CRYSTALLINE FORMS OF 1- (5 '- (5- (3,5-DICLORO-4-FLUOROFENYL) -5- (TRIFLUOROMETHIL) -4,5-DIHIDRO

专利摘要:
CRYSTALLINE FORMS OF 1- (5 '- (5- (3,5-DICLORO-4-FLUOROFENYL) -5- (TRIFLUOROMETHIL) -4,5-DIHIDROISOXAZOL-3-IL) -3'H-SPIRUS [AZETIDINE-3 , 1'-ISOBENZOFURAN] -1-IL) -2- (METHILSULFONIL) ETHANONE. The present invention concerns new crystalline modifications of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) - 3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone. The present invention also describes compositions and methods of treating an infection or parasitic infestation in an animal in need thereof. The present invention also relates to processes for the production of crystalline forms.
公开号:BR112015004135B1
申请号:R112015004135-3
申请日:2013-08-28
公开日:2020-12-08
发明作者:Denis Billen；Matthew Joseph Birchmeier；Ronald J. Vanderroest
申请人:Zoetis Llc；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[0001] The present invention relates to new crystalline forms of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, particularly Form A, to processes for preparing them, to compositions including such forms crystalline, and the use of such crystalline forms as a parasiticidal agent for the treatment of animals in need thereof. The present invention also contemplates the use of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3,1'- isobenzofuran] -1-yl) -2- (amorphous methylsulfonyl) ethanone prepared from Form A for compositions and methods of using it, as an anti-parasitic agent. BACKGROUND OF THE INVENTION
[0002] The chiral compound 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone has the following structure: Formula (1) which is also referred to here as Compound 1. The "*" represents chiral carbon.

[0003] Compound 1 and its preparation are described in WO2012 / 120399 (which is incorporated herein in its entirety), Example 9. WO publication further describes that the compound of Formula (1) is chiral and can be used as a parasiticide for use in treating animals with a parasitic infection or infestation. In the multistage process, the compound was released as a precipitator including about 90% of the amorphous S enantiomer and about 10% of the amorphous R enantiomer. The amorphous S enantiomer was obtained by precipitation of equimolar amounts of the S and R enantiomers, that is, the racemate. In addition, the racemate was separated by chiral HPLC. The S and R enantiomers obtained from the preparations were characterized by HPLC (elution time), 1H-NMR analysis, and mass spectrometry.
[0004] If a compound is developed as a pharmaceutical or veterinary agent, it is important to provide a form of this compound (commonly known as a drug substance or active pharmaceutical / veterinary agent / ingredient) that can be reliably prepared and purified in large scale and does not degrade under storage. A crystalline form, and preferably a high melting point of the compound, is therefore desirable, since crystalline solids with a high melting point tend to be easily purified and more stable than those of the non-crystalline (amorphous) form.
[0005] The crystalline forms of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1'- isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone has not been previously described or characterized.
[0006] Solid-state forms other than a pharmaceutical or veterinary compound may have materially different physical properties. Such differences in physical properties can have an impact, for example, on how a pharmaceutical or veterinary compound is made, processed, formulated or administered. For example, the crystalline form of a compound can have very different properties: solubility, dissolution rate, stability in suspension, stability during grinding, vapor pressure, mechanical and optical properties, hygroscopicity, crystal size, filtration properties, desiccation, density, melting point, degradation stability, stability against phase transformation into other crystalline forms, color and even chemical reactivity. Accordingly, the identification of new forms of solid state (ie crystalline or polymorphic forms) of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone that provides an advantage over other forms of state solid in the production, processing, formulation or administration of the compound are desirable.
[0007] As described, Compound 1 chiral in solid state is about 90:10 (S: R) when synthesized. The separation of the racemate (equimolar portions of the S and R enantiomers) from solid state (crystal) results in an almost pure amorphous S enantiomer, about 80% of the originally synthesized compound, which can then be readily crystallized, in an almost crystal state pure (~ 97 +%). The S and R enantiomers of the racemate can be further separated by chiral HPLC and crystallized.
[0008] When crystallized, each of the S and R enantiomers of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone form a single anhydrous crystalline form. The crystalline form of the S enantiomer is designated as Form A. The crystalline form of the R enantiomer is similar to Form A and the crystalline solid-state form of the S / R racemate is designated as the "crystalline racemate". SUMMARY OF THE INVENTION
[0009] The present invention relates to new crystalline forms of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (i.e. Formula 1; Compound 1) shown below,

[0010] The "*" represents chiral carbon.
[0011] One aspect of the present invention is the crystalline Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone.
[0012] Another aspect of the present invention is the crystalline form of (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di- hydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, which has a crystal form similar to that of Form A (S-enantiomer) .
[0013] In another aspect of the present invention is the crystalline form of the racemate, (S / R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4 , 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone.
[0014] Another aspect of the present invention is the amorphous S enantiomer of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystal Form A.
[0015] Another aspect of the present invention is (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -il) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone amor-fo, compositions thereof, and methods of use for treating an infection and parasitic infestation in an animal in need of it.
[0016] In a preferred aspect, the invention provides crystalline-specific forms of Compound 1. Each of these crystalline forms has a unique three-dimensional crystalline configuration that can be characterized, among other ways, in the way that the crystalline structure diffracts electromagnetic radiation (for example, powder X-ray diffraction (PXRD or pxrd) and Fourier transform infrared spectroscopy (FT-IR)), and their fusion characteristics (for example, by differential scanning calorimetry (DSC)) . For convenience, for each of these crystalline forms a descriptor has been allocated for characterization, although these descriptors have no inherent technical significance. As described here, the crystal forms of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3 'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone include Form A, which crystallizes from the S enantiomer, and the solid crystal form of the racemate. The crystalline form of the R enantiomer is similar to that of Form A. Form A is the preferred crystalline form of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- ( trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone.
[0017] Form A exhibits a powder X-ray diffraction pattern as shown in Figure 1. The characteristic peaks of Form A expressed in degrees 2θ [° 2-Theta] (± 0.2 °), interplanar spacings (spacing -d), and respective intensities (%) are shown in Table 1 below. Someone skilled in the art will recognize that peak intensities in the diffractogram are a function of the orientation of the crystals in the sample, so physical modifications such as milling or manual grinding, or the crystallization of a different solvent, can affect the peak intensity, while that its position remains unchanged, for the same crystal form.
[0018] Table 1. Crystalline Form A PXRD

[0019] In another aspect of the present invention, Form A crystal has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 14 , 10, 15.70, 17.18, 18.83, 19.12, 20.07, 20.97, 21.42, 22.03, 22.54, 23.62, and 28.42, all which have a relative density of at least 30%. In another aspect of the present invention, Form A crystal has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21 , 42, 22.54, and 28.42, all of which have a relative density of at least 40%. In another aspect of the present invention, crystal Form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21.42, and 28.42, all of which have a relative density of at least 50%. In yet another aspect of the present invention, crystal Form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83 and 20.07 , all of which have a relative intensity of at least 58%. In another aspect of the present invention, crystal Form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83 and 20.07. In another aspect of the present invention, crystal Form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83 and 20.07, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70, 9.39, 14.10, 15.70, 19.12, 20.97, 22.03, 21.42, 22.54, 23.62, and 28.42. In another aspect of the present invention, Form A crystal has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about the following positions: 17.18, 18.83 and 20.07, and additionally including at minus an additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of at least 21.42 and 28.42. In another aspect of the present invention, crystal Form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07 and 21.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21.42 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42, additionally including at least one diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70, 9.39, 14.10, 15.70, 19.12, 20.97, 22.03 and 23.62. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21.42, 22.54, 23.62 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 17.18, 18.83, 20.07, 21.42, 22.54, 23.62 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 17.18, 18.83, 19.12, 20.07, 21.42, 22.54, 23.62 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 14.10, 17.18, 18.83, 19.12, 20.07, 21.42, 22.54, 23.62 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 14.10, 15.70, 17.18, 18.83, 19.12, 20.07, 21.42, 22.54, 23.62 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 14.10, 15.70, 17.18, 18.83, 19.12, 20.07, 20.97, 21.42, 22.54, 23.62 and 28.42. In another aspect of the present invention, crystal form A has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 14.10, 15.70, 17.18, 18.83, 19.12, 20.07, 21.42, 22.03, 22.54, 23.62 and 28.42.
[0020] In another aspect of the present invention, Form A crystal also exhibits an infrared spectrum by Fourier transform (FT-IR) in the range of 1800 to 600 cm-1 substantially as shown in Figure 2. Characteristic peaks of FT- Form A IRs are shown in Table 2 below.
[0021] Table 2. FT-IR of Form A Crystalline

[0022] In another aspect of the present invention, Chrysalis Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133, 1023, 984, 912, 815, 757, 721, 659, and 625 cm -1.
[0023] In another aspect of the present invention, crystal Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133, 1023, 984, 912, 815, 757, 721, 659, and 625cm-1, and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 4.70, 9.39, 14.10, 15.70, 17.18, 18.83, 19.12, 20.07, 20.97, 21.42, 22.03, 22.54, 23, 62, and 28.42.
[0024] In another aspect of the present invention, crystal Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133, 1023, 984, 912, 815, 757, 721, 659, and 625cm-1, and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, and 20.07, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70, 9 , 39, 14.10, 15.70, 19.12, 20.97, 22.03, 21.42, 22.54, 23.62, and 28.42. In another aspect of the present invention, crystal Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133 , 1023, 984, 912, 815, 757, 721, 659, and 625cm-1, and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17,18 , 18.83, and 20.07, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 21.42 and 28.42. In another aspect of the present invention, crystal Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133 , 1023, 984, 912, 815, 757, 721, 659, and 625cm-1, and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17,18 , 18.83, 20.07, 21.42 and 28.42. In another aspect of the present invention, crystal Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133 , 1023, 984, 912, 815, 757, 721, 659, and 625cm-1, and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17,18 , 18.83, 20.07, 21.42, 22.54 and 28.42. In another aspect of the present invention, crystal Form A exhibits characteristic FT-IR peaks in the spectrum range from 1800 to 600 cm-1 in one or more of the following: 1662, 1459, 1352, 1304, 1191, 1166, 1133 , 1023, 984, 912, 815, 757, 721, 659, and 625cm-1, and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17,18 , 18.83, 20.07, 21.42, 22.54 and 28.42 and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70, 9.39, 14.10, 15.70, 19.12, 20.97, 22.03, and 23.62.
[0025] In another aspect of the present invention, crystal Form A also exhibits a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.53 ° Ç. In another aspect of the present invention, Form A crystal also exhibits a DSC thermogram substantially as shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.53 ° C with an endogenous principle. thermal at about 135.56 ° C.
[0026] In another aspect of the present invention, Form A crystal also exhibits a thermogram of (DSC) substantially as shown in Figure 3.2, which displays four different crystalline Form A samples, which is characterized by endotherm peaks predominant in about 144.01, 144.82, 146.32 and 146.92 ° C, with principles of endotherms at about 133.95, 136.29, 137.54 and 137.96 ° C, respectively. On average, the DSC thermogram (Figure 3.2) of the four samples is characterized by a predominant endotherm peak at about 145.52 ° C with an endotherm principle at around 136.44 ° C.
[0027] In another aspect of the present invention, Form A crystal also displays a DSC thermogram (Figure 3.2) with an endotherm principle at about 133.95, 136.29, 137.54 and 137.96 ° C , respectively. On average, the DSC thermogram of the four samples is characterized by a predominant endotherm peak at about 145.52 ° C with an endotherm principle at around 136.44 ° C.
[0028] In another aspect of the present invention, the crystalline Form A also exhibits a differential scanning calorimetry thermogram substantially as shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.52 ° C or as shown substantially in Figure 3.2, which shows a range of endotherm peaks prevalent at about 144.01 to 146.92 ° C and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) at about one or more of the following positions: 4.70, 9.39, 14.10, 15.70, 17.18, 18.83, 19.12, 20.07, 20.97, 21.42, 22.03, 22 , 54, 23.62, and 28.42. In another aspect of the present invention, crystal Form A also exhibits a DSC thermogram, which is characterized by a predominant endotherm peak at about 145.52 ° C or as shown substantially in Figure 3.2, which shows a range of peaks endotherms predominant at about 144.01 to 146.92 ° C and have characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, and, 20.07, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70, 9.39, 14.10, 15.70, 19.12, 20.97, 21.42, 22.54, 23.62, and 28.42. In another aspect of the present invention, crystal Form A also exhibits a DSC thermogram substantially as shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.53 ° C or as shown substantially in Figure 3.2, showing a range of predominant endotherm peaks at about 144.01 to 146.92 ° C and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) at about one or more of the following positions: 17, 18, 18.83, 20.07, 21.42 and 28.42. In another aspect of the present invention, Form A crystal also exhibits a DSC thermogram substantially as shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.53 ° C or as shown substantially in Figure 3.2, which shows a range of predominant endotherm peaks at about 144.01 to 146.92 ° C and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42. In another aspect of the present invention, Form A crystal also exhibits a DSC thermogram substantially as shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.53 ° C or as shown substantially in Figure 3.2, which shows a range of endotherm peaks predominant at about 144.01 to 146.92 ° C and has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) at about one or more of the following positions: 17.18, 18.83, 20.07, 21.42, 22.54 and 28.42, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks at about 4.70, 9.39, 14.10, 15.70, 19.12, 20.97, 22.03, and 23.62.
[0029] In another aspect of the present invention, crystal Form A exhibits characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about the following positions: 17.18, 18.83, and 20.07, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70, 9.39, 14.10, 15.70, 19.12, 20.97, 22.03, 21.42, 22.54, 23.62, and 28.42, and characteristic FT-IR peaks as substantially shown in Figure 2, and characteristic DSC thermograms as substantially shown in Figure 3.1 , which is characterized by a predominant endotherm peak at about 145.53 ° C or as substantially shown in Figure 3.2, which shows a range of predominant endotherm peaks at about 144.01 to 146.92 ° C. In another aspect of the present invention, crystal Form A exhibits characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) around the following positions: 17.18, 18.83, and 20.07, and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 21.42, 22.54, and 28.42, and characteristic FT-IR peaks as substantially shown in Figure 2, and characteristic DSC thermograms as substantially shown in Figure 3.1, which is characterized by a predominant endotherm peak at about 145.53 ° C or as substantially shown in Figure 3.2, which shows a range of peak peaks predominant endotherms at about 144.01 to 146.92 ° C.
[0030] In another aspect of the present invention, Form A crystal characteristic FT-IR peaks as substantially shown in Figure 2, and characteristic DSC thermograms as substantially shown in Figure 3.1, which is characterized by an endotherm peak predominant at about 145.53 ° C or as substantially shown in Figure 3.2, which shows a range of endotherm peaks prevalent at about 144.01 to 146.92 ° C.
[0031] In another aspect of the present invention, single Form A crystals exhibit a basic crystal structure that is monoclinic and has a P2 space group (1). The characteristic data of the crystal structure of the crystal Form A are shown in Table 3 below.
[0032] Table 3. Unique Crystallographic Data of the Crystalline Form

a, b, c = length of the ends of the unit cell α, β, Y = angles of the cell units Z = number of molecules in the unit cell
[0033] Another aspect of the present invention is the crystal form of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole racemate -3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, designated as the racemate. The racemate is the crystalline state of the racemic mixture of the approximately equimolar S and R enantiomers. The crystal racemate exhibits a PXRD pattern substantially as shown in Figure 4. The PXRD peaks characteristic of the crystal racemate expressed in degrees 2θ (± 0.2 °), the interplanar spacings (d), and the respective intensities (% ) are shown in Table 4, below.
[0034] Table 4. Crystal Racemate PXRD (Solid Racemate)


[0035] In yet another aspect of the present invention, the crystal racemate has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.4, 4.47, 4.74 , 5.23, 17.03, 18.94, 19.77, 20.18, 21.17, 22.63, and 24.18.
[0036] In yet another aspect of the present invention, the crystal racemate has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.4, 4.47, 4.74 , 18.94, 19.77, 20.18, and 22.63, all of which have a relative intensity of at least 30%. In yet another aspect of the present invention, the crystal racemate has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.40, 4.47, 4.74, 18, 94, and 20.18, all of which have a relative intensity of at least 50%. In yet another aspect of the present invention, the crystal racemate has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.40, 18.94, and 20.18, all which have a relative intensity of at least 75%. In another aspect of the present invention, Form A crystal has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 3.40, 18.94, and 20.18 , and additionally including at least one additional diffraction peak ex-pressure in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.47 and 4.74. In another aspect of the present invention, Form A crystal has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 3.40, 18.94, and 20.18 , and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.47, 4.74, 19.77, and 22.63. In another aspect of the present invention, Form A crystal has characteristic PXRD peaks expressed in degrees 2θ (± 0.2 °) in about one or more of the following positions: 3.40, 18.94, and 20.18 , and additionally including at least one additional diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.47, 4.74, 5.23, 17.03, 19.77 , 21.17, 22.63 and 24.18.
[0037] In another aspect of the present invention, the crystal racemate also exhibits an FT-IR spectrum in the range of 1800 to 600 cm-1 substantially as shown in Figure 5. Characteristic peaks of the crystal racemate are shown in Table 5 below .
[0038] Crystal Racemate FT-IR (Solid Racemate)


[0039] In another aspect of the present invention, the crystalline racemate also exhibits characteristic FT-IR peaks in the 1800 to 600 cm-1 spectrum range in one or more of the following: 1662, 1465, 1352, 1301, 1190, 1175, 1132, 1024, 983, 912, 811, 757, 722, 686, and 658 cm -1.
[0040] In another aspect of the present invention, the crystalline racemate also exhibits a DSC thermogram substantially as shown in Figure 6, which is characterized by a predominant endotherm peak at about 241.77 ° C with an endotherm principle at about 233.63 ° C.
[0041] In another aspect of the invention, the crystal racemate is characterized by PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.4, 4.47, 4.74, 5.23, 17.03, 18.94, 19.77, 20.18, 21.17, 22.63, and 24.18; and with characteristic FT-IR peaks in the 1800 to 600 cm-1 spectrum range in one or more of the following: 1662, 1465, 1352, 1301, 1190, 1175, 1132, 1024, 983, 912, 811, 757, 722 , 686, and 658 cm-1; and with a pre-dominant endotherm peak at about 241.77 ° C with an endotherm principle at about 233.63 ° C.
[0042] In another aspect of the invention, the crystal racemate is characterized by PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.4, 4.47, 4.74, 18.94, 19.77, 20.18, and 22.63; and with characteristic FT-IR peaks in the 1800 to 600 cm-1 spectrum range in one or more of the following: 1662, 1465, 1352, 1301, 1190, 1175, 1132, 1024, 983, 912, 811, 757, 722 , 686, and 658 cm-1; and with a predominant endotherm peak at about 241.77 ° C with an endotherm principle at about 233.63 ° C.
[0043] In another aspect of the invention, the crystal racemate is characterized by PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.40, 4.47, 4.74, 18.94, and 20.18; and with characteristic FT-IR peaks in the 1800 to 600 cm-1 spectrum range in one or more of the following: 1662, 1465, 1352, 1301, 1190, 1175, 1132, 1024, 983, 912, 811, 757, 722 , 686, and 658 cm-1; and with a predominant endotherm peak at about 241.77 ° C with an endotherm principle at about 233.63 ° C.
[0044] In another aspect of the invention, the crystal racemate is characterized by PXRD peaks expressed in degrees 2θ (± 0.2 °) in one or more of the following positions: 3.40, 18.94, and 20.18 ; and with characteristic FT-IR peaks in the 1800 to 600 cm-1 spectrum range in one or more of the following: 1662, 1465, 1352, 1301, 1190, 1175, 1132, 1024, 983, 912, 811, 757, 722 , 686, and 658 cm-1; and with a predominant endotherm peak at about 241.77 ° C with an endotherm principle at about 233.63 ° C.
[0045] Another aspect of the present invention is a composition including a therapeutically effective amount of crystalline Form A and a pharmaceutically or veterinarily acceptable excipient, diluent, vehicle or mixture.
[0046] Yet another aspect of the present invention is a composition including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4 , 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystalline Form A, and an excipient , pharmaceutically or veterinarily acceptable, diluent, vehicle or mixture thereof.
[0047] Yet another aspect of the present invention is a composition including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4 , 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (amorphous methylsulfonyl) ethanone, prepared from crystalline Form A, and a excipient, diluent, vehicle or mixture of these pharmaceutically or veterinarily acceptable.
[0048] Yet another aspect of the present invention is a composition including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4 , 5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (amorphous and crystalline Form A methylene sulfonyl) prepared from Form A crystalline, and a pharmaceutically or veterinarily acceptable excipient, diluent, carrier or mixture thereof.
[0049] Yet another aspect of the present invention is a composition including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4 , 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (amorphous methylsulfonyl) ethanone, prepared from crystalline Form A, (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , 1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystalline Form A, or crystalline racemate of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, or any mixture thereof, and a pharmaceutically or veterinarily acceptable excipient, diluent, carrier or mixture thereof.
[0050] In yet another aspect of the invention, the composition is a pharmaceutically or veterinarily acceptable composition.
[0051] Yet another aspect of the present invention is a method of treating a parasitic infection or infestation in an animal, including administering a therapeutically effective amount of crystalline Form A to an animal in need thereof.
[0052] Yet another aspect of the present invention is a method of treating a parasitic infection or infestation in an animal, including administering a therapeutically effective amount of (S) -1- (5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystalline Form A, to an animal in need thereof.
[0053] Yet another aspect of the present invention is a method of treating a parasitic infection or infestation in an animal, including administering a therapeutically effective amount of (S) -1- (5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) amorphous ethanone, prepared from crystalline Form A, to an animal in need of it.
[0054] Yet another aspect of the present invention is a method of treating a parasitic infection or infestation in an animal, including administering a therapeutically effective amount of (S) -1- (5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) amorphous and crystalline Form A ethanone, prepared from crystalline Form A, to an animal in need thereof.
[0055] Yet another aspect of the present invention is a method of treating a parasitic infection or infestation in an animal, including administering a therapeutically effective amount of (S) -1- (5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- amorphous (methylsulfonyl) ethanone and crystalline Form A, prepared from crystalline Form A, (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystalline Form A or crystalline racemate from 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3, 1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, or any mixture thereof.
[0056] Yet another aspect of the present invention is the use of a medicament, including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- ( trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (crystalline amorphous and methyl A sulfuryl), prepared from crystalline Form A, (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) - 3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystalline Form A, or from the racemate of 1- (5 '- (5- (3, 5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2 - (methylsulfonyl) ethanone, or any mixture thereof, for the treatment of an infection or parasitic infestation in an animal in need of it.
[0057] Yet another aspect of the present invention is a pharmaceutical or veterinary composition including a therapeutically effective amount of crystalline Form A in combination with at least one additional veterinary agent, and at least one pharmaceutically excipient, vehicle, diluent or mixture thereof. veterinarily acceptable.
[0058] Yet another aspect of the present invention is a pharmaceutical or veterinary composition including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (amorphous methylsulfonyl) ethanone, prepared in Form A crystalline, in combination with at least one additional veterinary agent, and at least one pharmaceutically or veterinarily acceptable excipient, vehicle, diluent or mixture thereof.
[0059] Yet another aspect of the present invention is a pharmaceutical or veterinary composition including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (crystalline amorphous and methylsulfonyl) ethanone , prepared from crystalline Form A, in combination with at least one additional veterinary agent, and at least one pharmaceutically or veterinarily acceptable excipient, vehicle, diluent or mixture thereof.
[0060] Yet another aspect of the present invention is a pharmaceutical or veterinary composition, including a therapeutically effective amount of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5 - (amorphous and Form A) (3- trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'- isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone crystalline, prepared from crystalline Form A, (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, prepared from crystalline Form A, or from the racemate of 1- (5 '- (5- ( 3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, or any mixture thereof, in combination with at least one additional veterinary agent, and at least one pharmaceutically or veterinarily acceptable excipient, vehicle, diluent or mixture of these.
[0061] In yet another aspect of the present invention, the additional veterinary agent is selected from the group consisting of abamectin, selamectin, moxideoctin, ivermectin, emamectin, doramectin, eprinaomectin, pyrantel, amitraz, albendazole, cambendazola, fenbendazole, flendendola, flubendazole , febantel, octadepsipeptides, oxfendazola, oxybendazola, para-herquamide, parbendazola, praziquantel, thiabendazola, tetramisola, triclabendazole, levamisole, oxantel, novaluron, morantel, milbemycin, oximetreine, diprimine, hydroquinone, diprazine, hydroxyamine , methoprene, metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyphene, spinosad, aminoacetonitrile derivative (s), or any mixture thereof.
[0062] In yet another aspect of the present invention, the additional veterinary agent is selected from moxidectin or pyrantel, or mixtures thereof. In yet another aspect of the present invention, the additional veterinary agent is selected from selamectin. In yet another aspect of the present invention, the additional veterinary agent is selected from moxidectin, pyrantel, and praziquantel, or any mixture thereof. In yet another aspect of the present invention, the additional veterinary agent is selected from pyrantel and milbemycin oxime, or a mixture thereof. In yet another aspect of the present invention, the additional veterinary agent is an aminoacetonitrile derivative.
[0063] In yet another aspect of the present invention, the animal is a companion animal, livestock, or bird. In yet another aspect of the present invention, the pet is a horse, dog or cat. In yet another aspect of the present invention, the livestock animal is cattle, a pig or a sheep.
[0064] In yet another aspect of the present invention, the composition is administered orally, topically or by injection. In yet another aspect of the present invention, the composition is administered orally. In yet another aspect of the present invention, the composition is administered topically. In yet another aspect of the present invention, the composition is administered by injection. In yet another aspect of the present invention, the injection is by subcutaneous, intramuscular, or intravenous administration.
[0065] In yet another aspect of the invention, Form A can be prepared by crystallizing 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5- dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone in a solvent including ethanol, n-heptane or mixed isomers of heptanes , n-butanol, ethyl acetate or isopropyl, or any mixture thereof. In addition, Form A can be prepared by diffusing steam between methanol and diisopropyl ether. Yet another aspect of the present invention is a process for the preparation of crystalline Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di- hydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone. Form A was prepared by adding (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) amorphous ethanone to a reaction vessel containing ethyl acetate (5%), n-heptane (5% ), and ethanol (60%). The reaction mixture was heated to about 60 ° C and then cooled to about 45 ° C for a period of about 1520 minutes. Crystal Form A seeds could then be added to the mixture. [The seeds were made by dissolving (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) amorphous ethanone in methanol and allowing vapor diffusion from an outer layer of diisopropyl ether to convert slowly the amorphous form to Form A for a period of about 5 days at room temperature]. Keep the reaction mixture at about 45 ° C for about 2 hours then cool to about 30 ° C at a rate of about 1.5 ° C per hour, then cool to 10 ° C for three hours, linearly, and then retain at 10 ° C for about 4.5 hours. Cool the white paste to about 0-1 ° C for 20 minutes and retain overnight (approximately 23 hours) to about 0-1 ° C. Alternatively, the reaction mixture can be cooled to about 20 ° C for 12.5 hours (about 2 ° C / h) linearly, and then retained to 20 ° C using n-heptane for 1 hour. Retain the mixture in 20 ° C for about 1 hour and then cool, and subsequently cool to -10 ° C for 10 hours and retain at -10 ° C for 3 hours. Add the mixture to a pre-cooled sintered glass filter and filter under vacuum. Rinse the remaining solids with a solvent mixture mixture containing about 40/60 to about 20/80 ethanol / n-heptane. The solvent mixture can be pre-cooled to about 0 ° C. The remaining solids can be washed again with n-heptane. The ethanol used in the procedure described here was denatured with 0.5% toluene. The solids can then be dried under vacuum for about 1 hour at room temperature and then under vacuum at 40 ° C overnight. Alternatively, the solids can be dried in a vacuum oven at 30 ° C for a period of 2.5 days, at a pressure of about 19.99-21.33 KPa (150-160 torr) with a nitrogen sweep . The resulting solids are crystalline Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3 'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, as confirmed by DSC. BRIEF DESCRIPTION OF THE FIGURES
[0067] Figure 1. Depicts a PXRD pattern illustrating crystalline Form A.
[0068] Figure 2. Depicts an illustrative FT-IR spectrum of crystalline Form A.
[0069] Figure 3.1. Depicts a DSC thermogram illustrating a single batch of crystalline Form A.
[0070] Figure 3.2. Depicts an illustrative DSC thermogram of 4 crystalline Form A lots.
[0071] Figure 4. Depicts a PXRD pattern illustrating the crystal racemate.
[0072] Figure 5. Depicts an FT-IR spectrum illustrating the crystal racemate.
[0073] Figure 6. Depicts a DSC thermogram illustrating the crystal racemate. DETAILED DESCRIPTION
[0074] The person skilled in the technique of crystallizing solid-state forms of pharmaceutical or veterinary active compound (s) / agent (s) will understand that the general approach involves finding conditions under which the active pharmaceutical / veterinary agent is soluble, and the other conditions in which the same compound is not soluble, and modify the conditions such that the solubility decreases and the crystals grow. Methods include changing the temperature, adding an anti-solvent, adding a concentrated solution of the compound to an anti-solvent, changing the pH, distilling the solvent, or some combination of these. Seeds can be added to encourage crystallization. General methods can be found in the prevalent literature, as, for example, in Crystallization, 4th Ed, J. W. Mullin, Butterworth-Heinemann, 2001, or Crystallization of Organic Compounds: An Industrial Perspective, by H.-H. Tung et al., 2009, Wiley-AIChE. In this way, a person skilled in the art can discover a variety of processes by which crystalline Form A and crystal racemate can be obtained, including other potential crystalline forms.
[0075] The solid form of a compound can materially affect the physical properties of the compound including: (1) packaging properties, such as molar volume, hygroscopic density, (2) thermodynamic properties, such as temperature melting, vapor pressure and solubility, (3) kinetic properties, such as dissolution rate and stability (including stability in ambient conditions, especially in humidity and under storage conditions), (4) surface properties such as, for example, surface area, wettability, interfacial tension and shape, (5) mechanical properties such as, for example, hardness, tensile strength, compactability, handling, fluidity and miscibility; or (6) filtration properties. The selection and control of the solid state form is particularly important for compounds that will be used as a pharmaceutical or veterinary agent. Careful selection and control of the solid state form can reduce synthesis, processing, formulation, and / or administration problems associated with the compound.
[0076] Crystallization of the compound of Formula (1) is expected with a number of appropriate solvents and antisolvents, and mixtures thereof, either by cooling by adding an antisolvent or by distilling a solvent. Non-limiting examples of solvent include methanol, ethanol, other alcohols, acetone, methyl ethyl ketone, methyl isobutyl ketone, other ketones, ethyl acetate, propyl acetate, butyl acetate, other acetates, toluene, acetonitrile, tetrahydrofuran, 2 -methyl tetrahydrofuran, acetic acid, dichloromethane, 1,2-dichloroethane, 2,2,2-trichloroethanol, other chlorinated organic solvents, and the like. Non-limiting examples of antisolvents include: water, heptane, hexane, octane, t-amyl alcohol, cyclohexane, t-butyl methyl ether, diisopropyl ether, ethyl ether, other ethers and other alkanes.
[0077] It was discovered that the specific crystal form, Form A, of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone according to the present invention exhibits advantages during processing in organic materials compared to the crystal racemate or the individual amorphous enantiomers of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole- 3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone.
[0078] The solubility of the crystal racemate is less than 10 mg / mL in acetone at room temperature (ie approximately 22 ° C). In contrast to this, the crystalline Form A solubility is greater than 300 mg / ml in acetone. In addition, the solubility of the crystal racemate and Form A in methyl t-butyl ether is <1 mg / ml and 11 mg / ml, respectively. This difference in solubility is also typical for other solvents.
[0079] This vast difference in solubility has some advantages. First, the separation of the enantiomerically pure S enantiomer racemate is carried out by filtering the racemate from the solution. The enantiomeric purity is then improved from approximately 80% enantiomeric excess (90:10) to approximately 98% enantiomeric excess (99: 1). Second, the greater solubility of the S enantiomer allows the production of solutions of much greater concentration for any work with liquid formulation. For example, the production of a spray-dried dispersion of the S enantiomer requires the dissolution of crystalline Form A. The greater the solubility, the shorter the processing time required, and the less the solvent required. Third, since Form A is much more soluble than the crystal racemate, this can correlate with greater bioavailability.
[0080] Another key difference between the crystal racemate and the crystal Form A is the particle size. The crystal racemate produces very small primary particles, usually less than 1 micron, which are agglomerated. These particles are very difficult to filter due to the small primary particle size. A filtration aid, such as celite, is often used to filter the crystal racemate. Crystal Form A crystallizes as larger particles, exhibiting primary particles in excess of 10 microns, even in excess of 100 microns on the longest axis. No filter aid or special equipment, such as a centrifuge, is needed to filter these particles from suspensions in, for example, ethanol / heptane or n-butanol mixtures. Using the filter aid to isolate the final Form A would present major challenges in removing the filter aid from the active ingredient (ie Form A). Although particle size is a function of how quickly crystals form, the solvent system employed, seeding, and other factors, the vast difference in particle size between the crystal racemate and the crystal Form A persisted through numerous crystallizations.
[0081] In contrast to the amorphous state isolated by evaporation of the solvent resulting in a foamy liquid, Form A crystal is a flowable powder. Crystal Form A also has a higher melting point than the amorphous state, which melts at 112-124 ° C as seen by hot-stage microscopy, making residual solvents easier to dry. Abbreviations and Definitions
[0082] The abbreviation “DSC” refers to differential scanning calorimetry.
[0083] The abbreviation “PXRD” or “pxrd” refers to powder X-ray diffraction, which can also be referred to as powder X-ray diffraction (XRPD).
[0084] The abbreviation "FT-IR" refers to Fourier transform infrared spectroscopy.
[0085] "Additional veterinary agent (s)" as used herein, unless otherwise stated, refers to other veterinary or pharmaceutical compound (s) ( s) that provide a therapeutically effective amount (pharmacologically and / or antiparasitically active) of such agent (s) that is / are useful for the treatment or control of an parasitic infection or infestation in an animal, as described herein.
[0086] "Animal (s)" as used here, unless otherwise stated, refers to an individual animal that is a mammal, bird, or fish. Specifically, a mammal refers to a vertebrate animal that is human and non-human, which are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include companion animals and livestock. Non-exclusive examples of a pet include: dog, cat, llama and horse. The preferred pets are dog, cat and horse. The most preferred is dog. Non-exclusive examples of livestock include: swine, camel, rabbits, goat, sheep, deer, elk, cattle (cattle), and bison. Favorite livestock animals are cattle and swine. Specifically, a bird refers to a vertebrate animal of the taxonomic class Birds. Birds have feathers, wings, are bipedal, endothermic, and lay eggs. Non-exclusive examples of birds include birds (for example, chicken, turkey, duck and goose), all of which are also referred to here as chickens. Specifically, a fish refers to the taxonomic class Chondrichthyes (cartilaginous fish, for example, sharks and rays) and Osteichthyes (bony fish) that live in water, have gills or skin covered in mucus for breathing, flippers, and may have Scales. Non-exclusive examples of fish include shark, salmon, trout, whitefish, catfish, tilapia, sea bass, tuna, halibut, brill, sole, plaice, striped sea bass, eel, vidriola, grouper, and the like.
[0087] "Chiral", as used here, unless otherwise indicated, refers to the structural characteristic of a molecule that makes overlapping in its mirror image possible (for example, the R and S enantiomers). The term is also portrayed as an asterisk (ie *) in some of the Examples and preparations.
[0088] "Compound (s) of the present invention", as used herein, unless otherwise stated, refers to the crystalline forms of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl ) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, of hereinafter, Form A crystal, and the crystal racemate. The phrase also refers to the amorphous S enantiomeric form of the compound that is subsequently prepared from the crystal Form A, for example, when present in a solid formulation as a result of a dry spray dispersion application.
[0089] "Crystalline form", as used herein, unless otherwise stated, refers to specific solid state forms of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, where the molecules are arranged to form a distinguishable crystal structure (i) including distinguishable unit cells and (ii) generating distinct diffraction peaks when subjected to X-ray radiation.
[0090] "Form A", as used herein, unless otherwise stated, refers to the specific crystal solid form of the 1- (5 '- (5- (3,5-) S-enantiomer dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- ( methylsulfonyl) ethanone, where the molecules are arranged to form a distinct crystal structure (i) including distinct unit cells and (ii) generating different diffraction peaks when subjected to X-ray radiation.
[0091] "Crystal racemate" or "crystalline racemate", as used here, unless otherwise stated, refers to the specific solid-state form of the 1- (5 '- ( 5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1 -il) -2- (methylsulfonyl) ethanone, where the molecules are arranged to form a distinct crystal structure (i) including different unit cells and (ii) generating different diffraction peaks when subjected to X-ray radiation.
[0092] "Parasite (s)", as used here, unless otherwise stated, refers to endoparasites and ectoparasites. Endoparasites are parasites that live inside their host's body and include helminths (eg, trematodes, cestodes, and nematodes) and protozoa. Ectoparasites are organisms of Arthropoda phylum (for example, arachnids and insects) that feed on or on their host's skin. Preferred arachnids are of the order Acarina, for example, ticks and mites. Preferred insects are flies, fleas, mosquitoes, biting flies (stable fly, horn fly, blowfly, horse fly, and the like), bedbugs, and lice. The compounds of the present invention can be used for the treatment of parasites, that is, the treatment of an infection or parasitic infestation.
[0093] "Therapeutically effective amount", as used herein, unless otherwise indicated, refers to an amount of a compound of the present invention alone or in combination with at least one additional veterinary agent, which (i) treat the particular parasitic infection or infestation, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular parasitic infection or infestation described here.
[0094] "Treatment", "treat", and the like, as used herein, unless otherwise stated, refer to the reversal, relief, or inhibition of the infection, infestation, or parasitic condition. As used here, these terms also involve, depending on the condition of the animal, the prevention of the principle of a disorder or condition, or symptoms associated with the disorder or condition, including reducing the severity of the disorder or condition or symptoms associated with it before. affliction with such infection or infestation. Therefore, treatment may refer to the administration of the compounds of the present invention to an animal that is not afflicted with infection or infestation at the time of administration. Treatment also involves preventing the recurrence of an infection or infestation or symptoms associated with it as well as references to "control" (eg, killing, repelling, removing, incapacitating, stopping, eliminating, relieving, minimizing and eradicating).
[0095] "Veterinary (or pharmaceutically) acceptable", as used here, unless otherwise indicated, indicates that the substance (eg, excipient, vehicle, diluent, or mixture thereof) must be chemically and / or toxicologically compatible , with the other ingredients including a formulation, composition, and / or the animal being treated with such, and is not harmful to the animal. For the purposes of the excipient, vehicle, and diluents, the terms refer to any acceptable ingredient other than the compound of the present invention or any additional veterinary agent used to formulate a final dosage form, for example, a lozenge, a solution or topical suspension, or solution for injection. Characterization of Crystalline Forms
[0096] The crystalline state of a compound can be described by several crystallographic parameters, including the unique crystal structure, powder X-ray diffraction pattern (PXRD), Fourier transform infrared absorption spectroscopy pattern ( FT-IR), and differential scanning calorimetry (DSC). Single Crystal X-Ray Analysis
[0097] The crystal structure of a single Form A crystal was determined by single crystal X-ray diffraction analysis. Data collection was performed on a Bruker APEX diffractometer at room temperature. The structure was solved by direct methods using the SHELX suite software in the space group P2 (1). The structure was subsequently refined by the method of least squares in total matrix. All different hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located in nitrogen and oxygen were found from the Fourier difference map and freely refined. The remaining hydrogen atoms were placed in calculated positions and allowed to move in their carrier atoms. The final refining included isotropic displacement parameters for all hydrogen atoms. The analysis of the absolute configuration was performed by examining the Flack parameter. In this case, the parameter = 0.002 with an estimated standard deviation of 0.018; within the range for determining the absolute configuration. The final R index was 3.7%. A final Fourier difference did not reveal missing or missing electron density. Fourier Transform Infrared Spectroscopy (FT-IR) Instrument and Method
[0098] The crystal Form A FT-IR spectrum and the crystal racemate, as described here, were acquired using a Bruker FT-IR Vertex 70 spectrometer equipped with a Pike Technologies MIRacle ATR single reflection ATR accessory (Plate Germanium Single Reflectance). The spectra were collected at a resolution of 4 cm -1 with a matching of 16 scans. Because FT-IR spectra are recorded using a single reflection ATR, no sample preparation was required. The use of FT-IR with ATR would cause a difference in relative intensity of infrared bands with those seen in an FT-IR transmission spectrum using preparations with KBr disc or Nujol reflector sample. Due to the nature of FT-IR with ATR, the bands with the lowest wave number are more intense than those with the highest wave number. The spectra were subtracted from a blank test and atmospheric compensation and vector normalization were performed. Powder X-Ray Diffraction Instrument and Method (PXRD)
[0099] The crystal structures of crystal Form A and crystal racemate, as found here, were analyzed using powder X-ray diffraction (PXRD). X-ray diffractograms were obtained using a Bruker AXS [Coventry, UK] Endeavor D4 equipped with a LynxEye detector operated with a fixed blade and a Cu source operated at 40 kV and 40 mA, with a K2a wavelength of 1.5406 angstroms. The diffractogram was obtained in the region of 3 to 50 degrees two theta. The step size was 0.020 degrees two theta, and the acquisition time per step was 0.5 seconds. During acquisition, the sample holder was rotated at 20 rpm. The samples were prepared for analysis by spreading loose solids on silica wafers with no precedent in a way to provide a level surface for the analysis. The data were analyzed in the EVA software package obtained from Bruker AXS.
[0100] As will be appreciated by the versed crystallographer, the relative intensities of the various peaks reported in the Tables and Figures here may vary due to a number of factors such as effects of orienting crystals in the X-ray beam or the purity of the material being analyzed, or the degree of crystallinity of the sample. The peak positions of PXRD can also change for variations in sample height, but the peak positions will remain substantially as defined in Tables 1 and 4, for crystal Form A and crystal racemate, respectively. The versed crystallographer will also appreciate that measurements using a different wavelength will result in different changes according to the Bragg equation - nA, = 2ci senθ. Such traditional PXRD patterns generated by the use of alternative wavelengths are considered to be alternative representations of the PXRD patterns of the crystalline materials of the present invention and, as such, are within the scope of the present invention. Differential Scanning Calorimetry (DSC) Instrument and Method
[0101] The analysis was performed on a Mettler Toledo DSC 823e in a 40 μL aluminum pan, with a compatible reference pan. The sample was heated to 10 ° C per minute from 25 ° C to a temperature high enough to achieve sample fusion. Data evaluation was completed in the StarE software package, version 11. General Scheme Preparations
[0102] In the scheme, preparations, and schemes below, the following catalysts / reagents and various abbreviations include: mobile phase (MP); N, N-dimethyl formamide (DMF); ethanol (EtOH); methyl tert-butyl ether (MTBE); methanol (MeOH), tetrahydrofuran (TF); ethyl acetate (EtOAc); trifluoroacetic acid (TFA); 1,3-bis (diphenylphosphino) propane (DPPP); amidacarbonyldiimidazole (CDI); isopropylmagnesium chloride-lithium chloride (iPrMgCl-LiCl); t-butyloxycarbonyl (BOC); palladium (II) acetate (Pd (OAc) 2); lithium borohydride (LiBH4); tert-butyl methyl ether (TBME); and 1,2-dichloroethane (DCE).
[0103] The compound of Formula (1), 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, can be prepared according to preparations and procedures as described in WO2012 / 120399. An alternative, but similar, preparatory scheme is shown below.

[0104] Synthesis of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone. The chalcone is achiral. The chiral phase transfer catalyst is used to close the 5-membered ring in a way that generates about 90% of the S enantiomer and 10% of the R enantiomer. Deprotection of the BOC group (tert-butoxycarbonyl) occurs in the presence benzenesulfonic acid and methanol, where chiral purity is maintained. The neutralized amine is then coupled with 2- (methylsulfonic) acetic acid providing the desired compound which is still about 90% S enantiomer and 10% R enantiomer. The racemate crystallizes, for example, with equimolar amounts of the enantiomers S and R which is filtered with the aid of a filter aid (Celite), leaving the enantiomerically pure S enantiomer as an amorphous solid. Pharmaceutical / Veterinary Compositions
[0105] The compound of the present invention can be administered alone or in a formulation suitable for the specific intended use, the particular species of host animal being treated and the parasite involved. It will generally be administered as a formulation in association with one or more pharmaceutically or veterinarily acceptable excipients, diluents, carriers or mixtures of these. The term "excipient", "diluent" or "carrier" is used here to describe any ingredient other than the compound of the present invention or any additional veterinary (e.g., antiparasitic) agent. The choice of an excipient, diluent, or vehicle will depend on a wide range of factors, for example, the particular mode of administration, the effect of the excipient, diluent, vehicle, or mixture of these, on solubility and stability, and the nature dosage form. In addition to the excipients, the amount of the compound of the present invention that is administered and the dosage regimen for treating a condition or disorder with the compound depends on a variety of factors, including the animal's age, weight, sex and medical condition, the severity of the disease, the route and frequency of administration, and therefore can vary widely.
[0106] In one aspect, the pharmaceutical composition includes Form A and a pharmaceutically or veterinarily acceptable excipient, diluent, carrier or mixture of these. In another aspect, the pharmaceutical composition includes the amorphous form of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole -3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone prepared from crystal Form A, and an excipient, diluent, carrier or mixture thereof pharmaceutically acceptable. The concentration range will vary depending on the composition (for example, oral, topical, or injectable). Oral doses of the active (i.e., the compound of Formula (1)) are about 0.1 to 50 mg / kg, preferably about 0.5 to 25 mg / kg, and even more preferably 0.5 to 10 mg / kg, and most preferably about 1 to 5 mg / kg. For dosage, a regimen of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, and 5 mg / kg is contemplated, including fractional amounts. For a topical solution, the active range is about 0.1 to 1000 mg / ml, and preferably about 0.5 to 500 mg / ml, and more preferably about 1 to 250 mg / ml, and even more preferably from about 2 to 200 mg / ml. The anticipated topical dose will range from about 1 to 50 mg / kg with a preferred dose of about 2 to 40 mg / kg, and more preferred from about 5 to 30 mg / kg, with an even more preferred dose of 10 to 25 mg / kg. Depending on the final volume (s) of the topical solution (s), the concentration of the asset may change from that described above. Injectable doses generally tend to be, but not always, lower in concentration.
[0107] Formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for their preparation can be found, for example, in Remington's Veterinary Sciences', 19th Edition (Mack Publishing Company, 1995; and “Veterinary Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman , Marcel Dekker, NY, 1980 (ISBN 0-8247- 6918-X).
[0108] A typical formulation can be prepared by mixing Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole- 3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone with a pharmaceutically or veterinarily acceptable excipient, diluent, vehicle or mixture thereof. A typical formulation can also be prepared by mixing the amorphous S enantiomer of the compound prepared from crystal Form A with a pharmaceutically or veterinarily acceptable excipient, diluent, carrier or mixture thereof. Suitable excipients, carriers and diluents are well known to those skilled in the art and include materials such as, for example, carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like . The particular excipient, diluent, vehicle or mixture of these will depend on the medium and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by people skilled in the art as safe to be administered to an animal. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacity agents, flow agents, processing aids, dyes, sweeteners, agents perfumers, flavoring agents and other additives known to provide an elegant presentation of the medicine (i.e., a compound of the present invention or a veterinary composition thereof) or to assist in the manufacture of the veterinary product (i.e., a medicine). The compound of the present invention will typically be formulated in veterinary dosage forms to provide an easily controllable dosage for administration.
[0109] Additionally, 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) crystal Form A -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone or the amorphous S enantiomer of the compound prepared from crystal Form A can be used in dry sprayed dispersions for form solid amorphous dispersions. The compound of the invention can exist within the solid amorphous dispersion as a pure phase, as a solid solution of the drug homogeneously distributed through the polymer, or as any combination of these states or the states that are intermediate between them. The dispersion is preferably substantially homogeneous such that the amorphous drug is dispersed as homogeneously as possible through the polymer. As used herein, "substantially homogeneous" means that the fraction of the drug that is present in relatively pure amorphous domains within the solid dispersion is relatively small, on the order of less than 20%, and preferably less than 10% of the total amount of the drug. By "amorphous" is meant simply that the drug in the dispersion is in a non-crystalline state. This solid amorphous dispersion can be used to formulate the compound of the present invention with other pharmaceutically or veterinarily acceptable excipients, diluents, carriers or a mixture of these.
[0110] Methods by which the compound of the present invention can be administered include oral, topical, and injectable (for example, parenteral and subcutaneous) administration.
[0111] The compound of the present invention can be administered orally by capsules, large pills, lozenges, powders, tablets, chewing gums, multi and nanoparticles, gels, solid solution, films, by spray, or in liquid form. This is a preferred method of administration and, as such, the development of the compound for oral administration is desirable. Such formulations can be employed as fillers in hard or soft capsules, soft or hard palatable chewing gums, which generally include a vehicle, for example, water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose, or an appropriate oil, and one or more emulsifying, flavoring, and / or suspending agents. Liquid forms include suspensions, solutions, syrups, stews and elixirs. Liquid formulations can also be prepared by reconstituting a solid, for example, a sachet. Oral stews are commonly prepared by dissolving or suspending the compound of the present invention in an appropriate medium (for example, glycol triethylene, benzyl alcohol, and the like). The compound of the present invention can also be formulated with a food substance, for example, a dietary mixture (food granules or bird powder).
[0112] The compound of the present invention can be administered topically to the skin or mucosa, that is, dermally or transdermally. This is another preferred method of administration and, as such, it is desired to develop the compound of the present invention to be suitable for such formulations, for example, liquid forms. Typical formulations for this purpose include pourable, spreadable, spreadable at multiple points, with tape application, with comb application, with roller application, dipping, spray, mousses, shampoo, powder formulations, gels, hydrogels, lotions, solutions, creams, ointments, dusts, sauces, foams, films, skin tapes, hoses, implants, sponges, fibers, bandages and micro emulsions. Lipos- Somos can also be used. Typical carriers include alcohol, water, mineral oil, liquid oil, white oil, glycerin, N-methyl formamide, glycol monomethyl ethers, polyethylene glycol, propylene glycol, and the like. Penetration enhancers can be incorporated - see, for example, in J Pharm. Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Dumpable or spreadable formulations can be prepared by dissolving the active ingredients in an acceptable vehicle, such as, for example, butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component such as propan -2-ol or a glycol ether. Alternatively, pourable, spreadable or spray formulations can be prepared by encapsulation, to leave an active ingredient residue on the animal's surface, this effect being able to ensure that the compound of the present invention has increased persistence of action and is more durable, for example. example, it can be more durable in water.
[0113] The compounds of the present invention can also be administered topically through a support matrix, for example, a resin, plastic, fabric, leather, or other natural or synthetic polymeric system in the form of a collar or ear tag. . Such a collar or ear tag may be coated, impregnated, layered, by any means such that it provides a veterinarily acceptable amount of a compound of the present invention alone, or with a pharmaceutically or veterinarily acceptable excipient, diluent, or vehicle and optionally a additional veterinary agent, or veterinarily accepted salt thereof. Such formulations are prepared in a conventional manner in accordance with standard medical or veterinary practice. In addition, these formulations will vary with respect to the weight of the active compound contained therein, depending on the species of the host animal to be treated, the severity and type of infection or infestation, and the body weight of the animal. The volume of the applied composition can be from about 0.2 ml / kg to 5 ml / kg and preferably from 1 ml / kg to 3 ml / kg.
[0114] Agents can be added to the formulations of the present invention to enhance the persistence of such formulations on the animal's surface on which they are applied, for example, to enhance their persistence on the animal's skin. It is particularly preferred to include such agents in a formulation that is to be applied as a pourable or spreadable formulation. Examples of such agents include acrylic copolymers and in particular fluorinated acrylic copolymers. A particular suitable reagent is the brand name reagent "Foraperle" (Redline Products Inc, Texas, USA). Certain topical formulations may include non-palatable additives to minimize oral exposure.
[0115] Injectable formulations (for example, subcutaneous and parenteral) can be prepared in the form of a sterile solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristate and polypropylene glycol fatty acid derivatives, as well as organic solvents such as, for example, pyrrolidin-2-one and formal glycerol. The formulations are prepared by dissolving or suspending compounds of the present invention alone or with an additional veterinary agent in the liquid carrier such that the final formulation contains about 0.01 to 30% by weight of the active ingredients.
[0116] Devices suitable for injectable administration include injectors with needles (including micro needles), injectors without a needle and infusion techniques. Injectable formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably up to a pH of 3 to 9), but, for some applications, they may be more appropriate if formulated as a non-aqueous solution. sterile water or as a dry powder form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water. The preparation of injectable formulations under sterile conditions, for example, by lyophilization, can be readily achieved using standard veterinary techniques well known to one skilled in the art. The solubility of a compound of the present invention used in the preparation of a solution for injection can be increased by the use of appropriate formulation techniques such as, for example, the incorporation of solubility enhancing agents.
[0117] The administration of a compound of the current invention is contemplated as being once a month. However, an extended duration formulation can allow dosing once every 2, 3, 4, 5 or 6 months. A dose of once a year is also contemplated. Method of Use
[0118] The present invention further includes methods for treating a parasitic infection in an animal with or being susceptible to such infection or infestation, by administering a therapeutically effective amount of a compound of the present invention to an animal in need thereof.
[0119] The compound, 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoro-methyl) -4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, is useful as an anti-parasitic agent, therefore, another aspect of the present invention is the use of a pharmaceutical composition or including a therapeutically effective amount of Form A or amorphous S enantiomer prepared from crystal Form A, and optionally a pharmaceutically or veterinarily suitable excipient, diluent, carrier, or mixture thereof for the treatment of a parasitic infection or infestation on an animal. Similarly, Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone or the amorphous S enantiomer of the compound prepared from crystal Form A can be used in the manufacture of an antiparasitic drug for the therapeutic applications described on here.
[0120] The compound of the present invention, and compositions including a therapeutically effective amount of such a compound and a pharmaceutically or veterinarily suitable excipient, diluent, carrier, or mixture thereof, are useful as ectoparasiticides for the control and treatment of infections or manifested infestations. for such ectoparasite in an animal. The compound of the present invention is useful as an ectoparasiticide, in particular, as an acaricide and an insecticide. The compound of the present invention can, in particular, be used in the fields of veterinary medicine, animal husbandry and maintenance of public health: against mites and insects that are parasitic on vertebrates, particularly warm-blooded vertebrates, including companion animals, livestock, and birds. Some non-limiting examples of ectoparasites include: ticks (for example, Ixodes spp. (For example, I.scapularis, I. ricinus, I. hexagonus), Rhipicephalus spp. (For example, R. sanguineus), Bo- ophilus spp. , Amblyomma spp. (For example, A. maculatum, A. triste, A. parvum, A. ovale, A. oblongoguttatum, A. aureolatum, A. cajennen- se, A.americanum), Hyalomma spp., Haemaphysalis spp. , Dermacentor spp. (For example, D. variabilis, D. andersoni, D. marginatus), Orithodorus spp., And the like); mites (for example, Dermanyssus spp., Cheyletiella spp., Sarcoptes spp. (for example, S. scabiei), Psoroptes spp. (for example, P. bovis), Otodectes spp., Chorioptes spp., Demodex spp., ( for example, D. folliculorum, D. canis, and D. brevis) and the like); biting and chewing lice (for example, Damalinia spp., Linognathus spp., Haematopinus spp., Solenoptes spp., Trichodectes spp., Felicola spp., and the like); fleas (for example, Cteno-cephalides spp., and the like); biting flies, flies, and mosquitoes (for example, Tabanus spp., Haematobia spp., Musca spp., Stomachox spp., Cochliomyia spp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp., Aedes spp., Culex spp., Anopheles spp., and the like); bedbugs (for example, insects within the genus Cimex and the family Cimicidae); and larvae (for example, Dermatobia spp., Hypoderma bovis, H. lineatum).
[0121] The compounds of the invention can also be used for the treatment of endoparasites, for example, cestodes (tapeworms), nematodes (round worms), and trematodes (flatworms). Non-exclusive examples of nematodes include roundworms, hookworms, nematode worms, and heartworms. Non-exclusive examples of roundworms include: Ostertagia ostertagi (including inhibited larvae), O. lyrata, Haemonchus placei, H. similis, H. contortus, Toxascaris leonine, Toxo- cara canis, T. cati, Trichostrongylus axei, T. colubriformis, T longispicularis, Cooperia oncophora, C. pectinata, C. punctata, C. surnabada (syn. mcmasteri), C. spatula, Ascaris suum, Hyostrongylus rubidus, Bunostomum phlebotomum, Capillaria bovis, B. trigonocephalum, Strongyloides papillosus, S. ransomi, Oesophagostomum radiatum, O. dentatus, O. columbianum, O. quadrispinulatum, Trichuris spp., and the like. Non-exclusive examples of hookworms (for example, Anilostoostoma caninum, A. tubeforme, A. braziliense, Uncinaria steno-cephala, and the like); pulmonary worms (for example, Dictyocaulus viviparus and Metastrongylus spp); eye worms (for example, Thelazia spp.); larvae in parasitic stages (for example, Hypoderma bovis, H. lineatum, Dermatobia hominis); kidney worms (for example, Stephanurus dentatus); bicheiras (for example, Cochliomyia hominivo-rax (larva); filarial nematodes of the Filarioidea superfamily and the Onchocercidae Family. Non-limiting examples of filarial nematodes within the Onchocercidae family include those of the genus Brugia spp. (ie, B.malayi, B. pahangi, B. timori, and the like), Wuchereria spp. (i.e., W. bancrofti, and the like), Dirofilaria spp. (i.e., D. immitis, D. ursi, D. tenuis, D.spectans, D. lutrae, and the like), Dipetalonema spp. (i.e., D reconditum, D. repens, and the like), Onchocerca spp. (i.e., O. gibsoni, O. gutturosa, O. volvulus, and the like), Elaeophora spp. (i.e., E.bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri, and the like), Mansonella spp. (i.e., M. ozzardi, M. perstans, and the like), and Loa spp (ie, L. loa). Non-exclusive examples of cestodes include: Taenia saginata, T.solium, T. taeniaformis, Hymenolepsis nana, H.diminuta, Dipylidium caninum; Diphyllobothrium latum; Echinococcus spp., Mesocestoides spp., and Sp irometra spp. Non-exclusive examples of trematodes include: Paragonimus kellicotti, Alaria spp., Naphyphyusus salmincola, Heterobiharzia Americana, Platynosomum fascosum, Schistosoma spp., And Fasciola spp.
[0122] The compositions of the invention can be administered in a manner appropriate to the specific intended use, the particular host animal and the weight of the host animal being treated, the parasite or parasites involved, the degree of infestation, etc., according to standard veterinary practice. The veterinary practitioner, or someone skilled in the art, will be able to determine the appropriate dosage for the particular animal, which may vary with species, age, weight, and response. The average doses are exemplary of the average case. Accordingly, greater or lesser dosages can be guaranteed, depending on the factors above, and are within the scope of this invention.
[0123] The compound of the present invention, or an appropriate combination of a compound of the present invention and at least one additional veterinary agent can be directly administered to the animal. The local environment where the animal lives (for example, rooms, enclosed spaces, and the like) can also be treated directly or indirectly (for example, with administration to the animal). Direct administration to the animal includes contact with the skin, fur or feathers of the animal in question with the compound of the present invention, either by feeding (for example, capsules, lozenges, palatable matrix, food mixture, and the like) or by injection. The compound of the present invention and a composition thereof, including those compositions including at least one other biological agent, are of value for the treatment and control of the various stages of the life cycle of insects and parasites including the stages of egg, nymph, larva, juvenile and adult.
[0124] The composition of the present invention can be administered alone, as described above, or in combination with at least one additional additional antiparasitic agent to form a multi-component parasiticide generating an even broader spectrum of pharmaceutical and / or veterinary utility. Therefore, the present invention also provides a veterinary combination composition with at least one other antiparasitic agent and may additionally include at least one veterinarily acceptable excipient, diluent, vehicle, or mixture thereof.
[0125] The following list of additional veterinary agents together with which the compound of the present invention can be used is intended to illustrate possible combinations, but does not impose any limitations. Non-limiting examples of additional veterinary agents include: amitraz, arylpyrazoles, amino acetonitriles, anthelmintics (eg, albendazole, cambendazole, dichlorvos, fenbendazola, flubendazola, levamisole, mebendazole, monapantel, morantel, octa-depsipeptide, oxendazole, oxendel, oxendel, oxendel, oxendel, oxendazole, oxendel, oxendazole, oxendol, oxendazole, oxendol, oxendol, oxendol, oxendol, oxendol, oxendol, oxendol, oxendol, oxendol, oxendazole, -herquamide, parbendazole, piperazines, praziquantel, pyrantel, thiabendazole, tetra-misola, triclabendazole, and the like), avermectins and derivatives thereof (eg, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin, miloxidactin) - cine, and the like), DEET, demiditraz, diethylcarbamazine, fipronil, insect growth regulators (e.g., lufenuron, novaluron, hydroprene, kinoprene, methoprene, and the like), metaflumizone, nicloamide, nitenpiram, permetrin, pyrethrins, pyriproxifene, spinosad, and the like. In certain cases, combinations of a compound of the present invention with at least one additional veterinary agent can result in a more than additive effect. Non-limiting examples of combinations include, but are not limited to: compound of the present invention with pyrantel, compound of the present invention with macrocyclic lactone and levamisole, compound of the present invention with macrocyclic lactone and pyrantel.
[0126] The veterinary composition for application to an animal can be packaged in a variety of ways depending on the method used for administering the compound of the present invention or combination thereof. Generally, an article for distribution includes a container with the veterinary composition deposited thereon in an appropriate manner. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container can also include tamper-proof mounting to prevent indiscriminate access to the contents of the package. In addition, a label describing the contents of the container is deposited on the container. The label may also include appropriate notices. EXAMPLES
[0126] Preparation 1: Terc-butyl 5'-bromo-3'H-spiro [azetidine-3,1'-isobenzofuran] -1-carboxylate
C) '' A * Nfíí:> 7rp
[0127] 4-Bromo-2- (chloromethyl) -1-iodobenzene (500 g, 1.509 moles) was dissolved in tetrahydrofuran (3750 ml) and cooled to -20 ° C. i- PrMgCl-LiCl (1.3 M THF solution) (1275 mL, 1.66 moles) was added at less than -15 ° C. The reaction mixture was cooled to -20 ° C. 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (310 g, 1.81 moles), as a solution in tetrahydrofuran (750 ml) was added. The reaction was heated to room temperature for 90 minutes, and then stirred overnight. A 1 M aqueous citric acid solution was added, followed by tert-butylmethyl ether (2 L). The mixture was stirred. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to generate an orange oil. The oil was dissolved in ethanol (2.5 L) and the solution was diluted with water (1 L). The mixture was allowed to stand at room temperature overnight. The resulting crystals of tert-butyl 5'-bromo-3'H-spiro [azetidine-3,1'-isobenzofuran] -1-carboxylate were filtered under reduced pressure and dried under vacuum at 50 ° C, generating 290 g. 1H NMR (CDCl3) δ ppm: 1.49 (9H, s), 4.15 (2H, d), 4.34 (2H, d), 5.11 (2H, s), 7.38 (2H, m), 7.56 (1H, d).
[0128] Preparation 2: Terc-butyl 5'-acetyl-3'H-spiro [azetidine-3,1'-isobenzofuran] -1-carboxylate

[0129] In a scintillation cooler containing 15 mL of ethanol, Pd (OAc) 2 (8.3 mg, 0.037 mmol) and DPPP (31 mg, 0.073 mmol) were added. The reaction vessel was purged with nitrogen gas, closed, and heated to 60 ° C for 18 hours. To this tert-butyl 5'-bromo-3'H-spiro [azetidine-3,1'-isobenzofuran] -1-carboxylate (Preparation 1, 250 mg, 0.74 mmol) and triethylamine (205 μL, 1, 5 mmol) and the mixture was heated to 90 ° C for 5 minutes. Butyl vinyl ether (190 μL, 1.5 mmol) was subsequently added and the reaction was heated to 90 ° C for 4 hours under nitrogen. The reaction was cooled and 1.0 N HCl (2 mL) was added at room temperature and stirred for 2 hours. The reaction was neutralized with saturated NaHCO3 and extracted with EtO-Ac. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude material was chromatographed (12 g of Redi-Sep column) eluting from 100% hexanes to 35:65 EtOAc: hexanes to generate the intermediate (172 mg, 77%) as a solid. 1HRMN (CDCl3) δ ppm: 8.01 (1H), 7.83 (1H), 7.58 (1H), 5.17 (2H) 4.35 (2H), 4.16 (2H), 2, 64 (3H), 1.51 (9H); m / z (CI) 204 ([M + H-100] +.
[0130] Preparation 3: 1- (4-chloro-3,5-difluorophenyl) -2,2,2-Trifluoroethanone
OF
[0131] 5-Bromo-2-chloro-1,3-difluorobenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and i-PrMgCl-LiCl (1.3 M THF solution ) was added for about 1 minute - with a very light exotherm perceived at ~ 30 ° C. The reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 mL) for about 1 minute - with a mild exotherm at ~ 40 ° C. The solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCl3) δ ppm: 8.05 (s, 2H).
[0132] Preparation 4: Terc-butyl 5 '- (3- (3,5-dichloro-4-fluorophenyl) - 4,4,4-trifluorobut-2-enoyl) -3'H-spiro [azetidine-3, 1'-isobenzofuran] -1- carboxylate

[0133] 1- (3,5-Dichloro-4-fluorophenyl) -2,2,2-trifluoroethanone (Preparation 3, 59.4 g, 227 mmoles) and tert-butyl 5'-acetyl-3'H-spiro [azetidine-3,1'-isobenzofuran] -1-carboxylate (Preparation 2, 60.0 g, 198 mmoles) were mixed with a 1: 1 mixture of toluene and trifluoromethylbenzene (250 mL) in a three-necked flask 1 L. One neck was equipped with a modified Dean-Stark short path head with a condenser on top, and the other with a very low flow nitrogen inlet (the nitrogen inlet is turned off at the start of the reaction). The reaction was heated to 110 ° C. The starting material rapidly dissolved and Cs2CO3 (5 g, 16 mmoles) was then added. A vigorous effervescence was observed and the nitrogen flow was connected. The reaction was stirred for 1 hour, emptying Dean-Stark's cockpit when necessary. HPLC-MS shows about 75% progress. Another 1 g of Cs2CO3 was added to the crude mixture and the reaction was stirred for an additional hour. An HPLC-MS shows conversion> 95%. The crude reaction was then poured into 500 ml of TBME and filtered through a 2 ”silica cake. The solvents are removed under vacuum, and the resulting brown gum is redissolved in a 1: 1 mixture of TBME: hexanes, filtered over a 0.127 meter (five inch) silica cake, and eluted with 2 L of the same solution. The organics were concentrated to dryness. The solids were dissolved in a 95: 5 mixture of hot heptane: TBME (approximately 250 ml). The solution was then slowly cooled to 0 ° C with stirring and seeded with solids from previous batches. A beige solid formed after 30 minutes. The paste was left stirring at 0 ° C for 2 hours. A pale beige solid was filtered (90 g, 83% yield), and showed> 99% purity by HPLC, and an 85:15 ratio of double bonded isomers. The remaining mother liquor was concentrated to an oil (approximately 30 g) and was purified on a silica cartridge (400 g, 10-100% TBME in hexanes for 12 CV, 12 mL / minute, ~ 254 nm). Additional 13 g of the material is isolated. Analytical method: Xbridge phenyl column (250 mm x 3.0 mm); 70% to 100% for 25 minutes, methanol with 0.1% TFA in water with 0.1% TFA, ~ 254 nm: 16.019 minutes (84.5% of the main isomer) and 16.439 minutes (14.9% , minority isomer). LC-MS method: Xbridge C18 column; 90% to 100% acetonitrile / methanol 1: 1 with water; [546] Ms + ~ 4.970 minutes, / 254 nm (single peak).
[0134] Preparation 5: Terc-butyl 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-chiral carboxylate

[0135] A solution of (Z) -tert-butyl 5 '- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-2-enoyl) -3'H-spiro [ azetidine-3,1'-isobenzofuran] -1- carboxylate (Preparation 4, 1.0 g, 1.83 mmol) in dichloroethane (8 mL) was cooled to -2 ° C. The catalyst, (2S) -1- (acridin-9-ylmethyl) -2 - ((R) -hydroxy (6-methoxyquinolin-4-yl) methyl) -5-vinylquinuclidin-1-bromide (180 mg, 0.037 mmol) was added and stirred to dissolve. In a separate flask, 10 N aqueous sodium hydroxide (0.42 m) was cooled to 5 ° C and hydroxylamine heated to 50% by weight (254 mg, 3.84 mmol) was added and stirred for 10 minutes. The basic solution was added in one go to the reaction solution. The resulting solution was stirred at 0 ° C for 1 hour. The reaction mixture was washed with water (2 x 10 ml). The solution was concentrated to a volume of 3 ml and then 15 ml of methyl tert-butyl ether were added and the heterogeneous mixture was mixed at room temperature for 15 minutes. The precipitated catalyst was removed by filtration. The organic solution at this point contained a 90:10 mixture of isoxazoline enantiomers. The organics were concentrated to a volume of 3 ml and the product was allowed to slowly crystallize at room temperature and was then cooled to 0 ° C. The product was isolated by filtration to generate 910 mg (89%) of white crystals. Crystallization generally provided an enantiomeric enhancement such that the percentage of the active isomer was> 95%. Chiral LC: 250 x 3.0 mm Chiralpak AD column, 70:30 hexane: ethanol (0.2% diethylamine), 1.0 mL / minute, detection at 260 nm. Retention times: 5.4 minutes and 12.4 minutes. 1H NMR, 600MHz (CDCl3) δ ppm: 7.70 (d, 1H), 7.60 (m, 4H), 5.18 (s, 2H), 4.36 (d, 2H), 4.15 ( m, 3H), 3.72 (d, 1H), 1.55 (s, 9H). m / z 462 ([M + H] -Boc). The asterisk (*) depicts a chiral center.
[0136] Preparation 6: 5 '- (5- (3,5-dichloro-4-fluorophenyl) hydrochloride - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran]

[0137] Terc-butyl 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1- chiral carboxylate (preparation 5, 1.1 g, 2.0 mmol) was dissolved in methanol (50 ml). A methanolic HCl solution (5 mL of a 1.25 M solution) was added and the reaction was heated to 60 ° C for 18 hours. The reaction was cooled and concentrated in vacuo to ensure that the intermediate (980 mg, 100%) was a solid. 1H NMR, 300MHz (d6- DMSO) δ ppm: 9.86 (1H), 9.45 (1H), 8.14 (1H), 7.82 (3H), 7.70 (1H), 5.15 (2H), 4.41 - 4.30 (6H); m / z (CI) 461 [M + H] (free amine). The asterisk (*) depicts a chiral center.
[0138] Preparation 7: 5 '- (5- (3,5-dichloro-4-fluorophenyl) - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro sulfonate [azetidine-3,1'-isobenzofuran] para-toluene chiral
NH -TsOH
[0139] Terc-butyl 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1- chiral carboxylate (Preparation 29, 162 g, 289 mmol) was dissolved in ethanol (1800 ml) and water (200 ml). P-toluenesulfonic acid monohydrate (113 g, 577 mmol) was added and the solution was heated to 75 ° C for 3 hours. The reaction was cooled to 20 ° C and filtered to isolate the product. The product was dried to generate 167.4 g (92%) of a white powder. 1H NMR, 600MHz (d6-DMSO) δ ppm: 8.98 (br s, 2H), 7.92 (d, 1H), 7.80 (m, 3H), 7.70 (s, 1H), 7 , 50 (d, 2H), 7.15 (d, 2H), 5.15 (s, 2H), 4.40 (m, 6H), 2.25 (s, 3H); m / z (CI) 461 [M + H] (free amine). The asterisk (*) depicts a chiral center.
[0140] Preparation 8: 5 '- (5- (3,5-dichloro-4-fluorophenyl) - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro sulfonate [azetidine-3,1'-isobenzofuran] chiral benzene
F3C O — NClN -PhSO3HH3
[0141] Terc-butyl 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1- chiral carboxylate (Preparation 5, 80 g, 140 mmol) was dissolved in ethanol (280 ml). Benzenesulfonic acid (28.5 g, 178 mmol) was added and the solution was heated to 62 ° C for 30 minutes. The reaction was cooled to 5 ° C and filtered to isolate the product. The product was dried to generate 81 g (92%) of a white powder. 1H NMR, 600MHz (d6- DMSO) δ ppm: 9.10 (br s, 1H), 8.90 (br s, 1H) 7.95 (d, 1H), 7.82 (m, 3H), 7 , 70 (s, 1H), 7.62 (d, 2H), 7.34 (m, 3H), 5.13 (s, 2H), 4.35 (m, 6H); m / z (CI) 461 [M + H] (free amine). The asterisk (*) shows a chiral center.
[0142] Example 1: 1- (5 '- (5- (3,5-Dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone

[0143] The 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' p-toluenesulfonic acid salt H-spiro [azetidine-3,1'-isobenzofuran] (Preparation 7, 157 g, 248 mmol) was stirred as a slurry in methyl tert-butyl ether (700 mL) at room temperature. To this was added 0.5 N aqueous sodium hydroxide (600 mL, 300 mmol) and the mixture was stirred for 15 minutes, after which the two layers were transparent. The aqueous layer was separated and the organics were washed with saturated brine (200 ml) and dried over sodium sulfate (5 grams). The organics were filtered to remove the solids.
[0144] In a separate flask, 43.2 g (297 mmol) of 2-methanesulfonylacetic acid were dissolved in DMF (300 mL) at room temperature. Carbonyldiimidazole (45.1 g, 271 mmol) was added in portions to the solution for 15 minutes at room temperature. The ethereal solution above the amine was added to this reaction in one portion. The resulting solution was stirred at room temperature for 30 minutes. Water (800 mL) was added to quench the reaction. After mixing for two minutes, the aqueous layer is rested and removed. The organic layer is stirred at room temperature for one hour. During this time, the racemate precipitated from the reaction mixture. The mixture is then filtered through a filter aid (Celite 545) to remove the racemic material. The sulfonamide remaining in the solution is greater than 99% of a single isomer (ie, S). The organic solution is washed with water twice (2 x 1 L) and concentrated to an opaque white solid (109.5 g, 76%). The residual color can be removed by dissolving the material in ethanol, stirring with 10% charcoal (Darco G-60), filtration, and concentration to a solid. The asterisk (*) depicts a chiral center.
[0145] Alternatively, the 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H basilate salt -spiro [azetidine-3,1'-isobenzofuran] chiral can be linked with methanesulfonylacetic acid using propylphosphonic anhydride through a simplified one-pot process instead of the two-pot method with CDI. Triethylamine (0.825 g, 1.3 eq) was added as drops for 1 minute at about 18-22 ° C in methanesulfonylacetic acid (0.615 g, 1.3 eq) and 5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5- dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] chiral (Preparation 8, 2,1 g, 3.39 mmol) in 9.3 mL of ethyl acetate (EtO-Ac). The addition funnel was rinsed with 0.5 ml of EtOAc and the resulting mixture was stirred for a minimum of 2 hours and cooled to <10 ° C. The addition funnel was then rinsed with 1.5 ml of EtOAc. The reaction mixture was heated to 35 ° C and mixed overnight (HPLC> 97% with <1% of starting material). To the reaction, 1.0 g of Celite filter aid was added and it was filtered through a plug of celite in a funnel of thick, finely porous glass and rinsed with 4 ml of EtOAc (2x). The chiral HPLC process resulted in 98.8% S enantiomer and 1.2% R enantiomer; HPLC> 97%. The filtrate was washed with 4 ml of water (3x), 4 ml of 10% NH4Cl, 4 ml of water and the organic layer was concentrated to the amorphous S form of 1- (5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) - 2- (methylsulfonyl) ethanone (foam, 70-80% yield). 1H NMR, 600MHz (d6- CDCl3) δ ppm: 7.65 (m, 5H), 5.19 (br s, 2H), 4.70 (m, 2H), 4.48 (d, 1H), 4 , 38 (d, 1H), 4.12 (d, 1H), 3.90 (d, 2H), 3.72 (d, 1H), 3.23 (s, 3H); m / z (CI) 581 [M + H].
[0146] Example 2: Preparation of Crystal Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3- il) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone - Crystallization of Amorphous S-Enantiomer
[0147] Originally, Form A crystal seeds were prepared by dissolving between 100 mg and 200 mg of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- amorphous S form) (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methilsulfonyl) ethanone in methanol at room temperature. A small aliquot of this solution was placed in an uncapped 4 mL glass vial. The 4 mL glass bottle was placed inside a larger 20 mL amber bottle containing several mL of diisopropyl ether and then the 20 mL bottle was capped. The solvent vapors were allowed to evaporate / diffuse for a period of 5 days, and, after this time, solids were noted. Examination of solids under microscopy with polarized light revealed highly birefringent crystalline particles. Hot-step microscopy analysis showed a melting point between 130 and 170 ° C. Further examination confirmed Form A (for example, the seed crystals).
[0148] Crystal Form A can be prepared by loading 15.4 grams of the amorphous S enantiomer described above, dissolved in 92 ml of ethanol and 7.7 ml of ethyl acetate, in a 1 L reaction with a fitted jacket with suspended agitation, temperature probe / reading, programmable cooler, free nitrogen purging, and a water-cooled suspended condenser. Then, 54 ml of n-heptane are added. The resulting system is heated to 60 ° C resulting in a solution. The solution is cooled to 45 ° C for 15 minutes, resulting in a milky or cloudy solution, with no signs of crystalline solid formation. 308 mg of Form A crystalline which was hand-ground with grail and pistil are then added. The seeds persist in the reactor. The system is maintained to 45 ° C, and then the reactor contents are cooled to 30 ° C at 1.5 ° C per hour linearly, and then cooled to 10 ° C for three hours linearly, and then maintained at 10 ° C for 4.5 hours. The result is a stirring white paste. The paste is cooled to 0-1 ° C for 20 minutes and kept overnight (about 23 hours) at 0-1 ° C. The reactor contents are transferred to a sintered glass filter and a vacuum is applied until a solid cake is observed. The cake is washed on the filter with about 40 ml of 60% n-heptane / 40% ethanol denatured with 0.5% toluene. The cake is additionally washed with approximately 300 ml of n-heptane. The pie is air dried by pulling vacuum for about 1 hour, then the pie is additionally dried in a vacuum oven overnight to 40 ° C. The 9.26 grams of Form A resulting from 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroiso-xazol-3-yl ) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone were confirmed by DSC.
[0149] Alternatively, crystal Form A can be prepared by loading 4 grams of the amorphous S enantiomer (isolated by rotavaporization to a foam) in a 50 mL MultiMax reactor equipped with jacket heating / cooling, suspended agitation, thermocouple, and a dispensing box. Add 24 mL of a solvent mixture consisting of 60% by volume of ethanol (denatured with 0.5% by volume of toluene), 35% of heptane, and 5% of ethyl acetate. Heat the mixture to 60 ° C, and the result is a clear solution. Cool to 45 ° C for 20 minutes, and then add crystalline Form A seeds (approximately 40 mg). The seeds persist in the reaction vessel. Hold for 2 hours at 45 ° C, then cool to 20 ° C for 12.5 hours (about 2 ° C / hour) linearly, then hold at 20 ° C while adding heptane (16 mL0 for 1 hour using the box At this point, a white paste is formed, so keep it 1 hour at 20 ° C, and subsequently cool to -10 ° C for 10 hours and keep it at -10 ° C for 3 hours. Filter the resulting paste into a pre-cooled sintered glass filter, then wash with 10 mL of 80% heptane / 20% ethanol (denatured with 0.5% by volume of toluene), preheated to approximately 0 ° C. a vacuum oven for 2.5 days at 30 ° C, at an absolute pressure of 19.99-21.33 KPa (150-160 torr) with a nitrogen sweep. The resulting 3.45 g of Form A of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, 1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone obtained from the filter were confirmed by DSC.
[0150] Alternatively, crystal Form A can be prepared by loading the amorphous S form to form a flask containing about 18 ml of diisopropyl ether, 1.1 ml of methanol, and Form A seeds. reaction was stirred. The reaction mixture was heated and cooled from 40 ° C to 2 ° C, with cooling for about 4 hours and heating for about 1 hour, for a duration of six heating and cooling cycles. The reaction mixture was maintained at about 1 ° C for 1 day. The mixture was reheated from 1 ° C to 55 ° C and then cooled to about 25 ° C for a period of about 3.3 hours (approximately 200 minutes), and then cooled again to about 1 ° C for a period about 1 hour. The mixture was kept at room temperature for about 24 hours and then cooled to about 1 ° C for about 30 minutes. The reaction mixture was maintained at 1 ° C for several hours. The solids were transferred to a finely porous thick glass funnel and washed with cyclohexane. The solids were vacuum dried.
[0151] Example 3: Preparation of Crystal Form A of (R) -1- (5'- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di- hydroisoxazol-3-yl) - 3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone - Crystallization of the Amorphous R Enantiomer
[0152] The crystalline form can be prepared with the addition of 50 mg of amorphous R enantiomer from above in a 20 ml glass vial with diethyl ether. The sample was heated and sonicated in a sonication bath for approximately 1 hour. The amorphous solids appeared to dissolve with heating / sonication, and then the solids were observed to come out of the solution. Inspection of the solids by microscopy with polarized light indicated very small particles that may be indicative of birefringence (an indicator of crystallinity). The suspension was removed from the 20 mL glass vial and placed in a sealed 15 mL pressure tube with a PTFE-coated magnetic stir bar (TeflonTM). This tube was heated and cooled from 60 ° C to -10 ° C repeatedly for about 20 hours, with a total of 5 heating / cooling cycles, heating for about 1 hour, cooling for about 3 hours, with magnetic stirring . Examination of the resulting suspension by microscopy with polarized light revealed crystals that were much larger than before the heating / cooling cycles. A small aliquot of the resulting solids was isolated from the suspension by filtration, dried at 30 ° C under vacuum at approximately 19.99 KPa (160 torr) of absolute pressure overnight, and analyzed by PXRD, giving a similar diffraction pattern to Form A. The solids were also analyzed by DSC, and exhibited a broad melting point of about 146 ° C (peak endotherm). HPLC Examination Methods
[0153] Chiral HPLC of sulfonamide enantiomers (approximately 90/10 (S / R)): Chiralpak IA column (250 x 3.0 mm), 50/50 methyl tert-butyl ether / isocratic ethanol with 0.2% of diethylamine, flow rate 1.0 mL / minute, detection at 260 nm. Retention times: 8.5 minutes (S enantiomer) and 16.5 minutes (R enantiomer). The isolated solid is about 99% S and about 1% or less of the inactive (R) isomer. Additional enantiomeric enrichment can be obtained by stirring in MTBE (for example) and filtering out any solids that form. The product was identical to the first enantiomer eluted from the racemate under the preparatory chiral SFC conditions previously described.1H NMR, 600MHz (d6-DMSO): 7.88 (d, 2H), 7.82 (d, 1H), 7.73 (m, 2H), 5.18 (s, 2H), 4.62 (dd, 2H), 4.42 (dd, 2H), 4.28 (m, 4H), 3.20 (s , 3H); m / z (CI) 582 [M + H]. Additional Chiral HPLC Examination Method
[0154] 3 micron column, Chiracel AD-3R, 150 x 4.6 mm. The flow rate of 1.5 mL per minute using a 75:25 methanol / acetonitrile isocratic solvent mixture. Column temperature 40 ° C. Detection at 260 nm. Elution times are: S isomer (4.0 minutes), R isomer (7.8 minutes). Running time 15 minutes. HPLC Examination Method for the S isomer
[0155] 150 x 4.6 mm column, ACE Excel 2 C18-AR. Column temperature of 50 ° C. Detection at 260 nm. The flow rate of 1.5 mL. Mobile phase A: 0.1% trifluorocetic acid in water. Mobile phase B: 0.1% TFA in acetonitrile. Running on a gradient: in the initial time, 45% B, in 4.5 minutes, 55% B, in 20 minutes, 100% B. The elution time of the S isomer is 9.8 minutes.

权利要求:
Claims (16)
[0001]
1. Crystalline form of (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) - 3'H-spiro [aze- tidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone, characterized by the fact that it exhibits at least one of the following properties: (a) a diffraction pattern in X-rays with characteristic peaks expressed in degrees 2θ (± 0.2 °) in about 17.18; 18.83 and 20.07, (b) an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83 and 20.07, including a diffraction peak expressed in degrees 2θ (± 0.2 °) selected from the group consisting of peaks of about 4.70; 9.39; 14.10; 15.70; 19.12; 20.97; 21.42; 22.03; 22.54; 23.62 and 28.42, (c) an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83 and 20.07, including a diffraction peak expressed in degrees 2θ (± 0.2 °) at about 21.42; 22.54 and 28.42; (d) an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83; 20.07; 21.42; 22.54 and 28.42; (e) a differential scan calorimeter thermogram with a single predominant endotherm at about 145.53 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.1; and (f) a differential scanning calorimeter thermogram with a single predominant endotherm in the range of 144.01 to 146.92 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.2.
[0002]
2. Crystalline form according to claim 1, characterized by the fact that it comprises: (i) at least one of the X-ray diffraction patterns selected from: (a) an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83 and 20.07, including a diffraction peak expressed in degrees 2θ (± 0.2 °) at about 21.42; 22.54 and 28.42, (b) an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83; 20.07; 21.42 and 28.42; and (ii) a differential scan calorimeter thermogram with a single predominant endotherm at about 145.53 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.1 or the differential scan calorimeter thermogram. with a single predominant endotherm in the range of 144.01 to 146.92 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.2.
[0003]
3. Crystalline form according to claim 1, characterized by the fact that it comprises an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83; 20.07; 21.42; 22.54 and 28.42.
[0004]
4. Crystalline form according to claim 1, characterized by the fact that it comprises: (a) an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) in about 17.18 ; 18.83; 20.07; 21.42; 22.54 and 28.42; and (b) a differential scan calorimeter thermogram with a single predominant endotherm at about 145.53 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.1 or the differential scan calorimeter thermogram. with a single predominant endotherm in the range of 144.01 to 146.92 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.2.
[0005]
5. Crystalline form according to claim 1, characterized by the fact that it comprises an infrared spectrum of Fourier Transform in the range of 1800 to 600 cm-1, substantially as shown in Figure 2.
[0006]
6. Crystalline form according to claim 1, characterized by the fact that it comprises an X-ray diffraction pattern with characteristic peaks expressed in degrees 2θ (± 0.2 °) at about 17.18; 18.83; 20.07; 21.42; 22.54 and 28.42.
[0007]
7. Crystalline form according to claim 1, characterized by the fact that it comprises a calorimeter thermogram by differential scanning with a single predominant endotherm at about 145.53 ° C at a scan rate of 10 ° C per minute , substantially as shown in Figure 3.1 or the differential scanning calorimeter thermogram with a single predominant endotherm in the range of 144.01 to 146.92 ° C at a scan rate of 10 ° C per minute, substantially as shown in Figure 3.2.
[0008]
8. Composition, characterized in that it comprises a therapeutically effective amount of crystalline Form A as defined in any one of claims 1 to 7 and a pharmaceutically or veterinarily acceptable excipient, diluent, vehicle, or mixture thereof.
[0009]
Composition according to claim 8, characterized in that it further comprises abamectin, selamectin, moxidectin, ivermectin, emamectin, doramectin, eprinomectin, pyrantel, amitraz, albendazole, cambendazole, fenbendazole, fluben- dazola, mebendazole, mebendazole, mebendazole, mebendazole, mebendazole, mebendazole, mebendazole, , oxfendazole, oxybendazole, para-herquamide, parbendazole, praziquantel, thiabendazole, tetramisola, triclabendazole, levamisole, oxantel, novalurone, mo-rantel, milbemycin, milbemycin oxide, demiditraz, diethylcarbamazine- , methoprene, metaflumizone, ni- closamide, permethrin, pyrethrins, pyriproxifene, spinosad, aminoacetonitrile derivative (s), or any mixture thereof.
[0010]
10. Use of a crystalline Form A as defined in any of claims 1 to 7, characterized by the fact that it is in the preparation of a pharmaceutical composition and / or medicament for treating an infection or parasitic infestation in an animal.
[0011]
Use according to claim 10, characterized in that it further comprises at least one additional veterinary agent selected from abamectin, selamectin, moxidectin, ivermectin, emamectin, doramectin, eprinomectin, pyrantel, amitraz, albendazole, cambendazole, fenbendazole , flubendazole, mebendazole, febantel, octadepsipeptides, oxfendazola, oxybendazola, para-herquamide, parbendazola, praziquantel, tiabendazola, tetramisola, triclabendazola, levamisole, oxantel, novaluron, moranilimine, hydroquinone, hydroquinone, - prene, quinoprene, methoprene, metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyphene, spinosad, aminoacetonitrile derivative (s), or any mixture thereof.
[0012]
12. Use according to claim 10 or 11, characterized by the fact that the animal is a pet or livestock animal and the pharmaceutical composition and / or medication are provided orally, topically, or by injection.
[0013]
13. Process for the preparation of crystalline Form A as defined in any of claims 1 to 7, characterized by the fact that it comprises: (a) loading of solids of (S) -1- (5 '- (5- (3, 5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2 - (methylsulfonyl) ethanone amor-fo to a solvent; (b) heating the mixture to about 60 ° C; (c) cooling the mixture to about 45 ° C; (d) adding Form A seeds and maintaining a about 45 ° C (e) slow cooling of the mixture; and (f) filtering, washing and drying the solids.
[0014]
Process according to claim 13, characterized in that the solvent contains about 60% ethanol, about 5% ethyl acetate, and about 35% n-heptane, or a mixture thereof.
[0015]
Process according to claim 14, characterized in that the mixture is cooled from about 60 ° C to about 45 ° C for a period of about 15 to 20 minutes, the seeds of Form A being added, the mixture is kept at 45 ° C for about 2 hours, then linearly cooled to 10 ° C, and maintained at 10 ° C for about 4.5 hours, cooled to 0-1 ° C and maintained at 0- 1 ° C for about 23 hours to obtain a paste.
[0016]
16. Process according to claim 15, characterized in that the paste is filtered under vacuum and the solids are washed with a solution including n-heptane and ethanol, and the solids are further dried under vacuum to obtain Form A resulting.

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同族专利:

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公开号 | 公开日

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SI2890699T1|2018-07-31|

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CN104812758A|2015-07-29|

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TR201807735T4|2018-06-21|

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EP2890699A1|2015-07-08|

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JP2015526522A|2015-09-10|

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HUE037667T2|2018-09-28|

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HRP20180861T1|2018-07-13|

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ES2671271T3|2018-06-05|

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CY1120611T1|2019-12-11|

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ZA201500728B|2016-08-31|

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MX351463B|2017-10-16|

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US20150183795A1|2015-07-02|

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BR112015004135A2|2017-07-04|

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PH12015500441A1|2015-04-20|

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NO2931268T3|2018-04-21|

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NZ704175A|2015-10-30|

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US9200003B2|2015-12-01|

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DK2890699T3|2018-06-14|

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LT2890699T|2018-06-25|

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RU2015107052A|2016-10-20|

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EP2890699B1|2018-04-11|

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CA2881467A1|2014-03-06|

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AU2013308887B2|2015-11-12|

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JP6109942B2|2017-04-05|

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MX2015002679A|2015-05-12|

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PL2890699T3|2018-10-31|

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CN104812758B|2017-05-03|

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KR20150038366A|2015-04-08|

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CA2881467C|2017-08-29|

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AR092409A1|2015-04-22|

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PT2890699T|2018-06-01|

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KR101736643B1|2017-05-16|

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CL2015000332A1|2015-05-15|

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PH12015500441B1|2015-04-20|

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AU2013308887A1|2015-02-19|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2018-03-20| B06I| Technical and formal requirements: publication cancelled|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-08-13| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-09-24| B09A| Decision: intention to grant|

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2020-12-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/08/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261695410P| true| 2012-08-31|2012-08-31|

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US61/695,410|2012-08-31|

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PCT/US2013/056945|WO2014036056A1|2012-08-31|2013-08-28|Crystalline forms of 1--5--4,5-dihydroisoxazol-3-yl)-3'h-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-ethanone|

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