ES2397342T3 - Crystal forms of a pharmaceutical compound - Google Patents

Abstract

A crystalline form of Compound I, in which Compound I has the formula ** Formula **

Description

Crystal forms of a pharmaceutical compound

Field of the Invention

The present invention relates to the crystalline forms of a compound and the use of said 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 outlined below is currently undergoing clinical trials for Parkinson's disease (Idrugs, 2003, 6 (4), 377-383).

This compound is hereinafter referred to as Compound I. The chemical name of Compound I is [9S- (9α, 10β, 12α)] methyl ester - 5,16-bis [(ethylthio) methyl] -2,3,9 , 10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1 Hdiindole [1,2,3-fg: 3 ', 2', 1'-kl] pyrrolo [ 3,4-i] [1,6] benzodiazocine-10-carboxylic.

The following references refer to Compound I, in particular the procedures for their preparation [J. Med. Chem. 1997, 40 (12), 1863-1869; Curr. Med. Chem. -Central Nervous System Agents, 2002, 2 (2), 143-155] and their potential medical uses, mainly in diseases of the central system (CNS), in particular, for the treatment of neurodegenerative diseases, by eg, Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, and ear injuries 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, WO9749406, US 5621100, EP 0651754 and EP 112 932.

By known procedures, Compound I was synthesized in a solid amorphous form. The inventors have now discovered 5 crystalline forms of Compound I (called alpha, beta, gamma, delta and epsilon) thus providing an opportunity to improve the manufacturing process of Compound I and its pharmaceutical use. There is a need for crystalline forms, which may have desirable and beneficial chemical and physical properties. There is also a need for reliable and reproducible procedures for the manufacture, purification, and formulation of Compound I that allow for feasible commercialization.

Summary of the Invention

In a first aspect, the present invention is directed to the crystalline Compound I, in particular the crystalline forms of Compound I.

Accordingly, the present invention provides a crystalline form of Compound I called alpha and characterized by one or more of: (i) the powder X-ray diffractogram shown in Figure 1 as measured using radiation of CuKα; (ii) a powder X-ray diffractogram as measured using 5.2, CuKα radiation having reflections at angles 2θ: 5.2, 7.3, 8.1, 10.1, 11.2 , 13.2, 15.1, 15.5, 17.3, 21.7, 23.8, 25.1; (iii) the solid-state carbon-13 NMR spectrum shown in Figure 8, (iv) the NIR reflectance spectrum shown in Figure 10.

In a further aspect, the present invention provides a crystalline form of Compound I called beta and characterized by one or more of: (i) the powder X-ray diffractogram shown in Figure 1 as measured using radiation from CuKα; (ii) a powder X-ray diffractogram as measured using CuKα radiation having reflections at angles 2θ: 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 solid-state carbon-13 NMR spectrum shown in Figure 8, (iv) the NIR reflectance spectrum shown in Figure 11.

In a more additional aspect the present invention provides a crystalline form of Compound I called gamma and characterized by one or more of: (i) the powder X-ray diffractogram shown in Figure 3 as measured using radiation of CuKα; (ii) a powder X-ray diffractogram as measured using CuKα radiation having reflections at angles 2θ: 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 solid-state carbon-13 NMR spectrum shown in Figure 9, (iv) the NIR reflectance spectrum shown in Figure 12.

In a further aspect the present invention provides a crystalline form of Compound I called delta and characterized by one or more of: (i) the powder X-ray diffractogram shown in Figure 13 as measured using CuKα radiation ; (ii) a powder X-ray diffractogram as measured using CuKα radiation having reflections at angles 2θ: 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 present invention provides a crystalline form of Compound I called epsilon and characterized by one or more of: (i) the powder X-ray diffractogram shown in Figure 15 as measured using CuKα radiation ; (ii) a powder X-ray diffractogram as measured using CuKα radiation having reflections at angles 2θ: 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 present invention further relates to processes for preparing the crystalline forms of the present invention and the use of said forms in the preparation of a medicament comprising Compound I as an active ingredient.

Brief description of the drawings

Figure 1: Shows a powder X-ray diffractogram of the alpha form of Compound I. Figure 2: Shows a powder X-ray diffractogram of the beta form of Compound I. Figure 3: Shows a powder X-ray 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 a solid-state NMR spectrum of carbon-13 of the alpha form of Compound I. Figure 8: Shows a solid-state NMR spectrum of carbon-13 of the beta form of Compound I. Figure 9: Shows a solid-state NMR spectrum of carbon-13 of the gamma form of Compound I. Figure 10: Shows an NIR reflectance spectrum of the alpha form of Compound I. Figure 11: Shows an NIR reflectance spectrum of the beta form of Compound I. Figure 12: Shows an NIR reflectance spectrum of the gamma form of Compound I. Figure 13: Shows a powder X-ray 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 powder X-ray diffractogram 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 packaging of the molecules in the alpha form of Compound I.

Additional details of the figures are disclosed in the following Examples.

Detailed description of the invention

The discovery of a crystalline form of a pharmaceutically useful compound provides an opportunity to improve the behavioral characteristics of the pharmaceutical product and the manufacturing process.

Differences in physical properties, such as stability (shelf life), bioavailability, solubility, and dissolution rate, presented by the different solid forms of a compound are important factors in the manufacture and formulation of a compound. Differences in stability may be the result of changes in chemical reactivity (for example, oxidation) or mechanical changes (for example, the shredding of tablets in storage can lead to conversion into a thermodynamically more stable crystalline form) or both . The physical properties of a solid form are important in processing, for example, a solid form can be more difficult to filter and remove impurities by washing. This may be due to differences in the shape and size distribution of the particles between one crystalline form with respect to the other and with the amorphous form.

Additionally, for drugs that exist in different crystalline forms and that are sold in solid form it is generally important for medical and commercial reasons to produce and commercialize a known crystalline form. The discovery of crystalline Compound I and the existence of 5 crystalline forms allow the development of a

definite crystalline form instead of a solid amorphous form. Also, the physical properties of crystalline Compound I offer advantages for the development of the formulation and preparation of the tablet, 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 air sensitivity and the sensitivity of Compound I to light.

The experiments were carried out in the Heraeus Suntest CPS + solar radiation simulator for the alpha, beta and gamma crystalline forms, where the solid compound was exposed to light for 14 to 650 W. Light treatment led to almost 60 % degradation 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 oxidation sensitivity requires great care during the purification of Compound I. The present invention, which enables the purification of Compound I by crystallization, reduces the levels of the oxidized compounds compared to the product obtained when the inventors have used other methods of purification such as chromatography. In addition, Compound I contains an active ester group that can undergo transesterification reactions and is also susceptible to hydrolysis.

In the final stage in the synthesis of Compound I, the desired ethyl thiol secondary 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 smell, which is undesirable in the pharmaceutical product. Isolation of Compound I as an amorphous solid resulted in the inclusion of ethyl mercaptan in the solid product, although the levels of this unwanted reagent were reduced by crystallization.

Additionally, the physical characteristics of the crystalline forms of the present invention improve the isolation stage by decreasing, for example, the filtration times, compared to the amorphous form of Compound I, which is of great importance for the large-scale manufacture of the Compound I. In this regard, it was found that the delta form has better filtration properties than the alpha form.

An additional difference in the physicochemical properties of crystalline forms compared to the amorphous form is that of higher melting points, see Table I below in Example 9, which can provide advantages in further processing.

As indicated above, the inventors have now discovered that Compound I can be prepared in a crystalline form and that there are at least 5 crystalline forms of Compound I, referred to herein as alpha, beta, gamma, delta and epsilon.

Thus, in a broad aspect, the present invention relates to crystalline Compound I, in particular to a crystalline form of Compound I. As used herein, the expression "a crystalline form of Compound I" comprises any crystalline form of Compound I, that is, in contrast to the amorphous form. In particular, the term "crystalline Compound I" includes the alpha, beta, gamma, delta and / or epsilon forms of Compound I, the forms of which are as defined herein.

The crystalline forms of a compound differ by the positions of the atomic nuclei in the unit cell of the solidified compound. The differences produce different macroscopic properties such as thermal behavior, vapor permeability and solubility that, as indicated above, have practical consequences in pharmacy. The various forms described herein can be distinguished from each other by the use of various analytical techniques known to a person normally skilled in the art. Such techniques include, but are not limited to X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance spectroscopy (NMR), and near-infrared (NIR) spectroscopy. The crystalline forms of a compound are more easily distinguished by X-ray analysis. Single crystal X-ray crystallography results in data that can be used to determine the positions of the nuclei, which at the same time can be visualized with models computer or mechanical, thus providing a three-dimensional image of the compound. Although single crystal X-ray studies provide unmatched structural information, they are expensive, and quality data can sometimes be difficult to acquire. In the pharmaceutical industry, powder X-ray diffraction is used more frequently than single crystal X-ray analysis to characterize new crystalline forms of drugs. X-ray powder diffraction results in a fingerprint that is unique to the crystalline form and is capable of distinguishing this from the amorphous compound and the different crystalline forms of the compound.

Accordingly, an embodiment of the present invention relates to a crystalline form of Compound I called alpha characterized by the powder X-ray diffractogram shown in Figure 1 as measured using CuKα radiation. In a further embodiment, the alpha form of Compound I is characterized by reflections in the powder X-ray diffractogram as measured using CuKα radiation at the 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 CuKα radiation at angles 2θ;

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, one. The alpha form of Compound I can also be characterized by the NMR spectrum of solid-state carbon 13 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 by having a melting point in the range of 180-190 ° C. The alpha form of Compound I can also be characterized by having the DSC thermogram substantially in accordance with which shown in Figure 4. The alpha form of Compound I can also be characterized by a DSC thermogram having an endotherm of about 170 ° C to about 200 ° C. The crystalline structure of the alpha form (Example 8.5) has a space in the crystalline network that may or may not be occupied by a smaller solvent, in particular, a water molecule or a methanol molecule. Thus, the crystalline alpha form of Compound I can be a solvate of varying amounts of water and / or methanol.

Accordingly, the present invention also relates to a crystalline form characterized by having a crystalline structure with the following characteristics at 122 K: Space group. P212121, Unit cell dimensions: a = 10,227 (2) Å, b = 23,942 (2) Å and c = 24,240 (2) Å, α = 90º, β = 90º,! = 90º, 2 molecules in the asymmetric unit. Since the asymmetric unit in this crystalline structure contains 2 molecules of Compound I and a solvent site, the total occupation of the solvent site leads to the formation of a hemisolvate. The present invention further relates to the crystalline structure indicated above having the positions of the atoms substantially as described by the coordinates in Tables 2-4.

When the data of the reflections of the powder X-ray diffractogram (peaks) is indicated herein, it is understood that the reflections are expressed in degrees (in 2θ angles, that is, in 2-theta angles).

A further embodiment relates to a crystalline form of Compound I called beta characterized by the powder X-ray diffractogram shown in Figure 2 as measured using CuKα radiation.

In a further embodiment, the beta form is characterized by reflections in the powder X-ray diffractogram as measured using CuKα 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 diffractogram as measured using CuKα radiation at angles 2θ: 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 NMR spectrum of solid-state carbon 13 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 by a thermogram of DSC that has an endotherm between approximately 205º C to approximately 220º C

A further embodiment relates to a crystalline form of Compound I called gamma characterized by the powder X-ray diffractogram shown in the Figure as measured using CuKα radiation. In one embodiment, the gamma form is characterized by reflections in the powder X-ray diffractogram as measured using CuKα 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 diffractogram as measured using CuKα radiation at angles 2θ: 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 NIR reflectance spectrum shown in Figure 12. The gamma form of Compound I can also be characterized by having a melting point in the range of 212-218 ° C. The gamma form of Compound I can also be characterized by 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 having an endotherm between about 210 ° C to about 225 ° C.

A further embodiment relates to a crystalline form of Compound I called delta characterized by the powder X-ray diffractogram shown in Figure 13 as measured using CuKα radiation. In one embodiment, the delta form is characterized by reflections in the powder X-ray diffractogram as measured using CuKα 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 CuKα radiation at angles 2θ: 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 by having a melting point in the range of 211-223 ° C. The delta form of Compound I can also be characterized by having a DSC thermogram substantially in accordance with that shown in Figure 14. The delta form of Compound I can also be characterized by having a DSC thermogram having an endotherm between about 210 ° C to about 228 ° C.

A further embodiment relates to a crystalline form of Compound I called epsilon characterized by the powder X-ray diffractogram shown in Figure 15 as measured using CuKα radiation. In one embodiment, the epsilon form is characterized by reflections in the powder X-ray diffractogram such

as measured using CuKα 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 CuKα radiation at angles 2θ: 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 by having a melting point in the range 180185 ° C. The epsilon form of Compound I can also be characterized by having a DSC thermogram substantially in accordance with that shown in Figure 16. The epsilon form of Compound I can also be characterized by having a DSC thermogram having an endotherm between about 175 ° C to about 190 ° C.

The present invention further relates to any mixture of the crystalline forms of the present invention, for example, a mixture of the alpha and gamma crystalline form of Compound I.

As used herein, expressions of the type "crystalline form of Compound I characterized by the powder X-ray diffractogram shown in Figure (1) as measured using CuKα" means the crystalline form of Compound I having a powder X-ray diffractogram substantially similar to Figure 1, that is, having a powder X-ray diffraction model as illustrated in said Figure and measured under comparable conditions as described in the Example 7.1 or by any comparable procedure using CuKα radiation. This definition is applied by changing what needs to be changed to the NMR and NIR Figures, and to the different X-ray data described herein (for example, X-ray peak data) and to the five crystalline forms identified, i.e. , alpha, beta, gamma, delta and epsilon, respectively, so that the margins of the analytical variations are taken into account.

The NMR spectra of the solid state carbon 13 referred to herein are preferably measured using a sample rotation speed of 5000 Hz in a spectrometer provided with a CP-MAS probe: Thus, the NMR spectrum is preferably provided as described in Example 7.2 or by any comparable procedure. The NIR reflectance spectra referred to herein are preferably provided as described in Example 7.3, or by any comparable procedure, in particular, with a resolution of 2 cm-1 and a correction of displacement and the slope with respect to the initial value with multiplicative dispersion correction (MSC).

In further embodiments, the present 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 alpha, beta, gamma, delta or epsilon form, has a purity of at least about 90% , which includes, for example, at least about 93%, and at least about 95%.

The amorphous form of Compound I melts at a temperature of approximately 150 ° C which is easy to distinguish from the melting points of the crystalline forms of Compound I described herein, see Table 1 in Example 9. According to this The crystalline Compound I having a melting point that is at least 175 ° C, or at least 180 ° C, such as in the range of 175 ° C225 ° C, 180 ° C-225, is also included in the present invention. ° C, 180 ° C-220 ° C, or 181 ° C-218 ° C, alternatively in the range of 180 ° C-190 ° C or 210-225 ° C.

The term "melting point" as used herein means the initial value of the melting endotherm measured as determined by DSC, see, for example, Example 7.4.

A further embodiment relates to solid Compound I containing the alpha form of crystalline Compound I. The present invention also relates to solid Compound I which consists mainly of the crystalline alpha 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 alpha crystalline form of the Compound I total present.

A further embodiment relates to solid Compound I containing the beta form of crystalline Compound I. The present invention also relates to solid Compound I which consists mainly of the beta crystalline 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 relates to solid Compound I containing the gamma form of crystalline Compound I. The present invention also relates to solid Compound I which consists mainly of the crystalline gamma 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 gamma form of the Compound I total present.

A further embodiment relates to solid Compound I containing the delta form of crystalline Compound I. The present invention also relates to solid Compound I which consists 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 relates to solid Compound I containing the epsilon form of crystalline Compound I. The present invention also relates to solid Compound I which consists 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.

Generally speaking, the novel crystalline forms of Compound I can be prepared by a variety of procedures, including, but not limited to, crystallizing Compound I from a suitable solvent. Compound I can be prepared using methods known in the art, such as those described herein. As a general guideline, Compound I can be mixed with a suitable solvent that can be heated to facilitate dissolution of Compound I. The combination of solvent and Compound I can also be heated to facilitate subsequent conversion aid to the form. crystalline Preferred temperatures in this regard may vary from about 30 ° C to about the boiling point (ie, reflux temperature) of the solvent. The most preferred temperatures may vary from about 60 ° C to about the boiling point of the solvent. The resulting mixture of the solvent and Compound I can be cooled to initiate and / or continue crystallization. The mixture is preferably cooled (ie, including natural cooling to room temperature) to a temperature ranging from, for example, about 20 ° C to about 20 ° C, for example, at 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 dried under vacuum at room temperature or at a slightly elevated temperature, for example, with a nitrogen purge.

Sowing crystals can be added to any crystallization mixture to stimulate crystallization.

As indicated above, the crystalline Compound I, in particular the different crystalline forms of the present invention can be prepared (a) by dissolving Compound I in a suitable solvent, (b) crystallizing by Compound I from the solvent, and (c) separating the solvent from the crystalline Compound I obtained, or alternatively by a process comprising the steps of: (a) suspending Compound I in a suitable solvent for a period of time sufficient to convert this into the crystalline form, and (b) separating the alcohol from the crystalline Compound I obtained. The following describes how different solvents can be used to prepare the different crystalline forms of Compound I, alpha, beta, gamma, delta and epsilon. In a preferred embodiment, the process of the present invention for preparing the crystalline Compound I, which includes the alpha, beta, gamma, delta or epsilon form, comprises precipitating crystallize Compound I from a suitable solvent and separating the solvent from the Crystalline compound I obtained. It should be understood that when the present document refers to the preparation of the different crystalline forms of the present invention, and to a product that can be obtained, or more specifically to a product obtained by said procedures, this also applies to "a Compound I solid containing the crystalline Compound I ", in particular as described above" a solid Compound I consisting mainly of a specific crystalline form of Compound I ", for example, the alpha, beta, gamma, delta or epsilon form.

Accordingly, in one aspect, the present invention relates to a process for preparing the 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% to about 8% water; (ii) a C3-C6 aliphatic alcohol (for example, 1-propanol, 1-butanol, 2-butanol, tert-butanol, 1-pentanol) with 4-8% water (for example, 1-butanol with 4% of water; 1-propanol with 4% water, 1-pentanol with 4% water, tert-butanol with 7% water, 2butanol with 4% water), (iii) an acetic acid ester with at least one 4% of water present, wherein said acetic acid ester is defined by the formula CH3CO2R, wherein R is a C1-C6 alkyl, for example, ethyl acetate or isopropyl acetate (for example, ethyl acetate with 4% water or isopropyl acetate with 6% water). The present invention also relates to crystalline Compound I which can be obtained, in particular, obtained by said process. In a preferred embodiment, this process leads to the formation of the alpha form of crystalline Compound I.

In a further aspect, the present invention relates to a process for preparing the crystalline Compound I, characterized in that said crystalline Compound I is formed in the isopropyl acetate solvent. The present invention also relates to crystalline Compound I which can be obtained, in particular, obtained by said process. In a preferred embodiment, this process leads to the formation of the beta form of crystalline Compound I.

In a further aspect, the present invention relates to a process for preparing the crystalline Compound I, characterized in that said crystalline Compound I is formed in a solvent selected from the group consisting of; (i) an aliphatic C1-C3 nitrile (for example, acetonitrile, propionitrile) with up to about 12% water (for example, propionitrile with 4% water or acetonitrile with 12% water), it should be understood that propionitrile (CH3CH2CN ) is a nitrile-C3; (II) ethanol with 0% to about 8% water. (iii) aliphatic C3-C6 alcohols (for example, 1-propanol or 1-butanol) with at least about 10% water (for example, 1propanol with 10% water, 1-butanol with 10% water), (iv) reactive quality ethyl acetate. The term "reactive quality ethyl acetate" means less than 0.5% water. The present invention also relates

to the crystalline Compound I that can be obtained, in particular it is obtained, by said process. In a preferred embodiment, this process leads to the formation of the gamma form of crystalline Compound I.

In a further embodiment the invention relates to a process for preparing the 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 (for example ethanol, cyclopropyl methanol or 1-propanol) with less than 4% water, for example, less than 3%, for example, approximately 2% (for example, cyclopropyl methanol, 1 propanol with 2% water, ethanol with 2% of water (without stirring) The present invention also relates to the crystalline Compound that can be obtained, in particular, it is obtained by said process In a preferred embodiment, this process leads to the formation of the delta form of the crystalline Compound I.

In a further embodiment, the present invention relates to a process for preparing the crystalline Compound I, characterized in that said crystalline Compound I is formed in the butyl nitrile solvent (CH3CH2CH2CN). The present invention also relates to crystalline Compound I which can be obtained, in particular, obtained by said process. In a preferred embodiment, this process leads to the formation of the epsilon form of crystalline Compound I.

It has also been found that each of the alpha and beta crystalline forms can be converted into the gamma crystalline 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 crystalline alpha form in the presence of methanol, as shown in Example 6.1.

The present invention also relates to a crystalline product, in particular the crystalline forms of compound I which can be obtained, or which is obtained in a preferred embodiment, by a process described herein for the preparation of crystalline Compound I.

The present invention in a further aspect relates to a process for the preparation of Compound I which comprises converting a crystalline form of Compound I (for example, the alpha, beta or gamma form as described herein or any of its mixtures) in the amorphous form of Compound I. Said process in a preferred embodiment comprises the steps of: (a) dissolving the crystalline Compound I in an aromatic solvent, that is, an aromatic hydrocarbon, preferably an alkylbenzene such as xylene or toluene, (b) precipitate Compound I from the aromatic solvent; and (c) separating the aromatic solvent from precipitated amorphous Compound I.

As indicated above, the formation of crystalline Compound I is very useful among others 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 present invention relates to a process for the manufacture of Compound I, the process of which comprises a step in which Compound I is converted to crystalline Compound I. It should be understood that the crystalline Compound I of the present invention can be prepared by a process described herein, precipitating, for example, Compound I in crystalline form from a solvent as described herein and separating the crystalline Compound I obtained from the solvent.

The invention relates in particular to a process for the manufacture of Compound I in which Compound I is converted to the crystalline Compound, which includes a crystalline form of the invention, for example, the alpha form

or gamma from a crude mixture of Compound I. The term "gross mixture" in this context means that the mixture comprises impurities, for example, oxidation products derived from Compound I that are to be removed. The crude mixture may be separated directly from the reaction mixture, or the crude reaction mixture may have undergone some initial purification, treating it, for example, 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.

Accordingly, the invention also relates to a process for the manufacture of a pharmaceutical composition of Compound I, which process comprises preparing said composition from crystalline Compound I as defined herein, obtained, for example, by a method as described herein, which includes a crystalline form or a solid of the present invention. A specific embodiment refers to said use of the alpha or gamma form of the present invention for the preparation of a pharmaceutical composition. As initially described, preparing the formulations from a defined crystalline form has the advantage of an improvement in purity and yield and of having well-defined properties, such as solubility. In this regard, the invention also provides a pharmaceutical composition comprising an effective amount of a Compound I that can be obtained or obtained by a process of the present invention for the preparation of crystalline Compound I, which includes a crystalline form of the invention, for example, from the alpha or gamma form. The pharmaceutical composition may be any composition that is 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, that is, including in particular the alpha, beta, gamma, delta or epsilon crystalline form, 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 usually has a sticky, oily or cerulean character. However, the vehicle can also be fluid at room temperature or even at a temperature below 5 ° C. Examples of vehicles can be mentioned polyethylene glycols (PEG), polaxamers, polyethylene glycol esters, waxes, glycerides, fatty acid alcohols, sugary alcohols , vitamin E and derivatives of vitamin E. The solid solution or the solid dispersion can be used as such or alternatively formulated in pharmaceutical compositions of the type tablets, capsules, etc. The solid solution and the solid dispersion can also be prepared by other methods such as for example by the solvent process or the fusion process (Serajuddin, A.T.M., Journal of Pharmaceutical Sciences, Vol. 88, 1058-1066). An embodiment of the invention relates to a pharmaceutical composition that is a solid solution prepared from the crystalline Compound I of the present invention, for example, from the alpha or gamma crystalline form of the present invention.

Thus, the crystalline product of the present invention, in particular the alpha, beta, gamma, delta or epsilon crystalline forms, or mixtures thereof, can be used in the preparation of a pharmaceutical composition with Compound I in solution, for example , a composition similar to those disclosed in US document

6,200,968.

Also included in the present invention is 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 or mixtures thereof. , and a pharmaceutically acceptable vehicle.

The crystalline product of the present invention, that is, including the alpha, beta, gamma, delta or epsilon crystalline form, or mixtures thereof, can be formulated in a variety of pharmaceutical compositions. Examples of such formulations comprising a crystalline product of the invention (for example, the alpha, beta, gamma, delta or epsilon crystalline 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, "Solid Compound I" means in this context a solid Compound I consisting primarily of in Crystalline Compound I compared to amorphous Compound.

The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as any other adjuvant and excipient, for example, according to techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition , Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions can be formulated specifically for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical route (which includes buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (which includes subcutaneous, intramuscular , intrathecal, intravenous and intradermal), with the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and the age of the subject to be treated, the nature of the condition to be treated and the active principle chosen.

In one embodiment of the pharmaceutical composition, Compound I is administered in an amount of between about 0.001 to about 100 mg / kg body weight per day. Compound I can, for example, be administered 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 may 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 to about 1000 mg, preferably between about 0.05 to about 500 mg. For parenteral routes such as intravenous, intrathecal, intramuscular and similar administrations, the doses are typically in the order of about half of the dose used for oral administration.

As indicated above, the following embodiments are comprised in the invention: the crystalline Compound I for use as a medicament; the crystalline alpha form for use as a medicine; the crystalline beta form for use as a medicine; 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 further relates to the use of 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, to

the treatment of a neurodegenerative disease, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, or ear injuries that include noise-induced hearing loss.

Similarly, a method of treating a neurodegenerative disease, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, or ear injuries including loss, is also included in the present invention. of 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 above medical uses and pharmaceutical compositions, for example, for the treatment of Parkinson's disease, of crystalline Compound I and the crystalline form of the invention, are equally applicable to solid Compound I defined herein which comprises a crystalline form of the invention, in particular, a solid Compound I consisting primarily of a crystalline form of the present invention.

The term "treatment" together with a disease as used herein also includes, as appropriate, prevention. The term "disease" as used herein also includes, as appropriate, a disorder.

Examples

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

Example 1. Preparation of the alpha crystalline form of Compound I

Procedure I:

6.0 g of amorphous Compound I was dissolved in 30 ml of acetone. 0.6 g of potassium carbonate were added and the suspension was stirred at room temperature for 1 hour before the potential minor insoluble impurities and inorganic salts were filtered. The filter cake was washed with acetone. The filtrate was then evaporated on a rotary evaporator under reduced pressure at 60 ° C to a final volume of 10 ml to which 100 ml of methanol was slowly added. The product separated as an oil, which dissolved almost completely by heating under reflux. Subsequently, residual insoluble impurities were removed by filtration. The filtrate was allowed to stir at room temperature. A crystalline solid was separated which was 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 (initial DSC value), Weight loss on heating: 0.5%,

Elemental analysis: 6.71% of N, 63.93% of C, 5.48% of H, theoretical values corrected for 0.5% of H2O: 6.79% of N, 64.05% of C, 5 , 43% of H. Analysis of XRPD according to the alpha form.

Procedure II:

5 g of amorphous Compound I was dissolved in 25 ml of acetone with gentle heating. 10 ml of methanol was 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 into the filtrate. The filtrate was heated until all the material dissolved again. Then cold methanol was added to the solution until precipitation was observed. The slightly cloudy solution was then heated until all the material passed into the solution. The solution was allowed to cool to room temperature, and the precipitate was removed by filtration. The second filter cake was discarded. During filtration, part of the material was separated in the filtrate. The heating again dissolved the initial crystallization in the filtrate. Then 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 min) the precipitation began. The precipitated pale yellow product was isolated by filtration and dried in vacuo at 50 ° C overnight. mp = 188.9º C (initial DSC value), Weight loss due to heating: 0.3%, Elemental analysis: 6.53% N, 64.33% C, 5.43% H, theoretical values : 6.82% of N, 64.37% of C, 5.37% of H. Analysis of XRPD according to the alpha form.

Procedure III:

0.5 g of Compound I in a mixture of isopropyl acetate (10 ml) and water (0.6 ml) were heated under reflux with stirring. The compound did not dissolve completely, so that isopropyl acetate (10 ml) and water (0.6 ml) were added and heated to reflux. Stirring was stopped and the experiment was allowed to cool to room temperature. The crystalline product obtained was isolated by filtration and dried under vacuum at 40 ° C. Yield = 0.25 g, mp = 183.7 ° C (initial DSC value). XRPD analysis according to the alpha form.

Procedure IV:

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

Example 2. Preparation of the beta crystalline form of Compound I

28.0 g of the amorphous Compound I was dissolved in 250 ml of tetrahydrofuran (THF) and evaporated in vacuo in 60 g of silica gel. The compound was purified by column chromatography on silica gel (Ø: 10 cm h: 5 cm with 2.71 THF / heptane 2/1). The eluent containing the desired compound was evaporated on a rotary evaporator under reduced pressure at 50 ° C to give a solid (26 g). The solid was suspended in 60 ml of isopropyl acetate and the suspension was heated to reflux until almost all of the material 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 in vacuo overnight at 50 ° C.

Yield: 16.9 g (61%), mp = 211.7 ° C (initial DSC value), Weight loss due to heating: 0.2%, Elemental analysis: 6.59% N, 64.63% C, 5.41% of H, theoretical values: 6.82% of N, 64.37% of C, 5.40% of H, XRPD analysis according to the beta form.

Example 3. Preparation of the crystalline gamma form of Compound I

Procedure I:

15 g of amorphous Compound I was dissolved in 75 ml of acetone. 1.5 g of potassium carbonate were added and the suspension was stirred for 90 minutes. The suspension was filtered. The filtrate was reduced to approximately 30 ml on a rotary evaporator under reduced pressure at 60 ° C. 150 ml of methanol was added to the reduced filtrate, and some of the sticky material was removed. The suspension was heated to reflux. During heating all the material dissolved. The solution was allowed to cool to room temperature by natural cooling, during this period the solid material was separated. The suspension was allowed to stir 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 yield of the intermediate is 10.2 grams (68%).

The dry filter cake was suspended in 100 ml of acetonitrile (ACN) and heated to reflux. At reflux, a cloudy solution was obtained. Additional acetonitrile was added until a clear solution was obtained; The filter cake was dissolved in a total in 200 ml of acetonitrile that included 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 (initial DSC value), Weight loss due to heating: <0.1%, Elemental analysis. 6.80% of N, 64.38% of C, 5.43% of H, theoretical values: 6.82% of N, 64.37% of C, 5.40% of H, Purity (HPLC,% of area): 98.6, XRPD analysis according to the gamma form.

Procedure II:

0.5 g of Compound I in a mixture of acetonitrile (8.8 ml) and water (1.2 ml) were heated at 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 (initial DSC value) XRPD analysis according to the gamma form.

Procedure III:

0.5 g of Compound I in ethyl acetate (5 ml) were heated at 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. Analysis of XRPD according to the gamma form.

Example 4. Preparation of the crystalline delta form of Compound I

Procedure I:

0.5 g of the alpha form of Compound I in cyclopropyl methanol (10 ml) was heated to 70 ° C. The solution was allowed to slowly cool to room temperature. After 2 days, the crystalline compound was isolated by filtration and dried under vacuum at 40 ° C. Yield = 0.24 g, mp = 212, 1 ° C (initial DSC value), XRPD analysis according to delta form.

Procedure II:

0.2 g of the alpha form of Compound i in ethanol (10 ml) was heated to 70 ° C with stirring. Stirring was stopped and the solution was allowed to slowly warm to room temperature. The next day, the crystalline product was isolated by filtration and dried under vacuum at 40 ° C. Yield = 0.15 g, mp = 221.6 ° C (initial DSC value), XRPD analysis according to delta form.

Procedure III:

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

Example 5. Preparation of the crystalline epsilon form of Compound I

0.5 g of the alpha form of Compound I in butylnitrile (10 ml) was heated at 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 (initial DSC value), XRPD analysis in accordance with the epsilon form.

Example 6. Transformation between different solid forms of Compound I

6.1 Conversions to crystalline Compound I

In the following examples, excess Solid Compound I is used, that is, in comparison with the solvent the amounts of Solid Compound I are such that not all solid material dissolves in the solution.

The amounts used varied between 25-50 mg of Solid Compound I and 2-5 ml of solvent. In the present context, "Solid Compound I" means amorphous Compound I or any of the crystalline forms of Compound I as indicated below.

(i)

 Excess amorphous Compound I was added to methanol and the resulting suspension was stored in a rotarix for 4 days at room temperature. After 4 days the solid was transformed into the alpha form as determined by powder X-ray diffraction.

(ii)

 The crystalline alpha form of Compound I in excess was added to methanol and the resulting suspension was stored in a rotarmix for 4 days at room temperature. After 4 days the solid was still in the alpha form as determined by powder X-ray diffraction.

(iii) The crystalline beta form of Compound I in excess was added to methanol and the resulting suspension was stored in a rotarmix for 4 days at room temperature. After 4 days the solid was transformed into the alpha form as determined by powder X-ray diffraction.

(iv)

 The crystalline gamma form of Compound I in excess was added to methanol and the resulting suspension was stored in a rotarmix for 4 days at room temperature. After 4 days the solid was still in the gamma form as determined by powder X-ray diffraction.

(v)

 A 1: 1 mixture of the alpha form and the gamma form of Compound I in excess was added to methanol and the resulting suspension was stored in a rotarmix for 4 days at room temperature. After 4 days, the main part of the solid was in the gamma form. After filtration of the supernatant, the solvent was allowed to evaporate. The resulting solid was in the alpha form as determined by powder X-ray diffraction.

(saw)

 Excess amorphous Compound I was added to acetonitrile (ACN) and the resulting suspension was stored in a rotarmix for 4 days at room temperature. After 4 days the solid was transformed into the gamma form as determined by powder X-ray diffraction.

(vii) The alpha crystalline form of Compound I in excess was added to ACN and the resulting suspension was stored in a rotarix for 4 days at room temperature. After 4 days the solid was transformed into the gamma form as determined by powder X-ray diffraction.

(viii) The crystalline beta form of Compound I in excess was added to ACN and the resulting suspension was stored in a rotarmix for 4 days at room temperature. After 4 days the solid was transformed into the gamma form as determined by powder X-ray diffraction.

(ix) The crystalline gamma form of Compound I in excess was added to ACN and the resulting suspension was stored in a rotarix for 4 days at room temperature. After 4 days the solid was still in the gamma form as determined by powder X-ray diffraction.

Conclusion:

The amorphous Compound I and the crystalline beta form can be converted into the crystalline alpha form into a suspension of methanol.

The amorphous Compound I, the crystalline alpha form and the crystalline beta form can be converted to the crystalline gamma form by suspending the excess solid material in acetonitrile.

6.2 Conversions of the alpha crystalline form to amorphous Compound I

15 g of the alpha crystalline form of Compound I was 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 decreased by 10 ml, and the solution was cooled overnight in a refrigerator. The resulting solid was isolated by filtration, dried under vacuum for two days at 40 ° C to give 13.2 g of a solid. The melting temperature of the solid was approximately 150 ° C, which characterizes the amorphous form of Compound I compared to the crystalline forms, see Table 1 below.

Example 7. Analytical procedures

(7.1) XRPD models were measured on a diffractometer under one of the following conditions

(i)

 STOE diffractometer Radiation. Cu (Kα1), germanium monochromator, ∀ = 1,540598 Å Position sensitive detector (PSD) covering 7th Scan type: stage scan, stages: 0.1 º, 125-150 s. per stage Interval. 5-45º 2θ Sample measurement procedure: Transmission

(ii)

 PANalytical X’Pert PRO X-ray diffractometer using CuKα1 X´celerator Detector radiation, which measures the range 5-40º 2º Sample measurement procedure: Reflection

(7.2) Solid state NMR was performed under the following conditions:

The CP / MAS NMR spectra (cross polarization / magic angle rotation) of carbon-13 at room temperature at 11.75 Tesla were acquired on a Bruker Advance DRX-500 spectrometer equipped with a CP / MAS probe of 4 mm The sample rotation speed was 5000 Hz and 10240 scans were acquired using a recirculation delay of 5 s. For cross polarization, radiofrequency fields with 50 kHz turn lock and a contact time of 5 ms were used.

(7.3) Near infrared (NIR) data was collected with a MB 160 FT / NIR spectrometer from Bomem with Powder SamplIR. NIR spectra data was recorded between 14,000-4000 cm-1 with a resolution of 2 cm-1 (16 scans, high gain). The displacement and slope of the initial values of the NIR spectra, which are often observed in dust with Multiplicative Dispersion Correction (MSC), were eliminated.

(7.4) Melting points in a DSC (Differential Scanning Calorimeter) were determined as the initial temperature of the melting endotherm. Approximately 2 mg of sample was heated in a loose lid crucible, at 5 ° C / min with N2 flow.

(7.5) The crystalline structure of the alpha form was determined under the following conditions: the diffraction data were collected on a Nonapprocessed KappaCCD diffractometer. Data collection was carried out at 122 K using monochromed MoKα radiation (∀ = 0.71073 Å).

Example 8. Analytical Results

8.1 X-ray powder data: The X-ray powder diffractogram (XRPD) 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 form is shown in Figure 15. The different crystalline forms were characterized by the different reflections (peaks) in the powder X-ray diffractogram as measured using CuKα radiation at the determined 2-theta angles:

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: Figures 4-6, 14, 16 show the DSC thermograms (alpha form in Figure 4; beta form in Figure 5; and gamma form in Figure 6, delta form in Figure 14 , the epsilon shape in Figure 16).

8.3 Solid state NMR data: Figure 7 shows the solid state NMR spectra data for the alpha form, Figure 8 for the beta form and Figure 9 for the gamma form.

8.4 NIR data: Figure 10 shows the data of the NIR spectra for the alpha form, in the

Figure 11 for the beta form and in Figure 12 for the gamma form.

8.5 Crystalline structure for the alpha form of Compound I: The crystalline 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 slow precipitation from MeOH and had the dimensions 0.5 X 0.3 X 0.2 mm.

The resulting crystalline structure shows that the alpha form of Compound I crystallizes in the orthorhombic space group P212121 with the cell dimensions at 122 K being: a = 10,227 (2) Å, b = 23,942 (2) Å and c = 24,240 (2 ) Å, α = 90 °, β = 90 °, γ = 90 °, V = 5935.3 (12) Å3, Z = 8, density = 1.378 g / cm3 (the numbers in parentheses are standard deviations in the last digit ). The unweighted agreement factor was R [I> 2σ (I)] = 0.0699.

The asymmetric unit of the crystal contains two units of Compound I, and a solvent molecule 0-1 the solvent molecule can be both MeOH and water. In determining the structure, the atoms corresponding to the solvent were found with an occupation of C2 ": 0.70, O1": 0.50 and 03 ": 0.36. Since the asymmetric unit contains 2 molecules of the Compound I and a solvent site, the complete occupation of the site would lead to the formation of a hemisolvate.Atomic numbering and conformation of the two molecules in the asymmetric unit are shown in Figures 17-18, and Figure 19 shows the packaging of the molecules in the crystal In the following Tables 2-4 the coordinates of the atom are provided.

Table 2: Atomic coordinates and equivalent isotropic displacement parameters for non-hydrogen atoms in molecule 1

Label

X Y z Ueq

C11

-0.1062 (9) 0.2071 (4) 0.3154 (5) 0.119 (4)

C12 C13 C14 C15 C16 C17 C18 C19

-0.0922 (7) 0.0402 (5) 0.1485 (4) 0.1730 (5) 0.2157 (4) 0.2642 (4) 0.3097 (3) 0.3347 (4) 0,2369 (3) 0,3338 (2) 0,37791 (19) 0.4125 (2) 0.388580 (16) 0.4561 (2) 0.42813 (15) 0.46402 (17) 0.2679 (4) 0.3022 (2) 0.290000 (19) 0.34227 (19) 0.24912 (17) 0.3444 (17) 0.24665 (15) 0.29167 (15) 0.097 (3) 0.0517 (13) 0.0414 (10) 0.0482 (12) 0.0331 (8) 0.0396 (9) 0.0278 (7) 0.0320 (8)

C20 C21 C22 C23 C24 C25 C26 C27

0.3600 (3) 0.4226 (3) 0.3963 (3) 0.4700 (3) 0.5184 (3) 0.5168 (3) 0.5911 (3) 0.5642 (3) 0.37367 (14) 0.42266 (13) 0.44422 (14) 0.48995 (14) 0.41458 (14) 0.44565 (13) 0.49186 (13) 0.51352 (14) 0.12235 (15) 0.125070 (14) 0.20324 (14) 0.22250 (14) 0.06419 (15) 0.11709 (13) 0.13513 (13) 0.18804 (13) 0.0271 (7) 0.0233 (6) 0.0238 (6) 0.0241 (6) 0.0264 (7) 0.0215 (6) 0.0213 (6) 0.0230 (6)

C28 C29 C30 C31 C32 C33 C34 C35

0.6972 (3) 0.7277 (3) 0.7685 (4) 0.8269 (4) 0.8676 (3) 0.8947 (4) 0.9449 (4) 0.7493 (5) 0.52525 (14) 0.56606 (14) 0.52346 (14) 0.60505 (15) 0.56175 (15) 0.60199 (15) 0.55929 (17) 0.6209 (3) 0.11306 (14) 0.15290 (13) 0.06360 (14) 0.14453 (16) 0.05494 (15) 0.09522 (16) 0.00224 (16) -0.0511 (2) 0.0228 (6) 0.0234 (6) 0.0253 (7) 0.0298 (7) 0.0269 (7) 0.0298 (7) 0.0334 (8) 0.0599 (15)

C36 C37 C38 C39 C40 C41 C42 C43 N10

0.6968 (6) 0.5095 (5) 0.4993 (4) 0.4323 (4) 0.4783 (4) 0.6244 (4) 0.4889 (4) 0.6494 (6) 0, 6453 (3) 0.5714 (4) 0.52590 (19) 0.54457 (16) 0.60294 (16) 0.64389 (17) 0.59817 (15) 0.61943 (15) 0.7018 (2) 0, 55884 (12) -0.0827 (3) 0.37193 (15) 0.31227 (14) 0.30392 (13) 0.34996 (14) 0.24601 (14) 0.24753 (14) 0.3880 (2) 0 , 19786 (12) 0.083 (2) 0.0392 (9) 0.0293 (7) 0.0297 (7) 0.0345 (9) 0.0279 (7) 0.0282 (7) 0.0550 (13) 0.0273 ( 6)

N8 N9 03 04 05 06 07 S1

0.4287 (3) 0.4351 (3) 0.5841 (3) 0.6272 (3) 0.2968 (3) 0.4183 (4) 0.5939 (3) 0.05826 (13) 0.377320 (12) 0.50175 (13) 0.42305 (12) 0.55359 (11) 0.60128 (12) 0.65298 (14) 0.66596 (12) 0.277639 (6) 0.07002 (13) 0.27731 (12) 0.02296 (11) 0.29230 (10) 0.30872 (10) 0.39104 (11) 0.33752 (12) 0.25442 (6) 0.0299 (6) 0.0276 (6) 0.0336 (6) 0.0294 (5) 0.0334 (6) 0.0475 (8) 0.0417 (7) 0.0573 (3)

S2

0.92480 (12) 0.61925 (5) -0.04247 (5) 0.0462 (3)

14

Table 3: Atomic coordinates and equivalent isotopic displacement parameters for non-dehydrogen atoms in molecule 2

Label xyz Ueq C11 '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) C15 '0.5818 (4) 0.29548 (15) 0.21266 (15) 0.0295 (7) C16' 0.6877 (3) 0.37626 (15) 0.22214 (15 ) 0.0264 (7) C17 '0.6562 (4) 0.29696 (16) 0.167676 (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) 0.5420 9 (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) C34' 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) 0.290000 (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) C42 '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) N10 '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) 0.1193 (12) 0.0251 (6) O3' 1.1773 (3) 0.56475 (12) 0.21928 (12) 0.0378 (6) O4 '0.8822 (3) 0.377370 (11) 0.02552 (10) 0.0306 (6) O5' 1.0630 (2) 0.30320 (10) 0.11731 (10) 0 , 0262 (5) O6 '0.9505 (3) 0.2174 5 (12) 0.00864 (13) 0.0396 (7) O7 '0.9482 (4) 0.20628 (14) 0.10012 (14) 0.0570 (10) S1' 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 occupations of atoms in the solvent entity

Label x and z Ueq Occupation O1 "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) O3 "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 above) obtained for the amorphous form and the solid form of alpha, beta, gamma, delta and crystalline epsilon of Compound 1 are shown in Table 1 below.

Table 1

Approximate melting temperature form:

Amorphous approx. 150 ° C α 181-189 ° C β approx. 211 ° C γ 212-218 ° C δ 211-223 ε approx. 182

Claims (14)

one.

 A crystalline form of Compound I, in which Compound I has the formula

2.

 A crystalline form according to claim 1, characterized by a powder X-ray diffractogram comprising reflections in: 5.2 degrees 2-theta, 10.1 degrees 2-theta, 10.4 degrees 2-theta, 13 , 2 degrees 2-theta, 15.1 and 25.1 degrees 2-theta, when measured using CuKα radiation.

3.

 The crystalline form of claim 2, characterized by an X-ray and powder diffractogram comprising reflections in 5.2 degrees 2-theta, 7.3 degrees 2-theta, 8.1 degrees 2-theta, 10.1 degrees 2 -theta, 10.4 degrees 2-theta, 11.2 degrees 2-theta, 13.2 degrees 2-theta, 15.1 degrees 2-theta, 15.5 degrees 2-theta, 17.3 degrees 2-theta , 21.7 degrees 2-theta, 23.8 fatty 2-theta, and 25.1 degrees 2-theta, when measured using CuKα radiation.

Four.

 A crystalline form according to claim 1, characterized by a crystalline structure with the following characteristics at 122 K; Space group: P212121, Unit cell dimensions: a = 10,227 (2) Å, b = 23,942 (2) Å and c = 24,240 (2) Å, α = 90 °, β = 90 °,! = 90 °, 2 molecules in the asymmetric unit.

5.

 A crystalline form according to claim 1, characterized by a powder X-ray diffractogram comprising reflections in: 6.6 degrees 2-theta, 8.9 degrees 2-theta, 10.7 degrees 2-theta, 11, 7 degrees 2-theta, 24.4 degrees 2-theta, and 30.6 degrees 2-theta, when measured using CuKα radiation.

6.

 The crystalline form of claim 5, characterized by the powder X-ray diffractogram comprising reflections at 6.6 degrees 2-theta, 8.9 degrees 2-theta, 10.7 degrees 2-theta, 11.4 degrees 2-theta, 11.7 degrees 2-theta, 13.7 degrees 2-theta, 17.0 degrees 2-theta, 18.5 degrees 2-theta, 18.8 degrees 2-theta, 19.2 degrees 2- theta, 20.3 degrees 2-theta, 24.4 degrees 2-theta, and 30.6 degrees 2-theta, when measured using CuKα radiation.

7.

 A crystalline form according to claim 1, characterized by a powder X-ray diffractogram comprising reflections in: 9.6 degrees 2-theta, 11.5 degrees 2-theta, 12.5 degrees 2-theta, 16, 7 degrees 2-theta, 19.3 degrees 2-theta, and 28.1 degrees 2-theta, when measured using CuKα radiation.

8.

 The crystalline form of claim 7, characterized by a powder X-ray diffractogram comprising reflections in: 7.5 degrees 2-theta, 8.3 degrees 2-theta, 9.6 degrees 2-theta, 11.5 degrees 2-theta, 11.8 degrees 2-theta, 12.5 degrees 2-theta, 15.9 degrees 2-theta, 16.3 degrees 2-theta, 16.7 degrees 2-theta, 17.2 degrees 2- theta, 18.0 degrees 2-theta, 19.3 degrees 2-theta, 21.0 degrees 2-theta, and 28.1 degrees 2-theta, as measured using CuKα radiation.

9.

 A crystalline form according to claim 1, characterized by a powder X-ray diffractogram comprising reflections in. 9.7 degrees 2-theta, 12.1 degrees 2-theta, 16.1 degrees 2-theta, 18.3 degrees 2-theta, 22.1 degrees 2-theta, 22.2 degrees 2-theta, 25, 7 degrees 2-theta, and 25.8 degrees 2-theta, when measured using CuKα radiation.

10.

 The crystalline form of claim 9, characterized by a powder X-ray diffractogram comprising reflections in: 7.3 degrees 2-theta, 8.3 degrees 2-theta, 9.7 degrees 2-theta, 11.1 degrees 2-theta, 11.7 degrees 2-theta, 12.1 degrees 2-theta, 15.6 degrees 2-theta, 16.1 degrees 2-theta, 17.3 degrees 2-theta, 18.3 degrees 2theta, 20.9 degrees 2-theta, 22.1 degrees 2-theta, 22.2 degrees 2-theta, 25.7 degrees 2-theta, and 25.8 degrees 2-theta, when measured using CuKα radiation.

eleven.

 A crystalline form according to claim 1, characterized by a powder X-ray diffractogram comprising reflections in: 8.9 degrees 2-theta, 9.2 degrees 2-theta, 10.2 degrees 2-theta, and 14 , 6 degrees 2-theta, when measured using CuKα radiation.

12.

 The crystalline form of claim 11, characterized by a powder X-ray diffractogram comprising reflections in: 8.9 degrees 2-theta, 9.2 degrees 2-theta, 10.2 degrees 2-theta, 12.6 degrees 2-theta, 14.2

grades 2-theta, 14.6 degrees 2-theta, 17.0 degrees 2-theta, 18.6 degrees 2-theta, 20.4 degrees 2-theta, 21.1 degrees 2theta, 23.9 degrees 2-theta , and 25.2 degrees 2-theta, when measured using CuKα radiation.

13.

 A pharmaceutical composition comprising an effective amount of a crystalline form of Compound I of any of claims 1-12.

14. A crystalline form of Compound I of any of claims 1-12 for use as a medicament. 15. A crystalline form of Compound I of any of claims 1-12 for use in the treatment of a CNS disease selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, or AIDS dementia 16. A crystalline form of Compound I of any of claims 1-12 for use in the preparation of a medicament.