WO2007114922A2

WO2007114922A2 - 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

Info

Publication number: WO2007114922A2
Application number: PCT/US2007/008346
Authority: WO
Inventors: Mengwei Hu; Sunil Paliwal; Neng-Yang Shih; Frank Guenter; Ingrid Mergelsberg
Original assignee: Schering Corporation
Priority date: 2006-04-05
Filing date: 2007-04-04
Publication date: 2007-10-11
Also published as: WO2007114922A3; PE20080353A1; AR060352A1; CL2007000947A1; TW200806666A

Abstract

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

Description

SALTS OF 8-K1 -( 3,5-Bis-(trifluoromethvnphenvπ-ethoxy>-methvn-8-phenvi-1 ,7- diaza-spiror4.51decan-2-one AND PREPARATION PROCESS THEREFOR

Field of the Invention

This patent application generally relates to pharmaceutically useful salts and a novel process to prepare pharmaceutically useful salts. It specifically relates to a novel process to synthesize pharmaceutically useful salts of 8-[{1-(3,5-Bis-

(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one.

Background of the Invention

The preparation of diazaspirodecan-2-ones named (in accordance with Bielstein nomenclature) 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methylj-8- phenyl-1 ,7-diaza-spiro[4.5]decan-2-one, for example, (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) is disclosed in Published U.S. Patent Application, No. 2003- 0158,173 A1 , filed on May 1 , 2000 (the '173 publication), which is incorporated herein by reference in its entirety.

I

The novel compounds disclosed in the '173 publication are classified as Tachykinin compounds, and are antagonists of neuropeptide neurokinin-1 receptors (referred to herein for convenience as "NK-1 receptor antagonists"). In general, NK-1 receptor antagonists are useful therapeutic agents. Some examples of NK-1 receptor antagonists are disclosed in: U.S. 5,760,018 (1998) that have been shown to be useful in the treatment of pain, inflammation, migraine and emesis. Additional examples of other NK-1 receptor antagonists are disclosed in each of U.S. Patent No. 5,620,989 (1997), and international publication nos. WO 95/19344 (1995), WO 94/13639 (1994), and WO 94/10165 (1994), that have been shown to be useful in the treatment of treatment of pain, nociception and inflammation. Additional examples of NKi 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 Rogiers et al, Tetrahedron 57. 8971-8981 (2001).

The novel NK-1 receptor antagonist compounds disclosed in the above- mentioned '173 publication include several novel diazaspirodecan-2-ones, including the compound of Formula I, which are believed to be useful therapeutic agents in the provision of anti-nausea and anti-emesis therapy.

As reported in the '173 publication, the compound of Formula I was characterized by TLC and by GC/MS techniques. The procedures described in the '173 publication yielded the compound of Formula I in the form of an amorphous white foam. Repeated attempts to crystallize the free base have not provided a crystalline material.

In general, compounds which have been identified as having therapeutic activity must be provided in a highly pure form for pharmaceutical use. Moreover, it is also desirable to provide compounds intended for pharmaceutical use in a form such that it is handled easily for incorporation into a medicament, and when incorporated into a medicament the compound possesses a sufficiently robust character that it is resistant to chemical degradation, and thereby imparts a long shelf life to the medicament. Objectives

In view of the foregoing, what is desired is a form of the therapeutic agent which lends itself to providing the therapeutic agent in a highly purified form. What is desired also is a form of the therapeutic agent which is robust toward degradation under the environmental conditions in which it is handled and stored.

Summary of the Invention

These and other objectives are advantageously provided by the present invention, which in one aspect provides the compound of Formula I in a salt form which is optionally crystalline and optionally incorporates one or more solvent molecules thereinto, for example, a crystalline monohydrate. In some embodiments the salt form of compound I is selected from a maleate, a mesylate, an oxalate, a bensylate, an esylate, a fumarate, a citrate, a tartarate, a succinate, a lactate, a glycolate, a 1-hydroxy-2-naphthoate, a malonate, a (-)L-malate, a hippurate, and a (IS)camsylate. In some preferred embodiments the salt form of compound I is a maleate.

Another aspect of the present invention is the provision of a crystalline maleate form I salt form of (5S,8S)-8-[{(1 R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]- δ-phenyl-1 ,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table I expressed in terms of diffraction angle (in 2 Θ, all values reflect an accuracy of ± 0.2) lattice "d" spacing (in angstroms) and relative peak intensities("RI"): Table I

Diffraction angle (2θ.± 0.2 Rl Lattice Spacing (A ± 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 present invention is the provision of a crystalline Maleate Form I salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8- phenyl-1 ,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table Il expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Table Il Diffraction angle ).± 0.2 Rl Lattice Soacinα (A ± 0.04)

4.8 Medium 18.47 12.0 Strong 7.38 24.5 Strong 3.64 28.9 Medium Broad 3.08

Another aspect of the present invention is the provision of a crystalline mesylate Form I salt of (5S,8S)-8-[{(1 R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}- methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table III expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Table III

Diffraction anqle (2G ),± 0.2 Rl Lattice Spacinα (A ± 0.04 ϊ

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 is the provision of a crystalline mesylate Form Il salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}- methylj-8-phenyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table IV, expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Table IV Diffraction angle !Θ.± 0.2 Rl Lattice Spacing (A ± 0.04)

6.2 Medium 14.20

9.6 Medium 9.24

19.9 Very Strong 4.46

21.2 Strong 4.19

Another aspect of the present invention is the provision of a crystalline mesylate Form III salt of (5S,8S)-8-[{(1 R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}- methyl]~8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table V expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Table V

Diffraction angle (2G. >,± 0.2 Rl Lattice Soacinq (A ± 0.04)

4.7 Strong 18.62

9.5 Medium 9.26

19.2 Very Strong 4.63

20.9 Medium Broad 4.25

Another aspect of the present invention is the provision of a crystalline oxalate salt of (5S,8S)-8-[{(1 R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl- 1 ,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table Vl, expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"): Table Vl Diffraction angle (2Θ.± 0.2 Rl Lattice Spacing (A ± 0.04)

5.6 Weak, Broad 12.37 19.8 Medium 4.84 21.0 Medium 4.57 22.8 Medium 4.18

Another aspect of the present invention is the provision of a crystalline esylate salt of (5S,8S)-8-[{<1 R)-1-(3,5-Bis-(trifluoromethyl)phenyi)-ethoxy}-methyl]-8-phenyl- 1 ,7-diazaspiro[4.5]decan-2-one which is characterized by the x-ray powder diffraction pattern shown in Table VII, expressed in terms of diffraction angle (in 2 θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Table VII

Diffraction angle (2* S.± 0.2 Rl Lattice Spacinα (A ± 0.04)

11.4 Medium 7.73

12.8 Medium 6.90

20.0 Strong 4.44

21.2 Medium 4.18

This invention further provides pharmaceutical compositions each containing a crystalline salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}- methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) selected from maleate forms I and II, mesylate forms I, Il and III, esylate, and oxalate, and methods of treating and/or preventing nausea and emesis using a medicament containing one or more of a crystalline salt forms of the compound of Formula I.

Brief Description Of The Figures

Figure 1 presents a characteristic x-ray powder diffraction pattern of the cyrstalline maleate salt form I (toluene solvate) of the compound of Formula I₁ [Vertical Axis: Intensity (CPS, counts (square root)) ; Horizontal Axis: Two Theta(degrees)]. Figure 2 presents a characteristic x-ray powder diffraction pattern of the cyrstalline maleate salt form Il (acetonitrile solvate) of the compound of Formula I, [Vertical Axis: Intensity (CPS, counts (square root)); Horizontal Axis: Two Theta(degrees)]. Figure 3 presents a characteristic infrared spectrum of the crystalline maleate salt form I (toluene solvate) of the compound of Formula I [Vertical Axis; Transmittance(Percent); Horizontal Axis: wavenumber (cm-1)].

Figure 4 presents a characteristic Raman spectrum of the crystalline maleate salt form I (toluene solvate) of the compound of Formula I, [horizontal axis; Raman shift in reciprocal centimeters, vertical axis; relative intensity versus background].

Figure 5 presents a characteristic infrared spectrum of the crystalline maleate salt form Il (acetonitrile solvate) of the compound of Formula I [Vertical Axis; Transmittance(Percent); Horizontal Axis: wavenumber (cm-1)].

Figure 6 presents a characteristic Raman spectrum of the crystalline maleate salt form Il (acetonitrile solvate) of the compound of Formula I, [horizontal axis; Raman shift in reciprocal centimeters, vertical axis; relative intensity versus background].

Figure 7 presents a characteristic differential scanning calorimetry thermogram of the crystalline maleate salt form I (toluene solvate) of the compound of Formula I, [Vertical Axis;Heat Flow in cal/sec/g; Horizontal Axis:Temperature in degrees centigrade].

Figure 8 presents a characteristic differential scanning calorimetry thermogram of the crystalline maleate salt form Il (acetonitrile solvate) of the compound of Formula I, [Vertical Axis;Heat Flow in cal/sec/g; Horizontal Axis:Temperature in degrees centigrade].

Figure 9 presents a characteristic x-ray powder diffraction pattern of the cyrstalline mesylate salt form I (crystallized from ethyl acetate / hexane mixed solvent) of the compound of Formula I, [Vertical Axis: Intensity (CPS, counts (square root)); Horizontal Axis: Two Theta(degrees)]. Figure 10 presents a characteristic x-ray powder diffraction pattern of the cyrstalline mesylate salt form Il (crystallized from toluene) of the compound of Formula I, [Vertical Axis: Intensity (CPS, counts (square root)) ; Horizontal Axis: Two Theta(degrees)].

Figure 11 presents a characteristic x-ray powder diffraction pattern of the cyrstalline mesylate salt form III (crystallized from toluene) of the compound of Formula I, [Vertical Axis: Intensity (CPS, counts (square root)) ; Horizontal Axis: Two Theta(degrees)].

Figure 12 presents a characteristic x-ray powder diffraction pattern of the crystalline oxalate salt form of the compound of Formula I, [Vertical Axis: Intensity (CPS, counts (square root)) ; Horizontal Axis: Two Theta(degrees)].

Figure 13 presents a characteristic x-ray powder diffraction pattern of the cyrstalline esylate salt form of the compound of Formula I, [Vertical Axis: Intensity (CPS, counts (square root)) ; Horizontal Axis: Two Theta(degrees)].

Detailed Description of the Invention

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 (the compound of Formula I)

Formula I

provide a drug beneficial in the treatment of nausea and emesis. Although the compounds of the present invention may be useful in the provision of anti-nausea and anti-emesis treatment for nausea and emesis arising from any cause, it is believed that the compound of Formula I will be most effective in the provision of anti-nausea and/or anti-emesis treatment for nausea and/or emesis associated with chemotherapy treatments, radiation treatments, and arising during a post-operative period. Additionally, the salt forms disclosed herein have processing advantages related to their improved solubility in polar solvents in comparison to the free base form of the compound which are beneficial in the provision of useful medicaments. Moreover, each of the toyslate, hydrochloride, malate, mesylate, oxalate, bensylate, and esylate salts have one or more crystalline forms which provide the compound of Formula I in a form having the following advantages compared to amorphous forms of the compound: lower impurity content and more consistent product quality i.e., more consistent physical characteristics including more consistent color, rate of dissolution and ease of handling; as well as a longer term stability when incorporated into a medicament.

As described in detail below, each of the crystalline salt forms of the compound of Formula I described herein can readily be distinguished from one another and from amorphous forms by examination of one or more of the characteristic X-ray Diffraction patterns (see Figures 1 , 2, and 9 to 13), the characteristic infrared spectra (see Figures 4 and 6) and the analytical Differential Scanning Calorimetry (DSC) thermograms (Figures 7 and 8) of the respective salt forms.

The inventors have unexpectedly discovered, as shown above in Formula II, that the diazaspirodecan-2-ones of Formula I contain a cycloamine nitrogen of sufficient basicity that it can be protonated by inorganic acids selected from benzene-, ethane-, and methane-sulfonic acids (to form, respective, the bensylate, esylate and mesylate salts of the compound of Formula I). It has been unexpectedly discovered also that the diazaspirodecan-2-ones of Formula I can be protonated by organic acids selected from malic, oxalic, furmaric, tartaric, citric, succinic, lactic, glycolic, malonic, 1-hydroxy-2-naphthoic, maleic, hippuric, and camsylic acids to form, respectively, the malate, oxalate, furmarate, tartarate, citrate, succinate, lactate, glycolate, malonate, 1- hydroxy-2-napththoate, maleate, hippurate, and camsylate salts of the compound of Formula I. Moreover, it has been found that the acid salts selected from the maleate, mesylate, oxalate, bensylate, and esylate salt forms can be provided in the form of a crystalline solid which optionally includes in the crystal structure (for each molecule of the protonated compound of Formula I), one or more molecules of solvent, for example, toluene, hexane or acetonitrile.

The salts of the invention offer a number of surprising advantages over the free base in their physical properties, for example, the ability to mill, micronize and solubilize the compound. Preferred crystalline forms of the salt are selected from maleate, and mesylate salt forms. It has been found that these salts are thermodynamrcally robust in addition to having desirable solubility and handling characteristics, thus providing the compound of Formula I in a salt form which is easily incorporated into a medicament and which is stable under a wide variety of environmental conditions.

As is known, therapeutic agents typically display poor absorption rates when they have an aqueous solubility of less than about 10 mg/ml over a pH range of from about pH 1 to about pH 7. Moreover, when orally administered therapeutic agents display a solubility of less than about 1 mg/ml within this pH range, typically such agents exhibit dissolution-rate limited absorption since solubility and absorption are related in orally administered medicaments. Accordingly, the improved solubility properties of these salts are important for the provision of an orally administered form of a medicament designed to deliver the compound of Formula I as a therapeutic agent. In addition to these desirable improved solubility properties, as described in detail below, selected salts displayed additional advantageous physical properties.

In general, the compound salt is prepared from a compound of Formula I and an acid selected from oxalic, maleic, methanesulfonic, benzenesulfonic, ethanesulfonic, furmaric, citric, tartaric, succinic, lactic, glycolic, 1 hydroxy-2-napthoic, malonic, malic, Hippuric, and camsylic acids accordance with the following procedure: i) with stirring, a 0.1 g quantity of the compound of Formula I

(approximately 0.2 mMol) and an equivalent amount (i.e. 0.2 mMol) of the selected acid is dissolved in about 3 ml of anhydrous ethanol contained in a vessel; ii) with continued stirring, anhydrous diethylether is added dropwise to the mixture until it becomes cloudy; iii) an amount of anhydrous ethanol just sufficient to clear the cloudiness is added to the cloudy mixture (typically several drops); iv) the stirring is discontinued and the vessel is covered with aluminum foil containing vent holes and left to stand quiescent for 24 to 48 hours during which time solids will precipitate; v) at the end of the quiescent period the solids are recovered by filtration, washed with solvent, and then dried first in the air for a period of from about 1 to about 18 hours and then vacuum dried at ambient temperature under house vacuum overnight, yielding the salt of the compound of Formula I.

For some salts, solvate forms of various crystals are prepared in accordance with the following general procedure. A sample of the salt prepared by reactive crystallization in accordance with the above procedure, or recrystallization of a salt initially precipitated as an amorphous material utilizing the above-described general procedure and subsequently crystallized by seeding a slurry of the amorphous salt, is weighed into a vial, typically from about 10 mg to about 50 mg. A solvent selected from ethanol, isopropanol, acetonitrile, water, toluene, ethyl acetate, methylene chloride and hexane, in an amount sufficient to completely immerse the solids is added to the vial. The solids and solvent are stirred under ambient conditions a period of time sufficient to provide solvate crystals, for example, for about seven days. When solvate crystals have been prepared, a sample of the suspended solvate crystals is dropped onto a sample holder for use in a powder X-ray diffraction spectrometer and air dried. These samples are then analyzed by X-ray spectroscopy according to procedures described herein.

ANALYTICAL PROCEDURES

Each of the crystalline salt forms of the compound of Formula I is characterized by one or more techniques including X-ray powder diffraction spectroscopy (PXRD), lnfared Spectroscopy (IR), and Raman Spectroscopy (Raman). Selected salt forms of compound I were also analyzed by differential scaning calorimetry (DSC), and/or further characterized by physical methods including solubility studies and stability studies.

X-Ray Powder Diffraction Spectroscopy

X-ray powder diffraction spectroscopy was obtained on samples using one of the following procedures. For the solvates prepared in accordance with the above- described procedure, analysis was carried out on a Rigaku according to the following procedure.

For analysis of samples obtained using a Rigaku Miniflex spectrometer, the following procedure was employed (PXRD method I). Specimens analyzed by PXRD method I were lightly packed onto a low-background plate. The specimens were exposed to the room environment with ambient temperature and humidity. The Rigaku spectrometer was equipped with a six-plate carousel that rotated the specimen at 54 rpm, minimizing preferred orientations of the crystals in the sample studied. The Rigaku spectrometer was equipped also with a copper Ka radiation source utilized without a Kα2 filter. The spectrometer was equipped also with a variable divergence slit and 0.3 mm receiving slit. Scan range was carried out from 2.0 to 40 °2Θ. Instrument calibration was verified using the Cu Kα1 peak for the 111 plane. During scanning, the step size was 0.02 degrees over step durations of 0.6 seconds. Data analysis was accomplished using Jade Plus (release 5.0.26) analysis software. The data ware smoothed with a Savitzky-Golay parabolic filter at 11 points. Typically "d" spacing values are accurate to within ± 0.04 A.

X-ray Powder Diffraction spectroscopy analysis was obtained for some samples using a Bruker D8 diffractometer manufactured in 2002 (PXRD method II). The Bruker diffractometer was equipped with a parallel optic configuration utilizing a GόBEL beam focusing mirror and a PSD detector equipped with a fixed radial soller slit. The Bruker diffractometer was used with an Anton Paar TTK450 temperature stage. The radiation source is copper (Kα).The divergence slits are fixed at 0.6mm. The Bruker diffractometer utilized a top-loading brass block sample holder. PSD fast scan was used to scan from 4.0° to 39.9°. To obtain a diffraction pattern, specimens were loaded onto the sample holder and leveled with a glass microscope slide. The sample chamber temperature was set at 25 ⁰C, 30⁰C or 120 ⁰C, under ambient humidity and not purged with nitrogen and not under vacuum. Instrument calibration was verified using mica standards. During scanning, the step size was 0.013 degrees to 0.02 degrees over step durations of 0.5 to 10 seconds. Data analysis was accomplished using EVA analysis software, version 7.0.0.1 , supplied by Bruker® written by SOCABIM ®. The data were smoothed by the software at 0.1 to 0.15.

Except for those solvate samples prepared in accordance with the above- described procedure, samples for analysis by X-ray Powder Diffraction ("PXRD"). were subjected to minimal preparation to prevent any form changes. Sample particles were lightly packed into the sample holder to insure that they formed a smooth surface and did not clump together. No solvents, drying or other preparation steps were used for other than the solvate samples prepared in accordance with the procedure described above.

Infrared Spectroscopy

Samples were characterized utilizing attenuated total reflectance (ATR) infrared spectroscopy using a Nicolet Instruments NEXUS 670 FTIR equipped with an Avatar Smart Miracle Attenuated Total Reflectrance (ATR) sample compartment. Spectra were collected utilizing the following parameters: DTGS KBr Detector; KBr beam splutter; scanning range 600 cm -1 to 4000 cm -1; aperature setting 100; resolution 2; 100 scans/sample. The analysis was carried out by collecting a background spectrum, then placing reference standard or particulate sample (typically 3 mg to 5 mg of sample) on the ATR crystal and applying force to the sample with the instrument's pressure arm in accordance with the manufacturers recommendations. A spectrum of the specimen (reference or sample) was then obtained as a ratio of the background and specimen spectra utilizing the manufacturers proprietary software. Raman Spectroscopy

Raman spectroscopy (Raman) was performed utilizing one of two procedures. Procedure I Raman analysis was performed on a Thermo Electron Nicolet Almega Dispersive Raman spectrometer in high-resolution mode. Samples were contained in NMR sample tubes and spectra were obtained under the following conditions: Scanning range 4000 cm-1 to 90 cm-1; Exposure time 1.0 second; 100 sample and 100 background exposures; Excitation Laser at 785 nm / 100 % power level / parallel laser polarization; Grating 1200 lines/ mm; 100 micron slit; Camera temperature — 50 ⁰C.

Procedure Il Raman analysis was carried out on a Thermo Electron Nicolet Almega Raman Microscope set for 50 X magnification. Samples were prepared by placing a small amount on a microscope slide without a cover glass and obtained under the following conditions: Scanning range 3481 cm-1 to 96 cm-1; Low resolution; Exposure time 5.0 second; 10 sample and 10 background exposures; Excitation Laser at 780 nm (depolarized) / 100 % power level ; Grating 1200 lines/ mm; 25 micron pinhole; Camera temperature - 48 ⁰C.

Differential Scanning Calorimetrv

Calorimetric studies were conducted utilizing a modulated Differential Scanning Calorimeter (DSC) from TA instruments. DSC scans were run at a heating rate of 10 C/min. in an open aluminium pan under nitrogen flowing at a rate of 40 ml/min.

Solubility tests were conducted by placing an excess of the compound in an aliquot of the solvent of interest and allowing the slurry to equilibrate under the selected temperature conditions (typically ambient). When the solvent was water, pH was adjusted to the desired value with hydrochloric acid and sodium hydroxide.

When the slurry mixture had equilibrated, the excess solids were centrifuged (water) or filtered (all other solvents) from the supernatant and the amount of compound which had been dissolved was quantified utilizing HPLC analysis of diluted aliquots of the supernatant liquid. Pharmaceutical grade solvents were employed.

Chemical stability tests were carried out on aliquots of the salt form of interest by placing a accurately weighed sample of the salt form of the compound of Formula I into a polyethylene bag. The bagged samples were enclosed in fiberboard tubes fitted with metal caps which were stored under the indicated conditions of humidity and temperature for the indicated time. Analysis was carried out by dissolving the contents of a vial and quantifying the amount of solute utilizing HPLC analysis. Where noted the aliquots were stored in capped amber vials under the conditions noted instead of polyethylene bags.

EXAMPLES

Maleate, mesylate, esylate, and oxalate salt forms of the compound of Formula I were prepared as described below. Each of the salt forms of the compound of Formula I were also characterized by various spectroscopic techniques including X- ray Powder Diffraction Spectoscopy, Infrared Spectroscopy, and Raman Spectroscopy, as discussed in detail below. Selected salt forms were analyzed for stability, solubility and other improved physical properties, including, for some salts, analysis by differential scanning calorimetry (DSC). Unless otherwise specified, for use in the preparation of the salts described herein, (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) was prepared in accordance with the procedures disclosed in pending Published U.S. Patent Application, No. 2003-0158,173 A1 , filed on May 1 , 2000 (the '173 publication), which is incorporated herein by reference in its entirety. All reactive crystallizations, recrystallization, and slurry procedures were carried out in commercially available solvents of the specified grade (generally pharmaceutical or food grade unless otherwise specified) and used as received (unless otherwise specified).

Maleate Salts of the Compound of Formula I

An amorphous maleate salt of the compound of Formula I will be prepared by dissolving 1g (2 mmol.) of the compound of Formula l in 4 ml of methyl tertiary-butyl- ether (MTBE) and stirring therewith 1 equivalent of maleic acid dissolved in 4 ml of isopropyl alcohol in accordance with the general procedures for preparation of salts of the compound of Formula I described above. The maleate form I salt of the compound of Formula I was prepared by slurrying in acetonitrile or isopropyl acetate the amorphous maleate salt prepared above, in accordance with the general slurrying procedures described herein above. The maleate salt form I of the compound of Formula I was characterized by X-ray, Infrared, and Raman spectroscopies and and analyzed by DSC utilizing the procedures described above. Figure 1 illustrates an X- ray powder diffraction spectrum of the maelate form I salt. Table VIM, below, lists 12 characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 1 , expressed in diffraction angle expressed in degrees 2 theta (°2 Θ), the corresponding "d" spacing in angstroms (A), and in an adjacent column represents the relative intensities of the signal ("Rl") in the following notation: S= strong, M = medium, W = weak; V = Very and D = diffuse:

Table VIII

Of the peaks characteristic of the maleate form I salt of the compound of Formula I shown in Table VIII, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 9.06, 10.0, 13.5, 16.5, 18.0, 20.2, 23.5, and 24.3, and the four most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 10.0, 13.5, 16.5, and 23.5. Figure 3 illustrates a transmission infrared spectrum of the crystalline maleate form I salt form of the compound of Formula I obtained using the procedure described above. Table IX lists the 12 most characteristic peaks of the spectrum illustrated in Figure 24, and in an adjacent column represents the relative absorption intensity of each listed peak utilizing the notation: S = Strong, M = Moderate, B = Broad, V = Very, W = Weak.

Table IX

Of the characteristic peaks shown in Table (X, the 8 most characteristic peaks of the compound are those appearing at 1695, 1319, 1276, 1183, 1117, 900, 866, and 682 reciprocal centimeters (cm^"1), and the four most characteristic peaks are those appearing at 1695, 1276, 1117, and 682 cm^"1. Figure 4 illustrates a Raman spectrum of the crystalline maleate form I salt form of the compound of Formula I obtained using the above-described procedure. Table X, below, lists the 12 most characteristic scattering peaks (in reciprocal centimeters, cm^"1) of the spectrum illustrated in Figure 4 and in an adjacent column represents the relative absorption intensity of each listed peak in the notation: S = Strong; M = Moderate; W = Weak; V = Very; B = Broad.

Table X

Of the characteristic peaks shown in Table X, the 8 most characteristic peaks of the compound are those appearing at 1694, 1620, 1380, 1203, 1002, 728, 273, and 152 cm^"1, and the four most characteristic peaks are those appearing at 1620, 1380, 1002, and 728 cm^'1. Figure 7 illustrates a DSC thermogram obtained from differential scanning calorimetry analysis of the crystalline maleate form I salt form of the compound of Formula I obtained using the procedure described above. With reference to Figure 7, the DSC thermogram contains a broad endotherm centered at approximately 180 ⁰C.

The maleate form Il salt of (5S,8S)-8-[{(1 R)-1-(3,5-Bis-(trifluoromethyl)phenyl)- ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the maleate form Il salt of the compound of Formula I) was prepared from the maleate salt of the compound of Formula I precipitated using the amorphous salt preparation procedure described above. Thus, the initially precipitated maleate salt prepared as described above, was slurried in toluene according to the general procedures for slurry preparation described herein, to yield crystalline maleate form Il salt of the compound of Formula I.

With reference to Figures 2, 5, 6, and 8 the maleate form Il salt of the compound of Formula I was characterized by X-ray, Infrared, and Raman spectroscopies and analyzed by DSC, using the procedures described above. Table Xl, below, lists 12 characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 23, listed as diffraction angle expressed in degrees 2 theta (°2 θ), the corresponding "d" spacing in angstroms (A), and relative intensities of the signal ("Rl") represented in the following notation: S= strong, M = medium, W = weak; V = Very and D = diffuse:

Table Xl

Of the peaks characteristic of the crystalline maleate form M salt of the compound of Formula I shown in Table Xl, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 4.8, 9.5, 10.5, 12.0, 15.1 , 17.5, 24.5, and 28.9, and the four most characteristic peaks are those appearing at diffraction angles (in °2 θ) equal to 4.8, 12.0, 24.5, and 28.9.

Figure 5 illustrates a transmission infrared spectrum of the crystalline maleate form Il salt form of the compound of Formula I obtained using the procedure described above. Table XII, below, lists the 12 most characteristic peaks of spectrum illustrated in Figure 5, and in an adjacent column represents the relative absorption intensity of each listed peak utilizing the notation: S = Strong, M = Moderate, W = Weak, B = Broad, V= Very.

Table XII

Of the characteristic peaks shown in Table XII, the 8 most characteristic peaks of the compound are those appearing at 1687, 1277, 1168, 1124, 897, 863, 766 and 682 reciprocal centimeters (cm^"1), and the four most characteristic peaks are those appearing at 1687, 1277, 1124, and 682 cm^'1.

Figure 6 illustrates a Raman spectrum of the crystalline maleate form Il salt form of the compound of Formula I obtained using the above-referenced procedure, Table XIII, below, lists the 12 most characteristic scattering peaks (in reciprocal centimeters, cm^"1) of the spectrum illustrated in Figure 6, and in an adjacent column represents the relative intensity of each listed peak utilizing the notation: S = Strong; M = Moderate; W - Weak; V = Very; B = Broad.

Table XIII

Of the characteristic peaks shown in Table XIII, the 8 most characteristic peaks of the compound are those appearing at 1700, 1623, 1384, 1202, 1003, 730, 621 , and 281 cm^"1, and the four most characteristic peaks are those appearing at 1623, 1384, 1003, and 281 cm^"1.

Figure 8 illustrates a differential scanning calorimetry thermogram of an analysis of the crystalline maleate form Il salt form of the compound of Formula I using the procedures described above. With reference to Figure 8, the thermogram contains a sharp endotherm centered at approximately 155 ⁰C.

Mesylate Salts of the Compound of Formula I

A crystalline mesylate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one (the mesylate form I salt of the compound of Formula I) is prepared by dissolving 1g (2 mmol.) of the compound of Formula I and one equivalent of methane sulfonic acid in an amount of anhydrous ethanol just sufficient to dissolve these starting materials (typically about 4 ml) followed by adding approximately 30 ml of anhydrous diethyl ether. Crystals of the mesylate form I salt of the compound of formula I are precipitated by leaving the mixture covered with a vented cover to stand quiescent under ambient conditions for a period of 1 to 2 days. These crystals are prepared for X-ray diffraction analysis by collecting them using vacuum filtration, washing them with anhydrous diethyl ether, and drying them by under house vacuum.

Crystalline mesylate form I salt of the compound of Formula I was characterized by X-ray Powder Diffraction Spectroscopy. Figure 9 illustrates an X-ray Powder Diffraction Spectrum of the mesylate form I salt of the compound of Formula I. Table XIV, below, lists 12 characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 9, listed in diffraction angle expressed in degrees 2 theta (°2 Θ), the corresponding "d" spacing in angstroms (A), and in an adjacent column represents the relative intensities of each listed peak ("Rl") in the following notation: S= strong, M = medium, W = weak; V = Very and D = diffuse:

Table XIV

Of the peaks characteristic of the mesylate form I salt form of the compound of Formula I shown in Table XIV, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 7.3, 10.2, 12.9, 18.2, 19.9, 22.7, 24.0, and 28.9, and the four most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 7.3, 10.2, 22.7, and 28.9.

An amorphous mesylate salt of the compound of Formula I will be prepared by dissolving 1g (2 mmol.) of the compound of Formula I in 4 ml of methyl tertiary-butyl- ether (MTBE) and stirring therewith 1 equivalent of methane sulfonic acid dissolved in 4 ml of isopropyl alcohol in accordance with the general procedures for preparation of salts of the compound of Formula I described above. This amorphous material is isolated by vacuum filtration. Two additional crystalline forms of a mesylate salt of the compound of Formula I can be prepared from this amorphous material by slurry crystallization.

Accordingly, the mesylate form Il salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifIuoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the mesylate form Il salt of the compound of Formula I) is prepared by slurrying, in accordance with the slurry procedure described herein, the amorphous mesylate salt prepared as described above, in an equal volume mixture of ethyl acetate and hexane mixed solvent. Crystals of mesylate form Il salt form of the compound of Formula I were analyzed by X-ray Powder Diffraction Spectroscopy in accordance with the above-described PXRD method I. Table XV, below, lists the diffraction angle of 12 characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 10, expressed in degrees 2 theta (°2 Θ), the corresponding "d" spacing in angstroms (A), and in an adjacent column represents the relative intensities ("Rl") of each listed peak in the following notation: S= strong, M = medium, W = weak; V = Very and B = Broad:

Table XV

Of the peaks characteristic of the mesylate form Il salt form of the compound of Formula I shown in Table XV, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 6.2, 9.6, 12.4, 19.9, 21.2, 22.7, 23.6, and 24.8, and the four most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 6.2, 9.6, 19.9, and 21.2.

The mesylate form III salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one (the mesylate form III salt form of the compound of Formula I) is prepared by dissolving 10 g of the amorphous mesylate salt prepared as described above in an amount of toluene just sufficient to dissolve the salt when it is warmed to a temperature of 40 ⁰C, and letting the solution cool to room temperature. The mesylate form III salt of the compound of Formula I was characterized by X-ray Powder Diffraction Spectroscopy. Figure 11 illustrates an X-ray Powder Diffraction Spectrum of the crystalline mesylate form III salt. Table XVI, below, lists 12 characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 11, listing their diffraction angle expressed in degrees 2 theta (°2 Θ), the corresponding "d" spacing in angstroms (A), and in an adjacent column represents the relative intensities ("Rl") of the listed peaks in the following notation: S= strong, M = medium, W = weak; V = Very and B = Broad:

Table XVI

Of the peaks characteristic of the mesylate form III salt form of the compound of Formula I shown in Table XVI, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 4.7, 9.5, 18.6, 19.2, 20.9, 22.1 , 24.1, and 25.7, and the four most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 4.7, 9.5, 19.2, and 20.9.

Oxalate Salts of the Compound of Formula I

An oxalate salt of the compound of Formula I is prepared by dissolving a mixture of one equivalent of the compound of (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) and one equivalent of oxalic acid in anhydrous ethanol, adding sufficient anhydrous diethyl ether to the mixture to induce a cloudy appearance, titrating additional ethanol into the mixture until the solution returned to a clear condition and leaving the solution sit quiescent for 48 hours until crystals of oxalate form I salt are precipitated, in accordance with the general procedure described above. The crystals of the oxalate form I salt form of the compound of Formula I are then collected by vacuum filtration and air dried.

Figure 12 illustrates an X-ray Powder Diffraction Spectrum of the oxalate form I salt form of the compound of Formula I. Table XVII, below, lists 11 characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 12, in diffraction angle expressed in degrees 2 theta (°2 Θ), the corresponding "d" spacing in angstroms (A), and, in an adjacent column represents the relative intensities ("Rl") of each listed peak utilizing the following notation: S= strong, M = medium, W = weak; V = Very, B = Broad, and D = diffuse:

Table XVII

Of the peaks characteristic of the oxalate form I salt form of the compound of Formula I shown in Table XVII, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 5.6, 9.2, 11.9, 19.8, 21.0, 21.5, 22.8, and 23.8, and the four most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 5.6, 19.8, 21.0, and 22.8.

Esylate Salts of the Compound of Formula I

An esylate salt of the compound of Formula I is prepared by dissolving a mixture of one equivalent of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)- ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) and one equivalent of ethyl sulfonic acid in anhydrous ethanol, adding sufficient anhydrous diethyl ether to the mixture to induce a cloudy appearance, titrating additional ethanol into the mixture until the solution returned to a clear condition, and leaving the solution sit quiescent for 48 hours until crystals of esylate form I salt form of the compound of Formula I are precipitated. The crystals of the esylate form I salt are collected by vacuum filtration and air dried.

Figure 13 illustrates an X-ray Powder Diffraction Spectrum of the esylate form I salt form of the compound of Formula I. The 12 most characteristic peaks of the X-ray Powder Diffraction spectrum shown in Figure 13 are listed in Table XVIII, below, in diffraction angle expressed in degrees 2 theta (°2 Θ), the corresponding "d" spacing in angstroms (A), and in an adjacent column, the relative intensities ("Rl") of each listed peak is represented in the following notation: S= strong, M = medium, W = weak; V = Very, B = Broad, and D = diffuse: Table XVIII

Of the peaks characteristic of the esylate form I salt form of the compound of Formula I shown in Table XVIII, the eight most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 9.9, 11.4, 12.8, 16.6, 18.3, 20.0, 21.2, and 22O, and the four most characteristic peaks are those appearing at diffraction angles (in °2 Θ) equal to 11.4, 12.8, 20.0, and 21.2.

Claims

What is claimed is:

1. A crystalline esylate salt form of (5S,8S)-8-[{(1 R)-1 -(3,5-Bis-

(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one: (Formula I)

Formula I

which is characterized by the following x-ray powder diffraction pattern expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RP'):

Diffraction anqle (2& Rl Lattice Soacinα (A ± 0.04}

11.4 Medium 7.73

12.8 Medium 6.90

20.0 Strong 4.44

21.2 Medium 18

A crystalline oxylate salt form of ((5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2- one (Formula I)

Formula I

which is characterized by the following x-ray powder diffraction pattern expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Diffraction angle Rl Lattice Spacing (A ± 0.04)

5.6 Weak, Broad 12.37

19.8 Medium 4.84

21.0 Medium 4.57

22.8 Medium 4.18

A crystalline Mesylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2- one which is characterized by the following x-ray powder diffraction pattern expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Diffraction angle (2Θ Rl Lattice SDacinα (A ± 0.04)

4.7 Strong 18.62

9.5 Medium 9.26

19.2 Very Strong 4.63

20.9 Medium Broad 4.25

A crystalline Mesylate salt form of (5S,8S)-8-[{(1 R)-1 -(3,5-Bis- (trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2- one which is characterized by the following x-ray powder diffraction pattern expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Diffraction anqle (2θ Rl Lattice SDacinα ( A ± 0.04}

2 Medium 14.02

6 Medium 9.24

19.9 Very Strong 4.46

21.2 Strong 4.19

5. A crystalline Mesylate salt form of (5S,8S)-8-[{(1 R)-1 -(3,5-Bis-

(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2- one which is characterized by the following x-ray powder diffraction pattern expressed in terms of diffraction angle (in 2 ©), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Diffraction anqle (20 Rl Lattice SDacinα (A ± 0.04)

7.3 Strong 12.17

10.2 Strong 8.69

22.7 Strong 3.92

28.9 Strong 3.08

6. A crystalline Maleate salt form of (5S,8S)-8-[{(1 R)-1-(3,5-Bis-

(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2- one which is characterized by the following x-ray powder diffraction pattern expressed in terms of diffraction angle (in 2 Θ), lattice "d" spacing (in angstroms) and relative peak intensities("RI"):

Diffraction angle (2Θ Rl Lattice Spacing (A ± 0.04) 10.0 Weak 8.84

13.5 Medium 6.55

16.5 Medium 5.36

23.5 Very Strong 3.79

7. A crystalline Mateate salt form of (5S,8S)-8-[{(1 R)-1 -(3,5-Bis-

Diffraction anqle (2Θ Rl Lattice Spacing (A ± 0.04)

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 of claims 1 to 7 and a pharmaceutically acceptable carrier.

9. A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal the crystalline salt of any of claims 1 to 7.

10. A method of treating and/or preventing nausea in a mammal which comprises administering to said mammal the crystalline salt of any of claims 1 to 10.

11. A salt of the compound (5S,8S)-8-[{(1 R)-1 -(3,5-Bis-(trifluoromethyl)phenyl)- ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one (Formula I)

Formula I

prepared by treating an ethanol solution of the compound of Formula I with an acid selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, succinic acid, lactic acid, glycolic acid, 1-hydroxy-2-napthoic acid, malonic acid, (-) L-malic acid, hippuric acid, and 1(S) camsylic acid.