ± 1 °C and/or the endothermic peak of the peak temperature of 251 ± 1 °C (heating rate 10 ° C / min).

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The poly(form 2) of the amino)-ethyl]-guanamine has a higher solubility than the polytype 1 and can be more easily purified, and if further purification is required, the 2-(2-methylamino group- Pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine The preparation is advantageously separated, for example by crystallization or slurrying with a suitable solvent system. Polymorph 2 is further characterized by a low hygroscopicity of about 0.4% water at 80% high relative humidity. In addition, if the higher solubility is for 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl- The desired pharmacological action of pyrimidin-2-yl-amino)-ethyl]-guanamine is advantageous, and it is suitable for use in a pharmaceutical composition or a drug.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 3 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine having an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode Characteristic reflection of the 2 sitt (2θ) angle expressed in degrees [°] at 15.2 ± 0.2, 15.9 ± 0.2, 17.3 ± 0.2, 19.2 ± 0.2, 22.2 ± 0.2, and 25.3 ± 0.2.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 3 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine having an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode Characteristic reflection of the 2 sitt (2θ) angle expressed in degrees [°] at 13.9 ± 0.2, 15.2 ± 0.2, 15.9 ± 0.2, 17.3 ± 0.2, 19.2 ± 0.2, 22.2 ± 0.2, 24.5 ± 0.2, 25.3 ± 0.2.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 3 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has a characteristic reflection imparted in the context in an X-ray powder diffraction pattern using CuK _α1 radiation in a reflective mode Any one or more of them.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Polymorph 3 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine having X-rays as shown in Figure 3 substantially obtained as CuK _α1 radiation that has been used in a reflection mode The powder diffraction pattern, in which the exact relative intensity of the reflection shown in Figure 3, is not a prerequisite and may vary and represent another specific example of the invention.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The polymorph 3 of the amino)-ethyl]-guanamine can be described from the following 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S )-1-amine A Hydrate 1 of mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine is obtained and reconverted to hydrate 1, and as hydrate 1 is used for purification 2-( 2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2-(phenyl-pyrimidin-2-yl-amino) The method of -ethyl]-guanamine is, for example, crystallized or slurried by a suitable solvent system.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 1 of benzyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode 5.3 ± 0.2, 13.5 ± 0.2, 17.9 ± 0.2, 19.5 ± 0.2, 21.5 ± 0.2, 24.9 ± 0.2 characteristic reflection of the 2 sitt (2θ) angle expressed in degrees [°].

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 1 of benzyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode 5.3±0.2, 11.1±0.2, 13.5±0.2, 17.9±0.2, 19.5±0.2, 21.5±0.2, 23.5±0.2, 24.9±0.2, 28.2±0.2, 2 塔 (2θ) angle expressed in degrees [°] Feature reflection.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has a characteristic reflection imparted in the context in an X-ray powder diffraction pattern using CuK _α1 radiation in a reflective mode Any one or more.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 1 of benzyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine having X-ray powder substantially as shown in Fig. 4 obtained by using CuK _α1 radiation in a reflection mode The diffraction pattern, in which the exact relative intensity of the reflection shown in Figure 4, is not a prerequisite and may vary and represent another specific example of the invention.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The hydrate 1 of the amino)-ethyl]-guanamine can also be characterized by its crystal structure parameters which have been determined by single crystal structure analysis. Hydrate 1 crystallizes to a space group P2 ₁ 2 ₁ 2 ₁ with the following lattice characteristics: Z = 4, a = 8.18650 (10) Å, b = 9.97420 (10) Å, c = 32.8707 (2) Å, α = β = γ = 90.00 ° (at 20 ° C).

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The hydrate 1 of the amino)-ethyl]-nonylamine can also be characterized by its properties in the differential scanning calorimetry (DSC), which causes a heat absorption peak between room temperature and 100 ° C, which can be The loss of water is related to a steep endothermic peak at about 170 ° C, an exothermic peak at 190 ° C, and a melting peak at about 253 ° C (heating rate 10 ° C / min).

In a specific embodiment of the invention, 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxyl-2-( Hydrate 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine contains 2 ± 0.3 mol of water, and in another embodiment 2 ± 0.1 mol of water, in another embodiment About 2 mol of water per mol of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-( Phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, the latter water content is determined by thermogravimetric analysis, for example. Hydrate 1 can therefore be called 2-(2- Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl-amino)-B Base]-guanamine dihydrate.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The hydrate 1 of the amino)-ethyl]-nonylamine has a higher solubility than the polytype 1 and can be more easily purified, and if further purification is required, the 2-(2-methylamino group- Pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine The preparation is advantageously separated, for example by crystallization or slurrying with a suitable solvent system. Hydrate 1 is further characterized by low hygroscopicity. In addition, if the higher solubility is for 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl- The desired pharmacological action of pyrimidin-2-yl-amino)-ethyl]-guanamine is advantageous, and it is suitable for use in a pharmaceutical composition or a drug.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which is present in an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode 2.9±0.2, 5.3±0.2, 8.3±0.2, 11.5±0.2, 17.1±0.2, 22.8±0.2 The characteristic reflection of the 2 sitt (2θ) angle expressed in degrees [°].

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which is present in an X-ray powder diffraction pattern using CuK _α1 (CuK-Aval 1) radiation in a reflective mode 2.9±0.2, 5.3±0.2, 6.2±0.2, 8.3±0.2, 9.5±0.2, 11.5±0.2, 14.0±0.2, 17.1±0.2, 18.0±0.2, 22.8±0.2, 2 sita expressed in degrees [°] 2θ) Characteristic reflection of the angle.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has a characteristic reflection imparted in the context in an X-ray powder diffraction pattern using CuK _α1 radiation in a reflective mode Any one or more.

A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) Hydrate 2 of benzyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine having X-ray powder substantially as shown in Fig. 5 obtained by using CuK _α1 radiation in a reflection mode The diffraction pattern, in which the exact relative intensity of the reflection shown in Figure 5, is not a prerequisite and may be varied and represents another specific example of the invention.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The hydrate 2 of the amino)-ethyl]-nonylamine can also be characterized by its properties in the differential scanning calorimetry (DSC), which causes an endothermic peak concentrated at about 99 ° C and 128 ° C at 146. A small endothermic peak at °C, an exothermic peak at 215 ° C and a melting peak at about 250 ° C (heating rate 10 ° C / min).

In a specific embodiment of the invention, 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxyl-2-( Hydrate 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine contains 6 ± 0.3 mol of water, and in another embodiment 6 ± 0.1 mol of water, in another embodiment About 6 mol of water per mol of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminocarboxamido-2-( Phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, the latter water content is determined, for example, by thermogravimetric analysis. Hydrate 2 can therefore be called 2-(2-A Aminoamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxy-2-(phenyl-pyrimidin-2-yl-amino)-ethyl ]-decylamine hexahydrate.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- Hydrate 2 of the amino)-ethyl]-nonylamine has a higher solubility than polytype 1 and can be more easily purified, and, if further purification is required, in 2-(2-methylamino group- Pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine The preparation is advantageously separated, for example by crystallization or slurrying with a suitable solvent system. In addition, if the higher solubility is for 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl- The desired pharmacological action of pyrimidin-2-yl-amino)-ethyl]-guanamine is advantageous, and it is suitable for use in a pharmaceutical composition or a drug.

A specific embodiment of the present invention relates to a purified 2-(2-methylamino-pyrimidin-4-yl)-1H-indole according to the nature of the polytype and hydrate, such as the solubility specified above. a method of -5-carboxylic acid [(S)-1-aminocarbamido-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine, wherein at least one 2-(2- Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl-amino)-B Poly-form 2, polymorph 3, hydrate 1 and hydrate 2 or any mixture of these are based on 2-(2-methylamino-pyrimidin-4-yl)-1H- Separation of indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine during preparation and purification .

The present invention further relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl-2-( A polymorph or hydrate of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine for use as a medicament or a medicament selected from the group consisting of polytypes 1, 2 and 3 And hydrates 1 and 2, or pack A mixture comprising at least one of a polymorph and a hydrate thereof, for example, according to the pharmacological activity of Compound I as described in detail in WO 2004/022553, US Pat. No. 7,285,560, WO 2004/022057 and US Pat. No. 7,462,638, for example. A specific example of the present invention relates to a polytype selected from the group consisting of polytypes 1 and 2, or a mixture comprising at least one polytype 1 and 2 polymorphs, for use as a medicine or a medicament. A specific example of the present invention relates to a polymorph 1 used as a medicine or a drug, or a mixture comprising at least one polytype 1 polymorph. A specific example of the present invention relates to a mixture of hydrates selected from hydrates 1 and 2, or polytypes and/or hydrates comprising at least one hydrate 1 and 2, for use as a medicine or a medicament.

A specific embodiment of the invention relates to a pharmaceutical composition comprising at least one 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid according to the invention [(S a polymorph or hydrate of 1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine selected from polytypes 1, 2 and And hydrates 1 and 2, or at least one of a mixture of polymorphs and hydrates thereof, and one or more pharmaceutically acceptable excipients, i.e., inactive materials such as diluents and other auxiliaries, and When Compound I is used as a medicine or a drug in human medicine or veterinary medicine, it can be employed. A specific embodiment of the invention relates to a pharmaceutical composition comprising at least one polytype 1 and 2, or a mixture comprising at least one polytype 1 and 2 polymorph, and one or more pharmaceutically acceptable excipient. A specific embodiment of the invention relates to a pharmaceutical composition comprising a polytype 1, or a mixture comprising at least one polytype 1 polymorph, and one or more pharmaceutically acceptable excipients. A specific example of the present invention relates to a pharmaceutical composition comprising a hydrate selected from the group consisting of hydrates 1 and 2. Or a polymorph and/or a mixture comprising at least one hydrate of hydrates 1 and 2, and one or more pharmaceutically acceptable excipients. If desired, the pharmaceutical compositions according to the invention may also contain one or more other suitable pharmacologically active compounds. The pharmaceutical, pharmaceutical and pharmaceutical compositions according to the invention may generally be administered, for example, by oral, inhalation, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. A specific embodiment of the present invention further relates to a method for preparing a pharmaceutical composition comprising at least one 2-(2-methyl group according to the present invention selected from the group consisting of polytypes 1, 2 and 3 and hydrates 1 and 2. Amino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl] a polymorph or hydrate of guanamine, together with one or more pharmaceutically acceptable and physiologically tolerated excipients, and if desired, one or more other suitable pharmacologically active compounds for administration and dosage Form.

Examples of pharmaceutical compositions are granules, powders, dragees, lozenges, (micro)capsules, suppositories, syrups, fruit juices, suspensions, emulsions, drops or injection solutions, and preparations with sustained release of active compounds, in which Auxiliary substances such as carrier materials, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavoring agents, sweeteners and co-solvents are used in the preparation. Commonly used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannose and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil Or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol. The pharmaceutical composition is preferably manufactured and administered in dosage unit, and each unit contains a specific dose of at least one polymorph or hydrate according to the present invention as an active ingredient. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, This dose may be up to about 1000 mg, preferably from about 50 mg to about 300 mg, and in the case of an ampule form of the injectable solution, up to about 300 mg, preferably from about 1 mg to about 100 mg. Dosages used when treating an individual (especially a mammal, in particular a human) with one or more compounds I of the polymorph and/or hydrate form according to the invention and effective to obtain the desired result of treatment or prevention The change is determined by the doctor's details of the specific situation. As is known in the art, the dosage will depend on a variety of factors such as, for example, the severity of the condition being treated, general health conditions, route of administration, weight, sex, diet, time and route of administration, desired The duration of treatment, the rate of absorption and excretion, combinations with other drugs, and others.

The pharmacological properties of Compound I as described in WO 2004/022553, US Pat. No. 7,285,560, WO 2004/022057 and US Pat. No. 7,462,638, for example, the polytypes and hydrates according to the present invention are useful for the prevention and treatment of all processes involving IκB kinase. Diseases with increased activity, for example, chronic diseases of the locamotory apparatus, such as acute and chronic arthritis of inflammation, immune or metabolic mediators, joint diseases, rheumatoid arthritis, or degenerative arthritis such as osteoarthritis (osteoarthroses), spinal cord degeneration (spondyloses), type II diabetes, inflammatory bowel disease, joint trauma or meniscus or body bone injury or ligament rupture after joint fixation for a considerable period of time after cartilage loss, or connective Tissue diseases such as collagen noses and periodontal disease, myalgia and bone metabolism disorders, or diseases due to excessive expression of tumor necrosis factor alpha (TNFα) or increased concentration of TNFα, such as cachexia, multiple sclerosis Symptoms, craniocerebral trauma, Crohn's disease and intestinal ulcers, or diseases such as atherosclerosis, stenosis, ulcers, Alzheimer's disease, muscles Crack, cancer disease (enhanced treatment with cytotoxic drugs), myocardial infarction, gout, sepsis, septic shock, endotoxic shock, viral infections such as influenza, hepatitis, HIV infection, AIDS or adenovirus or herpes virus , parasitic infections such as malaria or leprosy, fungal or yeast infections, meningitis, chronic inflammatory lung diseases such as chronic bronchitis or asthma, acute respiratory distress syndrome, acute synovitis, tuberculosis, psoriasis, diabetes, organ recipients Partial treatment of acute or chronic rejection of transplanted organs, chronic graft versus host disease and inflammatory vascular disease, and they may be further used to treat pain including acute and chronic pain, for example with inflammatory processes or osteoarthritis Related pain. Examples of chronic pain that can be treated are chronic musculoskeletal disorders such as back pain, pain associated with menstrual bleeding, pain associated with osteoarthritis or rheumatoid arthritis, pain associated with intestinal inflammation, and inflammation of the heart muscle Related pain, pain associated with multiple sclerosis, pain associated with neuritis, pain associated with cancer and sarcoma, pain associated with AIDS, pain associated with chemotherapy, pain associated with amputation, trigeminal neuralgia, headache, such as Migraine, or neuropathic pain, such as post-herpetic neuralgia. Examples of treatable acute pain are post-injury pain, post-operative pain, pain associated with acute gout attack, or acute pain following sacral surgery intervention.

A specific example of the present invention relates to a 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl group according to the present invention. a polymorph or hydrate of -2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine selected from polytypes 1, 2 and 3 and hydrates 1 and 2, A disease for treating an increase in the activity of the IκB kinase, including any one or more of the diseases mentioned herein, for example, for treating osteoarthritis or pain, and the like The use of a polymorph or hydrate for the manufacture of a medicament for the treatment of a disease whose process involves an increase in the activity of IκB kinase, including for the treatment of any one or more of the diseases mentioned herein, for example A method for treating osteoarthritis or pain, and a method of treating a disease in which the activity of the IκB kinase is increased, including treating any one or more of the diseases mentioned herein, such as treating osteoarthritis or pain. The method comprises an effective amount of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl-based according to the invention] A polymorph or hydrate of 2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine is administered to an individual in need thereof. A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminocarboxamidine) for the treatment of diseases. The polymorph of -2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, and the use thereof for the manufacture of a medicament, and the method for treating a disease, wherein the polytype system It is selected from the group consisting of polytypes 1 and 2, or a mixture comprising at least one polytype 1 and 2 polymorph. A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminocarboxamidine) for the treatment of diseases. The polymorph of -2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, and the use of the same for the manufacture of a medicament, and the method for treating a disease, wherein the polytype Is a mixture of polytype 1, or a polytype comprising at least one polytype 1. A specific example of the present invention relates to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminocarboxamidine) for the treatment of diseases. a hydrate of -2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, and the use of the same for the manufacture of a medicament, wherein the hydrate is selected from the group consisting of hydrates 1 and 2, Or a mixture comprising a polytype and/or at least one hydrate of hydrates 1 and 2.

The invention additionally relates to the preparation of 2-(2-methylamino groups) according to the invention Pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine A method of selecting polymorphs and hydrates of polytypes 1, 2 and 3 and hydrates 1 and 2. In general, the polymorphs and hydrates of the present invention can be crystallized or recrystallized from a solution of Compound I or a suspension of Compound I or from Solid Compound I under conditions suitable for the individual polytype or hydrate. I got it. A solution or suspension of Compound I for the preparation of the desired polymorph or hydrate can be obtained directly at the end of chemical synthesis of Compound I, or it can be obtained by dissolving or suspending previously obtained with another polymorph or hydrate. Obtained as Compound I in the form of a mixture of polymorphs and/or hydrates, not characterized by its associated crystalline nature. This compound I can be referred to as "crude compound I". More specifically, the polymorphs and hydrates of the present invention can be maintained, heated, cooled, and provided by providing a solution or suspension of Compound I, for example, by dissolving or suspending the crude Compound I in a suitable solvent or solvent mixture. / or concentrating the solution or suspension and / or adding one or more additional solvents and / or adding seed crystals of the desired polytype or hydrate, with or without agitation such as stirring to form the desired polymorph or hydrate The precipitate of the crystal is obtained by forming a desired polymorph or hydrate and isolating the desired polymorph or hydrate. The use of a small amount of the desired polymorph or hydrate seed crystal is a preferred step to promote crystallization of the desired form. The preparation of the polymorphs and hydrates of Compound I can be carried out using conventional equipment and according to standard procedures. For example, the concentrated solution or suspension can be carried out by partially or completely distilling off the solvent at atmospheric pressure or under reduced pressure. Separation of the polytype or hydrate can be carried out by any conventional technique such as filtration or vacuum filtration or centrifugation. Separation may also include washing and/or drying of the initially separated solids, for example at room temperature and atmospheric or elevated temperature and/or under reduced pressure.

Compound I, 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- 2-Base-amino)-ethyl]-guanamines, for example, can be prepared as described in WO 2004/022553 and US Pat. No. 7,285,560, and further described in detail below. Briefly, in order to synthesize the compound I2-[bis-(tris-butoxycarbonyl)]amino-3-(phenyl-pyrimidin-2-yl-amino)propanoate, as in WO 2004 Methyl 2-[di-(tris-butoxycarbonyl)amino]acrylate and 2-anilino-pyrimidine can be obtained as described in /022553 and US Pat. No. 7,285,560, for example, by treatment with an acid such as hydrochloric acid. And separating the obtained methyl 2-amino-3-(phenyl-pyrimidin-2-yl-amino)propanoate into a chiral phase by preparative high performance liquid chromatography under standard conditions. Mirroring isomers. The resulting methyl (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)propanoate and 2-(2-methylaminopyrimidin-4-yl)-1H-indole Indole-5-carboxylic acid, the synthesis of which is described in WO 2004/022553 and US Pat. No. 7,285,560, for example, using a coupling agent such as N,N,N',N'-tetramethyl-O-(7-nitrogen) Heterobenzotriazol-1-yl)-urea hexafluorophosphate (HATU) in the presence of a base such as diisopropylethylamine to give (S)-2-{[2-(2-methylamino) Pyrimidin-4-yl)-1H-indole-5-carbonyl]amino}-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester which reacts with ammonia in the last step To give 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxy-2-yl-phenylpyrimidin-2- Amino-amino)-ethyl]-guanamine, which may also be named, for example, (S)-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5- Carbonyl]amino}-3-(phenyl-pyrimidin-2-yl-amino)propanamide.

In the above 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2- In the synthesis of benzyl-amino)-ethyl]-guanamine, if the last step is by (S)-2-{[2-(2-methylaminopyrimidin-4-yl)-1H- Methyl-5-carbonyl]amino}-3-(phenyl-pyrimidin-2-yl-amino)propionate with ammonia Less than a saturated solution in methanol (such as a 7N solution of ammonia in methanol) is reacted at room temperature (i.e., at about 20 to 25 ° C) for a longer period of time, such as three days, and is carried out by direct separation of the precipitated solid by filtration, Then 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-) Polymorph 1 of benzyl-amino)-ethyl]-guanamine. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of polymorph 1 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, which comprises (S)-2-{[2-(2-methylaminopyrimidine- 4-yl)-1H-indole-5-carbonyl]amino}-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester and a solution of ammonia in methanol (for example, 7N solution) The reaction is allowed to react at room temperature for a sufficient period of time (such as about three days) and the precipitated solid is isolated.

Instead of reacting methyl (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)propionate with 2-(2-methylaminopyrimidin-4-yl)-1H - 吲哚-5-carboxylic acid and subsequent conversion of the ester group to amidino group by reaction with ammonia, 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylate The acid [(S)-1-aminocarbamido-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine can also be prepared according to other synthetic steps, for example by making 2-( 2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid, or a salt thereof (such as 2-(2-methylamino-pyrimidin-4-yl)) a sodium salt of -1H-indole-5-carboxylic acid, which is synthesized as described in WO 2006/128585 and US 2008/0214813, for example) with (S)-2-amino-3-(phenyl-pyrimidine) 2-yl-amino)-propanamide (which is synthesized as described in PCT/EP2011/063504, for example) in a coupling agent such as 1-(3-dimethylaminopropyl)-3-B In the presence of a carbodiimide hydrochloride, it is optionally reacted in the presence of a base, as further detailed below.

If the above (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)-propionamide 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidin-2-yl) -amino)-ethyl]-guanamine is carried out in a mixture of tetrahydrofuran and N-methylpyrrolidin-2-one as a solvent at room temperature (i.e., at about 20 to 25 ° C) and for final treatment, The reaction mixture is diluted with water and the precipitated solid is directly separated by filtration to obtain 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine Hydrate 1 of formazan-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of hydrate 1 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which comprises 2-(2-methylamino-pyrimidin-4-yl)-1H-indole哚-5-carboxylic acid or a salt thereof and (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)-propanamide in a coupling agent (for example, 1-(3-dimethyl) In the presence of a base, in the presence of a base, in a mixture of tetrahydrofuran and N-methylpyrrolidin-2-one at room temperature in the presence of a base The mixture was diluted with water and the precipitated solid was separated.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- The hydrate 1 of the amino)-ethyl]-nonylamine can be converted into other 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid in one or more steps [ Crystalline forms of (S)-1-aminocarbamimido-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine such as polytypes 1, 2 and 3 and hydrate 2 .

For example, polytypes 1 and 2 can be obtained by heating hydrate 1 in a suitable solvent, optionally crystallizing the desired crystal form, and cooling the mixture. For conversion to polytype 1, for example, hydrate 1 can be heated in acetone to a temperature of from about 35 ° C to about reflux temperature, for example to about 40 ° C, the mixture is seeded in a small amount of polytype 1, at 40 Hold at °C for a period of time (for example, about 5 to about 10 small) When, for example, about 6 hours), cool to room temperature and separate the solids. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of polymorph 1 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine which will comprise 2-(2-methylamino-pyrimidin-4-yl)-1H- Hydrate 1 of hydrazone-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine in acetone The seed crystal of Form 1 is heated, for example, to about 40 ° C for a period of from about 5 to about 10 hours, for example, for about 6 hours, the mixture is cooled to room temperature and the precipitated solid is separated.

For conversion to polytype 2, hydrate 1 can be heated in a mixture of diisopropyl ether and methanol to a temperature of from about 60 to about 70 ° C, for example to about reflux temperature or to about 68 ° C, at which temperature is maintained. For a period of time, such as from about 18 to about 30 hours, such as about 24 hours, cooling to room temperature and solids separation. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of polymorph 2 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine comprising 2-(2-methylamino-pyrimidin-4-yl)-1H- Hydrate 1 of hydrazone-5-carboxylic acid [(S)-1-aminecarboxy-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine in diisopropyl The mixture of ether and methanol is heated, for example, to about 60 to about 70 ° C for a period of from about 18 to about 30 hours, for example, for about 24 hours, the mixture is cooled to about 20 to 25 ° C and the precipitated solid is separated. This was followed by the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- In a specific embodiment of the method of polymorph 2 of 2-amino-amino)-ethyl]-nonylamine, the mixture of diisopropyl ether and methanol contains from about 3 to about 10% by weight, In another specific example, from about 4 to about 8%, and in another embodiment, about 6%, alcohol.

For conversion to polytype 3, hydrate 1 can be in material form at elevated temperatures and reduced pressure, for example at from about 50 to about 70 ° C, such as at about 60 ° C, and from about 20 to about 50 mbar, such as about 30 mbar, for example, dried in a standard dry box to convert the hydrate to the anhydrous form of polytype 3, for example, for about 18 to about 30 hours, such as about 24 hours. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of polymorph 3 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine comprising drying 2-(2-methylamino-pyrimidin-4-yl)-1H- Hydrate 1 of hydrazone-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-indolylamine is in the range of from about 50 to about A temperature of 70 ° C and a pressure of from about 20 to about 50 mbar are subjected to a period of from about 18 to about 30 hours.

Polytype 3 can be converted to hydrate 1 by exposing it to an atmosphere containing water vapor, for example, leaving it in air at room temperature (ie, at about 20 to 25 ° C) and atmospheric pressure to experience enough The time during which the anhydrous form is converted to the dihydrate, for example, is from about 15 to about 25 hours, such as about 17 hours. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of hydrate 1 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which comprises 2-(2-methylamino-pyrimidin-4-yl)-1H-indole The polymorph 3 of indole-5-carboxylic acid [(S)-1-aminocarbamido-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine is in the range of from about 20 to about Water is absorbed from the surrounding atmosphere at a temperature of 25 ° C for a period of from about 15 to about 25 hours.

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- Polymorph 2 of amino)-ethyl]-guanamine, which can be used as Obtained from hydrate 1 as outlined above, for example, by heating in a suitable solvent, optionally seeding with the desired crystalline form, and optionally cooling the mixture to convert to 2-(2-methylamino)- Pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine Polymorph 1 and hydrate 2.

For example, to convert to polytype 1, polytype 2 can be heated in a mixture of acetone and water to a temperature of from about 50 to about 60 ° C, for example to about reflux temperature or to about 60 ° C, at which temperature is maintained for a period of time. The time, for example from about 1 to about 5 hours, such as from about 2 to about 3 hours, is cooled to room temperature, and the solids are separated. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of polymorph 1 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine comprising 2-(2-methylamino-pyrimidin-4-yl)-1H- Poly-5 of 吲哚-5-carboxylic acid [(S)-1-amine-methylindol-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine in acetone and water The mixture is heated, for example, to about 50 to about 60 ° C for a period of from about 1 to about 5 hours, for example, for about 2 to about 3 hours, the mixture is cooled to about 20 to 25 ° C and the precipitated solid is separated. This was followed by the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- In a specific embodiment of the method of polymorph 1 of 2-yl-amino)-ethyl]-guanamine, the mixture of acetone and water contains from about 3 to about 6 parts of acetone per part of water, in another specific example Each portion of water ranges from about 3 to about 5 parts acetone, and in another embodiment about 4 parts acetone per portion of water, in each case in parts by volume.

For conversion to hydrate 2, polytype 2 can be heated in a mixture of acetone and water to a temperature of from about 30 to about 40 ° C, for example to about 40 ° C, at this temperature It is held for a period of time, for example from about 2 to about 10 hours, such as about 4 hours, cooled to room temperature and the solids are separated. An embodiment of the invention thus relates to the preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methylcarbonyl-2- A method of Hydrate 2 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which comprises 2-(2-methylamino-pyrimidin-4-yl)-1H-indole Poly-5 of 哚-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine in acetone and water The mixture is heated, for example, to about 40 ° C for a period of from about 2 to about 10 hours, for example, for about 4 hours, the mixture is cooled to about 20 to 25 ° C, and the precipitated solid is separated. Preparation of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) In a specific embodiment of the method of Hydrate 2 of -yl-amino)-ethyl]-nonylamine, the mixture of acetone and water contains from about 1 to about 3 parts of acetone per part of water, and in another specific example A portion of water is about 2 parts of acetone, in each case in parts by volume.

Figure 1. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxy-2-yl-phenyl-pyrimidine-2 X-ray powder diffraction pattern of polymorph 1 of -amino-amino)-ethyl]-nonylamine, measured in a reflection mode with CuK _α1 radiation at room temperature; x-axis: diffraction angle 2 West Tower (degrees); y-axis: intensity (counts expressed in arbitrary units).

Figure 2. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidine-2) X-ray powder diffraction pattern of polymorph 2 of -amino-amino)-ethyl]-nonylamine, which is measured at room temperature in a reflection mode with CuK _α1 radiation; x-axis: diffraction angle 2 West Tower (degrees); y-axis: intensity (counts expressed in arbitrary units).

Figure 3. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) X-ray powder diffraction pattern of polymorph 3 of -amino-amino)-ethyl]-nonylamine, which is measured at room temperature in a reflection mode using CuK _α1 radiation; x-axis: diffraction angle 2 West Tower (degrees); y-axis: intensity (counts expressed in arbitrary units).

Figure 4. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) X-ray powder diffraction pattern of hydrate 1 of hydroxy-amino)-ethyl]-nonylamine, which is measured in the reflection mode with CuK _α1 radiation at room temperature; x-axis: diffraction angle 2 (degrees); y-axis: intensity (counts expressed in arbitrary units).

Figure 5. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) X-ray powder diffraction pattern of hydrate- 2 of hydroxy-amino)-ethylamine-nonylamine, which is measured at room temperature in a reflection mode using CuK _α1 radiation; x-axis: diffraction angle 2 (degrees); y-axis: intensity (counts expressed in arbitrary units).

In the following, the formulation and the characterization of the polytypes and hydrates of the invention are described in detail by way of example.

Instance Example 1. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Formation of polymorph 1 of -yl-amino)-ethyl]-guanamine

(a) Methyl 2-amino-3-(phenyl-pyrimidin-2-yl-amino)propanoate

470 ml of 5N hydrochloric acid was added dropwise to 100 g (212 mmol) of 2-[bis-(tertiary-butoxycarbonyl)]amino-3-(phenyl-pyrimidin-2-yl-) at 15 °C. A solution of methylamino)propionate in 1000 ml of isopropyl acetate and the mixture was stirred for 2 h. The phases were then separated and the pH of the aqueous phase was adjusted to 8.5 by the addition of aqueous ammonia. The aqueous phase was extracted with EtOAc and EtOAc (EtOAc)EtOAc. (Phenyl-pyrimidin-2-yl-amino) methyl propionate.

MS (ESI): m/z = 277 (M ⁺ +1, ¹⁰⁰ %); ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.31 (d (double), J = 4.8 Hz, 2 H) , 7.40 (m (multimodal), 2 H), 7.33-7.20 (m, 3 H), 6.70 (t (trimodal), J = 4.8 Hz, 1 H), 4.18 (dd (doublet), J = 9.6 Und 14.4 Hz, 1 H), 4.05 (dd, J = 9.5 and 14.3 Hz, 1 H), 3.65 (t, J = 9.6 Hz, 1 H), 3.43 (s (single peak), 3 H), 1.88 ppm (bs (寛单峰), 2 H); HPLC (column: Chiralcel OJ-H, 250 x 4.6 mm; eluent: n-heptane + 0.1% diethylamine: ethanol + 0.1% diethylamine (85 : 15); flow rate: 1 ml/min; detection wavelength: 285 nm): residence time = 14.6 min (S image isomer) and 16.4 min (R image isomer).

(b) (R)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester and (S)-2-amino-3-(phenyl-pyrimidine-2 -yl-amino)methyl propionate

By preparative HPLC on the chiral phase (column: Chiralpak AS-H, 250 x 30 mm; eluent: n-heptane: ethanol (5:1); flow rate: 30 ml/min; detection wavelength: 257 Retention time of nm; S mirror isomer: 12.5 min, retention time of R mirror isomer: 18.1 min) 10 g of 2-amino-3-(phenyl-pyrimidin-2-yl-amino) Methyl propionate is separated into the image isomers. Get 2.6 g (52%) Methyl (R)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)propanoate and 2.6 g (52%) of (S)-2-amino-3-(benzene) Methyl-pyrimidin-2-yl-amino)propionate.

(c) (S)-2-{[2-(2-Methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]amino}-3-(phenyl-pyrimidin-2- Methyl-amino)propionate

4.01 g (10.6 mmol) of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)-hexafluorophosphate and 6.82 g (52.8 mmol) Diisopropylethylamine was added to 2.36 g (8.80 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid under cooling in an ice bath at 80 A solution of ml in dimethylformamide and the mixture was stirred at 0 ° C for 1.5 h. Then 2.40 g (8.80 mmol) of methyl (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)propanoate (98.9% ee (anomer of the image isomer)) A solution of dimethylformamide in 22 ml. The mixture was stirred for 2 h, and then an aqueous solution of sodium hydrogencarbonate and isopropyl acetate were added. The organic phase was separated, washed with a saturated solution of sodium chloride and concentrated in vacuo. The precipitated solid was filtered off with suction, dried in vacuo and purified by column chromatography (EtOAc, m. Obtained 2.35 g (50%) of (S)-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]amino}- Methyl 3-(phenyl-pyrimidin-2-yl-amino)propanoate.

MS (ESI): m/z = 520 (M ⁺ , 100%); ¹ H-NMR (600 MHz, DMSO-d ₆ ): δ = 11.7 (s, 1 H), 8.78 (m, 1 H), 8.40 (d, J = 4.8 Hz, 2 H), 8.32 (bs, 1 H), 8.05 (s, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.52 (d, J = 8.5 Hz) , 1 H), 7.40-7.14 (m, 7 H), 7.00 (bs, 1 H), 6.78 (t, J = 4.8 Hz, 1 H), 4.90 (m, 1 H), 4.68 (dd, J = 6.9 and 9.4 Hz, 1 H), 4.29 (dd, J = 7.1 and 9.3 Hz, 1 H), 3.54 (s, 3 H), 2.95 ppm (bs, 3 H); HPLC (column: Chiralcel OD-H , 250 x 4.6 mm; Lysis: n-heptane: ethanol (60:40), flow rate: 1 ml/min, detection wavelength: 254 nm): residence time = 10.1 min (R image isomer) and 15.0 min (S-mirror isomer); ee of the S-mirror isomer = 94.7%.

(d) 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) -yl-amino)-ethyl]-guanamine

2.20 g (4.21 mmol) of (S)-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]amino}-3-(phenyl) A solution of methyl pyrimidin-2-yl-amino)propionate (94.7% ee) in 220 ml of a 7N solution of ammonia in methanol was stirred at room temperature for three days. The precipitated solid was filtered off with suction and dried in vacuo. Obtained 1.75 g (82%) of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxamido- Polymorph 1 of 2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine was determined by its X-ray powder diffraction pattern.

MS (ESI): m/z = 507 (M ⁺ , 100%); ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 11.7 (s, 1 H), 8.40 (d, J = 4.8 Hz , 2 H), 8.34 (m, 2 H), 7.92 (s, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.43-7.10 (m, 9 H), 7.00 (bs, 1 H), 6.77 (t, J = 4.8 Hz, 1 H), 4.80 (m, 1 H), 4.53 (dd, J = 10.0 and 14.4 Hz, 1 H) , 4.25 (dd, J = 4.2 and 14.3 Hz, 1 H), 2.96 ppm (bs, 3 H); HPLC (column: Chiralcel OD-H, 250 x 4.6 mm; eluent: n-heptane: ethanol ( 50:50), flow rate: 1 ml/min, detection wavelength: 238 nm): residence time = 10.2 min (R image isomer) and 14.5 min (S image isomer); S image isomer ee = 99.2%.

Example 2. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Formation of Hydrate 1 of -yl-amino)-ethyl]-nonylamine

Add 40 ml of tetrahydrofuran and 10 ml of N-methylpyrrolidin-2-one to 5 g of (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amine at room temperature -propanamide, 5.65 g of sodium 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylate and 7 g of 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at room temperature for 2 h. Then slowly add 500 ml of water. From the resulting solution, the precipitated solid was filtered off with suction and washed with 50 ml of water and dried at room temperature until constant weight was achieved to yield 7.46 g of 2-(2-methylamino-pyrimidin-4-yl). -1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine hydrate 1 Its X-ray powder diffraction pattern is determined.

Example 3. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Formation of Hydrate 2 of -yl-amino)-ethyl]-nonylamine

1.52 g of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- Polyformate 2 of 2-yl-amino)-ethyl]-guanamine is heated to 40 ° C in 20 ml of a mixture of acetone and water (2:1 by volume) and the suspension is stirred at this temperature. 4 h. A sample of about 1 ml of the suspension was taken, the solid was filtered off with suction and dried at room temperature until a constant weight was reached to give 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5. - Hydrate [(S)-1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine hydrate 2, with its X-ray powder diffraction Figure OK.

Example 4. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidine-2) Formation of polymorph 3 of -yl-amino)-ethyl]-nonylamine

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidin-2-yl) Hydrate 1 of -amino)-ethyl]-nonylamine was placed in a vacuum oven and dried at a pressure of 30 mbar and a temperature of 60 ° C for 24 h to produce 2-(2-methylamino-pyrimidine) 4-(4-)-1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine Polymorph 3 is determined by its X-ray powder diffraction pattern. The water content of the product as determined by the Karl-Fischer titration method was 0.09%.

Example 5. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Formation of polymorph 2 of -yl-amino)-ethyl]-nonylamine

16.7 g of diisopropyl ether and 1.0 g of methanol were added to 0.5 g of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid in a reaction vessel. [(S)-1-Aminocarbamido-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine hydrate 1 and the suspension was placed in a vibrating device (Heidolph synthesis) 1. Adjust to 500 rpm) and heat to reflux at an internal temperature of 68 °C. The mixture was kept at this temperature for 24 hours and allowed to cool to room temperature. The solid was filtered off with suction and air dried at room temperature for 8 hours to give 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine Polymorph 2 of formazan-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine is determined by its X-ray powder diffraction pattern.

Example 6. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Formation of Hydrate 1 of -yl-amino)-ethyl]-nonylamine

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidin-2-yl) Polyamine 3 of -amino)-ethyl]-guanamine in air It was kept at room temperature for 17 h to give 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarboxyl-2-( Hydrate 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine was determined by its X-ray powder diffraction pattern.

Example 7. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine-2) Formation of polymorph 1 of -yl-amino)-ethyl]-guanamine

1.0 g of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- Polymorph 2 of 2-yl-amino)-ethyl]-guanamine and 15 ml of a mixture of acetone and water (4:1 by volume) were heated and stirred to an internal temperature of 60 °C. The mixture was held at this temperature for 2.5 h and then cooled to 24 ° C in 1 h. The solid was filtered off with suction, washed twice with 5 ml each of water and dried under vacuum at a pressure of 50 mbar and at a temperature of 60 ° C for 19 h to yield 0.89 g of 2-(2-methylamino group - Pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine The polytype 1 is determined by its X-ray powder diffraction pattern.

Example 8. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidine-2) Formation of polymorph 1 of -yl-amino)-ethyl]-guanamine

0.6 g of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-() in a reaction vessel Hydrate 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine and 15 ml of acetone were placed in a vibrating apparatus (Heidolph Synthesis 1, adjusted to 500 rpm). A small amount of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidine- Polymorph 1 of 2-yl-amino)-ethyl]-guanamine is seeded and heated to 40 The temperature inside °C, and kept at this temperature for 6 h. A sample of about 1 ml of the suspension was taken, the solid was filtered off and dried at room temperature until a constant weight was reached to give 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid. Polymorph 1 of [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine as determined by its X-ray powder diffraction pattern .

Analytical method X-ray powder diffraction (XRPD)

The X-ray powder diffraction measurement was performed in a reflection mode using a Bruker AXS D8 advanced diffractometer using CuK _α1 (CuK-Aval 1) radiation. X-ray powder diffraction was carried out at room temperature unless otherwise stated. The samples were studied in plate formulations. The measured data was visualized and evaluated using EVA Software 12.0.

The X-ray powder diffraction patterns of polymorphs 1, 2 and 3 of Compound I and hydrates 1 and 2 are shown in Figures 1 to 5. The observed X-ray reflectance data is given in the following form: angle 2 sitta (2θ), expressed in ° (degrees), followed by the intensity of the strongest reflection in parentheses (its intensity is set to 100%) (strength The relative intensity (in %) of the count measurement expressed in arbitrary units. The given data is rounded to a multiple of 0.1° and 1%, respectively. As indicated above, a given angle 2 sitt can be understood as falling at a margin of ±0.2°, and the relative intensity can be varied to a greater extent depending on the sample and measurement conditions, and the relative intensity is given to the accuracy. Values are not considered a prerequisite for the presence of crystalline forms. For classification, a reflection having a relative intensity greater than 60% of the strongest reflection, for example, may be referred to as a strong reflection, and a reflection having a relative intensity between 30% and 60% of the strongest reflection (for example) may be referred to as Strong reflection, and the medium strong reflection and / or strong reflection, used Polymorphs and hydrates of the exemplified compound I.

XRPD reflection of polymorph 1 (2 sitta [°], relative intensity [%])

5.6° (5%), 10.4° (21%), 11.1° (8%), 11.4° (10%), 12.8° (13%), 13.2° (6%), 13.9° (11%), 14.2 ° (13%), 14.9° (100%), 17.2° (8%), 17.5° (19%), 18.0° (19%), 19.4° (35%), 19.7° (67%), 20.0° (55%), 20.4° (10%), 21.0° (20%), 22.3° (96%), 23.3° (15%), 24.1° (7%), 24.6° (21%), 25.0° ( 82%), 26.1° (6%), 27.0° (6%), 27.7° (16%), 28.9° (7%), 29.6° (9%), 30.2° (10%), 31.3° (7) %), 31.9° (4%), 32.4° (6%), 33.1° (6%)

XRPD reflection of polymorph 2 (2 sitta [°], relative intensity [%])

5.8° (27%), 6.7° (100%), 8.2° (7%), 9.3° (60%), 9.9° (31%), 11.2° (65%), 13.5° (9%), 13.8 ° (8%), 14.3 ° (15%), 16.5 ° (25%), 17.0 ° (10%), 17.7 ° (21%), 18.1 ° (28%), 18.8 ° (24%), 19.4 ° (89%), 20.2° (15%), 20.4° (21%), 22.1° (41%), 24.2° (11%), 24.6° (8%), 25.5° (16%), 27.9° ( 12%), 30.0° (10%), 30.6° (8%)

XRPD reflection of polytype 3 (2 sitta [°], relative intensity [%])

5.1° (17%), 5.6° (12%), 7.0° (16%), 7.5° (16%), 9.7° (14%), 11.2° (13%), 12.7° (19%), 13.4 ° (20%), 13.9° (30%), 15.2° (76%), 15.9° (59%), 16.6° (18%), 17.3° (36%), 19.2° (100%), 22.2° (83%), 23.2° (23%), 24.5° (33%), 25.3° (42%), 27.9° (23%), 28.7° (27%)

XRPD reflection of hydrate 1 (2 sitta [°], relative intensity [%])

5.3° (33%), 9.2° (19%), 10.7° (9%), 11.1° (25%), 12.0° (8%), 13.5° (44%), 14.0° (17%), 16.1 ° (20%), 17.2 ° (5%), 17.9 ° (51%), 18.5 ° (12%), 19.5 ° (69%), 21.0 ° (12%), 21.5 ° (100%), 22.4 ° (11%), 23.5° (33%), 24.9° (37%), 25.8° (16%), 26.5° (20%), 27.2° (7%), 28.2° (26%), 28.6° ( 9%), 29.4° (12%), 30.2° (12%), 31.3° (4%), 32.3° (3%), 32.7° (4%), 33.3° (3%)

XRPD reflection of hydrate 2 (2 sitta [°], relative intensity [%])

2.9° (100%), 5.3° (29%), 6.2° (9%), 8.3° (33%), 9.5° (13%), 11.0° (3%), 11.5° (28%), 12.8 ° (4%), 14.0° (11%), 14.7° (4%), 16.1° (3%), 16.8° (4%), 17.1° (14%), 18.0° (11%), 18.8° (4%), 19.7° (3%), 20.3° (6%), 21.3° (11%), 21.9° (6%), 22.8° (14%), 23.5° (7%), 24.7° ( 5%), 25.5° (4%), 26.1° (9%), 27.3° (5%), 28.6° (5%), 29.6° (4%), 30.1° (3%), 31.4° (3) %), 31.8° (5%), 34.9° (4%)

Crystal structure determination

The crystal structure of the hydrate 1 of the compound I was determined by X-ray single crystal structure analysis using a crystal obtained by crystallization of a mixture of acetone and water (4:1) and sealed in a Lindemann glass capillary. Single-crystal X-ray diffraction data collected with Bruker/AXS three surround ray meters, equipped with SMART APEX area detector, cryogenic unit (model LT2) and copper micro-focus generator (IμS), operating at 45 kV/650 mA, and focusing Beam Montel multilayer optics with ~250 μm image focus diameter. Data processing is performed with the program SAINT+ version 6.45. The hydrate 1 of the compound I crystallizes in the orthorhombic space group P2 ₁ 2 ₁ 2 ₁ . The data of the unit slot is Z=4, a=8.18650(10)Å, b=9.97420(10)Å, c=32.8707(2)Å, α=β=γ=90.00°, slot volume=2684.02(5)Å ³ , molecular formula = C ₂₇ H ₂₅ N ₉ O ₂ . 2 H ₂ O, calculated density ρ = 1.345 Mgm ^-3 (at 20 ° C).

Differential Scanning Thermal Method (DSC)

DSC measurements were performed on a METTLER DSC822e instrument. Unless otherwise stated, 40 μl of Al-aluminum crucible with a sealed lid and holes was used and measured at a typical nitrogen flow rate of 50 ml/min with a typical heating rate of 10 ° C/min. The measured data was evaluated using the software STARe V8.10. With respect to polytype 1 of Compound I, a DSC melting point having a starting temperature of 253 ° C and a peak temperature of 257 ° C was observed. In the DSC analysis of the polymorph 2 of the compound I, an endothermic peak having a starting temperature of 222 ° C and a peak temperature of 225 ° C was observed, followed by an endothermic peak having a starting temperature of 248 ° C and a peak temperature of 251 ° C. The DSC properties of hydrates 1 and 2 of Compound I are as described above.

Thermogravimetric analysis (TG)

Thermogravimetric analysis was performed on a METTLER TGA851e instrument. 100 μl of Al-aluminum crucible with a sealed lid and holes was used and measured at a nitrogen flow rate of 50 ml/min. The measured data was evaluated using the software STARe V8.10. Volatile The TG measurement by infrared (IR) spectroscopy was carried out as described using a METTLER TGA851e instrument coupled to a Thermo-Nicolet 380 FT-IR spectrometer equipped with a gas phase measuring cell. The measured IR spectra were evaluated using the software OMNIC V.7.3. In the TG analysis of polymorph 1 and polytype 2 of compound I up to the melting point, negligible weight loss of 0.2% and 0.7%, respectively, was observed. In the TG analysis of hydrate 1 of Compound I, a 6.4% gradual weight loss was observed between room temperature and 120 °C. The FT-IR analysis of the evolved gas proved to be water. The observed weight loss corresponds to 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-) per mol. (Phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine Approximately 1.9 mol of water. In the TG FT-IR analysis of the hydrate 2 of the compound I, a weight loss of 17-18% of water was observed mainly in two steps between room temperature and 140 ° C, which corresponds to 2-(2 per mol) -Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminocarboxamido-2-(phenyl-pyrimidin-2-yl-amino)- Ethyl]-guanamine is about 6 mol of water.

Dynamic vapor adsorption (DVS)

To determine hygroscopicity, the moisture adsorption/desorption isotherm was recorded with a surface measuring system DVS-1 instrument. Two cycles were run at 25 ° C, where the relative humidity was gradually increased from 0% to 95% and then again dropped to 0%, and the weight of the sample was measured. Evaluate the data with the software DVSWin V.2.15. In the DVS analysis of polymorph 1 and polytype 2 of Compound I, the following weight gain was observed in the adsorption step of two cycles.

Determination of solubility

To determine the solubility in a mixture of acetone and water (4:1 by volume), a 0.5 mg to 50 mg sample of the test substance was suspended in a defined amount of solvent in a screw cap vial with a magnetic stir bar (800 In mg to 1200 mg), the bottle was placed in a temperature controlled multi-agitator (Avantium Crystal 16) for transport measurement. With stirring at 700 rpm, the bottle was cooled from room temperature to 0 ° C and then heated to 60 ° C at a heating rate of 3 ° C / h, held at 60 ° C for 2 hours and re-cooled to 0 at a cooling rate of 3 ° C / hour. °C. Determine whether the sample is dissolved (100% transmittance) or crystals by transmission measurement. For polytype 1, polytype 2, hydrate 1 and hydrate 2 of Compound I, the following solubility in a mixture of acetone and water (4:1 by volume) was measured.

Ripening experiment

The relative stability of polytypes 1 and 2 and hydrate 1 was investigated by a 20 ° C ripening experiment (slurry conversion).

A polymorphic mixture of 81 mg (a mixture of polytype 1 and polytype 2), 83 mg of polytype 1 and 60 mg of hydrate 1 was prepared. The mixture was subjected to XRPD analysis to confirm the presence of all three polytypes and then distributed in five capillaries. These samples were kept in suspension at 20 ° C for five days. After the X-ray powder diffraction of the suspension was measured, the suspensions were dried overnight at 40 ° C and <100 mbar and X-ray diffraction again. The ripening experiments (a) to (e) were started under the specific conditions with the above polytype mixture.

(a) Suspending the polytype mixture in water. After the suspension was stirred at 20 ° C for five days, the suspension was analyzed via XRPD and a mixture of polyform 1 and hydrate 1 was confirmed. After drying overnight at 40 ° C and <100 mbar, the resulting solid was analyzed via XRPD and again, only polytype 1 was found.

(b) The polytype mixture was suspended in water/methanol 1:1 (vol.: vol.). After the suspension was stirred at 20 ° C for five days, the suspension was analyzed via XRPD and it was confirmed that only polytype 1 was present. After drying overnight at 40 ° C and <100 mbar, The resulting solid was analyzed by XRPD and again, only polytype 1 was found.

(c) suspending the polytype mixture in 2-propanol. After the suspension was stirred at 20 ° C for five days, the suspension was analyzed via XRPD and it was confirmed that only polytype 1 was present. After drying overnight at 40 ° C and <100 mbar, the resulting solid was analyzed via XRPD and again, only polytype 1 was found.

(d) Suspending the polytype mixture in acetone. After the suspension was stirred at 20 ° C for five days, the suspension was analyzed via XRPD and it was confirmed that only polytype 1 was present. After drying overnight at 40 ° C and <100 mbar, the resulting solid was analyzed via XRPD and again, only polytype 1 was found.

(e) Suspending the polytype mixture in ethyl acetate. After the suspension was stirred at 20 ° C for five days, the suspension was analyzed via XRPD and it was confirmed that only polytype 1 was present. After drying overnight at 40 ° C and <100 mbar, the resulting solid was analyzed via XRPD and again, only polytype 1 was found.

In all the ripening experiments (a) to (e), the solid was completely converted to polytype 1 after drying. The ripening experiments carried out prove that polymorph 1 is thermodynamically most stable among polytypes 1, 2 and hydrate 1.

Claims (15)

2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-carbamoyl-2-(phenyl-pyrimidin-2-yl) a crystalline form of -amino)-ethyl]-guanamine selected from 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)- Polymorph 1, polymorph 2, polymorph 3, hydrate 1 and hydration of 1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine A series consisting of 2 and any mixture thereof. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl-2-(benzene) according to the scope of patent application Polymorph 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine, which has a 14.9±0.2 in an X-ray powder diffraction pattern using CuK-Aval 1 radiation in a reflective mode Characteristic reflection of 2 sita (2θ) angles (in degrees) of 19.4 ± 0.2, 19.7 ± 0.2, 20.0 ± 0.2, 22.3 ± 0.2, 25.0 ± 0.2. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl-2-(benzene) according to the scope of patent application Polymorph 2 of phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine having an X-ray powder diffraction pattern of CuK-Aval 1 radiation using a reflection mode of 5.8 ± 0.2 Characteristic reflection of 2 sita angles (expressed in degrees) of 2 sita angles (in degrees) of 6.7 ± 0.2, 9.3 ± 0.2, 11.2 ± 0.2, 19.4 ± 0.2, 22.1 ± 0.2. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl-2-(benzene) according to the scope of patent application Polymorph 3 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine having an X-ray powder diffraction pattern of CuK-Aval 1 radiation using a reflection mode at 15.2 ± 0.2 2Sita, 15.9±0.2, 17.3±0.2, 19.2±0.2, 22.2±0.2, 25.3±0.2 The characteristic reflection of the angle (in degrees). 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine-methyl fluorenyl-2-(benzene) according to the scope of patent application Hydrate 1 of benzyl-pyrimidin-2-yl-amino)-ethyl]-guanidamine having 5.3 ± 0.2 in an X-ray powder diffraction pattern using CuK-Aval 1 radiation in a reflective mode, Characteristic reflection of 2 Citaler angles (in degrees) of 13.5 ± 0.2, 17.9 ± 0.2, 19.5 ± 0.2, 21.5 ± 0.2, 24.9 ± 0.2. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl- Hydrate 2 of amino)-ethyl]-guanamine having 2.9±0.2, 5.3±0.2, 8.3±0.2 in an X-ray powder diffraction pattern using CuK-Aval 1 radiation in a reflective mode, Characteristic reflection of 2 Sita angles (expressed in degrees) of 11.5 ± 0.2, 17.1 ± 0.2, 22.8 ± 0.2. A pharmaceutical composition comprising at least one 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid according to any one of claims 1 to 6 of the patent application [ (S)-1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine polymorphs 1, 2 and 3 and hydrates 1 and 2, and One or more pharmaceutically acceptable excipients. A pharmaceutical composition according to item 7 of the scope of the patent application, which comprises 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid according to item 2 of the scope of the patent application [ S) 1-Aminomethylmercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine polymorph 1, and one or more pharmaceutically acceptable excipients . 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine formazan] according to any one of claims 1 to 6 Polytype 1, 2 or 3 or hydrate 1 or 2 of benzyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, It is used as medicine. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine formazan] according to any one of claims 1 to 6 Polytype 1, 2 or 3 or hydrate 1 or 2 of phenyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine for use in the treatment of IκB kinase A disease with increased activity. 2-(2-Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(benzene) according to item 2 of the scope of application Polymorph 1 of phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine is used for the treatment of diseases in which the activity of IκB kinase is increased according to the process of claim 10 of the scope of the patent application. A 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine prepared according to any one of claims 1 and 2 of the patent application scope A method of polymorph 1 of formazan-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, which comprises 2-(2- according to item 3 of the scope of the patent application Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl-amino)-B The polymorph 2 of the hydrazide is heated to a temperature of 50 to 60 ° C in a mixture of acetone and water, the mixture is cooled to 20 to 25 ° C and the precipitated solid is separated. A 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine prepared according to any one of claims 1 and 3 of the patent application scope A method of polymorph 2 of formazan-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, which comprises 2-(2- according to item 5 of the scope of the patent application Methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamido-2-(phenyl-pyrimidin-2-yl-amino)-B The hydrate 1 of the hydrazide was heated to a temperature of 60 to 70 ° C in a mixture of diisopropyl ether and methanol, and the mixture was cooled to 20 to 25 ° C and the precipitated solid was separated. A 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-amine prepared according to any one of claims 1 and 4 of the patent application scope A method of polymorph 3 of formazan-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-guanamine, which comprises a temperature of from 50 to 70 ° C and a temperature of from 20 to 50 mbar Drying under pressure according to item 5 of the patent application, 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminecarbamyl-2 - Hydrate 1 of (phenyl-pyrimidin-2-yl-amino)-ethyl]-nonylamine. Purification of 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylic acid [(S)-1-aminemethanthen-2-(phenyl-pyrimidin-2- A method of benzyl-amino)-ethyl]-guanamine wherein at least one of 2-(2-aminoamino-pyrimidine-4-) according to any one of items 1 and 3 to 6 according to the scope of the patent application is Poly(formula) of -1H-indole-5-carboxylic acid [(S)-1-amine-mercapto-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-decylamine 2. Polymorph 3, hydrate 1 and hydrate 2 or any mixture of them are separated.