Crystal Solvate Form of N-(4-(1-(2,6-Difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

Abstract

The present disclosure relates to crystalline solvated forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea. The present disclosure also relates to methods of making the disclosed crystalline forms, pharmaceutical compositions and kits containing the crystalline forms, and methods of treatment and uses comprising their administration. [Formula 1] JPEG2022551525000009.jpg59119

Description

Technical Field

[0001] Cross - Reference to Related Applications This application is a continuation of U.S. Patent Application No. 62 / 913,606, filed on October 10, 2019, the entire disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to crystalline solvated forms of N-(4-(1-(2,6 - difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 - methoxy - 3 - pyridazinyl)-2,4 - dioxo - 1,2,3,4 - tetrahydrothieno[2,3 - d]pyrimidin - 6 - yl)phenyl)-N'-methoxyurea, also referred to herein as Compound 1. The present disclosure also relates to methods of making the disclosed crystalline forms, pharmaceutical compositions and kits comprising the crystalline forms, and methods of treatment and uses including their administration.

Background Art

[0003] Background Compound 1, N-(4-(1-(2,6 - difluorobenzyl)-5-((dimethylamino)methyl)-3-(6 - methoxy - 3 - pyridazinyl)-2,4 - dioxo - 1,2,3,4 - tetrahydrothieno[2,3 - d]pyrimidin - 6 - yl)phenyl)-N'-methoxyurea, is a gonadotropin - releasing hormone (GnRH) antagonist that has been developed as a new pharmaceutical useful for treating excessive menstrual bleeding and other symptoms associated with uterine fibroids, pain and other symptoms associated with endometriosis, and various conditions including prostate cancer. Compound 1 may also be useful for treating other diseases or disorders. See, for example, U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, WO2018060501, and WO2018060463.

[0004] Compound 1 and the method for preparing Compound 1 are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, and U.S. Patent No. 9,758,528.

[0005] U.S. Patent No. 9,758,528, which is hereby incorporated by reference in its entirety, describes Compound 1 and certain synthetic intermediates, as well as a method for producing two crystalline forms of Compound 1: crystals of the tetrahydrofuran (THF) solvate of Compound 1 and crystals of the anhydrous form of Compound 1 (referred to herein as Form I of Compound 1). For reference, as detailed in U.S. Patent No. 9,758,528, Form I of Compound 1 can be characterized by an XRPD pattern having peaks at approximately 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4° 2θ.

[0006] Form I of Compound 1 can also be characterized by the XRPD pattern shown in Figure 4 of the present application. Form I of Compound 1 begins to melt at approximately 189 °C and begins to decompose at approximately 197 °C. Form I of Compound 1 exhibits an exothermic peak of approximately 237 °C by DSC and a decomposition at approximately 245 °C by TG. Figures 5 and 6 show the thermogravimetric analysis (TG) and differential scanning calorimetry (DSC) thermograms of Form I of Compound 1, respectively. SUMMARY OF THE INVENTION

[0007] Summary One aspect of the present disclosure relates to a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In certain such embodiments, the X-ray powder diffraction pattern comprises one or more peaks selected from the group consisting of 18.0°, 19.1°, and 21.5° ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is by an XRPD pattern substantially the same as the pattern shown in FIG. 1.

[0008] In some embodiments, Form XIII of Compound 1 is characterized by a thermogravimetric analysis thermogram showing a continuous weight loss of about 8.6% between about 32°C and about 120°C. In some embodiments, Form XIII of Compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in FIG. 2.

[0009] In some embodiments, Form XIII of Compound 1 is characterized by the onset of melting between about 99 °C and about 101 °C. In some embodiments, Form XIII of Compound 1 is characterized by the onset of melting at about 100 °C. In some embodiments, Form XIII of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak between about 105 °C and about 107 °C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram that includes an endothermic peak at about 106 °C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram that is substantially the same as the pattern shown in Figure 3.

[0010] In some embodiments, Form XIII of Compound 1 is as follows: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ; b) the onset of melting at about 100 °C as measured by DSC; and c) an endothermic peak at about 106 °C as measured by DSC and is characterized by having at least two of the foregoing.

[0011] One aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of the present disclosure and a pharmaceutically acceptable carrier.

[0012] Another aspect of the present disclosure relates to a method for preparing Form XIII of Compound 1, the method comprising: a) suspending a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1, in DMSO at room temperature; b) isolating the white suspension resulting from step a); and c) Isolating the precipitated solid from the white suspension to obtain Form XIII of Compound 1 comprises.

[0013] Another aspect of the present disclosure relates to a method for preparing Form XIII of Compound 1, the method comprising: a) Suspending a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1, in DMSO at room temperature; b) Isolating the white suspension resulting from step a); c) Subjecting the white suspension to a series of temperature cycles from about 15 °C to about 30 °C to about 15 °C, from about 10 °C to about 30 °C to about 10 °C, and from about 5 °C to about 35 °C to about 5 °C; and d) Isolating the precipitated solid from the white suspension to obtain Form XIII of Compound 1 comprises.

[0014] In some embodiments, there are 6 temperature cycles from about 15 °C to about 30 °C to about 15 °C. In some embodiments, there are 6 temperature cycles from about 10 °C to about 30 °C to about 10 °C. In some embodiments, there are 8 temperature cycles from about 5 °C to about 35 °C to about 5 °C.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

[0016] **Detailed Description** Described herein are crystalline solvate forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (Compound 1), methods of making the crystalline forms, pharmaceutical compositions and kits comprising the crystalline forms, and methods of treatment and uses comprising their administration. The chemical structure of Compound 1 is as follows.

[0017] **CHEMICAL STRUCTURE**

[0018] General Information The articles “a” and “an” are used in the present disclosure to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, “an element” means one element or a plurality of elements.

[0019] The term “and / or” is used in the present disclosure to mean either “and” or “or” unless otherwise indicated.

[0020] Crystalline Forms of the Present Disclosure Form XIII is the crystalline dimethyl sulfoxide (DMSO) solvate of Compound 1. As used herein, the term "solvate" includes stoichiometric solvates and non-stoichiometric solvates such as channel-type solvates formed by Compound 1 and a solvent. Examples of suitable solvents can include, but are not limited to, DMSO.

[0021] Form XIII of Compound 1 The present disclosure provides a crystalline form of Compound 1 characterized as Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 is a DMSO solvate. In some embodiments, Form XIII of Compound 1 is characterized by an XRPD pattern comprising at least 3 peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an XRPD pattern comprising at least 5 peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5° 2θ ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an XRPD pattern having peaks at 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In certain such embodiments, the XRPD pattern has one or more peaks selected from the group consisting of 18.0°, 19.1°, and 21.5° ± 0.2° 2θ. In some embodiments, Form XIII of Compound 1 is characterized by an XRPD pattern substantially the same as the pattern shown in Figure 1.

[0022] Form XIII of Compound 1 can also be characterized by thermogravimetric analysis (TG). In some embodiments, Form XIII of Compound 1 is characterized by a TG thermogram showing a continuous weight loss of about 8.6% between about 32 °C and about 120 °C. In some embodiments, Form XIII of Compound 1 is characterized by a TG thermogram substantially the same as the pattern shown in Figure 2.

[0023] Form XIII of Compound 1 can also be characterized by differential scanning calorimetry (DSC). In some embodiments, Form XIII of Compound 1 is characterized by the onset of melting between about 99 °C and about 101 °C. In some embodiments, Form XIII of Compound 1 is characterized by the onset of melting at about 100 °C. In some embodiments, Form XIII of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak between about 105 °C and about 107 °C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram containing an endothermic peak at about 106 °C. In some embodiments, Form XIII of Compound 1 is characterized by a DSC thermogram substantially the same as the pattern shown in Figure 3.

[0024] In some embodiments, Form XIII of Compound 1 is as follows: a) an XRPD pattern comprising at least three peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ; b) the onset of melting at about 100 °C as measured by DSC; and c) an endothermic peak at about 106 °C as measured by DSC and is characterized by having at least two of the above.

[0025] In some embodiments, the XRPD pattern includes peaks at 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.6°, 5.9°, and 9.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.6°, 5.9°, and 11.4° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.6°, 5.9°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.9°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.6°, 11.4° and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.9°, 9.1°, and 11.4° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.6°, 9.1°, and 11.4° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.6°, 9.1°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes peaks at 5.9°, 9.1°, and 14.1° 2θ ± 0.2° 2θ. In some embodiments, the XRPD pattern includes one or more peaks selected from the group consisting of 18.0°, 19.1°, and 21.5° ± 0.2° 2θ.

[0026] In some embodiments, the single crystal structure of Form XIII of Compound 1 has 1 to 5 molecules of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 1 molecule of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 2 molecules of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 2.5 molecules of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 3 molecules of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 4 molecules of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 5 molecules of DMSO and 1 molecule of Compound 1. In some embodiments, the single crystal structure of Form XIII of Compound 1 has 5 molecules of DMSO and 2 molecules of Compound 1.

[0027] In some embodiments, Form XIII of Compound 1 has about 1 wt% to about 10 wt% DMSO based on the total weight of Compound 1 present in Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 has about 7 wt% to about 9 wt% DMSO based on the total weight of Compound 1 present in Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 has about 8 wt% to about 9 wt% DMSO based on the total weight of Compound 1 present in Form XIII of Compound 1. In some embodiments, Form XIII of Compound 1 has about 8.6 wt% DMSO based on the total weight of Compound 1 present in Form XIII of Compound 1.

[0028] In some embodiments, Form XIII of Compound I disclosed herein can be characterized by an XRPD pattern having the peaks listed in Table 1. All peak lists are at °2θ ± 0.2°2θ.

[0029] [Table 1]

[0030] Impurity Profile of Crystalline Form XIII of Compound 1 Through the manufacture of Form XIII of Compound 1, the purity of the crystalline form of Compound 1 can be increased. Thus, high-purity Form XIII and Form I of Compound 1 can be obtained. Impurities such as U-1, U-2, and U-3 can be minimized in the desired crystalline forms of Compound 1 (e.g., Form I and XIII).

[0031] The aqueous purity of Form XIII of Compound 1 is summarized in Table 2.

[0032] [Table 2]

[0033] As shown in Table 2, Form XIII of Compound 1 has been shown to have high purity and low levels of impurities U-1, U-2, and U-3. When making pharmaceutical-grade compounds, impurities can be inert, toxic, or have other undesirable effects, so it is desirable and in some aspects necessary to minimize their amounts or control them below certain limits. U.S. Patent No. 9,758,528 discloses a tetrahydrofuran (THF) solvate form of Compound 1 as an intermediate in the manufacture of Form I of Compound 1. The higher purity of Form XIII of Compound 1 compared to the THF solvate of Form I may enable the production of higher-purity Form I of Compound 1.

[0034] Preparation of the Disclosed Crystalline Forms Form XIII of Compound 1 can be used during the synthesis or manufacture of Form I of Compound 1. Form I of Compound 1 and the method for preparing Form I of Compound 1 are described in U.S. Patent No. 9,758,528, which is hereby incorporated by reference in its entirety, particularly with respect to the synthesis and crystallization methods. The XRPD pattern of Form I of Compound 1 is represented in Figure 4. The methods for preparing Compound 1 prior to crystallization are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, and U.S. Patent No. 9,346,822, which are hereby incorporated by reference in their entirety.

[0035] In some embodiments, Form I of Compound 1 can be made by using Form XIII of Compound 1. For example, Form I of Compound 1 can be made by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:1.2) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 4 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0036] In some embodiments, Form I of Compound 1 can be made by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 6 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0037] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0038] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0039] For example, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:1.2) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 4 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0040] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 6 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, the mixture is seeded with a small amount of Form I of Compound 1.

[0041] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0042] In some embodiments, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some embodiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0043] The present disclosure provides a method for preparing Form XIII of Compound 1. In some embodiments, the THF solvate form of Compound 1 (see U.S. Patent No. 9,758,528) is added to a container containing DMSO, and the solid does not dissolve. Solid-to-solid polymorph transitions are known in the art. Without being bound by any particular theory, the THF solvate form of Compound 1 can convert to Form XIII of Compound 1 described herein, for example, via a solid-to-solid conversion. The solid is recovered from the container to obtain Form XIII of Compound 1.

[0044] In some embodiments, Form XIII of Compound 1 is prepared using Form I of Compound 1. In certain such embodiments, Form I of Compound 1 is suspended in DMSO at room temperature, and the solid precipitated from the resulting suspension is recovered to obtain Form XIII of the compound. In some embodiments, a small amount of Form XIII of Compound 1 is seeded into the mixture of Form I of Compound 1 in DMSO.

[0045] In some embodiments, a method for preparing Form XIII of Compound 1 comprises suspending Form I of Compound 1 in DMSO at room temperature; isolating the white suspension resulting from the suspension of Form I of Compound 1 in DMSO; subjecting the white suspension to a series of temperature cycles from about 15°C to about 30°C to about 15°C, from about 10°C to about 30°C to about 10°C, and from about 5°C to about 35°C to about 5°C; and isolating the precipitated solid from the white suspension to obtain Form XIII of Compound 1. In some embodiments, there are six temperature cycles from about 15°C to about 30°C to about 15°C. In some embodiments, there are six temperature cycles from about 10°C to about 30°C to about 10°C. In some embodiments, there are eight temperature cycles from about 5°C to about 35°C to about 5°C. In some embodiments, a small amount of Form XIII of Compound 1 is seeded into the mixture of Form I of Compound 1 in DMSO.

[0046] Pharmaceutical Compositions The disclosed crystalline Form XIII of Compound 1 can be used by itself, but when administered to a subject, it will generally be administered in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs,” M. E. Aulton, Churchill Livingstone, 1988, which is hereby incorporated by reference in its entirety.

[0047] As used herein, the term "carrier" may include carriers, excipients, and diluents, and refers to a material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material that is involved in transporting or delivering a pharmaceutical product, such as a crystalline form of the present disclosure, from one organ or part of the body to another organ or part of the body. The carrier should be selected based on the suitability of the desired dosage form and the release profile characteristics. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like. See, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

[0048] In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more crystalline forms disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising only one crystalline form disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form XIII of Compound 1. In other embodiments, the present disclosure provides a pharmaceutical composition comprising two crystalline forms disclosed herein. For example, a pharmaceutical composition comprising Compound 1 may comprise Form I of Compound 1 and Form XIII of Compound 1.

[0049] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form XIII of Compound 1 and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form I and Form XIII of Compound 1 and a pharmaceutically acceptable carrier.

[0050] Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 to about 99 weight percent (wt%), more specifically from about 0.05 to about 80 wt%, even more specifically from about 0.10 to about 70 wt%, and yet more specifically from about 0.10 to about 50 wt% of one or more of the disclosed crystalline forms, where all weight percents are based on the total composition. In some embodiments, the pharmaceutical composition is administered transdermally, transmucosally, or topically (e.g., to the skin or mucosa). In some embodiments, the pharmaceutical composition is administered as a vaginal suppository.

[0051] The pharmaceutical compositions of the present disclosure can include a therapeutically effective amount of one or more of the disclosed crystalline forms, formulated together with one or more pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers include sugars such as lactose, dextrose, mannitol, glucose and sucrose; starches such as corn, wheat or potato starch and other pharmaceutical grade starches such as sodium glycolate starch; cellulose and its derivatives such as carboxymethylcellulose sodium, methylcellulose, ethylcellulose, hydroxypropylcellulose, cellulose acetate, and microcrystalline cellulose; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; releasing agents; coating agents; sweetening, flavoring and aromatic agents; preservatives and antioxidants.

[0052] Methods of Treatment and Uses The present disclosure provides a method of treating a disorder in a subject in need thereof, comprising administering an effective amount of one or more crystalline forms described herein, or one or more pharmaceutical compositions comprising said one or more crystalline forms, thereby treating the disorder.

[0053] In some embodiments of the methods and uses of the present disclosure, the disorder is a hormone-dependent condition. Hormone-dependent conditions can include sex hormone-dependent cancers (such as prostate cancer, uterine cancer, breast cancer, and ovarian cancer), bone metastases of sex hormone-dependent cancers, benign prostatic hyperplasia, uterine fibroids (hysteromyoma(uterine fibroids)), adenomyosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovarian syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, heavy menstrual bleeding, and symptoms associated with these conditions. Such symptoms can include anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, frequent urination, incontinence, constipation, anxiety, sleep disturbances, decreased quality of life, difficulty with activities of daily living, female sexual dysfunction, and depression. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer. Additional disorders for which Compound 1 is useful in treatment are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, W02018060501, and W02018060463, which are hereby incorporated by reference in their entirety.

[0054] In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is prostate cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is breast cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is ovarian cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine fibroids. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain or other symptoms associated with uterine fibroids. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain associated with endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is adenomyosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is heavy menstrual bleeding.

[0055] A "patient" or "subject" is a mammal. Examples of mammals can include, but are not limited to, any member of the class Mammalia including humans; non-human primates such as chimpanzees, monkeys, baboons, and macaques; cows, horses, sheep, goats, and pigs; rabbits, dogs, and cats; and rodents such as rats, mice, and guinea pigs. In some embodiments, the patient or subject is a human.

[0056] As used in connection with one or more crystalline forms or pharmaceutical compositions of the present disclosure, the term "effective amount" or "therapeutically effective amount" can refer to an amount of the one or more crystalline forms or pharmaceutical compositions sufficient to provide the desired biological result. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disorder, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use can be an amount of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein necessary to provide a clinically significant reduction in a disorder. The appropriate "effective amount" in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0057] As used herein, the terms "treat," "treatment," or their cognates are meant to indicate the delay of the onset of a disorder; and / or the reduction of the severity of such symptoms that would or are expected to develop. That is, these terms can include improving existing disorder symptoms; preventing additional symptoms; improving or preventing the underlying cause of the symptoms; suppressing a disorder, e.g., preventing the onset of a disorder; alleviating a disorder; causing regression of a disorder; alleviating the symptoms caused by a disorder; or stopping or reducing the symptoms of a disorder.

[0058] As used in the present disclosure, the terms "administered," "administration," or "administering" can refer to directly administering any of one or more crystalline forms or pharmaceutical compositions of the present disclosure to a subject.

[0059] The present disclosure provides a method of treating a disorder, comprising administering an effective amount of Form XIII of Compound 1, thereby treating the disorder in a subject in need thereof. The present disclosure provides a method of treating a disorder, comprising administering an effective amount of a mixture of Form I and XIII of Compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0060] The present disclosure provides a method of treating a disorder, comprising administering an effective amount of one or more pharmaceutical compositions of the present disclosure, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder, comprising administering an effective amount of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder, comprising administering an effective amount of one or more pharmaceutical compositions comprising Form XIII of Compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disorder, comprising administering an effective amount of one or more pharmaceutical compositions comprising a mixture of Form I and XIII of Compound 1, thereby treating the disorder in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0061] The present disclosure provides one or more crystalline forms of the present disclosure or one or more pharmaceutical compositions of the present disclosure for use in treating a disorder in a subject in need thereof. In some embodiments, the one or more crystalline forms comprise Form XIII of Compound 1. In some embodiments, the one or more crystalline forms are a mixture of Form I and XII of Compound 1. In some embodiments, the one or more pharmaceutical compositions of the present disclosure comprise one or more crystalline forms disclosed herein. In some embodiments, the one or more pharmaceutical compositions of the present disclosure comprise Form XIII of Compound 1. In some embodiments, the one or more pharmaceutical compositions of the present disclosure comprise a mixture of Form I and XIII of Compound 1. In some embodiments, the disorder is a hormone-dependent condition.

[0062] The present disclosure provides the use of one or more crystalline forms of the present disclosure for treating disorders in a subject in need thereof. In some embodiments, the present disclosure provides the use of Form XIII of Compound 1 for treating disorders in a subject in need thereof. In some embodiments, the present disclosure provides the use of a mixture of Form I and XIII of Compound 1 for treating disorders in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0063] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure for treating disorders in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein for treating disorders in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIII of Compound 1 for treating disorders in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and XIII of Compound 1 for treating disorders in a subject in need thereof. In some embodiments, the disorder is a hormone-dependent condition.

[0064] The present disclosure provides the use of one or more crystalline forms of the present disclosure in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of Form XIII of Compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of a mixture of Form I and XII of Compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0065] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIII of Compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIII of Compound 1 in the manufacture of a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0066] The present disclosure provides the use of one or more crystalline forms of the present disclosure as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of Form XIII of Compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of a mixture of Form I and Form XIII of Compound 1 as a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0067] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising one or more crystalline forms disclosed herein as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising Form XIII of Compound 1 as a medicament for treating a disorder. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions comprising a mixture of Form I and Form XIII of Compound 1 as a medicament for treating a disorder. In some embodiments, the disorder is a hormone-dependent condition.

[0068] In some embodiments of the methods and uses of the present disclosure, only one pharmaceutical composition of the present disclosure is used in the method or use. In some embodiments of the methods and uses of the present disclosure, only one crystalline form of the present disclosure is used in the method or use.

[0069] For the therapeutic uses described herein, the dosage administered will, of course, vary depending on the one or more crystalline forms or pharmaceutical compositions used, the mode of administration, the desired treatment, and the disorder indicated. For example, the daily dosage of one or more crystalline forms of the present disclosure can range from about 0.05 micrograms per kilogram of body weight (μg / kg) to about 100 micrograms per kilogram of body weight (μg / kg) when inhaled. Alternatively, when one or more crystalline forms or pharmaceutical compositions are administered orally, in that case the daily dosage of one or more crystalline forms of the present disclosure can range from about 0.01 micrograms per kilogram of body weight (μg / kg) to about 100 milligrams per kilogram of body weight (mg / kg).

[0070] However, it will be understood that the total daily usage of one or more crystalline forms or pharmaceutical compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific crystalline form used; the specific pharmaceutical composition used; the age, weight, general health, gender, and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the specific crystalline form used; the duration of the treatment; drugs used in combination with or concurrently with the specific crystalline form used; and similar factors well known in the medical arts. A physician or veterinarian who is a person of ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of one or more crystalline forms or pharmaceutical compositions disclosed herein to treat, counteract, or prevent the progression of the disorder.

[0071] Combination Therapies In some embodiments, one or more of the crystalline forms or pharmaceutical compositions described herein may be used alone or administered together with or jointly with one or more other therapeutic agents or pharmaceutical compositions, or used in combination. Co-administration or combined use refers to the administration of two or more different compounds, crystalline forms, or pharmaceutical compositions such that a second compound, crystalline form, or pharmaceutical composition is administered while a previously administered compound, crystalline form, or pharmaceutical composition is still effective in the body. For example, different compounds, crystalline forms, or pharmaceutical compositions may be administered in any form of co-administration of the individual components of the treatment, simultaneously, sequentially, or separately, either in the same formulation or in separate formulations. In some embodiments, different compounds, crystalline forms, or pharmaceutical compositions can be administered to each other within about 1 hour, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about 1 week. That is, an individual undergoing such treatment can benefit from the combined effects of different compounds, crystalline forms, or pharmaceutical compositions.

[0072] In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with one or more other crystalline forms or pharmaceutical compositions of the present disclosure in the methods or uses of the present disclosure. In certain such embodiments, the combination of one or more other crystalline forms or pharmaceutical compositions of the present disclosure is used in a method of treating one or more of the disorders listed herein.

[0073] In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with estradiol or a corresponding amount of an estradiol equivalent. In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with a progestin. In some embodiments, one or more of the crystalline forms or pharmaceutical compositions of the present disclosure are used in combination with estradiol or a corresponding amount of an estradiol equivalent, and a progestin. In some embodiments, the progestin is norethindrone acetate.

[0074] In some embodiments, one or more combinations of crystalline forms or pharmaceutical compositions provided herein, or other known agents or pharmaceutical compositions and one or more combinations of crystalline forms or pharmaceutical compositions provided herein, are formulated into pharmaceutical compositions and medicaments useful in the methods and uses of the present disclosure. The present disclosure also provides for the use of such combinations in the treatment of one or more of the disorders listed herein.

[0075] In some embodiments of the present disclosure, one or more crystalline forms or pharmaceutical compositions of the present disclosure are administered at a sub-therapeutic dose, where a sub-therapeutic dose is a dose that, when administered alone, would be insufficient to treat one of the disorders listed herein.

[0076] Kits In some embodiments, the present disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with at least one crystalline form or pharmaceutical composition of the present disclosure. Such containers may optionally be accompanied by a notice in a form determined by a governmental agency that regulates the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting (a) approval by the governmental agency for manufacture, use, or sale for human administration, (b) instructions for use, or both.

[0077] The foregoing applies to any of the crystalline forms, pharmaceutical compositions, methods, and uses described herein. This disclosure specifically contemplates any combination of the features of such crystalline forms, pharmaceutical compositions, methods, and uses (alone or in combination) with the features described for the various kits in this section.

[0078] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and from the claims. In the specification and the appended claims, unless the context clearly dictates otherwise, the singular forms also include the plural. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are hereby incorporated by reference in their entirety.

[0079] Each embodiment described herein can be used alone or in combination with any one or more other embodiments.

[0080] Enumerated Embodiments Some embodiments of the present disclosure include those of Embodiment I.

[0081] Embodiment I-1. A crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form XIII of Compound 1.

[0082] Embodiment I-2. The crystalline form of Embodiment I-1, characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ.

[0083] The crystalline form of Embodiment I-1, characterized by an X-ray power diffraction pattern comprising at least five peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5° 2θ ± 0.2° 2θ.

[0084] The crystalline form of Embodiment I-1, characterized by an X-ray power diffraction pattern comprising peaks at 5.6°, 5.9°, 9.1°, 11.4°, and 14.1° 2θ ± 0.2° 2θ.

[0085] The crystalline form of Embodiment I-4, wherein the X-ray power diffraction pattern comprises one or more peaks selected from the group consisting of 18.0°, 19.1°, and 21.5° ± 0.2° 2θ.

[0086] The crystalline form of any one of Embodiments I-1 to I-5, characterized by an XRPD pattern substantially the same as the pattern shown in Figure 1.

[0087] The crystalline form of any one of Embodiments I-1 to I-6, characterized by a thermogravimetric analysis (TG) thermogram showing a continuous weight loss of about 8.6% between about 32°C and about 120°C.

[0088] The crystalline form of any one of Embodiments I-1 to I-7, characterized by a TG thermogram substantially the same as the pattern shown in Figure 2.

[0089] The crystalline form of any one of Embodiments I-1 to I-8, characterized by the onset of melting between about 99°C and about 101°C.

[0090] The crystalline form of any one of Embodiments I-1 to I-9, characterized by the onset of melting at about 100°C.

[0091] Crystal form of any one of Embodiments I-1 to I-10, characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 105°C and about 107°C.

[0092] Crystal form of any one of Embodiments I-1 to I-11, characterized by a DSC thermogram comprising an endothermic peak at about 106°C.

[0093] Crystal form of any one of Embodiments I-1 to I-12, characterized by a DSC thermogram substantially the same as the pattern shown in Figure 3.

[0094] Embodiment I-14: a) An XRPD pattern comprising at least three peaks selected from the group consisting of 5.6°, 5.9°, 9.1°, 11.4° and 14.1° 2θ ± 0.2° 2θ; b) The onset of melting at about 100°C as measured by DSC; and c) An endothermic peak at about 106°C as measured by DSC Characterized by having at least two of them, the crystal form of Embodiment I-1.

[0095] A pharmaceutical composition comprising one or more crystal forms of any one of Embodiments I-1 to I-14 and a pharmaceutically acceptable carrier.

[0096] The pharmaceutical composition of Embodiment I-15, wherein the pharmaceutical composition comprises a crystal form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1.

[0097] Embodiment I-17. A method of treating a disorder in a subject, comprising administering to the subject in need thereof an effective amount of one or more crystalline forms of any one of Embodiments I-1 to I-14.

[0098] Embodiment I-18. The method of Embodiment I-17, wherein the method comprises administering to the subject an effective amount of a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1.

[0099] Embodiment I-19. A method of treating a disorder in a subject, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of Embodiment I-15 or I-16.

[0100] Embodiment I-20. Any one of the methods of Embodiments I-17 to I-19, wherein the disorder is a hormone-dependent condition.

[0101] Embodiment I-21. The method of Embodiment I-20, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, benign prostatic hyperplasia, uterine fibroids, adenomyosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, infertility, transient heat sensation, endometriosis, adenomyosis, or menorrhagia.

[0102] Embodiment I-22. The method of Embodiment I-20 or I-21, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0103] Embodiment I-23. Any one of the methods of Embodiments I-20 to I-22, wherein the hormone-dependent condition is prostate cancer.

[0104] Embodiment I-24. A method according to any one of Embodiments I-20 to I-22, wherein the hormone-dependent condition is uterine cancer.

[0105] Embodiment I-25. A method according to any one of Embodiments I-20 to I-22, wherein the hormone-dependent condition is breast cancer.

[0106] Embodiment I-26. A method according to any one of Embodiments I-20 to I-22, wherein the hormone-dependent condition is ovarian cancer.

[0107] Embodiment I-27. A method according to Embodiment I-20 or I-21, wherein the hormone-dependent condition is uterine fibroids.

[0108] Embodiment I-28. A method according to Embodiment I-20, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids.

[0109] Embodiment I-29. A method according to Embodiment I-20, wherein the hormone-dependent condition is pain or other symptoms associated with uterine fibroids.

[0110] Embodiment I-30. A method according to Embodiment I-20 or I-21, wherein the hormone-dependent condition is endometriosis.

[0111] Embodiment I-31. A method according to Embodiment I-20 or I-21, wherein the hormone-dependent condition is adenomyosis.

[0112] Embodiment I-32. A method according to Embodiment I-20 or I-21, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0113] Embodiment I-33. A method according to any one of Embodiments I-17 to I-33, the method comprising administering estradiol or a corresponding amount of an estradiol equivalent to a subject.

[0114] Embodiment I-34. A method according to any one of Embodiments I-17 to I-33, the method comprising administering a progestin to a subject.

[0115] Embodiment I-35. A method according to any one of the methods of Embodiments I-17 to I-33, the method comprising administering estradiol, or a corresponding amount of an estradiol equivalent, and a progestin to a subject.

[0116] Embodiment I-36. The method of Embodiment I-34 or I-35, wherein the progestin is norethindrone acetate.

[0117] Embodiment I-37. One or more crystalline forms according to any one of Embodiments I-1 to I-14 for use in treating a disorder in a subject in need thereof.

[0118] Embodiment I-38. One or more crystalline forms for use according to Embodiment I-37, wherein the one or more crystalline forms for use comprise a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1, for use in treating a disorder in a subject in need thereof.

[0119] Embodiment I-39. One or more crystalline forms for use according to Embodiment I-37 or I-96, wherein the disorder is a hormone-dependent condition.

[0120] Embodiment I-40. One or more crystalline forms for use according to Embodiment I-39, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, benign prostatic hyperplasia, uterine fibroids, adenomyosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, or menorrhagia.

[0121] One or more crystalline forms for use according to embodiment I-39 or I-40, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0122] Embodiment I-42. One or more crystalline forms for use according to any one of embodiments I-39 to I-41, wherein the hormone-dependent condition is prostate cancer.

[0123] Embodiment I-43. One or more crystalline forms for use according to any one of embodiments I-39 to I-41, wherein the hormone-dependent condition is uterine cancer.

[0124] Embodiment I-44. One or more crystalline forms for use according to any one of embodiments I-39 to I-41, wherein the hormone-dependent condition is breast cancer.

[0125] Embodiment I-45. One or more crystalline forms for use according to any one of embodiments I-39 to I-41, wherein the hormone-dependent condition is ovarian cancer.

[0126] Embodiment I-46. One or more crystalline forms for use according to embodiment I-39 or I-40, wherein the hormone-dependent condition is uterine fibroids.

[0127] Embodiment I-47. One or more crystalline forms for use according to embodiment I-39, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids.

[0128] Embodiment I-48. One or more crystalline forms for use according to embodiment I-39, wherein the hormone-dependent condition is pain or other symptoms associated with uterine fibroids.

[0129] Embodiment I-49. One or more crystalline forms for use according to embodiment I-39 or I-40, wherein the hormone-dependent condition is endometriosis.

[0130] Embodiment I-50. One or more crystalline forms for use according to embodiment I-39 or I-40, wherein the hormone-dependent condition is adenomyosis.

[0131] Embodiment I-51. One or more crystalline forms for use in Embodiment I-39 or I-40, wherein the hormonal dependent condition is heavy menstrual bleeding.

[0132] Embodiment I-52. One or more crystalline forms for use in any one of Embodiments I-37 to I-51, wherein the one or more crystalline forms for use are used in combination with estradiol or a corresponding amount of an estradiol equivalent.

[0133] Embodiment I-53. One or more crystalline forms for use in any one of Embodiments I-37 to I-51, wherein the one or more crystalline forms for use are used in combination with a progestin.

[0134] Embodiment I-54. One or more crystalline forms for use in any one of Embodiments I-37 to I-51, wherein the one or more crystalline forms for use are used in combination with estradiol, or a corresponding amount of an estradiol equivalent, and a progestin.

[0135] Embodiment I-55. One or more crystalline forms for use in Embodiment I-53 or I-54, wherein the progestin is norethisterone acetate.

[0136] Embodiment I-56. A pharmaceutical composition according to Embodiment I-15 or I-16 for use in treating a disorder in a subject in need thereof.

[0137] Embodiment I-57. A pharmaceutical composition according to Embodiment I-56 for use, wherein the disorder is a hormonal dependent condition.

[0138] Embodiment I-58. A pharmaceutical composition for the use of Embodiment I-57, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, prostatic hyperplasia, uterine myoma, adenomyoma, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, infertility, transient heat sensation, endometriosis, adenomyosis, or heavy menstrual bleeding.

[0139] Embodiment I-59. A pharmaceutical composition for the use of Embodiment I-57 or I-58, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0140] Embodiment I-60. A pharmaceutical composition for the use of any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is prostate cancer.

[0141] Embodiment I-61. A pharmaceutical composition for the use of any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is uterine cancer.

[0142] Embodiment I-62. A pharmaceutical composition for the use of any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is breast cancer.

[0143] Embodiment I-63. A pharmaceutical composition for the use of any one of Embodiments I-57 to I-59, wherein the hormone-dependent condition is ovarian cancer.

[0144] Embodiment I-64. A pharmaceutical composition for the use of Embodiment I-57 or I-58, wherein the hormone-dependent condition is uterine myoma.

[0145] Embodiment I-65. A pharmaceutical composition for the use of Embodiment I-57, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine myoma.

[0146] Embodiment I-66. A pharmaceutical composition for the use of Embodiment I-57, wherein the hormone-dependent condition is pain or other symptoms associated with uterine myoma.

[0147] Embodiment I-67. A pharmaceutical composition for use according to Embodiment I-57 or I-58, wherein the hormone-dependent condition is endometriosis.

[0148] Embodiment I-68. A pharmaceutical composition for use according to Embodiment I-57 or I-58, wherein the hormone-dependent condition is adenomyosis.

[0149] Embodiment I-69. A pharmaceutical composition for use according to Embodiment I-57 or I-58, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0150] Embodiment I-70. A pharmaceutical composition for use according to any one of Embodiments I-56 to I-69, wherein the pharmaceutical composition for use is used in combination with estradiol or a corresponding amount of an estradiol equivalent.

[0151] Embodiment I-71. A pharmaceutical composition for use according to any one of Embodiments I-56 to I-69, wherein the pharmaceutical composition for use is used in combination with a progestin.

[0152] Embodiment I-72. A pharmaceutical composition for use according to any one of Embodiments I-56 to I-69, wherein the pharmaceutical composition for use is used in combination with estradiol, or a corresponding amount of an estradiol equivalent, and a progestin.

[0153] Embodiment I-73. A pharmaceutical composition for use according to Embodiment I-71 or I-72, wherein the progestin is norethisterone acetate.

[0154] Embodiment I-74. Use of one or more crystalline forms according to any one of Embodiments I-1 to I-14 for treating a disorder in a subject in need thereof.

[0155] Use of Embodiment I-74, wherein the use is for treating a disorder in a subject in need thereof, and is the use of a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1.

[0156] Use of the pharmaceutical composition of Embodiment I-15 or I-16 for treating a disorder in a subject in need thereof.

[0157] Use of one or more crystalline forms of any one of Embodiments I-1 to I-14 in the manufacture of a medicament for treating a disorder.

[0158] Use of Embodiment I-77, wherein the use is for treating a disorder in a subject in need thereof, and is the use of a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1.

[0159] Use of the pharmaceutical composition of Embodiment I-15 or I-16 in the manufacture of a medicament for treating a disorder.

[0160] Use of one or more crystalline forms of any one of Embodiments I-1 to I-14 as a medicament for treating a disorder.

[0161] Embodiment I-81. Use according to Embodiment I-80, which use comprises the use of the crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1, as a medicament for treating a disorder.

[0162] Embodiment I-82. Use of the pharmaceutical composition according to Embodiment I-15 or I-16 as a medicament for treating a disorder.

[0163] Embodiment I-83. Use according to any one of Embodiments I-74 to I-82, wherein the disorder is a hormone-dependent condition.

[0164] Embodiment I-84. Use according to Embodiment I-83, wherein the hormone-dependent condition is a sex hormone-dependent cancer, prostate cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of a sex hormone-dependent cancer, prostatic hypertrophy, uterine myoma, adenomyosis, uterine fibroid, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, infertility, transient heat sensation, endometriosis, adenomyosis, or menorrhagia.

[0165] Embodiment I-85. Use according to Embodiment I-83 or I-84, wherein the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer.

[0166] Embodiment I-86. Use according to any one of Embodiments I-83 to I-85, wherein the hormone-dependent condition is prostate cancer.

[0167] Embodiment I-87. Use according to any one of Embodiments I-83 to I-85, wherein the hormone-dependent condition is uterine cancer.

[0168] Embodiment I-88. Use according to any one of Embodiments I-83 to I-85, wherein the hormone-dependent condition is breast cancer.

[0169] Use according to any one of Embodiments I-83 to I-85, wherein the hormone-dependent condition is ovarian cancer.

[0170] Use according to Embodiment I-83 or I-84, wherein the hormone-dependent condition is uterine myoma.

[0171] Use according to Embodiment I-83, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine myoma.

[0172] Use according to Embodiment I-83, wherein the hormone-dependent condition is pain or other symptoms associated with uterine myoma.

[0173] Use according to Embodiment I-83 or I-84, wherein the hormone-dependent condition is endometriosis.

[0174] Use according to Embodiment I-83 or I-84, wherein the hormone-dependent condition is adenomyosis.

[0175] Use according to Embodiment I-83 or I-84, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0176] Use according to any one of Embodiments I-74 to I-95, wherein the use comprises the use of estradiol or a corresponding amount of an estradiol equivalent for treating a disorder.

[0177] Use according to any one of Embodiments I-74 to I-95, wherein the use comprises the use of a progestin for treating a disorder.

[0178] Use according to any one of Embodiments I-74 to I-95, wherein the use comprises the use of estradiol or a corresponding amount of an estradiol equivalent and a progestin for treating a disorder.

[0179] Use according to Embodiment I-97 or I-98, wherein the progestin is norethisterone acetate.

[0180] Embodiment I-100. A method for preparing any one of the crystalline forms of Embodiments I-1 to I-14, the method comprising: a) Suspending a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1, in DMSO at room temperature; b) Isolating the white suspension resulting from step a); and c) Isolating the precipitated solid from the white suspension to obtain Form XIII of Compound 1. A method comprising the above steps.

[0181] Embodiment I-101. A method for preparing any one of the crystalline forms of Embodiments I-1 to I-14, the method comprising: a) Suspending a crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized as Form I of Compound 1, in DMSO at room temperature; b) Isolating the white suspension resulting from step a); c) Subjecting the white suspension to a series of temperature cycles from about 15°C to about 30°C to about 15°C, from about 10°C to about 30°C to about 10°C, and from about 5°C to about 35°C to about 5°C; and d) Isolating the precipitated solid from the white suspension to obtain Form XIII of Compound 1. A method comprising the above steps.

Examples

[0182] General Methods of Examples X-ray powder diffraction (XRPD) The X-ray powder diffraction pattern was generated using a PANalytical X’Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using an Optix long high-precision focus source. An elliptical graded multilayer mirror was used to focus the Cu Kα X-rays onto the detector through the specimen. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the peak position of Si 111. The sample specimen was sandwiched between 3-μm-thick films and analyzed in transmission geometry. A beam stop, short scatter removal extension, and scatter removal knife edge were used to minimize the background generated by the atmosphere. Solar slits for the incident and diffracted beams were used to minimize the spread from axial divergence. The diffraction pattern was collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. The position of the peaks along the x-axis (°2θ) in both the figures and tables was determined using proprietary software (TRIADS™ v2.1). The peak position variability was given within ±0.2°2θ based on the recommendations outlined in the USP discussion on the variability of X-ray powder diffraction (United States Pharmacopeia, USP 42-NF 37 through S1, <941>, Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD), official from 8 / 1 / 2019). For the d-space list, the wavelength used to calculate the d-spacing was the Cu-Kα1 wavelength, 1.5405929 Å (Phys. Rev. A56(6) 4554-4568 (1997)).

[0183] Differential scanning calorimetry (DSC) Differential scanning calorimetry was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Tau lag adjustment is performed using indium, tin, and zinc. Temperature and enthalpy are calibrated with octane, phenyl salicylate, indium, tin, and zinc. The calibration is then verified with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a sealed aluminum DSC pan and the weight was accurately recorded. A hole was punched in the lid of the pan and then inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. Data was collected from -30 °C to 350 °C at 10 °C / min.

[0184] Thermogravimetric analysis (TG) TG analysis was performed using a TA Instrument Q5000 thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel (trademark). The sample was placed in a platinum pan and inserted into the TG furnace. The furnace was heated to 350 °C at a rate of 10 °C / min under a nitrogen purge.

[0185] Preparation and Characterization of Compound 1 in Form XIII Form I of Compound 1 The present disclosure provides a method for preparing Form I of Compound 1.

[0186] Method 1: Form I of Compound 1 can be prepared by using Form XIII of Compound 1. For example, Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:1.2) at a temperature of about 35 °C + / - 5 °C. The mixture is maintained at about 35 °C + / - 5 °C for about 4 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0187] Method 2: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 6 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0188] Method 3: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0189] Method 4: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:EtOH (1.7:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0190] Method 5: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:1.2) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 4 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0191] Method 6: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 35°C + / - 5°C. The mixture is maintained at about 35°C + / - 5°C for about 6 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0192] Method 7: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:5.5) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 11 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0193] Method 8: Form I of Compound 1 can be prepared by suspending Form XIII of Compound 1 in DMSO:THF:EtOH (1.7:0.11:8.6) at a temperature of about 25°C + / - 5°C. The mixture is maintained at about 25°C + / - 5°C for about 17 days. The solid precipitated from the resulting suspension is recovered to obtain Form I of Compound 1. In some experiments, a small amount of Form I of Compound 1 is seeded into the mixture.

[0194] Form XIII of Compound 1 The present disclosure provides a method for preparing Form XIII of Compound 1.

[0195] Method 1: A container was filled with DMSO (1.4V). Then, the THF solvate form of Compound 1 (see U.S. Patent No. 9,758,528) was added (1.0 equivalent). The solid did not dissolve in the solution. The solid was recovered to obtain Form XIII of Compound 1.

[0196] Method 2: When a clear solution of Compound 1, Form I was prepared in DMSO at ambient temperature, spontaneous precipitation occurred. A portion of the resulting white, thick suspension was subjected to a series of temperature cycle experiments including 6 cycles of 15 °C to about 30 °C to about 15 °C, 6 cycles of about 10 °C to about 30 °C to about 10 °C, and 8 cycles of 5 °C to about 35 °C to about 5 °C. Some of the resulting needle-like particles had single crystal quality and size. The temperature cycle experiments were performed using Crystal16™. In some experiments, the suspension was seeded with a small amount of Form XIII of Compound 1.

[0197] Method 3: Form I of Compound 1 was suspended in DMSO at room temperature. After 6 - 17 days, the solid precipitated from the resulting suspension was collected to obtain Form XIII of Compound 1. In some experiments, the suspension was seeded with a small amount of Form XIII of Compound 1.

[0198] XRPD Characterization of Form XIII of Compound 1 XRPD data for crystalline Form XIII of Compound 1 disclosed herein were collected as detailed above. The XRPD pattern for Form XIII of Compound 1 is detailed in Figure 1. The peaks present in this XRPD pattern are listed in Table 1 above. All peak lists are at °2θ ± 0.2°2θ. The single crystal structure of Form XIII of Compound 1 was found to have 1 molecule of Compound 1 associated with 2.5 molecules of DMSO (i.e., 2 molecules of Compound 1 with 5 molecules of DMSO).

[0199] Thermal Analysis (DSC and TG) of Form XIII of Compound 1 DSC and TG data for Form XIII of Compound 1 disclosed herein were collected as detailed above. The TG thermogram for Form XIII of Compound 1 is detailed in Figure 2. The DSC thermogram for Form XIII of Compound 1 is detailed in Figure 3. The thermal events in the DSC and TG of Form XIII of Compound 1 are detailed in the following table.

[0200]

Table 3

[0201] Characterization of Impurities Present in Form XIII of Compound 1 The amounts of impurities U-1, U-2, and U-3 present in Form XIII of Compound 1 were determined by HPLC. The aqueous purity of Form XIII of Compound 1 is summarized in the following table.

[0202]

Table 4

[0203] The HPLC data were collected using a Water-system including an Alliance(™) HPLC system with Empart software. The column used was Inertsil ODS-4, 4.6 mm × 150 mm, 3 μm (GL Sciences Corp.). The HPLC method was as follows.

[0204]

Table 5

[0205]

Table 6

Claims

1. Crystals of the dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, characterized by an X-ray powder diffraction pattern comprising at least three 2-theta (2θ ± 0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4° and 14.1°.

2. The crystals of claim 1, wherein the X-ray powder diffraction pattern comprises at least five 2-theta (2θ ± 0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5°.

3. The crystals of claim 1, wherein the X-ray powder diffraction pattern comprises 2-theta (2θ ± 0.2° 2θ) peaks at 5.6°, 5.9°, 9.1°, 11.4° and 14.1°.

4. The crystals of claim 3, wherein the X-ray powder diffraction pattern further comprises one or more 2-theta (2θ ± 0.2° 2θ) peaks selected from 18.0°, 19.1°, and 21.5°.

5. The crystals according to any one of claims 1 to 4, further characterized by a thermogravimetric analysis (TG) thermogram showing a continuous weight loss of 8.6% between 32°C and 120°C.

6. The crystals according to any one of claims 1 to 5, further characterized by the onset of melting between 99°C and 101°C.

7. The crystals according to any one of claims 1 to 6, further characterized by the onset of melting at 100°C.

8. The crystals according to any one of claims 1 to 7, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between 105°C and 107°C.

9. The crystals according to any one of claims 1 to 8, further characterized by a DSC thermogram comprising an endothermic peak at 106°C.

10. The following: a) the onset of melting at 100°C as measured by DSC; and b) an endothermic peak at 106°C as measured by DSC The crystals of claim 1, further characterized by having at least one of the above.

11. The single crystal structure of the crystal contains 1 to 5 molecules of DMSO and 1 molecule of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, and the crystal according to claim 1.

12. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. A method for preparing crystals of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, wherein the method comprises: a) Suspending anhydrous crystals of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in DMSO at room temperature; b) Isolating the white suspension resulting from step a); and c) Isolating the precipitated solid from the white suspension to obtain crystals of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea comprising, wherein the crystals of the dimethyl sulfoxide solvate are characterized by an X-ray powder diffraction pattern comprising at least three 2-theta (2θ ± 0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4° and 14.1°.

14. A method for preparing crystals of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, wherein the method comprises: a) Suspending anhydrous crystals of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea in DMSO at room temperature; b) Isolating the white suspension resulting from step a); c) Subjecting the white suspension to a series of temperature cycles of 15°C to 30°C to 15°C, 10°C to 30°C to 10°C, and 5°C to 35°C to 5°C; and d) Isolating the precipitated solid from the white suspension to obtain crystals of the dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea comprising wherein the crystals of the dimethyl sulfoxide solvate are characterized by an X-ray powder diffraction pattern comprising at least three 2-theta (2θ ± 0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4° and 14.1°, a method.

15. The method according to claim 13 or 14, wherein the anhydrous crystals of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea are characterized by an X-ray powder diffraction pattern comprising 2-theta (2θ) peaks at 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8° and 27.4°.

Images