TW200530254A - Crystalline forms of a phamaceutical compound - Google Patents

Abstract

Described are crystalline forms of the compound with the following structure: as well as methods for their use and preparation.

Description

200530254 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a crystalline form of a compound and the use of the crystalline form in the preparation of pharmaceuticals, which are particularly useful for the treatment of Parkinson's disease 〇 [prior art ] Compounds with the following structural formulas are currently in clinical trials for the treatment of Parkinson's disease (Drug Information, 2003, 6 (4), pages 377-3 83).

This compound is hereinafter referred to as Compound I. The chemical name of compound I is [98- (9α, 10β, 12α)] _ 5,16_ di [(ethylthio) methyl] 2,3,9,10,11,12-hexahydro-10-hydroxy -9-methyl_1_side oxygen_9,12_epoxy_11 ^ diindolo [1,2,3 ^ 8: 3 ,, 2,, 1,-] ^ 1] pyrrolo [ 3544] [1,6] benzodiazepine π-oct-10-methyl acid. The following references are about compound Ϊ, especially its preparation method [Journal of Medicinal Chemistry, 1997, 40 (12), page 863_1 869; modern medicinal chemistry-central nervous system conductive substances, 2002, 2 ( 2), pages 143- 丨 55] and its potential medical uses, mainly for the treatment of central nervous system 4 diseases (CNS), especially neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease (Alzheimer's Disease), Huntington's 6 200530254 Huntington's disease, peripheral neuropathy, AIDS dementia and ear damage such as hearing loss due to noise [Progress in Medicinal Chemistry (2002), 40 Pp. 23-62; Bioorganic Medicinal Chemistry, 2002, 12 (2), pp. 147-150; Neuroscience 'Oxford' 1998 '86 (2), pp. 461-472; Journal of Neurochemistry (2001)' 77 (3), pages 849-863; Journal of Neuroscience (2000), 20 (1), pages 43-50; Journal of Neurochemistry (2002), 82 (6), pages 1424-1434; Auditory Research, 2002, 166 (1-2), pp. 33_43]. The following patent documents pertain to compound I, including its medical use and synthesis ... WO 9402488, WO 9749406, US 5 621 100, EP 0651754 and EP 1 12 932. Using a known method, Compound I is formed in a solid amorphous form. The present inventors have now discovered five crystal forms (named α-form, β-form, γ-form, δ-form and ε-form) of Compound I, thereby providing an opportunity to improve the manufacturing method of Compound j and its medical use. There is always a need for a crystalline form that can exhibit the required and advantageous chemical and physical properties; in addition, there is also a need for a reliable and reproducible method of manufacturing, purifying, and formulating Compound I to make it suitable for commercialization. SUMMARY OF THE INVENTION In a first aspect, the present invention relates to a crystalline compound I, particularly a crystalline form of the compound I. Therefore, the present invention provides a crystalline form of compound I, named α form and characterized by one or more of the following: (i) the X-ray powder diffraction pattern shown in FIG. 1 'This is measured using CuKa radiation; ( ii) γ M green I + ㈠ measured with CuKcx radiation 7 200530254 ray ... 'x-ray cup end diffraction pattern, which has reflectivity at the corners: 5.2, 7.3 8.1, 101, 10.4, " 2 21 · 7, 23.8, 25 1 · r .. U Okaichi · 1, 15 · 5, 1 7.3, Γ, ± η 1〇.) The solid carbon-13 NMR spectrum shown in Figure 7; (1V) The ancestral reflection spectrum shown in FIG. 10. In a further aspect, the present invention mentions ^ Λ Π ^ B .. Eight crystals & objects I crystal form, named β Kai y and is characterized by the off-line powder surface shooting same as the night · (1) as shown in Figure 2 The X-ray image 'This is measured using the radiation of the mountain c; (ii) using the CuKa radiation station, and, once from v &v;

/, Ray, ray powder diffraction pattern, which has 8.9 10.7 at 2 Θ angle, " · 4, η · 7, 13 7, 17 〇, ΐ8.5, 18.8, 19 · 2, 2〇 · 3 , 24 4, 30 6 · r ··, upper ㈤ • 〇.6, (111) is shown as solid carbon-13 NMR photograms shown in Figure 8; ί 7 \ λ μ m 11 _ (VI) is shown in Figure 1 NIR reflection spectrum shown. In terms of progress, the present invention provides a crystal form of compound j, named Y-shape, and is characterized by one or more of the following: ⑴ As shown in the X-ray powder diffraction pattern shown in Figure 3, this is measured using CuKa radiation; ( ii) use

X-ray powder diffraction pattern measured by CuKa radiation, which has reflectivity at an angle of 2Θ: 7.5, 8.3, 9 6, u 5, u 8, 12, 5, 15, 16 16 16, 16 7, 17_2, 18.0, 19 · 3, 21 · 〇, 28 ″; (i) solid carbon 13 NMR spectrum shown in FIG. 9; (iv) NIR spectrum shown in FIG. In a further aspect, the present invention provides a crystalline form of compound I, named δ form and characterized by one or more of the following: ⑴ X-ray powder diffraction pattern shown in FIG. N, which is measured using CuKa radiation; The X-ray powder diffraction pattern measured by CuKa radiation has reflectivity at an angle of 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. 8 .200530254

In a further aspect, the present invention provides a compound named A-shaped and characterized by the following-or more: ⑴ as shown in Figure 15 ::: ray powder diffraction pattern, which is measured by the use of ㈣ radiation. : X-ray powder diffraction pattern measured by cardiac radiation, with reflectance: 8.9, 92, 102, "... ^ 10, 2, 12.6, 14.2, 14.6, 17 〇6, 20.4, 2U, 23.9 '25 2. 18. The present invention further relates to a method for preparing the crystalline form of the present invention, and the use of the crystalline form for preparing a pharmaceutical product containing Compound 1 as an active ingredient. [Embodiment] Detailed description of the invention

The discovery of crystalline forms of compounds useful in medicine provides the performance characteristics of pharmaceutical products and manufacturing methods. I The differences in physical properties such as stability (shelf life), bioavailability, solubility, and dissolution rate of different solid forms of compounds are important factors in the manufacture and formulation of compounds; differences in stability may be due to 7 chemical activity ( Such as oxidation) or mechanical changes (such as the crushing of tablets during storage, which may result in a conversion to a more thermodynamically stable crystal form) or both. The physical properties of a solid form are important in processing. For example, a solid form may be more difficult to filter and wash away impurities. This can be caused by the difference in particle shape and size distribution of this kind of ba- yy relative to other crystalline and amorphous forms. In addition, with regard to drugs that exist in different crystal forms and are sold in solid form, " for medical and commercial considerations, it is generally important to produce and market the already four crystal forms. The discovery of the crystalline compound Ϊ and the existence of five crystal forms 9 200530254 A clear crystal form was developed to replace the amorphous solid. X τ #, 5¾, last day compound! Its physical properties are also beneficial for formulation development and preparation, such as promoting direct dust shrinkage due to its definite crystal form. The crystalline compound is generally more stable than the corresponding amorphous compound, and this is especially important in the case of Compound I, which is sensitive to both air and light. The experiment of the crystal form of "," was performed using Heraeus Suntest CPS +, in which solid compounds were exposed to a 650 W light source for 14 hours; light treatment caused amorphous The substance is almost ⑼% degraded, while the crystalline form shows less than 30% degradation. The compound contains two sulfur atoms and is easily oxidized to a composite mixture of stone exhibition and sublithic wind. This oxidation sensitivity is in the purification of compound j The process needs to be extra careful. Compared with the product obtained by the inventors using other purification methods such as chromatographic analysis, the present invention makes compound j feasible by crystallization purification, thereby reducing the content of oxidized compounds; in addition, 'compound χ contains an active vinegar It may undergo transesterification reaction, and it is also easily hydrolyzed. In the final step of the synthesis of compound I, ethylthiol was used as a reactant to introduce the necessary thiol ethyl side chain [Journal of Pharmaceutical Chemistry, M " , 40 (12) 'p. 1 863_1869; modern medicinal chemistry-agents in the nervous system, 2002' 2 p. 143_155]. Ethyl mercaptan has a unique strong odor, which is not ideal for pharmaceutical products. Separation of compound j as an amorphous solid causes ethyl mercaptan ' to be included in the solid product and the content of this unwanted reactant is reduced via crystallization. In addition, the physical properties of the crystalline form of the present invention, such as improving the separation step by reducing the number of filtrations compared to the amorphous compound I, are of great significance for the large-scale production of compound I 10 200530254. In this regard, the delta shape was found to have better filtering properties than the ce shape. A further difference in the physicochemical properties of the crystalline form compared to the amorphous form is the higher melting point. Refer to Table 1 of Example 9 below, which can be beneficial for further processing. As shown above, the present inventors have now found that compound j

The crystalline form is prepared, and there are at least five crystalline forms of the compound j, which are named here as Form, / 5-form, γ-form, δ-form, and 6-form. Therefore, in a broad aspect, the present invention relates to the crystalline compound ΐ5, and particularly to the crystalline form of the compound. As used herein, the term "crystalline form of the compound!" Includes any of the crystalline forms of compound ϊ, that is, relative to the amorphous form. In particular, the term "crystalline compound J" refers to the crystalline forms of compound I, α, γ, δ, and / or £, which are as defined herein. The crystal form of the compound is different due to the “nucleus” in the unit cell of the cured compound unit. This difference results in different macroscopic properties, such as hot matter :, vapor permeability, and solubility. These are medically realistic as shown above = Importance. The different crystalline forms described herein can be distinguished from each other by using various analytical techniques known to those skilled in the art. Such techniques include but are limited to X-ray powder diffraction (XRD), differential scanning calorimeters (Dsc), -Π: magnetic resonance (R) spectrum and near-infrared light (NIR) spectrum. The crystal form of the second aunt is most easily distinguished by x-ray analysis. Single crystal x-radiation ::: The plutonium that determines the nuclear position can be used later to reveal the pattern. This provides three-dimensional spatial shadows of the compound. Early X-ray studies provide incomparable structural information, but they are very expensive and there are. It is difficult to obtain it. Compared to single crystal x-ray analysis, the pharmaceutical industry often uses powder x-ray diffraction to obtain the characteristics of the new crystal form of the drug. Powder x-ray diffraction obtains the fingerprint unique to this crystal form. It can distinguish it from the amorphous compound and all other crystal forms of the compound. In addition, a specific aspect of the present invention is the crystal form of the compound, which is named "form and is characterized in that shown in Figure i Use Cuu radiation

X-ray powder diffraction pattern measured by the line. In a further specific aspect, the morphology of the compound I: 0 is characterized by the reflectance in the X-ray powder diffraction pattern measured with CuKa radiation: 5.2, 10.1, 10.4, 13 2. Huakou The α-shape of the object I can also be characterized by having the reflectance in the X-ray diffraction pattern of V and J measured at 20 angles using CuKa radiation. 5 2, 7 3, 25 ". The α-form of compound j may also be characterized by a 13 NMR spectrum as shown in FIG. 7. The alpha shape of Huaren from τ > ° 1 can also be characterized by the NIR reflection spectrum shown in FIG. 10. The alpha shape of the human mouth object I can also be characterized by having a range of 180-19 (dazzling points in TC).

^ Consistent DSC thermogram. The CV form of compound I can also be characterized by a DSC thermogram of an ancient endothermic peak with a temperature of about 170M and about 200M. The α-shaped 9th solar body, mouth, and mouth (performed in Example 8.5) may or may not be occupied between the lattices—eight + t smaller lotions, especially one with water or methanol. Space. ^ π 〇, the α crystal form of D & 1 may be a solvate containing water and / or formaldehyde. Therefore, one of the characteristics of the present invention is also that the factory has a crystalline form with a crystal structure having the following characteristics at 122K 12 200530254: space group: pm, unit cell size: a = 10.227 (2) A, b = 23 942 (2) A, c = 24 24〇 (Hook A, 900 0 90, γ = 90, there are two molecules in this asymmetric unit. When the asymmetric unit in this crystal structure contains two compounds 〖Molecular and: Solvent positions' The complete occupation of the solvent position will cause a hemisolvate. The present invention further relates to the above-mentioned crystal structure having an atomic position substantially as described by the coordinates in Table 2-4.

In this article, I would like to point out the reflectance (spike) of the X-ray powder diffraction pattern data. The sun guard should understand that the reflectance is expressed in angles (at 20 degrees). A further specific aspect relates to a crystalline form of the compound 丨, which is named / 5 form and is characterized by an X-ray t-ray powder diffraction pattern measured with CuK using radiation as shown in FIG. 2. In a further specific aspect, the full form of Compound I is characterized by having the reflectance in the χ-ray diffraction pattern measured using CuKa radiation: 2 · 6, 8 · 9, 1 () · 7, ιΐ 7 , 24 4, 30.6. The / 5 form of compound I may also be characterized by having a reflectance in an X-ray diffraction pattern measured using CuK ^ rays at% angles: 6.6, 89, ι〇 · 7, ιΐ4,, 17.0, 18 · 5, 18 · 8, 19 · 2, 20.3, 24.4, 30.6.

、 0 of 1 thing 1 can also be distinguished by the solid carbon-1 3 NMR as shown in Figure 8

"The perfect shape of the chemical sigma 1 can also be characterized by the NIR reflection spectrum shown in Figure 丨 丨. The Θ-Γ of the compound I can also be characterized by having a melting point in the range of 209.2 " C ' Preferably, about 2ΐΓς, the compound ^ 0 form can also be characterized by having a DSC thermogram that is substantially different from 圄 s μ — + ,, and 囷 5. The / 3 liter of y can also be characterized by: DSC thermogram with an endothermic peak of about 22.0 °. 13 200530254 A further specific aspect is a crystal form of compound i, named γ-shaped and characterized by the use of CuKf radiation as shown in FIG. 3 Measured X-ray powder diffraction pattern. In a specific aspect, the gamma shape of Compound I is characterized by the reflectance in the X-ray powder diffraction pattern measured using CuKa radiation at an angle of 2-Θ: 9.6, 11.5, 12.5, 16.7, 19.3, 28.1. The γ-shape of compound I can also be characterized by having the reflectance in the X-ray diffraction pattern measured using CuK〇; radiation at μ angle: 7 5, 8 3, 9 6, 115, 11.8 , 12.5, 15.9, 16.3, 16.7, 17.2, 18 · 0, 19.3, 21.0, 2 8 · 1. The γ-shape of j can also be characterized by the solid carbon 13 NMR spectrum shown in Figure 9. The γ-shape of compound can also be characterized by the NIR reflection spectrum shown in Figure 12. The γ-shape of compound 1 can also be characterized by having Range 1 and melting point in 2 1 2-2 1 8 C; the γ form of compound I can also be characterized by having a DSC thermogram substantially the same as that shown in Figure 6. The 7 form of compound j can also be characterized by having A DSC thermogram of an endothermic peak of about 21 (rc to about 225 t).

A further specific state relates to a crystalline form of the compound, named δ-form, and is characterized by an X-ray powder diffraction pattern measured using CuKa radiation as shown in item 13. In a specific aspect, the δ shape of the compound 丨 is characterized by the reflectance of the measured Ka-ray powder diffraction pattern of CuKa radiation: 9.7, 12.b 16.b 18,22 b 22 2, 25.7, 25.8. The δ shape of compound j can also be characterized by having the reflectance in the X-ray diffraction pattern measured with _ radiation at an angle of 2 Θ: 7.3, 8.3, 9.7 ^ 11.1 ^ 1.7 ^ 2. ^ 15.6 ^ 6.1 ^ 7.3.18.3 ^ 0.9.22.1 ^ 22.2, 25.7, 25.8. The δ-shape of compound I can also be characterized by having a melting point in the range 14 200530254 between 2 1 1 -2231; and the δ-shape of compound I can also be characterized by having a DSC thermogram on a babe that is consistent with that shown in FIG. 14. The O form of compound 丨 may also be characterized by a DSC thermogram having an endothermic peak at about 210 ° C to about 228 ° C.

A further specific aspect relates to a crystalline form of compound I, which is named Form 6 and is characterized by an X-ray powder diffraction pattern measured using CuK ^ radiation as shown in FIG. 15. In a specific aspect, the 6-shaped characteristic of Compound I is that the reflectance in the X-ray powder diffraction pattern measured with CuKa radiation at 2 work angles is 8.9, 9.2, 10.2, 14.6. The 6-form of compound j can also be characterized by having the reflectance in the X-ray diffraction pattern measured at 20 angles using CuKQ! Radiation: 89, 9.2, 10.2, 12.6, 142, 14.6, 18, 6, 20 · 4, 21.1, 23.9, 25.2. Compound 6 can also be characterized by having a melting point in the range of 180-185 t :. The compounds e 幵 y may also be specifically characterized by having a heat map µ substantially identical to that shown in FIG. Form 6 of Compound 1 may also be characterized by a DSC thermogram having an endothermic peak of about 175 ° C to about 190 ° C. The present invention further relates to any one of the mixtures of the crystalline forms of the present invention, for example: a mixture of α and γ forms of Compound I. The wording used in this article is like "the crystal form of the compound, which is characterized by the χ-ray powder diffraction pattern measured using CuKa as shown in Figure」 ", which means that the crystal form of compound I has a shape substantially similar to the figure The powder J-ray pattern 'in other words' shows an X-ray powder diffraction pattern measured using C-ray radiation under conditions equivalent to those disclosed in Example 7 or by any-kind method as illustrated in the figure . This definition is also applicable to NMR and NIR diagrams after appropriate amendments 15 200530254. All other X-ray data (such as X-ray spike data) and all five confirmed crystal forms, which have been specified for a long time, are respectively … 0-, 7-, δ-, and ^ -shapes, so that the boundaries for analyzing variation are taken into account. The solid carbon] 3 NMR spectrum referred to herein is preferably measured on a spectrometer with a cp_MAS carbon needle using a sample rotation rate of 5000 Ηζ. Therefore, the NMR spectrum is preferably provided as described in Example 7.2 or by any equivalent method. The Teng reflection spectrum referred to herein is preferably provided as described in Example 7.3 or by any equivalent method, especially resolution and correction of baseline shift and slope with multiplicative scattering correction (MSC). In a further specific aspect, the invention relates to a crystalline form of compound I, which is substantially pure. The term "substantially pure" as used herein means the crystalline form of Compound I, such as an αγ, δ, or e-form, having a purity of up to y, a force of 90 / ', which includes, for example, at least about and at least about 95% 0 of Compound I The amorphous form melts at a temperature of about 150 ° C, which is easily distinguished from the melting point of the crystalline form of Compound I disclosed herein, see Table 1 of Example 9. Therefore, 'in the present invention there is also a melting point of at least n5 or at least 18 0C crystalline compound I, for example at 175. 〇_225 ° C, 180 ° C -225 ° C, 180 C -220 C or 181 ° C -218 ° C, or i80 ° C -190 ° C or 210 ° C-225 ° C By. The term "melting point" as used herein means the starting value of the endotherm of melting measured by DSC, see Example 7.4. A further specific aspect relates to the solid compound I containing the crystalline compound I alpha form. The invention also relates to solid compound I consisting essentially of the crystalline forms of the compounds described herein. Herein, the term "mainly means that the solid compound I is composed of at least 75%, such as at least 80%, or at least 95% of the total α crystal form of the total compound I. Further specific aspects are related to the point containing the crystalline compound I Compound I. The present invention also relates to a solid compound I consisting essentially of the crystalline form of the compound described herein. In this context, the term "main_" refers to the solid compound I and is composed of at least 75%, such as at least 80%, or at least 95 % Present in the crystalline form of the total compound I. A further specific aspect concerns the inclusion of the crystalline compound I 7 -body compound I. The invention also relates to the solid compound I consisting mainly of the compound ι form described herein. In this text The term "mainly the solid compound I is composed of at least 75%, such as at least 80%, at least 95% of the total γ crystal form of the total compound I. Further specific aspects are related to the crystalline compound j δ _ body compound I The present invention also relates to a solid compound I consisting mainly of the compounds described herein. In this context, the term "mainly this solid compound I is composed of at least 75%, such as at least 80% At least 95% of the δ crystal form of the total compound I is present. A further specific aspect relates to the compound I comprising the crystalline compound j. The present invention also relates to the solid compound I consisting mainly of the compound j form described herein. In this article, the term "mainly the solid compound I is composed of at least 75%, such as at least 80%, at least 95% of the total e crystal form of the total compound I. The α of 1" means 90% less solid. Leng Yao J means less than 90% shaped solid crystal 7 means "90% or shaped solid crystal" means 90% or shaped solid crystal "means 90% or 17 200530254 Broadly speaking, the crystalline form of this novel compound VII can be prepared by a variety of methods, including but not limited to allowing compound J to crystallize from a suitable solvent. Compound! It can be prepared using known methods of this technology, as disclosed herein. As a general guide, Compound I can be mixed with a suitable solvent and it can be heated to promote the dissolution of Compound 1. The combination of this solvent and Compound I can also be heated to help facilitate the subsequent conversion to crystalline form. In this respect, the range of scoop / dish can range from about 30 C to about the boiling point of the solvent (ie, the reflux temperature). A more preferred temperature range may be from about 6 generations to about the boiling point of the solvent. Yes; the mixture of solvent and compound 1 is cooled to initiate and / or continue to crystallize. ^ This composition is preferably cooled (in other words, contains natural cooling to the chamber 2 = around from about -20 ° c to about The temperature is to room temperature. This solid can be separated from the cooled mixture by you, or, or by centrifugation, and if necessary, the eroded field, state A α, said,, s 0 Solvent rinse, such as, but not limited to, the solvent used on the last day, and then under, for example, nitrogen flush. Dry in vacuum

Seed crystals can be added to any of the crystalline mixed characters φ I I ^ L _ to promote crystallization. The crystalline compound I s shown can be prepared by the following methods: In particular, different crystal forms of the present invention, the compound can be combined from a cold solvent in a suitable solvent, and (b) the salinity agent can be precipitated to separate it into 1 The resulting crystalline compound compound! A method comprising the following steps: the conversion time, and ib% ~% are sufficient to convert the dagger into the crystalline form and (b) the resulting crystalline compound. The following description is to use a centering agent to make compound shapes, maggots, and δ, which are all day-to-day shapes, that is, α-shape, / 5, and ... In a preferred specific form, the present invention 18 200530254 prepares crystalline compounds. The method including Form 1, Form 7, Delta, and e forms includes crystallization from a suitable solvent by precipitation of compound j to isolate ㈣i from the obtained crystalline compound 1. It is known that when the preparation of different crystalline forms of the present invention is mentioned herein, and by this method, $ ^ @ _ 1 J ^ Fan Li Ling Pao, or more specifically, the product obtained by this method is wrong It is also suitable for "a solid compound containing a crystalline compound 1"; in particular, as described above, ": a solid compound, which mainly contains a specific crystal form of compound I", such as: α-shape, Lu-shape, 7 Shape, delta shape or e shape. In addition, in the aspect, the present invention relates to a method for preparing the crystalline compound 1, which is characterized in that the crystalline compound is prepared in a solvent; and the solvent is selected from the group consisting of: Methanol to about 8% water; (ii) aliphatic C3_c0 alcohol (for example: 丨 _propanol, i_butanol, 2-butanol, tertiary butanol, bpentanol), which contains 8% water (For example: 1-butanol with *% water, propanol with 4% water, propanol with 4% water, tertiary butanol with 7% water, 2-butanol with 4% water) ; (IH) an acetate with at least 4% water, where the acetate is by definition, where R is W. alkyl, for example: ethyl acetate (for example: ethyl acetate with 4% water or Isopropyl acetate with 6% water). The invention also relates to the crystalline compound I which can be obtained by this method, in particular, which has been obtained by this method. In a preferred embodiment, this method results in the formation of the crystalline compound I alpha form. In a further aspect, the present invention relates to a method for preparing a crystalline compound, characterized in that the crystalline compound is formed in an isopropyl acetate solvent. The present invention also relates to || obtained by this method, in particular by this method 19 200530254 = two in two. : In a better specific form ’this method results in

In a further aspect, the present invention relates to a method for preparing a crystalline compound I, characterized in that the crystalline compound I is formed in a solvent selected from the group consisting of: ⑴ aliphatic Cl-C3 nitrile (Eg, acetonitrile, propionitrile) 'It contains up to about 12% of water (eg: propionitrile containing 4, or acetonitrile containing 12% water)' It should be understood that propionitrile (CH3CH2CN) is a kind of nitrile, ( 11) Methanol containing 0% to about 8% water; (iii) aliphatic C3-C6 alcohol (for example, b propanol or b butanol), which contains at least about 10% water (for example, containing 10% H propanol in water, κ-butanol containing 10% water); ㈣Test grade B & L B S The term "peony grade ethyl acetate" means less than μ% water. The invention also relates to the method obtained, and in particular to the specific form of lx L obtained by this method, which method results in the formation of a crystalline compound form. this

In a further specific aspect, the present invention relates to a method for preparing a crystalline compound I, which is characterized in that the crystalline compound is formed in a solvent. The solvent is selected from the group consisting of: ⑴ Fat CVC6 Alcohol (such as: ethanol, cyclopropyl methanol, or propanol, etc.), which contains less than 4% water ', for example: you Qy, less than 3, for example, about 2% (for example, cyclopropyl methanol, 3% ethanol in 2% water (without stirring). The present invention also relates to the fact that ..w is not to be paid, especially the crystalline compound obtained by this method. In a preferred embodiment, this method results in the formation of a crystalline compound I δ form. In the present state, the present invention relates to a method for preparing crystalline 20 200530254 compound i. The crystalline compound 1 (ch3Ch2CH class 1/1) The crystalline compound 1 is soluble in butyronitrile. This method obtains the crystalline compound I. I is preferably a specific example / ¥ causes the formation of the crystalline compound I e form. It has been found that in the presence of a acetonitrile represented by "" 1 is the same as in Example 6.1. As in the example: the person = one can convert the magic crystal to the α crystal form. In the presence of ㈣, the crystal form can be converted to this "Yue also about-a kind of crystalline product, especially The crystalline compound can be prepared by the method described in this article! The crystalline form of compound I described in the article has been gu, m, x, or in a preferred embodiment. The crystal form of compound I has been hunted in a preferred embodiment. The present invention is further developed. Aspects are related to the preparation of compounds !, which includes converting the _ seed crystal form of Compound I (eg, as described herein ", Lu, or γ 'or any mixture thereof) into compounds! This: method in: a better specific form The following steps are included ^ Compound I is bathed in an aromatic solvent, such as diphenylbenzene or toluene, and the compound is xylene, which is separated from the aromatic solvent, and the amidine is separated from the amorphous compound 1 of the Shendian. Aromatic solvents. &Quot; The formation of crystalline compound 1 is very useful, especially as a purification step in the manufacture of medical compound I. The invention relates in one aspect to a method for manufacturing compounds! It includes the "crystallization step described herein. Therefore, a specific aspect of the present invention is a method for manufacturing Compound 1 '. This method includes a step for converting the eight compound 1 into a crystalline compound 1. It should be understood that the present invention : It 21 200530254 The compound i can be prepared by the method described in this article, and the compound can be prepared as s 4, for example, by separating the obtained from a record and the agent order as described in this article. Shiyue's clams are precipitated, and the compounds are dissolved from the solvent. The present invention is particularly related to the manufacture and conversion to crystalline compounds, including the method of the present smoke method, wherein the compound I compound is mixed with the crude mixture. Or one of the crystal forms, such as from the chemical meaning that the mixture contains impurities, such as the text: crude mixture-the word means that it is necessary to remove. This crude mixture; :: oxidation product ': the crude reaction mixture may have been knifed off Or alkaline treatment. The invention is described in the "initial purification", such as the use of a crystalline compound T Chi Shiba a solid, which is a pharmaceutical product with sexual ingredients of "15". "3 There is a combination ... is a kind of activity so the present invention is also about a formula, ... k + A kind of "pharmaceutical composition of compound I / d from the crystalline compound J as disclosed herein, for example by as described herein The method obtainer includes the seed crystal form or a solid of the present invention to prepare the composition. Another particular embodiment relates to the use of the t α or γ form of the present invention for the preparation of a pharmaceutical composition. As described previously, 'the preparation of a formulation from a well-defined crystal form has the advantage of improving purity and yield' and has well-defined properties such as solubility. In this aspect, the present invention also provides a pharmaceutical composition comprising an effective amount of Compound I, which can be obtained by or has been prepared by the method of the present invention, including a crystalline form of the present invention, such as from an α or γ form. . The pharmaceutical composition may be any composition that has been found to be suitable for administration of Compound I, such as a solid dispersion formulation or a solid solution formulation. 22 200530254 In a specific aspect, 'the place of the invention S ▲ 4 Zhiyue's crystalline product, that is, specifically including α, / 5, γ, δ or 6 crystal form, formula Gan, B people w years old mixture, Can be formulated into a solid solution or a solid dispersion. The solid solution Kola J is shown below. The crystal product of the present invention is dissolved in a molten carrier. After cooling to room temperature, a carcass solution is formed. The solid dispersion can be prepared as follows: The crystalline product of the present invention is dispersed in a molten vehicle. Cooling to room temperature will form the solid dispersion. The carrier used to prepare the solid solution or solid dispersion can be a single component or a mixture of multiple components. The carrier used to prepare a solid solution or solid dispersion for m μ ^^ at room temperature is usually solid or semi-industrial + pure Ul, dry U body, and usually has a gel, oil, or insect-like feature. However, the carrier can also be a fluid at temperatures at or below 5 ° C. For A # 力 丨 y. U As examples of carriers, mention may be made of ... polyethylene glycol (PEG), poloxamer (ρ〇〇〇 ^ ^ like ethylene diazidyl esters, paraffin, glycerol S, fat Alcohols, fatty acids, sugars, vitamins β, and vitamin E. Any solid organism or solid solution ^ MM, τ is used as it is, or it is formulated into a fungal composition, such as a tablet sword, capsules. Solid solution And solid partition fluid can also be pulled by 1 other knife, such as Ding, A.T.M., Medical Science ^ ^, Shi Yi, Department of Medical Science, Issue 88, 1058-1066 A member The body shape is related to a kind of pharmaceutical composition, which is a solid solution prepared by the crystallization and synthesis of the present invention, for example, it is obtained by the present invention or the γ crystal form. Each ~ Therefore, 'the present invention's shape, or ... Heart especially — ", ..., crystal, can be used to prepare medical composition containing dissolved compound, such as the composition disclosed by TTo ^ w ^, 6,200,968. In the present invention, there is also a medicine A composition comprising an effective amount of a crystalline compound as described herein 23 200530254, especially Α-, 0-, 7-, δ-, or 6-shapes or mixtures thereof as defined herein, and a pharmaceutically acceptable carrier. The crystalline product of the present invention, that is, includes α, / ?, γ, δ, or e crystal form or its & substances' can be formulated into various pharmaceutical compositions. Examples of such formulations containing the crystalline product of the present invention (for example: α0γ, δ or e crystal form) are lozenges, capsules, granules, powders, suppositories And suspension. The wording "crystalline product of the invention" means crystalline compound I or solid compound I as described herein, in other words, it should be understood that "solid compound L is herein a solid compound composed mainly of crystalline compounds" J, which is compared with amorphous compounds. The pharmaceutical composition according to the present invention can be formulated with a pharmaceutically acceptable carrier or diluent and any other adjuvants and excipients, for example according to Rimington : Pharmaceutical Science and Practice, 帛 19th edition, edited by Junaruo, Mark Press, Easton, PA, 1995. Pharmaceutical compositions can be specifically formulated to pass through any appropriate Administered 'for example, oral, rectal, nasal, pulmonary, topical (including mouth and sublingual), transdermal, intracranial, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrajump, intravenous, and dermal Internal) route, of which oral is the preferred route. It should be understood that the preferred route depends on the general condition and age of the individual being treated, the nature of the condition being treated, and the active substance selected. In a specific aspect, the compound is administered in an amount of from about 0.001 to about 100 milligrams per kilogram of body weight per day. For example, the compound! May contain the compound in an amount of about 0.001 to 100 milligrams. Unit dose 24 200530254 type cast :. And the total daily dose is, for example, about. 〇5_500〇 〇 The formulation can be familiar with the # surrounding. Type is presented. Conveniently presented in unit dosage form by known methods. For karma for mother day 1 or guest 4 Μ, for example, a typical early-dose dosage form for oral administration 1 to 3 times per day may contain only 0.01 to about 1,000 g, preferably about 0.05 To about 500 mg. Pingyi 1 main direction 3, for parenteral branches, such as intravenous, intramuscular, intramuscular and similar dose-half degree.丨 A typical dose is about 7F, which is taken orally, and the following specific forms are in the crystalline compound 1 of the product of the present invention; it is used as the crystal form of Shangle; it is used as medicine. Said to be used as pharmaceuticals: 3: 7: crystal form; used as medicine ... crystal form; used as the crystalline compound as described herein ^ for example, magic, mouth shape, 7 shape, δ shape Or e-shaped or mixture of =, which is used to prepare products for treating CNS diseases, such as the treatment of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Henry; Peripheral neuropathy, Ams dementia, or ear damage, including hearing loss caused by noise. +: It seems that 5. There is also a treatment for neurodegenerative diseases in the present invention, such as: Parkinson's disease, Alzheimer's, Preparation > Methods for pathological changes, AIDS loss, Tington's disease, peripheral nerve injury, 1 scoop or ear damage including hearing loss caused by noise, and administration of a pharmaceutically effective amount of a crystalline compound For example, as described herein in the a-form or the 6-form or mixtures thereof. The form of “Jinyi ...” is the medical use and medicine group of the compound I and the crystalline form of the present invention. 25 200530254 The same applies to this article I 'especially mainly by metallurgy', also The term "comprising plant diseases" also includes products, such as those used in the treatment of Parkinson's disease, which are defined as solid compounds comprising the crystalline form of the present invention. As used herein, the disease-related term "prevention where possible. Terms used as used herein. Obstacles where possible. Restrictive implementation."

The invention disclosed herein is further illustrated by the following non-example. [Examples] In the following, the starting material "compound!" Can be prepared, for example, as disclosed by M. et al. On page 4 of "Journal of Medicinal Chemistry" of Satoshi No. 4Q. Example 1 · Preparation of α crystal form of compound I Method I: 6.0 g of amorphous compound was used! Dissolved in 3G ml of acetone. Add φ 0.6 g of potassium carbonate, and continue to suspend the suspension at room temperature for one hour, and then remove a small amount of insoluble impurities and inorganic salts. Rinse the filter cake with propane. The filtrate was then concentrated on a rotary evaporator under reduced pressure of Lihang to a final volume of 1 G ml, and then methanol was slowly added thereto. The product was separated into oil, which was almost dissolved from the < It is then filtered to remove residual insoluble impurities. Allow the transfer solution to stand at room temperature. A crystalline solid was separated by filtration. The fermented cake was rinsed with methanol and dried overnight under a vacuum. Yield 2.84 g (47%), dazzle point = 182 · π (· initial value), 26 200530254 Weight loss on heating: 0.5%; theoretical value of h2〇 correction: 6.79% N, 64.㈣c , 5 43% H, xRpD analysis and a shape. Method II:

5 g of amorphous compound is combined with gentle heating ... dissolved in 25 ml of propylene. A 1G ml of methanol was added very slowly until the solution became cloudy. The solution was allowed to cool to room temperature. The suspension was filtered and discarded. More material precipitated in the filtrate during filtration. The filtrate was added again until all the material was redissolved. Cold methanol was then added to the solution until observation: precipitation. The slightly cloudy solution is then heated until everything is dissolved: the solution is allowed to cool to room temperature and the precipitate is removed by filtration. Discard the second filter cake. Some material was separated from the filtrate during filtration. Heating = this initial crystal is redissolved in the filtrate. Cold methanol was then added to the solution until precipitation was observed. The suspension was heated until a clear solution was obtained. The radon solution was naturally cooled to room temperature. After a short period of time (5 minutes), precipitation began. The precipitated pale yellow product was isolated by filtration and dried overnight under vacuum at 50 ° C. Point = 188.9C (DSC initial value), heating weight loss · 0%, elemental analysis: 6.53% Ν, 64.33 C%, 5.43% H, theoretical values 6.82% Ν, 64_37% C, 5.37% The H, XRPD analysis is consistent with the alpha shape. Method III: Add 0.5 g of compound I to a mixture of isopropyl acetate (10 ml) and water (0.6 l), and heat to reflux while mixing. Compound incomplete 27 200530254 Soluble ’so isopropyl acetate (10 ml) and water (0.6 ml) were added and heated to reflux. Stop mixing and allow the experiment to cool to room temperature. The crystallized product obtained was isolated by transition and dried under a vacuum of 4 ° C. ^ a = 0.25 g 'refining point = 183.7 ° c (starting value) cXRPD analysis was consistent with the shape. Method IV : 0.5 g of the compound was added to a mixture of ethyl acetate (10 ml) and water (04 ml), and heated to 70 t with stirring. Allow the experiment to cool to room temperature. The obtained crystalline product Isolate by transition and dry under real work. XRPD analysis is consistent with α form. Example 2 Preparation of Compound I / 3 Crystal Form 28.0 g of amorphous compound J was dissolved in 25 ml of tetrahydrofuran (THF) And evaporated to 60 g of Shixi gum. The compound was purified by column chromatography on Shixi gum (0. 10 cm, h: 5 cm, 2.71 THF / n-hexane 2/1). The eluate containing the desired compound I was evaporated to a solid (26 g) under reduced pressure at 50 ° C in a rotary evaporator. The solid was suspended in 600 liters of isopropyl acetate, and the The suspension was heated to reflux until almost everything was dissolved. The suspension was cooled in a water / ice bath. The cooled suspension was passed through 'And the filter cake was rinsed with isopropyl acetate and dried under vacuum at 500c overnight. Yield: 16.9 g (61%), melting point = 211.7. (: (〇8 (: starting value), Weight loss during heating 0.2%; Elemental analysis: 6.59% N, 64.63% C, 5.41% H, theoretical values: 6.82, 64.37% C, 5.40% Η, XRPD analysis is consistent with / 3 form. 28 200530254 Example 3 Preparation method I of the γ crystal form of compound I: Dissolve 15 g of amorphous compound I in 75 ml of acetone. Add 1.5 g of potassium flavate, and stir the suspension for 90 minutes. Filter the suspension. The filtrate was reduced to about 30 ml in a rotary evaporator at 60 t under reduced pressure. 150 liters of methanol was added to the reduced filtrate, and some sticky substances were knifed out. The suspension was heated To reflux. During this heating process, everything is dissolved. The solution is allowed to cool to room temperature using natural cooling, during which time the solid form material is separated. The suspension is allowed to continue to fall at room temperature overnight. The solution was filtered and the filter cake was rinsed with methanol. The filter cake was placed under a vacuum of 50 ° C. Dry overnight. The intermediate yield is ι0.2 g (68%). The dried cake is suspended in 100 ml of acetonitrile (ACN) and heated to reflux. A cloudy solution is obtained at reflux. Additional acetonitrile is added until it is clear Solution; the entire filter cake was dissolved in 200 ml of acetonitrile, which contained 1 ml of the suspension. The solution was cooled to room temperature and left overnight. The crystalline product was separated by filtration the next day. Rinse with a small amount of acetonitrile and dry overnight under vacuum at 55 ° C. Yield: 6.17 g, 41%, melting point (Dsc initial value), weight loss due to heating <0.1%; wood element analysis, 6.80% N, 64.38%, 〇5.43% H, theoretical value, 6.82 % N, 64.37% C, 5.40% Η, purity (HPLC, area%) · 98 · 6, XRPD analysis was consistent with γ-shape. 29 200530254 Method II: Anion, 5 liters) and water (K2 milliliters): In a mixture of ^, w… to 70 C while stirring.瓖 Slowly pour the solution to a > dish. The next day, the products were separated by filtration, and the daily products were separated and dried at 40 ° C, melting point = 214 2. I starting value). The xrpd analysis was consistent with the shape of Ύ. Method III: Add 0.5 grams of compound] [to ethyl acetate (5 ml) and heat to 70 t with stirring. Allow the solution to cool slowly to room temperature. After 12 days, separate the crystalline product by filtration. Drying under vacuum at rc. XRPD analysis is consistent with γ-form. Example 4. Preparation of δ crystal form of compound 丨 Square I: 0.5 g of α-form compound J was added to cyclopropylmethanol (10 ml) The solution was heated to 70 C. The solution was slowly cooled to room temperature. After 2 days, the crystalline compound was separated by filtration and dried under a vacuum of 4 ° C. Yield = 0.24 g, melting point = 212 · Γ (: (DSC initial value), XRpD analysis is consistent with δ shape. Method II: ο · 2 g of α-shaped compound Ϊ is added to methanol (10 ml), and heated to 70 ° C while stirring. Stop stirring, The solution was allowed to cool slowly to room temperature. The crystallized product was separated by filtration the next day and under a vacuum of 4 (rc) Dry. Yield = 0.15 grams, melting point spoon phantom (initial value of DSC), analysis is consistent with δ shape. 30 200530254 Method III: Add 0.5 grams of compound to propanol (15 ml) while adding 敎 to 70 ° C. Stop the spectrum load ^ 4 & u 7〇 t t stop the material, and let the solution slowly cool to room temperature. The crystalline compound was separated by filtration and dried under the direct air of 1 μL of Gangshi. The rate was 0.23 g, and the XRPD analysis was consistent with the valley shape. Example 5 Preparation of the Crystal Form of Compound I 0.5 g of α-shaped compound! Add to Ding Shan (10 ml) while heating to 70 ° C. Let the The solution slowly cooled down again and again, "Okay, a dish. The crystalline compound was separated out with 遽 the next day" and dried under a vacuum of 4 (rc. Yield-0.33 g, dazzling point = 181 fC (DSC initial value), XRpD analysis is consistent with ^.

Example 6. Conversion between Different Solid Forms of Compound I 6.1 Conversion to Crystalline Compound I In the following examples, excess solid compounds were used, in other words, the substance (1) "Che Fang Fang, life agent 'solid compound & amp The amount of j is not all solid matter is dissolved. The amount used is between 25-50 mg of solid compound j and 2 ml of solution. The term "solid compound I" is used herein to mean amorphous compound 1, or as follows Any of the crystalline forms of the compounds shown. An excess of the amorphous compound j was added to methanol, and the resulting suspension was stored on a rotary mixer at room temperature for four days. Four days later, as measured by powder X-ray diffraction, the solid was ^ -shaped. The alpha crystal form of compound I was added to methanol over the day, and the resulting suspension was stored on a rotary mixer at room temperature for four days. After four days, as measured by powder X-ray diffraction, this solid was still in the shape of 31 (ii) 200530254. (iv) (-) The excess point crystal form of the compound was added to methanol, and the resulting suspension was stored on a rotary mixer at room temperature for four days. Four days later ', the solid was α-shaped as measured by powder X-ray diffraction. : γ crystals of K & I in K) were added to methanol, and the resulting suspension was stored on a rotary mixer at room temperature for four days. Four days later 'the solid was still in shape as measured by powder X-ray diffraction. (v) An excess of 7T <, α and 7-shaped 1: 1 mixtures were added to methanol 'and the resulting suspension was stored on a rotary mixer for four days at room temperature. After four days, most of the solid was τ-shaped. After the transition, the supernatant was left to allow the solvent to evaporate. The solid obtained was ^ -shaped, as measured by powder X-ray diffraction. (Vi) Add the amorphous compound J in j to acetonitrile (ACN), and store the suspension of Hujinzi on a rotary mixer for 4 days. Two days later, 'as measured by powder X-ray diffraction, this solid form' (V11) added excess crystal form of Compound 1 to ACN, and stored the resulting suspension on a rotary mixer at room temperature Four days. Four days later ’as measured by powder X-ray diffraction,

(viii) Add excess compound I, Lactobacillus to the ACN, and store the resulting suspension on a rotary mixer for four days at-as measured by powder X-ray diffraction. Or, this, y 32 200530254 shape. (ix) Add excess compound / day to the ACN, and 'store the resulting suspension on a rotary mixer for four days and days after temperature' as measured by exposure to X-ray diffraction. This solid is quadrilateral. f Conclusion: The amorphous compound I and / 3 crystal form can be converted into amorphous compound α crystal form and ^ crystal form in y 隹 TS sub suspension sweat solution. By suspending excess solid matter in acetonitrile, Conversion to γ crystal form. 6.2 Conversion from α crystal form to amorphous compound j 15 g of the α crystal form of compound I was heated to reflux in a mixture of methylbenzyl (1 ml) and methanol (1 ml); a clear solution was obtained. At minus 1, the bath volume is reduced by 10 ml, and the solution is allowed to cool in the refrigerator overnight. The obtained solid was separated by filtration and dried under a vacuum of 4 rc for 2 days to obtain 13.2 g of a solid. The melting temperature of this solid is about i 50 ° C, which is related to the crystalline form. The characteristics of this amorphous compound z are shown in the following table. Example 7. Analytical method (7.1) The XRPD pattern is obtained by using a diffractometer in the following cases: The following are measured: (i) STOE heat radiation: cu (Kai), germanium monochromator, λ = 1.554598 A position sensor (PSD) covers 7. Scanning mode: phased scanning, phase ·· 〇 · 丨. When scanning at each stage 33 200530254 125-150 seconds Range: 5-45 ° 2θ Sample measurement method: transmission mode (Η) PANalytical x, pert pro X-ray diffractometer using CuKal radiation. X’celerator detector, measuring range 5-40. 2 No sample measurement method: reflection mode_ (7.2) Solid state NMR is performed under the following conditions: Carbon-13 CP / MAS (Cross Polarization / Magic Angle Spin) NMR spectroscopy at room temperature with 11.75 tex Sierra was acquired with a Brook Avans DRX-500 spectrometer equipped with a 4mmCp / MAS carbon needle. The sample speed was 疋 5000 Hz, and 1024 scans were acquired with a 5 second loop delay. For cross polarization, the spin-locked radio frequency field is 50 kHz and a contact time of 5 ms. (7.3) Near-infrared light (NIR) data was collected with a ρ〇_Γ "Heh • Baumann MB 160FT / NIR spectrometer. The NIR reflection spectrum was recorded between 14.000-4.000 cm-i The resolution is 2 ° (16 scans, high gain). The baseline shift and slope of the NIR spectrum, which are common in powders, are eliminated by the multiplicative scattering correction method (MSC). (7.4) The refinement point is at The vertical (differential scanning calorimeter) was used to measure the onset temperature of the endothermic melting. In an aluminum crucible with a non-hermetic lid, a sample of about 2 mg was heated at 5 C / min under & extraction. (7 · 5) The shape of the crystal structure is determined in the following cases: Diffraction data is 34 200530254 collected using Noniers + "Kappa CDD Diffractometer". Data collection was performed at 122K under Litiankouguchi a with early coloration MοΚα, radiation (λ-0.70773 A). Example 8 · Analysis results ~ ray powder diffraction order (xrpD): α. Department of Physics ® 1 is shown in Figure 2 *, γ is shown in Figure 3, δ is shown in Figure 13, and e is shown in Figure 15

Therefore, the characteristics of Kailuan on the same day are different reflectances (peaks) in the X-ray powder diffraction pattern using CuKa radiation at 2-Θ kg: (5 · 2, 10,1, 10 · 4, 13.2, 15.1, 25.1; 5.2, 7.3, 8.1, 10.1, 1104, ΐι "" · 2, 13 · 2, 15. 15. Bu 15.5, 17.3, 21.7, 23 8, 25.1); ^ (6.6, 8.9, 10.7 " 4, 11.7, 13.7, 30.6);, 11.7, 24.4, 30.6; 6.6, 8.9, 10. · 7, Ρ.Ο, 18.5, 18.8, 19.2, 20.3, 24.4,

7 (9.6, 11.5, 12 5 U.5, 1 1.8, 12.5, 2ΐ · 〇, 28.1);, 16.7, 19.3, 28.1; 7.5, 8.3, 9.6, b.9, 16.3, 16.7, 17.2 , 18.0, 19.3, δ (9.7, 12.1, 16), 0 0, 18.3, 22.1, 22.2, 25.7, 25.8; 8.3, 9.7, 11.1, ι17, 121, 15.6, 161, 17 3, · 3 20 · 9, 22.1, 22.2, 25 · 7, 25.8); 6 (8.9 > 92 > ΐη〇 " • 0.2, H6; 8.9, 9.2, 10.2., 12.6, 14 (2, 8 2 6 17.0, 18.6, 20.4, 21.1, 23.9, 25.2). ~ ^ ^ The heat map is shown in Figures 4-6, 14, 16 35 200530254 (α crystal form in Figure 4, / 5 crystal form in Figure 5, and γ crystal form in Figure 6, δ crystal form in Figure 14, 6 crystal form 16). The 8J__data_1_ solid-state NMR spectrum alignment is shown in FIG. 7, the shape is shown in FIG. 8, and the γ-shape is shown in FIG. 9. 8.4 NIR number The NIR spectrum is shown in Figure 10, the shape system is shown in Figure 11, and the gamma shape is shown in Figure 12. ^ ~~ Compound? The crystal structure of the 2-shaped structure was measured by a single crystal X-ray diffraction at 122K. The crystals used for structure determination were obtained by slow precipitation from MeOH, and have a size of 0.5 × 0 · 3 × 0 · 2 mm. The obtained crystal structure shows that compound J crystallizes in ϊ22κ in the orthogonal space group PSJA crystal, Unit cell size: a = ι227 · 2 (2) persons, seven = 2 3.942 (2) A and c = 24.240 (2) A, ce = 90. , 0 = 90. , Γ = 90. , V = 5935.3 (12) A3, Z = 8, density = Κ378 g / cm3 (the numbers in parentheses represent the standard deviation of the last digit), and the unweighted consistency factor is R [I> 2σ (Ι)] = 〇6999 The asymmetric unit of the crystal contains two compound I units, and 0_j solvent molecules. The solvent molecule may be MeOH or water. In this structure measurement, the corresponding atoms of the 'bath agent' were found to have C2 ,, 0.70, 01, 0.50, and 03, 36. When the asymmetric unit contains two molecules of compound I and N9; position 9 ′, the complete occupancy of this position will result in a hemisolvate. Here, the atomic number and conformation of the two molecules in the asymmetric single TL are as shown in FIG. 17-18, and the molecular stacking system in this crystal is shown in FIG. The coordinates of the atom are provided in Table 2-4 below. 36 200530254 Table 2: Atomic coordinates and isotropic isotropic displacement parameters of non-hydrogen atoms in molecule 1

X y Z Ueq C11 -0.1069 (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) 0.0215 (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 0.5059 (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) 0.50157 (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) 0.65289 (14) 0.39104 (11) 0.0475 (8) 07 0.5939 (3) 0.66596 (12) 0.33752 (12 ) 0.0417 (7) S1 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) 37 200530254 Table 3: Atomic coordinates and other non-hydrogen atoms in molecule 2 Isotropic displacement parameter

X yz Ueq cir 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) C165 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) C2V 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) C2T 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 '13282 (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) 0.29800 (18) 0.04312 (16) 0.0338 (8) C385 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) N105 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) N95 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 (2) 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) 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) 38 • 200530254 Table 4 · Atomic coordinates and isotropic valley isotropic displacement parameters and occupancy ratios of the atoms in the heart palpitations 01 ” 0.7366 (10) C2, 0.6529 (11 1 occupancy — 0.4259 (10)-〇1〇61 (5) 0 143 ^ 〇 · 499 (16); 〇) also) Example 9 · Melting point

The amorphous and crystalline solid forms of compound 1 (see Example 7.4 above) have melting points shown in the following table. Brief description of the figure] Figure 1: X-ray powder diffraction pattern showing the compound I 〇_ shape. Figure 2: X-ray powder diffraction pattern showing the shape of compound I 1. Figure 3: X-ray powder diffraction pattern showing Compound I 1 form. Figure 4: DSC thermogram showing the form of compound I 1. Figure 5: DSC thermogram showing compound I. Figure 6: DSC thermogram showing Compound I: x-shaped. Figure Ί \ shows the 43 NMR spectrum of solid carbon in the form of compound I 〇>. Figure 8: Solid carbon-13 NMR spectrum showing the 11 form of the compound. Figure 9: Solid Carbon-13 NRR spectrum showing the I form of the compound. 39 200530254 Figure 10: Shows the NIR reflection spectrum of compound I i. Figure Π: Shows the NIR reflection spectrum of Compound I I form. Figure 12: Shows the NIR reflection spectrum of compound I i. FIG. 13: Shows the X-ray powder diffraction pattern of the compound I L shape. Figure 14: DSC thermogram showing the L-shape of the compound. Figure 15: X-ray powder diffraction pattern showing compound I shape. Figure 16: DSC thermogram showing Compound I form. Figure 17: Shows the configuration of one molecule (Molecule 1) in the form of Compound I i Figure 18: Shows the configuration of the other molecule (Molecule 2) in the form of Compound I i The accumulation of molecules. Further details of the drawings are shown in the following examples. Key component symbols] None 40

Claims (1)

200530254, patent application scope: 1 · a crystalline compound I, Η The compound has the crystal form of the following formula 2. A compound ϊ, the chemical formula H σ I as defined in the first item of the scope of interest has the crystal form of the "item of the 5th patent application", which is characterized by the following — The X-ray powder diffraction pattern shown at ⑴ = 1, which is measured by a sharp ray; (ii) The X-ray powder diffraction pattern measured at a 2 j angle using CuKa radiation at 6 jA Reflectances in: 5.2, 10.1, 104, η 7 — J · 2, 15 · 1, 25.1; (iii) The solid carbon-13 NMR spectrum shown in FIG. 7; (iv) As shown in FIG. 10 The NIR reflection spectrum shown in Figure 4. The crystal form of item 2 in the scope of the patent application is characterized by the reflectance in the X-ray powder diffraction pattern measured at 24 angles using CuKa radiation. 5.2, 7.3, 8.1, 10.1, 10 · 4, 1 1 · 2, 13.2, 15 j, •, 1 5 · 5, 17.3, 21.7, 23.8, 25.1. 5 · As for the crystalline form of item 2 of the scope of patent application, it is characterized by CuKo: Reflectance of X-ray powder diffraction pattern q τ measured at 2 angles: 5.2, 10.1, 10.4, 13.2, 15.1, 25.1 0.041 200530254 6. As requested The crystal form of item 2 of the patent scope is characterized by a crystal structure with the following characteristics at 122K days: space group: pin, unit cell size: a = ^ .227 (2) A, b = 23.942 (2 ) Λ, ό = There are 2 molecules in this asymmetric unit 24.240 (2) A '〇! = 90., / 3 = 90., γ = 90. 7. If the crystal form of item 2 of the scope of patent application, which It is characterized by one or more of the following: (i) X-ray powder diffraction pattern shown in FIG. 2, which is measured using CuK0; radiation; (ii) X measured using CuKa radiation at a 2-0 angle Reflectance in ray powder diffraction pattern: 6.6, 8.9, 10.7, 11.7, 24.4, 30th; (iii) solid carbon-13 NMR spectrum as shown in Fig. 8; (iv) NIR reflection as shown in Fig. 11 8. The crystal form of item 2 in the scope of patent application is characterized by the reflectance in the X-ray powder diffraction pattern measured at 2-0 angles using CuKa radiation: 6.6, 8.9, 10.7, 11.7, 24.4, 30.6. 9. The crystal form of item 2 in the scope of patent application is characterized by reflection in the X-ray powder diffraction pattern measured at 2-0 angle using CuKa radiation. Degrees: 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 · The crystal form 'item 2 of the scope of patent application is characterized by one or more of the following: (i) X-ray powder diffraction pattern shown in FIG. 3, which is measured using CuKa radiation; 42 -200530254 (ii) Reflectance in the χ-ray powder transmission pattern measured at a 2-Θ angle using CuKa radiation. 9.6, 11.5, 12.5, 16.7, ι9, 3, and 28. (iii) Solid state as shown in Figure 9 Carbon-13 NMR spectrum; (iv) NIR reflection spectrum shown in FIG. 1 1 · The crystal form of item 2 in the scope of patent application is characterized by the reflectance in the X-ray powder diffraction pattern measured at 2 work angles using CuKa radiation: 9.6, 1 1.5, 12.5, 16.7, 19.3, 28.1. 12. The crystal form of item 2 in the scope of patent application, which is characterized by the reflectance in the X-ray powder diffraction pattern measured at a 2-Θ angle using CiiK〇! , 15.9, 163, 167 17.2, 18.0, 19.3, 21.0, 28.1. 13. The crystal form of item 2 in the scope of patent application, which is characterized by an X-ray powder diffraction pattern measured using CuKa radiation as shown in FIG. 13. 14 • The crystal form of item 2 in the scope of the patent application is characterized by the reflectance in the X-ray powder diffraction pattern measured at 2 W angle using CuKa radiation: 9.7, 12.1, 16.1, 18 · 3, 22 · 1, 22.2, 25.7, 25 8. 15. The crystal form of item 2 in the scope of patent application, which is characterized by the reflectance in the X-ray powder diffraction pattern measured at 2-0 angles using CuKa radiation: 7.3, 8.3, 9.7, 11.1, 11.7, 12 · 1, 15 · 6, 161, 17.3, 18.3, 20.9, 22.1, 22.2, 25.7, 25.8. 16. The crystal form of item 2 in the scope of patent application, which is characterized by an X-ray powder diffraction pattern measured using CuKa radiation as shown in FIG. 15. 17. The crystal form of item 2 in the scope of the patent application is characterized by reflection in the X-ray powder diffraction pattern measured at 21 angles using CuKa radiation 43 200530254 degrees: 8.9, 9.2, ι0.2, 14 6. 18. The crystal form of item 2 in the scope of the patent application, which is characterized by the X-ray powder diffraction pattern measured with the radiation at the angle M ^^^: 8.9'9 · 2'1〇 · 2〇MS ,. 〇 ? 21.1, 23.9, 25.2. ϋ · 4. 19. If the scope of application for patents 2 to 18 is substantially pure. The shape of the heart B is 20 · -type solid compound containing the crystal form of the compound 1α. The compound 1 has a chemical formula as defined in item 1 of the scope of patent application. Group: If the scope of patent application is 帛 2. The solid of the item is mainly defined by "shape 22. Such as the patent application scope No. 20 or the member of the solid, which is as defined in the patent application Fanyuan certificate ^ Yue inch Bu J Ganwei brother 3 to 3 23. A solid compound containing the crystalline form of compound u, wherein compound 1 has a chemical formula as defined in item 1 of the scope of the patent application, 24. If the solid according to item 23 of the patent application is composed of the intangible material. ^ 25. A solid as claimed in the scope of patent application No. 23 or 24, wherein the exhaustive form is defined in any one of the scope of patent application scope Nos. 7-9. 26. A solid compound I containing a crystalline form of compound I, wherein the chelate 1 has a chemical formula as defined in item 1 of the scope of patent application. 27. If the solid according to item 26 of the patent application scope, it is mainly composed of the 7 form. 8. The solid of item 26 or 27 of Shi Shenyan's patent scope, wherein the γ-shape 44 200530254 is as defined in any one of items 10 to 12 of the scope of patent application. 29. A solid compound z containing a crystal form of compound δ, wherein compound 1 has a chemical formula as defined in item 1 of the scope of the patent application. The solid of item 29 in the scope of claim 1 is mainly formed by the δ-shaped 3 ^ The solid of item 29 or 3G in the scope of patent of claim 4, wherein the delta-shaped Ding Shiming patent is defined in any of items 13 to 15 . Into your Γ-a solid compound containing the crystal form of compound 1 e, which has a chemical formula as defined in item 1 of the patent scope. The group of 3 into 3. If you apply for the solids in the scope of the patent, it is mainly composed of the e-shaped = application: the solids in the scope of the patent, 32 or 33, of which ㈣ 糸 ": any of the scope of the patents 16 to 18 One is defined. 5. A method for preparing a crystalline compound J Xigutulin compound ^ A mouthpiece 1 'characterized by the crystallization. The compound I appears to be as high as 4 $ when it contains 0% to about 8% water. Jiuling Shanning is formed, in which 3 ", the chemical formula defined by the first item in the range. • Sigma, Patent No. 35 of the scope of patent, 1 ^ Compound I is H from the solvent-including precipitation by precipitation. Alas. aa sub-solvent and the obtained crystalline compound U 'are defined by the crystalline term. The scope 35 or 7 'is as described in the scope of the application for the patent 35 or 36: Compound 1 is as described in the scope of the application for the scope of patent 2 to 6 38. A crystalline compound I, which can be obtained by the method of applying 36. 39. A method of preparing a compound ' The method includes converting compound j 45 200530254 into a crystalline compound! Step, wherein the compound is a chemical formula as defined in item 1. Then, if the method of item No. 39 is applied, it involves removing the compound I from the solvent and separating the solvent from the obtained crystallized compound I. σ 41. If the method of applying for the scope of patents 39 or 40, wherein the company said that Compound 1 is as specified in any one of the scope of application for patents 2 to 18, 42. If the method of scope of applying for the patent 39, The crystalline compound is obtained according to claims 35 to 3 of the scope of patent application. The method of MIT's item has been obtained 43. If the method of any one of the 42nd items in the scope of patent application, the resumption includes the manufacture of a pharmaceutical composition containing compound I. 44. A composition for the preparation of chemical compounds, wherein compound I has the same properties as described above. The chemical formula as defined in item 1 of the patent. The method of item 44 is as defined in any one of item ^ 19 of the scope of the patent crystallization / patent scope ^ 19. The composition is the method of H patent scope 44 or 45, wherein the medicine is a solid dispersion or a solid solution formulation. 47 · A medicinal composition, Α 1 to] Q s 3 is effective. It is a crystalline compound as described in any of the items in the scope of the patent application. Γ.ΓΛ㈣ 料 ㈣Any of the items in the 1 to 19 items of crystals. 49 SiM is used by the 'Eight Lines' to make medicines for the treatment of CNS diseases. 9. Use according to item 48 of the scope of patent application, wherein the dysentery is a neurodegenerative disease. 50. According to item 48 of the scope of the patent application, the group is selected from the group consisting of Parkinson's disease, Alzheimer's disease, and Huntington's disease, which is peripheral neuropathy or AIDS dementia. , Dancing Kick Syndrome, Zhou Er-Kind of patent please come in the patent scope! To the use of compound I in any of 19 items, its application is made by & 52. A method for treating a neurodegenerative disease, which comprises administering a medically effective amount of the root shooter to any of U18 in the patent scope = Compound 1. 53. The method according to item 52 of the patent application scope, wherein the disease is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, and AIDS dementia Groups of people. 54. A method for treating Parkinson's disease, which includes administering a medically effective amount based on the patent claims! To 18 # of the crystalline compound I. Η ^ 一 、 Schematic: as next page 47