TW200404779A - Processes and polymorphs of diaryl-indolone GALR3 antagonists - Google Patents

Abstract

This invention relates to crystalline forms, as well as an amorphous form of Compound I [1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-1H-indol-2-oe], the processes for their preparation, compositions containing the same and the therapeutic use of such compositions. This invention further relates to a process for preparing Compound I.

Description

200404779 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel and more efficient method for manufacturing a compound, the chemical name of the compound I is phenyl_3 _ [[3_ (trifluoromethyl) Phenyl] imino] -l-fluoren-2-one. The present invention further relates to novel crystal forms of compound j that can be used as a medicament, methods of making and isolating crystal forms of such compounds, pharmaceutical compositions containing such crystal forms, and methods of using these crystal forms to treat human diseases. [Prior art] Compound I (1-phenyl-3-[[3- (trifluoromethyl) phenyl] imino > 1 whistle 丨 Koutuo-2-one) is a kind of compound that can be used to treat diarrhea And / or anxiety antagonist (Blackburn, T. et al., U.S. Serial No. 10 / 066,175, which is incorporated herein by reference in its entirety).

Z isomer E isomer

Compound I in a room temperature solution ' Compound I exists as a mixture of E and Z imine isomers that are rapidly interconverted, as shown in the above scheme. Compound I is available from Bionet Research Ltd., 3 Highfield 200404779

Industrial Estate, Camelford, Cornwall PL32 92Z, UK. Purchased in research volume (mg). However, this vendor does not provide large quantities (kg or mock) of Compound I, nor does it sell compounds I of a grade suitable for human pharmaceutical use. We have previously described and synthesized Compound I (Blackburn T et al., US Serial Number) 10 / 066,175). However, these synthetic methods may not be optimal for large-scale production of Compound I for medical use. Compound I is a derivative of 1-phenylisatin. We have reported that compound I can be prepared via imine formation between 1-phenylyihong and 3- (tridenylmethyl) benzene. There are many ways to prepare phenylphenyl red. The most direct methods include the use of metal catalysts and coupling agents such as tripartite M (D · M · T. Chan, Tetrahedron Lett ·, 1996, 37 9013-9016), aryl compounds (G · M · copp) 〇la, j. Heterocyclic Chem., 1987 '24, 1249-1251) or phenyllithonic acid (D.M.T.Chan, K.L.

Monaco, R. Wang and M. P. Winters, Tetrahedron Lett., 1998, 39, 2933-2936) perylene red N-arylation. These methods use stoichiometric amounts of catalyst, provide poor yields or incomplete reactions, and require intensive processing conditions and / or undesirable chromatography purification techniques to remove starting materials and by-products for isolation Desirable products. Furthermore, these methods lack "atom-economy," and are defined as (molecular weight of desired product / molecules of all products) x 100% (B · M. Trost, Science 1991, 274, 1441) ' It is an important environmental and economic consideration for manufacturing process design. Recently, there have been methods to mention the use of a catalytic amount of copper acetate (π) as a catalyst (ρ · Y. s. Lam? G. Vincent, CG Clark, S. Deudon and PK 200404779

Jadhav, Tetrahedron Lett 2001, 3415-3418). Although these reactions are performed under ambient conditions, these methods lack atomic economy and require equivalent phenylboronic acid coupling agents and stoichiometric amounts of amine oxides. Method using aryl-functional compounds as coupling agents (Α · κι_8,

Huang, and S. L. Buchwald, J. Am. Chem, Soc. 2002, 124, 7428 and references therein) often include long reaction times at high temperatures, resulting in black reaction mixtures that require undesired purification methods. Compound isolated. For cost-effective manufacturing, any of the above methods should be used in a private preparation method because this starting material may be expensive rather than adequately supplied. Alternatively, it can also be gasified via Lewis acid at elevated temperatures (M. Bryant et al., Synth. Commun., 1993, 23, 1617-1627), or at more ambient temperatures, between grasshopper gas and diphenylamine. The intermediate, phenylphosphonium red, is prepared by the reaction in the presence of or called osmium 2. Therefore, the existing 2 methods for synthesizing compound I are the second or third step of starting compounds that are easily available. -Therefore, there is still a need to develop effective methods for the preparation of compound compounds that can be manufactured in a reproducible manner from inexpensive and readily available materials. We also report that the existence of multiple crystalline and non-crystalline solid forms of the novel chemical formula f 'Yiyi, which meets these goals, can be detrimental to its development', because a consistent grade of substance must be reproducibly produced to meet the specified requirements . The aforementioned synthetic methods did not provide information about the existence of the crystalline form of the compound, nor did they provide information about the manufacture and isolation of the different crystalline forms of compound I. Therefore, there is still a need to determine the various crystalline forms of Compound I from the perspective of pharmaceutical development. At this point, we want to report on the compounds we obtained! Three kinds: and-compounds! Discovery of amorphous objects. Among these forms are: J to very stable at temperature and highly suitable for drug development purposes. [Summary of the Invention] The present invention relates to the-seed crystal form of compound 1, which is referred to herein as form j ', which can be attributed to the x-ray powder diffraction (xRpD) pattern listed in | 4, which has a > 10% relative intensity of 20 and relative intensity surface dry, such as in Shhnadzu XRD_6000 χ_ ray diffractometer or equivalent 22 = measured by CuKa radiation. Compound I form! It can be further characterized as having an XRPD pattern containing one or more 2Θ values as shown in Table 4, such as those measured using CuKa radiation on a Shimadzu xrd_6000 X-ray diffractometer or equivalent. Additionally or alternatively, compounds! Form 1 can be given by: XRpD spectrum measured using CuK0 radiation on a Shimadzu XRD 6000 ray diffractometer or equivalent, similar or substantially similar to that shown in Figure la. In addition, Form J of Compound I can also be obtained from a differential scanning calorimetry (SC) curve similar to or substantially similar to that shown in Figure 2 or Figure 3 using a TA Instruments differential scanning calorimeter 2920 or equivalent. Qualitative. Furthermore, Form j of Compound I can also be characterized by its Fourier transform infrared spectrum containing several peaks listed in Table 14 measured on Magna_IR 860 @ (Thermo Nicolet) or equivalent. Finally, the form of Compound I can also be obtained through the Raman Peak (Raman Peak) containing multiple peaks measured on an FT-Raman 960 (Thermo Nicolet) spectrometer or equivalent listed in Table 5 Atlases are qualitative. The present invention further relates to one or more methods for preparing Compound I form and / or preparing sterically pure Compound I Form I. The second aspect of the present invention relates to the second crystalline form of Compound I, referred to herein as Form n, which can be characterized by the XRPD pattern shown in Table 5, which is expressed in terms of 2 < 10% relative intensity < 9 and relative intensity indications, such as those measured using CuK wheel shots on a Shimadzu XRD-6000 X-ray diffractometer or equivalent. The form π of compound I can be further characterized as having an xrpd chart containing one or several 20 values measured using CuK α on a Shimadzu XRD-6000 X-ray diffractometer or equivalent shown in Table 5. . Additionally or alternatively, Form I of Compound I can be characterized via an XRpD pattern measured using CuK α radiation on a Shimadzu XRD-6000 X-ray diffractometer or equivalent on a Shimadzu XRD-6000 X-ray diffractometer or equivalent shown in Figure lb. . ^ In addition, the Form II of Compound I can also be obtained via a Differential Scanning Calorimetry (DSC) curve measured using a TA Instruments Differential Scanning Calorimeter 2920 or equivalent as shown in FIG. 4 Qualitative. Furthermore, Form Π of Compound I can also be used to contain Fourier Fourier peaks measured on Magna-IR 860⑧ (Thermo Nicolet) or equivalent as shown in Table I #. Infrared spectra are converted for characterization. Finally, Form I of Compound I can also be characterized by its Raman peak spectrum as shown in Table 5 and measured on a FT-Raman 960 (Thermo Nicolet) spectrometer or equivalent. The invention further relates to one or more methods for preparing compound j form π and / or preparing quasi-pure compound I form jj. The third aspect of the present invention relates to the third crystalline form of compound I, which is referred to herein as Form]] I, which can be characterized by an XRPD pattern shown in Table 6, which is based on having a relative intensity of > 10% 20 and relative intensity representation, as used on Shimadzu XRD_6000 χ_ray diffractometer or equivalent

CuK ex round shot surveyor. The form shown in Shimadzu Compound I shown in Figure 1 can be characterized using an xRPD pattern containing one or more 20 values measured using q on a table XRD-6000 X-ray diffractometer or equivalent. In addition to or instead of using CuK alpha radiation measurements on a Shilnadzu XR] radiometer or equivalent listed in the Figure 1c above, the form of the compound may be similar or substantially qualitative. XKD_6000 X-ray diffraction spectrum of XRPD In addition, the form m of compound I can also be transformed by similar or substantially

Qualitatively determined by a Lattice-transformed infrared spectrum of one or several peaks measured on Magna-IR 860® (Thermo Nicolet) or "containing the equivalent of 12 200404779 shown in Table 14. The final form of Compound I It can be characterized by using a Raman peak spectrum containing it as shown in Table 15 measured on an FT-Raman 960 (Thermo Nicolet) spectrometer or equivalent. The present invention further relates to one or more preparations of Compound I forms And / or a method for preparing a substantially pure form of melon of compound I. The fourth aspect of the present invention relates to an amorphous form of a compound, referred to herein as a non-monomorphic form, which may be similar or substantially similar As shown in the drawing, the XRPD spectrum measured using CuK α radiation on a Shimadzu XRD-6000 X-ray diffractometer or equivalent is used for qualitative analysis. In addition or instead, the amorphous form of the compound is also It can be characterized using a differential scanning calorimetry (DSC) curve similar to or only qualitatively similar to that shown in FIG. 6 and measured on a TA instruments differential scanning calorimeter 2920 or equivalent. Amorphous can also be used A differential scanning calorimetry curve similar to or substantially similar to that shown in Attachment 15 to make this differential scanning calorimeter 2920 or equivalent measured by thermal cycling to φ is qualitative. —Step About—or several methods for preparing the amorphous form of Compound I and / or the pure form of the amorphous form of Compound I. A specific example of the present invention is a compound I form I, form π form 111 Or amorphous composition. Another specific embodiment of the present invention is: a composition, which has a substantial percentage of the compound is in the form of the form Π form 冚 or amorphous. These percentages can be at least 99. 13 200404779, 98%, 95%, 90%, 85%, 80%, 75%, or 70%. Another embodiment of the present invention is a compound I form I, form II, form dish or amorphous A pharmaceutical composition of a type. Another embodiment of the present invention is a pharmaceutical composition in which a substantial percentage of the compound Z is in form I, form π, form m or amorphous. The percentage may be at least 99.9%. , 98%, 95%, 90%, 85%, 80%, 75%, or 70% These pharmaceutical compositions can be used to treat diseases in mammals suffering from the disease. A preferred specific example is such pharmaceutical compositions that can be used to treat depression, anxiety or other CNS disorders in humans. Benmemin is further related A method of treating a human disease, wherein the method comprises administering to a human individual suffering from these diseases a therapeutically effective amount of Compound I Form I, Form π, Form m, or an amorphous substance. Another specific example of the above method The disease is depression, anxiety, or other CNS disorders. In another example, the above method may further include: mixing a compound of formula 1 $ form π, a form or an amorphous substance with a pharmaceutically acceptable carrier. Animal husbandry, the present invention provides a method for the preparation of compounds, including: 本 this benzene: reacted with grass chlorine in an appropriate solvent, and then add 3 · (three defeated in a specific example, the reaction is in a pot In a specific example, oxalochloride is replaced with an equivalent agent selected from the group including, but not limited to, diethyl oxalate 14 200404779 or dioxalate oxalate. In a specific embodiment, the reaction system Operate in a solvent selected from the group consisting of, but not limited to, toluene, m-xylene, o-xylene, p-xylene, or appropriate solvents. In specific and specific examples, the reaction is at 0 ° C. -Operates in a temperature range of 200 ° C. In one embodiment, the reaction operates in a temperature range of 30 ° C-150 ° C. In another embodiment, the reaction operates at 50 ° C- Operates in a temperature range of 135 ° C. In another embodiment, the reaction is heated for a period of 1 to 48 hours. In a specific embodiment, the above method includes the following steps: diphenyl ether and grass Combining with chlorine to produce 丨 _phenyl isatin, then 3_ (trifluoromethyl) benzylamine is added. A specific example, the method further includes the step of crystallization and isolating the compound of j. [Embodiment

We performed polymorphic screening in an attempt to produce as many compounds as possible. I TT ^ α κ V and study their properties, the goal is to determine whether there is a chemical compound θ 丄 ^ ^ α Μ or Amorphous forms exist, and if they exist, which formula is the most suitable for pharmaceutical development. The techniques used for polymorphic screening include 200404779 fast-evaporation, slow-evaporation, slow-cooling, rotary evaporation, dazzling, low-temperature sinking, and vapor diffusion experiments. Then, the compound was identified with two different crystalline powders: ;; D ^ is called Form I,]] [and claws di U and m! Amorphous. The XRPD pattern of these polymorphs is shown in FIG. 1. Table 1 lists the polycrystalline compounds of the compounds obtained from the techniques of rapid evaporation, slow evaporation, slow cooling, and melting / quenching. Methods are based on weighed samples of compound I (usually 2.-3. Mg j Use _ microliters of the test solvent to treat the ultrasonic treatment mixture. When the solids are dissolved, filter the solution when the solid solution is dissolved, and add A to the solution. In an open vial under ambient conditions. For slow =, place the solution in a vial under ambient conditions that is approximately covered with a lid or with a ten-hole Shao Island. For rotary evaporation, use rotary Use an evaporator to evaporate the solvent. For slow cooling, ^ (45 ° C λλα X hand, place the sample port> valley at a temperature increase or 60C) in the test solvent. Pass the resulting solution quickly to one to maintain the same addition. The view of the tube on the board is within ^ of the heart, and then the heat source is turned off and the :: plate and the official bottle are cooled to room temperature. Then the bottle is left to stand at ambient temperature overnight. There is no measurement on the right For solids, place the vial in a refrigerator or freezer overnight. For quick After cooling, the solution is placed in Γ after the temperature of the human body and the pupa of the human is reached. The dazzling / quenching technique includes cooling the compound of compound 1 to the chamber / J0ZL ° Table 2 lists the crystallization from low temperature precipitation The obtained compound U. The compound 1 solution was added to a vial containing cold insoluble solution (pre-fired sintered in dry ice / propylene solution 16 200404779 or water cooled in an ice water bath). Table 3 lists the polymorphs of the compounds obtained from the vapor diffusion experiments. A saturated solution of compound VII was placed in a vial, which was placed in a larger vial containing antisolvent. The larger vial was then sealed and kept below ambient temperature ° These two sweeteners can be characterized by their # X · ray powder diffraction patterns and / or their differential scanning calorimetry (DSC) curves. Many of the samples produced in the polymorphic sieve showed better orientation. The preferred orientation is crystal, often plate-like or needle-like, and tends to arrange itself in a certain order. The better orientation can affect the peak intensity but not the position of the peak in the J XRPD spectrum. Reductions in better orientation may be required to obtain a representative XRPD pattern. L-ray powder diffraction (XRPD) analysis was performed using a Shimadzu XRD-6000 χ-ray powder diffractometer using CuKa radiation. This instrument is equipped with a fine focus X-ray tube. The voltage and amperage of the tube are set to kV and 40 mA, respectively. Set the divergence slit and the scattering slit to 1. And set the receiving slit to 0.15 mm. The diffracted radiation is detected by a NaI scintillation detector. Used with 3. / Min (0.4 sec / 〇 〇２〇 step) from 2.5 to 40. 20 0-20 continuous scanning. An silicon standard was analyzed to verify instrument calibration. Data were collected and analyzed using XRD-6000 V. 4 j. Place the sample in a silicon sample holder or an aluminum holder with a silicon socket to prepare it for analysis. Also used are equipped with a range of 2 6 »ranging from 120. The X-ray powder diffraction (XRPD) analysis was performed with an Ind xrg-300 diffractometer of a cps (curve position sensitive) detector. The real-time data was collected using Cu_Ka light 17 200404779 shot from about 4.20 to 0.03 〇2 0 decompression. "The resolution began to be collected. The voltage and current of the tube were set to 40 kV and 30 mA, respectively. Face suppression △ Koukougu set the early color state slit to 5 mm by 80 microns. The spectrum is from 2.5 to 40. 2 / g% -z, one U is not visible. The samples are stacked in the glass capillary of the wall to prepare for analysis The knife is used for corpse / 1. Both the female and the capillary are mounted on the goniometer head, which is driven by a motor to rotate the capillary during data acquisition. The sample is analyzed for 5 minutes. The instrument is calibrated with a silicon reference standard. .

Tables 4 to 6 list the values and relative intensities of the compounds with Forms I, Π, and D.C. having a relative intensity of> 10%. Poor dry scanning calorimetry (political) was implemented using TAA scans 2920. Place the sample in an aluminum Dsc pan and record its weight accurately. Cover the dish with a lid and keep it from wrinkling. Each sample was equilibrated at 25C and heated to a final temperature of 270C or 350 ° C at a rate of 10 or απ / min under a stream of nitrogen. The samples are also given at j or 5χ: / min plus Guda 15 (TC.… ^

Thermogravimetric (TG) analysis was performed using a TA Instruments 2505 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into a TG oven. The sample was first equilibrated at 2 ° C and heated to a final temperature of 35 ° C at a rate of 10 ° C / min under nitrogen. Nickel and AlumelTM were used as calibration standards. Figures 2, 4, 5 and 6 respectively TG analysis and DSC graphs of Form I, Thallium, Twisted, and Amorphous Forms of Compound I are shown. Figure 3 shows DSC patterns of Form j of Compound J under different temperature gradients. The forms can also be infrared (IR) and / Or Raman spectroscopy for qualitative analysis. 18 200404779 Infrared light 5 beasts were collected on a Magnz-IR 860 @ 富利 叶 Converted Infrared (jpT_iR) spectrometer (Thermo Nicolet). Raman spectroscopy was performed using FT_

Raman 960 spectrometer (Thermo Nicolet) collection. Table 14 provides each polymorph (forms i, D) of Compound I.

A list of spectral peaks. Table 15 lists the unique Raman spectral peaks of each polymorph (formal, Π, Π,) of compound j. Form I

Form I is crystallized from slow cooling from ethyl acetate solution or toluene solution, slow evaporation from methanol solution, rapid evaporation from diethyl ether solution, crystallization from ether / hexane antisolvent, and vapor diffusion experiments using isopropanol and water . Based on qualitative data, Form J is a crystalline non-hygroscopic substance that melts at about 14 rc (Dsc at i or 5 minutes rate). The thermogravimetric graph (Figure 2) shows the lowest weight loss at 14 ° C, and it can be inferred that the form was not solvated.

As described above, as in the case of CuKa radiation measurers on a Shimadzu XRD_6000 χ-ray diffractometer or equivalent, the combined form I shows an XRPD pattern as shown in Table 4. It should be noted that Form I of Compound I can be characterized as having-or several of the 20 values listed in Table 4. As in Shimadzu XRD_600 χ_ray diffractometer or equivalent

Using measured radiographs, the compound form can be further used or substantially similar to that listed in Figure la as in SchimadzuXF

The XR 19 200404779 spectrum of the 6_ X 'line diffractometer was measured using thorium radiation for characterization. * Alternatively, if measured using a TA lnstruments differential scanning calorimeter 2920 or its equivalent, the compound can also be characterized using the differential scanning calorimetry (DSC) curve shown in Figure 2. Depending on the test conditions, the DSC curve of 'Compound I Form I may be similar or substantially similar to that shown in Figure 2. Figure 3 shows four dsc patterns of Form j measured at different heating rates. For compound Ϊ form, differences in DSC patterns due to temperature gradients were observed. The obtained pattern was recorded at a heating rate of i / min. _ Call for two endothermic peaks at 140.66C and 143.91C and an exothermic peak occurring at 141 · 5 1 C between these two temperatures. This result can be explained as follows: under the slowly heated form I (rc / min). This form melts at about 14rc, and then the melt crystallizes to form I [(causing exotherm), which in turn melts at about 144 elsewhere. This result shows that form π is more stable than form at high temperatures. Alternatively, as measured on a Magna-IR 860® Fourier Transform Infrared (FT_IR) Spectrometer (Thermo Nicolet) or equivalent, Compound Form I displays unique peaks as listed in Table 14. It should be noted that the form of Compound I can be characterized as having one or more of the peaks listed in Table 14 (Form 1). Or 'as in the FT-Raman 960 spectrometer (Thermo Nicolet) or equivalent As measured above, Form I of Compound I exhibits unique peaks as listed in Table 15. It should be noted that Form J of Compound J can be characterized as having one or several as in 15 (Form I ). Spectral peaks listed in). Preparation of single crystal diffraction for Form I for single crystal hologram diffraction. 20 200404779 Compound I colorless plate with approximate dimensions of 0.35 X 0.30 X 0.05 mm was placed in a random orientation. On a glass fiber. Single crystals were prepared by vapor diffusion experiments from isopropanol and water. Initial inspection and data collection were carried out on a Nonius Kappa CCD diffractometer using Mo ruler radiation (again = 0.71073A). SHELX97 implementation on AlphaServer 2100 [Sheldrick, GM SHELX97, A Program for Crystal Structure Refinement, University of Gottingen, Germany, 1997]. The crystal map is using the program ORTEP [Johnson, CK ORTEPII, Report ORNL-513 8, Oak Ridge National Laboratory, TN, USA 1976] and CAMERON [Watkin, D.J., Prout, C.K., Pearce, LJ CAMERON, Chemical Crystallography Laboratory, University of Oxford, Oxford 1996]. Data collection The unit cell constant and orientation matrix used are refined from least squares and obtained using a setting angle of 20535 reflections in the range of 2 ° < 0 < 25 °. Pure inlay from DENZO / SCALEPACK Degree (Otwinowski, Z ·; Minor, W. Methods Enzymol. 1996, 276, 307) is 0.83 °, indicating a moderate crystal quality. The space group was measured with the program ABSEN [McArdle, P. C ·, J. Appl Cryst. 1996, 29, 3 06]. From the systemic presence of A0 // = and (U0 moxibustion ==, and subsequent purification from the least squares, the space group was determined to be corpse 2 " c (No. 14). Data was collected at a temperature of 150 ± 1 K to 51.5. The maximum 20 value of the unit cell and the calculated volume of the monoclinic system are: a = 7.2704 21 200404779 (2) A, b = 16.9251 m into ^ (5) A, c = 27.8017 (1 1) A , / 3 = 92.6340 (1〇) 〇, V = 3417 4 gates, X3 i7 · 4 (3) A3. Based on the formulas of z = 8 and 366.35, the density is calculated to be 142 years old / joint \\. Exchange / cubic centimeter. The space group was determined as Household 2 " c (No. 14). The TEP pattern of Compound I Form I is shown in FIG. The single structure data confirms that the compound I isomer is present in this form of crystal. The error shown in Figure 7 is that the stalk early contains two symmetrical independent molecules

. These two molecules differ in the torsion angle 0 "2 between the cCF3 aryl-N imine bond and the c aryl-N imine bond around the compound I, as shown in Table η. Figure Figures 8, 9 and 10 show the stacking diagrams viewed along the crystal axes of a and Moc respectively. For the sake of clarity, 'these atoms are not shown in these figures. The molecular pairs are roughly 々tc · axis is π_stacked 'As shown in head 9 (viewed along the ^ axis). The trifluoro group on one molecule shows rotational disorder, which can be clearly observed in the stacking diagrams. Form Π As described above, such as Using a CuKa radiation measurer on a Shimadzu XRD-6000 X-ray diffractometer or equivalent, the Form II of Compound 1 shows the xrpd pattern as shown in Table 5. It should be noted that the Form II of Compound I can be Characterized to have one or more values of 2 (9) listed in Table 5. Compound I form jj can be measured using a CuK α wheel shot on a Shimadzu XRD-6000 X-ray diffractometer or equivalent. Further similar or substantially similar to those listed in the attached Figure lb as shown in Schimadzu 22 200404779 XRD-6000 X-ray Diffractometer Qualitative measurement using CuKa radiation, XRPD pattern. Alternatively, as measured using TA Instruments Differential Scanning Calorimeter 2920 or equivalent, Form I of Compound I can also be used as listed in Figure 4. The differential scanning calorimetry (DSC) curve is qualitative. Depending on the test conditions, the DSC curve of Compound I Form Π may be similar or substantially similar to those listed in Figure 4. Table 1-3 further reveals Form Π It is the main product obtained from most of the crystallization attempts. Therefore, the form n is the most likely form obtained from any crystallization procedure in which no special measures are taken to control the crystallization. DSC shows that the A single endothermic peak at about 143π (1 or 20.0 / min). From the TG and DSC patterns (Figure 4), it can be seen that the form π melts at about 143.0 ° at a temperature gradient as early as i or 20 ° C / min. It is a crystalline substance that is not solvated. Or, as measured on a Magna-IR 860 @ 富利 叶 变 FTIR (ft_ir) Spectrometer (Thermo Nicolet) or equivalent, the compound form Π appears as所列 14 Spectral peaks. It should be noted that Form 1 of Compound 1 can be characterized as having-or several of the peaks listed in 纟 14 (Form II).… Or, as in the FT-Raman 960 spectrometer (Thermo Nicolet) or equivalent, the form I of compound I shows a unique peak as shown in Table 15: Phantom. It should be noted that the form η of a compound can be chemically stable, with-or several Spectral peaks as listed in Table H). The single crystal of form II is wound for single crystal χ_ray diffraction. Compound I orange plate having 23 200404779 0.38X 0.33X 0.13 mm approximate size was placed on glass fibers in a random orientation. Single crystals were prepared via slow cooling from an ethanol solution. Initial inspection and data collection were performed on a Nonius Kappa CCD diffractometer using Mo radiation (λ = 0.71073 A). The purification was performed on AlphaServer 2100 using SHELX97 [Sheldrick, G.M. SHELX97, A Program for Crystal Structure Refinement, University of Gottingen, Germany, 1 997]. The crystal map uses the program ORTEP [Johnson, CK ORTEPII, Report ORNL-5138, Oak Ridge National Laboratory, TN, USA 1976] and CAMERON [Watkin, D. J., Prout, C. K., Pearce, LJ CAMERON, Chemical Crystallography Laboratory, University of Oxford, Oxford 1996]. The cell constants and orientation matrix used for data collection were refined from least squares using 2. < 0 < Obtained from a setting angle of 13366 reflection in a range of 27 °. The purity of the back surface (Otwinowski, Zn; Minor, W. Method Enzymol, 1996, 276, 307) from DENZO / SCALEPACK is 0.32 °, indicating good crystal quality. Space groups were determined using the program ABSEN [McArdle, P.C., J. Appl. Cryst. 1996, 29, 306]. From the systematic existence of 0 / / = and 0A0 A: =, and from the subsequent least squares purification, it was determined that the space group was corpse 2 / c (No. 14). The data were collected at a temperature of 150 ± 1 K to a maximum value of 20 at 55 °. The monoclinic crystal unit cell parameters and calculated volume are: a = 14.7527 (2) A, b = 16-9524 (6) A, c = 7.0196 (5), and 100.8840. (19), V = 1724.0 (2) A3. For Z = 4 and 366.35 in Equation 24 200404779, the calculated density is i and mark / cubic cm. The space group was determined to be dead (No. 14). In this case, 、,: j: 立 4. Consider that the structure has only one molecule in the asymmetric unit ', which simplifies the structure relative to those seen in the crystal structure of Form I. The ORTEP mesh of the compound I molecule in the Form II crystal is shown in FIG. Its single crystal structure data confirms that the E isomer system of Compound I exists in this form of crystal φ. The asymmetric unit shown in Figure 11 contains one compound I molecule. Alas, Figures 12, 13, and 14 show the stacking diagrams viewed along the a, b, and C crystal axes, respectively. For clarity, hydrogen atoms are not shown in these figures. The molecular pairs are π · stacked along the C-axis, as shown in Fig. 13 (along the table of 圭 A and 目, see __). The disorder in trifluoromethyl is also clearly observed in the plots. Its molecular geometry is similar to one of the molecules contained in the asymmetric unit of Form I; see table ". Form m

The diethyl ether solution (as a mixture with the form π) is slowly cooled 'and crystallized from the anti-solvent crystallization using dichloromethane and hexane or ethyl acetate and hexane. As described above, if CuK α is radiated to a measurer on a Shimadzu XRD-6000 X-ray diffractometer or equivalent, the shape m of the compound z shows an XRPD pattern as shown in Table 6. It should be noted that the melon form of Compound 1 can be characterized as having-or several values listed in Table 6 as i 2 (9. 25 200404779 as on a Shimadzu XRD-6000 X-ray diffractometer or equivalent, As measured using CuK alpha radiance, the compound I form dish can be further measured with CuK alpha radiation similar to or substantially similar to that listed in the attached Figure lc as shown on a Schimadzu XRD-6000 X-ray diffractometer. The XRPD pattern of the subject is qualitative. Alternatively, as measured using a TA Instruments differential scanning calorimeter 2920 or equivalent, the form of compound I may also be measured using the differential scanning calorimetry shown in FIG. 5 ( The DSC) curve is qualitative. Depending on the test conditions, the dsc curve for compound I form m may be similar or substantially similar to that shown in Figure 5. The TG data shows a minimum weight loss of 14 {rc, which can be speculated The form of melon shellfish is combined with an agent. The DSC curve (heating rate 20.0 / c min) shows an endothermic peak at about 132t at a temperature gradient of 20, followed by an exothermic peak at about 和 and Endothermic peak at about ⑽. These events speculate that the substance dissolved Immediately after crystallization into another phase that melts at about 145.0 °, it may be in the form Π depending on the melting point. When slowing down the Dsc heating rate (rc / min), only a sharp endothermic peak was observed at about 144 c; possible Is the slow heating rate 5 |, the solid-state conversion of form m to form ϋ. This data speculates that form m melts and then recrystallizes into another form, as seen by formal workers at slow heating rates. This data also speculates The produced melon is a relatively unstable form at higher temperatures. According to qualitative data, the form melon is a crystalline non-thirsty substance, which is transformed at about 132 t under a temperature gradient of min / min and then recrystallized into It is likely to be another substance of form π. Or, as measured on a Magna-IR 860® Fourier Transformed Infrared (FT_IR) 26 200404779 spectrometer (Thermo Nicolet) or equivalent, the compound form III is shown The unique peaks are listed in Table 14. It should be noted that Form III of Compound I can be characterized as having one or several of the peaks listed in Table 4 (Form II). Alternatively, as in FT- Raman 960 Spectrometer let) or equivalent, the form m of compound j shows a unique peak as listed in Table i 5. It should be noted that the form m of compound j can be characterized as having one or several Spectral peaks as listed in Table 15 (Form m). Amorphous Amorphous is generated by rapid cooling of a material melt on a cold table. As in Shimadzu XRD-6000 x-ray As measured on a diffractometer or equivalent using CuK α radiation, the amorphous form of compound j can be similar to or substantially similar to that listed in the attached figure ld as shown in the SMmadzu XRD-6000 X-ray diffractometer The XRPD pattern of CuK α radiation was used to characterize it. Alternatively, if measured using a TA Instruments differential scanning calorimeter 2920 or equivalent, the amorphous form of compound j can also be characterized using a differential scanning calorimetry (DSC) curve as shown in Figure 6 . Depending on the test conditions, the DSC curve of Compound I amorphous may be similar or substantially similar to that shown in Figure 6. Additionally or alternatively, the amorphous form of the compound can also be similar or substantially similar to that shown in Figure 15 as measured by thermal cycling using a TA Instruments differential scanning calorimeter 2920 or equivalent27 200404779 The differential scanning calorimetry (DSC) curve of the measurer is about degrees at a temperature gradient of 20 ° C / min. The line is qualitative. These curves show the break-up transition temperature of 30 C amorphous. In addition, the TG curve shows as high as 140. . The minimum weight at can be inferred that the amorphous substance is not solvated. The substance is at M and P =. (: Two places show two passions: they are likely to be crystallization, then: there is a refining endothermic peak in the sintering can be inferred that under heating, the amorphous: crystallized into form Π. Tables 9 and 10 The slurry interactive transformation experiment described in the above reveals that either form η or form m can be converted to form j within hours to days by stirring the slurry form in an organic solvent. However, the opposite is not true. That is, Form I will not be converted to Form π or Form under these same conditions, but will remain unchanged. These results are shown at 25. The formal ratio of Form Π or I [Either It is more stable. However, the research mentioned above indicates that at。 140, form n is more stable than form J. All these data together can speculate that the form j and the form π system are related to the enantiomorphic phenomenon (Buerger, A .; Ramberger, R. -〇n the polymorphism of P armaceuticals and other molecular crystals. I.55 Mikrochim. Acta [Wein], 1979, n, 259_27l), where the form i is more stable at low M Form and Form Π are at higher temperatures (> 丨 〇〇〇) The car is stable. The thermal stress experiments described in Table 7 indicate that the forms Jπ and m are quite stable to thermal stress. All three polymorphs are also non-hygroscopic, as indicated by the data in Table 8. The single crystals of forms I and π were prepared for single crystal X-ray diffraction analysis 28 200404779 to determine what kind of imine stereoisomers are present in each of the two crystal forms. Forms I and Π Both crystals contain the compound J # E isomer t. Therefore, the 'forms ... are polymorphs of each other because they represent two different crystal forms of the same stereoisomer. The present invention presents The data further indicates that the form τ may be desirable for pharmaceutical development: one of the forms, because of its greater stability at ambient temperatures, its lack of solvation or hygroscopicity, and its crystallinity. "Compounds Form 1, Form 1, Lamp, Form Anal or Amorphous Pharmaceutical Composition can be blended with a compound of the present invention and a pharmaceutically acceptable carrier by combining ,, Λ, magutan " "therapeutic effective!" The solid carrier may include one or more substances, Substances are also derived from carriers (for example, nutritional internal agents, prefectures and nutritional carriers), flavoring agents, and lubricants: two agents, slip agents, shrinkage aids, binders, or tablets = Formula = The second carrier is a finely divided solid, which is blended with the finely divided compound "form m or amorphous. In tablets, the necessary compression properties of a M = 'form m or amorphous It is mixed with a carrier with shellfish in an appropriate ratio, = :::: r lozenges— ^ Includes, for example: Phosphorus ~ 二 = 晶 ::. Appropriate carrier packs: powder, mingmu, cellulose, low ionizers, = dextrin, liquid carriers are used to prepare suspensions for two or two: change resin. Calendar composition. These suspensions can be packaged and dispensed with sugar, tinctures and tinctures; ulcers, tinctures and pressurized compositions ~, before or at the time of administration from compound I to form 29 200404779 formula I , Form H, Form H [or Amorphous Preparation. Compound I, Form I, Form II, Form Melon, or Amorphous Form can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as an aqueous solution, an organic solvent, a pharmaceutically acceptable oil or fat, or any such mixture In. Liquid carriers may contain other suitable medicinal additives, such as ... emulsifiers, buffers, preservatives, sweeteners: flavouring agents, suspending agents, boosters, colorants, viscosity modifiers, tinctures or osmotic agents Savings. Suitable examples of liquid formulations for sigma and parenteral administration include alcohols (including mono- and polyhydric alcohols such as dibasic alcohols) and their derivatives, and oils ( Such as the leftover oil and peanut oil). For parenteral administration, the carrier may also be an oily brewer's such as ethyl oleate or isopropyl myristate. Sterile liquid carriers can be used in sterile liquid form compositions for parenteral administration. The liquid carrier used in the pressurized composition may be an ablative hydrocarbon or other pharmaceutically acceptable carrier. In addition, push…, 囷 solution or suspension liquid • ——V ， · ～ muscle concave 7 ^ is called from milk 1 through intrathecal, epidural, intraperitoneal or subcutaneous injection for use. None 丨

Liquids can also be administered intravenously. The compound form 1, form m or amorphous can be prepared as a sterile solid composition, which can be dissolved or suspended using a suitable sterile injection medium f. Carriers are expected to include:: inert binders, suspending agents, lubricants, flavoring agents, sweeteners': " 1 wood and coatings. The compound can also be prepared from oils containing other solutes; :: di-salts, gum arabic, gelatin, sorbitan monooleate, and acid 80 (sorbitol and its anhydride copolymerized with ethylene oxide) Analogous solutions or suspensions are administered orally. 30 200404779 Compound I is administered in the form of rhenium, n, m or amorphous intestines. Compositions suitable for oral administration can be administered orally or parenterally, such as pills , Capsules, granules, lozenges, and powders, in: solid forms, such as solutions, sugar polysaccharides, and suspensions. Can be used in non-menu: :: formula: for example, including sterile solutions, emulsions and suspensions. It should be noted that in this application, "The treatment substance can be effective in administering compound compounds: effective amount ', which is a combination of the other two pairs of diseases.

Any amount that causes amelioration, alleviation or regression of the disease. From ~ 4, but the patient is a vertebrate, mammal or human. ; The optimal dose to be given in case 3 can be familiarized with the technique, which varies with the particular compound used, the solid form, the strength of the preparation, the formula: and the progress of the disease state. Depending on the particular individual being treated, other factors may result in the need to adjust the dosage, including the patient's age, weight, gender, diet, and timing of administration.

In the specific example, the amount of the compound is about 001 mg to about 0.001 mg. The amount of the additional-specific compound is from about 001 mg to about 500 mg. In yet another specific example, the amount of the compound is from about 0.1 mg to about 250 mg. In another specific example, the amount of the compound is from about 0.1 mg to about 60 mg. In yet another embodiment, the amount of the compound is from about 1 mg to about 20 mg. Preparation of Compound I The present invention further provides a method for preparing 1 _phenyl_ 3 _ [[3_ (trifluoromethyl) phenyl] imino] -1 吲 -indetadonone (compound j) as described herein. Fang 31 yields the desired compound in a yield and a preferred polymorph (method. This method can be used in a single steel procedure to form I). The method of the present invention can be used in the following flow

1) CICOCOCI

νη2

Compound I is prepared in a ginger island from the reaction of a benzylamine, chloramphenicol, and 3- (trifluoromethyl) aniline in a suitable solvent such as methyl I φ M _ carbendine to make. The diphenylamine white toluene solution was slowly added to the thoronous solution of Titianbiao, a premature milk, while the reaction temperature was kept below 3G ° C. Then the mixture is heated to a small domain of the 6th generation or the reaction temperature can be kept dry during the addition of monoaniline

50 to 60 ° C. The resulting hypothetical formation of N, N-diphenyloxalamine (chloro) ((diphenylamino) fluorenylacetamidine) can then be used in the presence of Lewis acid or at high temperatures (ιOOC-130C). Forms ι_phenyl scattered red. After the cyclization reaction was completed, a toluene solution containing 3- (difluoromethyl) aniline was added. The water system generated during the reaction was removed through the Cooper / Freund Steaming Hall and collected in a Dean-Stark apparatus. To assist the crystallization and isolation of the product (compound j), a suitable solvent such as heptane can be added to the thermal reaction vessel. Under cooling, the desired compound crystallizes out of the reaction vessel to provide Compound I with high purity and high yield. The polymorph of Form I of Compound I can be obtained with high purity if the reaction slurry is stirred for an appropriate amount of time after cooling, and then filtered and collected by 32 200404779. i In particular, the present invention facilitates the formation of individual forms of compound j, form n, form " and amorphous form or the formation of each of these forms with substantial purity. '_Form I can be obtained in a direct way as follows: Compound j in any solid form', especially Form II or HI, is stirred in a slurry in which the compound can partially dissolve in a solvent for several hours, until the substance is completely transformed into Form I so far. The formation of form j can be analyzed by Dsc or preferably analytically. In a specific example of the present invention, a slurry of a solid compound in an organic solvent is generated by cooling a thermally saturated solution of the compound in an organic solvent to form crystals, and then the resulting slurry is stirred for several hours or days. Until the solid matter is substantially or completely converted into the form Σ. In a preferred embodiment, the thermally saturated solution of Compound A is generated on the spot in the one-pot synthesis procedure described above. Form Z can also be prepared by agitating Compound I Form II in a saturated methanol solution or a suitable solvent for several hours. The invention also includes a method of reproducibly and controllably producing a substantially pure Form Π, which comprises heating a mixture of Compound J in an organic solvent to or near the boiling point of the solvent until the compound is completely dissolved . The mixture is then allowed to cool until the crystals are just beginning to form, then quickly cooled to room temperature and filtered immediately before the parent can be converted to Form I. Compound I form π can also be prepared by crystallizing the solution of compound J slowly, rapidly, rotary or slowly. 33 200404779 uses a variety of solvents, including but not limited to acetone, dichloride. Methane, ethanol, methanol, tetrahydrofuran or toluene. Form II can be prepared by freeze-drying a solution of Compound I in didibutanol, or by using a solution system such as dioxane / hexane, ethyl acetate / hexane, or acetonitrile. Made by crystallization of low temperature antisolvent. The following examples are provided to illustrate the present invention, but they are not intended to limit the invention to the details of the examples. Example 1-Contains toluene (242 ml) and chlorchloride (172 8 g, 136 moles) Ear) stirring solution towel, under a stream of nitrogen, dropwise add a solution of human diphenylamine hydrazone 2 μg 'U Mol) in toluene (351 ml). In this addition of rhenium, the reaction was aided in an ice bath to finely react The temperature was kept below 纟 1 (rc. After the addition was completed, the reaction mixture was heated at 6 (rc) for one hour, during which time the HC1 gas evolution ceased and a transparent light brown solution was obtained. Then grave distillation (~ ⑺ with Take; pot temperature 72. The reaction solution to remove excess straw ^. After collecting about 300 milliliters of German extract 1, the dark reddish brown solution was heated at 12 generations for about 19 hours. The reaction solution was cooled to 95t A butane-Stark device was assembled on the flask. Then, a solution of 3- (trifluoromethyl) aniline (263 g, 163 mol) in toluene⑽ml) was added dropwise during about an hour. At the same time, the reaction temperature was maintained at 95-10 (rc. After the addition was completed, Rinse the dropping funnel with toluene (83 mL) and add the wash solution to the reaction solution. Heat the reaction until the collected water approaches the theoretical amount (22.6 mL). Cool the reaction mixture to 9 (rc 34 200404779 And distilled under vacuum (9l-95 ° C, ~ 380mmHg) about 440 milliliters of solvent. Then 丨 again add heptane (650 milliliters), while maintaining the steel temperature at 90-95 C, then make > The cereal was cooled to room temperature throughout the whole night. Heptane (400 ml) was added to the obtained thick pasty orange solid, the mixture was stirred vigorously and the solid was collected by filtration. The solid was placed in a vacuum oven Dry at 40 ° C (401.1 g, 87% yield). Compound I can be recrystallized by binding 3 ml of toluene to each gram of compound j. The mixture is heated M 60 nc until the bulk solids are dissolved. While The solution was filtered hot and allowed to cool to room temperature and stirred overnight. The orange solid was collected via vacuum filtration and dried in a vacuum oven at 80 ° C (80% recovery yield). DSC # XRPD analysis showed the compound was pure Form I. Example 2 A sample of 112 mg of the compound in the form of compound was suspended in a milliliter of a saturated methanol solution of compound I and stirred for 4 hours. The resulting solid was filtered and air-dried to obtain Form I of compound I. Example 3 102.5 mg of compound The sample I was dissolved in four liters of hot-spitting soil. The solution was passed through a 0.2-micron nylon transition device to Furan '. The vial was opened to quickly evaporate the solvent. The resulting solid was straightened into the bottle and air. Dry to give the form π of compound I. 一 35 200404779 Example 4 A 33.4 mg sample of compound I was dissolved in 0.1 ml of dichloromethane, and the solution was heated to 6 ° C. The solution was filtered through a warm, 0.2 micron-resistant, 'filter into 1.5 ml of hexane that had been placed in a dry ice / propylene 8 bath. After cooling the solution for 20 minutes, a solid was formed, which was collected by vacuum filtration and air-dried to obtain a chemically-formed dish. Example 5 Amorphous form of compound I is produced by removing the heat source and placing the melt

A sample of Compound I was melted and quenched to room temperature on a cold surface.

36 200404779 Table 1. Solvent conditions for polymorphic screening of Compound Ia XRPD results b Propionate FE II SE II SC (45 ° C) II Acetonitrile FE II (PO) SE II SC (60 ° C) II Dichloromethane (DCM) FE II (PO) +pk@5.5, 17.5Ο2 0 SE II (PO) +pk@5.5° 2 Θ SC (45 ° C) round rotovap II rotovap II diethyl ether FE I (PO) SE II ( PO) SC (45 ° C) III + II (PO) rotovap II (SS) N, N-Dimethylformamide (DMF) FE II (PO) SE PO Ethanol FE II (PO) SE II (PO) SC (60 ° C) II (PO) Quick Cooling II (PO) Ethyl acetate FE II FE II (PO) SE II SC (60 ° C) I Hexane slurry I Isopropanol FE II (PO) SE II SC (60 ° C) II (PO) Quick Cooling II (PO)

37 200404779 Solvent conditions a XRPD result b Methanol FE II (PO) SE I SC (60 ° C) II (PO) Quick Cooling II Toluene FE II SE II (PO) SC (60 ° C) I Tetrahydroenan (THF) ) FE II FE II FE II FE II FE II SE II SC (45 ° C)-rotovap II slurry I without melting / quenching amorphous

a. FE = rapid evaporation; SE = slow evaporation; SC = slow cooling; rotovap = rotary evaporator b. PO = better orientation; SS = small sample; pk = spectral peak 38 200404779 Table 2. Low temperature precipitation crystallization

Results of solvent antisolvent XRPD a Acetone water II Acetonitrile water II Dichloromethane hexane III III III III + 11 (a small amount) diethyl ether hexane I (PO) dimethylformamide water II ethanol hexane II (SS) ethyl acetate Ester Hexane III III Isopropanol water II Ethanol water II Tetrahydrofuran hexane a. PO = better orientation; SS = small sample; min = small amount

39 200404779 Table 3. XRPD results of solvent anti-solvent for vapor diffusion experimentsa Acetone water II Acetonitrile water II Digas methane hexane-diethyl ether hexane II (PO) Dimethylformamide water II (PO) Ethanol hexane-acetic acid Ethyl hexane-isopropyl alcohol water I (PO) Alcohol water II (PO) tetrahydrofuran hexane-toluene water-a. Ρ = = preferred orientation

40 200404779 Table 4. XRPD peak positions and intensities of all diffraction lines with relative intensities greater than 丨 0% in Compound 1 Form 1 _ ^-—- ___100 12/7 ___-__ 83 22.0__ · _ 14 24.9 __ 14 25.5 33 38.6 12 a · The listed peaks are all those with a relative intensity of> 10%. The 20 value is ± 0.1. Listed as listed in USP < 941 >. Since there is a large peak (due to better orientation), lower the lower limit to account for the relevant peaks.

41 200404779 Table 5. All 2 relative relative intensities (> 10%) of the XRPD peak positions and intensities of 10% relative intensities (> 10%) of compound I Form II a 6.0 100 12.1 31 13.2 26 13.7 12 16.0 45 16.3 60 16.7 33 18.2 77 19.0 50 19.9 38 20.8 28 21.7 38 22.0 64 24.5 49 25.1 23 25.6 63 26.8 47 29.1 14 30.2 16 33.1 12 ± 0.1. List, as listed in USP < 941>. 42 200404779 10% relative intensity around Table 6. All XRPD peak positions and intensities greater than the spectral line of Compound I Form III 2Θ Relative intensity (> 10%) a 6.1 173 12.2 27 15.5 15 16.0 51 16.4 34 17.2 45 18.4 28 19.3 24 20.3 41 21.2 100 21.6 22 22.3 12 23.1 11 24.4 12 25.0 21 25.7 52 26, 5 45 27.8 16 2 0 The value is ± 0.1. a. The listed peaks are all > 10% relative intensities. Listed as listed in USP < 941 >. 43 200404779 Table 7. Formal Results of Stress Study for Compound Ia Amorphous 8CKV 4 hours II Amorphous 120 ° C, 15 minutes II Amorphous 60 ° C / 17 hours III (LC) I 60oC, 4 days II 70 ° C, 4 days II 80oC, 4 days I II 60oC, 4 days II II 70oC, 4 days II II 80 ° C, 4 days II (PO) + spectrum @ 5 ° 2 0 III 60oC, 4 days III (SS ) III 70oC, 4 days III (SS) III 80oC, 4 days III (SS) III 135 ° C, 5 minutes III a · Ρ Ο = better orientation; SS = small sample, LC = low crystallinity

44 200404779 Table 8. Summary of Moisture Adsorption / Desorption Data for Compound I Forms Moisture Balance Results XRPD Results a I at 5% RH < 0.1% weight loss at 95% RH < 0.1% total weight gain I II at 5% RH < 0.1% weight loss at 95% RH < 0.1% total weight increase II III at 5% RH < 0.1% weight loss at 95% < 11 < 0.1% total Weight gain III amorphous at 5% RH < 0.1% weight loss 0.3% total weight gain amorphous at 95% RH amorphous a. XRPD results obtained on solids after moisture balance operation. Lu

45 200404779 Table 9. Slurry experiments of the crystalline forms of Compound I

Experimental form Solvent slurry conditions XRPD results a 1 I around MeOH, 11 days I (PO) 2 II MeOH around, 11 days I (PO) 3 II MeOH 25 ° C, 1 hour π + ι (small amount) 3 II MeOH 25 ° C, 4 hours I 3 II MeOH 25 ° C, 7 hours I 3 II MeOH 25 ° C, 12.5 hours I 4 II MeOH 25 ° C, 20 minutes II 4 II MeOH 25 ° C, 40 minutes II 4 II MeOH 25 ° C, 1 hour I + II 4 II MeOH 25 ° C, 1 hour 20 minutes I + II 4 II MeOH 25 ° C, 1 hour 40 minutes 1 + 11 (a small amount) 4 II MeOH 25 ° C, 2 hours I

46 200404779 Table 10. Solvent Stirring Time (Days) of the Interactive Transformation Experiment Form of Compound I XRPD Results a I / II IPA 11 II / III IPA 11 I II / III IPA 11 II / II EtOH / Water (4: 1) 13 II / III EtOH / water (4: 1) 13 I II / III EtOH / water (4: 1) 13 I (LC) I / II 1-butanol (52.07 II / II 1-butanol (52. 〇7 II / II 1-butanol (61 ° C) 7 II / II 1-butanol (61 ° C) 7 II / II 1-butanol (70. 0 :) 1 II / II 1-butanol ( 70 ° C) 1 II / II 1-butanol (80 ° C) 1 II / II 1-butanol (80 ° C) 1 II / II 1-octanol (100.01 II / II 1- Octanol (100.01 I aLC = low crystallinity

47 200404779 Table 1 1 Comparison of twist angles between symmetrically independent molecules in forms I and II of compound 1

Form 丄 Two Molecules 9 Form _ Form jj Molecules 1 WiJi '~ τ C23-N231-C232-C233 56.77 (0.91) C3-N30-C31-C32 C12-N11-C111-C112 -59.01 (0.28) 123.88 (0.64) C22- N21-C211-C212 -125.58 (0.65) C2-N1-C11-C12 125.54 (0.21) a • Atom numbers refer to Figures 7 and 11. b • Numbers in parentheses are standard deviations Table 12 · Crystal data and data collection parameters of Compound 1 Form I Chemical formula ~ — Formula space group a, A b, A c, A cold, degree V, person 3 z D calculated value Gram / cubic cm ^ 2ΐΗΐ3Ρ3Ν2〇366.35 P2x / c (No. 14) 7.2704 (2) 16.9251 (5) · 27.8017 (11) 92.6340 (10) 3417.4 (3) 8 1.424 Crystal size, mm temperature, K radiation (wavelength ) Linear absorption coefficient of monochromator, absorption correction transmission factor applied by mirf1: min, max 0.35x0.30x0.05 150 MO κ (0.71073 A) graphite 0.105 experimental a 0.65, 0.99 48 200404779 Diffractometer Nonius KappaCCD h ′ k '1 range -8 to 8, -20 to 20, -33 to 33 2 (9 range, degree 5.02-51.51 mosaic degree, degree 0.83 used program SHELXL-97 F〇oo 1504.0 weighted data collected 1 / [σ 2 (F02) + (〇. 1142P) 2] + 11.2475P] here PU + 2F3 / 3 20535 unique data 6479 ^ int 0.165 data used in purification 6457 R_ cutoff value used in factor calculation Fo2> 2.0a (Fo2) with data of 1> 2 · 0σ (ΐ) 4863 with a pure extinction coefficient of 0.0340 488 mesh maximum shift / last cycle an estimated value 0.05 R (F〇) 0.142 Rw (F〇2) with a good degree of 0.307 1.183 aOtwinowski Z. &. Minor, W Methods Enzymol, 1996, 276, 307..

49 200404779 Table 1 3. Crystal data and data collection parameters for Compound 1 Form II Chemical formula Formula Space group a, A b, A c, Person / 5, Degree v, A3 z D Calculated value 'g / cm3 Crystal size, Temperature in millimeters' K Radiation (wavelength) Monochromator linear absorption coefficient, absorption correction applied by mirf1: min, max Diffractometer h, k, 1 range 2 (9 range, degree mosaic, degree program used F〇〇〇The weighted data collected 1 / [σ 2 (Fo2) + (0.0851Ρ) 2] + 0.0000Ρ] Here 1 ^ (卩 .2 + 2 卩 /) / 3 Unique data

Rint Data used in refinement R-cutoff value used in factor calculation Data with 1> 2.0σ (Ι) Number of variables Maximum offset / estimated value in last period R (F)

Rw (F〇2) c21h13f3n2o 366.35 P2, / c (No. 14) 14.7527 (2) 16.9524 (6) 7.0196 (5) 100.8840 (19) 1724.0 (2) 4 1.411 0.38x0.33x0.13 150 ΜΚα (0 · 71073 A) Graphite 0.104 a 0 · 89, 0 · 99

Nonius KappaCCD -19 to 19, -22 to 15, -9 to 9 10.06-54.99 0.32 SHELXL-97 752.0 13366 3920 0.054 2995

Fo2 > 2.0ct (Fo2) 2061 262 0.00 0.051 0.129

50 200404779 Goodness of coordination_1.004_ aOtwinowski Z. & Minor, W. Methods Enzymol., 1996, 276, 307. Table 14. Unique infrared ridge form of the unique spectral ridges of forms I, II, and III (cnT1 ) 3 I 3462, 3285, 3106, 2770, 2752, 1991, 1882, 1747, 1696, 1656, 1651, 1332, 1253, 557S II 3468, 3291, 3111, 3076, 2962, 2807, 1995, 1967, 1896, 1751 , 1699, 1659, 1340, 1326, 1261, 1230, 1182 III 3450, 3297, 3058, 3101, 2810, 1982, 1972, 1930, 1888, 1820, 1742, 1691, 1663, 1336, 1288, 1250, 1196, 975 , 873 Data collected at a resolution of 4 cm-1 Table 1 5. Raman peaks unique to Forms I, II, and III

Spectral peak with unique form (cm · 1) 3 I 1739,1653 II 1742,1658 III 1734,1662, 1333, 1178 Data collected at 4 cm · 1 resolution 51 200404779 [Simplified illustration of the drawing] The present invention borrows The following drawings are referred to herein as those in FIG. 14 or FIG. 1-14 for further explanation or explanation. Figure 1. Representative X-ray powder diffraction patterns of crystalline forms I, π and melons and amorphous compounds of compound I. . Figure 2: Thermogravimetric analysis (tg) curve (top graph, 100 ° C / min) curve and differential scanning calorimetry (DSC) (bottom graph, I (rc / min) curve) of compound engineering. Figure 3 : Differential scanning calorimetry curve of compound j form.

Figure [· Compound! Thermogravimetric analysis curve of the form π (upper graph, coffee / min) and differential scanning calorimetry curve (lower graph, 20 ° C / min). Figure 5: Thermogravimetric analysis curve (top chart, ioct / min) and differential scanning calorimetry curve (bottom chart, 20 ° C / min) of compound form 羾. . Figure 6: Thermogravimetric analysis curve (upper graph, 10 C / min) and differential scanning calorimetry curve (lower graph, 20 it / min) of Compound I amorphous. Figure 7: Compound! Form ... Doraemon, where each atom is represented by a 50% probability anisotropic thermal ellipsoid.

a Figure 8: Stacking diagram of compound 1 form 1 (looking down the axis of a crystal and omitting hydrogen atoms for clarity). Looking at the crystal b axis downwards and Figure 9 · Compound 丨 form of the stacking diagram (along with hydrogen atoms omitted for clarity). Looking down the crystal axis Figure 10: Stacking diagram of Compound 1 Form I (along with hydrogen atoms omitted for clarity). Figure, atomic system is represented by 50% Figure Π: ortep probability anisotropy thermal ellipsoid of compound I form Π. 52 200404779 Figure 12: Stacking diagram of Compound 1 Form 11 (downwardly along the a-crystal axis and omitting the hydrogen atom for clarity). 1 Figure 13: Illustration of compound D form of compound 1 (along b crystal "η and omitting hydrogen atoms for clarity). Looking down the crystal axis Figure 14: Illustration of packing of compound I form Π (and omitted for clarity) Figure 1 5: Differential dryness of amorphous compound 1 Compound 1 unknown calorimetric (2 (TC / min) temperature cycle curve.

53

Claims (1)

200404779 Scope of patent application: 1 ·-compounds! Crystal Plastic I having an X-ray powder diffraction pattern including the following 20 values measured using CuK «radiation: 63. 2. A crystalline form I of compound ϊ, which has the following X-ray powder diffraction patterns measured using CuK α radiation of 20 values: 6 3, 19 〇 and 25 · 5 〇 3. As for the scope of patent application No. 2 The crystalline form j of the compound of the term, the diffraction pattern further includes the following values: 12 7, 22, 24.9, and 38.6. 4. A crystalline form of a compound having an X-ray powder diffraction pattern substantially similar to that measured using CuKa radiation shown in Figure u #. 5. A crystalline form 种 of Compound I, which has a differential scanning calorimetry curve substantially similar to those shown in FIG. 3. θ6. A crystalline form 1 of compound 1 having a differential scanning calorimetry curve measured at a temperature rise rate of It: / min including an endothermic peak at about 1411 and an endothermic peak at about 143C. 7. A crystalline form z of compound I having a Fourier transform infrared spectrum including at least one of the following infrared spectrum peaks: 3462, 3285, 3106 ·, 2770, 2752, 1991, 1882, 1747, 1696, 656, 1651, 1332, 1253 and 557. 8. A crystalline form j of Compound I, which has Raman peak spectra 1739 and 1653 including at least one of the following peaks as measured with a spectrometer. 9. A pharmaceutical composition useful for treating human diseases, comprising a crystalline form I of compound I and a pharmaceutically acceptable carrier. 10. If the composition of the scope of application for item 9 of the patent, there is a substantial percentage 54 200404779 ratio of Compound I exists in Form I. 11. The composition according to item 9 of the scope of patent application, wherein y, 990% of the compound I exists in the form I. · 12. The composition of item 9 in the scope of patent application, wherein at least% of the compound I exists in the form I. 98 3 · The composition of item 9 of the patent claim, in which at least% of the compound I exists in the form I. 5 14. The composition according to item 9 of the scope of patent application, in which 90% of the compound I exists in the form I. 15. The composition of item 9 in the scope of patent application, wherein at least 85% of the compound I exists in the form I. 16. The composition according to item 9 of the scope of patent application, wherein up to 80% of Compound I exists in a crystalline form. 17. The composition according to item 9 of the scope of patent application, wherein the disease is depression and anxiety. ^ P 1 8. A method for preparing a pharmaceutical composition, which comprises blending Form I of Compound I with a pharmaceutically acceptable carrier. 19. The method according to item 18 of the scope of patent application, which further comprises Form I of compound I having substantial purity. X 20 · —A method for treating human diseases, wherein the method comprises administering to a human patient suffering from the disease a therapeutically effective amount of the crystalline form I of compound I ° 2 1 Method, wherein the disease is a CNS disorder. … 55 200404779 22. If you apply for the method in item 20 of the patent scope, you should immediately address the concern or depression. Friends, m 扃 is the coke! The method of preparing Compound 1 Form 2 in 2: 3 ::: includes mixing the compound in cold W liquid II for a period of not less than _ hours. 2 4. If the method of applying for the special brake # w J 粍 Wai item 23, wherein the solvent is selected from the group consisting of toluene, heptane, m-xylene, o-xylene, p-dimethylbenzyl, isopropyl acetate A group consisting of ester, methanol, Γ, butyl alcohol, 1-butanol, and 1-octanol. 25. A crystal dish of compound 1 'having an X · ray powder diffraction pattern including at least one of the following measured 2Θ values using CUKa light emission: 61 and 2 1 · 2. _26. A crystalline form m 'of Compound 1 having X-ray powder diffraction patterns including the following 2Θ values measured using CuK α radiation: 6.1, 16.0, 21.2, and 25.7. 7. The crystal dish of Compound I in the scope of patent claim No. 24, in which the 4 X-ray diffraction pattern progresses-further includes the following 20 values measured using CuK α light emission: ι7 · 2, 2〇 · 3 and 26.5. 28. The crystalline melon of compound VII as claimed in claim 25, which further includes the following χ-ray powder diffraction pattern measured using CuKa radiation: 12.2,15 5,164,172,18 4,19 3, 20.3, 21.6, 22.3, 23.1, 24.4, 25.0, 26 ·, and 27 · 8. 29. A crystal form of a compound j having a χ-ray powder diffraction pattern substantially similar to that measured by CuK α radiation not used in FIG. 1 c. 30 · —The crystalline form 羾 of Compound I, which has a differential scanning calorimetry curve substantially similar to that shown in Figure 3 56 200404779. The crystal form of the compound 3i •, which is measured at a heating rate of rc / min, includes a differential scanning calorimetry curve including an endothermic peak at about 132 ° C. 32. A crystal dish of compound Γ having a Fourier transform infrared spectrum including at least one of the following infrared spectrum peaks: 3450, 3297, 3058 '3101, 2810, 1982, 1972, 1930, 1888, 1820, 1742, 1691 , 1663, 1336, 1288, 1250, 1196, 975, 873. 33. A crystalline melon of compound i having a Raman peak pattern including at least one of the following peaks as measured with a spectrometer: n34, 1662, 1 3 3 3, and 117 8. 34. A pharmaceutical composition useful for treating human diseases, comprising a crystal dish of Compound I and a pharmaceutically acceptable carrier. 35. For the composition in the scope of application for item 34, a substantial percentage of the compound I exists in a form. 36. If the composition according to item 34 of the patent application scope, at least 99.9% of the compound I exists in the form of melons. 37. The composition according to item 34 of the application, wherein at least 98% of the compound I exists in the form m. 38. As for the composition in the scope of application for item 34, at least 95% of the compound I exists as a crystalline melon. 39. As for the composition in the scope of application for item 34, at least 90% of the compound I exists as a crystalline melon. 40. The composition according to item 34 of the scope of patent application, wherein at least 85% of the compound I exists in the form m. 57 ZUU4U4 // y ⑼I1 :. The composition of the scope of application for item 34, at least 80% of the compounds! It exists as a crystalline melon. Xi You 80 / Yuan 2: The composition of the scope of patent application No. 34, wherein the disease is depression or anxiety. The disease is 43. A method for preparing a pharmaceutical composition, which comprises blending type b hydrazone with a pharmaceutically acceptable carrier. … 44. According to the scope of the patent application, ^ ^ ^ ^ can be obtained in the form of "Zhenzhen's method", which further includes obtaining a form of compound I having the purity of cylindrilum. Two-a method for treating human diseases, wherein The method includes a human congener of this disease, h ^ 羾. ^, Ό, a therapeutically effective amount of compound crystal I of compound I, CNS disorders 46. The method of claim 45, wherein the disease 47. Such as the patent application scope of anxiety or depression. The method of the member, wherein the edge disease is an amorphous form of the coke ld: fluorene compound 1, which has a substance substantially similar to the figure. Not used. Measured by cardiac radiation The χ · diffracted powder diffraction pattern of 49 'amorphous compounds' has a differential scanning calorimetry curve substantially similar to that shown in Figure 6. 50. One compound j; amorphous It has a differential scanning calorimetry curve substantially similar to that shown in the figure. Μ •-compounds! Amorphous material, which has a temperature rise rate measured at a temperature included in about ^, 0 c Differential scanning of slope transition temperature Heat curve. 52. A medicinal composition that can be used to treat human diseases, which comprises an amorphous form of Compound I and a pharmaceutically acceptable carrier. It has a substantial content of 53. The composition as in item 52 of the scope of patent application Compound I exists as an amorphous substance. Among them, at least 99 9 of which is at least 9 8%, of which at least 95 are of at least 90, of which at least 85 are of at least 80, of which at least 80. 54. Such as the composition of the 52nd scope of the patent application Compound I is present as an amorphous substance in the content%. 55. If the composition in the scope of patent application No. 52, Compound I is in the form of amorphous alloy. 56. If the composition in the scope of patent application is No. 52, % Of Compound I exists as an amorphous substance. 57. If the composition of the scope of the patent application No. 52,% of Compound I exists as the amorphous substance. 5 The composition of the scope of the patent application No. 52, % Of compound I exists as an amorphous substance. 59. If the composition of the scope of application for the patent No. 52,% of compound I exists as an amorphous substance. 60. If the scope of the application for patent: 52 workers' composition , Depression or anxiety. The disease is 61. A method for preparing a pharmaceutical composition, which comprises blending an amorphous compound with a pharmaceutically acceptable carrier. 62. The method according to item 61 of the scope of patent application, which further obtains An amorphous substance having a substantially pure compound. 63. A method for treating human diseases, wherein the method includes administering a therapeutically effective amount of Compound I to a human patient having such a disease. Amorphous matter 64. The method according to item 63 of the scope of patent application, wherein the disease has a CNS disorder. _ 65. The method according to item 63 of the patent application, wherein the disease is anxiety or depression. 66. A pharmaceutical composition useful for treating human diseases, comprising a crystalline form II of compound I and a pharmaceutically acceptable carrier. 67. The composition according to item 60 of the application, wherein the compound I having a real proportion exists in the form of ϋ. Bei 68. The composition of item 66 in the scope of the patent, among which at least 99.9% of the compound I exists in the form Π. Xi 69. According to the composition of the scope of application for patent No. 60, at least% of Compound 1 exists in the form Π. 70. The composition according to item 66 of the patent application scope, wherein at least% of Compound 1 exists in the form Π. 1. As stated in the composition of the scope of patent No. 66, at least% of the compound 1 exists in the form Π. 72. As stated in the composition of the scope of patent No. 66, at least% of Compound 1 exists in the form Π. 73. The composition according to item 66 of the patent application, wherein at least 80% of the compound I is in the crystalline form] I. 74. The composition as claimed in item 66 of the patent, wherein the disease is depression or anxiety. A, 200404779 75. A method for treating human diseases, wherein the method includes administering a therapeutically effective amount of Compound I crystal form jj to a human patient suffering from such a disease. 76. For example, the method of claim 75 in the scope of patent application, The disease is a CNS disorder. 77. The method of claim 75, wherein the disease is anxiety or depression. 78. Preparations 丨 _phenyl-3-[[3- (trifluoromethyl) phenyl] imino] · 1H 'indole = ketone (Compound D), which comprises reacting diphenylamine with chloramphenicol and 3- (difluoromethyl) aniline in a suitable solvent in a pot. 79 · —Preparation 丨 Phenyl _3 _ [[3 • (trifluorofluorenyl) phenyl] imine]] method of heart art (compound j;), which comprises diphenylamine with straw chlorine and 3_ (difluoromethyl) aniline in a Reaction in a suitable solvent, and then isolating 1-phenyl-3-[[3- (triImethyl) phenyl] imino] _iHm 2-one (compound I) in Form I. 80. As claimed in the patent It is selected from the group consisting of toluene, heptane, isopropyl isopropylate, methanol, and ethanol. The method according to item 78, wherein the reaction is a solution consisting of xylene, o-xylene, p-xylene, ethyl, 1-butanol, and 1-octanol. 81. The method according to item 78 in the scope of patent application 30 ° C -150 ° C. 82. The method according to item 78 of the patent application. Heating for a period of 1 to 48 hours. 83. The method according to item 78 of the patent application, wherein the reaction system is wherein the reaction system further includes combining 61 200404779 diphenylamine with chloramphenicol to produce 1-phenyl isatin, and then adding 3- (trifluorohydrazone) Group) aniline. 84. The method of claims 78 to 83 of the patent application scope further includes crystallization and isolation of Compound I. 85. The method of claim 78, further comprising collecting a solid after cooling to room temperature and stirring for 1 to 48 hours. Pick up, schema ... as next page 62