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WO2019210864A1 - 噻吩衍生物的晶型 - Google Patents

噻吩衍生物的晶型 Download PDF

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Publication number
WO2019210864A1
WO2019210864A1 PCT/CN2019/085327 CN2019085327W WO2019210864A1 WO 2019210864 A1 WO2019210864 A1 WO 2019210864A1 CN 2019085327 W CN2019085327 W CN 2019085327W WO 2019210864 A1 WO2019210864 A1 WO 2019210864A1
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Prior art keywords
methylsulfonyl
methoxyphenyl
dihydro
ethoxy
thieno
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PCT/CN2019/085327
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English (en)
French (fr)
Inventor
张冬雷
王立宇
常玉琨
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天津合美医药科技有限公司
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Application filed by 天津合美医药科技有限公司 filed Critical 天津合美医药科技有限公司
Priority to BR112020022190-2A priority Critical patent/BR112020022190A2/pt
Priority to CA3099071A priority patent/CA3099071A1/en
Priority to EP19797143.5A priority patent/EP3789389A4/en
Priority to KR1020207034757A priority patent/KR20210022556A/ko
Priority to AU2019263865A priority patent/AU2019263865B2/en
Priority to US17/052,128 priority patent/US20210139498A1/en
Priority to JP2021510509A priority patent/JP7542523B2/ja
Publication of WO2019210864A1 publication Critical patent/WO2019210864A1/zh

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    • C07D495/04—Ortho-condensed systems
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • C07—ORGANIC CHEMISTRY
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    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure generally relates to the fields of organic chemistry and medicinal chemistry.
  • PDE4 enzyme inhibitors are clinically effective against several inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and allergic dermatitis. It is also effective on animal models for a variety of other diseases including arthritis and sepsis.
  • COPD chronic obstructive pulmonary disease
  • the disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6- Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, in the X-ray powder diffraction (XRPD) pattern, at diffraction angle 2 ⁇ There are characteristic peaks at about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, in X-ray powder diffraction (XRPD) pattern, at diffraction angle 2 ⁇ is a characteristic peak at 5.3 ⁇ 0.2°, 9.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 26.2 ⁇ 0.2°, and 26.7 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, diffraction angle 2 ⁇ in X-ray powder diffraction (XRPD) pattern
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, diffraction angle 2 ⁇ in X-ray powder diffraction (XRPD) pattern
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide having X-ray powder diffraction substantially as shown in Figure 1 XRPD) map.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B which is substantially free of solvent.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl group substantially free of water.
  • the present disclosure is directed to a substantially pure compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl] Form I of -4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, in X-ray powder diffraction (XRPD) pattern, It has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) which is free of solvent and contains no water.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)B Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide and a pharmaceutically acceptable carrier, diluent or An excipient wherein said Form I has an X-ray powder diffraction (XRPD) pattern having diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, 26.7°. Characteristic peaks.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the preparation of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4, Method for the crystalline form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which comprises: (S)-N-[5 -[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[ 3,4-c]pyrrol-1-yl]acetamide is crystallized in acetonitrile to give the crystalline form I, wherein the crystalline form I is in an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2 ⁇ There are characteristic peaks at 5.3°
  • the present disclosure relates to the preparation of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4, Method for the crystalline form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which comprises: (S)-N-[5 -[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[ 3,4-c]pyrrol-1-yl]acetamide is crystallized from a mixture of dichloromethane and n-hexane to give the crystalline form I, wherein the crystalline form I is in an X-ray powder diffraction (XRPD) pattern It has characteristic peaks at XRPD
  • the present disclosure relates to the preparation of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4, A method of Form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which comprises:
  • the crystal form I has a characteristic peak in the X-ray powder diffraction (XRPD) pattern at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to a method of treating or preventing a disease or disease state mediated by a PDE4 enzyme, preferably a PDE4 enzyme, comprising administering to a subject in need of the method a therapeutically effective amount of a compound (S)-N- [5-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiophene Form I of [3,4-c]pyrrol-1-yl]acetamide or comprises the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl) Form I of 2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X-ray powder diffraction (XRPD) pattern Among them, they have characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X-ray powder diffraction (XRPD) pattern Among them, there are characteristic peaks at diffraction angles 2 ⁇ of 5.3 ⁇ 0.2°, 9.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 26.2 ⁇ 0.2°, and 26.7 ⁇ 0.2°.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X-ray powder diffraction (XRPD) pattern The diffraction angle 2 ⁇ , the interplanar spacing d, and the relative intensity of the diffraction peak are approximately:
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which has essentially the appearance shown in Figure 1.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to a method of reducing PDE4 enzymatic activity comprising administering to an individual in need thereof an effective amount of a compound (S)-N-[5-[1-(3-ethoxy-4-methyl) Oxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide
  • Form I or comprises the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-
  • Figure 1 shows the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4 of the present disclosure, X-ray powder diffraction (XRPD) pattern of Form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • XRPD X-ray powder diffraction
  • Figure 2 shows the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4 of the present disclosure, Differential Scanning Calorimetry (DSC) curve for Form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • DSC Differential Scanning Calorimetry
  • FIG. 3 shows the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4 of the present disclosure, Thermogravimetric analysis (TGA) curve for Form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • TGA Thermogravimetric analysis
  • Figure 4 shows the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4 of the present disclosure, Infrared spectrum (IR) of Form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • IR Infrared spectrum
  • Figure 5 shows the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4 of the present disclosure, The dissolution profile of crystal I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • references to “an embodiment” or “another embodiment” or “an embodiment” or “some embodiments” throughout this specification are meant to include, in at least one embodiment, the Specific reference to elements, structures or features.
  • the appearance of the phrase “a” or “an embodiment” or “an embodiment” Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • composition comprising a “pharmaceutically acceptable carrier, diluent or excipient” includes a pharmaceutically acceptable carrier, diluent or excipient, or two or more drugs acceptable Carrier, diluent or excipient.
  • compound of the present disclosure means (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)B 4-[6,6-Dioxy-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide having the structure shown below:
  • the use of the term “about” includes and describes the value or the parameter itself.
  • “about x” includes and describes “x” itself.
  • the term “about” refers to a change of +/- 5% when used in conjunction with or used to modify a numerical value, unit, constant, or numerical range.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • IR infrared spectrum
  • the term "substantially the same” as used in this disclosure when referring to the X-ray powder diffraction (XRPD) peak position means that typical peak position and intensity variability are considered.
  • the peak position (2[theta]) will exhibit some variability, typically as much as 0.1 to 0.2 degrees, depending on the solvent used and the means used to measure the diffraction.
  • the relative peak intensities will show variability between instruments and variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art. And should only be considered as a qualitative measurement.
  • the term "2 ⁇ value” or "2 ⁇ ” refers to an experimentally set peak position in degrees based on an X-ray powder diffraction (XRPD) experiment and is a common abscissa unit of a diffraction pattern.
  • the test setup requires that if the reflection is diffracted when the incident beam forms an angle ⁇ ( ⁇ ) with a certain crystal plane, the reflected beam is recorded at an angle 2 ⁇ (2 ⁇ ).
  • the specific 2 theta value for a particular crystalline form referred to in this disclosure is intended to mean the 2 theta value (in degrees) measured using the X-ray powder diffraction (XRPD) experimental conditions described in the present disclosure. For example, as described in the present disclosure, used As a source of radiation.
  • substantially pure refers to chemical purity and crystal form purity.
  • substantially free means containing no more than about 20% by weight.
  • substantially free of solvent means containing no more than about 20% by weight of solvent.
  • substantially free of water means water containing no more than 20% by weight.
  • the term "mammal” refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.
  • the term "patient” refers to an animal (eg, a human), a companion animal (eg, a dog, a cat, or a horse), and a domestic animal (eg, a cow, a pig, and a sheep).
  • the patient is a mammal comprising males and females.
  • the patient is a human.
  • the term "pharmaceutically acceptable” refers to carriers, carriers, diluents, excipients and/or salts which must be compatible with the other ingredients of the formulation and which are not deleterious to the recipient.
  • the term "pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration for use in humans or animals. , Glidants, sweeteners, thinners, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers
  • the agent or the like has various forms of carriers which do not have side effects in constituting the pharmaceutical composition.
  • carrier is defined as a compound that facilitates the introduction of a crystalline form of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • the term "pharmaceutical composition” refers to a formulation of Form I of a compound described in the present disclosure with a medium generally accepted by the art for delivery of a biologically activating compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers, diluents or excipients.
  • the term "therapeutically effective amount” refers to a crystal of a compound that ameliorates, attenuates or eliminates the symptoms of a particular disease or condition and a particular disease or condition, or avoids or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition.
  • the amount of Form I or the combination of Form I of the compound will vary depending on the Form I of the compound, the disease state and its severity, and the age, body weight, etc. of the mammal to be treated, but The amount of Form I of the compounds described in this disclosure can be determined by those skilled in the art in light of their own knowledge and the present disclosure.
  • treating encompasses a treatment-related disease or condition in a mammal, such as a human, having a related disease or condition, and includes:
  • disease and “disease state” may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology) Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.
  • physiologically acceptable refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • the disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6- Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, in the X-ray powder diffraction (XRPD) pattern, at diffraction angle 2 ⁇ There are characteristic peaks at about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, in X-ray powder diffraction (XRPD) pattern, at diffraction angle 2 ⁇ is a characteristic peak at 5.3 ⁇ 0.2°, 9.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 26.2 ⁇ 0.2°, and 26.7 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, diffraction angle 2 ⁇ in X-ray powder diffraction (XRPD) pattern
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, diffraction angle 2 ⁇ in X-ray powder diffraction (XRPD) pattern
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • the present disclosure relates to the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 Form I of dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide having X-ray powder diffraction substantially as shown in Figure 1 XRPD) map.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least one substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least two substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least three substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least four substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least five substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least six substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least seven appearances substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least eight appearances substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least nine substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least ten, substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least eleven present substantially as shown in Figure 1.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxy) of the present disclosure is used in thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form I has an endothermic peak at about 136.0 °C.
  • the compound (S)-N-[5-[1-(3) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to differential scanning calorimetry (DSC) for thermal analysis.
  • DSC differential scanning calorimetry
  • Form I of pyrrol-1-yl]acetamide has an endothermic peak at about 136.0 °C.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxy) of the present disclosure is used in thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form I has an endothermic peak at 136.0 ⁇ 6 °C.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxy) of the present disclosure is used in thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form I has an endothermic peak at 136.0 ⁇ 4 °C.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxy) of the present disclosure is used in thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form I has an endothermic peak at 136.0 ⁇ 2 °C.
  • the compound (S)-N-[5-[1-(3) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to differential scanning calorimetry (DSC) for thermal analysis.
  • DSC differential scanning calorimetry
  • Form I of pyrrol-1-yl]acetamide has an endothermic peak at 136.0 ⁇ 6 °C.
  • the compound (S)-N-[5-[1-(3) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to differential scanning calorimetry (DSC) for thermal analysis.
  • DSC differential scanning calorimetry
  • Form I of pyrrol-1-yl]acetamide has an endothermic peak at 136.0 ⁇ 4 °C.
  • the compound (S)-N-[5-[1-(3) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to differential scanning calorimetry (DSC) for thermal analysis.
  • DSC differential scanning calorimetry
  • Form I of pyrrol-1-yl]acetamide has an endothermic peak at 136.0 ⁇ 2 °C.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxy) of the present disclosure is used in thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form I has a DSC curve substantially as shown in FIG.
  • the compound (S)-N-[5-[1-(3) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to differential scanning calorimetry (DSC) for thermal analysis.
  • DSC differential scanning calorimetry
  • Form I of pyrrol-1-yl]acetamide has a DSC curve substantially as shown in Figure 2.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxy) of the present disclosure is used in thermal analysis using thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Type I has a TGA curve substantially as shown in FIG.
  • the compound (S)-N-[5-[1-(3-B) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Oxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole- Form I of 1-yl]acetamide has a TGA curve substantially as shown in Figure 3.
  • the intensity is approximately:
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-) of the present disclosure is in the infrared spectrum (IR).
  • IR infrared spectrum
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(A) of the present disclosure is compared to other solid forms Form I of sulfo)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide has at least one of the following advantages Properties: chemical purity, fluidity, solubility, dissolution rate, morphology or crystal, stability such as high temperature stability, accelerated stability, light stability, grinding stability, pressure stability, equilibrium stability of ethanol solution, equilibrium of aqueous solution Properties, low residual solvent content, low moisture absorption, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B, which is substantially free of solvent.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 20% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 20% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 10% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 10% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 5% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 5% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 3% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 3% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 1% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 1% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.5% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.5% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.2% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.2% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.1% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.1% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.01% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.01% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.001% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.001% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.0001% by weight of solvent, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.0001% by weight of solvent, In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl group substantially free of water.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 20% by weight of water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 20% by weight water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 10% by weight water, in X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 10% by weight water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 5% by weight of water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 5% by weight of water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 3% by weight water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 3% by weight water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 1% by weight water, in X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.7°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 1% by weight of water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.7°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.5% by weight of water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.5% by weight of water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.2% by weight of water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.2% by weight of water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.1% by weight water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.1% by weight of water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.01% by weight water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.01% by weight water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.001% by weight of water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.001% by weight water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.0001% by weight of water, at X In the ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide contains no more than about 0.0001% by weight of water, in use In the X-ray powder diffraction (XRPD) pattern under CuK ⁇ radiation conditions, it has characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the compound (S)-N-[5-[1-(3-B) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Oxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole- Form I of 1-yl]acetamide is heated to a weight loss of less than 5.0%, and no absorption/exothermic peak occurs before melting, indicating that no more than 5.0% of the weight loss is adsorbed water or solvent.
  • the compound (S)-N-[5-[1-(3-B) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Oxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole- Form I of 1-yl]acetamide is heated to a weight loss of less than 3.0%, and no absorption/exothermic peak occurs before melting, indicating that no more than 3.0% of the weight loss is adsorbed water or solvent.
  • the compound (S)-N-[5-[1-(3-B) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Oxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole- Form I of 1-yl]acetamide is heated to a weight loss of less than 2.0%, and no absorption/exothermic peak occurs before melting, indicating that no more than 2.0% of the weight loss is adsorbed water or solvent.
  • the compound (S)-N-[5-[1-(3-B) of the present disclosure is heated at a heating rate of 10 ° C/min when subjected to thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Oxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole- Form I of 1-yl]acetamide is heated to a melting weight loss of no more than 1.0%, and no absorption/exothermic peak occurs before melting, indicating that no more than 1.0% of the weight loss is adsorbed water or solvent.
  • the present disclosure relates to the substantially pure compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) of the present disclosure.
  • substantially pure compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) of the present disclosure Form I of ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X under CuK ⁇ radiation
  • XRPD ray powder diffraction
  • Form I of ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-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 Form I and less than about 5% by weight, preferably less than about 2% by weight, more preferably less than about 1% by weight of the compound having the present disclosure (S)-N-[5-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6- Other compounds of different chemical structures of dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • Form I of ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-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 Form I and less than about 5% by weight, preferably less than about 2% by weight, more preferably less than about 1% by weight of the compound of the present disclosure (S -N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro Any other crystal form of -4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) which is free of solvent and contains no water.
  • the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) is free of solvent and contains no water.
  • XRPD ray powder diffraction
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)B Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide and a pharmaceutically acceptable carrier, diluent or An excipient wherein said Form I has an X-ray powder diffraction (XRPD) pattern having diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, 26.7°. Characteristic peaks.
  • XRPD X-ray powder diffraction
  • the pharmaceutical compositions of the present disclosure are prepared as tablets, solutions, granules, patches, ointments for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use. , gels, capsules, aerosols or suppositories.
  • the pharmaceutical compositions comprise Form I of the compounds of the present disclosure, as well as pharmaceutically acceptable carriers, diluents or excipients.
  • Form I of a compound of the present disclosure for use in treating or preventing a PDE4 enzyme-associated, preferably PDE4 enzyme-mediated, disease-administering route to a mammal can be in a gastrointestinal or parenteral route.
  • the crystalline form I of a compound of the present disclosure for use in treating or preventing a PDE4 enzyme-related, preferably PDE4 enzyme-mediated, disease-administering route to a mammal can be administered orally.
  • the crystalline form I of a compound of the present disclosure for treating or preventing a PDE4 enzyme-related, preferably PDE4 enzyme-mediated, disease-administering route to a mammal can be a transdermal route.
  • the compounds described in the present disclosure may be obtained in any suitable form such as tablets, capsules, powders, oral solutions, suspensions, patches, ointments, gels, or aerosols.
  • suitable form such as tablets, capsules, powders, oral solutions, suspensions, patches, ointments, gels, or aerosols.
  • Illustrative examples of such tablets include, but are not limited to, plain tablets, sugar coated tablets, and film coated tablets.
  • Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvants, carriers, excipients, aids that have been approved by the U.S. Food and Drug Administration for use in humans or animals. Flowing agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, osmotic pressure agents, solvents or emulsifiers, etc.
  • Various forms of carriers that have no side effects on the composition of the pharmaceutical composition are well known in the pharmaceutical arts and are for example found in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990). The description is hereby incorporated by reference in its entirety.
  • the pharmaceutical composition of the present disclosure can be administered by any method that achieves its intended purpose.
  • administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal or oral. get on.
  • the route of administration may be a parenteral route, an oral route, and an intrarectal route.
  • the dosage administered will depend on the age, health and weight of the recipient, and, if concurrent, depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.
  • Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, drages, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, lozenges. , gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which may be prepared according to methods known in the art.
  • Particularly suitable for oral administration are ordinary tablets (primary tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration, suppositories, suitable Parenteral administration is a solution, an oil-based solution or an aqueous solution, in addition to a suspension, emulsion or implant, and suitable for topical use are ointments, creams or powders.
  • the product of the present disclosure may also be lyophilized, and the resulting lyophilizate is used, for example, to prepare an injection.
  • the formulations given may be sterilized and/or contain adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying osmotic pressure, buffer substances, Dyestuffs, flavoring agents and/or numerous additional active ingredients, such as one or more vitamins.
  • adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying osmotic pressure, buffer substances, Dyestuffs, flavoring agents and/or numerous additional active ingredients, such as one or more vitamins.
  • compositions of the present disclosure are prepared as tablets, solutions, granules, patches, for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use. Ointment, capsule, aerosol or suppository.
  • Preservatives can be provided in the pharmaceutical compositions.
  • sodium benzoate, ascorbic acid, and an ester of p-hydroxybenzoic acid can be added as a preservative.
  • antioxidants and suspending agents can be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate , magnesium aluminate aluminate, synthetic aluminum silicate, calcium carbonate, calcium hydrogencarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc. can be used as an excipient; magnesium stearate, talc, hardened oil, etc.
  • coconut oil olive oil, sesame oil, peanut oil, soybean can be used as a suspension or lubricant; vinegar cellulose as a derivative of sugars such as cellulose or sugar, or as a derivative of polyethylene
  • a methyl acetate-methacrylate copolymer of the substance can be used as a suspension; and a plasticizer such as a phthalate ester can be used as a suspension.
  • Suitable routes of administration may, for example, include oral administration, rectal administration, transmembrane administration, parenteral delivery, transdermal administration, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, Intravenous, intramedullary, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular.
  • parenteral delivery includes intramuscular injection, subcutaneous injection, Intravenous, intramedullary, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular.
  • the compounds can also be extended at a predetermined rate and/or in a sustained release or controlled release dosage form including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, and the like. Timing, pulsed administration.
  • compositions of the present disclosure can be produced in a known manner, for example, by conventional methods of mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, entrapping or tableting.
  • the pharmaceutical composition used can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the treatment of the active compound into A pharmaceutically acceptable formulation.
  • physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the treatment of the active compound into A pharmaceutically acceptable formulation.
  • suitable formulations will depend on the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as appropriate and understood in the art.
  • the injection can be prepared in the following conventional form: as a solution or suspension, a solid dosage form suitable as a solution or suspension prior to injection, or as an emulsion.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like.
  • the injectable pharmaceutical composition may contain a small amount of non-toxic auxiliary such as a wetting agent, a pH buffering agent and the like.
  • Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer.
  • Absorption enhancing formulations e.g., liposomes
  • the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • a carrier enables the compound of the present invention to be formulated into tablets, pills, troches, capsules, liquids, gels, syrups, ointments, suspensions, solutions, powders and the like.
  • the pharmaceutical preparation for oral administration can be obtained by mixing the active compound with a solid excipient, grinding the resulting mixture arbitrarily and processing the granule mixture, if necessary, after adding a suitable adjuvant to obtain a tablet or Lozenge core.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, a Cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP).
  • a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar or alginic acid or alginate such as sodium alginate may be added if necessary.
  • the coating core is suitably coated.
  • a concentrated sugar solution may optionally be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer A solution and a suitable organic solvent or solvent mixture.
  • a dye or pigment may be added to the tablet or lozenge coating.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable Organic solvent or solvent mixture.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol.
  • the push-fit capsules can comprise the active ingredient in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer.
  • the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
  • a stabilizer may be added. All formulations for oral administration should achieve a dosage suitable for such administration.
  • compositions of the present disclosure may comprise from 0.1% to 95% of Form I of the disclosed compounds.
  • compositions of the present disclosure may comprise from 1% to 70% of Form I of the compounds of the present disclosure.
  • composition or formulation to be administered will contain a certain amount of Form I of the compounds of the present disclosure in an amount effective to treat the disease/condition of the subject being treated.
  • the present disclosure relates to the preparation of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4, Method for the crystalline form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which comprises: (S)-N-[5 -[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[ 3,4-c]pyrrol-1-yl]acetamide is crystallized in acetonitrile to give the crystalline form I, wherein the crystalline form I is in an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2 ⁇ There are characteristic peaks at 5.3°
  • the present disclosure relates to the preparation of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4, Method for the crystalline form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which comprises: (S)-N-[5 -[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[ 3,4-c]pyrrol-1-yl]acetamide is crystallized from a mixture of dichloromethane and n-hexane to give the crystalline form I, wherein the crystalline form I is in an X-ray powder diffraction (XRPD) pattern It has characteristic peaks at XRPD
  • (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 -Dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide is dissolved in a mixture of dichloromethane and n-hexane until completely dissolved; hot filtered and cooled to Crystals were precipitated at 35-45 ° C; continue to cool to 0-10 ° C; and filtered and vacuum dried to give (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)- Form I of 2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide.
  • (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6 -Dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide is dissolved in a mixture of dichloromethane and n-hexane, heated to 45 ° C, stirred and fully dissolved After hot filtration, the filtrate was cooled to 40 ° C, stirred at isothermal temperature, and crystallized; further cooling to 5 ° C, isothermal stirring; and filtration and vacuum drying to obtain (S)-N-[5-[1-(3-ethoxy) 4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1- Form I of
  • the present disclosure relates to the preparation of the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4, A method of Form I of 6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which comprises:
  • Form I has a characteristic peak in the X-ray powder diffraction (XRPD) pattern at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.7°, 26.2°, and 26.7°.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to a method of treating or preventing a disease or disease state mediated by a PDE4 enzyme, preferably a PDE4 enzyme, comprising administering to a subject in need of the method a therapeutically effective amount of a compound (S)-N- [5-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thiophene Form I of [3,4-c]pyrrol-1-yl]acetamide or comprises the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl) Form I of 2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide
  • the individual is a mammal.
  • the individual is a human.
  • diseases or disease states that can be used in the present disclosure include, but are not limited to, inflammatory diseases or disease states, infectious diseases or disease states, immune-like diseases or disease states, and cancer-like diseases or Disease state.
  • illustrative examples of diseases or conditions that can be used in the present disclosure include, but are not limited to, head cancer, thyroid cancer, neck cancer, eye cancer, skin cancer, oral cancer, throat cancer, esophageal cancer, Thoracic, bone, blood, bone marrow, lung, colon, sigmoid, rectal, stomach, prostate, breast, ovarian, kidney, liver, pancreas, brain, bowel, heart cancer, Adrenal cancer, subcutaneous tissue cancer, lymph node cancer, pigmentoma, malignant glioma, HIV, hepatitis, adult respiratory distress syndrome, bone resorption, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, inflammatory skin disease, specificity Dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, reperfusion injury after ischemia, meningitis, psoriasis, fibrotic diseases, Cachexia, graft rejection of
  • a method of treating or preventing a PED4 enzyme-associated, preferably PED4 enzyme-mediated, disease comprises administering to a subject in need of the method 1 mg to 10 g of Form I of a compound of the present disclosure.
  • a method of treating or preventing a PED4 enzyme-mediated disease comprising administering 10 mg to 3000 mg of Form I of a compound of the present disclosure to an individual in need of such a method.
  • a method of treating or preventing a PED4 enzyme-associated, preferably PED4 enzyme-mediated, disease comprises administering from 1 mg to 200 mg of Form I of the present disclosure to an individual in need of such a method.
  • a method of treating or preventing a PED4 enzyme-related, preferably PED4 enzyme-mediated, disease comprising administering to a subject in need of 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 Form I of the compounds of the present disclosure.
  • Form I of at least one compound of the present disclosure or a pharmaceutical composition comprising Form I of at least one compound of the present disclosure may be used in any suitable systemic and/or topical delivery of Form I of the compounds of the present disclosure. Any method performed by the method is administered to the patient.
  • Non-limiting examples of methods of administration include (a) administration by the oral route, including administration in the form of capsules, tablets, granules, sprays, syrups, or the like; (b) by non- Oral administration, for example, rectal, vaginal, intraurethral, intraocular, intranasal or intraaural, the administration includes an aqueous suspension, an oily preparation, or the like, or in the form of drops, sprays, suppositories, ointments, ointments, and the like.
  • administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrathoracic injection, etc., including infusion pump Delivery; (d) local administration such as injection directly into the kidney region or cardiac region, such as by depot implantation; and (e) topical administration; as is known to those skilled in the art
  • a suitable mode of administration is considered to be that the crystalline form I of the compound described in the present disclosure is in contact with living tissue.
  • the administration includes administration in the form of an ointment, a cream, a gel, an aerosol, a suspension, an emulsion or the like.
  • compositions suitable for administration include those in which an effective amount of the active ingredient is included in such compositions.
  • the dose required for a therapeutically effective amount of the pharmaceutical composition described in this disclosure depends on the route of administration, the type of animal being treated, including the human, and the physical characteristics of the particular animal in question. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medical therapy, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a crystalline form of a compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease, or to prolong the life of the individual being treated. The actual ability of a person skilled in the art can well determine a therapeutically effective amount, particularly in accordance with the detailed disclosure provided by the present disclosure.
  • the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and the type of mammal being treated, the crystalline form of the particular compound employed, and the The specific use of the crystalline form of these compounds.
  • Those skilled in the art will be able to achieve the objective of determining an effective dosage level, i.e., the dosage level necessary to achieve the desired effect, using conventional pharmacological methods.
  • human clinical application of the product begins at a lower dosage level as the dosage level increases until the desired effect is achieved.
  • an established in vitro study can be used to establish an effective dosage and route of administration of the compositions identified by the methods using established pharmacological methods.
  • the application of potential products begins at a higher dose level, as the dose is reduced until the desired effect is no longer achieved or the undesirable side effects disappear.
  • the dosage range can be broader depending on the desired effect and therapeutic indication.
  • the dosage can be from about 10 [mu]g/kg body weight to 1000 mg/kg body weight, and in certain embodiments from about 100 [mu]g/kg body weight to 300 mg/kg body weight.
  • the dosage can be based on and calculated from the body surface area of the patient.
  • each physician can select the exact formulation, route of administration and dosage of the pharmaceutical compositions described in this disclosure based on the condition of the patient.
  • the dosage of the composition administered to the patient can range from about 0.5 mg/kg to 1000 mg/kg of patient body weight.
  • the dose may be administered once or two or more times during one or several days depending on the needs of the patient.
  • the human dosage form of the crystalline form of the compound is established by at least some of the conditions, the present disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the determined human dose, in some embodiments.
  • the dosage range in the protocol ranges from 25% to 250% of the determined human dose.
  • a suitable human dose can be administered from a half effective dose or a median dose of the infectious dose, or from other suitable values from in vitro or in vivo studies. Inferred, as quantified in the Institute of Toxicity Research and Performance in Animals.
  • the attending physician will know how and when to terminate, interrupt or adjust the administration. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level.
  • the size of the administered dose in the treatment of the condition of interest will vary with the severity of the condition being treated and the route of administration. The severity of the disease state can be assessed, for example, in part by standard prognostic evaluation methods.
  • the dosage and possible dosage frequency will also vary depending on the age, weight, and response of the individual patient. A protocol comparable to the above discussed protocol can be used in veterinary medicine.
  • the daily dosing regimen for an adult patient is, for example, an oral dose of from 0.1 mg to 2000 mg of each active ingredient, and in certain embodiments from 1 mg to 2000 mg of each active ingredient, for example from 5 mg to 1500 mg of each active ingredient.
  • the intravenous, subcutaneous or intramuscular dose of each active ingredient used is from 0.01 mg to 1000 mg, and in certain embodiments from 0.1 mg to 1000 mg, such as from 1 mg to 800 mg.
  • the dosage can be calculated as the free base.
  • the composition is administered from 1 to 4 times daily.
  • compositions described in this disclosure may be administered by continuous intravenous infusion, in certain embodiments at doses up to 2000 mg of each active ingredient per day.
  • doses up to 2000 mg of each active ingredient per day.
  • the compound is administered during continuous treatment, such as one week or weeks, or months or years.
  • the dose and dosing interval can be adjusted individually to provide a plasma level sufficient to maintain an adjustment effect or an active fraction of the lowest effective concentration (MEC).
  • MEC lowest effective concentration
  • the MEC of each compound is different, but the MEC can be evaluated from in vitro data.
  • the dosage required to achieve MEC will depend on the individual characteristics and route of administration. However, plasma concentration can be determined using HPLC (High Performance Liquid Chromatography) assay or bioassay.
  • the medication interval can also be determined using the MEC value. Treatments that maintain plasma levels above the MEC over a period of 10-90% of the time, in some embodiments, 30-90% of the time, and in some embodiments, 50-90% of the time should be used.
  • the regimen is administered to the composition.
  • the effective local concentration of the drug is independent of plasma concentration.
  • the amount of the composition to be administered depends on the individual to be treated, depending on the weight of the individual, the severity of the pain, the mode of administration, and the judgment of the prescribing physician.
  • the potency and toxicity of the compounds described in this disclosure can be assessed using known methods.
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties such as a mammalian cell line and, in certain embodiments, a human cell line
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties can be established by measuring the toxicity of the cell line in vitro.
  • the results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, toxicity in humans.
  • the toxicity of a particular compound in an animal model such as a mouse, rat, rabbit or monkey can be determined using known methods.
  • the efficacy of a particular compound can be determined using a number of accepted methods, such as in vitro methods, animal models, or human clinical trials.
  • the composition can be placed into a pack or dispenser device, which can contain one or more unit dosage forms containing the active ingredient.
  • the package may for example comprise a metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be provided with instructions for administration.
  • the packaging or dispensing device may also carry precautions associated with the container, the precautions being prescribed by a government agency that manages the manufacture, use or sale of the drug, the precaution reflecting that the drug form has been Approved for human or veterinary administration. Such considerations, for example, may be labels for prescription drugs approved by the State Food and Drug Administration or the US Food and Drug Administration, or approved product specifications.
  • Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in a compatible pharmaceutical carrier may also be prepared in a suitable container and labeled for use. Treatment for a given disease state.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X-ray powder diffraction (XRPD) pattern Among them, they have characteristic peaks at diffraction angles 2 ⁇ of about 5.3°, 9.2°, 16.1°, 17.7°, 20.6°, 26.2°, and 26.7°.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X-ray powder diffraction (XRPD) pattern Among them, there are characteristic peaks at diffraction angles 2 ⁇ of 5.3 ⁇ 0.2°, 9.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 26.2 ⁇ 0.2°, and 26.7 ⁇ 0.2°.
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity.
  • XRPD powder diffraction
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, X-ray powder diffraction (XRPD) pattern Among them, the diffraction angle 2 ⁇ , the d interval, and the relative intensity of the diffraction peak are about:
  • XRPD powder diffraction
  • the present disclosure relates to a compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-B having PDE4 enzyme inhibitory activity Form I of 4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, which has essentially the appearance shown in Figure 1.
  • XRPD X-ray powder diffraction
  • the present disclosure relates to a method of reducing PDE4 enzymatic activity comprising administering to an individual in need thereof an effective amount of a compound (S)-N-[5-[1-(3-ethoxy-4-methyl) Oxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide
  • Form I or comprises the compound (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-
  • CDI 1,1'-carbonyldiimidazole
  • 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 tetrabutyl Ammonium fluoride
  • EDC ⁇ HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Fmoc 9-fluorenylmethoxycarbonyl
  • MOM methoxymethyl
  • MEM Methoxyethoxymethyl
  • MTM methylthiomethyl
  • SEM 2-(trimethylsilyl)ethoxymethyl
  • Method 1 Add 0.1 g of (S)-1-amino-5-(1-(3-ethoxy-4-methoxybenzene) to a 50 ml round bottom flask equipped with an electromagnetic stirring, reflux condenser and drying tube. 2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione and 0.005 g of DMAP, 10 ml of acetic anhydride, heated to 60 ° C and stirred for 6 hours. The solvent was evaporated to dryness.
  • Method 2 Add 0.1 g of (S)-1-amino-5-(1-(3-ethoxy-4-methoxybenzene) to a 50 ml round bottom flask equipped with an electromagnetic stirring, reflux condenser and drying tube. 2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione and 5 ml of pyridine, 0.2 ml of acetyl chloride was added dropwise in an ice bath, and stirred at room temperature for 1 hour. .
  • the differential scanning calorimetry (DSC) test parameters were as follows: The heat absorption and release information of the sample during the heating process was obtained using a Japanese Seiko, SII 6220 Differential Scanning Calorimeter (DSC). The heating rate was 10 ° C / min, nitrogen protection.
  • Form I has an endothermic melting peak at 136.0 ⁇ 6 ° C (peak melting point) during the temperature increase.
  • thermogravimetric analysis (TGA) test parameters are as follows: Using the Japanese Seiko, SII 6200 Thermogravimetric Tester (TG) to obtain the weight loss information of the sample during the heating process. The heating rate was 10 ° C / min, nitrogen protection.
  • Form I was heated to a melt weight loss of 1.0%. No absorption and exothermic peaks appeared before melting, indicating that 1.0% of the weight loss is adsorbed water or solvent. Form I is neither a hydrate nor a solvate.
  • the infrared test parameters are as follows: The test instrument is PerkinElmer, Spectrum 65.
  • the dissolution profile is shown in Figure 5.
  • Form I has good chemical stability under high temperature and high temperature and high humidity conditions.

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Abstract

公开了化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。

Description

噻吩衍生物的晶型
相关申请的引用
本公开要求2018年5月2日向中华人民共和国国家知识产权局提交的申请号为201810407741.X、发明名称为“(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺多晶型物及其制备及应用”的发明专利申请的全部权益，并通过引用的方法将上述发明专利申请的全部内容并入本公开。
领域
本公开大体上涉及有机化学与药物化学领域。
背景
PDE4酶抑制剂在临床表现出对数种炎症性疾病有效，包括哮喘、慢性阻塞性肺病(COPD)、过敏性鼻炎和过敏性皮炎等。在动物模型上对其他包括关节炎和败血症等在内的多种疾病也有效。
概述
一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
另一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
再一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面 间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000001
又一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000002
另一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图 谱。
再一方面，本公开涉及基本上不含溶剂的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
又一方面，本公开涉及基本上不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
另一方面，本公开涉及基本上纯的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
再一方面，本公开涉及不含溶剂且不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
又一方面，本公开涉及药物组合物，其包含化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I以及药物可接受的载体、稀释剂或赋形剂，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
另一方面，本公开涉及制备化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙 酰胺在乙腈中结晶，从而得到所述晶型I，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
再一方面，本公开涉及制备化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺在二氯甲烷与正己烷的混合物中结晶，从而得到所述晶型I，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
又一方面，本公开涉及制备化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：
将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；以及
热过滤并降温，等温加入蒸馏水和(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I晶种，从而得到所述晶型I；
其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
另一方面，本公开涉及治疗或预防与PDE4酶相关的，优选PDE4酶介导的疾病或疾病状态的方法，其包括向需要所述方法的个体给予治疗有效量的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I或包含化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的治疗有效量的药物组合物，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
再一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
又一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
另一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000003
再一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000004
Figure PCTCN2019085327-appb-000005
又一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
另一方面，本公开涉及降低PDE4酶活性的方法，其包括向需要所述方法的个体给予有效量的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I或包含化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的有效量的药物组合物，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
附图简要说明
图1示出了本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的X射线粉末衍射(XRPD)图谱。
图2示出了本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的差示扫描量热法(DSC)曲线。
图3示出了本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的热重分析法(TGA)曲线。
图4示出了本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的红外图谱(IR)。
图5示出了本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶体I的溶出曲线。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其他方法、部件、材料等的情况下可实现实施方案。
除非本公开中另外要求，在整个说明书和其后的权利要求书中，词语“包括”和“包含”应解释为开放式的、含括式的意义，即“包括但不限于”。
在本公开和所附权利要求书中使用时，除非上下文另有明确规定，否则不带数量指示的单数指称物包括复数指称物。
在整个本说明书中提及的“一实施方案”或“另一实施方案”或“实施方案”或“某些实施方案”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“一实施方案”或“实施方案”或“另一实施方案”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本公开的说明书和所附的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包含“药物可接受的载体、稀释剂或赋形剂”的药物组合物包括一种药物可接受的载体、稀释剂或赋 形剂，或两种或多种药物可接受的载体、稀释剂或赋形剂。
定义
因此，除非另有相反的说明，否则说明书及所附权利要求中所用的下列术语具有以下的意思：
在本公开中，术语“本公开的化合物”系指(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺，其具有如下所示的结构：
Figure PCTCN2019085327-appb-000006
在本公开中，术语“约”的使用包括和描述了数值或参数本身。例如，“约x”包括和描述了“x”本身。在某些实施方案中，结合测量使用或用于修饰数值、单位、常数或数值范围时，术语“约”是指+/-5％的变化。
在本公开中，涉及X射线粉末衍射(XRPD)图谱、差示扫描量热法(DSC)曲线、热重分析法(TGA)曲线、红外图谱(IR)时，术语“基本上如……中所示的”表示不必定与本公开中描绘的那些相同的图谱和曲线，但由本领域普通技术人员考虑时，落入实验误差或偏差的限制内。
在本公开中，当提及X射线粉末衍射(XRPD)峰位置时，本公开所用的术语“基本上相同的”意指考虑典型峰位置及强度可变性。举例而言，本领域的技术人员理解，峰位置(2θ)会显示一定的可变性，通常，多达0.1至0.2度，视所用溶剂以及用于量测衍射的装置而定。进而言之，本领域的技术人员理解，相对峰强度会显示仪器间的变异性以及由结晶度、优选定向、所制备的试样表面及本领域的技术人员已知的其它因素造成的变异性，且仅应视为定性测量。
在本公开中，术语“2θ数值”或“2θ”系指基于X射线粉末衍射(XRPD)实验的实验设置的以度计的峰位置且是衍射图谱的常见横坐 标单位。所述试验设置要求如果在入射光束与某一晶面形成角θ(θ)时反射被衍射，则以角2θ(2θ)记录反射的光束。应当理解，本公开所提及具体晶型的具体2θ数值意欲指使用本公开所述的X射线粉末衍射(XRPD)实验条件测量的2θ数值(以度计)。举例而言，如本公开所述，使用
Figure PCTCN2019085327-appb-000007
作为辐射源。
在本公开中，为了晶面间距(d-spacing)的目的，术语“约”系指
Figure PCTCN2019085327-appb-000008
在本公开中，术语“基本上纯”系指化学纯度和晶型纯度。
在本公开中，术语“基本上不含”系指含有不大于约20％重量比。例如，基本上不含溶剂系指含有不大于约20％重量比的溶剂。基本上不含水系指含有不大于20％重量比的水。
在本公开中，术语“哺乳动物”是指包括例如狗、猫、牛、羊、马和人类等的动物。在某些实施方案中，哺乳动物包括人类。
在本公开中，术语“患者”系指动物(例如，人)、伴侣动物(例如，狗、猫或马)和家畜(例如，牛、猪和羊)。在某些实施方案中，患者是包括雄性和雌性的哺乳动物。在某些实施方案中，患者为人类。
在本公开中，术语“药物可接受的”系指必须与制剂的其它成分相容并且不会对其接受者有害的载体、载剂、稀释剂、赋形剂和/或盐。
在本公开中，术语“药物可接受的载体、稀释剂或赋形剂”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
在本公开中，术语“载体”定义为有利于将化合物的晶型引入细胞或组织的化合物。例如二甲亚砜(DMSO)通常用作载体，这是因为它易于将某些有机化合物引入生物体的细胞或组织中。
在本公开中，术语“药物组合物”系指本公开中所述的化合物的晶型I与通常被本领域所接受的将生物活化化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、 稀释剂或赋形剂。
在本公开中，术语“治疗有效量”指改善、减弱或消除特定疾病或病况和特定疾病或病况的症状、或者避免或延迟特定疾病或病况或者特定疾病或病况的症状的发病的化合物的晶型I或化合物的晶型I组合的量。根据化合物的晶型I、疾病状态及其严重性、以及待治疗哺乳动物的年龄、体重等，构成“治疗有效量”的本公开中所述的化合物的晶型I的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本公开中所述的化合物的晶型I的量。
本公开所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物例如人类中治疗相关的疾病或疾病状态，并且包括：
(i)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(ii)抑制疾病或疾病状态，即阻止其发生；或者
(iii)缓解疾病或疾病状态，即使疾病或疾病状态消退或不进展。
正如本公开所用的那样，术语“疾病”和“疾病状态”可以相互交换使用，或者可以是不同的，因为特殊的疾病或疾病状态可能并没有已知的致病因子(因此不能用病因学解释)，因此其不被公认为是疾病，而是被认为是不期望的疾病状态或病症，其中临床医生已经鉴定出或多或少的特定系列的症状。
在本公开中，术语“生理可接受的”系指不消除化合物的生物活性和性质的载体或稀释剂。
具体实施方式
一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图 谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
另一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
在某些实施方案中，化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
再一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000009
在某些实施方案中，化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000010
Figure PCTCN2019085327-appb-000011
又一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000012
在某些实施方案中，化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000013
Figure PCTCN2019085327-appb-000014
另一方面，本公开涉及化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少一个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少两个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1- 基]乙酰胺的晶型I具有呈现至少三个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少四个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少五个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少六个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少七个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少八个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少九个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少十个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有呈现至少十一个基本上如图1中所示的X射线粉末衍射(XRPD)图谱的特征峰的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在约136.0℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在约136.0℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在136.0±6℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在136.0±4℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在136.0±2℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在136.0±6℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲 氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在136.0±4℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I在136.0±2℃处具有吸热峰。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有基本上如图2所示的DSC曲线。
在某些实施方案中，在使用差示扫描量热法(DSC)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有基本上如图2所示的DSC曲线。
在某些实施方案中，在使用热重分析法(TGA)进行热分析时，以本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有基本上如图3所示的TGA曲线。
在某些实施方案中，在使用热重分析法(TGA)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有基本上如图3所示的TGA曲线。
在某些实施方案中，在红外图谱(IR)中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的吸收峰位置和强度约为：
吸收峰位置(cm -1) 吸收峰强度(％)
3441.18 65.98
3299.26 65.59
3115.56 74.71
吸收峰位置(cm -1) 吸收峰强度(％)
2978.81 70.47
2930.33 68.72
1758.76 43.82
1701.59 20.94
1589.94 42.15
1557.4 50.03
1517.27 44.9
1443.5 64.61
1429.22 65.06
1393.78 56.23
1372.26 53.19
1334.48 43.59
1298.5 30.29
1264.01 41.49
1235.94 40.5
1137.06 38.92
1088.54 47.63
1028.06 60.83
966.48 70.09
944.46 75.31
881.39 73.77
811.65 78.09
769.81 72.57
735.31 61.87
695.56 76.79
641.58 74.76
602.59 74.88
581.06 76.5
531.75 68.96
吸收峰位置(cm -1) 吸收峰强度(％)
487.88 71.37
454.52 74.62
在某些实施方案中，在红外光谱(IR)中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有基本上如图4所示的红外图谱(IR)。
在某些实施方案中，与其它固态形式的比较，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I具有以下至少一种有利性质：化学纯度，流动性，溶解度、溶解速率，形态或晶癖，稳定性例如高温稳定性、加速稳定性、光照稳定性、研磨稳定性、压力稳定性、乙醇溶液平衡稳定性、水溶液平衡稳定性，低残留溶剂含量，较低的吸湿性，流动性以及有利的加工和处理特性例如压缩性和堆积密度。
另一方面，本公开涉及基本上不含溶剂的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，基本上不含溶剂的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约20％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、 26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约20％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约10％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约10％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约5％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约5％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约3％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、 26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约3％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约1％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约1％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.5％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.5％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.2％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、 26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.2％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.1％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.1％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.01％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.01％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.001％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、 20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.001％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.0001％重量比的溶剂，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.0001％重量比的溶剂，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，不含溶剂的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，不含溶剂的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
再一方面，本公开涉及基本上不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有 特征峰。
在某些实施方案中，基本上不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约20％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约20％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约10％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约10％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约5％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、 26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约5％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约3％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约3％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约1％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.7°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约1％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.7°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.5％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、 26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.5％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.2％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.2％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.1％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.1％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.01％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、 26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.01％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.001％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.001％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.0001％重量比的水，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有不大于约0.0001％重量比的水，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，在使用热重分析法(TGA)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I加热至熔融失重不大于5.0％，熔化前并未出现任何吸/放热峰，说明不大于5.0％的失重为吸附水或溶剂。
在某些实施方案中，在使用热重分析法(TGA)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I加热至熔融失重不大于3.0％，熔化前并未出现任何吸/放热峰，说明不大于3.0％的失重为吸附水或溶剂。
在某些实施方案中，在使用热重分析法(TGA)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I加热至熔融失重不大于2.0％，熔化前并未出现任何吸/放热峰，说明不大于2.0％的失重为吸附水或溶剂。
在某些实施方案中，在使用热重分析法(TGA)进行热分析时，以10℃/分钟的加热速率，本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I加热至熔融失重不大于1.0％，熔化前并未出现任何吸/放热峰，说明不大于1.0％的失重为吸附水或溶剂。
另一方面，本公开涉及基本上纯的本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，基本上纯的本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，基本上纯的本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I包含至少约95％重量比、优选至少约98％重量比、更优选至少约99％重量比的晶型I和小于约5％重量比、优选小于约2％重量比、更优选小于约1％重量比的具有与本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺不同的化学结构的其他化合物。
在某些实施方案中，基本上纯的本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I包括至少约95％重量比、优选至少约98％重量比、更优选至少约99％重量比的晶型I和小于约5％重量比、优选小于约2％重量比、更优选小于约1％重量比的本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的任何其他晶型。这意味着本公开的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I含有小于约5％重量比的其他化合物和小于约5％重量比的任何其他形式(也称作“相均匀性”)。
再一方面，本公开涉及不含溶剂且不含水的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，不含溶剂且不含水的化合物(S)-N-[5-[1-(3-乙 氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
又一方面，本公开涉及药物组合物，其包含化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I以及药物可接受的载体、稀释剂或赋形剂，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，本公开的药物组合物被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、凝胶剂、胶囊剂、气雾剂或栓剂。
药物组合物
在某些实施方案中，药物组合物包含本公开的化合物的晶型I，以及药物可接受的载体、稀释剂或赋形剂。
在某些实施方案中，本公开的化合物的晶型I用于治疗或预防与PDE4酶相关的，优选PDE4酶介导的疾病给予哺乳动物时的给药途径可以为肠胃途径或非肠胃途径。
在某些实施方案中，本公开的化合物的晶型I用于治疗或预防与PDE4酶相关的，优选PDE4酶介导的疾病给予哺乳动物时的给药途径可以为口服途径。
在某些实施方案中，本公开的化合物的晶型I用于治疗或预防与PDE4酶相关的，优选PDE4酶介导的疾病给予哺乳动物时的给药途径可以为经皮途径。
可以以任何合适的形式如片剂、胶囊剂、粉剂、口服溶液、悬浮液、贴剂、膏剂、凝胶剂、或气雾剂等获得本公开中所述的化合物。所述的片剂的示例性实例包括但不限于素片、糖衣片和薄膜衣片。
能够用于本公开的药物组合物中的药物可接受的载体的实例包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的 任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗透压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。用于治疗用途的可接受载体或稀释剂在药物领域是公知的，并且例如在Remington’s Pharmaceutical Sciences(雷明顿制药学),18th Ed.,Mack Publishing Co.,Easton,PA(1990))中有描述，本文将其全部内容引入作为参考。
本公开中的药物组合物可以通过任何实现其预期目的的方法被施用。例如，施用可以通过口服、胃肠外、局部、肠内、静脉内、肌内、吸入、鼻、关节内、脊柱内、经气管、经眼、皮下、腹膜内、经皮或口含等途径进行。给药途径可以为非肠胃途径、口服途径以及直肠内途径。所施用的剂量将取决于接受者的年龄、健康状况和体重，如果有并行治疗，还取决于并行治疗的种类、治疗的频率，以及所需效果的性质。
合适的剂型包括但不限于胶囊剂、片剂、小丸、糖锭剂(dragee)、半固体制剂、散剂、颗粒剂、栓剂、软膏剂、乳膏剂、洗剂、吸入剂、注射剂、泥罨剂、凝胶剂、带剂(tape)、滴眼剂、溶液剂、糖浆剂、气雾剂、混悬剂、乳剂，其可以根据本领域已知的方法制备。
特别适合口服施用的是普通片剂(素片)、糖衣片、薄膜衣片、丸剂、胶囊剂、散剂、颗粒剂、糖浆剂、汁液(juice)或滴剂，适合直肠施用的是栓剂，适合胃肠外施用的是溶液剂，也可以是基于油的溶液或水溶液，此外还有混悬剂、乳剂或植入剂，适合局部使用的是软膏剂、乳膏剂或散剂。本公开中的产品也可以被冻干，生成的冻干物用于例如制备注射剂。所给出的制剂可以被灭菌和/或包含辅助剂(assistant)，如润湿剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于改变渗透压的盐、缓冲物质、染料、矫味剂和/或众多另外的活性成分，例如一种或多种维生素。
在某些实施方案中，本公开中的药物组合物被制备成胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
在药物组合物中可以提供防腐剂、稳定剂、染料、甜味剂、芳香剂、香料等。例如，可加入作为防腐剂的苯甲酸钠、抗坏血酸以及对羟基苯甲酸的酯。另外，可以使用抗氧化剂和混悬剂。
在不同的实施方案中，醇、酯、硫酸化脂族醇等可用作表面活性剂；蔗糖、葡萄糖、乳糖、淀粉、结晶纤维素、甘露醇、轻质无水硅酸盐、铝酸镁、铝酸甲基硅酸镁、合成硅酸铝、碳酸钙、碳酸氢钙、磷酸氢钙、羟甲基纤维素钙等可用作赋形剂；硬脂酸镁、滑石、硬化油等可用作光滑剂；椰子油、橄榄油、麻油、花生油、大豆可用作混悬剂或润滑剂；作为诸如纤维素或糖等糖类的衍生物的醋酞纤维素、或作为聚乙烯的衍生物的乙酸甲酯-异丁烯酸酯共聚物可用作混悬剂；以及诸如酞酸酯等的增塑剂可用作混悬剂。
合适的给药途径可以例如包括口服给药、直肠给药、透膜给药、肠胃外输送、经皮给药、局部给药或肠内给药；肠胃外输送包括肌内注射、皮下注射、静脉注射、髓内注射以及鞘内注射、直接心室内注射、腹膜内注射、鼻内注射或眼内注射。化合物也能够在包括储库型注射(depot injections)、渗透泵、丸剂、透皮(包括电迁移)贴片等在内的缓释或控释的剂型中以预先确定的速率进行延长和/或定时、脉冲给药。
本公开中的药物组合物可按已知的方法进行生产，例如，通过常规的混合、溶解、粒化、制造锭剂、研磨、乳化、包囊、截留或压片等操作方法进行生产。
因此根据本公开，所使用的药物组合物可使用一种或多种包含赋形剂和辅助剂的生理可接受的载体以常规方法配制，该赋形剂和辅助剂有利于将活性化合物处理成为药学可用的制剂。合适的制剂取决于所选的给药途径。可以如本领域中适合的并理解的那样使用任何公知的技术、载体和赋形剂。
能够将注射剂制备成下列常规形式：作为溶液或混悬液，在注射前适合制成溶液或混悬液的固体剂型，或作为乳剂。合适的赋形剂是，例如水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、盐酸半胱氨酸等。另外，如果需要，注射剂药物组合物可以含有少量 无毒的辅助物，例如湿润剂、pH缓冲剂等。生理适合的缓冲剂包括但不限于Hank溶液、Ringer溶液或生理盐水缓冲液。如果需要，可使用吸收增强制剂(例如脂质体)。
对于口服给药，通过组合所述活性化合物与本领域公知的药物可接受的载体，能够容易地组方所述化合物。为了使待治疗患者口服摄取，这样的载体能使本发明化合物被配制为片剂、丸剂、锭剂、胶囊、液体、凝胶、糖浆、膏剂、混悬液、溶液、粉剂等。能够通过下述方法获得用于口服的药物制剂：将活性化合物与固体赋形剂混合，任意研磨所得混合物并且将加工颗粒混合物，如果需要，在加入合适的辅助剂后进行加工以获得片剂或锭剂核。合适的赋形剂特别是诸如糖等的填充剂，包括乳糖、蔗糖、甘露醇或山梨醇；纤维素制剂，例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯酮(PVP)。如果需要可加入崩解剂，例如交联的聚乙烯吡咯烷酮、琼脂或海藻酸或诸如海藻酸钠的海藻酸盐。对锭剂核进行合适的包被。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶(carbopol gel)、聚乙二醇和/或二氧化钛、紫胶漆溶液以及合适的有机溶剂或溶剂混合物。为了识别或表征活性化合物剂量的不同组合，可向片剂或锭剂包衣中加入染料或色素。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、紫胶漆溶液、以及合适的有机溶剂或溶剂混合物。
能够用于口服的药物制剂包括明胶制成的推入配合胶囊，以及诸如甘油或山梨醇的明胶和增塑剂制成的软的、密封的胶囊。推入配合胶囊能够包含与诸如乳糖的填充剂、诸如淀粉的粘合剂和/或诸如滑石或硬脂酸镁的润滑剂以及任选的稳定剂混合的活性成分。在软胶囊中，活性成分可溶解或悬浮在合适的液体中，例如脂肪油、液状石蜡或液状聚乙二醇。另外，可加入稳定剂。所有口服给药的制剂应该达到适于这种给药的剂量。
在某些实施方案中，本公开的药物组合物可以包含0.1％-95％的本 公开的化合物的晶型I。
在某些实施方案中，本公开的药物组合物可以包含1％-70％的本公开的化合物的晶型I。
在任何情况下，待施用的组合物或制剂将含有一定量的本公开的化合物的晶型I，其量可有效治疗受治疗的受试对象疾病/病况。
另一方面，本公开涉及制备化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺在乙腈中结晶，从而得到所述晶型I，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.7°、26.2°、26.7°处具有特征峰。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；热过滤并将滤液降温，析出(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；热过滤并将滤液降温至-10℃至-30℃，析出(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；以及过滤并将滤液降温至-20℃，析出(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；过滤并将滤液降温至-20℃，析出晶体；以及将晶 体加入异丙醇中，过滤并真空干燥，得到(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中，加热至回流温度，搅拌全溶；热过滤后，滤液快速降温至-20℃，搅拌，析出晶体；加入异丙醇搅拌，过滤；以及真空干燥得到(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
再一方面，本公开涉及制备化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺在二氯甲烷与正己烷的混合物中结晶，从而得到所述晶型I，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.7°、26.2°、26.7°处具有特征峰。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于二氯甲烷与正己烷的混合物中至完全溶解；以及热过滤并降温，析出(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于二氯甲烷与正己烷的混合物中至完全溶解；以及热过滤并降温至35-45℃，析出(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于二氯甲烷与正己烷的混合物中至完全溶解；以及热过滤并降温至40℃，析出(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6- 二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于二氯甲烷与正己烷的混合物中至完全溶解；热过滤并降温至35-45℃，析出晶体；继续降温至0-10℃；以及过滤并真空干燥得到(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于二氯甲烷与正己烷的混合物中，加热至45℃，搅拌全溶；热过滤后，滤液降温至40℃，等温搅拌，析晶；继续降温至5℃，等温搅拌；以及过滤并真空干燥得到(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
又一方面，本公开涉及制备化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：
将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；以及
热过滤并降温，等温加入蒸馏水和(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I晶种，从而得到所述晶型I；
其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.7°、26.2°、26.7°处具有特征峰。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；热过滤并降温，等温加入蒸馏水和(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I晶种；以及搅拌降温至0℃，过滤并 真空干燥，从而得到所述晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；热过滤并降温至25-40℃，等温加入蒸馏水和(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I晶种；以及搅拌降温至0℃，过滤并真空干燥，从而得到所述晶型I。
在某些实施方案中，将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中，升温至45℃，搅拌全溶；热过滤后，滤液降温至32℃，加入蒸馏水，等温搅拌，并加入(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I晶种；在32℃下等温搅拌，降温至0℃等温搅拌，以及过滤并真空干燥得到(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
另一方面，本公开涉及治疗或预防与PDE4酶相关的，优选PDE4酶介导的疾病或疾病状态的方法，其包括向需要所述方法的个体给予治疗有效量的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I或包含化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的治疗有效量的药物组合物，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，所述个体为哺乳动物。
在某些实施方案中，所述个体为人类。
在某些实施方案中，能够用于本公开的疾病或疾病状态的示例性实例包括但不限于炎症性疾病或疾病状态、感染性疾病或疾病状态、免疫类疾病或疾病状态以及癌症类疾病或疾病状态。
在某些实施方案中，能够用于本公开的疾病或疾病状态的示例性 实例包括但不限于头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、结肠癌、乙状结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、色素瘤、恶性神经胶质瘤、HIV、肝炎、成人呼吸窘迫综合症、骨吸收病、慢性阻塞性肺病、慢性肺炎、皮炎、炎性皮肤病、特异性皮炎、囊性纤维变性、败血症性休克、脓毒症、内毒素性休克、血液动力性休克、脓毒病综合症、局部缺血后再灌注损伤、脑膜炎、银屑病、纤维变性疾病、恶病质、移植物抗宿主疾病的移植排斥、自身免疫病、类风湿性脊椎炎、关节炎病症(如类风湿性关节炎或骨关节炎)、骨质疏松症、节段性回肠炎、溃疡性结肠炎、肠炎、多发性硬化病、系统性红斑狼疮、麻风病中的麻风性结节性红斑(ENL)、辐射损伤、哮喘、富氧性肺损伤、微生物感染和微生物感染综合症。
在某些实施方案中，治疗或预防与PED4酶相关的，优选PED4酶介导的疾病的方法，包括对需要所述方法的个体给予1mg-10g的本公开的化合物的晶型I。
在某些实施方案中，治疗或预防与PED4酶相关的，优选PED4酶介导的疾病的方法，包括对需要所述方法的个体给予10mg-3000mg的本公开的化合物的晶型I。
在某些实施方案中，治疗或预防与PED4酶相关的，优选PED4酶介导的疾病的方法，包括对需要所述方法的个体给予1mg-200mg的本公开的晶型I。
在某些实施方案中，治疗或预防与PED4酶相关的，优选PED4酶介导的疾病的方法，包括对需要所述方法的个体给予1mg、5mg、10mg、30mg、40mg、50mg、60mg、70mg、90mg、100mg、120mg、150mg、或200mg的本公开的化合物的晶型I。
给药方法
可将本公开的至少一种化合物的晶型I或包含至少一种本公开的化合物的晶型I的药物组合物以任何适宜系统的和/或局部的输送本公 开的化合物的晶型I的任何方法进行的方法对患者进行给药。给药方法的非限制性实例包括(a)通过口服途径给药，该给药包括以胶囊、片剂、颗粒剂、喷雾剂、糖浆剂或其它这类形式进行给药；(b)通过非口服途径给药，例如直肠、阴道、尿道内、眼内、鼻内或耳内，所述给药包括以水性悬浮液、油性制剂等或以滴剂、喷雾剂、栓剂、药膏、软膏等方式进行给药；(c)经皮下注射、腹膜内注射、静脉内注射、肌内注射、皮内注射、眶内注射、囊内注射、脊柱内注射、胸骨内注射等进行给药，包括输液泵输送；(d)诸如直接在肾脏区域或心脏区域中进行注射的局部(locally)给药，例如通过储库型植入；以及(e)局部(topically)给药；如本领域中技术人员所认为的适当的给药方式是本公开中所述的化合物的晶型I与活组织接触。例如经皮给药，该给药包括以软膏剂、乳膏剂、凝胶剂、气雾剂、混悬剂、乳剂或其它这类形式进行给药。
最适合途径取决于被治疗疾病状态的性质与严重性。本领域技术人员也熟悉确定给药方法(口腔、静脉内、吸入、皮下、直肠等)、剂型、适当医药赋形剂及与将化合物的晶型传递至有需要的对象有关的其它事项。
适于给药的药物组合物包括其中含有有效量的活性成分以达到其预期效果的组合物。本公开中所述的药物组合物的治疗有效量所需的剂量取决于给药途径、包括人在内的被治疗动物的类型以及所考虑的特定动物的身体特征。可以调整剂量以达到期望的效果，但是这将取决于下列因素：体重、饮食、同时的药物治疗以及其它医学领域的技术人员公认的其它因素。更具体地，治疗有效量指有效阻止、减轻或改善疾病症状，或延长接受治疗个体寿命的化合物的晶型的量。本领域技术人员的实际能力可很好地确定治疗有效量，特别是按照本公开所提供的详细公开。
正如本领域技术人员所显而易见的，用于体内给药的剂量和具体的给药方式的变化将取决于年龄、体重和所治疗的哺乳动物的种类、所使用的具体化合物的晶型以及所使用的这些化合物的晶型的具体用途。本领域技术人员使用常规的药理学方法可达到确定有效剂量水平 的目的，即达到确定预期效果所必需的剂量水平的目的。通常，以较低剂量水平开始进行产物的人体临床应用，随着剂量水平的增加直至达到所期望的效果。或者，采用已确立的药理学方法，能够使用可接受的体外研究来建立本方法鉴定的组合物的有效剂量和给药途径。
在非人动物研究中，潜在产物的应用以较高剂量水平开始，随着剂量的减少直至不再实现所期望的效果或者不良副作用消失。取决于预期效果和治疗适应症，剂量范围可较宽泛。通常，剂量可为约10μg/kg体重至1000mg/kg体重，在某些实施方案中为约100μg/kg体重至300mg/kg体重。或者，正如本领域技术人员所理解的，剂量可基于患者的体表面积并且按照其计算。
各医师能够根据患者的状况来选择本公开中所述的药物组合物的确切制剂、给药途径和剂量。通常，向患者给药的组合物的剂量范围可以为约0.5mg/kg至1000mg/kg患者体重。根据患者需要，剂量可在一天或数天期间单独一次给予或两次或多次给予。在化合物的晶型的人用剂量因至少某些条件已确立的情况下，本公开将使用那些相同的剂量，或剂量范围为约0.1％至500％的确定的人用剂量，在某些实施方案中剂量范围为25％至250％已确定的人用剂量。在没有确定的人用剂量的情况下，如新发现的药物化合物的情况，适宜的人用剂量能够从半数有效量或感染剂量中位数数值，或来自体外或体内研究的其它合适的值进行推断，正如在动物中的毒性研究和效能研究所定量化的。
应当指出，由于毒性和器官功能障碍，主治医师将知道如何且何时终止、中断或调整给药。相反，如果临床反应不充分(排除毒性)，则主治医生也将知道将治疗调整至较高水平。在所关注病症的治疗中给药剂量的大小将随着待治疗疾病状态的严重性和给药途径的变化而变化。例如部分通过标准的预后评价方法可评价所述疾病状态的严重性。此外，所述剂量和可能的剂量频率也将根据个体患者的年龄、体重、以及反应的变化而变化。与上述讨论方案相当的方案可用于兽医学中。
虽然可基于逐一的药物分析(drug-by-drug)可决定确切的剂量，但 是在大多数情况下，能够就药剂进行某些概括。成人患者的日给药方案为，例如口服剂量为0.1mg至2000mg各活性成分，在某些实施方案中为1mg至2000mg各活性成分，例如5mg至1500mg各活性成分。在其它实施方案中，所使用的各活性成分的静脉内、皮下或肌内剂量为0.01mg至1000mg，在某些实施方案中为0.1mg至1000mg，例如1mg至800mg。在给予药物可接受盐的情况下，可按照游离碱来计算剂量。在某些实施方案中，每日1至4次将所述组合物进行给药。或者，本公开中所述的组合物可通过连续的静脉输注进行给药，在某些实施方案中以每日高达2000mg的各活性成分的剂量进行给药。正如本领域技术人员所理解的，在某些情形中，为了有效且迅速地治疗迅速发展的疾病或感染，以超过或远远超过上述剂量范围的量给予本公开中所述的化合物是必要的。在某些实施方案中，将所述化合物在连续治疗期间进行给药，例如一周或数周、或数月或数年。
可以个别地调整剂量和用药间隔以提供足以维持调整效果或最低有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC不同，但是能够从体外数据评估MEC。达到MEC的所需剂量取决于个体特征和给药途径。然而，能够使用HPLC(高效液相色谱)测定或生物测定来确定血浆浓度。
使用MEC值还能够测定用药间隔。应使用在10-90％的时间内、在某些实施方案中在30-90％的时间内、以及在某些实施方案中在50-90％的时间内将血浆水平维持在MEC以上的治疗方案对组合物进行给药。
在局部给药或选择性吸收的情况下，药物的有效局部浓度与血浆浓度无关。
当然，被给药的组合物的量取决于待治疗的个体，取决于所述个体的体重、痛苦的严重性、给药方式以及开处方医师的判断。
使用已知的方法能够对本公开中所述的化合物的效能和毒性进行评估。例如，通过在体外测定细胞系的毒性可建立特定化合物或共享某些化学部分的该化合物子集的毒理学，所述细胞系例如哺乳动物细胞系并且在某些实施方案中为人的细胞系。这类研究的结果通常可预 测诸如哺乳动物等的动物体内的毒性，或更具体地，可预测人体内的毒性。或者，使用已知方法可测定特定化合物在诸如小鼠、大鼠、家兔或猴等动物模型中的毒性。使用若干公认的方法，例如体外方法、动物模型或人体临床试验，可确定特定化合物的效能。几乎对每类疾病状态都存在着公认的体外模型，该疾病状态包括但不限于癌症、心血管疾病和多种免疫机能障碍。类似地，可接受的动物模型可用于确定治疗这些疾病状态的化学药物的效能。当选择模型测定效能时，技术人员能够在本领域现有技术的指导下选择合适的模型、剂量和给药途径以及治疗方案。当然，人体临床试验还能够用于测定化合物在人体内的效能。
如果需要，可将所述组合物置于包装或分配装置中，该包装或分配装置可以包含一种或多种含有活性成分的单位剂型。所述包装可以例如包括金属或塑料箔，例如泡罩包装。所述包装或分配装置可带有给药说明书。所述包装或分配装置还可以带有与所述容器相关的注意事项，该注意事项是由管理药物生产、使用或销售的政府机构规定的，该注意事项反映了所述药物形式已经由该机构批准用于人类或兽类给药。这类注意事项，例如，可以是由国家食品药品监督管理总局或美国食品和药物管理局批准的用于处方药的标签，或者是批准的产品说明书。还可以在合适的容器中制备、放置在相容的药物载体中组方的包含本公开的化合物、其立体异构体或其药物可接受的盐在内的组合物，并对其标记以用于指定的疾病状态的治疗。
再一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
在某些实施方案中，具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、 16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
又一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
在某些实施方案中，具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
另一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、d间隔、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000015
在某些实施方案中，具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其衍射角2θ、d间隔、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000016
再一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、d间隔、衍射峰相对强度约为：
Figure PCTCN2019085327-appb-000017
在某些实施方案中，具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱中，其衍射角2θ、d间隔、衍射峰相 对强度约为：
Figure PCTCN2019085327-appb-000018
又一方面，本公开涉及具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
在某些实施方案中，具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的采用CuKα辐射条件下的X射线粉末衍射(XRPD)图谱。
另一方面，本公开涉及降低PDE4酶活性的方法，其包括向需要所述方法的个体给予有效量的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I或包含化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的有效量的药物组合物，其中所述晶型I在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
下文中，本公开将通过如下实施例进行详细解释以便更好地理解本申请的各个方面及其优点。然而，应当理解，以下的实施例是非限制性的而且仅用于说明本申请的某些实施方案。
实施例
制备实施例
(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的制备
缩写语
CDI：1,1’-羰基二咪唑；DCM：二氯甲烷；THF：四氢呋喃；TFA：三氟乙酸；DMAP：4-(N,N-二甲基胺基)吡啶；TEA：三乙胺；DMF：N,N-二甲基甲酰胺；DMSO：二甲基亚砜；HOBt：1-羟基苯并三氮唑；DCC：N,N-二环己基碳二亚胺；TBFA：四丁基氟化铵；EDC·HCl：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；Fmoc：9-芴甲氧羰基；MOM：甲氧甲基；MEM：甲氧基乙氧基甲基；MTM：甲硫基甲基；SEM：2-(三甲基硅基)乙氧基甲基；TMSE：2-(三甲基硅基)乙基；DIC：N,N’-二异丙基碳化二亚胺；HOAt：1-羟基-7-偶氮苯并三氮唑；BOP：卡特缩合剂(苯并三唑-1-基-氧-三-(二甲氨基)鏻六氟磷酸盐)；Cl-HOBt：6-氯-1-羟基苯并三氮唑；DEPBT：3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮；HATU：双(二甲基氨基)甲叉-三唑[4,5-B]吡啶-3-氧化物六氟磷酸盐；HBTU：苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸酯；HCTU：6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯；HOOBt：3-羟基-1,2,3-苯并三嗪-4(3H)-酮；PyBOP：六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷；TATU：O-(7-偶氮苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸酯；TBTU：O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸酯；OMS：甲磺酸酯基；OTS：对甲苯磺酸酯基。
化合物1
4-甲氧基-3-乙氧基苯甲醛
在装有机械搅拌和惰性气体导管的500ml三口瓶中加入30.5克异香兰素，55.2克碳酸钾，49.9克碘乙烷，140ml DMF，室温搅拌过夜。倾倒入1400ml水中，用乙酸乙酯萃取2次，每次600ml。合并乙酸乙酯层，用饱和Na 2CO 3洗3次，每次200ml，200ml水洗，200ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，得淡黄色固体，用乙酸乙酯：石油醚＝1：4的混合溶剂重结晶，得白色针状晶体32.9克。MS(m/z)：181[M+1] +。
化合物2
1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)-N-(三甲基硅基)乙胺
在装有磁力搅拌和惰性气体导管的500ml三口瓶中加入3.7克二甲砜，160ml THF，冷却至-78℃，滴加22ml正丁基锂(2.2M正己烷溶液)，滴完后保持-78℃搅拌30分钟，得A。在装有磁力搅拌和惰性气体导管的250ml三口瓶中加入7.1克化合物1，冰盐浴冷却，滴加43ml双三甲基硅基氨基锂(1.06M THF溶液)，滴完后搅拌15分钟，滴加10ml三氟化硼乙醚溶液，滴完后搅拌5分钟，得B。将B转移入A中，转移后缓慢升温至室温(约1.5小时)，加入200ml 1.6N K 2CO 3溶液淬灭反应，搅拌30分钟后分液，水层再用乙酸乙酯萃取3次，每次200ml，合并所有有机层，200ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，得淡黄色泡沫状固体10克。
化合物3
1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙胺
在装有磁力搅拌的500ml单口瓶中加入10克化合物2，100ml乙醚，100ml 4N HCl，室温搅拌30分钟，分液，有机层用4N HCl萃取3次，每次100ml，合并水层，冰浴下用4N NaOH调节pH＝12，用乙酸乙酯萃取3次，每次200ml，合并有机层，200ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，柱色谱纯化后得白色固体1.5克。 1H NMR(CDCl 3)：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] +；手性HPLC(异丙醇/正己烷/二乙胺＝35/65/0.1，
Figure PCTCN2019085327-appb-000019
OJ-H柱，250×4.6mm，1.0mL/min，@234nm)：15.2min(R-isomer,49.8％),17.3min(S-isomer,50.2％)。
化合物4a
(S)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙胺·N-乙酰基-L-缬氨酸盐
在装有磁力搅拌、回流冷凝装置和惰性气体导管的100ml单口瓶中加入6.920克化合物3，2.418克N-乙酰基L-缬氨酸，50ml无水甲醇，加热回流1小时，室温搅拌3小时，抽滤，得白色固体，将此固体再加入无水甲醇25ml回流1小时，室温搅拌3小时，抽滤，得白色固体6.752克。
化合物4b
(S)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)-乙胺
在装有磁力搅拌的250ml单口瓶中加入6.752克化合物4a，150ml二氯甲烷和150ml水，冰浴下滴加5％NaOH水溶液，调节pH＝11，分液，水层再用150ml二氯甲烷萃取一次，合并二氯甲烷层，100ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，得白色固体2.855克(99.0％ee)。MS(m/z)：274[M+1] +；手性HPLC(异丙醇/正己烷/二乙胺＝35/65/0.1，
Figure PCTCN2019085327-appb-000020
OJ-H柱，250×4.6mm，1.0mL/min，@234nm)：15.2min(R-isomer,0.5％),17.3min(S-isomer,99.5％)。
化合物5
3,4-二氰基噻吩
在装有机械搅拌、回流冷凝装置和惰性气体导管的2000ml三口瓶中加入96.8克3,4-二溴噻吩、104克氰化亚铜和100ml干燥的DMF，加热回流4小时后，冷却至室温，向反应液中加入400克FeCl 3·6H 2O溶在700ml 1.7N盐酸中的溶液，并维持在60-70℃反应30分钟，充分冷却后加入500ml DCM。将所得反应混合物分成300ml一份，用DCM(300ml×2)萃取，合并所有DCM层。将萃取液分成600ml一份， 依次用50ml×26N的盐酸、水、饱和Na 2CO 3水溶液及饱和食盐水溶液洗，无水MgSO 4干燥，过滤，蒸干溶剂得黄色固体，用乙酸乙酯：石油醚＝1：1的混合溶剂洗涤，过滤得白色固体21g。 1H NMR(CDCl 3)：δ8.07(s,2H)。
化合物6
噻吩-3,4-二羧酸
在装有电磁搅拌和回流冷凝装置的500ml圆底烧瓶中，加入15.978克化合物5、43.997克KOH及174ml乙二醇，回流4小时。待冷却后，向反应混合物中加350ml水，用乙醚(100ml×2)萃取，弃去乙醚层，在冰浴冷却下向水层加入过量的浓盐酸直到出现白色沉淀，过滤后将固体溶解于乙醚中(大约需要2000ml)，滤液用乙醚(300ml×3)萃取，合并所有乙醚层，无水MgSO 4干燥，过滤，蒸干溶剂，得白色固体15克，用水重结晶。 1H NMR(DMSO-d 6)：δ10.35(brs,2H)，8.17(s,2H)；MS(m/z)：171[M-1] +。
化合物7
噻吩[3,4-c]呋喃-1,3-二酮
在装有电磁搅拌、回流冷凝装置和干燥管的250ml圆底烧瓶中，加入15克化合物6和120ml乙酸酐，回流3小时，蒸干溶剂，得褐色固体13克。
化合物8
2-硝基噻吩-3,4-二羧酸
在装有电磁搅拌和干燥管的250ml圆底烧瓶中加入40ml发烟硝酸(含量95％)，用冰浴将其冷却至0-5℃，分批(每次1克)加入10克化合物7，加完后，在此温度下反应30分钟(有黄色固体析出)。将反应混合物倒入80克冰水混合液中，用乙酸乙酯(100ml×3)萃取，合并所有乙酸乙酯层，依次用50ml×2水及饱和食盐水溶液洗，无水MgSO 4干燥，过滤，蒸干溶剂，得黄色固体10g。MS(m/z)：216[M-1] +。
化合物9
4-硝基噻吩[3,4-c]呋喃-1,3-二酮
在装有电磁搅拌、回流冷凝装置和干燥管的250ml圆底烧瓶中加入10克化合物8和100ml乙酸酐，回流3小时，蒸干溶剂，得褐色固体9克。
化合物10
(S)-1-硝基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
在装有电磁搅拌和干燥管的250ml圆底烧瓶中加入1.99克4-硝基噻吩[3,4-c]呋喃-1,3-二酮(化合物9)，2.73克(S)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)-乙胺(化合物4b)，100ml THF，室温搅拌过夜。加入1.944克CDI，油浴回流2小时。晾至室温，加入200ml乙酸乙酯和150ml水，萃取，分液，有机层用100ml 0.5N HCl洗，100ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，柱色谱纯化后得淡黄色固体3.485克。MS(m/z)：453[M-1] +。
化合物11
(S)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
在装有电磁搅拌、回流冷凝装置和干燥管的250ml圆底烧瓶中加入2.27克(S)-1-硝基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮和100ml THF，加热回流，加入1.4克还原铁粉，回流2小时。抽滤，滤液蒸干，加入200ml乙酸乙酯和150ml水，萃取，分液，有机层用100ml水洗，100ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，柱色谱纯化后得黄褐色固体1.53克。MS(m/z)：425[M+1] +。
化合物12
(S)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二 氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
方法一：在装有电磁搅拌、回流冷凝装置和干燥管的50ml圆底烧瓶中加入0.1克(S)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮和0.005克DMAP，10ml乙酸酐，加热至60℃，搅拌6小时。蒸干溶剂，柱色谱纯化后得标题化合物0.022克。
方法二：在装有电磁搅拌、回流冷凝装置和干燥管的50ml圆底烧瓶中加入0.1克(S)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮和5ml吡啶，冰浴下滴加0.2ml乙酰氯，室温搅拌1小时。蒸干溶剂，加入50ml乙酸乙酯和20ml水，萃取，分液，有机层用20ml 2N HCl洗，20ml饱和NaCl洗，无水MgSO 4干燥，过滤，蒸干溶剂，柱色谱纯化后得标题化合物0.083克。MS(m/z)：465[M-1] +；手性HPLC(无水乙醇/正己烷/二乙胺＝40/60/0.1，
Figure PCTCN2019085327-appb-000021
OJ-H柱，250×4.6mm，1.0mL/min，@230nm)：9.8min(R-isomer,1.2％),13.8min(S-isomer,98.8％)。 1H NMR(CDCl 3)：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)。
实施例1
晶型I的制备
将5.00g(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶解于10mL乙腈中，加热至回流温度，搅拌全溶。热过滤后，滤液快速降温至零下20摄氏度，搅拌5分钟析出晶体。搅拌30分钟后
过滤、真空干燥得到白色粉末固体4.20g(收率84％)，即为(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
实施例2
晶型I的制备
将0.527g(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶解于20mL二氯甲烷与30mL正己烷的混合溶液中，加热至45摄氏度，搅拌全溶。热过滤后，滤液降温至40摄氏度，等温搅拌30分钟析晶。继续降温至5摄氏度，等温搅拌0.5小时，过滤、真空干燥得到白色固体粉末0.388g(收率74％)，即为(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
实施例3
晶型I的制备
将2.439g(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶解于30mL乙腈中，升温至45摄氏度，搅拌全溶。热过滤后，滤液降温至32摄氏度，加入50mL蒸馏水，等温搅拌15分钟后加入0.100g(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。32摄氏度等温搅拌30分钟，降温至0摄氏度，等温搅拌1小时，过滤、真空干燥得白色固体粉末1.566g(收率62％)，即为(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
实施例4
X射线粉末衍射(XRPD)
X射线粉末衍射(XRPD)测试参数如下：使用配置了Cu阳极(40mA,45kV)、布鲁克D8Advance X射线粉末衍射仪获得X射线粉末衍射(XRPD)图谱。扫描范围为2-Theta＝2-40°，步长为0.02°，扫描速率8°/分钟。
根据实施例1所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其X射线粉末衍射(XRPD)图谱如图1所示。
(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的X射线粉末衍射(XRPD)图谱在2θ＝5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°具有特征峰，在其他角度无明显衍射峰。
根据实施例2所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其X射线粉末衍射(XRPD)图谱基本上与图1所示的X射线粉末衍射(XRPD)图谱相同。
根据实施例3所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其X射线粉末衍射(XRPD)图谱基本上与图1所示的X射线粉末衍射(XRPD)图谱相同。
实施例5
差示扫描量热法(DSC)测试
差示扫描量热法(DSC)测试参数如下：使用日本精工，SII 6220差示扫描量热仪(DSC)获得升温过程样品吸放热信息。升温速率为10℃/min，氮气保护。
根据实施例1所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其DSC曲线如图2所示。
根据实施例2所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其DSC曲线基本上与图2所示的DSC曲线相同。
根据实施例3所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙 酰胺的晶型I，其DSC曲线基本上与图2所示的DSC曲线相同。
晶型I在升温过程中在136.0±6℃(峰值熔点)处具有一个吸热熔融峰。
实施例6
热重分析法(TGA)测试
热重分析法(TGA)测试参数如下：使用日本精工，SII 6200热重检测仪(TG)获得升温过程样品失重信息。升温速率为10℃/min，氮气保护。
根据实施例1所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其TGA曲线如图3所示。
根据实施例2所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其TGA曲线基本上与图3所示的TGA曲线相同。
根据实施例3所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其TGA曲线基本上与图3所示的TGA曲线相同。
晶型I加热至熔融失重1.0％。熔化前并未出现任何吸放热峰，说明1.0％的失重为吸附水或溶剂。晶型I既非水合物，亦非溶剂化物。
实施例7
红外图谱(IR)
红外测试参数如下：测试仪器为PerkinElmer,Spectrum 65。
根据实施例1所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其红外图谱(IR)如图4所示。
根据实施例1所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在红外图谱(IR)中，吸收峰位置和强度约为：
吸收峰位置(cm -1) 吸收峰强度(％)
3441.18 65.98
3299.26 65.59
3115.56 74.71
2978.81 70.47
2930.33 68.72
1758.76 43.82
1701.59 20.94
1589.94 42.15
1557.4 50.03
1517.27 44.9
1443.5 64.61
1429.22 65.06
1393.78 56.23
1372.26 53.19
1334.48 43.59
1298.5 30.29
1264.01 41.49
1235.94 40.5
1137.06 38.92
1088.54 47.63
1028.06 60.83
966.48 70.09
944.46 75.31
881.39 73.77
811.65 78.09
769.81 72.57
735.31 61.87
695.56 76.79
641.58 74.76
吸收峰位置(cm -1) 吸收峰强度(％)
602.59 74.88
581.06 76.5
531.75 68.96
487.88 71.37
454.52 74.62
根据实施例2所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其红外图谱(IR)基本上与图4所示的红外图谱(IR)相同。
根据实施例3所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其红外图谱(IR)基本上与图4所示的红外图谱(IR)相同。
实施例8
溶出速率
使用根据实施例1所述方法制备的(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I进行测试。
将约25mg(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I加入900mL水中，并于37℃下等温搅拌90分钟，转速100转/分钟。取上清液过滤并稀释，通过紫外分光光度计测定稀释后溶液浓度(a mg/mL)。按照公式900a/25×100％计算溶出速率。
(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的溶出速率如表1所示。
表1.溶出速率测定结果
时间(min) 溶出速率(％)
时间(min) 溶出速率(％)
0 0
15 40.0
30 55.9
45 65.2
60 71.4
75 75.5
90 78.0
溶出曲线如图5所示。
实施例9
压力稳定性
运用单冲压片机对(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I压片。片剂直径6mm，硬度为25-30牛。将压片后粉末进行DSC测试，具有与图2基本相同的DSC曲线。结果表明，晶型I具有良好的稳定性。
实施例10
乙醇溶液平衡稳定性
将0.2g(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I加入10mL乙醇中，并于25℃下等温搅拌3小时。混悬液过滤，湿固相干燥后进行X射线粉末衍射(XRPD)测试。晶型结果如表2所示。
表2.乙醇平衡晶型稳定性试验结果
原晶型 平衡温度(℃) 平衡时间(h) 平衡后晶型
I 25 3 I
实施例11
高温和高温高湿稳定性
分别将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I放置在40℃(高温)下或40℃和RH＝75％(高温高湿)下1个月，到期后检测(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I有关物质含量，结果如表3所示。
表3.高温稳定性和高温高湿稳定性试验结果
Figure PCTCN2019085327-appb-000022
结果表明，晶型I在高温以及高温高湿条件下具有良好的化学稳定性。
实施例12
吸湿稳定性
将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I放置在盛有饱和氯化铵溶液(RH＝80％)的干燥器中保存至重量平衡，到期后检测(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型稳定性，结果如表4所示。
表4.吸湿稳定性试验结果
原晶型 吸湿后晶型
I I
结果表明，晶型I在高湿条件下具有良好的晶型稳定性。
实施例13
光照稳定性
将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I放置在4500lux光照箱内下1个月，到期后检测(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型化学稳定性，结果如表5所示。
表5.光照稳定性试验结果
晶型 0天有关物质含量(％) 光照条件 1个月有关物质含量(％)
I 0.06 4500lux 0.06
结果表明，晶型I在光照条件下具有良好的化学稳定性。
在本公开中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
从前述中可以理解，尽管为了示例性说明的目的描述了本公开的具体实施方案，但是在不偏离本公开的精神和范围的条件下，本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本公开所附权利要求的范围。

Claims (34)

  1. 化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
  2. 化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
  3. 化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
    Figure PCTCN2019085327-appb-100001
  4. 化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
    Figure PCTCN2019085327-appb-100002
    Figure PCTCN2019085327-appb-100003
  5. 化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
  6. 如权利要求1至5中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在使用差示扫描量热法(DSC)进行热分析时，其在约136.0℃处具有吸热峰。
  7. 如权利要求1至6中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在使用差示扫描量热法(DSC)进行热分析时，其在136.0±6℃处具有吸热峰。
  8. 如权利要求1至7中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在使用差示扫描量热法(DSC)进行热分析时，其具有基本上如图2所示的DSC曲线。
  9. 如权利要求1至8中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在使用热重分析法(TGA)进行热分析时，其具有基本上如图3所示的TGA曲线。
  10. 如权利要求1至9中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在红外图谱(IR)中，其吸收峰位置和强度约为：
    吸收峰位置(cm -1) 吸收峰强度(％) 3441.18 65.98 3299.26 65.59 3115.56 74.71 2978.81 70.47 2930.33 68.72 1758.76 43.82 1701.59 20.94 1589.94 42.15 1557.4 50.03 1517.27 44.9 1443.5 64.61 1429.22 65.06 1393.78 56.23 1372.26 53.19 1334.48 43.59 1298.5 30.29 1264.01 41.49 1235.94 40.5 1137.06 38.92 1088.54 47.63
    吸收峰位置(cm -1) 吸收峰强度(％) 1028.06 60.83 966.48 70.09 944.46 75.31 881.39 73.77 811.65 78.09 769.81 72.57 735.31 61.87 695.56 76.79 641.58 74.76 602.59 74.88 581.06 76.5 531.75 68.96 487.88 71.37 454.52 74.62
  11. 如权利要求1至10中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在红外光谱(IR)中，其具有基本上如图4所示的红外图谱(IR)。
  12. 基本上不含溶剂的权利要求1至11中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
  13. 基本上不含水的权利要求1至12中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
  14. 基本上纯的权利要求1至13中任一权利要求所述的化合物 (S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
  15. 不含溶剂且不含水的权利要求1至14中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I。
  16. 药物组合物，其包含权利要求1至15所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I以及药物可接受的载体、稀释剂或赋形剂。
  17. 如权利要求16所述的药物组合物，其被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、凝胶剂、胶囊剂、气雾剂或栓剂。
  18. 制备权利要求1至15中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺在乙腈中结晶，从而得到所述晶型I。
  19. 如权利要求18所述的方法，其包括：
    将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；以及
    过滤并将滤液降温，析出所述晶型I。
  20. 制备权利要求1至15中任一权利要求所述的化合物 (S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺在二氯甲烷与正己烷的混合物中结晶，从而得到所述晶型I。
  21. 如权利要求20所述的方法，其包括：
    将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于二氯甲烷与正己烷的混合物中至完全溶解；以及
    热过滤并降温，析出所述晶型I。
  22. 如权利要求21所述的方法，其还包括继续降温至0-10℃，过滤并真空干燥。
  23. 制备权利要求1至15中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I的方法，其包括：
    将(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺溶于乙腈中至完全溶解；以及
    热过滤并降温，等温加入蒸馏水和(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I晶种，从而得到所述晶型I。
  24. 如权利要求23所述的方法，其还包括继续搅拌，降温至0℃，过滤并真空干燥，从而得到所述晶型I。
  25. 治疗或预防与PDE4酶相关的，优选PDE4酶介导的疾病或疾病状态的方法，其包括向需要所述方法的个体给予治疗有效量的权利 要求1至15中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I或治疗有效量的权利要求16或17所述的药物组合物。
  26. 如权利要求25所述的方法，其中所述个体为哺乳动物，优选人类。
  27. 如权利要求25或26所述的方法，其中所述疾病或疾病状态选自炎症性疾病或疾病状态、感染性疾病或疾病状态、免疫类疾病或疾病状态以及癌症类疾病或疾病状态。
  28. 如权利要求25至27中任一权利要求所述的方法，其中所述头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、结肠癌、乙状结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、色素瘤、恶性神经胶质瘤、HIV、肝炎、成人呼吸窘迫综合症、骨吸收病、慢性阻塞性肺病、慢性肺炎、皮炎、炎性皮肤病、特异性皮炎、囊性纤维变性、败血症性休克、脓毒症、内毒素性休克、血液动力性休克、脓毒病综合症、局部缺血后再灌注损伤、脑膜炎、银屑病、纤维变性疾病、恶病质、移植物抗宿主疾病的移植排斥、自身免疫病、类风湿性脊椎炎、关节炎病症(如类风湿性关节炎或骨关节炎)、骨质疏松症、节段性回肠炎、溃疡性结肠炎、肠炎、多发性硬化病、系统性红斑狼疮、麻风病中的麻风性结节性红斑(ENL)、辐射损伤、哮喘、富氧性肺损伤、微生物感染和微生物感染综合症。
  29. 具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角 2θ约为5.3°、9.2°、16.1°、17.7°、20.6°、26.2°、26.7°处具有特征峰。
  30. 具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ为5.3±0.2°、9.2±0.2°、16.1±0.2°、17.7±0.2°、20.6±0.2°、26.2±0.2°、26.7±0.2°处具有特征峰。
  31. 具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
    Figure PCTCN2019085327-appb-100004
  32. 具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，在X射线粉末衍射(XRPD)图谱中，其衍射角2θ、晶面间距d、衍射峰相对强度约为：
    Figure PCTCN2019085327-appb-100005
    Figure PCTCN2019085327-appb-100006
  33. 具有PDE4酶抑制活性的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
  34. 降低PDE4酶活性的方法，其包括向需要所述方法的个体给予有效量的权利要求1至15中任一权利要求所述的化合物(S)-N-[5-[1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基]-4,6-二氧-5,6-二氢-4H-噻吩并[3,4-c]吡咯-1-基]乙酰胺的晶型I或有效量的权利要求16或17所述的药物组合物。
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