Crystal form of a thiophene derivative

Abstract

Crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide is disclosed.

Description

[0001] Citation of relevant applications

[0002] This disclosure claims the entire benefit of patent application No. 201810407741.X, filed with the State Intellectual Property Office of the People's Republic of China on May 2, 2018, entitled "(S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide polymorphs thereof and their preparation and application", and the entire contents of the aforementioned patent application are incorporated herein by reference. field

[0003] This disclosure pertains broadly to the fields of organic chemistry and medicinal chemistry. background

[0004] PDE4 enzyme inhibitors have shown clinical efficacy against several inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and allergic dermatitis. They have also demonstrated efficacy in animal models against various other diseases, including arthritis and sepsis. Overview

[0005] On the one hand, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0006] On the other hand, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which, in X-ray powder diffraction (XRPD) patterns, has characteristic peaks at diffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2°, and 24.4±0.2°.

[0007] Furthermore, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, whose diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks are approximately as follows in X-ray powder diffraction (XRPD) patterns:

[0008]

[0009] On another note, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, whose diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks are approximately as follows in X-ray powder diffraction (XRPD) patterns:

[0010]

[0011]

[0012] On the other hand, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, which has essentially the following properties: Figure 1 The X-ray powder diffraction (XRPD) pattern shown is shown.

[0013] Furthermore, this disclosure relates to a substantially solvent-free compound, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0014] On the other hand, this disclosure relates to a substantially anhydrous compound, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0015] On the other hand, this disclosure relates to the essentially pure compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0016] Furthermore, this disclosure relates to a solvent-free and anhydrous compound, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0017] In another aspect, this disclosure relates to pharmaceutical compositions comprising crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide and pharmaceutically acceptable carriers, diluents, or excipients, wherein crystal form II has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0018] On the other hand, this disclosure relates to a method for preparing crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, comprising: dissolving (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- 4,6-Dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide was crystallized in ethyl acetate to obtain crystal form II, wherein crystal form II has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0019] Furthermore, this disclosure relates to a method for treating or preventing diseases or disease states associated with, preferably, PDE4 enzyme-mediated diseases, comprising administering to an individual requiring the method a therapeutically effective amount of crystalline form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide or a compound comprising (S)-N-[5-[1- A therapeutically effective amount of a pharmaceutical composition of crystal form II of (3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, wherein crystal form II has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0020] On another front, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0021] On the other hand, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which has characteristic peaks at diffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2°, and 24.4±0.2° in X-ray powder diffraction (XRPD) patterns.

[0022] Furthermore, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, a compound exhibiting PDE4 enzyme inhibitory activity, with diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks approximately as follows in X-ray powder diffraction (XRPD) patterns:

[0023]

[0024] On another front, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, a compound with PDE4 enzyme inhibitory activity, whose diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks are approximately as follows in X-ray powder diffraction (XRPD) patterns:

[0025]

[0026]

[0027] On the other hand, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which has essentially the following properties: Figure 1 The X-ray powder diffraction (XRPD) pattern shown is shown.

[0028] In another aspect, this disclosure relates to a method for reducing PDE4 enzyme activity, comprising administering to an individual requiring the method an effective amount of crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide or containing compound (S)-N-[5-[1-(3-ethoxy-4-methoxy]ethyl]acetamide. A pharmaceutical composition comprising an effective amount of crystal form II of phenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, wherein crystal form II has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°. Brief description of the attached figures

[0029] Figure 1 The X-ray powder diffraction (XRPD) pattern of crystal form II of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide disclosed herein is shown.

[0030] Figure 2Differential scanning calorimetry (DSC) curves of crystal form II of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide are shown.

[0031] Figure 3 Thermogravimetric analysis (TGA) curves of crystal form II of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide are shown.

[0032] Figure 4 The infrared spectrum (IR) of crystal form II of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide is shown.

[0033] Figure 5 The DSC curve of crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide is shown after tableting.

[0034] Detailed Explanation

[0035] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that embodiments can be implemented without employing one or more of these specific details, but using other methods, components, materials, etc.

[0036] Unless otherwise required in this disclosure, throughout the specification and the claims, the words “comprising” and “including” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0037] When used in this disclosure and the appended claims, a singular designation without a quantity indication includes a plural designation unless the context clearly specifies otherwise.

[0038] Throughout this specification, the terms "an embodiment," "another embodiment," "an embodiment," or "certain embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "an embodiment," "an embodiment," or "another embodiment" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0039] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated herein. Thus, a pharmaceutical composition comprising, for example, a “pharmaceutical-acceptable carrier, diluent, or excipient” includes one, or two or more, pharmaceutically acceptable carriers, diluents, or excipients.

[0040] definition

[0041] Therefore, unless otherwise stated, the following terms used in the specification and appended claims shall have the following meanings:

[0042] In this disclosure, the term "compound of this disclosure" refers to (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide having the following structure:

[0043]

[0044] In this disclosure, the term "about" is used to include and describe the numerical value or parameter itself. For example, "about x" includes and describes "x" itself. In certain embodiments, when used in conjunction with measurement or to modify a numerical value, unit, constant, or range of values, the term "about" refers to a change of + / - 5%.

[0045] In this disclosure, when referring to X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) curves, thermogravimetric analysis (TGA) curves, and infrared (IR) spectra, the term "substantially as shown" means that it is not necessarily the same as those depicted in this disclosure, but falls within the limits of experimental error or deviation when considered by a person skilled in the art.

[0046] In this disclosure, when referring to X-ray powder diffraction (XRPD) peak positions, the term "substantially identical" as used herein means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak position (2θ) will exhibit some variability, typically up to 0.1 to 0.2 degrees, depending on the solvent used and the apparatus used to measure the diffraction. Furthermore, those skilled in the art will understand that relative peak intensities will exhibit instrument-to-instrument variability as well as variability caused by crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered only as qualitative measurements.

[0047] In this disclosure, the term "2θ value" or "2θ" refers to the peak position in degrees based on an experimental setup for X-ray powder diffraction (XRPD) experiments and is a common unit of measurement for the horizontal axis of diffraction patterns. The experimental setup requires that the reflected beam be diffracted at an angle θ (θ) between the incident beam and a crystal plane, and the reflected beam be recorded in angle 2θ (2θ). It should be understood that the specific 2θ value for a particular crystal form mentioned in this disclosure is intended to refer to the 2θ value (in degrees) measured using the X-ray powder diffraction (XRPD) experimental conditions described in this disclosure. For example, as described in this disclosure, using CuKα... As a radiation source.

[0048] In this disclosure, for the purposes of d-spacing, the term "about" refers to

[0049] In this disclosure, the term "substantially pure" refers to both chemical purity and crystal form purity.

[0050] In this disclosure, the term "substantially free" means containing no more than about 20% by weight. For example, "substantially free of solvents" means containing no more than about 20% by weight of solvents. "Substantially free of water" means containing no more than 20% by weight of water.

[0051] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In some embodiments, mammals include humans.

[0052] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In some embodiments, the patient is a mammal that includes both males and females. In some embodiments, the patient is a human.

[0053] In this disclosure, the term "drug-acceptable" means a carrier, delivery unit, diluent, excipient, and / or salt that must be compatible with other components of the formulation and not be harmful to the recipient.

[0054] In this disclosure, the term "drug-acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or animals and has no adverse effects on the composition of the pharmaceutical composition.

[0055] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound's crystal form into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it readily introduces certain organic compounds into the cells or tissues of an organism.

[0056] In this disclosure, the term "pharmaceutical composition" refers to a formulation formed by the crystal form II of the compound described in this disclosure and a medium generally accepted in the art for delivering a bioactive compound to a mammal such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0057] In this disclosure, the term "therapeuticly effective amount" refers to the amount of crystal form II of a compound or a combination of crystal forms II of a compound that improves, reduces, or eliminates a particular disease or condition and its symptoms, or avoids or delays the onset of a particular disease or condition or its symptoms. The amount of crystal form II of the compound described in this disclosure constituting a "therapeuticly effective amount" will vary depending on the crystal form II of the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated; however, those skilled in the art can conventionally determine the amount of crystal form II of the compound described in this disclosure based on their own knowledge and this disclosure.

[0058] As used in this disclosure, "to treat" or "to treat" encompasses the treatment of a related disease or condition in mammals, such as humans, suffering from the related disease or ailment, and includes:

[0059] (i) To prevent the occurrence of disease or disease state in mammals, especially when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state;

[0060] (ii) Suppress the disease or disease state, that is, prevent it from occurring; or

[0061] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides or does not progress.

[0062] As used in this disclosure, the terms “disease” and “disease state” may be used interchangeably or may be different, because a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather as an undesirable disease state or symptom in which a clinician has identified a more or less specific set of symptoms.

[0063] In this disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not eliminate the biological activity and properties of the compound. Detailed Implementation

[0064] On the one hand, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0065] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0066] On the other hand, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which, in X-ray powder diffraction (XRPD) patterns, has characteristic peaks at diffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2°, and 24.4±0.2°.

[0067] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2°, and 24.4±0.2° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0068] Furthermore, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, whose diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks are approximately as follows in X-ray powder diffraction (XRPD) patterns:

[0069]

[0070] In some embodiments, the crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, in X-ray powder diffraction (XRPD) under CuKα irradiation conditions, has a diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks of approximately:

[0071]

[0072] On another note, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, whose diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks are approximately as follows in X-ray powder diffraction (XRPD) patterns:

[0073]

[0074]

[0075] In some embodiments, the crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, in X-ray powder diffraction (XRPD) under CuKα irradiation conditions, has a diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks of approximately:

[0076]

[0077]

[0078] On the other hand, this disclosure relates to crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, which has essentially the following properties: Figure 1 The X-ray powder diffraction (XRPD) pattern shown is shown.

[0079] In some embodiments, the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide has crystal form II, which has essentially the same as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is obtained under CuKα radiation conditions.

[0080] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least one substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0081] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least two substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0082] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least three substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0083] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least four substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0084] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least five substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0085] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least six substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0086] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least seven substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0087] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least eight substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0088] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least nine substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0089] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least ten substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0090] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least eleven substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0091] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least twelve substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0092] In some embodiments, the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least a dozen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0093] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least fourteen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0094] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least fifteen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0095] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least sixteen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0096] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least seventeen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0097] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least eighteen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0098] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II exhibiting at least nineteen substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is an X-ray powder diffraction (XRPD) pattern of characteristic peaks.

[0099] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits an endothermic peak at approximately 174.2 °C.

[0100] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, the crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide has an endothermic peak at about 174.2 °C.

[0101] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure, crystal form II, exhibits an endothermic peak at 174.2 ± 6 °C.

[0102] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure, crystal form II, exhibits an endothermic peak at 174.2 ± 4 °C.

[0103] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure, crystal form II, exhibits an endothermic peak at 174.2 ± 2 °C.

[0104] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II of the disclosed compound, exhibits an endothermic peak at 174.2 ± 6 °C.

[0105] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, the crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide has an endothermic peak at 174.2 ± 4 °C.

[0106] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, the crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide has an endothermic peak at 174.2 ± 2 °C.

[0107] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II substantially as shown in [the diagram]. Figure 2 The DSC curve shown.

[0108] In some embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC) at a heating rate of 10 °C / min, the crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide has substantially the following properties: Figure 2 The DSC curve shown.

[0109] In some embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), the compound of this disclosure, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, in crystal form II, has substantially the following properties: Figure 3 The TGA curve shown.

[0110] In some embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA) at a heating rate of 10 °C / min, the crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide has substantially the following properties: Figure 3 The TGA curve shown.

[0111] In some embodiments, in infrared (IR) spectra, the absorption peak position and intensity of crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide are approximately as follows:

[0112]

[0113]

[0114]

[0115] In some embodiments, in infrared (IR) spectroscopy, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide of this disclosure has crystal form II substantially as Figure 4 The infrared spectrum (IR) shown.

[0116] In some embodiments, compared with other solid forms, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II of the present disclosure has at least one of the following advantageous properties: chemical purity, fluidity, solubility, dissolution rate, morphology or crystal habit, stability such as high temperature stability, accelerated stability, light stability, grinding stability, pressure stability, ethanol solution equilibrium stability, aqueous solution equilibrium stability, low residual solvent content, low hygroscopicity, fluidity, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0117] Furthermore, this disclosure relates to a substantially solvent-free compound, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0118] In some embodiments, the essentially solvent-free compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0119] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 20% by weight of solvent, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0120] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 20% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0121] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 10% by weight of solvent, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0122] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 10% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0123] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 5% by weight of solvent, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0124] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 5% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0125] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 3% by weight of solvent, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0126] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 3% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0127] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 1% by weight of solvent, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0128] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 1% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0129] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.5% by weight of solvent, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0130] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.5% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0131] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.2% by weight of solvent, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0132] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.2% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0133] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.1% by weight of solvent, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0134] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.1% by weight of solvent, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0135] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.01% by weight of solvent, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0136] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.01% by weight of solvent, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0137] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains a solvent of no more than about 0.001% by weight, which has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0138] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains a solvent of no more than about 0.001% by weight, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0139] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains a solvent of no more than about 0.0001% by weight, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0140] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains a solvent of no more than about 0.0001% by weight, which has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0141] In some embodiments, the solvent-free compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0142] In some embodiments, the solvent-free compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0143] On the other hand, this disclosure relates to a substantially anhydrous compound, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0144] In some embodiments, the essentially anhydrous compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0145] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 20% water by weight, and has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0146] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 20% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0147] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 10% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0148] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 10% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0149] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 5% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0150] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 5% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0151] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 3% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0152] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 3% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0153] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 1% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0154] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 1% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0155] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.5% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0156] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.5% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0157] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.2% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0158] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.2% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0159] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.1% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0160] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.1% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0161] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.01% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0162] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.01% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0163] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.001% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0164] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.001% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0165] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.0001% water by weight, and has characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

[0166] In some embodiments, the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II contains no more than about 0.0001% water by weight, and has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0167] In some embodiments, the anhydrous compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0168] In some embodiments, the anhydrous compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0169] In some embodiments, when performing thermal analysis using thermogravimetric analysis (TGA), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II was heated to a melting weight loss of no more than 5.0% at a heating rate of 10 °C / min. No endothermic / exothermic peaks were observed before melting, indicating that the weight loss of no more than 5.0% was due to adsorbed water or solvent.

[0170] In some embodiments, when performing thermal analysis using thermogravimetric analysis (TGA), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II was heated to a melting weight loss of no more than 3.0% at a heating rate of 10 °C / min. No endothermic / exothermic peaks were observed before melting, indicating that the weight loss of no more than 3.0% was due to adsorbed water or solvent.

[0171] In some embodiments, when performing thermal analysis using thermogravimetric analysis (TGA), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II was heated to a melting weight loss of no more than 2.0% at a heating rate of 10 °C / min. No endothermic / exothermic peaks were observed before melting, indicating that the weight loss of no more than 2.0% was due to adsorbed water or solvent.

[0172] In some embodiments, when performing thermal analysis using thermogravimetric analysis (TGA), the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II was heated to a melting weight loss of no more than 0.3% at a heating rate of 10 °C / min. No endothermic / exothermic peaks were observed before melting, indicating that the weight loss of no more than 0.3% was due to adsorbed water or solvent.

[0173] On the other hand, this disclosure relates to the essentially pure (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0174] In some embodiments, the essentially pure (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0175] In some embodiments, the essentially pure (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II comprises at least about 95% by weight, preferably at least about 98% by weight, more preferably at least about 99% by weight of crystal form II and less than about 5% by weight, preferably less than about 2% by weight, more preferably less than about 1% by weight of other compounds having a different chemical structure from the (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide.

[0176] In some embodiments, the essentially pure polymorph II of the presently disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide comprises at least about 95% by weight, preferably at least about 98% by weight, more preferably at least about 99% by weight of polymorph II and less than about 5% by weight, preferably less than about 2% by weight, more preferably less than about 1% by weight of any other polymorph of the presently disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide. This means that the crystal form II of the disclosed compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide contains less than about 5% by weight of other compounds and less than about 5% by weight of any other form (also referred to as "phase homogeneity").

[0177] Furthermore, this disclosure relates to a solvent-free and anhydrous compound, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0178] In some embodiments, the solvent-free and water-free compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0179] In another aspect, this disclosure relates to pharmaceutical compositions comprising crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide and pharmaceutically acceptable carriers, diluents, or excipients, wherein crystal form II has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation conditions.

[0180] In some embodiments, the pharmaceutical compositions of this disclosure are prepared as tablets, solutions, granules, patches, ointments, gels, capsules, aerosols or suppositories for parenteral, dermal, mucosal, nasal, buccal, sublingual or oral use.

[0181] Pharmaceutical Composition

[0182] In some embodiments, the pharmaceutical composition comprises crystal form II of the compound disclosed herein, as well as a pharmaceutically acceptable carrier, diluent, or excipient.

[0183] In some embodiments, when the crystal form II of the compound disclosed herein is administered to mammals for the treatment or prevention of PDE4 enzyme-related, preferably PDE4 enzyme-mediated, diseases, the route of administration may be gastrointestinal or non-gastrointestinal.

[0184] In some embodiments, when the crystal form II of the compound disclosed herein is administered to mammals for the treatment or prevention of PDE4 enzyme-related, preferably PDE4 enzyme-mediated, diseases, the route of administration may be oral.

[0185] In some embodiments, when the crystal form II of the compounds disclosed herein is administered to mammals for the treatment or prevention of PDE4 enzyme-related, preferably PDE4 enzyme-mediated, diseases, the route of administration may be transdermal.

[0186] The compounds described in this disclosure can be obtained in any suitable form, such as tablets, capsules, powders, oral solutions, suspensions, patches, ointments, gels, or aerosols. Exemplary examples of tablets include, but are not limited to, uncoated tablets, sugar-coated tablets, and film-coated tablets.

[0187] Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, any adjuvants, carriers, excipients, gliding agents, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or animals and have no adverse effects on the composition of the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), the entire contents of which are incorporated herein by reference.

[0188] The pharmaceutical compositions of this disclosure can be administered by any method to achieve their intended purpose. For example, administration can be via oral, parenteral, local, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, tracheal, ocular, subcutaneous, intraperitoneal, percutaneous, or sublingual routes. Routes of administration can be non-gastrointestinal, oral, or rectal. The dosage administered will depend on the recipient's age, health condition, and weight, and if any, the type and frequency of concurrent treatments, as well as the nature of the desired effect.

[0189] Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semi-solid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalers, injections, muds, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be prepared according to methods known in the art.

[0190] Particularly suitable for oral administration are plain tablets, sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices, or drops; suitable for rectal administration are suppositories; suitable for parenteral administration are solutions, which can also be oil-based solutions or aqueous solutions; in addition, there are suspensions, emulsions, or implants; suitable for topical use are ointments, creams, or powders. The products of this disclosure can also be lyophilized, and the resulting lyophilized products are used, for example, to prepare injections. The given formulations can be sterilized and / or contain assistants such as wetting agents, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for altering osmotic pressure, buffering substances, dyes, flavoring agents, and / or numerous other active ingredients, such as one or more vitamins.

[0191] In some embodiments, the pharmaceutical compositions of this disclosure are prepared as tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for parenteral, dermal, mucosal, nasal, buccal, sublingual or oral use.

[0192] Preservatives, stabilizers, dyes, sweeteners, flavorings, and fragrances can be provided in pharmaceutical compositions. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. Additionally, antioxidants and suspensions can be used.

[0193] In different implementation schemes, alcohols, esters, sulfated aliphatic alcohols, etc., can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc., can be used as excipients; magnesium stearate, talc, hardened oil, etc., can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean oil, etc., can be used as suspensions or lubricants; cellulose acetate, as a derivative of sugars such as cellulose or sugar, or methyl acetate-isobutylene ester copolymer, as a derivative of polyethylene, can be used as suspensions; and plasticizers such as phthalates can be used as suspensions.

[0194] Suitable routes of administration may include, for example, oral, rectal, transmembrane, parenteral, transdermal, local, or enteral administration; parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, or intraocular injection. Compounds can also be administered at a predetermined rate and / or timed, pulsatile manner in sustained-release or controlled-release dosage forms, including depot injections, osmotic pumps, pellets, and transdermal (including electromigration) patches.

[0195] The pharmaceutical compositions disclosed herein can be produced by known methods, such as conventional methods of mixing, dissolving, granulating, manufacturing tablets, grinding, emulsifying, encapsulating, retaining or compressing tablets.

[0196] Therefore, according to this disclosure, the pharmaceutical compositions used can be formulated using conventional methods with one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the treatment of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers, and excipients can be used as suitably understood and appreciated in the art.

[0197] Injectable formulations can be prepared in the following conventional forms: as solutions or suspensions, solid dosage forms suitable for preparation as solutions or suspensions prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, etc. Additionally, if desired, the injectable pharmaceutical composition may contain small amounts of non-toxic excipients, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption-enhancing agents (e.g., liposomes) may be used.

[0198] For oral administration, the active compound can be readily formulated by combining it with a pharmaceutically acceptable carrier known in the art. Such a carrier allows the compounds of the present invention to be formulated into tablets, pills, lozenges, capsules, liquids, gels, syrups, ointments, suspensions, solutions, powders, etc., for oral ingestion by a method in which the active compound is mixed with a solid excipient, the resulting mixture is ground in any manner, and the granulated mixture is processed, if necessary, with the addition of a suitable excipient to obtain a tablet or lozenge core. Suitable excipients are particularly fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginate or alginate such as sodium alginate can be added if necessary. The tablet core is appropriately coated. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound dosages, dyes or pigments may be added to the tablet or tablet coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures.

[0199] Oral pharmaceutical formulations include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All oral formulations should be administered at a dose suitable for this administration.

[0200] In some embodiments, the pharmaceutical composition of this disclosure may comprise 0.1% to 95% of crystal form II of the compound of this disclosure.

[0201] In some embodiments, the pharmaceutical composition of this disclosure may comprise 1% to 70% of crystal form II of the compound of this disclosure.

[0202] In any case, the composition or formulation to be administered will contain an amount of crystal form II of the compound disclosed herein, in an amount that is effective in treating the disease / condition of the subject being treated.

[0203] On the other hand, this disclosure relates to a method for preparing crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, comprising: dissolving (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide. -5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide is crystallized in ethyl acetate to obtain crystal form II, wherein crystal form II has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα radiation conditions.

[0204] In some embodiments, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide is dissolved in ethyl acetate until completely dissolved; and the solution is filtered and the filtrate is heated to 60°C to precipitate crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide.

[0205] In some embodiments, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide is dissolved in ethyl acetate and stirred until completely dissolved at room temperature; after hot filtration, the filtrate is heated to 50-70°C and isothermally evaporated under normal pressure until crystalline powder precipitates; the filtrate is filtered and vacuum dried to obtain crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide.

[0206] In some embodiments, (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide is dissolved in ethyl acetate and stirred until completely dissolved at room temperature; after hot filtration, the filtrate is heated to 60°C and isothermally evaporated at normal pressure until crystalline powder precipitates; the filtrate is filtered and vacuum dried to obtain crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide.

[0207] Furthermore, this disclosure relates to a method for treating or preventing diseases or disease states associated with, preferably, PDE4 enzyme-mediated diseases, comprising administering to an individual in need of the method a therapeutically effective amount of crystalline form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide or containing compound (S)-N-[5-[1- A therapeutically effective amount of a pharmaceutical composition of crystal form II of (3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, wherein crystal form II has characteristic peaks in an X-ray powder diffraction (XRPD) pattern at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4°.

[0208] In some implementations, the individual is a mammal.

[0209] In some implementations, the individual is a human being.

[0210] In some implementations, exemplary examples of diseases or disease states that can be used for the purposes of this disclosure include, but are not limited to, inflammatory diseases or disease states, infectious diseases or disease states, immune diseases or disease states, and cancer diseases or disease states.

[0211] In some implementations, exemplary examples of diseases or disease states that can be used with this disclosure include, but are not limited to, head cancer, thyroid cancer, neck cancer, eye cancer, skin cancer, oral cancer, pharyngeal cancer, esophageal cancer, chest cancer, bone cancer, leukemia, bone marrow cancer, lung cancer, colon cancer, sigmoid colon cancer, rectal cancer, stomach cancer, prostate cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, pancreatic cancer, brain cancer, intestinal cancer, heart cancer, adrenal cancer, subcutaneous tissue cancer, lymph node cancer, melanoma, malignant glioma, HIV, hepatitis, adult respiratory distress syndrome, bone resorption disease, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, inflammatory skin diseases, and specific diseases. Dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, septic syndrome, ischemia-reperfusion injury, meningitis, psoriasis, fibrotic diseases, cachexia, graft-versus-host disease, autoimmune diseases, rheumatoid spondylitis, arthritis conditions (such as rheumatoid arthritis or osteoarthritis), osteoporosis, segmental ileitis, ulcerative colitis, enteritis, multiple sclerosis, systemic lupus erythematosus, leprosy-related erythema nodosum (ENL) in leprosy, radiation injury, asthma, oxygen-enriched lung injury, microbial infections and microbial infection syndromes.

[0212] In some embodiments, methods for treating or preventing diseases associated with, preferably PED4 enzyme-mediated, PED4 enzyme include administering 1 mg to 10 g of crystal form II of the compound disclosed herein to an individual requiring the method.

[0213] In some embodiments, methods for treating or preventing diseases associated with, preferably PED4 enzyme-mediated, PED4 enzyme include administering 10 mg to 3000 mg of crystal form II of the compound disclosed herein to an individual requiring the method.

[0214] In some embodiments, methods for treating or preventing diseases associated with, preferably PED4 enzyme-mediated, PED4 enzyme include administering 1 mg to 200 mg of the crystal form II of this disclosure to an individual in need of the method.

[0215] In some embodiments, a method for treating or preventing diseases associated with, preferably PED4 enzyme-mediated, PED4 enzymes includes administering to an individual requiring the method 1 mg, 5 mg, 10 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 90 mg, 100 mg, 120 mg, 150 mg, or 200 mg of crystal form II of the compound of this disclosure.

[0216] Administration method

[0217] The patient may be administered a crystal form II of at least one compound of the present disclosure or a pharmaceutical composition comprising a crystal form II of at least one compound of the present disclosure by any suitable systemic and / or local delivery method of the crystal form II of the compound of the present disclosure. Non-limiting examples of administration methods include (a) oral administration, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) non-oral administration, such as rectal, vaginal, urethral, ​​intraocular, intranasal, or intraauricular administration, including administration in aqueous suspensions, oily preparations, or in drops, sprays, suppositories, ointments, creams, etc.; (c) administration by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal, or intrasternal injection, including delivery by an infusion pump; (d) localized administration, such as direct injection into the renal or cardiac region, for example, via a reservoir implant; and (e) topically administration; a suitable administration method as would be considered by those skilled in the art is contact between crystal form II of the compound described in this disclosure and living tissue. For example, transdermal administration includes administration in the form of ointments, creams, gels, aerosols, suspensions, emulsions, or other such forms.

[0218] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients, and other matters related to delivering the crystal form of the compound to the recipient.

[0219] Suitable pharmaceutical compositions for administration include compositions containing an effective amount of the active ingredient to achieve their intended effect. The required therapeutically effective dose of the pharmaceutical composition described in this disclosure depends on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the specific animal under consideration. The dose can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent drug treatment, and other factors recognized by those skilled in the art. More specifically, a therapeutically effective dose refers to the amount of a crystalline form of the compound that effectively prevents, alleviates, or improves disease symptoms, or prolongs the lifespan of the individual receiving treatment. The therapeutically effective dose can be well determined by the practical ability of those skilled in the art, particularly in accordance with the detailed disclosure provided herein.

[0220] As will be apparent to those skilled in the art, the dosage and specific route of administration for in vivo administration will vary depending on age, weight, the species of mammal being treated, the specific crystal form of the compound used, and the specific purpose of using those crystal forms. Those skilled in the art can determine the effective dose level—that is, the dose level necessary to determine the desired effect—using conventional pharmacological methods. Typically, human clinical application of the product is initiated at a low dose level, increasing the dose level until the desired effect is achieved. Alternatively, established pharmacological methods can be used to establish the effective dose and route of administration of the compositions identified by this method using acceptable in vitro studies.

[0221] In non-human animal studies, the application of a potential product begins at a higher dose level and is gradually reduced until the desired effect is no longer achieved or adverse side effects disappear. The dose range can be broad, depending on the expected effect and therapeutic indication. Typically, the dose can range from about 10 μg / kg body weight to 1000 mg / kg body weight, and in some embodiments from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as those skilled in the art will understand, the dose can be based on and calculated according to the patient's body surface area.

[0222] Physicians can select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described in this disclosure based on the patient's condition. Typically, the dosage range of the composition administered to a patient can be from about 0.5 mg / kg to 1000 mg / kg of patient body weight. Depending on the patient's needs, the dosage may be given once or twice or more over a day or several days. Where the human dosage of the crystalline form of the compound has been established under at least certain conditions, this disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosage, and in some embodiments, dosages ranging from 25% to 250% of the established human dosage. In the absence of a determined human dosage, such as in the case of a newly discovered pharmaceutical compound, an appropriate human dosage can be inferred from the median effective dose or the median infectious dose, or other suitable values ​​from in vitro or in vivo studies, as quantified in toxicity studies and efficacy studies in animals.

[0223] It should be noted that, due to toxicity and organ dysfunction, the attending physician will know and when to terminate, interrupt, or adjust medication. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The dosage administered in the treatment of the condition of interest will vary depending on the severity of the disease state and the route of administration. For example, the severity of the disease state can be assessed in part using standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on the individual patient's age, weight, and response. Protocols equivalent to those discussed above can be used in veterinary medicine.

[0224] While an exact dosage can be determined based on drug-by-drug analysis, in most cases, some generalizations about the dosage can be made. Daily dosing regimens for adult patients are, for example, oral doses of 0.1 mg to 2000 mg of each active ingredient, or in some embodiments, 1 mg to 2000 mg of each active ingredient, such as 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous, or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, or in some embodiments, 0.1 mg to 1000 mg, such as 1 mg to 800 mg. In the case of administering acceptable saline solutions, the dosage can be calculated based on free base. In some embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions described in this disclosure can be administered by continuous intravenous infusion, or in some embodiments, at doses of up to 2000 mg of each active ingredient daily. As those skilled in the art will understand, in certain situations, it is necessary to administer the compounds described in this disclosure in amounts exceeding or far exceeding the above-described dosage range for the effective and rapid treatment of a rapidly progressing disease or infection. In some embodiments, the compounds are administered during continuous treatment, for example, for one or several weeks, or for several months or years.

[0225] Dosage and dosing intervals can be individually adjusted to provide plasma levels sufficient to maintain the modulated effect or minimum effective concentration (MEC) of the active moiety. The MEC varies for each compound, but it can be assessed from in vitro data. The required dose to achieve the MEC depends on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC (high-performance liquid chromatography) or bioassays.

[0226] The MEC value can also be used to determine the dosing interval. The composition should be administered using a treatment regimen that maintains plasma levels above the MEC for 10-90% of the time, 30-90% of the time in some embodiments, and 50-90% of the time in some embodiments.

[0227] In cases of local administration or selective absorption, the effective local concentration of a drug is independent of its plasma concentration.

[0228] Of course, the amount of the administered composition depends on the individual being treated, the individual's weight, the severity of their pain, the route of administration, and the prescribing physician's judgment.

[0229] The efficacy and toxicity of the compounds described in this disclosure can be evaluated using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing certain chemical motifs can be established by determining the toxicity of cell lines in vitro, such as mammalian cell lines and, in some embodiments, human cell lines. The results of such studies can generally predict toxicity in animals such as mammals, or more specifically, toxicity in humans. Alternatively, the toxicity of a particular compound in animal models such as mice, rats, rabbits, or monkeys can be determined using known methods. The efficacy of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for almost every type of disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents for treating these disease states. When selecting a model to determine efficacy, a person skilled in the art can choose an appropriate model, dosage, route of administration, and treatment regimen under the guidance of prior art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0230] If desired, the composition may be placed in a packaging or dispensing device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispensing device may include instructions for use. The packaging or dispensing device may also include precautions related to the container, prescribed by a government agency regulating the production, use, or sale of the drug, reflecting that the drug form has been approved by that agency for human or animal administration. Such precautions may, for example, be labels approved for prescription drugs by the National Food and Drug Administration or the U.S. Food and Drug Administration, or approved product instructions. Compositions containing the compounds of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof may also be prepared in suitable containers, formulated in compatible drug carriers, and labeled for the treatment of specified disease states.

[0231] On another front, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which exhibits characteristic peaks at diffraction angles of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns under CuKα irradiation.

[0232] On the other hand, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, a compound exhibiting PDE4 enzyme inhibitory activity, which, in X-ray powder diffraction (XRPD) patterns under CuKα irradiation, exhibits diffraction angles 2θ of 8.3±0.2°, 11.9±0.2°, and 13.8±0°. Characteristic peaks are present at 0.2°, 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, 19.3±0.2°, 20.2±0.2°, 21.6±0.2°, 22.3±0.2°, 23.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.8±0.2°, 27.5±0.2°, and 30.4±0.2°.

[0233] Furthermore, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, a compound exhibiting PDE4 enzyme inhibitory activity. In X-ray powder diffraction (XRPD) patterns under CuKα irradiation, its diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks are approximately:

[0234]

[0235] On another front, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, a compound exhibiting PDE4 enzyme inhibitory activity. In X-ray powder diffraction (XRPD) patterns under CuKα irradiation, its diffraction angle 2θ, interplanar spacing d, and relative peak intensities are approximately:

[0236]

[0237]

[0238] On the other hand, this disclosure relates to crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, which has essentially the following properties: Figure 1 The X-ray powder diffraction (XRPD) pattern shown is obtained under CuKα radiation conditions.

[0239] In another aspect, this disclosure relates to a method for reducing PDE4 enzyme activity, comprising administering to an individual requiring the method an effective amount of crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide or a compound comprising (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2- An effective amount of a pharmaceutical composition comprising crystal form II of [(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, wherein crystal form II has characteristic peaks at diffraction angles 2θ of approximately 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in an X-ray powder diffraction (XRPD) pattern under CuKα irradiation conditions.

[0240] In the following sections, this disclosure will be explained in detail through the following embodiments to provide a better understanding of the various aspects of this application and its advantages. However, it should be understood that the following embodiments are non-limiting and are only used to illustrate certain implementations of this application.

[0241] Example

[0242] Preparation Examples

[0243] Preparation of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide

[0244] abbreviations

[0245] CDI: 1,1'-carbonyldiimidazolium; DCM: dichloromethane; THF: tetrahydrofuran; TFA: trifluoroacetic acid; DMAP: 4-(N,N-dimethylamino)pyridine; TEA: triethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; HOBt: 1-hydroxybenzotriazole; DCC: N,N-dicyclohexylcarbodiimide; TBFA: tetrabutylammonium fluoride; EDC·HCl: 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride; Fmoc: 9-fluorenylmethoxycarbonyl; MOM: methoxymethyl; MEM: methoxyethoxymethyl; MTM: methylthiomethyl; SEM: 2-(trimethylsilyl)ethoxymethyl; TMSE: 2-(trimethylsilyl)ethyl; DIC: N,N'-diisopropylcarbodiimide; HOAt: 1-hydroxy-7-azobenzotriazole; BOP: Carter condenser (benzotriazole-1-yl-oxo-tris-(dimethylamino)phosphonium) Hexafluorophosphate); Cl-HOBt: 6-chloro-1-hydroxybenzotriazole; DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4-one; HATU: bis(dimethylamino)methylenetriazole[4,5-B]pyridine-3-oxide hexafluorophosphate; HBTU: benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; HCTU: 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate Ester; HOOBt: 3-hydroxy-1,2,3-benzotriazine-4(3H)-one; PyBOP: benzotriazine-1-yl-oxytripyrrolylphosphine hexafluorophosphate; TATU: O-(7-azobenzotriazine-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate; TBTU: O-(benzotriazine-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate; OMS: methanesulfonate group; OTS: p-toluenesulfonate group.

[0246] Compound 1

[0247] 4-Methoxy-3-ethoxybenzaldehyde

[0248] In a 500 ml three-necked flask equipped with a mechanical stirrer and an inert gas delivery system, add 30.5 g of isovalin, 55.2 g of potassium carbonate, 49.9 g of iodoethane, and 140 ml of DMF. Stir overnight at room temperature. Pour into 1400 ml of water and extract twice with 600 ml of ethyl acetate each time. Combine the ethyl acetate layers, wash three times with 200 ml of saturated Na₂CO₃ each time, followed by washing with 200 ml of water and 200 ml of saturated NaCl. Dry the mixture on anhydrous MgSO₄, filter, and evaporate the solvent to obtain a pale yellow solid. Recrystallize from the solid using a 1:4 mixture of ethyl acetate and petroleum ether to give 32.9 g of white needle-like crystals. MS (m / z): 181 [M+1] + .

[0249] Compound 2

[0250] 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-(trimethylsilyl)ethylamine

[0251] In a 500 ml three-necked flask equipped with a magnetic stirrer and an inert gas delivery system, 3.7 g of dimethyl sulfone and 160 ml of THF were added. The flask was cooled to -78 °C, and 22 ml of n-butyllithium (2.2 M n-hexane solution) was added dropwise. After the addition was complete, the flask was stirred at -78 °C for 30 minutes to obtain compound A. In a 250 ml three-necked flask equipped with a magnetic stirrer and an inert gas delivery system, 7.1 g of compound 1 was added. The flask was cooled in an ice-salt bath, and 43 ml of bis(trimethylsilylamino)lithium (1.06 M THF solution) was added dropwise. After the addition was complete, the flask was stirred for 15 minutes, and then 10 ml of boron trifluoride diethyl ether solution was added dropwise. After the addition was complete, the flask was stirred for 5 minutes to obtain compound B. Transfer B into A, and slowly heat to room temperature (about 1.5 hours). Add 200 ml of 1.6 N K2CO3 solution to quench the reaction. Stir for 30 minutes and separate the layers. Extract the aqueous layer three times with 200 ml of ethyl acetate each time. Combine all organic layers, wash with 200 ml of saturated NaCl, dry with anhydrous MgSO4, filter, and evaporate the solvent to obtain 10 g of pale yellow foamy solid.

[0252] Compound 3

[0253] 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine

[0254] 10 g of compound 2, 100 ml of diethyl ether, and 100 ml of 4N HCl were added to a 500 ml single-necked flask equipped with a magnetic stirrer. The mixture was stirred at room temperature for 30 minutes. The layers were separated, and the organic layer was extracted three times with 100 ml of 4N HCl each time. The aqueous layers were combined, and the pH was adjusted to 12 with 4N NaOH under ice bath conditions. The mixture was then extracted three times with 200 ml of ethyl acetate each time. The organic layers were combined, washed with 200 ml of saturated NaCl, dried over anhydrous MgSO4, filtered, and the solvent was evaporated. The solid was purified by column chromatography to give 1.5 g of white solid. 1 H NMR (CDCl3): δ6.93-6.84(m,3H), 4.60(d,1H,J=8Hz), 4.12(q,2H,J=4Hz), 3.87(s,3H) , 3.37-3.21 (m, 2H), 2.92 (s, 3H), 1.86 (s, 2H), 1.48 (t, 3H, J = 4Hz); MS (m / z): 274 [M+1] + Chiral HPLC (isopropanol / n-hexane / diethylamine = 35 / 65 / 0.1), OJ-H column, 250×4.6mm, 1.0mL / min, @234nm): 15.2min (R-isomer, 49.8%), 17.3min (S-isomer, 50.2%).

[0255] Compound 4a

[0256] (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine·N-acetyl-L-valine salt

[0257] 6.920 g of compound 3, 2.418 g of N-acetyl-L-valine, and 50 ml of anhydrous methanol were added to a 100 ml single-necked flask equipped with a magnetic stirrer, reflux condenser, and inert gas delivery tube. The mixture was heated under reflux for 1 hour, stirred at room temperature for 3 hours, and filtered to obtain a white solid. This solid was then added to 25 ml of anhydrous methanol, refluxed for 1 hour, stirred at room temperature for 3 hours, and filtered to obtain 6.752 g of white solid.

[0258] Compound 4b

[0259] (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine

[0260] 6.752 g of compound 4a, 150 ml of dichloromethane, and 150 ml of water were added to a 250 ml single-necked flask equipped with a magnetic stirrer. Under ice bath conditions, a 5% NaOH aqueous solution was added dropwise to adjust the pH to 11. The mixture was separated, and the aqueous layer was extracted once more with 150 ml of dichloromethane. The dichloromethane layers were combined, washed with 100 ml of saturated NaCl, dried over anhydrous MgSO4, filtered, and the solvent was evaporated to obtain 2.855 g (99.0% ee) of a white solid. MS (m / z): 274 [M+1] + Chiral HPLC (isopropanol / n-hexane / diethylamine = 35 / 65 / 0.1), OJ-H column, 250×4.6mm, 1.0mL / min, @234nm): 15.2min (R-isomer, 0.5%), 17.3min (S-isomer, 99.5%).

[0261] Compound 5

[0262] 3,4-Dicyanothiophene

[0263] In a 2000 ml three-necked flask equipped with a mechanical stirrer, reflux condenser, and inert gas delivery tube, 96.8 g of 3,4-dibromothiophene, 104 g of cuprous cyanide, and 100 ml of dry DMF were added. The mixture was heated under reflux for 4 hours, then cooled to room temperature. A solution of 400 g of FeCl3·6H2O dissolved in 700 ml of 1.7 N hydrochloric acid was added, and the reaction was maintained at 60-70 °C for 30 minutes. After thorough cooling, 500 ml of DCM was added. The resulting reaction mixture was divided into 300 ml portions and extracted with DCM (300 ml × 2). All DCM layers were combined. The extract was divided into 600 ml portions and washed successively with 50 ml × 2 6 N hydrochloric acid, water, saturated Na2CO3 aqueous solution, and saturated sodium chloride aqueous solution. The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated to obtain a yellow solid. The solid was washed with a 1:1 mixture of ethyl acetate and petroleum ether and filtered to obtain 21 g of a white solid. 1 H NMR (CDCl3): δ8.07 (s, 2H).

[0264] Compound 6

[0265] Thiophene-3,4-dicarboxylic acid

[0266] In a 500 ml round-bottom flask equipped with an electromagnetic stirrer and reflux condenser, 15.978 g of compound 5, 43.997 g of KOH, and 174 ml of ethylene glycol were added, and the mixture was refluxed for 4 hours. After cooling, 350 ml of water was added to the reaction mixture, and the mixture was extracted with diethyl ether (100 ml × 2). The ether layer was discarded, and excess concentrated hydrochloric acid was added to the aqueous layer under ice bath cooling until a white precipitate appeared. After filtration, the solid was dissolved in diethyl ether (approximately 2000 ml was required), and the filtrate was extracted with diethyl ether (300 ml × 3). All ether layers were combined, dried over anhydrous MgSO4, filtered, and the solvent was evaporated to obtain 15 g of white solid, which was recrystallized from water. 1 H NMR(DMSO-d6): δ10.35(brs,2H), 8.17(s,2H); MS(m / z): 171[M-1] + .

[0267] Compound 7

[0268] Thiophene[3,4-c]furan-1,3-dione

[0269] In a 250 ml round-bottom flask equipped with an electromagnetic stirrer, a reflux condenser, and a drying tube, 15 g of compound 6 and 120 ml of acetic anhydride were added. The mixture was refluxed for 3 hours, and the solvent was evaporated to dryness to obtain 13 g of brown solid.

[0270] Compound 8

[0271] 2-Nitrothiophene-3,4-dicarboxylic acid

[0272] 40 ml of fuming nitric acid (95% purity) was added to a 250 ml round-bottom flask equipped with a magnetic stirrer and a drying tube. The flask was cooled to 0-5 °C in an ice bath. 10 g of compound 7 was added in portions (1 g each time). After the addition was complete, the mixture was reacted at this temperature for 30 minutes (a yellow solid precipitated). The reaction mixture was poured into an 80 g ice-water mixture and extracted with ethyl acetate (100 ml × 3). All ethyl acetate layers were combined and washed successively with 50 ml × 2 water and saturated saline solution. The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated to obtain 10 g of a yellow solid. MS (m / z): 216 [M-1] + .

[0273] Compound 9

[0274] 4-Nitrothiophene[3,4-c]furan-1,3-dione

[0275] 10 g of compound 8 and 100 ml of acetic anhydride were added to a 250 ml round-bottom flask equipped with an electromagnetic stirrer, a reflux condenser and a drying tube. The mixture was refluxed for 3 hours and the solvent was evaporated to obtain 9 g of brown solid.

[0276] Compound 10

[0277] (S)-1-nitro-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene

[0278] [3,4-c]pyrrolo-4,6-dione

[0279] In a 250 mL round-bottom flask equipped with a magnetic stirrer and a drying tube, 1.99 g of 4-nitrothiophene[3,4-c]furan-1,3-dione (compound 9), 2.73 g of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine (compound 4b), and 100 mL of THF were added and stirred overnight at room temperature. 1.944 g of CDI was added, and the mixture was refluxed in an oil bath for 2 hours. After cooling to room temperature, 200 mL of ethyl acetate and 150 mL of water were added, and the mixture was extracted. The layers were separated, and the organic layer was washed with 100 mL of 0.5 N HCl and 100 mL of saturated NaCl. The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated. After purification by column chromatography, 3.485 g of a pale yellow solid was obtained. MS (m / z): 453 [M-1] + .

[0280] Compound 11

[0281] (S)-1-Amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene

[0282] [3,4-c]pyrrolo-4,6-dione

[0283] In a 250 mL round-bottom flask equipped with an electromagnetic stirrer, reflux condenser, and drying tube, 2.27 g of (S)-1-nitro-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione and 100 mL of THF were added. The mixture was heated to reflux, and 1.4 g of reduced iron powder was added. The mixture was refluxed for 2 hours. The mixture was filtered, and the filtrate was evaporated to dryness. 200 mL of ethyl acetate and 150 mL of water were added, and the mixture was extracted. The layers were separated, and the organic layer was washed with 100 mL of water and 100 mL of saturated NaCl. The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated to dryness. After purification by column chromatography, 1.53 g of a yellowish-brown solid was obtained. MS (m / z): 425 [M+1] + .

[0284] Compound 12

[0285] (S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrolo-1-yl)acetamide

[0286] Method 1: In a 50 ml round-bottom flask equipped with an electromagnetic stirrer, reflux condenser, and drying tube, add 0.1 g of (S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione and 0.005 g of DMAP, along with 10 ml of acetic anhydride. Heat to 60 °C and stir for 6 hours. Evaporate the solvent, and purify by column chromatography to obtain 0.022 g of the title compound.

[0287] Method 2: In a 50 ml round-bottom flask equipped with an electromagnetic stirrer, reflux condenser, and drying tube, add 0.1 g of (S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione and 5 ml of pyridine. Add 0.2 ml of acetyl chloride dropwise under ice bath conditions and stir at room temperature for 1 hour. Evaporate the solvent, add 50 ml of ethyl acetate and 20 ml of water, extract, separate the layers, wash the organic layer with 20 ml of 2N HCl and 20 ml of saturated NaCl, dry with anhydrous MgSO4, filter, evaporate the solvent, and purify by column chromatography to obtain 0.083 g of the title compound. MS (m / z): 465 [M-1] + Chiral HPLC (anhydrous ethanol / n-hexane / diethylamine = 40 / 60 / 0.1), OJ-H column, 250×4.6mm, 1.0mL / min, @230nm): 9.8min (R-isomer, 1.2%), 13.8min (S-isomer, 98.8%). 1H NMR (CDCl3): δ9.27 (s, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 7.05 (s, 1H), 6.81 (d, 1H, J = 6Hz), 5.81 (dd, 1H, J = 3Hz, J = 7Hz), 4.54 (dd, 1H) ,J=8Hz,J=11Hz), 4.08(q,2H,J=3Hz), 3.84(s,3H), 3.73(dd,1H,J=8Hz,J=11Hz), 2.86(s,3H), 2.27(s,3H), 1.45(t,3H,J=5Hz).

[0288] Example 1

[0289] Preparation of crystal form II

[0290] 0.356 g of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide was dissolved in 40 mL of ethyl acetate and stirred at room temperature until completely dissolved. After filtration, the filtrate was heated to 60 °C and isothermally evaporated under normal pressure until crystalline powder precipitated. After filtration and vacuum drying, 0.190 g of white solid powder (yield 53%) was obtained, which is crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide.

[0291] Example 2

[0292] X-ray powder diffraction (XRPD)

[0293] The X-ray powder diffraction (XRPD) test parameters are as follows: X-ray powder diffraction (XRPD) patterns were obtained using a Bruker D8 Advance X-ray powder diffractometer equipped with a Cu anode (40mA, 45kV). The scanning range was 2-Theta = 2-40°, the step size was 0.02°, and the scanning rate was 8° / min.

[0294] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, has the following X-ray powder diffraction (XRPD) pattern: Figure 1 As shown.

[0295] X-ray powder diffraction (XRPD) patterns of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide in crystal form II at 8.3±0.2°, 11.9±0.2°, 13.8±0.2°, 14.5±0.2°, 15.1±0.2°, and 16.8± Characteristic peaks are observed at 0.2°, 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, 19.3±0.2°, 20.2±0.2°, 21.6±0.2°, 22.3±0.2°, 23.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.8±0.2°, 27.5±0.2°, and 30.4±0.2°, while no obvious diffraction peaks are observed at other angles.

[0296] Example 3

[0297] Differential Scanning Calorimetry (DSC) Test

[0298] The differential scanning calorimetry (DSC) test parameters are as follows: A Seiko SII 6220 differential scanning calorimeter (DSC) was used to obtain the heat absorption and release information of the sample during the heating process. The heating rate was 10℃ / min, and nitrogen protection was used.

[0299] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, has the following DSC curve: Figure 2 As shown.

[0300] Crystal form II exhibits an endothermic melting peak at 174.2±6℃ (peak melting point) during the heating process.

[0301] Example 4

[0302] Thermogravimetric analysis (TGA) test

[0303] Thermogravimetric analysis (TGA) test parameters are as follows: A Seiko SII 6200 thermogravimetric analyzer (TG) was used to obtain sample weight loss information during the heating process. The heating rate was 10℃ / min, under nitrogen protection.

[0304] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, has the TGA curve shown in Figure 1. Figure 3 As shown.

[0305] Crystal form II loses 0.3% of its weight upon heating to the point of melting. No endothermic or exothermic peaks were observed before melting, indicating that the 0.3% weight loss is due to adsorbed water or solvent. Crystal form II is neither a hydrate nor a solvate.

[0306] Example 5

[0307] Infrared Spectroscopy (IR)

[0308] The infrared test parameters are as follows: The test instrument is a PerkinElmer Spectrum 65.

[0309] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, has the following infrared spectrum (IR): Figure 4 As shown.

[0310] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, has the following absorption peak positions and intensities in its infrared (IR) spectrum:

[0311]

[0312]

[0313]

[0314] Example 6

[0315] High temperature stability

[0316] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, was placed in a sealed oven at 40°C for one month and then subjected to liquid chromatography and DSC analysis. The results regarding the relevant substances and crystal forms are shown in Table 1. The experimental results show that (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits good high-temperature stability.

[0317] Table 1. Results of stability test at 40℃

[0318]

[0319] Example 7

[0320] Accelerate stability

[0321] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II sample prepared according to the method described in Example 1 was placed in a stability test chamber at 40°C and RH = 75% for one month, and then subjected to liquid chromatography and DSC tests. The results of related substances and crystal forms are shown in Table 2. The test results show that (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide crystal form II has good high temperature and high humidity stability.

[0322] Table 2. Results of Accelerated Stability Tests

[0323]

[0324] Example 8

[0325] Light stability

[0326] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, was placed in a 4500 lux light chamber and subjected to DSC testing after one month. The results of the relevant substances and crystal forms are shown in Table 3.

[0327] Table 3. Results of light stability test

[0328] Original crystal form Lighting conditions Crystal form after 1 month of storage II 4500 lux II

[0329] Example 9

[0330] Grinding stability

[0331] The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, prepared according to the method described in Example 1, was ground in a glass mortar for 5 minutes. The ground sample was then subjected to XRPD testing. The crystal form results are shown in Table 4. The results indicate that (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, exhibits good grinding stability.

[0332] Table 4. Results of Grinding Stability Test

[0333] Original crystal form Grinding method Crystal form after grinding II Grind in a glass mortar for 5 minutes II

[0334] Example 10

[0335] Pressure stability

[0336] (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide (crystal form II) was tableted using a single-punch tablet press. The tablets had a diameter of 6 mm and a hardness of 25-30 N. The tableted powder was subjected to DSC testing, and the results are as follows: Figure 5 As shown in the figure. The results indicate that crystal form II has good stability.

[0337] Example 11

[0338] Equilibrium stability of ethanol solutions

[0339] 0.2 g of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide (crystal form II) was added to 10 mL of ethanol and stirred isothermally at 25 °C for 3 hours. The suspension was filtered, dried in wet solid state, and then subjected to X-ray powder diffraction (XRPD). The crystal form results are shown in Table 5.

[0340] Table 5. Results of Ethanol Equilibrium Crystal Form Stability Test

[0341] Original crystal form Equilibrium temperature (°C) Equilibrium time (h) Equilibrium crystal form II 25 3 II

[0342] Example 12

[0343] hygroscopic

[0344] Hygroscopicity of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, was studied. The hygroscopicity was measured after storage in a desiccator containing a saturated aqueous solution of ammonium chloride (RH = 80%) until weight equilibrium was reached, and the crystal form was determined by XRPD.

[0345] The test was performed using crystal form II of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide prepared according to the method described in Example 1.

[0346] The hygroscopicity test results for crystal form II are shown in Table 6. The results show that crystal form II is almost non-hygroscopic. Crystal form II does not change its crystal structure after being stored at 80% humidity.

[0347] Table 6. Results of Hygroscopicity Test

[0348] Original crystal form mAPI(g) Increase in weight (g) Moisture absorption (%) Crystal form after moisture absorption II 0.497 -0.001 0 II

[0349] In this disclosure, relational terms such as first and second are used merely to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0350] As will be understood from the foregoing, although specific embodiments of this disclosure have been described for illustrative purposes, various modifications or alterations can be made by those skilled in the art without departing from the spirit and scope of this disclosure. All such modifications or alterations should fall within the scope of the appended claims.

Claims

1. The crystalline form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide exhibits characteristic peaks at diffraction angles 2θ of 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1°, and 24.4° in X-ray powder diffraction (XRPD) patterns.

2. The crystalline form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide exhibits characteristic peaks at diffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2°, and 24.4±0.2° in X-ray powder diffraction (XRPD) patterns.

3. The crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, in its X-ray powder diffraction (XRPD) pattern, has the following diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks:

4. The crystal form II of compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, in its X-ray powder diffraction (XRPD) pattern, has the following diffraction angle 2θ, interplanar spacing d, and relative intensity of diffraction peaks:

5. The compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, as described in any one of claims 1 to 4, exhibits an endothermic peak at 174.2°C when thermally analyzed using differential scanning calorimetry (DSC).

6. The compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, as described in any one of claims 1 to 4, exhibits an endothermic peak at 174.2 ± 6°C when thermally analyzed using differential scanning calorimetry (DSC).

7. The compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, as described in any one of claims 1 to 4, has the DSC curve shown in Figure 2 when thermally analyzed using differential scanning calorimetry (DSC).

8. The compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, as described in any one of claims 1 to 4, has the TGA curve shown in Figure 3 when thermally analyzed by thermogravimetric analysis (TGA).

9. The (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide, as described in any one of claims 1 to 4, has the following absorption peak positions and intensities in its infrared (IR) spectrum:

10. The compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, as described in any one of claims 1 to 4, has the infrared spectrum (IR) shown in Figure 4.

11. A pharmaceutical composition comprising crystal form II of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide as claimed in any one of claims 1 to 10, and a pharmaceutically acceptable carrier, diluent, or excipient.

12. The pharmaceutical composition of claim 11, wherein it is prepared as a tablet, solution, granule, patch, ointment, gel, capsule, aerosol or suppository for parenteral or oral use.

13. The pharmaceutical composition of claim 11, wherein it is prepared as a tablet, solution, granule, patch, ointment, gel, capsule, aerosol or suppository for transdermal, mucosal, nasal, buccal or sublingual use.

14. A method for preparing crystal form II of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide according to any one of claims 1 to 10, comprising: (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide was crystallized in ethyl acetate to obtain the crystal form II.

15. The method of claim 14, further comprising: Dissolve (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiopheno[3,4-c]pyrrolo-1-yl]acetamide in ethyl acetate until completely dissolved; and Filter the solution and heat the filtrate to 50-70°C to precipitate crystal form II.

16. Use of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, as described in any one of claims 1 to 10, in the preparation of a medicament for the treatment or prevention of diseases associated with PDE4 enzymes in an individual.

17. The use as claimed in claim 16, wherein the PDE4 enzyme-related disease is a PDE4 enzyme-mediated disease.

18. The use as claimed in claim 16, wherein the individual is a mammal.

19. The use as claimed in claim 18, wherein the mammal is a human.

20. The use as described in claim 16 or 17, wherein the disease is selected from inflammatory diseases, infectious diseases, immune diseases, and cancerous diseases.

21. The use as described in claim 16 or 17, wherein the disease is selected from thyroid cancer, cervical cancer, eye cancer, skin cancer, oral cancer, pharyngeal cancer, esophageal cancer, bone cancer, leukemia, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, pancreatic cancer, brain cancer, heart cancer, adrenal cancer, subcutaneous tissue cancer, lymph node cancer, HIV, hepatitis, adult respiratory distress syndrome, bone resorption disease, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, cystic fibrosis. Degeneration, septic shock, sepsis, endotoxin shock, hemodynamic shock, sepsis syndrome, ischemia-reperfusion injury, meningitis, psoriasis, fibrotic diseases, cachexia, graft-versus-host disease, autoimmune diseases, rheumatoid spondylitis, arthritis, osteoporosis, enteritis, multiple sclerosis, leprosy-related erythema nodosum, radiation injury, asthma, oxygen-enriched lung injury, microbial infection and microbial infection syndrome.

22. The use as described in claim 16 or 17, wherein the disease is selected from sigmoid colon cancer, inflammatory skin disease, segmental ileitis, ulcerative colitis, rheumatoid arthritis, and osteoarthritis.

23. The use as described in claim 16 or 17, wherein the disease is selected from head cancer, chest cancer, bone marrow cancer, melanoma, malignant glioma, and intestinal cancer.

24. The use as described in claim 16 or 17, wherein the disease is selected from atopic dermatitis and systemic lupus erythematosus.

25. Use of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl]acetamide, crystal form II, as described in any one of claims 1 to 10, in the preparation of a medicament for reducing PDE4 enzyme activity.

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