TW200806666A - Salts of 8-[(1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy)-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor - Google Patents

Abstract

Disclosed are crystalline salt forms of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I and methods of preparing the same.

Description

200806666 IX. Description of the invention: [Technical field to which the invention pertains] The novel system of the present patent application relates to a pharmaceutically useful salt and a novel method for preparing a salt useful in medicine. Specifically, it relates to a medicine for synthesizing 8_[^_(3,5-bis-(trifluoromethyl)phenyl)ethoxymethyl]phenyldiazo-spiro[4,5]nonan-2-one A novel method of learning useful salts. [Prior Art] 8-[{1_(3,5_bis-(difluoromethyl)phenyl)ethoxymethaneb 8_phenyl'7_), a snail ketone (according to the Bielstein nomenclature) Diazo-spiro =, 5] indol-2-one, such as phenyl)ethoxy}methyl]-8-phenyl-1,7-diazaspiro[4,5]nonan-2-one The preparation of the chemical substance of I is disclosed in the published US Patent Application No. 2003-0158, No. 173 (No. 173) filed on May i. The manner of full reference is incorporated herein.

The novel compounds disclosed in Publication No. 173 are classified as tachykinin compounds and are antagonists of the neuropeptide neurokinin-1 receptor (herein referred to as

Therapeutic agent. Kappa-丨 receptor antagonism disclosed in u.s. 5, 76〇5〇18 (1998) 119709.doc 200806666 Some examples of agents have been shown to be useful in the treatment of pain, inflammation, migraine and vomiting. Other NK- disclosed in U.S. Patent No. 5,620,989 (1997) and International Publication No. WO 95/19344 (1995), WO 94/13639 (1994), and WO 94/10165 (1994). Additional examples of 1 receptor antagonists have been shown to be useful in the treatment of pain, irritations, and inflammation. Additional examples of receptor antagonists have been described in the following publications: Wu et al.

Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001) and R0giers et al, Tetrahedron 57, 8971-8981 (2001). The novel NK-1 receptor antagonist compounds disclosed in the above-mentioned publication No. 173 include several novel diazepyrdin-2-ones (including compounds of formula I) which are believed to be useful for providing anti-caries and A therapeutic agent for the treatment of anti-η area vomiting. The compounds of formula I are characterized by TLC and GC/MS techniques as reported in publication No. 173. The procedure described in the No. 173 publication provides a compound of formula I in the form of an amorphous white foam. Repeating the crystallization of the free base did not provide a crystalline material. In general, compounds which have been identified as having therapeutic activity must be provided in high purity form for medical use. In addition, there is also a need to provide a form of a compound intended for pharmaceutical use that facilitates the incorporation of a compound into a medicament, and which, when incorporated into a medicament, has sufficiently stable properties against chemical degradation and thereby imparts Long shelf life of the drug. SUMMARY OF THE INVENTION In the foregoing, there is a need for a form of therapeutic agent that facilitates the provision of therapeutic agents in highly purified form. There is also a need for a form of therapeutic agent for degradation in the environmental zone of treatment and storage 119709.doc 200806666. The present invention advantageously provides such and whitish, in one aspect, a compound of formula I, in the form of a salt, in the form of a salt, optionally as a crystalline form and optionally incorporated into a solvent molecule, For example, in the single embodiment of the compound, the compound! The salt form of a shellfish is selected from the group consisting of maleate, methanesulfonate, oxalate, barium benzoate, ^ | acetamidine, fumarate, citrate, tartaric acid Salt, broken shots, Xiaouan shaft® salt, lactate, glycolate, 1-jing

Base-2-naconate, malonic acid lysate (a) L-malate, horse urate and (1S) oxime acid salt. In the case of her every second pregnant mussel, the salt form of Compound I is maleate. Another aspect of the invention provides a (5S, 8S) winter... (8) small (3,5-bis-(-fluoromethyl)phenyl)ethoxy bromide 8_phenyl],? · Crystalline maleate salt of diazoxide [4,5]nonan-2-one, in the form of a pseudo-salt salt, which is represented by the diffraction angle according to the table (in terms of 2 ' 'all values reflect ± 〇 • The accuracy of 2), the lattice spacing d (in angstroms), and the relative peak intensity (,, ri,) are characterized by the diffraction pattern of the X-ray powder:

Table I diffraction angle (2 0.2 0.2) RI lattice spacing (A soil 0.04) 10.0 weak 8.84 13.5 medium 6.55 16.5 medium 5.36 23.5 strong 3.79 Another aspect of the invention provides a (5S, 8S)-8-[ {(lR)-l-(3,5,bis(difluoromethyl)phenyl)ethoxymethyl]_8-phenyl d,7-diazaspiro[4,5]癸一119709.doc 200806666 2 a ketone crystal maleate form 1]; a salt, which is represented by the diffraction angle (in units of 2 Å), lattice spacing (in angstroms) and relative peak intensity (shown in Table π) "RI") is characterized by an X-ray powder diffraction pattern:

Table II Diffraction angle (2Θ士〇·2) RI Lattice spacing (A soil 0.04) 4.8 Medium 8.47 12.0 Strong 7.38 24.5 Strong 3.64 28.9 Medium 'Width 3.08 Another aspect of the invention provides one-of-a-kind (5S, 8S )-8-[{(lR)-l_(3,5-bis-(trifluoromethyl)phenyl)ethoxy}_fyl l·8-phenyl-l,7-diazaspiro[4, 5] 癸- 2-ketone crystalline carbamate Form I salt, which is shown in Table III according to the diffraction angle (in units of 2 Å), 'crystal spacing' d'' (in angstroms) And the relative peak intensity (''RI') is not characterized by the X-ray powder diffraction pattern: Table III diffraction angle (2Θ ± 0.2) RI lattice spacing (A soil 0.04) 7.3 strong 12.17 10.2 strong 8.69 22.7 strong 3.92 28.9 Strong 3.08 Another aspect of the present invention provides a (tria-indenyl)phenyl)ethoxy}-methyl]-8-phenyldiazospiro[4,5;]癸_ 2, a crystalline form A Sulfonate form „salt, which is shown by the diffraction angle (in 2Θ), lattice spacing “d” (in angstroms) and relative peak intensity H9709.doc 200806666 degrees (&quot ;RI") not X-ray, line powder diffraction map Signs: Table IV diffraction angle (2 0.2 0.2) RI lattice spacing (human ± 0.04) 6.2 medium 14.20 9.6 medium 9.24 19.9 extremely strong 4.46 21.2 strong 4.19 Another aspect of the invention provides a (58, 88) _8- Crystallization of [{(1 illusion_1_(3,5_bis-(trifluoromethyl)phenyl)ethoxy)methyl]_8-phenyl 4,^diazaspiro[4,5]indole-2-one The methanesulfonate salt is formed as an X-ray powder represented by the diffraction angle (in units of 2 Å), the spacing of the wafers in 1 dπ (in angstroms), and the relative peak intensity (nRIn) shown in Table V. The diffraction pattern is used to characterize: Table V diffraction angle (2Θ ± 0.2) RI lattice spacing (Α0.04) 4.7 strong 18.62 9.5 medium 9.26 19.2 extremely strong 4.63 20.9 medium, width 4.25 Another aspect of the invention provides one ( Trifluoromethyl)phenyl)ethoxydimethyl]Iphenyl], 7-dioxaspiro[4,5]癸_ 2^ crystalline oxalate, which is represented by the diffraction angle according to the table X-ray powder diffraction pattern (in units of ^), wafer spacing "d" (in angstroms) and relative peak intensity (, illusion):

Table VI 119709.doc -10- 200806666 Diffraction angle (2 Θ soil 0.2) RI lattice spacing (human ± 0·04) 5.6 weak, width 12.37 19.8 medium 4.84 21.0 medium 4.57 22.8 medium 4.18 Another aspect of the invention provides (5S,8S)-8-[{(;lR)_l-(3,5-bis-(trifluoromethyl)phenyl)ethoxy}-methyl]-8-phenyl-l,7 a crystalline ethanesulfonate salt of diaziro[4,5]nonan-2-one, which is represented by the diffraction angle (in units of 2 Å) and lattice spacing "d'' X-ray powder diffraction pattern represented by angstrom unit and relative peak intensity (nRI''):

Table VII diffraction angle (2 Θ 0.2) RI lattice spacing (A soil 0.04) 11.4 medium 7.73 12.8 medium 6.90 20.0 strong 4.44 21.2 medium 4.18 The present invention further provides that each of them is selected from the group consisting of maleic acid forms I and II, (5 3,83)-8-[{(111)-1-(3,5-bis-(trifluoromethyl)) mesylate form I, II and hydrazine, ethanesulfonate and oxalate A pharmaceutical composition in the form of a crystalline salt of phenyl)ethoxy bromide]-8-phenyl-1,7-diazaspiro[4,5]nonan-2-one (compound of formula I), and the use of one or more A method of treating a compound in the form of a crystalline salt of a compound and/or preventing sputum nausea and π-region vomiting. [Embodiment] (5S, 8S) I[{(1R) small (3,5-bis-(trifluoromethyl)phenyl)ethoxy bromide 119709.doc -11 - 200806666 base] winter phenyl- Salt form of 1,7-diazaspiro[4,5]indole-2-one (4)

Provide a drug that is beneficial for the treatment of nausea and vomiting. Although the compounds of the present invention are useful for providing anti-nausea and anti-obesity treatment for nausea and vomiting caused by any cause, 'the formula is believed to be the most effective for providing treatments related to chemotherapy, radiation therapy and Anti-nausea and/or anti-vomiting treatment for nausea and/or vomiting that occurs later in the surgery. In addition, the salt forms disclosed herein have the processing advantages associated with improved solubility in polar solvents as compared to free assay forms of compounds useful for <RTIgt; Further, each of the tosylate, the hydrochloride, the malate, the methanesulfonate, the oxalate, the besylate, and the ethanesulfonate has one or more crystalline forms, and the crystalline forms provide the compound The amorphous form has a more consistent physical character than a formula having the following advantages: a compound · a lower impurity content and a more consistent product quality, that is, a more consistent color, dissolution rate, and ease of handling; And longer term stability when incorporated into the agent. As described in detail below, the characteristic X-ray diffraction pattern (see Figures 1, 2 and 9 to 13), the characteristic infrared spectrum (see Figures 4 and 6), and the analytical differential scanning heat can be detected by detecting individual salt forms. The crystalline salt forms of the various compounds of formula I described herein are readily distinguished from each other and from the amorphous form by determining one or more of the (DSC) thermograms (Figs. 7 and 8). 119709.doc -12- 200806666 As shown in the above formula 11, the inventors have unexpectedly discovered that the diazepyr-2-one of the formula i contains a cyclic amine nitrogen of sufficient basicity such that it can be selected from the group consisting of benzenesulfonate The inorganic acids of acid, ethanesulfonic acid and sulfonic acid are protonated (forms the besylate, ethanesulfonate and methanesulfonate of the compound of formula j, respectively). It has also unexpectedly been found that the diazepam-2-one can be selected from the group consisting of malic acid, oxalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, lactic acid, glycolic acid, malonic acid, and hydrazine. The organic acids of -2-naphthoic acid, maleic acid, hippuric acid and camphorsulfonic acid are protonated to form malate, oxalate, fumarate, tartrate, citric acid, respectively, of the compound of formula I Salt, succinate, lactate, glycolate, malonate, hydrazine-hydroxynaphthoate, maleate, hippurate and camphor sulfonate. Furthermore, it has been found that an acid salt selected from the group consisting of maleic acid salt, methanesulfonate, oxalate, benzenesulfonate and ethanesulfonate can be provided in the form of a crystalline solid, the crystal structure of which By protonation of each molecule of the compound of formula I) optionally includes one or more solvent molecules such as toluene, hexane or acetonitrile. The salts of the present invention provide a number of surprising advantages over physical properties in terms of physical properties, such as milling, micron sizing, and ability to dissolve compounds. The preferred crystalline form of the salt is selected from the group consisting of maleic acid salts and methanesulfonate salts. These salts have been found to have thermodynamic stability in addition to the desired solubility and handling characteristics to provide a compound of formula I in a salt form which is readily incorporated into the agent and which is stable under a variety of environmental conditions. As is known, when the therapeutic agent has a water solubility of less than about 10 mg/ml in a pH range from about pH 1 to about pH 7, it typically exhibits a poor rate of absorption. In addition, when administered orally, the therapeutic agent exhibits a solubility of less than 119709.doc 13 200806666 of about 1 mg/ml in this pH range, since solubility is related to absorption in the oral administration d. Limited by dissolution rate ^ Absorption Thus, the improved solubility characteristics of such salts are important for providing oral administrations that are designed to deliver compounds that are therapeutic agents. As described in detail below, in addition to these desired improved solubility characteristics, the physical properties of the selected salt exhibits (4). The compound of the formula is a compound of the formula j and is selected from the group consisting of oxalic acid dibasic acid, methyl benzoic acid, benzoic acid, ethyl benzoic acid, and butyl succinic acid, tartaric acid, tartaric acid, lactic acid, and thiol Acetic acid, ..., Cai; bismuth-acid, • fruit acid, hippuric acid, and camphor acid acid are prepared according to the following procedure: & 0 under the scrambling, the compound of formula 1 in an amount of 0·1 § About 〇2 blessing and equivalent (ie, G.2 mMGl) the selected acid is dissolved in about 3 ml of absolute ethanol in the container; (1) under continuous mixing, anhydrous hydrazine is added dropwise until it is mixed. Become turbid; out) will be just enough to transport, the joy, the main sputum to make thirst, the amount of anhydrous ethanol added to the turbid mixture (usually a few drops); V) (n) stop ΐ (four) and contain vents (4) Covering the container, and the container is allowed to stand for 24 to 48 hours, during which the solid sinks the temple; " At the end of the rest time, the solid is recovered by passing through, :, and then first dried in the air about! ~ (4) small; : ... and then dried overnight in an indoor vacuum at ambient temperature to obtain a salt of a compound of formula I. One or two 氡 I19709.doc -14- 200806666 For some gg a - gas direction S ', various crystalline forms of the granules were prepared according to the following general procedure. M丄, the reaction is reactively crystallized according to the above procedure, or is first precipitated in the form of an amorphous substance by the above-mentioned general-purpose & and then by adding an amorphous salt, and right 曰# 旦 7 'Night day A sample of the salt prepared by recrystallization of the salt of the crystal is placed in a vial, 10% to about 50 mg of sputum. The granules are added to a vial sufficient to completely immerse the dimer, and the solvent is selected from the group consisting of ethanol, isopropylidene, acetonitrile, field, f, ethyl acetate, dichloromethane, and hexane. The solid and solvent are stirred under ambient conditions to provide a solvate crystal such as about 7 days. When a solvate crystal has been prepared, a sample of the suspension solvent is dropped on a sample for use in a powder X-ray diffraction spectrometer and air dried. #分析分析的分析分析的分析。 X-ray spectroscopy was used to analyze these samples according to the procedures described herein. Analytical Procedures The crystalline salt forms of the various chelates are characterized by techniques such as X-ray powder diffraction spectroscopy (PXRD), infrared ray diffraction (IR), and Raman spectroscopy (Raman). The salt form of the selected compound is further characterized by differential scanning calorimetry (DSC) and/or by physical methods including solubility studies and stability studies. X-ray powder diffraction spectroscopy The X-ray powder diffraction spectrum of the sample was obtained using one of the following procedures. For the solvate prepared according to the above procedure, the analysis was carried out on Rigaku according to the following procedure. For the analysis of the sample obtained using the Rigaku Miniflex spectrometer, the following procedure was used (PXRD method 〇. The sample analyzed by the PXRD method was lightly 119709.doc -15-200806666 on the low moon hall, on the plate. The sample was exposed to the surrounding The temperature and humidity of the indoor 裒i brother RlgakU knife light is equipped with six analysis disk transfer rack, which makes the sample rotate at 54 ah, thus the preferred orientation of the crystal in the sample under study is minimized. Rigaku spectrometer also Equipped with copper without Κα2 chopper 〖with radiation source. Spectrometer is also equipped with variable divergence slit and G 3 with receiving slit. From 2.0 to 4 〇. 20 performs scanning range. Use Cu for lu plane Μ The peak verifies the calibration of the instrument. During the scan, the step size of the step of 6 seconds is 〇.〇2 degrees. The data analysis is performed using the Jade P1US (version 5〇26) analysis software. The Savitzky-Golay parabolic filter is used. The data of 丨i points form a smooth curve. Usually, the d" spacing value is accurate within ± 〇〇 4 8 . For some samples, the X-ray powder is obtained using a Bruker D8 diffractometer manufactured in 2 〇〇 2 years. Diffraction spectrum Learning analysis (pxRD method H). The huker diffractometer has parallel optics (4) using a G0BEL beam focusing mirror and a PSD money device with a fixed radial sampling slit. The Bruker diffractometer is used with the Ant〇n Paar TTK450 temperature stage. The source of the nucleus is copper (κα). The divergence slit is fixed at 0.6 ug. The Bruker diffractometer uses a top loaded brass block sample holder. Use PSD to quickly scan from 4. 〇 to 39.9. Photograph_, the sample is loaded on the sample holder and leveled with the glass display (four). The sample chamber temperature is set to hunger, machine (four) generation under the humidity and without nitrogen purge and not under vacuum. Fresh calibration instrument calibration. During the scanning period, the stepping time of G.U1G seconds is 0.013 degrees to G.G2 degrees. Data analysis is performed using the EVA analysis software version ".ο" written by Bruker8 s〇cabim8 The data from 软ι to 0 · 1 5 is formed by the software to form a smooth curve. H9709.doc -16- 200806666 In addition to the solvate samples prepared according to the above procedure, it is used for X-ray powder diffraction ('' PXRD") sample of analysis Subject to minimal preparation to prevent any form of change. Gently load the sample particles into the sample holder to ensure that they form a smooth surface and do not clump together. For samples other than the solvate samples prepared according to the above procedure, Solvent, drying or other preparative steps were used. Infrared spectroscopy The samples were characterized using attenuated total reflectance (ATR) infrared spectroscopy using a Nicolet Instruments NEXUS 670 FTIR equipped with an Avatar Smart Miracle Attenuated Total Reflection (ATR) sample chamber. The spectra were collected using the following parameters: DTGS KBr side detector; KBr beam splitter; scan range: 600 cm-1 to 4000 cnT1; gap setting: 100; resolution: 2; 100 scans per sample. By collecting the background spectrum, a reference standard or particle sample (usually a sample of 3 mg to 5 mg) is placed on the ATR crystal and analyzed by applying pressure to the sample using the pressure arm of the instrument according to the waste recommendation. The spectrum of the sample (reference or sample) is then obtained as a background to sample spectral ratio using vendor proprietary software. Raman spectroscopy Raman spectroscopy (Raman) is performed using one of two procedures. Program I Raman analysis was performed on a Thermo Electron Nicolet Almega Dispersive Raman spectrometer in a high resolution mode. The sample was housed in an NMR sample tube and the spectra were obtained under the following conditions: scan range: 4000 cm "to 90 cm·1; exposure time · 1.0 second; 100 samples and 100 background exposures; 785 nm excitation laser / 100 % power level / parallel laser polarization; 119709.doc -17- 200806666 per millimeter grid 1200 rows; 100 micron slit; camera temperature: -50 ° C. Thermo Electron Nicolet Almega pull set at 50 times magnification Procedure II Raman analysis was performed on a Man microscope. Samples were prepared by placing a small amount of the compound on a microscope slide without using a coverslip, and the spectra were obtained under the following conditions: scan range 3481 cm·1 to 96 cnT1; low resolution Exposure time: 5.0 seconds; 10 samples and 10 background exposures; 780 nm excitation laser (depolarization) / 100% power level; 1200 lines per mm grid; 25 micron pinhole; camera temperature: -48 °C. Differential Scanning Calorimetry Thermal analysis was performed using a TA Instruments modulated differential scanning calorimeter (DSC) at a nitrogen flow rate of 40 ml/min at a heating rate of 10 °C/min. In the open aluminum plate DSC scanning. Solubility testing is performed by placing excess compound in an aliquot of the solvent of interest and equilibrating the slurry under selected temperature conditions (usually ambient temperature). When the solvent is water, hydrochloric acid and hydrogen are used. Sodium oxide adjusts the pH to the desired value. When the slurry mixture is equilibrated, excess solids are centrifuged (water) from the supernatant or filtered (all other solvents) and HPLC is applied to the aliquot of the diluted supernatant. Analysis to quantify the amount of dissolved compound. A pharmaceutical grade solvent was used. Chemical stability tests were performed on aliquots of the salt form of interest by placing a precisely weighed sample of the salt form of the compound of formula I in a polyethylene bag. The sample contained in the bag is sealed in a fiberboard tube equipped with a metal cap, which is stored under specified humidity and temperature for a specified time. By dissolving the contents of the vial and analyzing the amount of dissolved matter by HPLC analysis 119709.doc -18- 200806666 Analysis. If there are specific notes, store the aliquot in a capped amber vial under the conditions mentioned in place of the polyethylene bag. EXAMPLES The maleic acid salt, the chloroformic acid tartrate, the ethanesulfonate salt and the oxalate salt form of the compound of formula I are prepared as follows, as described in detail below, also by including X-ray powder diffraction spectroscopy, infrared spectroscopy. Various spectral techniques of Raman spectroscopy and Raman spectroscopy to characterize the salt forms of the various compounds of formula I. Analyze the stability, solubility and other improved physical properties of the selected form, including differential scanning calorimetry for certain steps (DSC) analysis, unless otherwise specified, in accordance with the disclosure of U.S. Patent Application Serial No. 2003-0158, No. 173, No. 173, filed on May 1, 2000. The procedure disclosed in the present invention) is used to prepare (5S,8S)-8-[{(lR)-l-(3,5-bis-(trifluoromethyl))benzene for the preparation of the salts described herein. Ethyloxy}-indenyl]-8-phenyl-1,7-diazaspiro[4,5]nonan-2-one (a compound of the formula). All reactive crystallization, recrystallization, and pulping procedures are carried out in commercially available solvents at specified grades (unless otherwise specified as pharmaceutical or food grade) and are used in recognized standard form (unless otherwise specified). The maleic acid salt of the compound of formula I is prepared by dissolving ig (2 mmol) of a compound of formula I in 4 ml of methyl tert-butyl ether (MTBE) according to the general procedure described above for the preparation of a salt of a compound of formula I The amorphous maleate salt of the compound of formula I was prepared by scrambling it with 1 equivalent of maleic acid dissolved in 4 ml of isopropanol. According to the general I table private sequence described above, the preparation of the compound of the formula is prepared by slurrying the amorphous maleate prepared above in acetonitrile or isopropyl acetate. H9709.doc -19 - 200806666 Butenoic acid salt form 1 salt. The maleic acid salt form I of the compound of the formula was characterized by x-ray, infrared and Raman spectroscopy using the above procedure and by Dsc. Figure 1 illustrates the gamma-ray, v-ray ray of the maleate salt form. Table VIII below lists 12 characteristic peaks of the diffraction spectrum of the X-ray powder shown in Figure 1, which are based on the diffraction angle expressed in 2 Θ (〇 2θ), and the corresponding "d" in angstroms (Α). The spacing is expressed, and the relative strength of the signal is indicated by the following symbols in adjacent columns: S = strong, M = medium, W =: weak, V = pole, and D = diffusion:

Table VIII Diffraction angle (°2Θ ± 0.2^ d spacing (Α, ± 〇·〇4) Relative strength 9.06 9.75 W 10.0 8.84 W 13.5 6.55 Μ 16.5 5.36 Μ 18.0 4.91 Μ 18.8 4.72 Γ Μ 19.9 1 4.46 Μ 20.2 4.39 Μ 21.7 4.08 Μ 23.5 3.79 S 24.3 3.65 Μ 25.3 3.52 中 Of the characteristic peaks of the maleate form I salt of the compound of formula 1 shown in Table vm, the 8 most characteristic peaks are at the diffraction angle Equal to 9.%, 1〇·〇, 13.5, 16.5, 18.0, 2, 23.5, and 24.3 (in .2 in units) where Φ occurs, and the 4 most characteristic peaks are at a diffraction angle equal to 10 · Peaks appearing at 0, 13·5 '16·5 and 23.5 (in units of .2Θ). Figure 3 illustrates the crystals of the phantom compound obtained using the above procedure. cis gui 119709.doc -20- 200806666 diacid salt Transmission infrared spectroscopy in the form of Form I salt. Table IX lists the 12 most characteristic peaks of the spectrum illustrated in Figure 3, and the following symbols are used in adjacent columns to indicate the relative absorption intensities of the listed peaks: S = Strong, M== medium, 3 = wide, V=polar, weak.

Table IX Absorption peak wave number (cm1) Relative intensity 1 1695 S 1576 WB 3 1379 MB 4 1319 Μ ~ 5 1276 S 6 1183 S 7 1117 SB 8 1900 ~ S 9 866 10 767 "s ~ 11 682 Is ~ ' 12 644 ^SB ~ The peak of the acupoint is the peak appearing at 1695, 1319, 1276, 1183, 1117, then, 866 and (8) centimeters (cm-1), and the four most characteristic peaks are Peaks appearing at 1695, 1276, 1117, and 682 cnT1. Figure 4 illustrates the Raman spectrum of the crystalline cisacid form 1 salt form of the phantom compound obtained using the above procedure. Table X below lists the 12 most characteristic scattering peaks of the spectrum shown in Figure 4 (reciprocal in centimeters, c:) and the following columns are in the adjacent columns - the following payment tables are not The relative absorption intensities of the columns are .S,, M = medium, w = weak, v = pole, b = width. 119709.doc -21 - 200806666 Table x

Scattering ♦ Relative strength of wave number Λ ---- icitT1) 1 r% " 1694 MB λ 1--- J^20_ MB Λ ^380 MB 4 1203 M 5 c "· ---- T〇36 ~ WB 6 1002 s 7 〇---- 728 M 〇9 ^ 620 YT WR 10 ^ 13⁄4 VV JJ WB 11 'τη MB 12 '^ 752 ' SB Among the characteristic peaks in Table X, the 8 of the compounds are the most The characteristic peaks are peaks appearing at 1694, 1620, 138, and 1203' and the four most characteristic peaks are peaks appearing at 162G, 1380, 1002, and 728 cmf1.

Figure 7 is a graph showing the D s C thermogram obtained by differential scanning calorimetry analysis of the crystalline cis-butene-acid salt form I salt form of the compound of the formula ι obtained using the above procedure. Referring to Figure 7, the DSC thermogram contains a broad endotherm focused on approximately the assignment. (9), called 8-[{(1R) o,5_bis-((trifluoromethyl)phenyl)ethoxymethyl]-t-phenylphenyl-1,7_:aziro[4,5]pyrene The olefinic acid salt form (the cis succinate form 11 salt of the compound of formula I) is prepared from the maleic acid salt of the compound of formula I which is precipitated using the amorphous salt preparation procedure described above. Therefore, according to the preparation of the slurry described herein, k is prepared by slurrying the maleic acid salt prepared as described above in the acetaminophen to obtain the formula: 匕 119709.doc -22 . 200806666 Crystalline maleate form π salt. Referring to Figures 2, 5, 6 and 8, the characteristic peak program is characterized by X-ray, infrared and Raman spectroscopy and the cis-butane salt form II salt of the compound of formula I is analyzed by DSC. Table XI below lists 12 characteristic peaks of the X-ray powder diffraction spectrum shown in Figure 2, which are based on the diffraction angle expressed in degrees (20) and the corresponding "d" in angstroms (Α). Spacing and signal relative strength (nRI·') expressed by the following symbols: S = strong, M = medium, weak, V dipole and D = diffusion listed:

Table XI Diffraction angle (°2Θ ± 0.2) d spacing (A, soil 0.04) Relative strength 4.8 18.47 Μ 9.5 9.26 Μ 10.5 8.45 Μ 12.0 7.38 S 15.1 5.88 Μ 17.5 5.07 Μ 20.0 4.44 MB 20.3 4.38 MB 22.8 3.89 MB 24.0 3.70 M 24.5 3.64 S 28.9 3.08 MB -------------——1 In the characteristic peaks of the U salt of the crystalline maleate form of the compound shown in Table XI] The eight most characteristic peaks are those at diffraction angles (in .2 )) equal to 4.8, 9.5, 10.5, 12.0, 15.1, 175, 24.5, and 28.9, and the four most characteristic peaks. It is the peak appearing at the diffraction angle (in bits of .20 for $bit) equal to 4·8, 12.0, 24.5, and 28.9. Figure 5 shows the transmission of infrared spectroscopy of the salt form of the salt form of the oxime compound obtained by the above procedure using the above procedure butyl 119709.doc -23 - 200806666. The table below lists the 12 most characteristic peaks of the nucleus illustrated in Figure 5, and uses the following symbols in adjacent columns to indicate the relative absorption intensities of the listed peaks: s = strong, μ = medium, weak, Β = width, v = pole.

Table XII

Absorption peak (cnT1) Relative intensity 1 1687 ~~ S 2 145Γ~ ~~ Μ 3 Τ434~ ~~ MB 4 1382~ S 5 ~1342 Μ 6 1277 ~~ S 7 Il68 ~~ SB 8 1124 ^VB 9 *897 ~ ~ 10 863 S 11 766 M 12 682 S Among the characteristic peaks shown in Table XII, the 8 most characteristic peaks of the compound are reciprocal at 1687, 1277, 1168, 1124, 897, 863, 766 and 682 cm. The peak appearing at (cm·1), and the four most characteristic peaks are the peaks appearing at 1687, 1277, 1124, and 682 cnT1. BRIEF DESCRIPTION OF THE DRAWINGS The Raman spectrum of the crystalline cis-succinate form II salt form of the compound of formula I obtained using the above procedure is illustrated. The table below lists the 12 most characteristic scattering peaks of the spectrum illustrated in Figure 6 (represented by the reciprocal of the cent, cnr1), and the following symbols are used in adjacent columns to indicate the relative intensity of the listed peaks. M = medium, weak, polar, B = wide. 119709.doc -24- 200806666

Table XIII Scattering Peaks - 'ϊϊ (cm4) Relative Intensity 1 Τ700 ~ΜΒ 2 ^1623 "mb 3 ^454~~' WB MB ~~ 4 ] 5 ~ 1|84~~~ ^202~' MB — ^ 6 1003~— "s ^— 7 〇~~ "m ^ 8 9 10 Λ Λ J04 ~~~ |m ~ ^621 ~ — [M ^ 519 WB 11 ^281 ~~~ "mb 12 1?1 Among the characteristic peaks shown in Table XIII, the eight most characteristic peaks of the compound at 281 cm·1, and the four most characteristic peaks are at Mu, 1384, 1003, and 281 cm·1. The peak that appears. Figure 8 illustrates a differential scanning calorimetry thermogram of the analysis of the crystalline cis-succinate salt form II salt form of the compound using the procedure described above. Referring to Figure 8, the thermogram contains a concentration of approximately 155. The heat absorbing peak of the cockroach. The mesylate salt of the compound of formula I is prepared by dissolving 1 g (2 mmol of JSJ compound and hydrazine equivalent methanesulfonic acid in absolute ethanol (usually about 4 mi) in an amount sufficient to dissolve the starting materials, followed by addition. Preparation of (58,88)_8-[{(111)-1-(3,5-bis-(trifluoromethyl)phenyl)ethoxymethyl]phenyl_1,7_2 from 30 ml of anhydrous diethyl ether Crystalline methanesulfonate of the snail [4,5]nonan-2-one (formula: [methanesulfonate form I salt of the compound). The mixture is allowed to stand under ambient conditions to 2 by covering the mixture with a venting cap. The crystals of the mesylate salt of the compound of formula I were precipitated over a period of time. These crystals were collected by vacuum filtration using 119709.doc -25-200806666, which was washed with anhydrous ethyl acetate and dried under vacuum in a room. These crystals are prepared for X-ray diffraction analysis. The crystalline mesylate salt form 1 salt of the compound of formula I is discriminated by X-ray powder diffraction spectroscopy. Figure 9 illustrates the mesylate salt form of the compound of formula I. X-ray diffraction diffraction spectrum of salt. Table XIV below lists 12 characteristic peaks of the X-ray powder (7) radiant 图 shown in Figure 9, which is expressed in terms of 2 Θ. The angle of incidence, the corresponding "d" spacing in angstroms (Α) is listed, and the relative intensity of each column peak is shown in the following column with the following symbols: 8 = strong, · secondary school 'W-weak ' V= extremely, diffusion:

Table XIV

In particular, the peak of the salt form of the compound of formula 1 is shown in the form of the salt form of the salt form, and the eight most characteristic peaks are the peaks at 7.3, 10.2, 12.9, and 勹. And the four most characteristic 's: 9 2 22.7, 24.G and 28.9 are equal to 7.3' Π). 2, 22.7 and appear at the diffraction angle (in units of (9)) 8·9 peak. According to the above general procedure for the preparation of the salt of the compound of the formula 1, by H9709.doc ' 26 - 200806666 g (2 mmol) of the compound of the formula I is dissolved in 4 ml of methyl tert-butyl ether and it is combined with hydrazine The methanesulfonic acid equivalently dissolved in 4 ml of isopropanol was stirred to prepare an amorphous mesylate salt of the formula. This non-3⁄4-shaped substance is separated by a vacuum transition. Two additional crystalline forms of the mesylate salt of the compound of formula I can be prepared from the amorphous material by crystallization of the slurry. According to the pulping procedure described herein, (5S, 8S) is prepared by slurrying the amorphous mesylate salt prepared as described above in an equal volume of a mixed solvent of ethyl acetate and hexane. [{(1R) small (3,5-bis-(trifluoromethyl)phenyl)ethoxy}_methyl]_8_phenyl], 7-diaza snail with a, 酉夂 幵/Formula II salt (formula salt of the compound of formula I). According to the above PXRD method] [analyze the mesylate form of the formula compound by the χ ray powder diffraction spectroscopy „ salt form crystal. The following table χ ν lists the X-ray powder diffraction spectrum shown in Fig. 1〇 The diffraction angle of the 12 characteristic peaks (indicated by 2θ degrees (2Θ)), the corresponding "d, spacing in angstroms (Α), and the relative symbols in the adjacent columns are represented by the following symbols Strength (,, ri") : s=strong, · medium, weak, V=polar and D, scattered:

Table XV

Winding angle (°2Θ ±〇.2) d spacing 1^±0.04) Relative strength __6.2 __14.20 Μ __9.24 Μ 10.0 __8.87 W 12.4 _7.16 MB __14.3 6.18 WB __5. 85 WB __4.46 VS ---2D _ _ 4.19 S __22Ό _4.03 M 119709.doc -27- 200806666

22.7 — Μ 23.6 -376_ MB 2^8 MB Of the specific peaks of the mesylate salt form II salt form of the compound of formula 1 in Table Xv, the eight most characteristic peaks are at the diffraction angle ( In 〇2Θ, it is equal to the peaks at 6.2, 9.6, 12.4, 19.9, 21.2, 22.7, 23.6, and 24·8, and the four most characteristic peaks are at the diffraction angle (in .2Θ) Equal to the peaks appearing at 6.2, 9.6, 19.9, and 21.2. By preparing 10 g of the amorphous mesylate salt prepared as described above, it is prepared by dissolving in an amount of toluene which is sufficient to dissolve the salt at a temperature of 40 C and allowing the solution to cool to room temperature.卜^以^幻心-^^bis-trifluoromethyl)phenyl)ethoxymethyl]-8-phenyl-indole, 7-diazaspiro[4,5]indole-2-one Salt form 111 salt form (methanesulfonate form III salt form of the compound of formula I) ° Characterization of the formazin form 111 salt of the compound of formula I by X-ray powder diffraction spectroscopy. Figure 11 illustrates crystallization 曱X-ray powder diffraction spectrum of the sulfonate form III salt. Table XVI lists 12 characteristic peaks of the X-ray powder diffraction spectrum shown in Fig. 11, which are listed as 2 turns (° 2 Θ). The angle of incidence, in angstroms (Α), d' spacing, and the relative intensity of the listed peaks in the adjacent columns ("RI"): S = strong, medium, w = weak V=polar and B=width:

Table XVI diffraction angle (〇2^±0^d spacing f A, soil 〇·〇4) Relative strength 4.7 18.62 S ~ 8.0 11.10 W 9.5 9.26 Μ — 17.4 ------ 5.09 WD — 119709.doc - 28- 200806666

In the special peak of the mesylate salt form of the compound of formula 1 shown in Table XVI, the 'eight most characteristic peaks are at the diffraction angle (in units of .2 )) equal to (7, 9.5). Peaks appearing at 18.6, 192, 2〇9, 221, 241, and 257, and the four most characteristic peaks are at the diffraction angle (in units of .2 )) equal to (7, 9.5, 19·2 and The peak of the compound of formula I. The oxalate salt of the compound of formula I according to the above general procedure, equivalence (equivalent (trifluoromethyl)phenyl)ethoxymethyl]_8_phenyl=1,7-diaza snail A mixture of [4,5]癸_2-ketone compound (formula compound) and an equivalent of oxalic acid is dissolved in absolute ethanol, and sufficient anhydrous ether is added to the mixture to induce turbidity, and additional ethanol is titrated into the mixture until The solution returned to a clear state and the solution was allowed to stand for 48 hours until the oxalate form [crystal salt of the salt] was used to prepare the oxalate salt of the compound of formula I. The oxalic acid of the compound of formula I was then collected by vacuum. Crystals in the form of a salt form I salt and air dried. Figure 12 illustrates the cross-section of the oxalate salt form I salt of the compound of formula I Powder diffraction spectrum. Table XVII below shows the diffraction angle of 11 characteristic points (.20) of 11 characteristic peaks of the X-ray powder diffraction optical error shown in Fig. 12, in units of angstroms (a). "d" spacing, and use the relative intensity of the peaks listed in Table 8 in the adjacent columns (nRI") ·· S is strong, medium, weak, v== 119709.doc -29- 200806666

Pole, B = wide and D = diffusion: Table XVII

Among the characteristic peaks of the oxalate form J salt form of the compound of formula I in Table XVII, the eight most characteristic peaks are at the diffraction angle (in units of .2β) equal to 5.6, 9.2, U. 9, 19.8, 21.〇, 21 5, 22 8 and 23 8 peaks appear and 4 of the most characteristic peaks are at the diffraction angle (in units of (9)) equal to 5.6, 19·8, 21.0 And the peak that appeared at 22.8. The ethanesulfonate salt of the compound of formula I will have 1 equivalent of (5S,8S)-8-[{(1R)-l-(3,5-bis-(trifluoromethyl)phenyl)ethoxy}-methyl ]-8-Phenyl-π-diazaspiro[4,5]癸·2 drying (a mixture of the formula [compound) and 1 equivalent of ethanesulfonic acid is dissolved in absolute ethanol, and sufficient anhydrous B is added to the mixture to induce The turbidity is %, the additional ethanol is titrated into the mixture until the solution returns to a clear state, and the solution is allowed to stand for 48 hours until the crystal of the compound of the formula 1 is in the form of a salt of the salt form, thereby preparing the compound of the formula I The ethanesulfonate. The crystals of the ethanesulfonate Form I salt were collected by vacuum filtration and air dried. 119709.doc -30- 200806666 Figure 13 illustrates the x-ray diffraction spectrum of the sulfonate salt form I salt of the compound of formula I. The following table χνπ lists the diffraction angles expressed by 20 degrees (.20) of the 12 most characteristic peaks of the X-ray powder diffraction spectrum shown in Fig. 13 in units of angstroms (Α). ,, d" spacing, and the relative intensity of the listed peaks in the adjacent columns ("RI")·· strong, medium, weak, v=polar, wide and diffuse:

Table XVIII

Diffraction angle (°2Θ0.2) d spacing (A, ± 0.04) Relative strength 7.1 12.37 WB 9.9 8.89 WD 11.4 7.73 Μ 12.2 7.27 W 12.8 6.90 Μ 16.6 5.33 WD 18.3 4.84 Μ 19.4 4.57 Μ 20.0 4.44 S 20.5 4.32 W 21.2 4.18 Μ 22.0 4.04 WD Special peaks 'The eight most characteristic peaks are at the diffraction angle (in units) equal to 9·9, 11·4, 12·8, 16·6, 18 3, 2 〇〇, 212 and 22 〇 = = = peak, and the four most characteristic peaks are at the diffraction angle (to be a single peak for U.4, 12.8, 20, 0 and 21.2) [Simple description of the diagram] Human L1 represents the characteristic X-ray powder diffraction pattern of the crystalline cis-succinate form of the compound of formula 1 (m-benzene solvent °), [vertical vehicle: strength (cps, H9709) .do, "31-200806666 count (square root)); horizontal axis: 2 Θ (degrees)]. Figure 2 shows the characteristic of the compound of formula I as a diacid salt form π (acetonitrile solvent) X-ray powder diffraction pattern 瑨, [vertical axis: intensity (CPS, ° 卞 (square root)); horizontal axis · · 2 Θ (degrees)]. Figure 3 shows the crystal of the compound of formula I Intrinsic infrared spectrum of the succinate form 1 (toluene solvent port), [longitudinal · # u ^ station · 袖 sleeve · transmittance (percent); horizontal glaze · wave number (cm · 1); Diacid form 1 (toluene solvent Raman shift (cm reciprocal); diacid form 11 (acetonitrile solvent • transmittance (percent); cross-section 4 shows the crystalline cis-butyl compound of formula I) Raman spectroscopy, [horizontal axis: vertical axis: relative intensity compared to background] Figure 5 shows the characteristic infrared spectrum of the crystalline cis-but compound of the compound of formula I, [vertical axis: wave number (cnT1) )] - Figure 6 shows the deliberate tearing spectrum of the crystalline maleate form of the formula ϊ (acetonitrile solvent), [horizon axis: Raman shift (reciprocal reciprocal); vertical axis · and The relative strength of the background is compared with the background. Figure 7 shows the characteristic difference of the crystalline maleate form 1 (toluene solvent) of the compound of the formula, and does not scan the calorimetric thermogram, [vertical axis··heat flow (eal/sec/g); horizontal axis: temperature (degrees Celsius) Figure 8 shows the crystalline maleate form of the compound of formula I^( Characteristic differential scanning calorimetry thermogram of nitrile solvent), [vertical axis: heat flux (Cal/sec/g); horizontal axis: temperature (degrees Celsius)]. Figure 9 shows the crystalline methanesulfonic acid of the compound of formula I. Characteristic X-ray powder diffraction pattern of salt form][(crystallized from ethyl acetate/hexane mixed solvent), [vertical axis: 119709.doc -32-200806666 intensity (CPS, count (square root)); horizontal axis· · 2Θ (degrees)]. Figure 10 is a graph showing the characteristic X-ray powder diffraction pattern of the crystalline form of the compound of the formula I, yttrium yttrium (crystallized from toluene), [vertical axis: intensity (cps, count (square root)); horizontal axis: 2 Θ (degrees)] . Figure 11 shows a characteristic X-ray powder diffraction pattern of the crystalline oxime sulfonate form of the compound of formula I (crystallized from toluene), [vertical axis: strength (cps, count (square root)); horizontal axis: 2 Θ (degrees) ]. Figure 12 shows a characteristic X-ray powder diffraction pattern of the crystalline oxalate form of the compound of formula I, [longitudinal: strength (cps, count (square root)); horizontal axis: 2 Θ (degrees)]. Figure 13 is a graph showing the characteristic X-ray powder diffraction pattern of the crystalline ethanesulfonate salt form of the compound of Formula 1, [longitudinal cylinder, rug, strength (CPS, number of leaves (square root)); horizontal axis: 2 Θ ( degree)]. 119709.doc -33 -

Claims (1)

200806666 X. Patent application scope: base}-methyl]·8·phenyl], 7-diazaspiro[4,5]癸_2, (form of crystalline ethanesulfonate - species (melon called (four) small (3,5_bis-(trifluoro-f-phenyl) ethoxy) is characterized by the following diffraction angle (in 2 Θ), lattice spacing "d" Diffraction pattern of 乂 ray powder expressed in units) and relative peak intensity ("RI"): diffraction angle (2Θ) RI lattice spacing (person 11.4 medium 7.73 12.8 medium 6.90 20.0 strong 4.44 21.2 medium 18 2. A (58,88)-8-[{(1&)-1-(3,5-bis-(trifluoromethyl)phenyl)ethoxy}-methyl]-8-phenyl- 1,7-A nitrogen snail [4,5] 癸 (Formula I)! Glutinous acid form Formula I is characterized by the following diffraction angle (in units of 2 Å), lattice spacing, d, (in 119709.doc 200806666 angstroms) and relative peak intensity ("RI") Diffraction pattern: diffraction angle (? Θ) RI lattice spacing (Α ± 〇·〇4) 5.6 weak, width 12.37 19.8 medium 4.84 21.0 medium 4.57 22·8 medium 4.18 3. one (58,88)_8- [{(1))-1-(3,5-bis-(trifluoromethyl)phenyl)ethoxy} fluorenyl]-8-phenyl-1,7-diazaspiro[4,5]癸-2 - ketone crystal carbamate 幵"" is characterized by the following diffraction angle (in units of 20), lattice spacing ''d' (in angstroms) and relative peak intensity (, , RI") indicates the diffraction pattern of χ ray powder: diffraction angle (2 Θ) RI lattice spacing (human ± 〇 · 〇 4) 4.7 strong 18.62 9.5 medium 9.26 19.2 extremely strong 4.63 20.9 medium, width 4.25. 4. A kind of (8) ^^(1) is called bismuth bis(tri)fluoromethyl group ethoxylate}methyl]8phenyl_1,7-diazaspiro[4,5]癸_2_嗣 crystallized stone yellow An acid salt form characterized by a diffraction angle (in units of 2 Å), a lattice spacing d (in the early position of angstroms), and a relative peak intensity (real) in the final diffraction pattern: 1 119709. Doc 200806666 Diffraction angle (2Θ) RI Lattice spacing (human ± 〇·〇4) 2 Medium 14.02 6 Medium 9.24 19.9 Extreme 4.46 21.2 Strong 4.19 〇 One (58,88)-8-[{(ΐκ)- 1β(3,5_bis(trifluoromethyl)phenyl)ethoxy}_methyl]-8-phenyl],7-diazaspiro[4,5]癸_2_ residual crystalline methyl salt Form, characterized by a diffraction angle at the following diffraction angle (in units of 2 、), crystal pitch "d" (in angstroms), and relative peak intensity (, Rr): diffraction angle (2Θ) RI lattice spacing (human ± 〇 · 〇 4) 7.3 strong 12.17 10.2 strong 8.69 22.7 strong 3.92 28.9 strong 3.08 〇 6 · - species (5S, 8S) I [{ (1R) small (3, 5 winter ( Trifluoromethyl)phenyl)ethoxy}methyl]8-benzyl-1,7--azaspiro[4,5] A crystalline form of anthrone, a cis-succinic acid salt, characterized by the following diffraction angle (in units of 2 Å), lattice spacing "d" (in angstroms), and relative peak intensity ("Rl. X-ray powder diffraction pattern: diffraction angle (2Θ) 10.0 13.5 16.5 23.5 119709.doc RI lattice spacing (human ± 0·04) ^ 8.84 medium 6.55 medium 5.36 extremely strong 3.79. 200806666 - species (gut called 8^^ ^,5-Bis-(tris-methyl)phenyl) phenylmethyl-phenyl--azine-like crystalline cis-succinate form 'characterized by the following diffraction angle (in Μ ), line powder diffraction pattern: ' ^ fWd^ Μ single (4) and relative + intensity ("RI") X-ray diffraction angle (2 Θ) RI lattice spacing 4.8 weak 18.47 12.0 medium 7.38 24.5 strong 3.64 28.9 medium 3.08 ° 8 A pharmaceutical composition comprising the crystalline salt of any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 9. A method of treating and/or preventing vomiting in a mammal, Including the administration of the crystalline salt of the mammal as claimed in any one of the items 7 to 1. Or a method of preventing nausea in a mammal comprising administering to the mammal a crystalline salt of any one of claims 1 to 。. η· A compound (5S,8S)-8_[{(iR)-i-(3,5-bis-(trifluoromethyl)phenyl)ethoxy}-indenyl]-8-phenyl-1 ,7-diazaspiro[4,5]nonanone (salt salt, Cf3 Formula I is prepared by the 119709.doc 200806666 ethanol solution of the acid-treated compound selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid butyric acid, and anti-butyl Aenedioic acid, citric acid, tartaric acid, acid, glycolic acid, 1-hydroxy-2-naphthoic acid, malonic acid, hippuric acid and 1 (S) camphorsulfonic acid. , oxalic acid, cis succinic acid, milk, (-) L-category 119709.doc