(S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, novel crystalline forms thereof and co-crystalline forms thereof

Abstract

The present invention relates to novel crystalline forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, processes for their preparation, medicaments, and pharmaceutical compositions containing these forms.

Description

Technical Field

[0001] Field of the Invention The present invention relates to novel crystalline forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, processes for their preparation, and pharmaceuticals and pharmaceutical compositions containing these forms.

Background Art

[0002] Background of the Invention WO 2020 / 152132 A1 (Compound 25) discloses (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide after chiral resolution by HPLC. WO 2020 / 152132 A1 describes the process for its manufacture and the yield in the amorphous state of the compound. Apart from this, no dedicated crystalline forms of the compound are mentioned in WO 2020 / 152132 A1.

[0003] However, when the active substance is intended as the active ingredient of a pharmaceutical product, the amorphous state, which is generally a more thermodynamically unstable form, has disadvantages in terms of chemical and physical stability, and has an adverse effect on the dissolution rate, bioavailability, effectiveness, and storage of the drug.

[0004] Therefore, the object of the present invention is the development of alternative solid forms that overcome these disadvantages.

[0005] Summary of the Invention Surprisingly, the inventors have discovered a novel crystalline anhydrous form called A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0006] Furthermore, the inventors have discovered new hydrated forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, namely NF2, NF3, NF4, and NF12.

[0007] In addition, the inventors have discovered a new anhydrous pure crystalline co-crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide with 3-hydroxybenzoic acid, which exhibits improved solubility in a biorelevant intestinal environment (FaSSIF) compared to the crystalline 3-hydroxybenzoic acid of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, and has been further named monofumaric acid co-crystal form A1 and hemifumaric acid co-crystal form A2. In addition to the above-mentioned monofumaric acid co-crystal form A1 and hemifumaric acid co-crystal form A2, NF1 and NF2 have been identified as hemifumaric acid co-crystal forms. Furthermore, the inventors have surprisingly discovered a new anhydrous pure crystalline co-crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide with 3-hydroxybenzoic acid, and has been further named monohydrated 3-hydroxybenzoic acid co-crystal forms NF1 and NF2.

[0008] Finally, the inventors surprisingly discovered novel crystalline co-crystal forms of hemi(S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide with tartaric acid, 1,5-naphthalenedisulfonic acid, D-malic acid, and 3,4-dihydroxybenzoic acid, which were further named hemi-tartaric acid co-crystal forms NF1 and NF2, mono D-malic acid co-crystal form NF1, 1,5-naphthalenedisulfonic acid co-crystal form NF1, and mono 3,4-dihydroxybenzoic acid co-crystal form NF1, respectively.

[0009] The newly discovered crystal forms are thermodynamically more stable than the amorphous state and have favorable effects on dissolution rate, bioavailability, efficacy, and storage when (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is used in pharmaceutical products.

[0010] Accordingly, one aspect of the present invention is a crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0011] Another aspect of the present invention is the crystalline anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0012] Another aspect of the present invention is a hydrate form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide selected from the group consisting of hydrate forms NF2, NF3, NF4, and NF12.

[0013] Accordingly, an additional aspect of the present invention is a crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, selected from the group consisting of: a) Monofumaric acid cocrystal form A1, b) Hemifumaric acid cocrystal form A2, c) Hemifumaric acid cocrystal form NF1, d) Hemifumaric acid cocrystal form NF2 e) Mono-3-hydroxybenzoic acid cocrystal form NF1, f) Mono-3-hydroxybenzoic acid cocrystal form NF2, g) Hemitartaric acid cocrystal form NF1, h) Hemitartaric acid cocrystal form NF2, i) Mono-D-malic acid cocrystal form NF1, j) 1,5-Naphthalenedisulfonic acid cocrystal form NF1, and, k) Mono-3,4-dihydroxybenzoic acid cocrystal NF1.

[0014] The novel crystalline anhydrous form A1 exhibits the following properties in comparison to the amorphous state of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide: - Crystal form, very good crystallinity - Anhydrous form - Slightly hygroscopic according to Ph. Eur., no tendency to undergo hydrate formation upon exposure to rising RH levels

[0015] Accordingly, another aspect of the present invention is the crystalline anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the crystalline anhydrous form A1 has characteristic peaks: [Table 1]

[0016] Another aspect of the present invention is the monofumaric acid co-crystal form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the monofumaric acid co-crystal form A1 has characteristic peaks: [Table 2]

[0017] The novel monofumaric acid co-crystal form A1 exhibits the following properties in comparison to the amorphous state of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide: - Crystal form, very good crystallinity - Anhydrous form - 1:1 ratio of API:fumaric acid - Slightly hygroscopic according to Ph. Eur., no tendency to form hydrates upon exposure to increasing RH levels

[0018] Another aspect of the present invention is the hemifumaric acid co-crystal form A2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemifumaric acid co-crystal form A2 has characteristic peaks:

Table 3

[0019] Another aspect of the present invention is the hemifumaric acid co-crystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemifumaric acid co-crystal form NF1 has characteristic peaks:

Table 4

[0020] Another aspect of the present invention is the hemifumaric acid co-crystal form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemifumaric acid co-crystal form NF2 has characteristic peaks:

Table 5

[0021] Another aspect of the present invention is the mono-3-hydroxybenzoic acid co-crystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono-3-hydroxybenzoic acid co-crystal form NF1 has characteristic peaks:

Table 6

[0022] The novel mono 3-hydroxybenzoic acid co-crystalline form NF1 exhibits the following advantages in comparison to the amorphous state of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide: - Crystal form, extremely good crystallinity - Anhydrous form - Ratio of 1:1 API:3-hydroxybenzoic acid - In accordance with Ph. Eur., no hygroscopicity, no tendency to undergo hydrate formation upon exposure to increasing RH levels

[0023] Another aspect of the present invention is the mono 3-hydroxybenzoic acid co-crystalline form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono 3-hydroxybenzoic acid co-crystalline form NF2 has characteristic peaks: [Table 7]

[0024] Another aspect of the present invention is the mono 3,4-dihydroxybenzoic acid co-crystalline form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono 3,4-dihydroxybenzoic acid co-crystalline form NF1 has characteristic peaks: [Table 8]

[0025] Another aspect of the present invention is the hemitartaric acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemitartaric acid cocrystal form NF1 has characteristic peaks: [Table 9]

[0026] Another aspect of the present invention is the hemitartaric acid cocrystal form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemitartaric acid cocrystal form NF2 has characteristic peaks: [Table 10]

[0027] Another aspect of the present invention is the 1,5-naphthalenedisulfonic acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the 1,5-naphthalenedisulfonic acid cocrystal form NF1 has characteristic peaks: [Table 11]

[0028] Another aspect of the present invention is the mono-D-malic acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono-D-malic acid cocrystal form NF1 has the following characteristic peaks: [Table 12]

[0029] All forms can be characterized according to standard methods, which can be found, for example, in the following: - Rolf Hilfiker, ‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH. Weinheim 2006 (Chapter 6: X-Ray Diffraction, Chapter 6: Vibrational Spectroscopy, Chapter 3: Thermal Analysis, Chapter 9: Water Vapour Sorption, and references therein) - H.G. Brittain, ‘Polymorphism in Pharmaceutical Solids, Vol. 95, Marcel Dekker Inc., New York 1999 (Chapter 6, and references therein)

[0030] The invention also relates to (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide containing one or more cocrystal forms according to the invention.

[0031] A further aspect according to the invention is (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide consisting essentially of one or more cocrystal forms according to the invention.

[0032] The cocrystal form according to the present invention is prepared by suspending (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in an organic solvent, preferably acetone, at a high temperature, adding an equal amount of a coformer, starting cooling crystallization, and finally separating and drying the residue.

[0033] Thus, another aspect of the present invention is a method for preparing a cocrystal form according to the present invention, which comprises suspending (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in an organic solvent at a high temperature, adding an equal amount of a coformer, and performing cooling crystallization.

[0034] As already described, the crystal form according to the present invention is thermodynamically stable and is thus particularly suitable as a pharmaceutical product. As described in WO 2020 / 152132 A1, (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide can be used for the treatment and / or prevention of physiological and / or pathophysiological conditions selected from the group consisting of proliferative and infectious diseases and disorders, in particular for the treatment and / or prevention of cancer.

[0035] The active ingredient can of course also be used as a mixture of crystal forms according to the present invention and can contain more than 10% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, more than 60% by weight, more than 70% by weight, more than 80% by weight, or more than 90% by weight of the crystal form according to the present invention. According to the present invention, mixtures having more than 70% by weight, particularly preferably more than 80% by weight, and particularly preferably more than 90% by weight of the crystal form according to the present invention are preferred according to the present invention.

[0036] The present invention thus also relates to a medicament comprising one or more crystalline forms according to the invention or mixtures thereof in any ratio for use in the treatment and / or prevention of cancer.

[0037] Another aspect of the present invention is the use of one or more crystalline forms according to the invention, or mixtures thereof in any ratio, for the preparation of a medicament for use in the treatment and / or prevention of cancer.

[0038] Another aspect of the present invention is a method for the treatment and / or prevention of cancer, wherein one or more crystalline forms according to the invention or mixtures thereof are administered to a person in need thereof.

[0039] In addition, the present invention relates to a pharmaceutical formulation comprising one or more crystalline forms according to the invention or mixtures thereof in any ratio and optionally further excipients and / or adjuvants.

[0040] Another aspect of the present invention is a process for the preparation of a pharmaceutical formulation, characterized in that one or more crystalline forms according to the invention or mixtures thereof in any ratio are brought into a suitable dosage form together with solid, liquid or semi-liquid excipients or adjuvants.

[0041] Even if there are no further aspects, it is assumed that a person skilled in the art can use the above description in the broadest scope. Preferred aspects are therefore not in any way absolutely limiting and should merely be regarded as illustrative disclosure.

[0042] All references cited herein are incorporated by reference into the disclosure of the invention herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0043]

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[0044] Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, but preferred examples are described below. In the examples, standard reagents and buffers that are free of contaminating effects (whenever feasible) are used. These examples are not limited to the combinations of features explicitly presented, but should be construed more particularly as being able to recombine the exemplified features without limitation provided that the technical problems of the present invention are solved. Similarly, the features of any claim can be combined with the features of one or more other claims. Although the present invention has been described in summary and in detail, it is not limited or defined by the following examples.

[0045] Abbreviations: 2,4-DHBA: 2,4-Dihydroxybenzoic acid 3,4-DHBA: 3,4-Dihydroxybenzoic acid 3-HBA: 3-Hydroxybenzoic acid DSC: Differential Scanning Calorimetry TGA: Thermogravimetric Analysis SGF: Simulated Gastric Fluid FESSiF: Fed-State Simulated Intestinal Fluid FASSiF: Fasting-State Simulated Intestinal Fluid

Examples

[0046] Example 1 - Preparation of Amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0047] WO 2020 / 152132 A1 describes the chiral separation of intermediates by chiral HPLC yield in an amorphous material of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0048] The powder X-ray diffraction pattern was obtained by the standard method described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 1 (monochromatic Cu-Kα1 radiation, λ = 1.5406, Stoe StadiP 611 KL transmission diffractometer).

[0049] The amorphous state is characterized by the following physical properties: The thermal behavior shows no significant enthalpy phenomenon and exhibits a total weight loss of 2.9% (w / w) up to 150 °C in TGA. The DSC and TGA profiles are shown in Figures 2A and 2B. The DSC scan of the amorphous state was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas of 50 mL / min. The TGA scan of the amorphous state was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas of 50 mL / min (for the DSC and TGA scans of the amorphous state, see Figures 2A and 2B).

[0050] The water vapor sorption behavior reveals that the water uptake level exceeds 22% (w / w) in the entire relative humidity (RH) range of 0 - 98% RH. The amorphous state can be classified as hygroscopic according to the Ph. Eur. criteria (section 5.11.) and shows a tendency to deliquesce when the humidity level exceeds 90% RH. The water vapor sorption isotherm (25 °C) is shown in Figure 3 (water vapor sorption isotherm (25 °C) of the amorphous state). The water vapor sorption isotherm was obtained with a DVS proprietary system from SMS.

[0051] Example 2 - Process for the preparation of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in crystalline anhydrous form A1

[0052] Laboratory scale: Approximately 210 mg of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was stirred in 2 mL of acetone at 50 °C for 2 hours. Thereafter, the suspension was centrifuged and dried at 50 °C for 12 hours under a N2 stream.

[0053] Gram scale: Approximately 1.9 g of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was separated from 20 mL of acetone, stored overnight at 0 °C, separated and dried. Thereafter, the suspension was centrifuged and dried at 50 °C and at less than 10 mbar for 90 hours.

[0054] The powder X-ray diffraction pattern of A1 was obtained by the standard method described in European Pharmacopeia 6th Edition chapter 2.9.33 and characterized by the powder X-ray diffraction diagram shown in Figure 4 (monochromatic Cu-Kα1 radiation, λ = 1.5406, Stoe StadiP 611 KL transmission diffractometer). The powder X-ray peak list of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in A1 form is shown in Table 1.

[0055]

Table 13

[0056] Single crystal X-ray structure data was also obtained for the A1 form (Oxford Diffraction Supernova Single Crystal X-ray Diffractometer equipped with a graphite monochromator and a CCD detector) at 298 K (see Figure 5).

[0057] The A1 form crystallizes in the non-centrosymmetric monoclinic space group P21 with lattice parameters a = 9.1 ± 0.1 Å, b = 22.5 ± 0.1 Å, c = 10.4 ± 0.1 Å, and β = 103.5 ± 0.5° (α = γ = 90°). It is evident from the single crystal structure that form A1 is the anhydrous form.

[0058] The A1 form is characterized by the following physical properties: The thermal behavior of the A1 form indicates that melting (at approximately 213 °C) overlaps with the TGA step. This is due to the heat release of strongly bound residual solvents in the aggregates. The DSC and TGA profiles are shown in Figures 6A and 6B. The DSC scan of the A1 form was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas of 50 mL / min. The TGA scan of the A1 form was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas of 50 mL / min.

[0059] The water vapor sorption behavior of the A1 form revealed that the water uptake level is extremely low, less than 1% (w / w), in the entire relative humidity (RH) range of 0 - 98% RH. The A1 form can be classified as slightly hygroscopic according to the Ph. Eur. criteria (section 5.11.). The water vapor sorption isotherm (at 25 °C) of the A1 form is shown in Figure 7. The water vapor sorption isotherm was obtained using the DVS proprietary system of SMS.

[0060] Example 3 - Process for the preparation of the hydrate form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0061] Approximately 17 mg of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was stirred in 500 μL of water at room temperature for approximately 7 days. The solid residue was centrifuged and not dried.

[0062] The powder X-ray diffraction pattern of the hydrate form NF2 was obtained by the standard technique described in European Pharmacopeia 6 th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 8 (monochromatic Cu-Kα1 radiation, λ = 1.5406, Stoe StadiP 611 KL transmission diffractometer).

[0063] Example 4 - Process for the preparation of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in hydrate form NF3

[0064] Approximately 17 mg of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was stirred in 500 μL of water at room temperature for approximately 7 days. The solid residue was centrifuged and dried under ambient conditions.

[0065] The powder X-ray diffraction pattern of the hydrate form NF3 was obtained by the standard technique described in European Pharmacopeia 6 th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 9 (monochromatic Cu-Kα1 radiation, λ = 1.5406, Stoe StadiP 611 KL transmission diffractometer).

[0066] Process for the preparation of the hydrate form NF4 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0067] Approximately 5 mg of the hydrate form NF4 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was suspended in 1 mL of FeSSIF [pH 5.0] at 37 °C for 24 hours. Solid / liquid separation was carried out by centrifugation.

[0068] The powder X-ray diffraction pattern of the hydrate form NF4 was obtained by the standard technique described in European Pharmacopeia 6 th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 10 (monochromatic Cu-Kα1 radiation, λ = 1.5406, Stoe StadiP 611 KL transmission diffractometer).

[0069] Process for the preparation of the hydrate form NF12 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0070] Approximately 5 mg of the hydrate form NF12 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was suspended in 1 mL of USP phosphate buffer [pH 3.2] at 37 °C for 24 hours. Solid / liquid separation was carried out by centrifugation.

[0071] The powder X-ray diffraction pattern of the hydrate form NF12 was obtained by the standard technique described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 11 (monochromatic Cu-Kα1 radiation, λ = 1.5406, Stoe StadiP 611 KL transmission diffractometer).

[0072] Example 7 - Process for the cocrystal screening of (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide of 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid

[0073] Cocrystal screening was carried out for (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide of 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid (Compound 53 of WO 2019 / 025099).

[0074] A wide range of experimental types (such as eutectic melting, grinding, cooling crystallization, etc.) were used, but surprisingly, only very few coformers in a 1:1 ratio, namely 3-hydroxybenzoic acid, tartaric acid, and 2,4-dihydroxybenzoic acid, were obtained together. In a larger-scale test, the most promising results were obtained in the cooling crystallization test. Since (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide of 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid is not the subject of the present invention, detailed physicochemical information is not included.

[0075] Based on the results of the cocrystal screening, since both compounds are structurally similar, only cooling crystallization was applied to (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, followed partially by vapor diffusion experiments.

[0076] Table 3 below describes the experimental type and the conformers used for 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide. [Table 14]

[0077] Example 8 - Process for the cocrystal screening of (S)-7-oxa-2-azaspiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0078] Based on the knowledge from the experiments of 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide and the structural similarity between 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide and (S)-7-oxa-2-azaspiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, the successful experimental type "cooling crystallization" was further applied to (S)-7-oxa-2-azaspiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide. In a few experiments without solid residue, an additional experimental step (vapor diffusion) was performed. [Table 15]

[0079] Example 9 - Preparation process for the novel monofumaric acid cocrystal form A1

[0080] Lab scale: (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in its anhydrous form A1, approximately 19 mg, was dispersed in 0.7 mL of acetone at 50 °C. Approximately 6 mg of fumaric acid was added and the cooling ramp was started three times (50 to 5 °C, 0.1 K / min). The suspension was centrifuged for liquid / solid separation and the solid was then dried at room temperature.

[0081] kg-scale: Approximately 4.3 kg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in its anhydrous form A1 and approximately 1.3 kg of fumaric acid were suspended in approximately 15 V of acetone at 25 °C for at least 10 minutes at a moderate stirring rate. The suspension was heated to approximately 65 °C over 1 hour. Then, the cooling ramp was started (from approximately 65 to approximately 10 °C over 7 hours). The suspension was stirred at approximately 10 °C for at least 4 hours, filtered by suction for liquid / solid separation, and finally washed with 1 V of acetone. The solid was vacuum dried at approximately 70 °C for at least 8 hours.

[0082] The powder X-ray diffraction pattern of the monofumaric acid co-crystal form A1 was obtained by the standard technique described in chapter 2.9.33 of the European Pharmacopeia 6th Edition and is characterized by the powder X-ray diffraction diagram shown in Figure 12 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0083] NMR data of the monofumaric acid co-crystal form A1: 11H NMR (700 MHz, DMSO-d6) δ 13.18 - 13.06 (m, 2H), 11.39 - 11.30 (m, 1H), 7.94 (s, 1H), 6.62 (s, 2H), 6.25 - 6.23 (m, 1H), 4.29 (q, J = 2.8 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.66 - 3.42 (m, 5H), 3.40(d, J = 11.3 Hz, 1H), 3.31 - 3.28 (m, 1H), 3.26 - 3.08 (m, 1H), 2.57 - 2.53 (m, 2H), 1.90 - 1.74 (m, 1H), 1.74 - 1.47 (m, 5H).

[0084] [Table 16]

[0085] Single crystal X-ray data was obtained for monofumaric acid co-crystal form A1 (Oxford Diffraction Supernova Single Crystal X-ray Diffractometer equipped with a graphite monochromator and a CCD detector) as shown in Figure 13.

[0086] Monofumaric acid co-crystal form A1 crystallizes in the monoclinic space group P21 with lattice parameters a = 8.9 ± 0.1 Å, b = 24.1 ± 0.1 Å, c = 12.5 ± 0.1 Å, β = 101.3 ± 0.5° (α = γ = 90°). It is clear from the single crystal structure that monofumaric acid co-crystal form A1 represents the monofumaric acid co-crystal anhydrous form.

[0087] Monofumaric acid co-crystal form A1 is characterized by the following physical properties: - 1 eq. fumaric acid (determined by NMR) - The thermal behavior of the monofumaric acid co-crystal form A1 shows a minor weight loss (less than 1% (w / w) before melting / decomposition) and a repetitive melting / decomposition process (above 207 °C). The DSC and TGA profiles are shown in Figures 14A and 14B. The DSC scan of the monofumaric acid co-crystal form A1 was obtained using a nitrogen purge gas at 50 mL / min with a Mettler-Toledo DSC1 at a heating rate of 5 K / min. The TGA scan of the monofumaric acid co-crystal form A1 was obtained using a nitrogen purge gas at 50 mL / min with a Mettler-Toledo TGA 851 at a heating rate of 5 K / min. - The water vapor sorption behavior of the monofumaric acid co-crystal form A1 shows a very low water uptake level of less than 3% (w / w) over the entire relative humidity (RH) range of 0 - 98% RH. The monofumaric acid co-crystal form A1 can be classified as slightly hygroscopic according to the Ph. Eur. criteria (section 5.11.). The water vapor sorption isotherm (25 °C) of the monofumaric acid co-crystal form A1 is shown in Figure 15. The water vapor sorption isotherm was obtained with the DVS Intrinsic system from SMS. - The concentration levels of the monofumaric acid co-crystal form A1 were determined at 15 and 30 minutes after a non-sink dissolution experiment at 37 °C.

[0088]

Table 17

[0089] The following describes a few examples where the formation of the monofumaric acid co-crystal form A1 failed.

Table 18-1

Table 18-2

[0090] Example 10 - Preparation process for the novel hemifumaric acid co-crystal form A2

[0091] Preparation process: About 140 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 8 mL of isopropanol at 50 °C, and the cooling lamp was started (50 - 5 °C, 0.1 K / min). Precipitation was observed at 5 °C.

[0092] NMR data of hemifumaric acid co-crystal form A2 1 H NMR (500 MHz, DMSO-d6) δ 13.31 - 12.94 (m, 1H), 11.44 - 11.23 (m, 1H), 7.94 (s, 1H), 6.61 (s, 1H), 6.26 - 6.22 (m, 1H), 4.29 (q, J = 2.8 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.68 - 3.40 (m, 5H), 3.40 (d, J = 11.2 Hz, 1H), 3.35 - 3.30 (m, 1H), 3.26 - 3.08 (m, 1H), 2.58 - 2.53 (m, 2H), 1.90 - 1.73 (m, 1H), 1.73 - 1.46 (m, 5H)

[0093] The powder X-ray diffraction pattern of hemifumaric acid co-crystal form A2 was obtained by the standard technique described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 16 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0094]

Table 19

[0095] Single crystal X-ray data were also obtained for hemifumaric acid co-crystal form A2 (Oxford Diffraction Supernova Single Crystal X-ray Diffractometer equipped with a graphite monochromator and a CCD detector). See Figure 17.

[0096] Hemifumaric acid co-crystal form A2 crystallizes in the triclinic space group P1 with lattice parameters a = 9.96 ± 0.1 Å, b = 15.7 ± 0.1 Å, c = 17.2 ± 0.1 Å, α = 66.5 ± 0.5°, β = 77.5 ± 0.5°, and γ = 76.9 ± 0.5°. It is clear from the single crystal structure that hemifumaric acid co-crystal form A2 represents the anhydrous form.

[0097] Hemifumaric acid co-crystal form A2 is characterized by the following physical properties: - 0.5 eq. fumaric acid (determined by NMR) - The thermal behavior of hemifumaric acid co-crystal form A2 shows a minor weight loss (less than 1% (w / w) before melting / decomposition) and a repetitive melting / decomposition process (above 207 °C). The DSC and TGA profiles are shown in Figures 18A and 18B. The DSC scan of hemifumaric acid co-crystal form A2 was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. The TGA scan of hemifumaric acid co-crystal form A2 was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. - The water vapor sorption behavior of hemifumaric acid co-crystal form A2 reveals a very low water uptake level of 0.7% (w / w) or less in the relative humidity (RH) range of 0 - 80% RH. Hemifumaric acid co-crystal form A1 can be classified as slightly hygroscopic according to the Ph. Eur. criteria (section 5.11.). The water vapor sorption isotherm (25 °C) of hemifumaric acid co-crystal form A2 is shown in Figure 19. The water vapor sorption isotherm was obtained using the SMS DVS proprietary system. - The concentration levels of hemifumaric acid co-crystal form A2 were determined at 37 °C after 15 and 30 minutes of non-sink dissolution experiments.

[0098]

Table 20

[0099] Example 11 - (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide of hemifumaric acid cocrystal form NF1

[0100] Preparation process for novel hemifumaric acid cocrystal form NF1 Approximately 15 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 500 μL of 1,4-dioxane at 25 °C and stirred for 5 days. The suspension was centrifuged for liquid / solid separation, and the solid was dried at room temperature.

[0101] NMR data of hemifumaric acid cocrystal form NF1 1 H NMR (500 MHz, DMSO-d6) δ 11.36 - 11.29 (m, 1H), 7.94 (s, 1H), 6.25 - 6.22 (m, 1H), 4.29 (q, J = 2.8 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.67 - 3.38 (m, 6H), 3.34 - 3.28 (m, 2H), 2.58 - 2.53 (m, 2H), 1.90 - 1.75 (m, 1H), 1.73 - 1.47 (m, 5H).

[0102] The powder X-ray diffraction pattern of the hemifumaric acid co-crystal form NF1 was obtained by the standard technique described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 20 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0103]

Table 21

[0104] The hemifumaric acid co-crystal form NF1 is characterized by the following physical properties: -0.5 eq. fumaric acid (determined by NMR) - The thermal behavior of the hemifumaric acid co-crystal form NF1 shows a small endothermic phenomenon with a slight weight loss (less than 1% (w / w) before melting) before melting at approximately 220 °C. The DSC and TGA profiles are shown in Figures 21A and 21B. The DSC scan of the hemifumaric acid co-crystal form NF1 was acquired using a Mettler-Toledo DSC1 at a heating rate of 10 K / min with a nitrogen purge gas at 50 mL / min. The TGA scan of the hemifumaric acid co-crystal form NF1 was acquired using a Mettler-Toledo TGA 851 at a heating rate of 10 K / min with a nitrogen purge gas at 50 mL / min.

[0105] Example 12 - Hemifumaric acid co-crystal form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide Hemifumaric acid co-crystal form NF2

[0106] Preparation process for the novel hemifumaric acid co-crystal / salt form NF2 (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide A1 in its anhydrous form A1, approximately 60 mg, was dispersed in 2.5 mL of acetone / methanol (mixture 1:1) at 50 °C. Approximately 17 mg of fumaric acid was added and the cooling ramp was started three times (50 to 5 °C, 0.1 K / min). Precipitation was observed at 5 °C.

[0107] NMR data of the hemifumaric acid co-crystal / salt form NF2 1 H NMR (500 MHz, DMSO-d6) δ 11.41 - 11.23 (m, 1H), 7.93 (s, 1H), 6.25 - 6.22 (m, 1H), 4.29 (q, J = 2.8 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.67 - 3.10 (m, 6H), 3.31 (d, J = 11.3 Hz, 2H), 2.58 - 2.52 (m, 2H), 1.90 - 1.74 (m, 1H), 1.73 - 1.46 (m, 5H).

[0108] The powder X-ray diffraction pattern of the hemifumaric acid co-crystal form NF2 was obtained by the standard technique described in chapter 2.9.33 of the European Pharmacopeia 6th Edition and is characterized by the powder X-ray diffraction diagram shown in Figure 22 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0109]

Table 22

[0110] The hemifumaric acid co-crystal form NF2 is characterized by the following physical properties: - 0.5 eq. fumaric acid (determined by NMR) - The thermal behavior of the hemifumaric acid cocrystal form NF2 involves a slight weight loss (less than 1% (w / w) before melting / decomposition) and shows a repeated melting / decomposition process (above 191 °C). The DSC and TGA profiles are shown in Figures 23A and 23B. The DSC scan of the hemifumaric acid cocrystal form NF2 was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. The TGA scan of the hemifumaric acid cocrystal form NF2 was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min.

[0111] Example 13 - (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide of 3-hydroxybenzoic acid cocrystal form NF1

[0112] Preparation process for the novel mono 3-hydroxybenzoic acid cocrystal form NF1 Approximately 16 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in anhydrous form A1 was dispersed in 0.7 mL of acetone at 50 °C. Approximately 7 mg of 3-hydroxybenzoic acid was added and the cooling lamp was started three times (50 to 5 °C, 0.1 K / min). Precipitation was observed at 5 °C.

[0113] NMR data of the mono 3-hydroxybenzoic acid cocrystal form NF1 11H NMR (500 MHz, DMSO-d6) δ 12.79 - 12.68 (m, 1H), 11.35 - 11.26 (m, 1H), 9.67 (s, 1H), 7.94 (s, 1H), 7.39 - 7.35 (m, 1H), 7.34 - 7.32 (m, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.26 - 6.22 (m, 1H), 4.29 (q, J = 2.8 Hz, 2H), 4.00 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.67 - 3.42 (m, 5H), 3.41 (d, J = 11.2 Hz, 1H), 3.32 (d, J = 11.2 Hz, 1H), 3.26 - 3.12 (m, 1H), 2.58 - 2.52 (m, 2H), 1.90 - 1.74 (m, 1H), 1.74 - 1.46 (m, 5H)

[0114] The powder X-ray diffraction pattern of the mono 3-hydroxybenzoic acid cocrystal form NF1 was obtained by the standard technique described in the European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 24 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0115]

Table 23

[0116] The mono 3-hydroxybenzoic acid cocrystal form NF1 is characterized by the following physical properties: -3-hydroxybenzoic acid content ( 1 determined by 1H-NMR spectroscopy) reveals 1 eq. of 3-hydroxybenzoic acid. The thermal behavior of the mono 3-hydroxybenzoic acid co-crystalline form NF1 shows a small weight loss step before melting (Dm @116 °C: 0.4% (w / w), Dm 116 - 175 °C: 0.8% (w / w)) and a strong weight loss in the TGA profile above 175 °C. This can be attributed to the release of residual solvents, followed by the decomposition process of the mono 3-hydroxybenzoic acid co-crystalline form NF1. The DSC and TGA profiles are shown in Figures 25A and 25B. The DSC scan of the mono 3-hydroxybenzoic acid co-crystalline form NF1 was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. The TGA scan of the mono 3-hydroxybenzoic acid co-crystalline form NF1 was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. The water vapor sorption isotherm (25 °C) of the mono 3-hydroxybenzoic acid co-crystalline form NF1 is shown in Figure 26.

[0117] Example 14 - (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide 3-hydroxybenzoic acid co-crystal form NF2

[0118] Preparation process for the mono 3-hydroxybenzoic acid co-crystalline form NF2 Approximately 13 mg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 0.5 mL of tetrahydrofuran at 50 °C. Approximately 5 mg of 3-hydroxybenzoic acid was added and the cooling lamp was started three times (50 - 5 °C, 0.1 K / min). Since no precipitation was observed at 5 °C, n-pentane was used as an anti-solvent and a vapor diffusion experiment was added. After four months, hardly any particles were obtained.

[0119] NMR data of the mono 3-hydroxybenzoic acid co-crystalline form NF2 1 1H NMR (500 MHz, DMSO-d6) δ 13.02 - 12.37 (m, 1H), 11.37 - 11.21 (m, 1H), 9.73 - 9.62 (m, 1H), 7.93 (s, 1H), 7.38 - 7.35 (m, 1H), 7.34 - 7.32 (m, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.00 - 6.97 (m, 1H), 6.25 - 6.22 (m, 1H), 4.29 (q, J = 2.7 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.67 - 3.43 (m, 5H), 3.40 (d, J = 11.4 Hz, 1H), 3.32 (d, J = 11.5 Hz, 1H), 3.26 - 3.10 (m, 1H), 2.58 - 2.52 (m, 2H), 1.89 - 1.78 (m, 1H), 1.72 - 1.47 (m, 5H).

[0120] The powder X-ray diffraction pattern of the mono 3-hydroxybenzoic acid cocrystal form NF2 was obtained by the standard technique described in chapter 2.9.33 of the European Pharmacopeia 6th Edition and is characterized by the powder X-ray diffraction diagram shown in Figure 27 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0121]

Table 24

[0122] The mono 3-hydroxybenzoic acid cocrystal form NF2 is characterized by the following physical properties: 3-hydroxybenzoic acid content ( 1 determined by 1H-NMR spectroscopy) shows 1 eq. of 3-hydroxybenzoic acid.

[0123] Example 15-(S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide 3,4-dihydroxybenzoic acid cocrystal form NF1

[0124] Preparation process for mono 3,4-dihydroxybenzoic acid cocrystal form NF1 Approximately 14 mg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 0.7 mL of acetone at 50 °C. Approximately 10 mg of 3,4-dihydroxybenzoic acid was added and the cooling ramp was started three times (from 50 to 5 °C at 0.1 K / min). Since no precipitation was observed at 5 °C, n-pentane was used as an anti-solvent and a vapor diffusion experiment was added. After four months, hardly any particles were obtained.

[0125] NMR data for mono 3,4-dihydroxybenzoic acid cocrystal form NF1 1 H NMR (500 MHz, DMSO-d6) δ 12.41 - 12.11 (m, 1H),11.40 - 11.17 (m, 1H), 9.74 - 9.39 (m, 1H), 9.

[0126] The powder X-ray diffraction pattern of the mono 3,4-dihydroxybenzoic acid cocrystal form NF1 is obtained by the standard technique described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 28 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer). [Table 25]

[0127] The mono 3,4-dihydroxybenzoic acid cocrystal form NF1 is characterized by the following physical properties: - 3,4-dihydroxybenzoic acid content ( 1 determined by 1H-NMR spectroscopy) reveals 1.1 eq. of 3,4-dihydroxybenzoic acid.

[0128] Example 16 - (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide tartrate cocrystal form NF1

[0129] Preparation process for the tartrate cocrystal form NF1 Approximately 13 mg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 0.7 mL of acetone at 50 °C. Approximately 7 mg of tartaric acid was added and the cooling lamp was started three times (50 to 5 °C, 0.1 K / min). Precipitation was observed at 5 °C.

[0130] NMR data of the tartrate cocrystal form NF1 11H NMR (500 MHz, DMSO-d6): δ 12.73 - 12.53 (m, 1H), 11.35 - 11.23 (m, 1H), 7.94 (s, 1H), 6.25 - 6.22 (m, 1H), 5.13 - 4.93 (m, 1H), 4.31 (s, 1H), 4.29 (q, J = 2.8 Hz, 2H), 4.00 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.66 - 3.43 (m, 5H), 3.41 (d, J = 11.3 Hz, 1H), 3.32 (d, J = 11.2 Hz, 1H), 3.26 - 3.12 (m, 1H), 2.58 - 2.53 (m, 2H), 1.91 - 1.75 (m, 1H), 1.73 - 1.47 (m, 5H).

[0131] The powder X-ray diffraction pattern of the hemitartaric acid cocrystal form NF1 was obtained by the standard technique described in chapter 2.9.33 of the European Pharmacopeia 6th Edition and is characterized by the powder X-ray diffraction diagram shown in Figure 29 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0132]

Table 26

[0133] The hemitartaric acid cocrystal form NF1 is characterized by the following physical properties: - Tartaric acid content ( 1 determined by 1H-NMR spectroscopy) reveals 0.6 eq. of tartaric acid. - The dissolution level of the hemitartaric acid cocrystal form NF2 in simulated fasting intestinal fluid [FaSSIF, pH 6.5] at 37 °C was determined to be approximately 145 μg / mL (after 30 minutes). - The thermal behavior of the hemitartaric acid cocrystal form NF1 is accompanied by a weight loss step (less than 1.8% (w / w) up to approximately 85 °C) in the TGA profile Exhibits a broad endothermic phenomenon (<100 °C). This can probably be attributed to the release of water from a slightly crystalline bulk phase. The broad melting / decomposition process can be observed at 13 °C (onset) in the DSC trace. The DSC and TGA profiles are shown in FIGS. 30A and 30B. The DSC scan of the hemitartaric acid cocrystal form NF1 was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. The TGA scan of the hemitartaric acid cocrystal form NF1 was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min.

[0134] Example 17 - (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide of tartaric acid cocrystal form NF2

[0135] Preparation process for hemitartaric acid cocrystal form NF2 Approximately 67 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in anhydrous form A1 was dispersed in 1.5 mL of acetone at 50 °C. Approximately 12 mg of tartaric acid was added and the cooling ramp was started three times (50 to 5 °C, 0.1 K / min).

[0136] NMR data for hemitartaric acid cocrystal form NF2 11H NMR (500 MHz, DMSO-d6) δ 13.11 - 12.14 (m, 1H), 11.29 (s, 1H), 7.93 (s, 1H), 6.25 - 6.22 (m, 1H), 5.24 - 4.70 (m, 1H), 4.31 (s, 1H), 4.29 (q, J = 2.8 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.68 - 3.45 (m, 5H), 3.40 (d, J = 11.4 Hz, 1H), 3.33 - 3.29 (m, 1H), 3.26 - 3.09 (m, 1H), 2.58 - 2.52 (m, 2H), 1.89 - 1.75 (m, 1H), 1.72 - 1.46 (m, 5H).

[0137] The powder X-ray diffraction pattern of hemitartaric acid cocrystal form NF2 was obtained by the standard technique described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 31 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0138]

Table 27

[0139] Hemitartaric acid cocrystal form NF2 is characterized by the following physical properties: - Tartaric acid content ( 1 determined by 1H-NMR spectroscopy) reveals 0.5 eq. tartaric acid. - The dissolution level of hemitartaric acid cocrystal form NF2 in simulated fasting intestinal fluid [FaSSIF, pH 6.5] at 37 °C was determined to be approximately 145 μg / mL (after 30 minutes).

[0140] Example 18 - (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide of naphthalene-1,5-disulfonic acid co-crystal form NF1

[0141] Preparation process for naphthalene-1,5-disulfonic acid co-crystal form NF1 Approximately 15 mg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 0.7 mL of acetone at 50 °C. Approximately 12 mg of naphthalene-1,5-disulfonic acid was added and the cooling lamp was started three times (from 50 to 5 °C at 0.1 K / min). Precipitation was observed at 5 °C.

[0142] The powder X-ray diffraction pattern of naphthalene-1,5-disulfonic acid co-crystal form NF1 was obtained by the standard technique described in European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 32 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0143]

Table 28

[0144] Naphthalene-1,5-disulfonic acid co-crystal form NF1 is characterized by the following physical properties: - The thermal behavior of the 1,5-naphthalenedisulfonic acid cocrystal form NF1 showed no significant enthalpy events before decomposition. In the temperature range up to 110 °C, a weight loss of 2.2% (w / w) was observed, followed by a second weight loss step of 1.0% (w / w) from 110 to 184 °C. The DSC and TGA profiles are shown in Figures 33A and 33B. The DSC scan of the 1,5-naphthalenedisulfonic acid cocrystal form NF1 was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. The TGA scan of the 1,5-naphthalenedisulfonic acid cocrystal form NF1 was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min.

[0145] Example 19 - D (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide of malic acid cocrystal form NF1

[0146] Mono D - Preparation process for malic acid cocrystal form NF1 Approximately 12 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in the anhydrous form A1 was dispersed in 0.5 mL of acetone at 50 °C. Approximately 8 mg of D - malic acid was added, and the cooling ramp was started three times (50 to 5 °C, 0.1 K / min). Precipitation was observed at 5 °C.

[0147] Mono D - NMR data of malic acid cocrystal form NF1 11H NMR (500 MHz, DMSO-d6) δ 12.57 - 12.11 (m, 2H), 11.30 (s, 1H), 7.94 (s, 1H), 6.26 - 6.22 (m, 1H), 5.49 - 5.29 (m, 1H), 4.29 (q, J = 2.8 Hz, 2H), 4.26 (dd, J = 7.7, 4.9 Hz, 1H), 4.00 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 3.66 - 3.43 (m, 5H), 3.41 (d, J = 11.2 Hz, 1H), 3.32 (d, J = 11.2 Hz, 1H), 3.25 - 3.12 (m, 1H), 2.61 (dd, J = 15.6, 4.9 Hz, 1H),2.58 - 2.53 (m, 2H), 2.44 (dd, J = 15.6, 7.8 Hz, 1H), 1.89 - 1.74 (m, 1H), 1.74 - 1.46 (m, 5H).

[0148] Mono D The powder X-ray diffraction pattern of the mono-malic acid co-crystal form NF1 was obtained by the standard technique described in the European Pharmacopeia 6th Edition chapter 2.9.33 and is characterized by the powder X-ray diffraction diagram shown in Figure 34 (monochromatic Cu-Kα1 radiation, λ = 1.5406 Å, Stoe StadiP 611 KL transmission diffractometer).

[0149]

Table 29

[0150] Mono D The mono-malic acid co-crystal form NF1 is characterized by the following physical properties: ‐ Malic acid content ( 1 determined by 1H-NMR spectroscopy) reveals 1 eq. of malic acid. ‐ Mono D- The thermal behavior of the malic acid cocrystal form NF1 shows a very small endothermic phenomenon at about 137 °C. This can be attributed to the melting process of the mono D-malic acid cocrystal form NF1. A weight loss of 2.8% (w / w) was observed in the temperature range up to 136 °C. The DSC and TGA profiles are shown in Figures 35A and 35B. Mono D - The DSC scan of the malic acid cocrystal form NF1 was obtained using a Mettler-Toledo DSC1 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min. Mono D - The TGA scan of the malic acid cocrystal form NF1 was obtained using a Mettler-Toledo TGA 851 at a heating rate of 5 K / min with a nitrogen purge gas at 50 mL / min.

[0151] Brief Description of the Drawings Figure 1 shows the powder X-ray diffraction pattern of the prior art amorphous state form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0152] Figure 2 shows the DSC scan (5 K / min) and TGA scan (5 K / min) of the amorphous state form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0153] Figure 3 shows the water vapor sorption isotherm (25 °C) of the amorphous state form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0154] Figure 4 shows the powder X-ray diffraction pattern of the crystalline anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0155] Figure 5 shows the single crystal X-ray structure data of the crystalline anhydrous form A1.

[0156] Figure 6 shows the (6A) DSC scan of the crystalline anhydrous form A1 (5 K / min) and the (6B) TGA scan of the crystalline anhydrous form A1 (5 K / min).

[0157] Figure 7 shows the water vapor sorption isotherm (25 °C) of the crystalline anhydrous form A1.

[0158] Figure 8 shows the powder X-ray diffraction pattern of the hydrate form NF2.

[0159] Figure 9 shows the powder X-ray diffraction pattern of the hydrate form NF3.

[0160] Figure 10 shows the powder X-ray diffraction pattern of the hydrate form NF4.

[0161] Figure 11 shows the powder X-ray diffraction pattern of the hydrate form NF12.

[0162] Figure 12 shows the powder X-ray diffraction pattern of the monofumaric acid co-crystal form A1.

[0163] Figure 13 shows the single crystal structure of the monofumaric acid co-crystal form A1.

[0164] Figure 14 shows the (14A) DSC scan (5 K / min) of the monofumaric acid co-crystal form A1 and the (14B) TGA scan (5 K / min) of the monofumaric acid co-crystal form A1.

[0165] Figure 15 shows the water vapor sorption isotherm (25 °C) of the monofumaric acid co-crystal form A1.

[0166] Figure 16 shows the powder X-ray diffraction pattern of the hemifumaric acid co-crystal form A2.

[0167] Figure 17 shows the single crystal structure of hemifumaric acid co-crystal form A2.

[0168] Figure 18 shows the (18A) DSC scan (5 K / min) of hemifumaric acid co-crystal form A2 and the (18B) TGA scan (5 K / min) of hemifumaric acid co-crystal form A2.

[0169] Figure 19 shows the water vapor sorption isotherm (25 °C) of hemifumaric acid co-crystal form A2.

[0170] Figure 20 shows the powder X-ray diffraction pattern of hemifumaric acid co-crystal form NF1.

[0171] Figure 21 shows the (21A) DSC scan (10 K / min) of hemifumaric acid co-crystal form NF1 and the (21B) TGA scan (10 K / min) of hemifumaric acid co-crystal form NF1.

[0172] Figure 22 shows the powder X-ray diffraction pattern of the hemifumaric acid co-crystal of NF2.

[0173] Figure 23 shows the (23A) DSC scan (5 K / min) of hemifumaric acid co-crystal form NF2 and the (23B) TGA scan (5 K / min) of hemifumaric acid co-crystal form NF2.

[0174] Figure 24 shows the powder X-ray diffraction pattern of mono 3-hydroxybenzoic acid co-crystal NF1.

[0175] Figure 25 shows the (25A) DSC scan (5 K / min) of mono 3-hydroxybenzoic acid co-crystal form NF1 and the (25B) TGA scan (5 K / min) of mono 3-hydroxybenzoic acid co-crystal form NF1.

[0176] Figure 26 shows the water vapor sorption isotherm (25 °C) of mono 3-hydroxybenzoic acid co-crystal form NF1.

[0177] Figure 27 shows the powder X-ray diffraction pattern of mono 3-hydroxybenzoic acid co-crystal form NF2.

[0178] Figure 28 shows the powder X-ray diffraction pattern of the mono 3,4-dihydroxybenzoic acid co-crystal form NF1.

[0179] Figure 29 shows the powder X-ray diffraction pattern of the hemitartaric acid co-crystal form NF1.

[0180] Figure 30 shows the (30A) DSC scan (5 K / min) of the hemitartaric acid co-crystal form NF1 and the (30B) TGA scan (5 K / min) of the hemitartaric acid co-crystal form NF1.

[0181] Figure 31 shows the powder X-ray diffraction pattern of the hemitartaric acid co-crystal form NF2.

[0182] Figure 32 shows the powder X-ray diffraction pattern of the 1,5-naphthalenedisulfonic acid co-crystal NF1.

[0183] Figure 33 shows the (33A) DSC scan (5 K / min) of the 1,5-naphthalenedisulfonic acid co-crystal form NF1 and the (33B) TGA scan (5 K / min) of the 1,5-naphthalenedisulfonic acid co-crystal form NF1.

[0184] Figure 34 shows the powder X-ray diffraction pattern of the mono D-malic acid co-crystal form NF1.

[0185] Figure 35 shows the D (35A) DSC scan of the -malic acid co-crystal form NF1 and the D (35B) TGA scan of the -malic acid co-crystal form NF1.

Claims

1. (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide in crystalline form.

2. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 1, wherein the crystalline form is crystalline anhydrous form A1.

3. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 1, wherein the crystalline form is selected from the group consisting of hydrate forms NF2, NF3, NF4, and NF12.

4. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 1, wherein the crystalline form is a co-crystalline form selected from the following group: a) Monofumaric acid co-crystalline form A1, b) Hemifumaric acid co-crystalline form A2, c) Hemifumaric acid co-crystalline form NF1, d) Hemifumaric acid co-crystalline form NF2 e) Mono-3-hydroxybenzoic acid co-crystalline form NF1, f) Mono-3-hydroxybenzoic acid co-crystalline form NF2, g) Hemitartaric acid co-crystalline form NF1, h) Hemitartaric acid co-crystalline form NF2, i) Mono D - malic acid cocrystal form NF1, j) 1,5-Naphthalenedisulfonic acid co-crystalline form NF1, and k) Mono-3,4-dihydroxybenzoic acid co-crystalline NF1.

5. The crystalline anhydrous form A1 has the following characteristic peaks: 【Table 1】 The crystalline anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 2.

6. The monofumaric acid co-crystalline form A1 has the following characteristic peaks: 【Table 2】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

7. The hemifumaric acid co-crystalline form A2 has the following characteristic peaks: 【Table 3】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

8. The hemifumaric acid co-crystalline form NF1 has the following characteristic peaks: 【Table 4】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

9. The hemifumaric acid co-crystalline form NF2 has the following characteristic peaks: 【Table 5】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

10. The mono-3-hydroxybenzoic acid co-crystalline form NF1 has the following characteristic peaks: 【Table 6】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

11. The mono-3-hydroxybenzoic acid co-crystalline form NF2 has the following characteristic peaks: 【Table 7】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

12. The mono-3,4-dihydroxybenzoic acid co-crystalline form NF1 has the following characteristic peaks: 【Table 8】 The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

13. The hemitartaric acid cocrystal form NF1 has the following characteristic peaks: 【Table 9】 The crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

14. The hemitartaric acid cocrystal form NF2 has the following characteristic peaks: 【Table 10】 The crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein

15. The 1,5-naphthalenedisulfonic acid cocrystal form NF1 has the following characteristic peaks: 【Table 11】 The crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

16. Things D - The malic acid cocrystal form NF1 has the following characteristic peaks: 【Table 12】 The crystal form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4.

17. (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide containing one or more of the crystal forms according to any one of claims 1 to 16.

18. (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide essentially containing one or more of the crystal forms according to any one of claims 1 to 16.

19. A method for the preparation of the crystal form according to claim 4, characterized in that (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is suspended in an organic solvent at a high temperature, an equal amount of coformer is added, and cooling crystallization is carried out.

20. A medicament for use in the treatment and / or prevention of cancer, comprising one or more crystalline forms according to any one of claims 1 to 16, or a mixture thereof in any ratio.

21. A pharmaceutical preparation comprising one or more crystalline forms according to any one of claims 1 to 16, or a mixture thereof in any ratio, and optionally further comprising excipients and / or adjuvants.

22. A process for the preparation of a pharmaceutical preparation, characterized in that one or more crystalline forms according to any one of claims 1 to 16, or a mixture thereof in any ratio, are made into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant.

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