Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• This present invention relates to a novel and more efficient process of manufacturing Compound I, which is known by the chemical name l-phenyl-3- [ [3- (trifluoromethyl)phenyl] imino] -lH-indol-2-one .
• This present invention further relates to novel crystalline forms of Compound I useful as pharmaceutical agents, to methods of production and isolation of such crystalline, forms of Compound I, to pharmaceutical compositions containing such crystalline forms, and to methods of treating human disorders using such crystalline forms .
• Compound I (l-phenyl-3- [ [3-
• Compound I can be purchased in research quantities (milligrams) from Bionet Research Ltd., 3 Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ, UK. However, this vendor does not offer large quantities (kilograms or tons) of Compound I, nor does it sell Compound I in a grade that is suitable for pharmaceutical use in humans .
• Compound I is a derivative of 1-phenylisatin .
• Compound I can be prepared by imine formation- between 1-phenylisatin and 3- (trifluoromethyl) aniline .
• a coupling reagent such as a triarylbismuth (D. M. T. Chan, Tetrah dron Lett . , 1996, 37, 9013-9016), an aryl halide (G. M. Coppola , J. Heterocyclic Chem . , 1987, 24, 1249-1251), or a phenylboronic acid (D. M. T.
• the use of any of the above approaches requires the employment of a method for isatin preparation, because this starting material can be costly and not in abundant supply.
• the intermediate, 1- phenylisatin can also be prepared by reaction between oxalyl chloride and diphenyla ine at high temperatures (W. M. Bryant et al , Synth . Commun . , 1993, 23, 1617- 1627) or at more ambient temperatures in the presence of a Lewis acid such as aluminum chloride or BF 3 OEt 2 .
• a Lewis acid such as aluminum chloride or BF 3 OEt 2
• the present invention relates to a crystalline form of Compound I, hereby designated as Form I, which may be characterized by the X-ray powder diffraction (XRPD) pattern presented in Table 4, expressed in terms of the 2 ⁇ and relative intensities with a relative intensity of >10% as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• XRPD X-ray powder diffraction
• Form I of Compound I may be further characterized as having an ' XRPD pattern containing one or several of the 2 ⁇ values presented in Table 4, as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form I of Compound I may be characterized by the XRPD pattern similar or substantially similar to that set forth in the accompanying Figure la as measured on a Shimadzu XRD- 6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form I of Compound I may also be characterized by differential scanning calorimetric (DSC) curves similar or substantially similar to that set forth in the accompanying Figure 2 or Figure 3 as measured using a TA Instruments differential scanning calorimeter 2920 or equivalent.
• DSC differential scanning calorimetric
• Form I of Compound I may also be characterized by its Fourier transform infrared pattern containing one or several of peaks presented in Table 14, as measured on a Magna-IR 860® (Thermo Nicolet) or equivalent .
• Form I of Compound I may also be characterized by its Raman peak pattern containing one or several of peaks presented in Table 15, as measured on an FT-Raman 960 (Thermo Nicolet) spectrometer or equivalent.
• the present invention further relates to one or several processes for the preparation of Form I of Compound I and/or the preparation of substantially pure Form I of Compound I .
• the second aspect of the present invention relates to a second crystalline form of Compound I, hereby designated as Form II, which may be characterized by XRPD pattern presented in Table 5, expressed in terms of the 20 and relative intensities with a relative intensity of >10% as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form II of Compound I may be further characterized as having an XRPD pattern containing one or several of the 2 ⁇ values presented in Table 5, measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form II of Compound I may be characterized by an XRPD pattern similar or substantially similar to that set forth in the accompanying Figure lb as measured on a Shimadzu XRD- 6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form II of Compound I may also be characterized by the differential scanning calorimetric (DSC) curve similar or substantially similar to that set forth in -the accompanying Figure 4, as measured using a TA Instruments differential scanning calorimeter 2920 or equivalent .
• DSC differential scanning calorimetric
• ' Form- II of Compound I may also be characterized by its Fourier transform infrared pattern containing one or several of peaks presented in Table 14, as measured on a Magna-IR 860® (Thermo Nicolet) or equivalent .
• Form II of Compound I may also be characterized by its Raman peak pattern containing one or several of peaks presented in Table 15, as measured on an ' FT-Raman
• the present invention further relates to one or several processes for the preparation of Form II of Compound I and/or the preparation of substantially pure Form II of Compound I .
• the third aspect of the present invention relates to a third crystalline form of Compound I, hereby designated as Form III, which may be characterized by the X-ray powder diffraction (XRPD) pattern presented in Table 6, expressed in terms of the 2 ⁇ and relative intensities with a relative intensity of >10% as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• XRPD X-ray powder diffraction
• Form III of Compound I may be further characterized as having an XRPD pattern containing one or several of the 2 ⁇ values presented in Table 6, as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form III of Compound I may be characterized by an XRPD pattern similar or substantially similar to that set forth in the accompanying Figure lc as measured on a Shimadzu XRD- 6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form III of Compound I may also be characterized by the differential scanning calorimetric
• Form III of Compound I may also be characterized by its Fourier transform infrared pattern containing one or several of peaks presented in Table 14, as measured on a Magna-IR 860® (Thermo Nicolet) or equivalent.
• Form III of Compound I may also be characterized by its Raman peak pattern containing one or several of peaks presented in Table 15, as measured on an FT-Raman 960 (Thermo Nicolet) spectrometer or equivalent .
• the present invention further relates to one or several processes for the preparation of Form III of Compound I and/or the preparation of substantially pure Form III of Compound I .
• the fourth aspect of the present invention relates to an amorphous form of Compound I, hereby designed as Amorphous Form, which may be characterized by an XRPD pattern similar or substantially similar to that set forth in the accompanying Figure Id as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Amorphous Form of Compound I may also be characterized by the differential scanning calorimetric (DSC) curve similar or substantially similar to that set forth in the accompanying Figure 6 as measured using a TA Instruments differential scanning calorimeter 2920 or equivalent.
• DSC differential scanning calorimetric
• Amorphous Form of Compound I may also be characterized by the differential scanning calorimetric (DSC) curves similar or substantially similar to that set forth in the accompanying Figure 15 as measured with thermal cycling using a TA Instruments differential scanning calorimeter 2920 or equivalent.
• DSC differential scanning calorimetric
• the present invention further relates to one or several processes for the preparation of Amorphous Form of Compound I and/or the preparation of substantially pure Amorphous Form of Compound I .
• One embodiment of the present invention is a composition comprising Form I, Form II, Form III, or Amorphous Form of Compound I.
• a further embodiment of this present invention is a composition wherein a substantial percentage of Compound I is present as Form I, Form II, Form III or Amorphous Form. Such a percentage can be in the range of at least 99.9%, 98%, 95%, 90%, 85%, 80%, 75% or 70%.
• Another embodiment of the present invention is a pharmaceutical composition comprising Form I, Form II, Form III or Amorphous Form of Compound I.
• a further embodiment of this present invention is a pharmaceutical composition wherein a substantial percentage of Compound I is present as Form I, Form II, Form III or Amorphous Form. Such a percentage can be in the range of at least 99.9%, 98%, 95%, 90%, 85%, 80%, 75% or 70%.
• Such a pharmaceutical composition is useful for treatment of a disease in a mammal suffering from such disease.
• One preferred embodiment is such a pharmaceutical composition useful for treatment of human depression, anxiety or other CNS disorders.
• Another embodiment of the present invention is the use of a polymorphic form of Compound I for the preparation of a medicament useful for treatment of a human disease.
• the polymorphic form of Compound I can be Form I, Form II, Form III, or Form II. It may further -exist as a mixture of two or more polymorphic forms of Compound I.
• the present invention further relates to a method for treatment of a human disease, wherein the method comprises administering to a human subject suffering from such disease a therapeutically effective amount of Form I, Form II, Form III or Amorphous Form of Compound I.
• the human disease is depression, anxiety or other CNS disorders .
• the method described above may further comprise admixing Form I, Form II, Form III or Amorphous Form of Compound I with a pharmaceutically acceptable carrier.
• the present invention provides a process of preparing Compound I, which comprises reacting diphenylamine with oxalyl chloride in a suitable solvent followed by addition of 3- (trifluoromethyl) aniline .
• the reaction is carried out in one pot.
• oxalyl chloride is replaced with an equivalent reagent from the group consisting of, but not limited to diethyloxalate or dimethyloxalate .
• reaction is run in a solvent selected from the group consisting of, but not limited to toluene, meta-xylene, ortho-xylene, para-xylene or an appropriate solvent.
• the reaction is run at a temperature range of 0°C-200°C.
• the reaction is run at a temperature range of 30°C-150°C.
• the reaction is run at a temperature range of 50°C-135°C.
• reaction is heated for a period from 1 to 48 hours.
• the process described above comprises the steps of combining diphenylamine with oxalyl chloride to produce 1-phenyl isatin followed by adding 3- (trifluoromethyl) aniline.
• the process described above further comprises steps to crystallize and isolate Compound I.
• the term of “substantial percentage” shall have the meaning of a percentage of at least 50%.
• the term of “substantial purity” shall have the meaning of a purity of at least 50%.
• composition shall have the meaning of a composition suitable for human pharmaceutical use.
• human disease shall have the meaning of a human disease condition. It shall include, but not be limited to, depression, anxiety and other CNS-related disorder. Depression may further comprise, but not be limited to, bipolar disorders, major depressive disorders, and dysthymic disorders. Anxiety may further include, but not be limited to, obsessive compulsive disorder (OCD) , generalized anxiety disorder (GAD) and panic disorder (PD) .
• OCD obsessive compulsive disorder
• GAD generalized anxiety disorder
• PD panic disorder
• the symptomatology and diagnostic criteria for these diseases and others are set out in the DSMIV guidelines (American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders) .
• CNS disorder shall have the meaning of a human disease which relates to central nervous system.
• Figure 4 Thermogravimetric Analysis (top, 10 °C/min) and Differential Scanning Calorimetry (bottom, 20 °C/min) Curves for Form II of Compound I.
• Figure 5 Thermogravimetric Analysis (top, 10 °C/min) and Differential Scanning Calorimetry (bottom, 20 °C/min) Curves for Form III of Compound -I.
• Figure 7 ORTEP Drawing of Form I of Compound I, wherein atoms are represented by 50% probability anisotropic thermal ellipsoids .
• Figure 8 Packing diagram of Form I of Compound I (viewed down the a crystallographic axis and hydrogen atoms are omitted for clarity) .
• Figure 9 Packing Diagram of Form I of Compound I (viewed down the b crystallographic axis and hydrogen atoms are omitted for clarity) .
• Figure 11 ORTEP Drawing of -Form II of Compound I. Atoms are represented by 50% probability anisotropic thermal ellipsoids .
• Figure 12 Packing diagram of Form II of Compound I (viewed down the a crystallographic axis and hydrogen atoms are omitted for clarity) .
• Figure 13 Packing diagram of Form II of Compound I (viewed down the b crystallographic axis and hydrogen atoms are omitted for clarity) .
• Figure 14 Packing diagram of Form II of Compound I (viewed down the c crystallographic axis and hydrogen atoms are omitted for clarity) .
• Table 1 lists the polymorphic forms of Compound I that were obtained from fast evaporation, slow evaporation, slow cool, rotary evaporation, and melt/quench techniques. For these methods, a weighed sample of Compound I (usually 20 - 30mg) was treated with 100 ⁇ L aliquots of the test solvent. The mixture was sonicated between additions. When the solids dissolved the solution was filtered. For fast evaporation, the solution _ was left in an open vial under ambient conditions. For slow evaporation, the solution was left under ambient conditions in a vial that was either loosely covered with a cap or covered with aluminum foil containing pinholes . For rotary evaporation, the solvent was evaporated using a rotary evaporator.
• the sample was dissolved in a test solvent at an elevated temperature (either 45 or 60 °C) .
• the resulting solution was rapidly filtered into a vial kept on the same hotplate.
• the heat source was then turned off and the hotplate and vial were allowed to cool to room temperature.
• the vial was then allowed to stand at ambient temperature overnight. If no solids were detected, the vial was placed in a refrigerator or freezer for overnight.
• the hot solution was placed in the freezer as soon as the solution cooled to room temperature.
• the melt/quench technique involved cooling a melt of compound I to room temperature.
• Table 2 lists the polymorphic forms of Compound I that were obtained from cold precipitation crystallizations.
• a solution of Compound I was added into a vial containing a cold antisolvent (hexanes cooled in dry ice/acetone slurryor water cooled in an ice water bath) .
• Table 3 lists the polymorphic forms of Compound I that were obtained from vapor diffusion experiments. A saturated solution of Compound I was placed in a vial that was placed in a larger vial containing an antisolvent. The larger vial was then sealed and kept at ambient temperature.
• the crystalline forms may be characterized by their x- ray powder diffraction patterns (XRPD) and/or by their differential scanning calorimetric (DSC) curves.
• XRPD x- ray powder diffraction patterns
• DSC differential scanning calorimetric
• Many samples generated in the polymorph screen exhibited preferred orientation.
• Preferred orientation is the tendency for crystals, usually plates or needles, to align themselves with some degree of order. Preferred orientation can affect peak intensities but not peak positions in XRPD patterns. Reduction of preferred orientation may be necessary to obtain representative XRPD patterns.
• X-ray powder diffraction (XRPD) analyses were performed using a Shimadzu XRD-6000 X-ray powder diffractometer using Cu K ⁇ radiation. The instrument was equipped with a fine focus X-ray tube.
• the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
• the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm.
• Diffracted radiation was detected by a Nal scintillation detector.
• a theta- two theta continuous scan at 3 °/min (0.4 sec/0.02° step) from 2.5 to 40 °2 ⁇ was used.
• a silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1. Samples were prepared for analysis by placing them in a silicon sample holder or aluminum holder with silicon insert.
• X- ray powder diffraction (XRPD) analyses were also performed using an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2 ⁇ range of 120°.
• Real time data were collected using Cu-K ⁇ radiation starting at approximately 4 ° 2 ⁇ at a resolution of 0.03 °2 ⁇ .
• the tube voltage and amperage were set to 40 kV and 30 mA, respectively.
• the monochromator slit was set at 5 mm by 80 ⁇ m. The pattern is displayed from 2.5-40 ° 2 ⁇ .
• Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for 5 in. Instrument calibration was performed using a silicon reference standard.
• Tables 4 to 6 list the 2 ⁇ values and relative intensities of all lines with a relative intensity > 10% for samples of Compound I that are Forms I, II, and III respectively.
• DSC Differential scanning calorimetry
• Thermogravimetric (TG) analyses were performed using a TA Instruments 2050 or 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. Samples were first equilibrated at 25 °C, then heated under nitrogen at a rate of 10 °C/min, up to a final temperature of 350 °C. Nickel and AlumelTM were used as the calibration standards .
• Figures 2,4,5, and 6 show TG analysis and DSC traces for Compound I, Forms I, II, III and amorphous form respectively.
• Figure 3 shows DSC traces for Form I of Compound I at different temperature gradients.
• the crystalline forms may also be characterized by infrared (IR) and/or Raman spectroscopy .
• Infrared spectra were acquired on a Magna-IR 860 ® Fourier transform infrared (FT-IR) (Thermo Nicolet) .
• Raman spectra were acquired using an FT-Raman 960 spectrometer (Thermo Nicolet) .
• Table 14 provides a list of peaks from IR spectra that are unique to each of the polymorphic forms of Compound I (Form I, II, and III) .
• Table 15 lists peaks from Raman spectra that are unique to each of the polymorphic forms of Compound I (Form I, II, and III) .
• Form I was crystallized from the slow cooling of ethyl acetate or toluene solutions, slow evaporation of methanol solutions, fast evaporation of diethyl ether solutions, a diethyl ether/hexanes anti-solvent crystallization, and from a vapor diffusion experiment using isopropanol and water. Based on the characterization data, Form I is a crystalline, nonhygroscopic material that melts at approximately 141 °C (DSC at 1 or 5 °C/min) . The thermogravimetric trace ( Figure 2) , shows minimal weight loss at 140 °C, which suggests that Form I is not solvated.
• Form I of Compound I displays the XRPD pattern as shown in Table 4. It should be noted that Form I of Compound I may be characterized as having one or several of the 2 ⁇ values as set forth in Table 4.
• Form I of Compound I may further be characterized by XRPD pattern similar or substantially similar to that set forth in the accompanying Figure la as measured on a Shimadzu XRD- 6000 X-ray diffractometer using CuK ⁇ radiation.
• Form I of Compound I may also be characterized by the differential scanning calorimetric (DSC) curve as set forth in the accompanying Figure 2.
• DSC differential scanning calorimetric
• Figure 3 shows four DSC traces for Form I measured at different rates of heating. Differences in the DSC traces were observed for Form I of Compound I depending on the temperature gradient. The trace recorded at a heating rate of 1 °C/min shows two endotherms at 140.66
• Form I of Compound I displays unique peaks as listed in Table 14. It should be noted that Form I of Compound I may be characterized as having one or several of the peaks as set forth in Table 14 (Form I) . Alternatively, as measured on an FT-Raman 960 spectrometer (Thermo Nicolet) or equivalent, Form I of Compound I displays unique peaks as listed in Table 15. It • should be noted that Form I of Compound I may ' be characterized as having one or several of the peaks as set forth in Table 15 (Form I) .
• Single crystals of Form I were prepared for single crystal X-ray diffraction.
• a colorless plate of Compound I having approximate dimensions of 0.35 * 0.30 x 0.05 mm was mounted on a glass fiber in .random orientation.
• Single crystals were prepared from a vapor diffusion experiment from isopropanol and water.
• Refinements were performed on an AlphaServer 2100 using SHELX97 [Sheldrick, G. M. SHELX97, A Program for Crystal Structure Refinement, University of Gottingen, Germany, 1997].
• the crystallographic drawings were obtained using the programs ORTEP [Johnson, C. K.
• Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 20535 reflections in the range 2° ⁇ ⁇ ⁇ 25°.
• the refined mosaicity from DENZO/SCALEPACK [Otwinowski, Z . ; Minor, W. Methods
• the data were collected to a maximum 2 ⁇ value of 51.5°, at a temperature of 150 ⁇ 1 K.
• Z 8 and formula weight of 366.35 the calculated density is 1.42 g cm -3 .
• the space group was determined to be P2 1 / c (no. 14) .
• FIG. 7 An ORTEP drawing of Compound I, Form I is shown in Figure 7.
• the single crystal structure data demonstrates that the_ E isomer of Compound I is present in the crystals of this form.
• the asymmetric unit shown in Figure 7 contains two symmetry independent molecules . These two molecules differ in the torsion angles, ii and ⁇ 2 around the C C F 3 aryi-Ni m i n o and C ar yi _ Nimino bonds of Compound I, as listed in Table 11.
• Packing diagrams viewed along the a , b, and c crystallographic axis are shown in Figures 8, 9 and 10, respectively. Hydrogen atoms are not shown in these figures for clarity. Pairs of molecules are pi-stacked roughly along the c-axis, as shown in Figure 9 (view along b axis) .
• the trifluoro group on one molecule displays rotational disorder, which is observed clearly in the packing diagrams .
• Form II of Compound I displays the XRPD pattern, as shown in Table 5. It should be noted that Form II of Compound I may be characterized as having one or several of the 2 ⁇ values as set forth in Table 5.
• Form II of Compound I may further be characterized by ' an XRPD pattern similar or substantially similar to that set forth in the accompanying Figure lb as measured on a Shimadzu XRD-6000 X-ray diffractometer using CuK ⁇ radiation.
• Form II of Compound I may also be characterized by the differential scanning calorimetric (DSC) curve as set forth in the accompanying Figure 4.
• DSC differential scanning calorimetric
• Tables 1-3 further reveal that Form II was the predominant product from a majority of the crystallizations attempted. Thus, Form II is the most likely form to result from any crystallization process in which no particular measures are taken to control the crystallization.
• the DSC shows a single endotherm at approximately 143 °C (1 or 20 °C/min) which is due to the melt of the material. From the TG and DSC traces ( Figure 4), Form II is a crystalline, non-solvated material that melts at approximately 143 °C at temperature gradient of 1 or 20°C/min.
• Form II of Compound I displays unique peaks as listed in Table 14. It should be noted that Form II of Compound I may be characterized as having one or several of the peaks as set forth in Table 14 (Form II) . . .
• Form II of Compound I displays unique peaks as listed in Table 15. It should be noted that Form II of Compound I may be characterized as having one or several of the peaks as set forth in Table 15 (Form II) .
• Single crystals of Form II were prepared for single crystal X-ray diffraction.
• An orange plate of Compound I having approximate dimensions of 0.38 x 0.33 * 0.13 mm was mounted on a glass fiber in random orientation.
• Single crystals were prepared from the slow cooling of an ethanol solution.
• Refinements were performed on an AlphaServer 2100 using SHELX97 [Sheldrick, G. M. SHELX97 , A Program for Crystal Structure Refinement, University of Gottingen, Germany, 1997.].
• the crystallographic drawings were obtained using the programs ORTEP [Johnson, C. K. ORTEPII, Report
• Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 13366 reflections in the range 5° ⁇ ⁇ ⁇ 21 ° .
• the refined osaicity from DENZO/SCALEPACK [Otwinowski, Z . ; Minor, W. Methods Enzymol . 1996, 276, 307] was 0.32° indicating good crystal quality.
• the data were collected to a maximum 2 ⁇ value of 55°, at a temperature of 150 ⁇ 1. K.
• For 2 4 and formula weight of 366.35 the calculated density is 1.41 g/crtf 3 .
• the space group was determined to be P2 /c (No. 14) .
• the structure has only one molecule in the asymmetric unit, which simplifies the structure relative to that seen for the Form I crystal structure .
• Compound I is present in the crystals of this form.
• the asymmetric unit shown in Figure 11 contains one molecule of Compound I.
• Packing diagrams viewed along the a , b, and c crystallographic axis are shown in Figures 12, 13 and 14, respectively. Hydrogen atoms are not shown in these figures for clarity. Pairs of molecules are pi- stacked along the c-axis, as shown in Figure 13 (b view) .
• the disorder in the trifluoromethyl groups is also observed clearly in the packing diagrams .
• the molecular geometry is similar to one of the molecules in the asymmetric unit of Form I; see Table 11.
• Form III was crystallized from the slow cooling of a diethyl ether solution (as a mixture with Form II), and from anti-solvent crystallization using dichloromethane and hexanes or ethyl acetate and hexanes.
• Form III of Compound I displays the XRPD pattern as shown in Table 6. It should be noted that Form III of Compound I may be characterized as having one or several of the 2 ⁇ values as set forth in Table 6.
• Form III of Compound I may further be characterized by an XRPD pattern similar or substantially similar to that set forth in the accompanying Figure lc as measured on a Shimadzu XRD-6000 X-ray diffractometer or equivalent using CuK ⁇ radiation.
• Form III of Compound I may also be characterized by the differential scanning calorimetric (DSC) curve as set forth in the accompanying Figure 5.
• DSC differential scanning calorimetric
• the TG data shows a minimal weight loss at 140 °C, suggesting that the Form III material is not solvated.
• the DSC curve (heating rate 20 °C/min) displays an endotherm at approximately 132 °C at temperature gradient of 20, immediately followed by an exotherm at approximately 134 °C and an endotherm at approximately 145 °C. These events suggest that the material melted and immediately recrystallized to another phase which melts at approximately 145 °C, likely Form II based on the melting point.
• the DSC heating rate (1 °C/min) , only one sharp endotherm is observed at approximately 144 °C; it is likely that the slow heating rate causes a solid state transformation of Form III to Form II.
• Form III melts and subsequently recrystallizes to another form, as was seen with Form I at slow heating rates. This data also suggests that Form III is a less stable form at higher temperatures. Based on the characterization data, Form III is a crystalline, nonhygroscopic material that melts at approximately 132 °C at temperature gradient of 20°C/min and subsequently recrystallizes to another material that is likely Form II. Alternatively, as measured on a Magna-IR 860 ® Fourier transform infrared (FT-IR) (Thermo Nicolet) or equivalent, Form III of Compound I displays unique peaks as listed in Table 14. It should be noted that Form III of Compound I may be characterized as having one or several of the peaks as set forth in Table 14 (Form III) .
• FT-IR Fourier transform infrared
• Form III of Compound I displays unique peaks as listed in Table 15. It should be noted that Form III of Compound I may be characterized as having one or several of the peaks as set forth in Table 15 (Form III) .
• Amorphous material was generated by rapidly cooling a melt of the material on a cold countertop.
• Amorphous Form of Compound I may be characterized by an XRPD pattern similar or substantially similar to that set forth in the accompanying Figure Id as measured on a Shimadzu XRD-6000 X-ray diffractometer using CuK ⁇ radiation.
• Amorphous Form of Compound I may also be characterized by the differential scanning calorimetric (DSC) curve as set forth in the accompanying Figure 6.
• DSC differential scanning calorimetric
• Amorphous Form of Compound I may also be characterized by the differential scanning calorimetric (DSC) curves similar or substantially similar to that set forth in the accompanying Figure 15 as measured with thermal cycling using a TA Instruments differential scanning calorimeter 2920 or equivalent. These curves show a glass transition temperature for Amorphous Form of approximately 30 °C at temperature gradient of 20°C/min.
• DSC differential scanning calorimetric
• the TG curve shows a minimal weight loss up to 140 °C, suggesting that the amorphous material is not solvated.
• the material displays two exothermic events at 85 and 97 °C, which are likely ' crystallizations, followed by a melting endotherm at 144 °C, suggesting that upon heating, Amorphous Form crystallizes to Form II.
• Form I may be one of the desirable forms for pharmaceutical development, because of its greater stability at ambient temperature, and its lack of solvation or hygroscopicity, and its crystallinity .
• compositions of Form I, Form II, Form III or Amorphous Form of Compound I can be made by admixing a therapeutically effective amount of the compound of this invention with a pharmaceutically acceptable carrier.
• a solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers) , flavoring agents, lubricants, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents;
• the carrier is a finely divided solid which is in admixture with the finely divided Form I, Form II, Form III or Amorphous Form of Compound I.
• Form I, Form II, Form III or Amorphous Form of Compound I is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain up to 99% of Form I, Form II, Form III or Amorphous Form of Compound I.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, low melting waxes and ion exchange resins.
• Liquid carriers are used in preparing suspensions, emulsions, syrups, elixirs and pressurized compositions.
• Such suspensions, emulsions, syrups, elixirs and pressurized compositions may be prepared from Form I, Form II, Form III or Amorphous Form of Compound I either prior to packaging and distribution to patients or at the time of administration.
• Form I, Form II, Form III or Amorphous Form of Compound I 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 a mixture of any of these.
• the liquid carrier can contain other suitable pharmaceutical additives such as emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators .
• suitable pharmaceutical additives such as emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators .
• suitable examples of liquid carriers for oral and parenteral administration may include alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil) .
• the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate.
• Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
• Form I, Form II, Form III or Amorphous Form of Compound I may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration us-ing appropriate sterile injectable medium.
• Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
• the compound can also be administered orally in the form of a solution or suspension containing other solutes or suspending agents, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like .
• Form I, II, III and Amorphous Form of Compound I can be administered orally or parenterally.
• Compositions suitable for oral administration may include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
• Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions .
• a "therapeutically effective amount” is any amount of Compound I which, when administered to a subject suffering from a disease against which Compound I is effective, causes reduction, remission, or regression of the disease.
• a "subject” is a vertebrate, a mammal or a human.
• Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular solid Form of Compound I in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
• the amount of the compound is from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg. In yet another embodiment, the amount of the compound is from about 0.1 mg to about 250 mg. In another embodiment, 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.
• the present invention further provides a process for the preparation of l-phenyl-3- [ [3- (trifluoromethyl) phenyl] imino] -lH-indol-2-one (Compound I) as described herein.
• the process produces the desired compound in high yield and in the preferred polymorphic form (Form I) in a single pot process.
• Compound I is produced in one pot from the reaction between diphenylamine, oxalyl chloride and 3- (trifluoromethyl) aniline in a suitable solvent such as toluene.
• a toluene solution of diphenylamine is added slowly to a toluene solution of oxalyl chloride while maintaining the reaction temperature below 30 °C.
• the mixture is then heated to 60 °C for one hour.
• the reaction temperature can be maintained at approximately 50 to 60 °C during the addition of diphenylamine.
• N,N-diphenyl oxamic chloride (diphenylamino) oxoacetyl chloride) that is presumably formed can then be cyclized to form 1- phenylisatin in the presence of a Lewis acid or at high temperatures (100 °C - 130 °C) .
• a toluene solution containing 3- (trifluoromethyl) aniline is added.
• the water that is generated during the reaction is removed and collected via azeotropic distillation into a Dean-Stark apparatus.
• a suitable solvent such as heptane may be added to the hot reaction vessel.
• the desired compound Upon cooling, the desired compound crystallizes from the reaction vessel to afford compound I in high purity and yield.
• the Form I polymorph of Compound I may be obtained in high purity if after cooling, the reaction slurry is allowed to stir for an appropriate amount of time before collection of the solids by filtration.
• suitable solvent shall include, but not be limited to, toluene and other solvents listed in this application. Upon following the teachings of this application, a person skilled in the art should be able to identify other solvents which may be applicable.
• this present invention provides for the formation of each of Form I, Form II, Form III and Amorphous Form of Compound I or the formation of each of these forms of substantial purity.
• Form I can be obtained in a straightforward fashion by ' stirring a slurry of any solid form of Compound I, and particularly Form II or III, in an organic solvent, in which Compound I is partially soluble, for several hours until the material converts completely to Form I.
• Formation of Form I can be analyzed through DSC or, preferably, XRPD analysis.
• a slurry of solid Compound I in an organic solvent is generated by cooling a hot, saturated solution of Compound I in an organic solvent, allowing crystals 'to form, then stirring the resulting slurry for several hours or a few days until the solid material converts substantially or completely to Form I.
• the hot, saturated solution of Compound I is generated in situ in the one-pot synthetic process described above.
• Form I can also be prepared by slurrying for several hours Compound I, Form II in a saturated methanol solution or in an appropriate solvent.
• This invention also includes a method for the reproducible and controlled generation of substantially pure Form II, which comprises heating a mixture of Compound I in an organic solvent to a temperature at or near the -boiling point of the solvent until the compound completely dissolves . The mixture is then allowed to cool until crystals just begin to form, then cooled rapidly to room temperature and filtered immediately, before interconversion to Form I can occur.
• Compound I, Form II can also be prepared by crystallization from the slow or fast evaporation, rotary evaporation, or slow cooling of solutions of Compound I using a variety of solvents, including but not limited to acetone, dichlorortiethane, ethanol, methanol, tetrahydrofuran, or toluene.
• Form III can be prepared from lyophilizing a solution of Compound I in t-butanol, or from a cold antisolvent crystallization using dichloro ethane/hexanes, ethyl acetate/hexanes, or isopropylacetate/heptane solvent systems .
• reaction mixture is cooled to 90 °C and approximately 440 mL solvent is distilled under vacuum (91 - 95 °C, -380 mm Hg) .
• Heptane (650 L) is then added slowly while maintaining a pot temperature of 90 - 95 °C and the solution is then allowed to cool to room temperature while stirring for overnight.
• heptane (400 L) is added, the mixture is stirred vigorously and the solid is collected by filtration. The solid is placed in a vacuum oven to dry at 40 °C (401.1 g, 87 % yield) .
• Compound I may be recrystallized by combining 3 L toluene per gram of Compound I . The mixture is heated to 60 °C - 70 °C until most of the solids dissolve. The solution is hot filtered and allowed to cool to room temperature, while stirring, for overnight. The orange solids are collected by vacuum filtration and dried in a vacuum oven at 40 °C (80% recovery yield) . Analysis by DSC and XRPD shows that the compound is pure Form I.
• a sample of Compound I was melted and quenched to room temperature by removing the heat source and placing the melt on a cool surface to yield Amorphous Form of Compound I .
• Peaks listed are >10% relative intensity. 2 ⁇ values are listed ⁇ 0.1° as listed in the USP ⁇ 941>. Due to the presence of one large peak (due to preferred orientation) threshold was lowered to account for the relevant peaks.
• Peaks listed are >10% relative intensity. 2 ⁇ values are listed ⁇ 0.1° as listed in the USP ⁇ 941>.
• XRP-D Phraseak—LocatdLons_and-Intensi ies of all
• Peaks listed are >10% relative intensity. 2 ⁇ values are listed ⁇ 0.1° as listed in the USP ⁇ 941>.
• Atoms numbering refers to Figures 7 and 11.
• Numbers in parenthesis refer to standard deviation
• Fooo 1504.0 weighting l/[ ⁇ 2 (F o ) + (0.1142P) 2 +11.2475P] where P (F 0 2 42F C 2 ) /3 data collected 20535 unique data 6479
• Fooo 752.0 weighting l/[ ⁇ 2 (F o 2 ) + (0.0851P) 2 +0.0000P] where P (F 0 +2F c 2 )/3 data collected 13366 unique data 3920

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• 2003
  • 2003-07-29 AR AR20030102714A patent/AR040720A1/es not_active Application Discontinuation
  • 2003-08-04 UY UY27925A patent/UY27925A1/es not_active Application Discontinuation
  • 2003-08-05 PE PE2003000786A patent/PE20040756A1/es not_active Application Discontinuation
  • 2003-08-06 TW TW092121466A patent/TW200404779A/zh unknown
  • 2003-08-07 WO PCT/US2003/025012 patent/WO2004014855A1/en not_active Application Discontinuation
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