MXPA06009148A - Crystalline forms of a pharmaceutical compound - Google Patents

Abstract

Described are crystalline forms of the pharmaceutical compound"[9S-(9alpha, 10ss, 12alpha)]- 5,16-Bis [(ethylthio)methyl]-2, 3, 9, 10, 11, 12-hexahydro-10 -hydroxy-9-methyl -1-oxo-9, 12-epoxy- 1H-diindolo[1, 2, 3-fg:3', 2', 1'-kl]pyrrolo[3, 4-i][1, 6]benzodiazocine -10-carboxylic acid methyl ester", as well as methods for their use and preparation.

Description

CRYSTAL FORMS OF A PHARMACEUTICAL COMPOUND FIELD OF L? INVENTION The present invention relates to crystalline forms of a compound and to the use of that type of forms in the preparation of a medicament, in particular, for the treatment of Parkinson's disease.

BACKGROUND OF THE INVENTION The compound with the structure shown below is currently in clinical trials for Parkinson's disease (Idrugs, 2003, 6 (4), 377-383).

This compound is called hereafter, Compound I. The chemical designation of Compound I is' methyl ester of [9S- (9a, lOß, 12a.)] -5, 16-Bis [(ethylthio) methyl] -2 acid. , 3, 9, 10, 11, 12-hexahydro-10-hydroxy-9- methyl-l-oxo-9, 12-epoxy-lH-diindolo [1, 2, 3-fg: 3 ', 2', 1 '-kl] pyrrolo [3,4-i] [1,6] benzodiazocin- 10-carboxylic. The following references relate to Compound I, in particular to methods for their preparation [J. Med. Chem. 1997, 40 (12), 1863-1869; Curr .. Med. Chem. -Central Nervous System Agents, 2002, 2 (2), 143-155] and its potential medical uses, mainly in diseases in the central nervous system (CNS), in particular for the treatment of neurodegenerative diseases , for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, and auditory lesions such as noise-induced hearing loss [Progress in Medicinal Chemistry (2002), 40, 23 -62; Bioorg. Med. Chem. Lett. 2002, 12 (2), 147-150; Neuroscience, Oxford, 1998, 86 (2), 461-472; J. Neurochemistry (2001), 77 (3), 849-863; J. Neuroscience (2000), '20 (1), 43-50; J. Neurochemistry (2002), 82 (6), 1424-1434; Hearing Research, 2002, 166 (1-2), 33-43]. The following patent documents refer to Compound I, including its medical use and synthesis: WO 9402488, WO 9749406, US Patent 5621100, European Patent 0651754 and European Patent 112 932. By the known methods, Compound I is synthesized in a solid amorphous form. The inventors have now discovered 5 crystalline forms of Compound I (designated alpha, beta, gamma, delta and epsilon) thereby providing an opportunity to improve the manufacturing process of Compound I and its pharmaceutical use. There is a need to provide crystalline forms, which can exhibit desirable and beneficial chemical and physical properties. There is also a need for reliable and reproducible methods for the manufacture, purification and formulation of Compound I, to allow its feasible commercialization.

BRIEF DESCRIPTION OF THE INVENTION In a first aspect, the present invention relates to crystalline Compound I, in particular to the crystalline forms of Compound I. Accordingly, the invention provides a crystalline form of Compound I called alpha and characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 1 as measured using CuKa radiation; (ii) an X-ray powder diffractogram as measured using CuKa radiation having reflections at angles 2 ?: 5.2, 7.3, 8.1, 10.1, 10.4, 11.2, 13.2, 15.1, 15.5, 17.3, 21.7, 23.8, 25.1 ( iii) the NMR spectrum of Carbon-13 in the solid state shown in Figure 7; (iv) the NIR reflectance spectrum shown in Figure 10. In a further aspect the invention provides a crystalline form of Compound I called beta and characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 2 as measured using CuKa radiation; (ii) an X-ray powder diffractogram as measured using CuKa radiation with reflections at angles 2 ?: 6.6, 8.9, 10.7, 11.4, 11.7, 13.7, 17.0, 18.5, 18.8, 19.2, 20.3, 24.4, 30.6; (iii) the NMR spectrum of Carbon-13 in the solid state shown in Figure 8; (iv) the NIR reflectance spectrum shown in. Figure 11. In yet another aspect, the invention provides a crystalline form of Compound I called gamma and characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 3 as measured using CuKa radiation; (ii) an X-ray powder diffractogram as measured using CuKa radiation with reflections at angles 2 ?: 7.5, 8.3, 9.6, 11.5, 11.8, 12.5, 15.9, 16.3, 16.7, 17.2, 18.0, 19.3, 21.0, 28.1; (iii) the NMR spectrum of Carbon-13 in the solid state shown in Figure 9; (iv) the NIR reflectance spectrum shown in Figure 12.

In a further aspect, the invention provides a crystalline form of Compound I called delta and characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 13 as measured using CuKa radiation; (ii) an X-ray powder diffractogram as measured using CuKa radiation with reflections at angles 2 ?: 7.3, 8.3, 9.7, 11.1, 11.7, 12.1, 15.6, 16.1, 17.3, 18.3, 20.9, 22.1, 22.2, 25.7 , 25.8. In a further aspect, the invention provides a crystalline form of Compound I termed epsilon and characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 15 as measured using CuKa radiation; (ii) an X-ray powder diffractogram as measured using CuKa radiation with reflections at angles 2 ?: 8.9, 9.2, 10.2, 12.6, 14.2, 14.6, 17.0, 18.6, 20.4, 21.1, 23.9, 25.2. The invention further relates to methods for preparing the crystalline forms of the invention and to the use of such forms in the preparation of a medicament comprising Compound I as an active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Shows an X-ray powder diffractogram of the alpha form of Compound I.

Figure 2: Shows an X-ray powder diffractogram of the beta form of Compound I. Figure 3: Shows an X-ray powder diffractogram of the gamma form of Compound I. Figure 4: Shows a DSC thermogram of the alpha form of Compound I. Figure 5: Shows a DSC thermogram of the beta form of Compound I. Figure 6: Shows a DSC thermogram of the gamma form of Compound I. Figure 7: Shows an NMR spectrum of Carbon-13 in the solid state of the form alpha of Compound I. Figure 8: Shows a solid-state Carbon-13 NMR spectrum of the beta form of Compound I. Figure 9: Shows a solid-state Carbon-13 NMR spectrum of the gamma form of Compound I Figure 10: Shows a NIR reflectance spectrum of the alpha form of Compound I. Figure 11: Shows a NIR reflectance spectrum of the beta form of Compound I. Figure 12: Shows a NIR reflectance spectrum of the gamma form of Compound I. Figure 13: Shows an X-ray powder diffractogram of the delta form of Compound I.

Figure 14: Shows a DSC thermogram of the delta form of Compound I. Figure 15: Shows a diffractogram of X-ray powder of the epsilon form of Compound I. Figure 16: Shows a DSC thermogram of the epsilon form of Compound I . Figure 17: Shows the conformation of one of the molecules (molecule 1) in the alpha form of Compound I. Figure 18: Shows the conformation of the other molecule (molecule 2) in the alpha form of Compound I. Figure 19: Shows the packing of the molecules in the alpha form of Compound I. Other details for the figures are disclosed in the Examples that appear below.

DETAILED DESCRIPTION OF THE INVENTION The discovery of a crystalline form of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of the pharmaceutical product and the manufacturing process. Differences in physical properties, such as stability (shelf life), bioavailability, solubility, and dissolution index, shown by the different solid forms of a compound, are factors important in the manufacture and formulation of a compound. Differences in stability can be the result of changes in chemical reactivity (eg, oxidation) or mechanical changes (eg, tablets are shredded into storage that can lead to conversion to a thermodynamically more stable crystalline form) or both of them. The physical properties of a solid form are important in processing, for example, a solid form can be more difficult to filter and wash free of impurities. This may be due to differences in the shape and size distribution of the particles between one crystalline form relative to the other and the amorphous form. Additionally, for drugs that exist in different crystalline forms and which are sold in solid form, it is generally important both for medical and commercial reasons to produce and market a known crystalline form. The discovery of crystalline Compound I and the existence of 5 crystalline forms allow the development of a defined crystalline form instead of an amorphous solid. Also, the physical properties of crystalline Compound I offer advantages for the development of formulations and the preparation of tablets, for example, direct compression is facilitated by having a defined crystalline form.

The crystalline compounds are generally more stable than the corresponding amorphous compound, and this is particularly important in the case of the light sensitive and sensitive Compound I. Experiments wcarried out on a Heraeus Suntest CPS + for crystalline forms alpha, beta and gamma whthe solid compound was exposed to light for 14 hours at 650 watts. The treatment with light led to a degradation of almost 60% of the amorphous substance while the crystalline forms showed less than 30% degradation. Compound I contains two sulfur atoms and is easily oxidized to a complex mixture of sulfones and sulfoxides. This sensitivity to oxidation requires great care during the purification of Compound I. The present invention, which makes possible the purification of Compound I by crystallization, reduces the levels of oxidized compounds in comparison with the product obtained when the inventors have used other purification methods such as chromatography. Additionally, compound I contains an active ester group which can undergo transesterification reactions and is also susceptible to hydrolysis. In the final step in the synthesis of Compound I, the desired thiol-ethyl side chains are introduced using ethyl mercaptan as a reagent [J. Med. Chem. 1997, 40 (12), 1863-1869; Curr. Med. Chem. - Central Nervous System Agents, 2002, 2 (2), 143-155]. Ethyl mercaptan has a characteristic strong odor, which is undesirable in a pharmaceutical product. Isolation of Compound I as an amorphous solid results in the inclusion of ethylmercaptan in the solid product, while the levels of this undesired reagent are reduced through crystallization. Additionally, the physical characteristics of the crystalline forms of the invention improve the isolation step, for example, by decreasing the filtration times compared to the amorphous form of Compound I, which is of great importance for the large-scale manufacture of the Compound. 1. In this regard, it was discov that the delta form has better filtration properties than the alpha form. A further diffce in the physicochemical properties of the crystalline forms compared to the amorphous form is the higher melting points, see Table I which appears later in Example 9, which may provide advantages in the further processing. As indicated above, the inventors have now discov that Compound I can be prepared in a crystalline form and that thare at least 5 forms Crystallines of Compound I, designated hn as alpha, beta, gamma, delta and epsilon. Thore, in a broad aspect, the invention relates to crystalline Compound I, in particular to a crystalline form of Compound I. As used hn, the term "a crystalline form of Compound I" comprises any crystalline form of the Compound I, that is, in contrast to the amorphous form. In particular, the term "Crystalline Compound I" includes the crystalline form alpha, beta, gamma, delta and / or epsilon of Compound I. Said forms are as defined hn. The crystalline forms of a compound are difftiated by the positions of the atomic nuclei in the unit cell of the solidified compound. The diffces produce difft macroscopic properties such as thermal behavior, vapor permeability and solubility, which as indicated above have practical consequences in pharmacy. The various forms described hn can be distinguished from each other through the use of various analytical techniques known to one skilled in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRD, short for the English expression "X-ray powder diffraction"), difftial scanning calorimetry.

(DSC, "difftial scanning calorimetry"), nuclear magnetic resonance spectroscopy (NMR, short for "nuclear magnetic resonance") in solid state and near infrared spectroscopy (NIR, abbreviation of the term "Near-infrared"). they are more easily distinguishable by X-ray analysis. Single crystal X-ray crystallography produces information that can be used to determine the positions of the nuclei, which in turn can be visualized with computer or mechanical models, thereby providing a Three-dimensional composite image While single-crystal X-ray studies provide mismatched structural information, they are costly and quality data is sometimes difficult to acquire X-ray powder diffraction is most often used by the pharmaceutical industry to characterize new crystalline forms of drugs that the X-ray analysis of e unique crystal, the diffraction of • X-ray powder produces a fingerprint that is unique to the crystalline form and is able to distinguish it from the amorphous compound and all other crystalline forms of the compound.

Accordingly, one embodiment of the invention relates to a crystalline form of Compound I called alpha, characterized by the X-ray powder diffractogram shown in Figure 1 as measured using CuKa radiation. In a further embodiment, the alpha form of Compound I is characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 5.2, 10.1, 10.4, 13.2, 15.1, 25.1. The alpha form of Compound I can also be characterized by having reflections in the X-ray diffractogram as measured using CuKa radiation at 2T angles: 5.2, 7.3, 8.1, 10.1, 10.4, 11.2, 13.2, 15.1, 15.5, 17.3, 21.7 , 23.8, 25.1. The alpha form of Compound I can also be characterized by the NMR spectrum of Carbon-13 in the solid state shown in Figure 7. The alpha form of Compound I can also be characterized by the NIR reflectance spectrum shown in Figure 10. The alpha form of Compound I can also be characterized as having a melting point in the range of 180-190 ° C. The alpha form of Compound I can also be characterized as having a DSC thermogram substantially in accordance with that shown in Figure 4. The alpha form of Compound I can also be characterized by a DSC thermogram having an endotherm of approximately 170 ° C a approximately 200 ° C. The crystal structure of the alpha form (Example 8.5) has a space in the crystal lattice that may or may not be occupied by a smaller solvent, in particular a water molecule or a methanol molecule. Therefore, the alpha-crystalline form of Compound I can be a solvate of varying amounts of water and / or methanol. Accordingly, the invention also relates to a crystalline form characterized by having a crystalline structure with the following characteristics at 122 K: Spatial group: P2? 2? 2 ?, unit cell dimensions: a = 10.227 (2) A, b = 23.942 (2) A and c = 24.240 (2) A, a = 90 °, ß = 90 °,? = 90 °, 2 molecules in the asymmetric unit. Since the asymmetric unit in this crystal structure contains 2 molecules of Compound I and one solvent site, the complete occupation of the solvent site leads to a hemisolvate. The invention further relates to the aforementioned crystal structure having atomic positions substantially as described by the coordinates in Tables 2-4. When indicated herein for the X-ray powder diffractogram data, the-reflections (peaks) are understood to mean that the reflections are expressed in degrees (at angles 20, that is, at 2-theta angles).

A further embodiment refers to a crystalline form of Compound I, termed beta, characterized by the X-ray powder diffractogram shown in Figure 2 as measured using CuKa radiation. In a further embodiment, the beta form is characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 6.6, 8.9, 10.7, 11.7, 24.4, 30.6. The beta form of Compound I can also be characterized by having reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 6.6, 8.9, 10.7, 11.4, 11.7, 13.7, 17.0, 18.5, 18.8 , 19.2, 20.3, 24.4, 30.6. The beta form of Compound I can also be characterized by the solid-state Carbon-13 NMR spectrum shown in Figure 8. The beta form of Compound I can also be characterized by the NIR reflectance spectrum shown in Figure 11. The beta form of Compound I can also be characterized by having a melting point in the range of 209-213 ° C, preferably about 211 ° C. The beta form of Compound I can also be characterized as having a DSC thermogram substantially in accordance with that shown in Figure 5. The beta form of Compound I can also be characterized by a DSC thermogram which has an endotherm from about 205 ° C to about 220 ° C. A further embodiment refers to a crystalline form of Compound I called gamma, characterized by the X-ray powder diffractogram shown in Figure 3 as measured using CuKa radiation. In one embodiment, the gamma shape is characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 9.6, 11.5, 12.5, 16.7, 19.3, 28.1. The gamma form of Compound I can also be characterized by having reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 7.5, 8.3, 9.6, 11.5, 11.8, 12.5, 15.9, 16.3, 16.7 , 17.2, 18.0, 19.3, 21.0, 28.1. The gamma form of Compound I can also be characterized by the solid-state Carbon-13 NMR spectrum shown in Figure 9. The gamma form of Compound I can also be characterized by the spectrum by NIR-reflectance shown in Figure 12 The gamma form of Compound I can also be characterized as having a melting point in the range 212-218 ° C. The gamma form of Compound I can also be characterized as having a DSC thermogram substantially in accordance with that shown in Figure 6. The gamma form of Compound I can also be characterized by a DSC thermogram which has an endothermy of about 210 ° C to about 225 ° C. An additional embodiment refers to a crystalline form of Compound I, called a delta, characterized by the X-ray powder diffractogram shown in Figure 13 as measured using CuKa radiation. In one embodiment, the delta shape is characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 9.7, 12.1, 16.1, 18.3, 22.1, 22.2, 25.7, 25.8. The delta form of Compound I can also be characterized by having reflections in the X-ray diffractogram as measured using CuKa radiation at angles 20: 7.3, 8.3, 9.7, 11.1, 11.7, 12.1, 15.6, 16.1, 17.3, 18.3, 20.9 , 22.1, 22.2, 25.7, 25.8. The delta form of Compound I can also be characterized as having a melting point in the range of 211-223 ° C. The delta form of Compound I can also be characterized as having a DSC thermogram substantially in accordance with that shown in Figure 14. The delta form of Compound I can also be characterized by a DSC thermogram having an endotherm of approximately 210 °. C at approximately 228 ° C. An additional embodiment refers to a crystalline form of Compound I, called epsilon, characterized by the X-ray powder diffractogram shown in Figure 15 as measured using CuKa radiation. In one embodiment, the epsilon form of Compound I is characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 8.9, 9.2, 10.2, 14.6. The epsilon form of Compound I can also be characterized by having reflections in the X-ray diffractogram as measured using CuKa radiation at angles 2 ?: 8.9, 9.2, 10.2, 12.6, 14.2, 14.6, 17.0, 18.6, 20.4, 21.1, 23.9, 25.2. The epsilon form of Compound I can also be characterized as having a melting point in the range of 180-185 ° C. The epsilon form of Compound I can also be characterized as having DSC thermogram substantially in accordance with that shown in Figure 16. The epsilon form of Compound I can also be characterized by a DSC thermogram having an endotherm of about 175 °. C at approximately 190 ° C. The invention further relates to any mixture of the crystalline forms of the invention, for example, a mixture of the alpha and gamma crystalline form of Compound I. As used herein, the terms "crystalline form of Compound I characterized by The X-ray powder diffractogram shown in Figure (1) as measured using CuKa "means the crystalline form of Compound I having an X-ray powder diffractogram substantially similar to Figure 1, ie, showing an X-ray powder diffraction pattern as exemplified in that Figure and measured under comparable conditions as described in Example 7.1 or by any comparable method using CuKa radiation.This definition is also applicable muta tis mutandis to the NMR and NIR Figures, and all other X-ray data described herein ( example, data of X-ray peaks) and for the totality of the five crystalline forms identified, that is, alpha, beta, gamma, delta and epsilon, respectively, so that margins of analytical variations are taken into account. of Carbon-13 in the solid state referred to herein, are preferably measured using a sample rotation speed of 5000 Hz in a spectro with a CP-MAS probe. Therefore, the NMR spectrum is preferably provided as described in Example 7.2 or by any comparable method. The NIR reflectance spectra referred to herein, are preferably provided as described in Example 7.3 or by any comparable method, in particular with a resolution of 2 cm-1 and correction of the change of baseline and inclination with Multiplicative Dispersion Correction (MSC, abbreviation of the English expression "Multiplicative Scatter Correction"). In further embodiments, the invention relates to a crystalline form of Compound I, which is substantially pure. The term "substantially pure" as used herein, means that the crystalline form of Compound I, for example, the form alpha, beta, gamma, delta or epsilon, is having a purity of at least about 90% including, for example, at least about 93% and at least about 95%. The amorphous form of Compound I is melted at a temperature of about 150 ° C which is easy to distinguish from the melting points of the crystalline forms described herein in Compound I, see Table 1 in Example 9. Accordingly , within the invention is also crystalline Compound I having a melting point which is at least 175 ° C, or at least 180 ° C, such as in the range of 175 ° C-225 ° C, 180 ° C-225 ° C, 180 ° C-220 ° C or 181 ° C-218 ° C, alternatively in the range of 180 ° C-190 ° C or 210 ° C-225 ° C. The term "melting point" as used herein, means the start value of the. fusion endotherm as measured by DSC, see example 7.4.

A further embodiment refers to solid Compound I containing the crystalline alpha form of Compound I. The invention also relates to solid Compound I consisting mainly of the crystalline alpha form of Compound I described herein. The term "mainly" in the present context means that the solid Compound I consists of at least 75%, such as at least 80%, at least 90%, or at least 95% of crystalline alpha form of Compound I total present. A further embodiment refers to solid Compound I which contains the crystalline beta form of Compound I. The invention also relates to solid Compound I consisting mainly of the crystalline beta form of Compound I described herein. The term "primarily" in the present context means that the solid Compound I consists of at least 75%, such as at least 80%, at least 90%, or at least 95% of the crystalline beta form of the Compound I total 'present. A further embodiment refers to solid Compound I containing the crystalline gamma form of Compound I. The invention also relates to solid Compound I consisting mainly of the crystalline gamma form of Compound I described herein. The term "mainly" in the present context means that the solid Compound I consists of at least 75%, such as at least 80%, at least 90%, or at least 95% of the crystalline gamma form of the total Compound I present. A further embodiment refers to solid Compound I which contains the crystalline delta form of Compound I. The invention also relates to solid Compound I consisting mainly of the crystalline delta form of Compound I described herein. The term "mainly" in the present context means that the solid Compound I consists of at least 75%, such as at least 80%, at least 90%, or at least 95% of the crystalline delta form of the Compound I total present. A further embodiment refers to solid Compound I which contains the crystalline epsilon form of Compound I. The invention also relates to solid Compound I consisting mainly of the crystalline epsilon form of Compound I described herein. The term "mainly" in the present context means that the solid Compound I consists of at least 75%, such as at least 80%, at least 90%, or at least 95% of the crystalline epsilon form of the Compound I total present. Broadly speaking, the novel crystalline forms of Compound I can be prepared by a variety of methods, including but not limited to, crystallizing Compound I from a solvent suitable. Compound I can be prepared using methods known in the art, such as those described herein. As a general guide, Compound I can be mixed with a suitable solvent, which can be heated to facilitate the dissolution of Compound I. The combination of solvent and Compound I can also be heated to facilitate subsequent conversion to the crystalline form. Preferred temperatures in this regard may range from about 30 ° C to about the boiling point (ie, the reflux temperature) of the solvent. More preferred temperatures may range from about 60 ° C to about the boiling point of the solvent. The resulting mixture of solvent and Compound I can be cooled to initiate and / or continue crystallization. The mixture is preferably cooled (i.e. including natural cooling to room temperature) to a temperature ranging, for example, from about minus 20 ° C to about 20 ° C, for example, up to room temperature. The precipitated solids can be isolated from the cooled mixture by, for example, filtration or centrifugation, and if necessary, washed with a suitable solvent such as, but not limited to the solvent used for crystallization, and vacuum-dried at room temperature. environment or slightly elevated, for example, under a nitrogen purge. The seed crystals can be added to any crystallization mixture to promote crystallization. As indicated above, crystalline Compound I, in particular the different crystalline forms of the invention can be prepared by (a) dissolving Compound I in a suitable solvent, (b) crystallizing by precipitation Compound I of the solvent, and (c) separating the solvent from the obtained crystalline Compound I; or alternatively by a process comprising the steps of: (a) suspending Compound I in a suitable solvent for a sufficient period of time to convert it into the crystalline form, and (b) separating the alcohol from the obtained crystalline Compound I. The way in which different solvents can be used to prepare the different crystalline forms of Compound I, alpha, beta, gamma, delta and epsilon is described below. In a preferred embodiment, the method of the invention for preparing crystalline Compound I, including the alpha, beta, gamma, delta or epsilon form, comprises precipitating crystallization of Compound I from a suitable solvent and separating the solvent from the form of the crystalline Compound I obtained. It is understood that when reference is made herein to the preparation of the different crystalline forms of the invention, and a product obtainable or more specifically a product obtained by such methods, this is also applicable to "a solid Compound I containing Compound I crystalline ", in particular as described above" a solid Compound I consisting mainly of a crystalline form in particular of Compound I ", for example, the form alpha, beta, gamma, delta or epsilon. Accordingly, in one aspect, the invention relates to a method for preparing crystalline Compound I, characterized in that said crystalline Compound I is formed in a solvent selected from the group consisting of: (i) methanol with 0% up to about 8% water; (ii) an aliphatic C3-C6 alcohol (eg, 1-propanol, 1-butanol, 2-butanol, terbutanol, 1-pentanol) with 4-8% water (eg, 1-butanol with 4% water); 1-propanol with 4% water, 1-pentanol with 4% water, tert-butanol with 7% water, 2-butanol with 4% water); (iii) an acetic acid ester with at least 4% water present, wherein said acetic acid ester is defined by the formula CH 3 CO 2 R, where R is a C 1 -C 6 alkyl, for example ethyl acetate or ethyl acetate; isopropyl (for example ethyl acetate with 4% of water or isopropyl acetate with 6% water). The invention also relates to crystalline Compound I obtainable, in particular obtained by such a method. In a preferred embodiment, this method leads to the formation of the alpha form of crystalline Compound I. In a further aspect, the invention relates to a method for preparing crystalline Compound I, characterized in that said crystalline Compound I is formed in the isopropyl acetate solvent. The invention also relates to crystalline Compound I obtainable, in particular obtained by such a method. In a preferred embodiment, this method leads to the formation of the beta form of crystalline Compound I. In a further aspect, the invention relates to a method for preparing crystalline Compound I, characterized in that said crystalline Compound I is formed in the solvent selected from the group consisting of: (i) an aliphatic C1-C3 nitrile (e.g. , acetonitrile, propionitrile) with up to about 12% water (for example, propionitrile with 4% water or acetonitrile with 12% water), it is understood that propionitrile (CH3CH2CN) is a C3 nitrile; (ii) ethanol with 0% to about 8% water; (iii) an aliphatic C3-C6 alcohol (e.g., 1-propanol or 1-butanol) with at least about 10% water (e.g., 1-propanol) % water, 1-butanol 10% water); (iv) ethyl acetate reactive grade. By the term "ethyl acetate reactive grade" is meant less than 0.5% water. The invention also relates to crystalline Compound I obtainable, in particular obtained by such a method. In a preferred embodiment, this method leads to the formation of the gamma form of crystalline Compound I. In a further embodiment, the invention relates to a method for preparing crystalline Compound I, characterized in that said crystalline Compound I is formed in a solvent selected from the group consisting of: (i) an aliphatic C2-C6 alcohol (e.g. , ethanol, cyclopropylmethanol or 1-propanol) with less than 4% water, for example less than 3%, for example about 2% (for example cyclopropylmethanol, 1-propanol 2% water, ethanol 2% water (without stirring). The invention also relates to crystalline Compound I obtainable, in particular obtained by such a method In a preferred embodiment, this method leads to the formation of the delta form of crystalline Compound I. • In a further embodiment, the invention relates to a method for preparing crystalline Compound I, characterized in that said crystalline Compound I is formed in the solvent butylenitrile (CH3CH2CH2CN) The invention also relates to the Compound Crystalline I obtainable, in particular obtained by such a method. In a preferred embodiment, this method leads to the formation of the epsilon form of crystalline Compound I. It has also been found that each of the crystalline alpha and beta forms can be converted to the crystalline gamma form in the presence of a suitable solvent, in particular acetonitrile as shown in Example 6.1. The crystalline beta form can be converted to the alpha crystalline form in the presence of methanol as shown in Example 6.1. The invention also relates to a crystalline product, in particular the crystalline forms of Compound I obtainable, or in a preferred embodiment obtained by a process described herein for the preparation of crystalline Compound I. The invention in a further aspect relates to a process for the preparation of Compound I which comprises converting a crystalline form of Compound I (e.g., the alpha, beta or gamma form as described herein or any mixture thereof) in the amorphous form of Compound I. That kind of. process in a preferred embodiment comprises the steps of: (a) dissolving crystalline Compound I in an aromatic solvent, i.e. an aromatic hydrocarbon, preferably an alkylbenzene such as xylene or toluene, (b) precipitating Compound I of the aromatic solvent; and (c) separating the aromatic solvent from the precipitated amorphous Compound I. As indicated above, the formation of crystalline Compound I is very useful, among other things, as a purification step in the manufacture of Compound I for pharmaceutical use. The invention in one aspect relates to a process for the manufacture of Compound I comprising a crystallization step as described herein. Thus, one embodiment of the invention relates to a method for the manufacture of Compound I, which method comprises a step in which Compound I is converted to crystalline Compound I. It is understood that the crystalline Compound I of the invention can be prepared by a method as described herein, for example by precipitating Compound I in crystalline form from a solvent as described herein and by separating the crystalline Compound I obtained from the solvent . The invention relates in particular to a method for the manufacture of Compound I, in which Compound I is converted to crystalline Compound I, including a crystalline form of the invention, for example, the form, alpha or gamma of a mixture Raw of Compound I. The term crude mixture in this context means that the mixture comprises impurities, for example oxidation products derived from Compound I which are desired to be removed. The crude mixture can be separated directly from the reaction mixture, or the crude reaction mixture may have been subjected to some initial purification, for example, by treating it with a base. The invention further relates to the use of a crystalline Compound I or a solid of the invention in the preparation of a medicament comprising Compound I as an active ingredient. Therefore, the invention also relates to a method for the manufacture of a pharmaceutical composition of Compound I. Said method comprises preparing said crystalline Compound I composition as defined herein, for example obtained by a method as described herein, including a crystalline form or a solid of the invention. A specific embodiment refers to that type of use of the alpha or gamma form of the invention, for the preparation of a pharmaceutical composition. As described above, the preparation of the formulations from a defined crystalline form has the advantage of improved purity and improved yield and having well-defined properties, such as solubility. Regarding this, the invention also provides a pharmaceutical composition comprising an effective amount of Compound I obtainable or obtained by a method of the invention for the preparation of crystalline Compound I, including a crystalline form of the invention, for example of the alpha or gamma form. The pharmaceutical composition can be any composition that is found suitable for the administration of Compound I, for example, a solid dispersion formulation or a solid solution formulation. In one embodiment, the crystalline product of the invention, i.e. including in particular the crystalline form alpha, beta, gamma, delta or epsilon, or mixtures thereof, can be formulated in a solid solution or a solid dispersion. A solid solution can be prepared by dissolving the crystalline product of the invention in a molten vehicle. The solid solution is formed after cooling to room temperature. A solid dispersion can be prepared by dispersing the crystalline product of the invention in a molten vehicle. The solid dispersion is formed after cooling to room temperature. The vehicle used to prepare the solid solution or the solid dispersion can be a component or a mixture of more components. The vehicle used to prepare the solid solution or the solid dispersion is usually solid or semi-solid at room temperature and It usually has a sticky, oily or waxy character. However, the vehicle can also be fluid at room temperature or even at a temperature below 5 ° C. As examples of vehicles, mention may be made of polyethylene glycols (PEG), poloxamers, polyethylene glycols esters, waxes, glycerides, fatty acid alcohols, fatty acids, sugar alcohols, vitamin E and vitamin E derivatives. The solid solution or the Solid dispersions can be used as they are or alternatively they can be formulated into pharmaceutical compositions such as tablets, capsules etc. The solid solution and the solid dispersion can also be prepared by other methods such as for example by the solvent method or the fusion method (Serajuddin, A.T.M., Journal of Pharmaceutical Sciences, Vol. 88, 1058-1066). One embodiment of the invention relates to a pharmaceutical composition which is a solid solution prepared from crystalline Compound I of the invention, for example, from the crystalline alpha or gamma forms of the invention. Therefore, the crystalline product of the invention, in particular the crystalline forms alpha, beta, gamma, delta or epsilon, or their mixtures, can be used in the preparation of a pharmaceutical composition with Compound I in solution, for example a composition similar to that described in U.S. Patent No. 6,200,968. Within the invention there is also a pharmaceutical composition comprising an effective amount of crystalline Compound I as described herein, in particular the alpha, beta, gamma, delta or epsilon forms defined herein, and a pharmaceutically acceptable carrier. The crystalline product of the invention, i.e. including the alpha, beta, gamma, delta or crystalline epsilon form, or mixtures thereof, can be formulated in a variety of pharmaceutical compositions. Examples of such formulations comprising a crystalline product of the invention (e.g., crystalline alpha, beta, gamma, delta or epsilon forms) are tablets, capsules, granules, powders, suppositories and suspensions. The term "crystalline product of the invention" means a crystalline Compound I or a solid Compound I as described herein, ie by "Compound I solid" in the present context is understood as a solid Compound I consisting primarily of the Crystalline Compound I compared to the amorphous Compound. The pharmaceutical compositions according to the invention can be formulated with carriers or diluents pharmaceutically acceptable as well as any other adjuvant and excipient, for example, according to techniques such as those described in Remington: The Science and Practice of Pharmacy, Edition no. 19, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions can be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including the buccal route). and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), the oral route is preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. In one embodiment of the pharmaceutical composition, Compound I is administered in an amount between about 0.001 and about 100 mg / kg of body weight per day. Compound I can be administered, for example, in a unit dosage form containing said compound in an amount of about 0.01 to 100 mg. The total daily dose is, for example, in the range of about 0.05-500 mg. The formulations can conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain between 0.01 and about 1000 mg, preferably between about 0.05 and about 500 mg. For parenteral routes such as intravenous, intrathecal, intramuscular and similar routes, typically doses are in the order of about half the dose used for oral administration. As indicated above, the following embodiments are within the invention: Crystalline Compound I for use as a medicament; the crystalline alpha form for use as a medication; the crystalline beta form for use as a medication; the crystalline gamma form for use as a medicine, the crystalline delta form for use as a medicine; the crystalline epsilon form for use as a medicine. The invention also relates to the use of the Crystalline compound I as described herein, for example the alpha, beta, gamma, delta or epsilon form defined herein or mixtures thereof, in the preparation of a medicament for the treatment of a CNS disease, for example , for the treatment of a neurodegenerative disease, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, or hearing damage including noise-induced hearing loss. Similarly, within the invention there is also a method for treating a neurodegenerative disease, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, or hearing damage including loss of consciousness. noise induced hearing, which comprises administering a pharmaceutically effective amount of crystalline Compound I as described herein, for example the alpha, beta, gamma, delta or epsilon form defined herein or mixtures thereof. The aforementioned medical uses and pharmaceutical compositions, for example for the treatment of Parkinson's disease, of the crystalline Compound I and a crystalline form of the invention, are likewise applicable to the solid Compound I defined herein as comprising a crystalline form of the invention , in particular a solid Compound I consisting mainly of a crystalline form of the invention. The term "treatment" related to a disease as used herein also includes prevention as the case may be. The term "disease" as used herein also includes a disorder as the case may be. The invention described herein is further illustrated by the following non-restrictive examples.

EXAMPLES In the following, the starting material, "Compound I" can be prepared, for example, as described by Kaneko M. et al in J. Med. Chem. 1997, 40, 1863-1869.

Example 1. Preparation of the crystalline alpha form of Compound I Method I): 6.0 g of amorphous Compound I was dissolved in 30 ml of acetone. 0.6 g of potassium carbonate was added and the suspension was stirred at room temperature for 1 hour before being filtered to remove potential insoluble minor impurities and inorganic salts. The filter cake was washed with acetone. Then, the filtrate was evaporated in a rotary evaporator under reduced pressure at 60 ° C to a final volume of 10 ml to which were added 100 ml of methanol slowly. The product was separated as an oil, which almost dissolved with heating to reflux. Subsequently, residual insoluble impurities were removed by filtration. The filtrate was left with stirring at room temperature. A crystalline solid was separated and isolated by filtration. The filter cake was washed with methanol and dried under vacuum at 60 ° C overnight. Yield 2.83 g (47%), mp = 182.4 ° C (start value by DSC), Weight loss by heating: 0.5%, Analysis of elements: 6.71% N, 63.93% C, 5.48% H, theoretical values corrected for 0.5% H20: 6.79% N, 64.05% C, 5.43% H. The XRPD analysis corresponds to the alpha form.

Method II): 5 g of amorphous Compound I was dissolved in 25 ml of acetone with gentle heating. 10 ml of methanol were added very slowly until the solution became cloudy. The solution was allowed to cool to room temperature by natural cooling. The suspension was filtered and the filter cake was discarded. During filtration, more material precipitated in the filtrate. The filtrate was heated until all the material was redissolved. Then, the cold methanol was added to the solution until precipitation was observed. Then, he heated the slightly cloudy solution until all the material was in solution. The solution was allowed to cool to room temperature, and the precipitate was removed by filtration. The second filter cake was discarded. During the filtration, some material was separated in the filtrate. The heating redissolved the initial crystallization in the filtrate. Then the cold methanol was added to the solution until precipitation was observed. The suspension was heated until a clear solution was obtained. The solution was allowed to reach room temperature by natural cooling. After a short period of time (15 minutes) the precipitation began. The pale yellow product precipitated was isolated by filtration and dried under vacuum at 50 ° C overnight. pf = 188.9 ° C (Start value of DSC), Weight loss by heating: 0.3%, Analysis of elements: 6.53% N, 64.33% C, 5.43% H, theoretical values: 6.82% N, 64.37% C, 5 , 37% H. The XRPD analysis corresponds to the alpha form.

Method III: 0.5 g of Compound I was heated in a mixture of isopropyl acetate (10 ml) and water (0.6 ml) to reflux with stirring. The compound was not completely dissolved, then acetate was added Isopropyl (10 ml) and water (0.6 ml) and heated to reflux. Stirring was stopped and the experiment allowed to cool to room temperature. The crystalline product obtained was isolated by filtration and dried in vacuum at 40 ° C. Yield = 0.25 g, mp = 183.7 ° C (DSC start value). The XRPD analysis corresponds to the alpha form.

Method IV: 0.5 g of Compound I was heated in a mixture of ethyl acetate (10 ml) and water (0.4 ml) to 70 ° C with stirring. The experiment was allowed to cool to room temperature. The obtained crystalline product was isolated by filtration and dried under vacuum at 40 ° C. The XRPD analysis corresponds to the alpha form.

Example 2. Preparation of crystalline beta form of Compound I 28.0 g of amorphous Compound I was dissolved in 250 ml of tetrahydrofuran (THF) and evaporated on 60 g of silica gel. The compound was purified by column chromatography on silica gel (0: 10 cm h: 5 cm with 2.7 1 THF / heptane 2/1). The eluent containing the desired compound was evaporated in a rotary evaporator under reduced pressure at 50 ° C until a solid (26 g) was obtained. He The solid was suspended in 600 ml of isopropyl acetate and the suspension was heated to reflux until almost all the material was dissolved. The suspension was cooled in a water / ice bath. The cold suspension was filtered, and the filter cake was washed with isopropyl acetate and dried under vacuum overnight at 50 ° C. Yield: 16.9 g (61%), mp = 211.7 ° C (DSC start value), Weight loss by heating: 0.2%, Element analysis: 6.59% N, 64.63% C, 5.41% H, theoretical values: 6.82% N, 64.37% C, 5.40% H, The analysis of XRPD corresponds to the beta form.

Example 3. Preparation of the crystalline gamma form of Compound I Method I: 15 g of amorphous Compound I was dissolved in 75 ml of acetone. 1.5 g of potassium carbonate was added and the suspension was stirred for 90 minutes. The suspension was filtered. The filtrate was reduced to approximately 30 ml in a rotary evaporator under reduced pressure at 60 ° C. 150 ml of methanol was added to the reduced filtrate, and some sticky material was removed. The suspension was heated to reflux. During the heating, all the material is dissolved. The solution was allowed to cool to room temperature environment by natural cooling, during this period the solid material was separated. The suspension was left with stirring at room temperature overnight. The suspension was filtered and the filter cake was washed with methanol. The filter cake was dried under vacuum at 50 ° C overnight. The intermediary yield is 10.2 grams (68%). The dried filter cake was suspended in 100 ml of acetonitrile (ACN) and heated to reflux. A cloudy solution was obtained at reflux. Additional acetonitrile was added until a clear solution was obtained; In total the filter cake was dissolved in 200 ml of acetonitrile including the 100 ml used for the suspension. The solution was cooled to room temperature overnight. The next day the crystalline product was isolated by filtration. The filter cake was washed with a small amount of acetonitrile and dried under vacuum at 55 ° C overnight. Yield: 6.17 g, 41%, mp = 218.0 ° C (DSC start value), Weight loss by heating: < 0.1%, Analysis of elements: 6.80% N, 64.38% C, 5.43% H, theoretical values: 6.82% N, 64.37% C, 5.40% H, Purity (HPLC,% area): 98.6, the XRPD analysis agrees with the gamma form.

Method II: 0.5 g of Compound I was heated in a mixture of acetonitrile (8.8 ml) and water (1.2 ml) to 70 ° C with stirring. The solution was allowed to cool slowly to room temperature. The next day, the crystalline product was isolated by filtration and dried under vacuum at 40 ° C, mp = 214.2 ° C (DSC start value). The XRPD analysis agrees with the gamma form.

Method III: 0.5 g of Compound I was heated in ethyl acetate (5 ml) to 70 ° C with stirring. The solution was allowed to cool slowly to room temperature. After 12 days, the crystalline product was isolated by filtration and dried under vacuum at 40 ° C. The XRPD analysis agrees with the gamma form.

Example 4. Preparation of the crystalline Delta form of Compound I Method I: 0.5 g of the alpha form of Compound I was heated in cyclopropylmethanol (10 ml) to 70 ° C. The solution was allowed to cool slowly to room temperature. After 2 days, the crystalline compound was isolated by filtration and vacuum drying at 40 ° C. Performance = 0.24 g, mp = 212.1 ° C (DSC start value), the XRPD analysis agrees with the delta shape.

Method II 0.2 g of the alpha form of Compound I was heated in ethanol (10 ml) to 70 ° C with stirring. Stirring was stopped and the solution allowed to cool slowly to room temperature. The next day, the crystalline product was isolated by filtration and dried under vacuum at 40 ° C. Performance = 0.15 gr .. pf = 221.6 ° C (DSC start value), the XRPD analysis agrees with the delta shape.

Method III: 0.5 g of Compound I in 1-propanol (15 ml) was heated to 70 ° C with stirring. Stirring was stopped and the solution allowed to cool slowly to room temperature. The next day, the crystalline compound was isolated by filtration and dried under vacuum at 40 ° C. Performance = 0.23 g, the analysis of XRPD agrees with the delta form.

Use 5. Preparation of crystalline Epsilon orma of Compound I 0.5 g of the alpha form of Compound I was heated in butylnitrile (10 ml) to 70 ° C with stirring. The solution was allowed to cool slowly to room temperature. The next day, the crystalline product was isolated by filtration and dried under vacuum at 40 ° C. Yield = 0.3 g, mp = 181.8 ° C (DSC start value), the XRPD analysis agrees with the epsilon form.

Example 6. Transformation between the different solid forms of Compound I 6. 1 Conversions to crystalline Compound I In the following examples excess solid Compound I is used, i.e., in comparison with the solvent, the amounts of solid Compound I are such that not all solid material dissolves. The amounts used varied between 25-50 mg of solid Compound I and 2-5 ml of solvent. In the present context, by "Solid Compound I" is meant amorphous Compound I or any of the crystalline forms of Compound I as indicated below. (i) Excess of amorphous Compound I was added to methanol, and the resulting suspension was stored in a "rotarmix" (rotary mixer) for 4 days at room temperature. After 4 days, the solid was the alpha form as determined by X-ray powder diffraction. (Ii) Excess of the crystalline alpha form of Compound I was added to methanol, and the resulting suspension was stored in a rotary mixer during 4 days at room temperature. After 4 days, the solid was still the alpha form as determined by X-ray powder diffraction. (Iii) Excess of the crystalline beta form of Compound I was added to methanol, and the resulting suspension was stored in a rotary mixer. for 4 days at room temperature. After 4 days, the solid was the alpha form as determined by X-ray powder diffraction. (Iv) Excess was added. crystalline gamma form of Compound I to methanol, and the resulting suspension was stored in a rotary mixer for 4 days at room temperature. After 4 days, the solid was still the gamma form as determined by X-ray powder diffraction. (v) An excess of the alpha form and gamma form of Compound I was added to methanol, and the resulting suspension was stored in a rotary mixer for 4 days at room temperature. After 4 days, most of the solid was the gamma form. After filtration, the supernatant was left for evaporation of the solvent. The resulting solid was the alpha form as determined by X-ray powder diffraction. (Vi) An excess of amorphous Compound I was added to acetonitrile (ACN), and the resulting suspension was stored in a rotary mixer for 4 days at room temperature. ambient. After 4 days, the solid was the gamma form as determined by X-ray powder diffraction. (Vii) An excess of the crystalline alpha form of Compound I was added to ACN, and the resulting suspension was stored in a mixer rotating for 4 days at room temperature. After 4 days, the solid was the gamma form as determined by X-ray powder diffraction. (Viii) An excess of the crystalline beta form of Compound I was added to ACN, and the resulting suspension was stored in a rotary mixer. for 4 days at room temperature. After 4 days, the solid was the gamma form as determined by X-ray powder diffraction. (ix) An excess of the crystalline gamma form of Compound I was added to ACN, and the resulting suspension was stored in a rotary mixer for 4 days at room temperature. After 4 days, the solid was still the gamma form as determined by X-ray powder diffraction.

Conclusion: Amorphous Compound I and the crystalline beta form can be converted to the crystalline alpha form in a methanol suspension. Amorphous Compound I, the alpha crystalline form and the crystalline beta form can be converted to the crystalline gamma form by suspension of an excess of the solid material in acetonitrile. 6. 2 Conversions of the crystalline alpha form to amorphous Compound I 15 g of the crystalline alpha form of Compound I were heated to reflux in a mixture of toluene (110 ml) and methanol (1 ml); a clear solution was obtained.

Under reduced pressure, the volume of the solvent was decreased by 10 ml and the solution was cooled during the night in a freezer. The resulting solid was isolated by filtration, dried in vacuo for two days at 40 ° C to give 13.2 g of a solid. The melting temperature of the solid was about 150 ° C, which is characteristic of. the amorphous form of Compound I compared to the crystalline forms, see Table 1 below.

Example 7 Analytical Methods (7.1) The XRPD standards were measured on a diffractometer under one of the following conditions: Xi ^ $ yy ^ '(i) STOE diffractometer Radiation: Cu (Kal), monochromatic germanium spectroscope,? = 1.540598 Á Sensitive Position Detector (PSD, acronym for "Position Sensitive Detector") covering 1 ° Explorer Type: Stage Scanner, stages: 0.1 °, 125-150 sec. per stage Interval: 5-45 ° 2? Method of sample measurement: Transmission (ii) PANalytical X 'Pert PRO X-ray Diffractometer that uses CuKa radiation ?. X'celerator detector, which measures the interval 5-40 ° 2T. Sample measurement method: Reflection (7.2) NMR (nuclear magnetic resonance) in solid state was carried out under the following conditions: NMR spectra by CP / MAS of Carbon-13 (cross-polarization / rotation ("spinning" ") • magical angle) were acquired at room temperature at 11.75 Tesla on a Bruker Avance DRX-500 spectrometer equipped with a 4 mm CP / MAS probe. The rotation speed of the sample was 5000 Hz, and 10240 scans were acquired using a recycle delay of 5 sec. For cross-polarization, 50 kHz spin lock radiofrequency fields and a contact time of 5 msec were used. (7.3) Data was collected near the infrared region of the spectrum (NIR, "Near-infrared") with a Bomem MB 160 FT / NIR spectrometer with Powder SamplIR. The reflectance spectra of NIR (near infrared) were recorded between 14,000-4,000 cm-1 with resolution 2 cm-1 (16 scans, high gain). Displacement of the baseline and tilt in NIR spectra, often seen in powder, were removed with Dispersion Correction Multiplicative (MSC, acronym of "Multiplicative Scatter Correction"). (7.4) Melting points They were determined in a DSC (Differential Scanning Calorimeter) (Differential Scanning Calorimeter) as the start temperature of the melting endotherm. Approximately 2 mg of sample was heated in an aluminum crucible with a loose lid at 5 ° C / min under N2 flow. (7.5) The crystal structure of the alpha form was determined under the following conditions: The diffraction data were collected on a Nonius KappaCCD diffractometer. The data collection was carried out at 122 K using MoKa radiation, monochromatized (? = 0.71073 Á).

Example 8. Analytical results 8. 1 X-ray powder data: The X-ray powder diffractogram (XRPD, abbreviation of the "X-ray powder diffractogram") of; the alpha form is shown in Figure 1; the beta form is shown- in Figure 2; the gamma form is shown in Figure 3; the delta shape is shown in Figure 13; the epsilon shape is shown in Figure 15. The different crystalline forms are characterized by different reflections (peaks) in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles determined: Alpha (5.2, 10.1, 10.4, 13.2, 15.1, 25.1, 5.2, 7.3, 8.1, 10.1, 10.4, 11.2, 13.2, 15.1 , 15.5, 17.3, 21.7, 23.8, 25.1); Beta (6.6, 8.9, 10.7, 11.7, 24.4, 30.6, 6.6, 8.9, 10.7, 11.4, 11.7, 13.7, 17.0, 18.5, 18.8, 19.2, 20.3, 24.4, 30.6); Gamma (9.6, 11.5, 12.5, 16.7, 19.3, 28.1, 7.5, 8.3, 9.6, 11.5, 11.8, 12.5, 15.9, 16.3, 16.7, 17.2, 18.0, 19.3, 21.0, 28.1); Delta (9.7, 12.1, 16.1, 18.3, 22.1, 22.2, 25.7, 25.8, 7.3, 8.3, 9.7, 11.1, 11.7, 12.1, 15.6, 16.1, 17.3, 18.3, 20.9, 22.1, 22.2, 25.7, 25.8); Epsilon (8.9, 9.2, 10.2, 14.6, 8.9, 9.2, 10.2, 12. 6, 14.2, 14.6, 17.0, 18.6, 20.4, 21.1, 23.9, 25.2). 8. 2. DSC thermograms: DSC thermograms are shown in Figures 4-6, 14, 16 (the alpha form in Figure 4, the beta form in Figure 5, and the gamma form in Figure 6, the form delta in Figure 14, the epsilon shape in Figure 16). 8. 3. NMR data in solid state: The NMR spectra in solid state are shown in Figure 7 for the alpha form, in Figure 8 for the beta form and in Figure 9 for the gamma form. 8. 4 NIR (Near Infrared) Data: The NIR spectra are shown in Figure 10 for the alpha form, in Figure 11 for the beta form and in Figure 12 for the gamma form. 8. Crystal Structure for the alpha form of Compound I: The crystal structure of the alpha form was determined by X-ray diffraction of single crystal at 122 K. The crystal used for the determination of the structure was obtained by the slow precipitation of MeOH and It had dimensions 0.5x0.3x0.2 mm. The resulting crystal structure shows that the alpha form of Compound I crystallizes in the orthorhombic space group P2? 2? 2? - with the cell dimensions at 122 K of: a = 10.227 (2) A, b = 23.942 (2) A and c. = 24.240 (2) Á, a = 90 °, ß = 90 °,? = 90 °, V = 5935.3 (12) Á3, Z = 8, density = 1.378 g / cm3 (the numbers in parentheses are standard deviations in the last digit). The unweighted match factor was R [I >; 2s (I)] = 0.0699. The asymmetric unit of the crystal contains two units of Compound I, and 0-1 solvent molecule. The solvent molecule can be either MeOH or water. In the determination of the structure, the atoms corresponding to the solvent were found with an occupation of C2": 0.70, 01": 0.50 and 03": 0.36 As' the asymmetric unit contains 2 molecules of Compound I and a solvent site, the total occupation of the site would lead to a hemisolvate.Atomic numeration and conformation of the two molecules in the asymmetric unit are shown in Figures 17-18, and the packing of the molecules in the crystal is shown in Figure 19. The atomic coordinates they are provided 'in Tables 2-4 which appear below.

Table 2: Atomic coordinates and equivalent isotropic displacement parameters for non-hydrogen atoms in molecule 1 Label X and z Ueg Cll -0.1062 (9) 0.2071 (4) 0.3154 (5) 0.119 (4) C12 -0.0922 (7) 0.2369 (3) 0.2679 (4) 0.097 (3) C13 0.0402 (5) 0.3338 (2) 0.3022 (2) 0.0517 (13) C14 0.1485 (4) 0.37791 (19) 0.29800 (19) 0.0414 (10) C15 0.1730 (5) 0.4125 (2) 0.34227 (19) 0.0482 (12) C16 0.2157 (4) 0.38580 (16) 0.24912 (17) 0.0331 (8) C17 0.2642 (4) 0.4561 (2) 0.34044 (17). 0.0396 (9) C18 0.3097 (3) 0.42813 (15) 0.24665 (15) 0.0278 (7) C19 0.3347 (4) 0.46402 (17) 0.29167 (15) 0.0320 (8) C20 0.3600 (3) 0.37367 (14) 0.12235 (15) 0.0271 (7) C21 0.4226 (3) 0.42266 (13) 0.15070 (14) 0.0233 (6) C22 0.3963 (3) 0.44422 (14) 0.20324 (14) 0.0238 (6) C23 0.4700 (3) 0.48995 (14) 0.22250 (14) 0.0241 (6) C24 0.5184 (3) 0.41458 (14) 0.06419 (15) 0.0264 (7) C25 0.5168 (3) 0.44565 (13) 0.11709 (13) OR ".0215. (6) C26 0.5911 (3) 0.49186 (13) 0.13513 (13) 0.0213 (6) C27 0.5642 (3) 0.51352 (14) 0.18804 (13) 0.0230 (6) C28 0.6972 (3) 0.52525 (14) 0.11306 (14) 0.0228 (6) C29 0.7277 (3) 0.56606 (14) 0.15290 (13) 0.0234 (6) C30 0.7685 (4) 0.52346 (14) 0.06360 (14) 0.0253 (7) C31 0.8269 (4) 0.60505 (15) 0.14453 (16) 0.0298 (7) C32 0.8676 (3) 0.56175 (15) 0.05494 (15) 0.0269 (7) C33 0.8947 (4) 0.60199 (15) 0.09522 (16) 0.0298 (7) C34 0.9449 (4) 0.55929 (17) 0.00224 (16) 0.0334 (8) C35 0.7493 (5) 0.6209 (3) -0.0511 (2). 0.0599 (15) C36 0.6968 (6) 0.5714 (4) -0.0827 (3) "- 0.083 (2) C37 0.5095 (5) 0.52590 (19) 0.37193 (15) 0.0392 (9) C38 0.4993 (4) 0.54457 (16) 0.31227 (14) 0.0293 (7) C39 0.4323 (4) 0.60294 (16) 0.30392 (13) 0.0297 (7) C40 0.4783 (4) 0.64389 (17) 0.34996 (14) 0.0345 (9) C41 0.6244 (4) 0.59217 (15) 0.24601 (14) 0.0279 (7) C42 0.4889 (4) 0.61943 (15) 0.24753 (14) 0.0282 (7) C43 0.6494 (6) 0.7018 (2) 0.3803 (2) 0.0550 (13) N10 0.6453 (3) 0.55884 (12) 0.19786 (12) 0.0273 (6) N8 0.4287 (3) 0.37320 (12) 0.07002 (13) 0.0299 (6) N9 0.4351 (3) 0.50175 (13) 0.27731 (12) 0.0276 (6) 03 0.5841 (3) 0.42305 (12) 0.02296 (11) 0.0336 (6) 04 0.6272 (3) 0.55359 (11) 0.29230 (10) 0.0294 (5) 05 0.2968 (3) 0.60128 (12) 0.30872 (10) 0.0334 (6) 06 0.4183 (4) 0.65298 (14) 0.39104 (11) - 0".0475 (8) 07 0.5939 (3) 0.66596 (12) 0.33752 (12) 0.0417 (7) YES 0.05826 (13) 0.27639 (6) 0.25442 (6) 0.0573 (3) S2 0.92480 (12) 0.61925 (5) -0.04247 (5) - 0.0462 (3) Table 3: Atomic coordinates and equivalent isotropic displacement parameters for non-hydrogen atoms in molecule 2 label x and z t ^ Cll '0.3351 (9) 0.2274 (4) 0.3741 (4) 0.107 (3) C12 '0.4501 (6) 0.2572 (2) 0.3960 (2) 0.0535 (12) C13 '0.5141 (4) 0.32653 (17) 0.30754 (16) 0.0320 (8) C14 '"0.5962 (3) 0.33381 (15) 0.25640 (15) 0.0284 (7) C151 0.5818 (4) 0.29548 (15) 0.21266 (15) 0.0295 (7) C16 '0.6877 (3) 0.37626 (15) 0.25214 (15) 0.0264 (7) C17 '0.6562 (4) 0.29896 (16) 0.16476 (15) 0.0309 (8) C18 '0.7644 (3) 0.38027 (14) 0.20460 (14) 0.0245 (7) C19 '0.7470 (3) 0.34216 (14) 0.16046 (14) 0.0246 (7) C20' 0.9106 (4) 0.48618 (16) 0.27155 (15) 0.0295 (7) C21 '0.9305 (3) 0.46300 (14) 0.21451 (13) 0.0242 (6) C22 '0.8668 (3) 0.41839 (14) 0.18834 (14) • 0.0241 (7) C23' 0.9068 (3) 0.40231 (14) 0.13561 (13) 0.0228 (6) C24 '1.0826 (4) 0.53365 (16 ) 0.22661 (16) 0.0315 (8) C25"1.0299 (3) 0.49163 (14) 0.18830 (14) 0.0250 (7) C26 '1.0715 (4) 0.47630 (14) 0.13450 (14) 0.0254 (7) C27' 1.0087 (3) ) 0.43081 (14) 0.10898 (14) 0.0244 (6) C28 '1.1674 (4) 0.49705 (15) 0.09601 (15) 0.0268 (7) C29' 1.1603 (4) 0.46218 (15) 0.04887 (15) 0.0285 (7) C30 '1.2564 (4) 0.54209 (16) 0.09568 (16) 0.0306 (7) C31 '1.2411 (4) 0.47048 (16) 0.00324 (16) 0.0345 (8) C32' 1.3357 (4) 0.55112 (17) 0.05095 (17) 0.0339 (8) C33 '1.3282 (4) 0.51493 (18) 0.00434 (18) 0.0374 (9) C341 1.4330 (4) 0.59844 (19) 0.0511 (2) 0.0440 (10) C35 '1.2623 (6) 0.6661 (3) -0.0105 (4) 0.077 (2) C36' 1.2183 (8) 0.7019 (6) 0.0358 (4) 0.136 (5) C37 '0.7433 (4) 0.29800 (18) 0.04312 (16) 0.0338 (8) C38' 0.8600 (3) 0.33047 (15) 0.06463 (14) 0.0262 (7) C39 ' 0.9950 (3) 0.29655 (14) 0.06725 (13) 0.0230 (6) C40 '0.9652 (3) 0.23557 (15) 0.05516 (16) 0.0300 (7) C41' 1.0178 (4) 0.38189 (15) 0.01728 (14) 0.0296 ( 7) C421 1.0759 (4) 0.32366 (14) 0.02225 (14) 0.0267 (7) C43 '0.9026 (12) 0.1491 (3) 0.0916 (4) 0.121 (4) NlO '1.0640 (3) 0.42245 (12) 0.05746 (12) 0.0279 (6) N8 '1.0092 (3) 0.53082 (14) 0.27242 (14) 0.0346 (7) N9 '0.8335 (3) 0.35665 (13) 0.11793 (12) 0.0251 (6) 03 '1.1773 (3) 0.56475 (12) 0.21928 (12)' 0.0378 (6) 04"0.8822 (3) 0.37370 (11) 0.02552 (10) 0.0306 (6) 05 '1.0630 (2) 0.30320 (10) 0.11731 (10) 0.0262 (5) 06 '0.9505 (3) 0.21745 (12) 0.00864 (13) 0.0396 (7) 07 '0.9482 (4) 0.20628 (14) 0.10012 (14) 0. "0570 (10) YES '0.57873 (14) 0.26806 (5) 0.34631 (5) 0.0507 (3) S2 '1.42524 (15) 0.64612 (5) -0.00597 (6) 0.0561 (3) Table 4: Atomic coordinates and equivalent isotropic displacement parameters and occupation for atoms in the solvent entity Tag X Ueg Occupation 01"0. 7366 (10) 0.4173 (4) -0.0687 (3) 0.080 (4) 0.499 (16) C2"0. 6529 (11) 0.4259 (10) -0.1061 (5) 0.143 (10) 0.70 (3) 03"0. 5557 (18) 0.4565 (8) -0.0933 (5) 0.097. (8) 0.36 (2) Example 9 Melting points The melting points (see Example 7.4 above) obtained for the amorphous form and the crystalline solid form alpha, beta, gamma, delta and epsilon of the Compound I are shown in Table 1 below. Table 1 Form Melting temperature approx. Amorfa approx. 150 ° C at 181-189 ° C ß approx. 211 ° C? 212-218 ° C d 211-223 e approx. 182

Claims (51)

1. Crystalline compound I, compound that has the formula
2. 2. Crystalline Form of Compound I, wherein Compound I has the formula defined in claim 1.
3. 3. Crystalline form according to claim 2, characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 1 as measured using CuKa radiation; (ii) reflections in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 5.2, 10.1, 10.4, 13.2, 15.1, 25.1; (iii) the NMR spectrum of Carbon-13 in the solid state shown in Figure 7; (iv) the NIR reflectance spectrum shown in Figure 10.
4. 4. Crystalline form according to claim 2, characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 5.2, 10.1, 10.4, 13.2, 15.1, 25.1.
5. 5. Crystalline form according to claim 2, characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 5.2, 7.3, 8.1, 10.1, 10.4, 11.2, 13.2, 15.1, 15.5, 17.3, 21.7, 23.8, 25.1.
6. 6. Crystalline form according to claim 2, characterized by having a crystalline structure with the following characteristics in 122 K: Spatial group: P2? 2? 2 ?, Unitary cell dimensions: a = 10.227 (2) A, b = 23.942 ( 2) Á and c = 24.240 (2) Á, a = 90 °, ß = 90 °,? = 90 °, 2 molecules in the asymmetric unit.
7. 7. Crystalline form according to claim 2, characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 2 as measured using CuKa radiation; (ii) reflections in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 6.6, 8.9, 10.7, 11.7, 24.4, 30.6; (iii) the NMR spectrum of Carbon-13 in the solid state shown in Figure 8; (iv) the NIR reflectance spectrum shown in Figure 11.
8. 8. Crystalline form according to claim 2, characterized by reflections in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 6.6, 8.9, 10.7, 11.7, 24.4, 30.6.
9. 9. Crystalline form according to claim 2, characterized by reflections in the difractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 6.6, 8.9, 10.7, 11.4, 11.7, 13.7, 17.0, 18.5, 18.8, 19.2, 20.3, 24.4, 30.6.
10. 10. Crystalline form according to claim 2, characterized by one or more of: (i) the X-ray powder diffractogram shown in Figure 3 as measured using CuKa radiation; (ii) reflections in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 9.6, 11.5, 12.5, 16.7, 19.3, 28.1; (iii) the NMR spectrum of Carbon-13 in the solid state shown in Figure 9; (iv) the NIR reflectance spectrum shown in Figure 12.
11. 11. Crystalline form according to claim 2, characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 9.6, 11.5, 12.5, 16.7, 19.3, 28.1.
12. 12. Crystalline form according to claim 2, characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 7.5, 8.3, 9.6, 11.5, 11.8, 12.5, 15.9, 16.3, 16.7, 17.2, 18.0, 19.3, 21.0, 28.1.
13. 13. Crystalline form according to claim 2, characterized by the X-ray powder diffractogram shown in Figure 13 as measured using CuKa radiation.
14. 14. Crystalline form according to claim 2, characterized by reflections in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 9.7, 12.1, 16.1, 18.3, 22.1, 22.2, 25.7, 25.8.
15. 15. Crystalline form according to claim 2, characterized by reflections in the diffractogram of X-ray powder as measured using CuKa radiation in 2-theta angles: 7.3, 8.3, 9.7, 11.1, 11.7, 12.1, 15.6, 16.1, 17.3, 18.3, 20.9, 22.1, 22.2, 25.7, 25.8.
16. 16. Crystalline form according to claim 2, characterized by the X-ray powder diffractogram shown in Figure 15 as measured using CuKa radiation.
17. 17. Crystalline form according to claim 2, characterized by reflections in the diffractogram of X-ray powder as measured using CuKa radiation at 2-theta angles: 8.9, 9.2, 10.2, 14.6.
18. 18. Crystalline form according to claim 2, characterized by reflections in the X-ray powder diffractogram as measured using CuKa radiation at 2-theta angles: 8.9, 9.2, 10.2, 12.6, 14.2, 14.6, 17.0, 18.6, 20.4, 21.1, 23.9, 25.2.
19. 19. Crystalline form according to any of claims 2-18, which is substantially pure.
20. 20. Solid Compound I containing the alpha form of crystalline Compound I, wherein Compound I has the formula defined in claim 1.
21. 21. Solid according to claim 20, which consists mainly of the alpha form.
22. 22. Solid according to claim 20 or 21, wherein the alpha form is as defined in any of claims 3-6.
23. 23. Solid Compound I containing the beta form of crystalline Compound I, wherein Compound I has the formula defined in claim 1.
24. 24. Solid according to claim 23, which consists mainly of the beta form.
25. 25. Solid according to claim 23 or 24, wherein the beta form is as defined in any of claims 7-9.
26. 26. Solid Compound I containing the gamma form of crystalline Compound I, wherein Compound I has the formula defined in claim 1.
27. 27. Solid according to claim 26, which consists mainly of the gamma form.
28. 28. Solid according to claim 26 or 27, wherein the gamma form is as defined in any of claims 10-12.
29. 29. Solid Compound I containing the delta form of crystalline Compound I, wherein Compound I has the formula defined in claim 1.
30. 30. Solid according to claim 29, which consists mainly of the delta form.
31. 31. Solid according to claim 29 or 30, wherein the delta shape is as defined in any of claims 13-15.
32. 32. Solid Compound I containing the epsilon form of crystalline Compound I, wherein Compound I has the formula defined in claim 1.
33. 33. Solid according to claim 32, which consists mainly of the epsilon form.
34. 34. Solid according to claim 32 or 33, wherein the shape is as defined in any of claims 16-18.
35. 35. Method for preparing crystalline Compound I, characterized in that the crystalline Compound I is formed in a methanol solvent with 0% to about 8% water, wherein Compound I has the formula defined in claim 1.
36. 36. The method according to claim 35, which comprises crystallizing by precipitation Compound I from the solvent and separating the solvent from the obtained crystalline Compound I.
37. 37. The method according to claim 35 or 36, wherein the crystalline Compound I is as defined in any of claims 2-6.
38. 38. Crystalline compound I obtainable by the method according to claim 35 or 36.
39. 39. Method for the manufacture of compound I, which method comprises a step in which Compound I is converted to crystalline Compound I, wherein Compound I has the formula defined in claim 1.
40. 40. The method according to claim 39, comprising the precipitation of Compound I in crystalline form from a solvent and separating the solvent from the obtained crystalline Compound I.
41. 41. The method according to claim 39 or 40, wherein the crystalline Compound I is as defined in any of claims 2-18.
42. 42. The method according to claim 39, wherein the crystalline Compound I is obtained according to the method of any of claims 35-37.
43. 43. The method according to any of claims 39-42, further comprising preparing a pharmaceutical composition comprising Compound I.
44. 44. Method for the manufacture of a pharmaceutical composition of Compound I, which method comprises preparing the composition from crystalline Compound I, wherein Compound I has the formula defined in claim 1.
45. 45. The method according to claim 44, wherein the crystalline Compound I is as defined in any of claims 2-19.
46. 46. Method according to claim 44 'or 45, wherein the pharmaceutical composition is a solid dispersion or solid solution formulation.
47. 47. Pharmaceutical composition comprising an effective amount of crystalline Compound I according to any of claims 1-19.
48. 48. Use of the crystalline Compound I according to any of claims 1-19 in the preparation of a medicament for the treatment of a CNS disease.
49. 49. Use according to claim 47, in which the CNS disease is a neurodegenerative disease.
50. 50. Use according to claim 48, wherein the disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, or AIDS dementia.
51. 51. Use of crystalline Compound I according to any of claims 1-19 in the preparation of a medicament for the treatment of Parkinson's disease.