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    • 专利摘要:
    CRYSTAL OF DIAMINE DERIVATIVE AND METHOD OF PRODUCTION THEREOF. It is an object of the present invention to provide a new crystal form of a compound which has inhibitory effect on activated blood coagulation factor X and is useful as a pharmaceutical compound for prevention and/or treatment of thrombotic and/or embolic diseases. The present invention provides a new crystal form of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate, and method for producing the same.
    公开号:BR112012023649B1
    申请号:R112012023649-0
    申请日:2011-03-14
    公开日:2021-06-08
    发明作者:Tetsuya Suzuki；Makoto Ono
    申请人:Daiichi Sankyo Company, Limited；
    IPC主号:
    专利说明:

    Technical Field
    [001] The present invention relates to crystals of a compound which has an inhibitory effect on activated blood coagulation factor X (FXa) and is useful as an agent for prevention and/or treatment of thrombotic diseases. Prior Art
    [002] N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,,) monohydrate 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate represented by the following formula (I) (in the present specification, also referred to as compound I):
    is known as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and is useful as a preventive and/or therapeutic drug for thrombotic diseases (Patent Documents 1 to 9). Crystals described in Patent Document 9 (in the present specification, also referred to as "Form I crystals of compound I" or "Form I crystals") are known as compound I crystals. Citation List Patent Document Patent Document 1: WO03 /000657 Patent Document 2: WO03/000680 Patent Document 3: WO03/016302 Patent Document 4: WO04/058715 Patent Document 5: WO05/047296 Patent Document 6: WO07/032498 Patent Document 7: WO08/129846 Patent Document 8: WO08 /156159Patent Document 9: Japanese Patent Open to Public Inspection No. 2010-254615Summary of the InventionTechnical Problem
    [003] An object of the present invention is to provide new crystals of compound I. Problem Solving
    [004] In an attempt to obtain new crystals of compound I, the inventors of the present invention have not been able to reproducibly and stably obtain new crystals of compound I, even under different crystallization conditions in commonly used stirring or slurry recrystallization methods for polymorph crystal searches. However, as a result of trial and error, the inventors of the present invention have discovered that new crystals (in the present specification, also referred to as "Compound I Form II Crystals" or "Form II Crystals"; Compound I Form II" and "Form II Crystals" are used interchangeably in the present specification) can be obtained reproducibly and stably only under special conditions involving converting compound I temporarily to a lower or amorphous crystalline solid and exposing the solid lower crystalline or amorphous to solvent vapor. Based on this finding, the present invention has been completed.
    [005] Specifically, the present invention relates to the following:[1] Form II crystals of compound I comprising a peak at a diffraction angle (2θ) of 22.3 ± 0.2 or 23.2 ± 0. 2 (°) in powder x-ray diffraction obtained using Cu-Kα rays;[2] the crystals, according to [1], comprising peaks at diffraction angles (2θ) of 22.3 ± 0.2 and 23.2 ± 0.2 (°) in powder x-ray diffraction obtained using Cu-Kα rays;[3] the crystals, according to [1], additionally comprising a peak at a diffraction angle (2θ) of 21.5 ± 0.2 or 22.0 ± 0.2 (°) in powder x-ray diffraction obtained using Cu-Kα rays;[4] the crystals, according to [1], comprising peaks in diffraction angles (2θ) of 13.9 ± 0.2, 14.2 ± 0.2, 15.8 ± 0.2, 16.2 ± 0.2, 18.2 ± 0.2, 21.5 ± 0.2, 22.0 ± 0.2, 22.3 ± 0.2, 23.2 ± 0.2, and 24.3 ± 0.2 (°) in powder x-ray diffraction obtained using Cu-Kα rays;[5] the crystals, according to [1], in which the X-ray powder diffraction obtained using Cu-Kα rays shows a pattern represented by (2) of Figure 1(a) or Figure 3; [6] the crystals, according to [1], wherein the crystals have a differential thermal analysis (DTA) profile having at least one endothermic peak in any of the ranges from 160 °C to 170 °C and 215 °C to 225 °C;[7] the crystals, according to [1], comprising any absorption band selected from the group consisting of 3313 ± 5, 839 ± 1, and 828 ± 1 (cm-1) in a Fourier transform infrared absorption spectrum pattern;[8] the crystals, according to [1], wherein the crystals possess at least one characteristic selected from the group consisting of the following (a) to (d): (a) a differential thermal analysis profile having at least one endothermic peak in each of the ranges of 160°C to 170°C, 215°C to 225°C, and 260°C at 270°C; (b) differential thermal analysis (DTA) and thermogravimetry (TG) profiles represented by Figure 5; (c) a Fourier transform infrared absorption spectrum pattern represented by Figure 6; and (d) a Fourier transform infrared absorption spectrum pattern showing absorption bands and their intensities described in table A below:
    [9] a method for producing Form II Crystals of compound I comprising a peak at a diffraction angle (2θ) of 22.3 ± 0.2 (°) or 23.2 ± 0.2 (°) in diffraction X-ray powder obtained using Cu-Kα rays, the method comprising the steps of (a) converting compound I to a lower or amorphous crystalline solid; and(b) exposing the lower or amorphous crystalline solid to solvent vapor;[10] the method according to [9], wherein step (a) comprises preparing the lower or amorphous crystalline solid by spraying, melting and cooling , freeze-drying or spray drying of compound I;[11] the method according to [9], wherein step (a) comprises preparing the lower or amorphous crystalline solid by freeze-drying compound I;[12] the method, according to [9], wherein step (a) comprises preparing the lower or amorphous crystalline solid by dissolving compound I in water, dioxane, aqueous dioxane or dimethylsulfoxide followed by lyophilization;[13] the method according to [ 9], wherein step (a) comprises preparing the lower or amorphous crystalline solid by dissolving compound I in aqueous dioxane followed by lyophilization; [14] the method according to [9], wherein the solvent used in the exposure of steam in step (b) is anisole, acetone, 2-butanone, toluene, acetonitrile, dimethoxyethane, or dimethoxymethane ;[15] the method according to [9], in which the steam exposure temperature in step (b) is 0°C to 50°C;[16] the method according to [9], in that the vapor exposure time in step (b) is 1 day to 10 days;[17] the method according to [9], wherein the compound I in step (a) is Form I crystals of compound I ;[18] the method according to [9], wherein the Form II crystals comprise peaks at diffraction angles (2θ) of 22.3 ± 0.2 (°) and 23.2 ± 0.2 ( °) in powder x-ray diffraction obtained using Cu-Kα rays; [19] the method according to [9], wherein the Form II crystals additionally comprise a peak at a diffraction angle (2θ) of 21.5 ± 0.2 or 22.0 ± 0.2 (° ) in powder x-ray diffraction obtained using Cu-Kα rays;[20] the method, according to [9], in which Form II crystals comprise peaks at diffraction angles (2θ) of 13.9 ± 0.2, 14.2 ± 0.2, 15.8 ± 0.2, 16.2 ± 0.2, 18.2 ± 0.2, 21.5 ± 0.2, 22.0 ± 0, 2, 22.3 ± 0.2, 23.2 ± 0.2, and 24.3 ± 0.2 (°) in powder x-ray diffraction obtained using Cu-Kα rays;[21] the method, according to [9], in which Form II crystals exhibit a pattern represented by (2) of Figure 1(a) or Figure 3 in an X-ray powder diffraction obtained using Cu-Kα rays;[22] the method according to [9], wherein the Form II crystals exhibit a differential thermal analysis (DTA) profile having at least one endothermic peak in any of the ranges from 160°C to 170°C and 215°C at 225°C;[23] the method according to [9], wherein the Form II crystals comprise any r absorption band selected from the group consisting of 3313 ± 5, 839 ± 1, and 828 ± 1 (cm-1) in a Fourier transform infrared absorption spectrum pattern;[24] the method, according to [9], wherein Form II crystals have at least one characteristic selected from the group consisting of the following (a) to (d): (a) a differential thermal analysis (DTA) profile having at least one endothermic peak in each one of the ranges of 160°C to 170°C, 215°C to 225°C, and 260°C to 270°C; (b) differential thermal analysis (DTA) and thermogravimetry (TG) profiles represented by Figure 5; (c) a Fourier transform infrared absorption spectrum pattern shown in Fig. 6; and (d) a Fourier transform infrared absorption spectrum pattern showing absorption bands and their intensities described in the above-mentioned table A;[25] Form II crystals of compound I obtained by a method according to any one of [9] to [24];[26] pharmaceutical drug containing Form II crystals of compound I according to any one of [1] to [8] or [25] or Form II crystals of compound I obtained by a method according to any one of [9] to [24];[27] the pharmaceutical drug, according to [26], wherein the pharmaceutical drug is an activated blood coagulation factor X inhibitor:[28] the pharmaceutical drug, according to [27], in which the pharmaceutical drug is an agent for the prevention and/or treatment of thrombosis or embolism;[29] the pharmaceutical drug, according to [28], in which the pharmaceutical drug is an agent for prevention and/ or treatment of cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, c syndrome. acute coronary artery, non-valvular atrial fibrillation accompanied by thrombus and/or embolism (NVAF), deep vein thrombosis, deep vein thrombosis after surgery, thrombosis after joint/prosthetic valve replacement, thromboembolism after total hip replacement (THR), thromboembolism after total knee replacement (TKR), thromboembolism after hip fracture surgery (HFS), thrombosis and/or reocclusion after revascularization, Buerger's disease, disseminated intravascular coagulation syndrome, systemic inflammatory response syndrome (SIRS), kidney dysfunction syndrome multiple organ (MODS), thrombosis at the time of cardiopulmonary bypass, or blood clotting at the time of blood collection.[30] a pharmaceutical composition comprising Form II crystals of compound I, according to any one of [1] to [8] or [25], or Form II crystals of compound I obtained by a method, according to any one of [ 9] to [24], and a pharmaceutically acceptable carrier; and [31] a pharmaceutical composition comprising compound I, wherein the pharmaceutical composition comprises Form II crystals of compound I according to any one of [1] to [8] or [25], or Form II crystals of compound I obtained by a method, according to any one of [9] to [24], in an amount of 0.01% by weight to 99.9% by weight with respect to the total weight of the compound I in a pharmaceutical composition. Advantageous Effects of the Invention
    [006] The present invention provides a new crystal form of compound I and a method for producing the same.
    [007] [Figure 1] Figure 1 shows the X-ray diffraction pattern of compound I powder obtained by solvent vapor exposure method-lyophilization in Example 3(4). In each of diagrams (a) through (c), the vertical axis shows intensity (cps), and the horizontal axis shows diffraction angle (2θ (°)). These diagrams show the x-ray powder diffraction results of crystals obtained using (a) acetonitrile, (b) water, or (c) ethanol as the solvent on exposure to steam. In each of diagrams (a) to (c), (1) it shows the powder x-ray diffraction pattern of the starting substance (Form I crystals) before lyophilization, and (2) it shows the diffraction pattern X-ray powder of the substance obtained after exposure to solvent vapor-lyophilization.
    [008] [Figure 2] Figure 2 shows summarized results of determining the ratio of the maximum diffraction line for the historical coefficient around 2θ = 10° (S/B ratio) for the substance obtained by solvent vapor exposure method - lyophilization in example 3(4), and the crystal form of the substance.
    [009] [Figure 3] Figure 3 shows the powder X-ray diffraction pattern of Form II crystals obtained in Example 4. The vertical axis shows intensity (cps) and the horizontal axis shows diffraction angle (2θ (°) )).
    [0010] [Figure 4] Figure 4 shows the characteristic peaks (2θ (°)), d value (Â), and relative intensity (%) in an X-ray powder diffraction of Form II crystals obtained in Example 4 .
    [0011] [Figure 5] Figure 5 shows the DTA profile (top) and TG profile (bottom) of Form II crystals obtained in Example 4. In the DTA diagram, the vertical axis shows heating flux (μV), and the horizontal axis shows temperature (°C). In the TG diagram, the vertical axis shows change in weight (%), and the horizontal axis shows temperature (°C).
    [0012] [Figure 6] Figure 6 shows the infrared absorption spectrum pattern of Form II crystals obtained in Example 4. The vertical axis shows transmittance (%), and the horizontal axis shows wavenumber (cm-1) .
    [0013] [Figure 7] Figure 7 shows characteristic absorption bands and their assignments and intensities in the infrared absorption spectrum of Form II crystals obtained in Example 4.
    [0014] [Figure 8] Figure 8 shows the absorption and desorption behavior of Form II crystals obtained in Example 4. The vertical axis shows weight (% change), and the horizontal axis shows relative humidity (%).
    [0015] [Figure 9] Figure 9 shows the dissolution behavior in water (filled circle) or acetate buffer pH 4.5 (open circle) of Form II crystals obtained in Example 4, and the dissolution behavior in water ( filled square) or acetate buffer pH 4.5 (open square) of Form I crystals. The vertical axis shows concentration (mg/mL), and the horizontal axis shows time (h) after dissolution in each solution.
    [0016] [Figure 10] Figure 10 shows the powder x-ray diffraction pattern of Form I crystals obtained in Example 2. The vertical axis shows intensity (cps), and the horizontal axis shows diffraction angle (2θ ( °)).
    [0017] [Figure 11] Figure 11 shows the DTA profile and TG profile of Form I crystals obtained in Example 2. The vertical axis shows heating flux (μV) and change in weight (%), and the horizontal axis shows temperature (°C).
    [0018] [Figure 12] Figure 12 shows the infrared absorption spectrum pattern of Form I crystals of compound I obtained in Example 2. The vertical axis shows transmittance (%), and the horizontal axis shows wavenumber (cm -1).Description of Modalities
    [0019] Hereinafter, the present invention will be described in detail.
    [0020] N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide represented by the following formula (II) (hereinafter, also referred to as compound II):
    is a free form of compound I and is called edoxaban (N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5 -methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl]oxamide) as International Common Name (INN).
    [0021] No specific limitation is imposed on a method for producing compound II, and compound II can be produced by, for example, a method described in Patent Documents 1 to 9 or an equivalent method thereto.
    [0022] Compound I is called edoxaban tosylate hydrate (written in English) as Japanese Accepted Names for Pharmaceuticals (JAN).
    [0023] No specific limitation is imposed on the method for producing compound I, and compound I can be produced by, for example, a method described in Patent Documents 1 to 9 or an equivalent method thereto, for example involving the adding a solution of p-toluenesulfonic acid in ethanol to compound II, then dissolving compound II by adding more aqueous ethanol, and depositing crystals by cooling the reaction solution to obtain a crystalline compound. The compound I crystals thus synthesized exhibit an X-ray powder diffraction pattern represented by Figure 10 as a diffraction angle (2θ (°)) in X-ray powder diffraction obtained using Cu-Kα rays and possess peaks characteristics at diffraction angles (2θ (°)) of 5.38 ± 0.2, 8.08 ± 0.2, 10.8 ± 0.2, 13.5 ± 0.2, 15.0 ± 0. 2, 16.9 ± 0.2, 17.6 ± 0.2, 20.5 ± 0.2, 21.1 ± 0.2, 22.7 ± 0.2, 23.5 ± 0.2, 26.0 ± 0.2, 27.3 ± 0.2, 27.6 ± 0.2, and 30.0 ± 0.2 (°). In the present specification, crystals of compound I which are produced by a method described in Patent Documents 1 to 9 or an equivalent method thereto and exhibit an x-ray powder diffraction pattern represented by Figure 10 are also referred to as " Form I crystals of compound I" or "Form I crystals". The terms "Form I crystals of compound I" and "Form I crystals" are used interchangeably in the present specification. The Form I crystals of compound I still possess any characteristic selected from the group consisting of the following (v) to (z): (v) a DTA profile having two endothermic peaks at approximately 250 °C to approximately 270 °C; (w) a DTA profile represented by Fig. 11;(x) an infrared absorption spectrum comprising any absorption band selected from the group consisting of 3344 ± 5, 1675 ± 2, 1614 ± 2, 1503 ± 2, 1222 ± 1, 1171 ± 1, 1033 ± 1, 1012 ± 1, 843 ± 1, 825 ± 1, and 802 ± 1 (cm-1); (y) an infrared absorption spectrum pattern represented by Figure 12; and/or(z) a melting point (decomp.) of approximately 246°C to approximately 250°C.
    [0024] In the present specification, the "amorphous solid" refers to a non-crystalline solid having no regular three-dimensional crystal structure. The compound of interest is confirmed to be amorphous, for example, when a broad powder x-ray diffraction (halo) profile without specific peaks is generated in an x-ray powder diffraction analysis of the compound.
    [0025] In the present specification, "low crystalline solid" means metastable crystals with low crystallinity that do not exhibit as broad a powder x-ray diffraction profile as that of the amorphous solid, but do exhibit weak peaks in x-ray diffraction of powder.
    In the present specification, "amorphous solid" and "little crystalline solid" are also collectively referred to as amorphous solid etc.
    One embodiment of the present invention relates to Form II crystals of compound I.
    [0028] The results of X-ray powder diffraction analysis obtained using Cu-Kα rays in the Form II crystals of the present invention are shown in (2) of Figure 1(a), Figure 3 or Figure 4. In the present specification, the X-ray powder diffraction analysis value is a value obtained using Cu-Kα rays, unless otherwise specified. When x-rays other than Cu-Kα rays are used, 2θ (°) varies according to the formula 2dsinθ = nA (d represents the space between two planes; n represents any integer; A represents the x-ray wavelength ). However, these are merely indicated by another method substantially equivalent to the Form II crystals of the present invention and included within the scope of the present invention. This can be readily understood by those skilled in crystallography. Also, the relative intensities of the peaks shown in these graphs can vary depending on, for example, the degree of crystallinity of the sample or a method of preparation. 2θ (°) is substantially invariant, but may vary within an error range (usually ±0.2°) recognized by those skilled in crystallography.
    [0029] An embodiment of the present invention relates to Form II crystals of compound I comprising a peak at a diffraction angle (2θ (°)) of 22.3 ± 0.2 (°) in x-ray diffraction of powder obtained using Cu-Kα rays. Another embodiment of the present invention relates to Form II crystals of compound I comprising a peak at a diffraction angle (2θ (°)) of 23.2 ± 0.2 (°) in X-ray powder diffraction obtained using Cu-Kα rays. A further embodiment of the present invention relates to Form II crystals of compound I comprising peaks at diffraction angles (2θ (°)) of 22.3 ± 0.2 (°) and 23.2 ± 0.2 (° ) in powder x-ray diffraction obtained using Cu-Kα rays. A further embodiment of the present invention relates to Form II crystals of compound I comprising a peak at a diffraction angle (2θ (°)) of 22.3 ± 0.2 (°) or 23.2 ± 0.2 (°) in X-ray powder diffraction obtained using Cu-Kα rays and further comprising therein a peak at a diffraction angle (2θ (°)) of 21.5 ± 0.2 or 22.0 ± 0.2 (°). Furthermore, a further embodiment of the present invention relates to Form II crystals of compound I comprising peaks at diffraction angles (2θ (°)) of 13.9°, 14.2°, 15.8°, 16, 2°, 18.2°, 21.5°, 22.0°, 22.3°, 23.2°, and 24.3° in powder x-ray diffraction obtained using Cu-Kα rays.
    [0030] The Form II crystals of compound I of the present invention are preferably crystals comprising a peak at a diffraction angle (2θ (°)) of 22.3 ± 0.2 (°) or 23.2 ± 0.2 (°) in X-ray powder diffraction obtained using Cu-Kα rays, more preferably crystals comprising at least two peaks selected from the group consisting of peaks in 21.5 ± 0.2, 22.0 ± 0.2, 22.3 ± 0.2, and 23.2 ± 0.2(°). Furthermore, the Form II crystals of compound I of the present invention are preferably crystals having a graph or peaks represented by (2) of Figure 1(a), Figure 3 or Figure 4 as diffraction angles (2θ (°)) in X-ray powder diffraction obtained using Cu-Kα rays. These peaks are particularly useful in discriminating between Form II crystals and Form I crystals of compound I.
    [0031] The compound can be determined to be crystalline from X-ray powder diffraction results. For example, sharp peaks shown in (1) of Figure 1(a), (2) of Figure 1(a), (1) of Figure 1(b) and (1) of Figure 1(c) can demonstrate that the compound is crystalline. In contrast, a broad pattern, except for a peak around 2θ = 17.5, shown in (2) of Figure 1(b) can demonstrate that the compound is poorly crystalline. Form II crystals exhibit a lower history/signal ratio (S/B Ratio) in an X-ray powder diffraction pattern than Form I crystals, suggesting that Form II crystals are less crystalline than Form II crystals. Form I crystals. In crystal analysis using X-ray powder diffraction, if two or more polymorphs are contained in a sample, a crystal form having a lower history/signal ratio may be hidden by the peak of the crystal form having higher historical/signal ratio and thus difficult to detect in terms of powder x-ray diffraction analysis properties.
    [0032] The results of differential thermal analysis (DTA) and thermogravimetry (TG) on the Form II crystals of compound I of the present invention are shown in Figure 5. One embodiment of the present invention relates to Form II crystals of compound I which exhibit a DTA profile having at least one endothermic peak at approximately 160°C to approximately 170°C or exhibit a DTA profile having at least one endothermic peak at approximately 215°C to approximately 225°C. Another embodiment of the present invention relates to Form II crystals of compound I which exhibit a DTA profile having at least one endothermic peak in each of the ranges of approximately 160°C to approximately 170°C, approximately 215°C to approximately 225 °C, and approximately 260 °C to approximately 270 °C or exhibit DTA and TG profiles represented by Figure 5. The Form II crystals of the present invention preferably exhibit a DTA profile having at least one endothermic peak at approximately 160 °C at approximately 170°C or approximately 215°C to approximately 225°C.
    [0033] The Fourier transform infrared (FT-IR) absorption spectrum pattern of the compound of the present invention is shown in Figure 6, Figure 7 and table A. In the present specification, the infrared absorption spectrum was measured by Fourier transform infrared spectroscopy, unless otherwise specified. Each absorption band in the infrared absorption spectrum pattern is substantially invariant from the value described in the present specification so that it is measured using the same type of infrared spectroscopy. In this context, the term "substantially invariant" means that each peak in the infrared absorption spectrum may vary within an error range recognized by those skilled in crystallography (see, for example, Instruction Manual of the Japanese Pharmacopoeia, 15th ed., 2006, B-211 to B-217).
    [0034] An embodiment of the present invention relates to Form II crystals of compound I having an absorption band of 3313 ± 5 (cm-1) in a Fourier transform infrared absorption spectrum. Another embodiment of the present invention relates to Form II crystals of compound I having an absorption band of 3354 ± 5 (cm-1) in a Fourier transform infrared absorption spectrum. One embodiment of the present invention relates to Form II crystals of compound I having an absorption band of 839 ± 1 (cm-1) in a Fourier transform infrared absorption spectrum. One embodiment of the present invention relates to Form II crystals of compound I having an absorption band of 828 ± 1 (cm-1) in a Fourier transform infrared absorption spectrum. The Form II crystals of compound I of the present invention preferably comprise any absorption band selected from the group consisting of 3313 ± 5, 828 ± 1, and 839 ± 1 (cm-1).
    [0035] More preferably, the Form II crystals of compound I of the present invention possess, in addition to the aforementioned characteristics of the powder x-ray diffraction pattern, any other characteristic selected from the group consisting of the following: (y) a profile DTA having at least one endothermic peak in each of the ranges of 160°C to 170°C, 215°C to 225°C, and 260°C to 270°C; (z) DTA and TG profiles represented by Figure 5; (aa) a Fourier transform infrared absorption spectrum pattern shown in Fig. 6; and (bb) a Fourier transform infrared absorption spectrum pattern showing absorption bands and their intensities described in table A above.
    An embodiment of the present invention relates to a method for producing Form II crystals of compound I. This method comprises the steps of (a) converting compound I to a lower or amorphous crystalline solid and (b) exposing the lower crystalline solid or amorphous to solvent vapor. No specific limitation is imposed on the crystalline state of compound I used as a starting material in step (a), as long as it is compound I. Examples thereof include Form I crystals, a mixture of Form I crystals and a low crystalline solid or amorphous of compound I, Form I crystals containing Form II crystals as impurities, compound I whose crystalline state is unconfirmed, compound I in a different form than Form I crystals or Form II crystals, and Form I crystals containing compound I in a form other than Form I crystals or Form II crystals as impurities. The compound I used as the starting material in step (a) is preferably Form I crystals of compound I.
    [0037] Examples of methods of preparation for the amorphous solid etc. of compound I include, but are not limited to, spraying the compound I, melting and cooling the same, lyophilizing the same, and spray drying the same and preferably include the melting and cooling method and the freeze-drying method, with the method of lyophilization being more preferable.
    [0038] When compound I is converted to amorphous solid etc. by dissolving compound I in a solvent followed by lyophilization, examples of the solvent include, but are not particularly limited to, water, dioxane, aqueous dioxane, dimethylsulfoxide, a mixed solution of dioxane/dimethylsulfoxide, a mixed solution of water/dioxane/dimethyl sulfoxide, methanol, acetonitrile, tetrahydrofuran, aqueous tetrahydrofuran, dimethylformamide and dimethylacetamide, and preferably include 1,4-dioxane, aqueous 1,4-dioxane, a mixed solution of 1,4-dioxane/dimethyl sulfoxide, and a mixed solution of water/1,4-dioxane/dimethyl sulfoxide, with aqueous 1,4-dioxane being more preferable. In the case where the solvent is an aqueous solvent, no specific limitation is imposed on its percent water content. Examples thereof include solvents having a percent water content of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% and preferably include solvents having a 30%, 40%, 50%, 60% or 70% percent water content, with solvents having a 40%, 50%, or 60% percent water content being more preferable. The amount of the solvent is not particularly limited and is, for example, 100 ml to 500 ml per g of the compound, preferably 200 ml to 400 ml per g of the compound. Freeze-drying time and temperature are not particularly limited and freeze-drying can be achieved, for example, at -80°C to 30°C for a few hours to 24 hours.
    The lower or amorphous crystalline solid of compound I thus obtained may be exposed to solvent vapor to thereby prepare Form II crystals of compound I. Form II crystals may be prepared by exposing the amorphous solid etc. of compound I to solvent vapor, for example, by the following procedures: a first container (preferably an airtight container) and a second container which is smaller than the first container and is capable of being housed in the first container are initially prepared. The exposure solvent is placed in the first container and the amorphous solid etc. of compound I is placed in the second container, respectively, and left until they reach the exposure temperature condition. When each container reaches the exposure temperature condition, the second container is placed in the first container without being hermetically sealed. The first container is hermetically sealed with a lid, a paraffin film, or the like, wherein the second container is in the first container. The amorphous solid etc. is exposed to the solvent at the temperature of interest for the time of interest. Then, the first container is opened, and crystals in the second container can be collected to obtain Form II crystals of compound I. In this context, examples of the types of the first and second containers include, but are not particularly limited to, beakers and bottles. The types of the first and second containers can be suitably selected according to the amount of Form II crystals of compound I to be prepared. Likewise, examples of materials for the first and second containers include, but are not particularly limited to, glass or metal containers. These materials can be suitably selected by those skilled in the art.
    [0040] The exposure temperature to solvent vapor is not particularly limited and is, for example, 0°C to 50°C, preferably 5°C to 40°C, more preferably 5°C, 25°C, or 40 °C, even more preferably 5°C.
    [0041] The exposure time to solvent vapor is not particularly limited and can be adjusted accordingly according to the exposure temperature. Exposure time is generally 1 day to 10 days, preferably 2 days to 5 days, preferably 3 days, 4 days or 5 days.
    [0042] The amount of solvent placed in the first container is not particularly limited and is generally an amount in which the entire bottom of the first container is covered by an amount reaching approximately 1 cm below the mouth of the second container, preferably an amount that reaches 1 cm deep at the bottom of the first container.
    [0043] Examples of the solvent used in vapor exposure include water, acetone, anisole, 1-butanol, 2-butanol, methyl-tert-butyl ether, cumene, ethyl acetate, diethyl ether, isopropyl acetate, methyl acetate, methyl-ethyl-ketone (2-butanone), 2-methyl-1-propanol, 1-propanol, 2-propanol, toluene, acetonitrile, dimethoxyethane, dimethoxymethane, and acetic acid. Preferable examples of the solvent used in the vapor exposure include anisole, acetone, 2-butanone, toluene, acetonitrile, dimethoxyethane and dimethoxymethane, with acetone, acetonitrile, and dimethoxymethane being more preferable.
    [0044] When acetonitrile is used as the solvent in steam exposure, its temperature is not particularly limited and is generally 0°C to 50°C, preferably 5°C to 40°C, more preferably 5°C, 25 °C or 40 °C, even more preferably 5°C. Furthermore, the amount of acetonitrile placed in the first container is not particularly limited and is generally an amount where the entire bottom of the first container is covered by an amount reaching approximately 1 cm below the mouth of the second container, preferably an amount that reaches 1 cm deep at the bottom of the first container. The exposure time to acetonitrile vapor is not particularly limited and is generally 2 to 10 days, preferably 3 days, 4 days or 5 days.
    [0045] The obtained crystals can be examined for their physical properties using various instruments useful in crystal analysis, including powder x-ray diffractometers and other instruments, eg infrared spectrometers, thermal analyzers (eg differential thermal analyzers and thermogravimeters) and water vapor adsorption analyzers.
    [0046] The thus-obtained Form II crystals of compound I of the present invention are useful as an inhibitor of activated blood coagulation factor X (also referred to as FXa), an anticoagulant agent, or an agent for preventing and/or treating thrombosis or embolism. The Form II crystals of compound I of the present invention are useful as a pharmaceutical drug for mammals including humans, activated blood coagulation factor X inhibitor, an anticoagulant agent, or an agent for preventing and/or treating thrombosis and/or embolism , an agent for preventing and/or treating thrombotic diseases, and in addition, an agent for preventing (in the present specification, prevention includes secondary prevention) and/or treating cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, infarction of the myocardium, angina pectoris, acute coronary syndrome, non-valvular atrial fibrillation accompanied by thrombus and/or embolism (NVAF), deep vein thrombosis, deep vein thrombosis after surgery, thrombosis after joint/prosthetic valve replacement, thromboembolism after total hip replacement (THR), thromboembolism after total knee replacement (TKR), thromboembolism after hip fracture surgery (HFS), thrombosis and/or reocclusion are after revascularization, Buerger's disease, disseminated intravascular coagulation syndrome, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombosis at the time of cardiopulmonary bypass or blood coagulation at the time of blood collection or as bulk pharmaceuticals for these agents for disease prevention and/or treatment.
    The pharmaceutical drug comprising the Form II crystals of compound I of the present invention as an active ingredient is preferably provided in the form of a pharmaceutical composition comprising the Form II crystals of compound I of the present invention and one or two or more carriers pharmaceutically acceptable. No specific limitation is imposed on the dosage form of the pharmaceutical drug of the present invention, and the pharmaceutical drug of the present invention can be administered orally or parenterally and, preferably, administered orally.
    The present invention also relates to a pharmaceutical composition comprising compound I. The pharmaceutical composition of the present invention comprises the Form II crystals of the present invention as at least a portion of compound I. The pharmaceutical composition may contain a form of crystal (eg Form I crystals) different from Form II crystals as compound I. The proportion of Form II crystals contained in a pharmaceutical composition may range from 0.01% by weight to 99.9% by weight , for example, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 5% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, 90% by weight or more, 95% by weight or more, 96% by weight or more, 97% by weight or more, 98% by weight or more, 9 9% by weight or more, 99.5% by weight or more, 99.6% by weight or more, 99.7% by weight or more, 99.8% by weight or more, or 99.9% by weight or more, with respect to the total of compound I in a pharmaceutical composition. Form II crystals of compound I can be confirmed as present in a pharmaceutical composition by an instrumental analysis method (e.g., powder x-ray diffraction, thermal analysis, and infrared absorption spectroscopy) described in the present specification.
    [0049] Examples of pharmaceutically acceptable carriers used in the production of the pharmaceutical composition may include, but are not limited to, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases, solubilizing agents or auxiliaries solubilizers, tonicity agents, pH adjusters, stabilizers, propellants and adhesion agents.
    [0050] Examples of preparations suitable for oral administration may include tablets, powders, granules, capsules, solutions, syrups, elixirs and oily or aqueous suspensions. Furthermore, examples of preparations suitable for parenteral administration may include injections, drops, suppositories, inhalers and patches.
    [0051] The dose of a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient is not particularly limited and can be appropriately selected according to various conditions, such as age , body weight and patient symptoms. The pharmaceutical composition is preferably administered once to several times a day, preferably once to twice a day, at a dose of 1 mg to 1000 mg, preferably 5 mg to 500 mg, more preferably 5 mg to 300 mg, even more preferably 5 mg to 100 mg of the active ingredient per day in an adult according to symptoms.
    [0052] Hereinafter, Examples will be described. However, the present invention should not be limited thereto.Examples (Example 1) Synthesis of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl ]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl) ethandiamide (compound II)
    Compound II was synthesized according to a method described in Patent Documents 1 to 9. (Example 2) Synthesis of Form I crystals of N1-(5-chloropyridin-2-yl)-N2-((( 1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino }cyclohexyl)ethanediamide p-toluenesulfonate (compound I)
    4.1 g of the compound obtained in example 1 were suspended in 50 ml of 15% aqueous ethanol at 60°C. The compound was dissolved by adding 7.42 mL of a 1 mol/L solution of p-toluenesulfonic acid in ethanol and then a further 40 mL of 15% aqueous ethanol. Then the solution was cooled to room temperature and stirred for 1 day. Deposited crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain 4.7 g of the title crystals (86%). Melting point (decomp.): 246 to 250°C. (Example 3) Search for polymorph crystal of compound I
    [0055] In this Example, X-ray powder diffraction was performed under the following conditions: Source: Cu-Kα rays, filter: absent, detector: proportional counter, tube voltage: 40 kV, tube current: 50 mA, scan mode: continuous, crust rate: 0.015° 2θ/s, scan range: 2θ = 5-40°, apparatus: X'pert MPD PW3040 (manufactured by PANalytical).(1) Slurry agitation method
    [0056] Approximately 100 mg of Form I crystals of compound I were weighed into each of 32 glass vials, and 1 mL of each of 32 types of solvents (water, acetone, anisole, 1-butanol, 2-butanol , n-butyl acetate, methyl-t-butyl ether, cumene, ethanol, ethyl acetate, diethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol , methyl ethyl ketone (butanone), methyl isobutyl ketone (3-methyl-2-butanone), 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, toluene, dichloromethane , acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethoxyethane and dimethoxymethane) was added thereto. Samples supplemented with diethyl ether or pentane were stirred at a constant temperature of 20°C for 61 hours or more. The samples supplemented with the other solvents were stirred by slurry at 50°C for 50 hours and then cooled to 20°C.
    Each sample thus slurried was centrifuged and the supernatant removed using a Pasteur pipette. Residual solvent was further removed on a filter paper, and the residue was then air dried overnight.
    [0058] All 32 types of crystals obtained using each solvent exhibited an x-ray powder diffraction pattern equivalent to Form I crystals prior to slurry agitation. Thus, the slurry stirring method failed to produce a new polymorph of compound I.(2) Recrystallization method using simple solvent
    8 ml of methanol were added to approximately 500 g of Form I crystals of compound I, and the crystals were dissolved by heating in a hot bath (60°C). Then, the solution was left at room temperature to deposit crystals. The obtained crystals were collected by filtration and air dried overnight.
    [0060] Recrystallization was attempted by dissolving Form I crystals of compound I by heating in the same manner as in methanol, except that the solvent was changed to water, ethanol, acetonitrile, dimethylsulfoxide, or dimethylformamide.
    [0061] When methanol, water, ethanol, acetonitrile or dimethylformamide were used alone as a simple solvent, crystals were deposited. However, all of these crystals exhibited an x-ray powder diffraction pattern equivalent to Form I crystals prior to recrystallization. Use of dimethylsulfoxide as a simple solvent failed to deposit solids.(3) Recrystallization method using aqueous solvent
    10 mL of 10% aqueous methanol was added to approximately 500 mg of Form I crystals of compound I, and the crystals were dissolved by heating in a hot bath (60°C). The solution was thermally filtered. The filtrate was left at room temperature to deposit crystals. The obtained crystals were collected by filtration and air dried overnight.
    [0063] Recrystallization was attempted by dissolving Form I crystals of compound I by heating in the same manner as using 10% aqueous methanol as a solvent, except that the solvent was changed to 20% aqueous methanol, 50% aqueous methanol, 80 % aqueous methanol, 10% aqueous ethanol, 20% aqueous ethanol, 50% aqueous ethanol, 80% aqueous ethanol, 10% aqueous acetone, 20% aqueous acetone, 50% aqueous acetone, 80% aqueous acetone, 10% aqueous acetonitrile, 20 % aqueous acetonitrile, 50% aqueous acetonitrile, 80% aqueous acetonitrile, 10% aqueous 1-propanol, 20% aqueous 1-propanol, 50% aqueous 1-propanol, 80% aqueous 1-propanol, 10% aqueous 2-propanol, 20 % aqueous 2-propanol, 50% aqueous 2-propanol, or 80% aqueous 2-propanol.
    [0064] When 24 types of solvents were used, crystals were deposited in all cases. However, all of these crystals exhibited an X-ray powder diffraction pattern equivalent to Form I crystals prior to recrystallization. (4) Solvent vapor exposure method-lyophilization
    [0065] 120 ml of water were mixed with 120 ml of 1,4-dioxane to prepare a mixed solution of water/1,4-dioxane (1:1). Approximately 500 mg of Form I crystals of compound I were dissolved by the addition of 200 ml of the mixed water/1,4-dioxane solution (1:1), and the solution was divided into six 100-ml beakers and lyophilized.
    [0066] Each lyophilized cake obtained was placed together with the beaker in a metal drum (Sanko Astec Inc., stainless container, 4 L, CTH-18) containing a small amount of each solvent for exposure to steam (water, ethanol, or acetonitrile). Two beakers were used at each exposure to solvent vapor for reproducibility. The metal drum was stored in a refrigerator for 5 days, and the freeze-dried cake was then removed from the container and dried overnight at normal pressure. The lyophilized cake exposed to solvent vapor was gently mixed using a spatula.
    [0067] Figure 1 shows the x-ray powder diffraction pattern of compound I obtained by solvent vapor exposure method-lyophilization. Reproducibility was obtained between two test tubes in all solvent vapor exposure operations. Figure 1 shows typical results of compound I obtained from any of the beakers on each exposure to solvent vapor.
    The sample exposed to steam and the sample exposed to acetonitrile vapor exhibited a diffraction pattern different from that of Form I crystals (Figure 1(a)).
    [0069] Figure 2 shows summarized results of determining the ratio of the maximum diffraction line to the historical coefficient around 2θ = 10° (S/B Ratio) for compound I obtained by solvent vapor exposure method-lyophilization , the diffraction angle of the main diffraction line, and the crystal form of compound I.
    [0070] The sample exposed to acetonitrile vapor showed different diffraction lines with an S/B ratio of 5 or more and was thus determined to be crystalline. The sample exposed to acetonitrile vapor differed both in the diffraction angle of the main diffraction line and the diffraction pattern of the Form I crystals and thus appeared to have a different crystal shape than the Form I crystals (Figures 1 (a) and 2).
    [0071] The sample exposed to water vapor had an S/B ratio of 5 or more, but had very few diffraction lines as much as two or three lines compared to normal crystalline samples and very broad pattern of diffraction lines and was then determined to be poorly crystalline (Figures 1(b) and 2).
    [0072] The sample exposed to ethanol vapor showed different diffraction lines with an S/B ratio of 5 or more and was thus determined to be crystalline. The crystal form of the sample exposed to ethanol vapor had the diffraction angle of the main diffraction line and a diffraction pattern equivalent to Form I crystals and thus appeared to be Form I crystals (Figures 1(c) and 2 ). (Example 4) Form II crystals of compound I
    [0073] 2.5 g of Form I crystals of compound I were dissolved by the addition of 1000 ml of the water/1,4-dioxane mixed solution, and approximately 80 ml/beaker of the solution was distributed into fourteen glass beakers. 100-ml and lyophilized.
    [0074] Each lyophilized cake obtained was placed together with the beaker in a metal drum (Sanko Astec Inc., stainless container, 4 L, CTH-18) containing a small amount of acetonitrile and exposed to solvent vapor in a refrigerator (approximately 5°C) for 8 days. The freeze-dried cake was removed from the container and stored at room temperature for 6 days in a desiccator containing silica gel. The freeze-dried cakes exposed to solvent vapor were collected from the fourteen beakers and combined into one portion, which was then subjected to the following Test Examples 1 to 5. (Test Example 1)
    [0075] The Form II crystals obtained in Example 4 were prepared for analysis and analyzed for their crystal form using an X-ray powder diffractometer. Conditions for X-ray powder diffractometry were the same as in Example 3.
    [0076] The results of the X-ray powder diffraction pattern are shown in Figure 3, and characteristic peaks and their relative intensities are shown in Figure 4. (Test Example 2)
    [0077] The Form II crystals obtained in Example 4 were prepared for analysis and tested by thermal analysis (TG/DTA). Test conditions for a thermal analysis (TG/DTA): atmosphere: 200 mL/min nitrogen, heating rate: 10°C/min, sample quantity: approximately 3 mg, instrument: TG/DTA6200 (manufactured by SII NanoTechnology Inc .).
    [0078] The results are shown in Figure 5. The crystals obtained in Example 4 exhibited a thermal analysis profile (DTA) having at least one endothermic peak in each of the ranges from approximately 160°C to approximately 170°C, approximately 215 °C to approximately 225°C, and approximately 260°C to approximately 270°C. (Test Example 3)
    [0079] The Form II crystals obtained in Example 4 were prepared for analysis and analyzed by infrared absorption spectroscopy. Conditions for infrared absorption spectroscopy: method: KBr tablet method, apparatus: FT-720 (manufactured by HORIBA, Ltd.).
    [0080] The results are shown in Figures 6 and 7. The crystals obtained in Example 4 exhibited an infrared absorption spectrum pattern having characteristic absorption bands around 3300 to 3400 (cm-1) and around 900 to 700 (cm-1). (Test Example 4)
    [0081] Approximately 20 mg of the Form II crystals obtained in Example 4 were analyzed for time-dependent change in weight over a relative humidity range of 10 to 90% using a water vapor adsorption analyzer (SGA-100, VTI Corporation).
    [0082] The results are shown in Figure 8. (Example of Test 5)
    The Form II crystals obtained in Example 4 and Form I crystals of compound I were analyzed for their solubility in water and an acetate buffer (pH 4.5) at 37°C.
    [0084] The results are shown in Figure 9. (Example of Preparation)
    [0085] Form II crystals (40.4 mg) of the compound, mannitol (99.2 mg), pregelatinized starch (42.0 mg), crospovidone (10.7 mg), hydroxypropyl cellulose (6.1 mg), and magnesium stearate (1.6 mg) are used to make tablets according to a widely known method. Tablets can be coated if necessary.
    权利要求:
    Claims (15)
    [0001]
    1. Method for producing Form II crystals of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-methyl-4,5,6,7-tetrahydrothiazol[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate represented by the following formula (I):
    [0002]
    2. Method according to claim 1, CHARACTERIZED by the fact that step (a) comprises preparing the lower or amorphous crystalline solid by spraying, melting and cooling, lyophilizing or spray drying the compound represented by formula (I).
    [0003]
    3. Method according to claim 1, CHARACTERIZED by the fact that step (a) comprises preparing the lower or amorphous crystalline solid by lyophilization of the compound represented by formula (I).
    [0004]
    4. Method according to claim 1, CHARACTERIZED by the fact that step (a) comprises preparing the lower or amorphous crystalline solid by dissolving the compound represented by formula (I) in water, dioxane, aqueous dioxane or dimethyl sulfoxide followed by by lyophilization.
    [0005]
    5. Method according to claim 1, CHARACTERIZED by the fact that step (a) comprises preparing the lower or amorphous crystalline solid by dissolving the compound represented by formula (I) in aqueous dioxane followed by lyophilization.
    [0006]
    6. Method according to claim 1, CHARACTERIZED by the fact that the steam exposure temperature in step (b) is from 0 °C to 50 °C.
    [0007]
    7. Method according to claim 1, CHARACTERIZED by the fact that the steam exposure time in step (b) is from 1 day to 10 days.
    [0008]
    8. Method according to claim 1, CHARACTERIZED by the fact that the compound represented by formula (I) in step (a) is Form I crystals of the compound represented by formula (I).
    [0009]
    9. Method according to claim 1, CHARACTERIZED by the fact that Form II crystals comprise peaks at diffraction angles (2θ) of 22.3 ± 0.2 (°) and 23.2 ± 0.2 ( °) in powder x-ray diffraction obtained using Cu-Kα rays.
    [0010]
    10. The method according to claim 1, CHARACTERIZED by the fact that the Form II crystals additionally comprise a peak at a diffraction angle (2θ) of 21.5 ± 0.2 or 22.0 ± 0.2 ( °) in powder x-ray diffraction obtained using Cu-Kα rays.
    [0011]
    11. Method according to claim 1, CHARACTERIZED by the fact that Form II crystals comprise peaks at diffraction angles (2θ) of 13.9 ± 0.2, 14.2 ± 0.2, 15.8 ± 0.2, 16.2 ± 0.2, 18.2 ± 0.2, 21.5 ± 0.2, 22.0 ± 0.2, 22.3 ± 0.2, 23.2 ± 0 .2 and 24.3 ± 0.2 (°) in powder x-ray diffraction obtained using Cu-Kα rays.
    [0012]
    12. Method according to claim 1, CHARACTERIZED by the fact that Form II crystals exhibit a pattern represented by (2) of the following diagrams:
    [0013]
    13. Method according to claim 1, CHARACTERIZED by the fact that Form II crystals exhibit a differential thermal analysis profile having at least one endothermic peak in any of the ranges from 160 °C to 170 °C and 215° C to 225 °C.
    [0014]
    14. Method according to claim 1, CHARACTERIZED by the fact that Form II crystals comprise any one absorption band selected from the group consisting of 3313 ± 5, 839 ± 1 and 828 ± 1 (cm-1) in a Fourier transform infrared absorption spectrum.
    [0015]
    15. Method according to claim 1, CHARACTERIZED by the fact that Form II crystals have at least one characteristic selected from the group consisting of the following (a) to (d): (a) a differential thermal analysis profile ( DTA) having at least one endothermic peak in each of the ranges from 160 °C to 170 °C, 215 °C to 225 °C and 260 °C to 270 °C; (b) differential thermal analysis and thermogravimetry profiles represented by following diagrams: (c) a Fourier transform infrared absorption spectrum pattern represented by the following diagram: (d) a Fourier transform infrared absorption spectrum pattern showing absorption bands and their intensities described in the following table A:
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    同族专利:
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    CN102791719B|2015-07-29|
    JP5692873B2|2015-04-01|
    CA2793413C|2015-11-24|
    EP2548879A4|2013-07-31|
    KR101708528B1|2017-02-20|
    JPWO2011115066A1|2013-06-27|
    CA2793413A1|2011-09-22|
    TW201141874A|2011-12-01|
    EP2548879B1|2015-12-09|
    CN102791719A|2012-11-21|
    TWI461429B|2014-11-21|
    KR20130016225A|2013-02-14|
    US20130035356A1|2013-02-07|
    US8541443B2|2013-09-24|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-01-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-03-12| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2021-04-27| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 14/03/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    JP2010063693|2010-03-19|
    JP2010-063693|2010-03-19|
    PCT/JP2011/055955|WO2011115066A1|2010-03-19|2011-03-14|Crystal of diamine derivative and method of producing same|
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