Crystalline forms of compounds and their uses

Abstract

This application provides crystalline forms A and B of the free base of a compound represented by formula (I), and the use of crystalline forms A and B. TIFF2026524527000018.tif65170

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biopharmaceuticals, and specifically relates to crystalline forms of compounds and uses thereof. BACKGROUND ART

[0002] Rifamycin is a natural product with potential antimicrobial activity. Naturally derived rifamycin (e.g., rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV, and rifamycin Y (Brufani, M., Cerrini, S., Fedeli, W., Vaciago, AJ Mol. Biol. 1974, 87, 409-435)) has limited therapeutic applications due to poor pharmacokinetics, low oral bioavailability, weak activity against Gram-negative pathogens, and low distribution to infected tissues. Conventional techniques have produced various semi-synthetic rifamycin derivatives with improved antimicrobial spectra and pharmacological properties through chemical modification. Among these semi-synthetic compounds, for example, rifampicin and rifabutin have been developed as therapeutic agents and are currently used to treat tuberculosis and other microbial infections (Farr, BFRifamycins, in Principles and Practice of Infectious Diseases; Mandell, GL, Bennett, J.E., Dolin, R., Eds.; Churchill Livingstone Philadelphia; pp.348-361). TNP-2198 is a bispecific rifamycin-nitroimidazole conjugate that exhibits potent activity against microaerophilic and anaerobic bacterial pathogens and also shows good activity against strains resistant to both rifamycin and nitroimidazole. However, innovative pharmaceutical molecules with such antibacterial activity often face difficulties in development and application due to their physicochemical properties, such as the high relative molecular weight of their free form, high lipophilicity, low water solubility and hygroscopicity, as well as their bioavailability and stability (chemical stability, thermal stability, melting point, and crystalline stability), making it difficult to meet the developmental potential of pharmaceutical formulations. Therefore, the search for and screening of new molecular entities (e.g., salt or crystalline forms) of such drug substance molecules plays an extremely important role in achieving their therapeutic effects. [Overview of the Initiative]

[0003] This application aims to overcome the shortcomings of the prior art described above by providing a crystalline form of free base of compounds that can satisfy diverse pharmaceutical needs.

[0004] In one embodiment, the present application provides a crystalline form A of the free base of a compound represented by formula (I), having characteristic peaks at diffraction angle 2θ values ​​of 5.28°±0.2°, 7.17°±0.2°, 8.50°±0.2°, 10.66°±0.2°, 14.33°±0.2°, 15.84°±0.2°, and 18.60°±0.2° as determined by X-ray powder diffraction. TIFF0007936646000001.tif68170

[0005] In some embodiments, crystal form A has one or more characteristic peaks with diffraction angle 2θ values ​​of 12.61°±0.2°, 14.83°±0.2°, 15.26°±0.2°, 16.57°±0.2°, 19.97°±0.2°, and 21.97°±0.2°.

[0006] In some embodiments, crystal form A has characteristic peaks at diffraction angle 2θ values ​​of 12.61°±0.2°, 14.83°±0.2°, 15.26°±0.2°, 16.57°±0.2°, 19.97°±0.2°, and 21.97°±0.2°.

[0007] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal form A substantially matches that of Figure 1.

[0008] In some embodiments, the above crystal form A has an endothermic peak at approximately 169.3°C in the differential scanning calorimetry curve.

[0009] In some embodiments, the differential scanning calorimetry (DSC) pattern of crystal form A substantially coincides with that of Figure 2B.

[0010] In some embodiments, the crystalline form A is anhydrous.

[0011] In another embodiment, the present invention provides a crystalline form A of the free base of a compound represented by formula (I), which has an endothermic peak at approximately 169.3°C in the differential scanning calorimetry curve.

[0012] In some embodiments, the differential scanning calorimetry (DSC) pattern of crystal form A substantially coincides with that of Figure 2B.

[0013] In some embodiments, the crystalline form A is an anhydrous and / or solvate.

[0014] In another embodiment, the present invention provides a crystalline form B of the free base of a compound represented by formula (I), having characteristic peaks at diffraction angle 2θ values ​​of 4.89°±0.2°, 6.67°±0.2°, 7.12°±0.2°, 13.41°±0.2°, 14.62°±0.2°, 15.19°±0.2°, and 18.23°±0.2° as determined by X-ray powder diffraction.

[0015] In some embodiments, crystal form B has one or more characteristic peaks with diffraction angle 2θ values ​​determined by X-ray powder diffraction at 7.84°±0.2°, 10.67°±0.2°, 14.25°±0.2°, 16.07°±0.2°, 17.10°±0.2°, 17.41°±0.2°, 17.74°±0.2°, and 20.73°±0.2°.

[0016] In some embodiments, crystal form B has characteristic peaks at diffraction angle 2θ values ​​of 7.84°±0.2°, 10.67°±0.2°, 14.25°±0.2°, 16.07°±0.2°, 17.10°±0.2°, 17.41°±0.2°, 17.74°±0.2°, and 20.73°±0.2° as determined by X-ray powder diffraction.

[0017] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal form B substantially matches that of Figure 3.

[0018] In some embodiments, the above crystalline Form B has endothermic peaks at about 85.6°C, about 130.7°C and about 144.3°C in the differential scanning calorimetry curve.

[0019] In some embodiments, the differential scanning calorimetry (DSC) pattern of the above crystalline Form B is substantially consistent with Figure 4B.

[0020] In some embodiments, the above crystalline Form B is obtained by subjecting crystalline Form A described in the present application to transformation in a toluene reagent.

[0021] In some embodiments, the above crystalline Form B is a toluene solvate.

[0022] In some embodiments, the molar ratio of the compound represented by Formula (I) to the toluene molecule in the above crystalline Form B is from 1:2 to 1:1.

[0023] According to another aspect, the present application provides crystalline Form B of the free base of the compound represented by Formula (I), which has endothermic peaks at about 85.6°C, about 130.7°C and about 144.3°C in the differential scanning calorimetry curve.

[0024] In some embodiments, the differential scanning calorimetry (DSC) pattern of the above crystalline Form B is substantially consistent with Figure 4B.

[0025] In some embodiments, the above crystalline Form B is obtained by subjecting crystalline Form A described in the present application to transformation in a toluene reagent.

[0026] In some embodiments, the above crystalline Form B is a toluene solvate.

[0027] In some embodiments, the molar ratio of the compound represented by Formula (I) to the toluene molecule in the above crystalline Form B is from 1:2 to 1:1.

[0028] In another embodiment, the present application provides a pharmaceutical composition comprising crystalline form A and / or crystalline form B described herein, and an optionally pharmaceutically acceptable carrier.

[0029] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent.

[0030] In some embodiments, the second therapeutic agent is selected from proton pump inhibitors, acid secretion inhibitors, efflux pump inhibitors, anesthetics, antifungal agents, antiviral agents, antibacterial agents, antiprotozoal agents, anti-inflammatory agents, anticoagulants, platelet aggregation inhibitors, antipyretics, lipid-lowering agents, and zinc salts.

[0031] In another embodiment, the present application provides a kit comprising one or more of the crystalline form A, crystalline form B, and pharmaceutical compositions described herein.

[0032] In some embodiments, the kit further includes instructions for use in physical and / or machine-readable electronic form.

[0033] In another embodiment, the present application provides a method for manufacturing a pharmaceutical product using crystal form A and / or crystal form B described herein.

[0034] In another embodiment, the present application provides a method for inhibiting or preventing bacterial growth, comprising administering one or more of the following in an effective amount: crystalline form A, crystalline form B, the pharmaceutical composition, and the kit described herein.

[0035] In another embodiment, the present application provides a method for preventing, treating, or alleviating a disease or related condition, comprising administering one or more of the following to a patient in need: crystalline form A, crystalline form B, the pharmaceutical composition, and the kit described herein, in an effective amount.

[0036] In some embodiments, the patient requiring the above is infected with bacteria.

[0037] In some embodiments, the bacteria are selected from Helicobacter pylori, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridioides difficile, Lactobacillus acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharoritica, Prevotella vivia, Cutibacterium acnes, and Veillonella parbra.

[0038] In another aspect, the present application provides a use for inhibiting or preventing bacterial growth of the crystalline form A, the crystalline form B, the pharmaceutical composition, and / or the kit described herein.

[0039] In another aspect, the present application provides the use of the crystalline form A described in the present application, the crystalline form B described in the present application, the pharmaceutical composition described in the present application, and / or the kit described in the present application in the manufacture of a pharmaceutical for the prevention, treatment, or alleviation of a disease caused by a bacterial infection or a related pathological condition.

[0040] In some embodiments, the bacteria are selected from Helicobacter pylori, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridioides difficile, Lactobacillus acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharoritica, Prevotella vivia, Cutibacterium acnes, and Veillonella parbra.

[0041] In some embodiments, the above-mentioned disease or related pathological condition is selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, suppurative arthritis, liver abscess, sinusitis, pelvic inflammatory disease and bacteremia, as well as upper respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, lung infections, intra-abdominal infections, eye infections, ear infections, oral infections and surgical infections.

[0042] In another embodiment, the present application provides a pharmaceutical composition or kit described herein for preventing, treating, or alleviating a disease caused by bacterial infection or a related pathological condition.

[0043] In some embodiments, the bacteria are selected from Helicobacter pylori, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridioides difficile, Lactobacillus acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharoritica, Prevotella vivia, Cutibacterium acnes, and Veillonella parbra.

[0044] In some embodiments, the above-mentioned disease or related pathological condition is selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, suppurative arthritis, liver abscess, sinusitis, pelvic inflammatory disease and bacteremia, as well as upper respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, lung infections, intra-abdominal infections, eye infections, ear infections, oral infections and surgical infections.

[0045] In another embodiment, the present application provides a method for producing crystalline form A as described in the present application, comprising crystallizing a compound represented by formula (I) in a solvent containing an alcohol-based solvent which is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.

[0046] Furthermore, the method for producing crystalline form A described in this application includes crystallizing the compound represented by formula (I) in an alcohol-based solvent.

[0047] In some embodiments, the alcohol-based solvent is methanol, ethanol, or a combination thereof.

[0048] In some embodiments, the method further includes concentrating the alcohol-based solvent to obtain a concentrated wet product, and drying the concentrated wet product.

[0049] In another aspect, the present application provides a crystalline form A of the free base of a compound represented by formula (I), obtained by a method for producing crystalline form A described in the present application.

[0050] In another embodiment, the present application provides a method for producing crystal form B described in the present application, which includes crystallizing crystal form A described in the present application in a toluene solvent.

[0051] In another aspect, the present application provides a crystalline form B of the free base of a compound represented by formula (I), obtained by a method for producing crystalline form B described in the present application.

[0052] Those skilled in the art will readily understand other aspects and advantages of the Application from the following detailed description. Only exemplary embodiments of the Application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of the Application allows those skilled in the art to modify the specific embodiments disclosed without departing from the spirit and scope of the invention. Therefore, the drawings and descriptions in the specification are merely illustrative and not limiting. [Brief explanation of the drawing]

[0053] The specific features of the invention described herein are set forth in the attached claims. The features and advantages of the invention described herein can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows: [Figure 1] This figure shows the XRPD pattern of crystal form A of the present invention. [Figure 2A] This figure shows the TGA pattern of crystal form A of the present invention. [Figure 2B] This figure shows the DSC pattern of crystal form A of the present invention. [Figure 3] This figure shows the XRPD pattern of crystal form B of the present invention. [Figure 4A] This figure shows the TGA pattern of crystal form B of the present invention. [Figure 4B] This figure shows the DSC pattern of crystal form B of the present invention. [Figure 5] This figure shows the 1H NMR spectrum of crystal form A of the present invention. [Figure 6A] This figure shows the PLM observation results for crystal form A of the present invention. [Figure 6B] This figure shows the PLM observation results for crystal form A of the present invention. [Figure 7A] This figure shows the initial 1H NMR spectrum of crystal form B of the present invention. [Figure 7B] This figure shows the 1H NMR spectrum of crystal form B of the present application after heating at 115°C. [Figure 7C] This figure shows the 1H NMR spectrum of crystal form B of the present application after heating at 140°C. [Figure 8] This figure shows a comparison of the XRPD patterns of crystal form B of the present invention before and after heating. [Figure 9A] This figure shows the XRPD pattern of crystal form C1 of the present invention. [Figure 9B] This figure shows the XRPD pattern of crystal form C2 of the present invention. [Figure 9C] This figure shows the XRPD pattern of crystal form C3 of the present invention. [Figure 9D] This figure shows the XRPD patterns of crystal forms C1, C2, and C3 after drying. [Figure 10] This figure shows the results of the DVS experimental analysis of crystal form A of the present invention. [Figure 11] This figure shows the comparison results of the XRPD patterns before and after the DVS experiment for crystal form A of the present invention. [Figure 12] This figure shows the comparison results of XRPD patterns in the evaluation of the solid stability of crystal form A of this application. [Figure 13] This figure shows the comparison results of HPLC chromatograms used in the evaluation of the solid stability of crystal form A of this application. [Figure 14] This figure shows the structural formula of impurity RRT0.98 in the crude product of compound (I) of the present invention. [Modes for carrying out the invention]

[0054] Embodiments of the present invention will be described below with reference to specific examples. Those skilled in the art will readily understand other advantages and effects of the present invention from the information disclosed herein.

[0055] Definition of Terms In this application, the term "substantially identical to (Figure)..." usually refers to information such as the number of characteristic peaks in the pattern, the location (or distribution) of characteristic peaks, and the laws of geometric topology being nearly identical or similar. For example, characteristic peaks relating to this application include diffraction peaks in X-ray powder diffraction (XRPD) patterns, endothermic peaks in differential scanning calorimetry (DSC) patterns, and nuclear magnetic resonance ( 1This could be a chemical shift peak in a 1H NMR spectrum or an absorption peak in a high-performance liquid chromatography (HPLC) chromatogram. For example, the term "substantially matches (Figure)..." may mean that at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of characteristic peaks in the pattern are shown in the Figure.

[0056] In this application, all terms relating to X-ray powder diffraction (XRPD) patterns, such as "value of 2θ (also called 2-theta or diffraction peak)," are expressed in degrees (°). When referring to data in patterns and / or figures, the term "diffraction peak" usually refers to features that are not classified as background noise by those skilled in the art. For X-ray powder diffraction peaks of crystalline forms described in this application, experimental errors may occur in the measured values ​​of 2θ or diffraction peaks of the X-ray powder diffraction pattern. These errors may occur between instruments and samples, and there may be slight differences in the measured values ​​of 2θ or diffraction peaks of the X-ray powder diffraction pattern. The experimental error or difference may be in units of ±0.2, ±0.1, or ±0.05. Therefore, the value of 2θ or diffraction peak cannot be considered absolute.

[0057] In some embodiments, experimental errors may occur in the differential scanning calorimetry (DSC) curve of the crystal form. These errors can occur between instruments and between samples, and there may be slight differences in the position and peak value of the endothermic peak. The experimental error or difference may be less than 5°C, less than 4°C, less than 3°C, less than 2°C, or less than 1°C. Therefore, the position or peak value of the DSC endothermic peak cannot be considered absolute.

[0058] In some embodiments, experimental errors may occur in the thermogravimetric analysis (TGA) of the crystalline form. These errors may occur between instruments or between samples, and there may be slight differences in the weight loss temperature and weight loss amount. The experimental error or difference may be approximately ±0.1 units, approximately ±0.05 units, or approximately ±0.01 units. Therefore, the values ​​of the weight loss temperature and weight loss amount cannot be considered absolute.

[0059] Regardless of whether the terms “approximately” or “about” are used in this application, all numerical values ​​disclosed herein are approximations, and there may be differences of, for example, ±1%, ±2%, or ±5% in the value of each numerical value. The terms “approximately” or “about” usually refer to being within the tolerance range of a particular value as determined by those skilled in the art, and this depends in part on how the value is measured or determined, i.e., the limits of the measuring system. For example, “approximately” or “about” may mean within or exceeding one standard deviation according to the convention of the art. Alternatively, “approximately” or “about” may mean a range of at most 10% or 20% (i.e., ±10% or ±20%). For example, approximately 3 mg may include any number between 2.7 mg and 3.3 mg (in the case of 10%) or between 2.4 mg and 3.6 mg (in the case of 20%). Furthermore, particularly with respect to biological systems or processes, this term may mean at most a value of one order of magnitude or at most a value of five times. Where specific values ​​or compositions are shown in this specification and the appended claims, unless otherwise specified, the meaning of “about” or “approximately” should be assumed to be within the tolerance range of those specific values ​​or compositions.

[0060] In this application, the terms "solvated compound" and "solvate" are interchangeable and usually refer to an association or complex of one or more solvent molecules with a compound described in this application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0061] In this application, the term “pharmaceutically acceptable carrier” typically refers to one or more non-toxic materials that do not interfere with the efficacy of the biological activity of the active ingredient. Such formulations may typically include salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. Such pharmaceutically acceptable formulations may further include compatible solid or liquid fillers, diluents, or encapsulating materials suitable for administration to humans. Other conceivable carriers, excipients, and / or additives that may be used in the formulations described herein may include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients (such as serum albumin, gelatin, and casein), and salt-forming ions (such as sodium). These and other known pharmaceutically acceptable carriers, excipients, and / or additives suitable for the formulations described herein are well known in the art and are listed, for example, in "Remington: The Science & Practice of Pharmacy," 21st edition, Lippincott Williams & Wilkins (2005) and "Physician's Desk Reference," 60th edition, Medical Economics, Montvale, New Jersey (2005). A suitable pharmaceutically acceptable carrier can be determined by routinely selecting the desired or required method of administration, solubility, and / or stability.

[0062] In this application, the term “therapeutic agent” usually refers to a compound (including, but not limited to, its pharmaceutically acceptable salts, hydrates, solvates, crystalline forms, prodrugs, metabolites, or deuterides), mixtures of compounds, compositions, biomacromolecules, or extracts made from biomaterials that, when appropriately administered to a patient, can induce a desired therapeutic effect, prevent the onset of a particular pathological condition, or alleviate an associated pathological condition.

[0063] In this application, the term "bacteria" generally refers to prokaryotes that do not possess a distinct nucleus and membranous organelles. These bacteria may include spherical, rod-shaped, or spiral-shaped organisms. These bacteria may also include species that grow in an interconnected manner. For example, genera such as Escherichia, Salmonella, Shigella, Klebsiella, Vibrio, Pasteurella, Borrelia, Leptospira, Campylobacter, Clostridium, Corynebacterium, Yersinia, Treponema, Rickettsia, Chlamydia, and Mycoplasma. These include *Coxiella*, *Neisseria*, *Listeria*, *Haemophilus*, *Helicobacter*, *Legionella*, *Pseudomonas*, *Bordetella*, *Brucella*, *Staphylococcus*, *Streptococcus*, *Enterococcus*, *Bacillus*, *Mycobacterium*, and *Nocardia*. The term "bacterial infection" usually refers to any disorder caused by the proliferation and / or presence of the bacteria described herein, either intracellularly or within a subject. Bacterial infections can be caused by the proliferation of bacteria (e.g., pathogenic bacteria), the production of toxins and other metabolites.

[0064] In this application, the term “patients in need” may typically include human patients and other mammalian subjects receiving preventive or therapeutic treatment. Other mammalian subjects include, but are not limited to, non-human primates, laboratory animals such as rabbits, dogs, rats, and mice, and other animals. These “patients in need” may, exemplarily, be subjects with a confirmed specific disease, subjects receiving treatment related to a specific disease, or subjects with a tendency or risk of developing a specific disease.

[0065] In this application, the term “administration” usually refers to introducing a pharmaceutical or a composition containing a pharmaceutical (e.g., the therapeutic agent relating to this application) into a patient’s body via any introduction or delivery route. Any method known to those skilled in the art can be used to bring cells, organs, or tissues into contact with the pharmaceutical or its composition.

[0066] In this application, the term “effective dose” usually refers to an amount sufficient to obtain, or at least partially obtain, the desired therapeutic effect. “Effective dose” of a pharmaceutical or therapeutic agent usually refers to an amount sufficient to cure, or at least partially prevent, a disease and its complications in a patient suffering from the disease. The effective dose for this use depends on the severity of the infection and the overall state of the patient’s own immune system.

[0067] In this application, the term "including" generally means including the explicitly specified features but not excluding other elements. The terms "greater than or equal to" and "less than or equal to" generally mean including a reference numerical value.

[0068] In this application, the term "selected from" generally refers to the selected subjects and all combinations thereof. For example, "(:) selected from A, B and C" means including all combinations of A, B and C, e.g., A, B, C, A+B, A+C, B+C, or A+B+C. Detailed Description of the Invention

[0069] In one embodiment, the present application provides a crystalline form A of the free base of a compound represented by formula (I), having characteristic peaks at diffraction angle 2θ values ​​of 5.28°±0.2°, 7.17°±0.2°, 8.50°±0.2°, 10.66°±0.2°, 14.33°±0.2°, 15.84°±0.2°, and 18.60°±0.2° as determined by X-ray powder diffraction.

[0070] In another embodiment, the present invention provides a crystalline form A of the free base of a compound represented by formula (I), which has an endothermic peak at approximately 169.3°C in the differential scanning calorimetry curve.

[0071] In another embodiment, the present invention provides a crystalline form B of the free base of a compound represented by formula (I), having characteristic peaks at diffraction angle 2θ values ​​of 4.89°±0.2°, 6.67°±0.2°, 7.12°±0.2°, 13.41°±0.2°, 14.62°±0.2°, 15.19°±0.2°, and 18.23°±0.2° as determined by X-ray powder diffraction.

[0072] In another embodiment, the present invention provides a crystalline form B of the free base of a compound represented by formula (I), which has endothermic peaks at approximately 85.6°C, 130.7°C, and 144.3°C in a differential scanning calorimetry curve.

[0073] In another embodiment, the present application provides a pharmaceutical composition comprising crystalline form A and / or crystalline form B described herein, and an optionally pharmaceutically acceptable carrier.

[0074] In another embodiment, the present application provides a kit comprising one or more of the crystalline form A, crystalline form B, and pharmaceutical compositions described herein.

[0075] In another embodiment, the present application provides a method for manufacturing a pharmaceutical product using crystal form A and / or crystal form B described herein.

[0076] In another embodiment, the present application provides a method for inhibiting or preventing bacterial growth, comprising administering one or more of the following in an effective amount: crystalline form A, crystalline form B, the pharmaceutical composition, and the kit described herein.

[0077] In another embodiment, the present application provides a method for preventing, treating, or alleviating a disease or related condition, comprising administering one or more of the following to a patient in need: crystalline form A, crystalline form B, the pharmaceutical composition, and the kit described herein, in an effective amount.

[0078] In another aspect, the present application provides a use for inhibiting or preventing bacterial growth of the crystalline form A, the crystalline form B, the pharmaceutical composition, and / or the kit described herein.

[0079] In another aspect, the present application provides the use of the crystalline form A described in the present application, the crystalline form B described in the present application, the pharmaceutical composition described in the present application, and / or the kit described in the present application in the manufacture of a pharmaceutical for the prevention, treatment, or alleviation of a disease caused by a bacterial infection or a related pathological condition.

[0080] In another embodiment, the present application provides a pharmaceutical composition or kit described herein for preventing, treating, or alleviating a disease caused by bacterial infection or a related pathological condition.

[0081] Crystalline form of the free base of the compound (I) This application provides crystal forms A and B, and optionally further provides crystal forms C1, C2, and C3. The following examples will provide a further understanding of these crystal forms described in this application, as well as their manufacturing methods, uses, and technical effects, but these examples will not limit the scope of the present invention.

[0082] Pharmaceutical composition In some embodiments, the pharmaceutical compositions described herein can be formulated into any dosage form. For example, the pharmaceutical compositions may be in the form of solutions, aerosols, gels, ointments, sprays, or suspensions, and compositions of these forms can be prepared using conventional methods known in the art. For example, pharmaceutically acceptable carriers may be selected from excipients to increase solubility, thickeners to increase viscosity, and auxiliaries to increase permeability.

[0083] In some embodiments, the pharmaceutical composition may further comprise a second therapeutic agent. For example, the second therapeutic agent may be selected from other rifamycin-based drugs or their analogues, proton pump inhibitors, acid secretion inhibitors, efflux pump inhibitors, anesthetics, antifungal agents, antiviral agents, antibacterial agents, antiprotozoal agents, anti-inflammatory agents (such as nonsteroidal anti-inflammatory drugs or steroids), anticoagulants, platelet aggregation inhibitors, antipyretics, lipid-lowering agents, and zinc salts. All therapeutic agents used in the pharmaceutical compositions described herein are currently known and can be used within the dosage ranges used in these formulations.

[0084] kit In some embodiments, the kit described herein may include the crystalline form and / or the pharmaceutical composition described herein. The kit may further include at least one container for containing the crystalline form and / or the pharmaceutical composition. For example, the kit may further include one or more components, and may include a second, third, and / or other container separate from the container, which may contain the one or more components separately. For example, the kit may further contain various combinations of the crystalline form and / or the pharmaceutical composition in the container. For example, the kit may further include a buffering reagent, a device for mixing different components, a measuring device, a component sorting device, and / or a labeling device. For example, the kit may further include packaging for containing the various containers. For example, the kit may further include instructions on how to use the components of the kit. For example, the instructions may be in physical paper form and / or machine-readable electronic form.

[0085] Method of administration In some embodiments, a method for inhibiting or preventing the growth of the bacteria described herein may include administering an effective amount of the crystalline form, the pharmaceutical composition, and / or the kit described herein by any route. In some embodiments, this method includes bringing the crystalline form, the pharmaceutical composition, and / or the kit described herein into contact with a site infected with bacteria. For example, the infected site may be inside or on the surface of an animal, inside or on the surface of a plant.

[0086] In some embodiments, a method for preventing, treating or alleviating the disease or related condition of the present application may include administering an effective amount of the crystalline form, the pharmaceutical composition, and / or the kit described herein to a patient in need via any route. In some embodiments, the method may further include mixing the crystalline form, the pharmaceutical composition, and / or the kit described herein with other therapeutic agents. In some embodiments, the method may include systemic delivery to a patient in need of the crystalline form, the pharmaceutical composition, and / or the kit described herein to expose a large portion of the body. This step may be carried out by any means known in the art and includes, but is not limited to, intravenous, intra-arterial, intracavitary, subcutaneous, and intraperitoneal delivery. In some other embodiments, the method may include topical delivery to a patient in need of the crystalline form, the pharmaceutical composition, and / or the kit described herein to directly reach or directly contact a bacterially infected site within the organism or on the surface of the organism. For example, the above-mentioned local delivery does not preclude systemic pharmacological effects. In some embodiments, the above method may include administering an effective amount of the crystalline form, the pharmaceutical composition, and / or the kit described herein to a patient in need by means of intramuscular injection, subcutaneous or intradermal injection, intravenous injection, intrasacral injection, inhalation, oral administration, or topical application.

[0087] Bacteria and diseases or related conditions caused by bacterial infections In some embodiments, the patients described in this application are infected with bacteria or suffering from a disease or related condition caused by a bacterial infection. For example, the bacteria may be selected from Helicobacter pylori, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus species, Prevotella, Clostridium perfringens, Clostridioides difficile, Lactobacillus acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharoritica, Prevotella vivia, Cutibacterium acnes, and Veillonella parbra. In this application, the bacteria may further include drug-resistant strains of the bacteria. For example, the above-mentioned drug-resistant strains may be resistant to rifamycin alone, nitrimidazole alone, or both rifamycin and nitrimidazole. For example, the above-mentioned drug-resistant strains may be resistant to macrolides such as clarithromycin, azithromycin, and roxithromycin; fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin; aminoglycosides such as streptomycin and amikacin; β-lactams such as ampicillin and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidinones such as linezolid and tedizolid; nitrofurans such as furazolidone; glycopeptides such as vancomycin; diarylquinolines such as bedaquiline; and other antibiotics such as clofazimine.

[0088] For example, the above diseases may be selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, suppurative arthritis, liver abscess, sinusitis, pelvic inflammatory disease, and bacteremia. For example, the above conditions may be selected from upper respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, lung infections, intra-abdominal infections, eye infections, ear infections, oral infections, and surgical infections.

[0089] While not limited by any theory, the following examples are merely for illustrative purposes to illustrate the crystalline form, manufacturing method, and use of the compound of the present invention, and do not limit the scope of the present invention. [Examples]

[0090] Example 1 Preparation and evaluation of crystal forms A and B of the present application (1) Preparation of crystal form A 40.05 g of the crude compound of formula (I) was weighed out and mixed with 5 times the volume of methanol or ethanol. The mixture was stirred at 25°C for 30 minutes, and a clear solid precipitate formed. After continuing stirring for 2-3 hours, the mixture was filtered, and the filter cake was washed with 80 mL of methanol or ethanol. The filter cake was dried at 42°C under reduced pressure for 52 hours, finally yielding 36.12 g of crystalline product. The yield was approximately 67.9%, and the purity by high-performance liquid chromatography (HPLC) was 99.6%. This crystalline product was sampled and subjected to X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and liquid nuclear magnetic resonance spectroscopy (Solution). 1 ¹H NMR analysis and polarized light microscopy (PLM) observation were performed. The results are shown in Figure 1, Table 1, Figures 2A-2B, Figure 5, and Figures 6A-6B.

[0091] From the evaluation results for crystal form A, the XRPD diffraction peak (Figure 1) indicates high crystallinity of crystal form A. 1The absence of solvent residue observed in the 1H NMR (Figure 5) indicates that crystal form A is an anhydrous and / or solvated form. The TGA / DSC results (Figures 2A-2B) showed a 1.36% weight loss when the crystal form A sample was heated to 150°C, and it had one endothermic peak at 169.3°C (peak temperature). The PLM results (Figures 6A-6B) showed that the sample was flattened and rod-shaped, with a particle size of approximately 10-50 μm.

[0092] TIFF0007936646000002.tif251170TIFF0007936646000003.tif87170

[0093] (2) Preparation of crystal forms C1 to C3 40.05 g of the crude compound of formula (I) was weighed out and mixed with five times the volume of ethanol. The mixture was stirred at 25°C for 30 minutes, and a clear solid precipitate formed. After continuing to stir for 2-3 hours, the mixture was filtered, and the filter cake was washed with 80 mL of ethanol. Three different solvate crystal forms C1, C2, and C3 were detected from the wet, undried compound of formula (I) formed in ethanol. Their XRPD results are shown in Figures 9A-9C, Tables 2-1, 2-2, and 2-3. However, crystal forms C1, C2, and C3 all changed to crystal form A after drying, and the XRPD results are shown in Figure 9D.

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[0095] TIFF0007936646000006.tif250170TIFF0007936646000007.tif38170

[0096] TIFF0007936646000008.tif250170TIFF0007936646000009.tif31170

[0097] (3) Preparation of crystal form B Crystal form B was obtained by shaking the crystalline product (crystal form A) of this example (1) in toluene solvent at room temperature for 24 hours, and the crystalline form did not change even after air drying at room temperature for 24 hours. The XRPD results are shown in Figure 3 and Table 3. The TGA / DSC results (Figures 4A-4B) showed that the sample of crystal form B had a weight loss of 9.33% when heated to 120°C and a weight loss of 5.36% when heated to 150°C, and that the sample had three endothermic peaks at 85.6°C, 130.7°C, and 144.3°C (peak temperatures). 1 The 1H NMR result (Figure 7A) showed that the molar ratio of residual solvent toluene to API in the sample was 1.6 (13.5 wt%). To further investigate the large TGA weight loss in the sample of crystal form B, heating experiments were performed. The XRPD result (Figure 8) showed that the crystal form of the sample of crystal form B did not change after being heated to 115°C and cooled to room temperature, but after being heated to 140°C and cooled to room temperature, the sample of crystal form B changed to crystal form A, but the crystallinity decreased. 1 The 1H NMR results (Figures 7B and 7C) showed that after heating the sample to 115°C and cooling to room temperature, the molar ratio of residual solvent toluene to API was 1.2 (10.5 wt%), and after heating the sample to 140°C and cooling to room temperature, no toluene solvent residue was detected. Considering the change in crystal form after heating, the large decrease in TGA weight, and the solvent residue shown in the nuclear magnetic resonance results after heating, it can be inferred that crystal form B is a toluene solvate.

[0098] TIFF0007936646000010.tif251170TIFF0007936646000011.tif61170

[0099] Example 2 Evaluation of crystal form A in this application (1) Hygroscopicity experiment (dynamic water vapor adsorption experiment or DVS) DVS curves were collected using SMS (Surface Measurement Systems) DVS Intrinsic and DVS Intrinsic plus. Relative humidity at 25°C was calibrated by the deliquescence points of LiCl, Mg(NO3)2, and KCl. The DVS results (Figure 10) showed that the sample of crystalline form A exhibited 2.880% water adsorption under 25°C / 80%RH conditions, demonstrating hygroscopicity, while the result for amorphous crystalline form under the same test conditions was 5.941%, indicating that the hygroscopic effect of crystalline form A is superior to that of amorphous crystalline form. Furthermore, the XRPD results before and after the DVS test of crystalline form A (Figure 11) showed no change in the crystal form of the sample, indicating good stability of crystalline form A. On the other hand, crystalline forms B, C1, C2, and C3 had low crystal form stability and all changed to crystalline form A after heating or drying.

[0100] (2) Solid state stability Crystal form A was left open at 60°C for 24 hours, and then left open at 25°C / 60%RH and 40°C / 75%RH for one week. The physical and chemical stability of the sample was then tested by XRPD and HPLC. The stability evaluation results are summarized in Table 4, the XRPD results are shown in Figure 12, and the HPLC results are shown in Table 5 and Figure 13. The results showed that the sample of crystal form A did not undergo any significant change in purity or crystal form after being left under the three conditions described above.

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[0102] TIFF0007936646000013.tif58170

[0103] (3) Purification / impurity removal effect In this example, the effects of the crystalline form A sample and the amorphous sample of the compound of formula (I) on the purification and impurity removal of the crude product of the compound of formula (I) were further evaluated and compared.

[0104] Amorphous slurry preparation step: Approximately 0.5 g of compound (I) was placed in a 25 mL glass bottle with a magnetic stirrer, 5 mL of a different solvent was added, and the mixture was slurryed at room temperature. The mixture was filtered, the filter cake was removed, and its purity was measured by high-performance liquid chromatography. Here, the selection of different solvents was performed by mixing solvents with high solubility for compound (I) (e.g., methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate (EA), isopropyl acetate (IPAC), tetrahydrofuran (THF), toluene, dichloromethane (DCM), dimethylformamide (DMF), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), etc.) and solvents with low solubility for compound (I) (e.g., water, methyl-tert-butyl ether (MTBE), and n-heptane) in a volume ratio of 1:1 and screening for solvent systems that could precipitate a solid. The selected amorphous slurry solvent systems and their corresponding purification effects are shown in Table 6.

[0105] Purification process for crystalline form A: 3.5 g of the crude product of compound (I) was placed in a 50 mL reaction bottle equipped with a magnetic stirrer, 17.5 mL of ethanol was added, the mixture was stirred at 25°C for 15 minutes, filtered, the filter cake was washed with 5 mL of ethanol, and the wet material was dried under reduced pressure to obtain the crystalline compound (I). The purity was measured by high-performance liquid chromatography.

[0106] TIFF0007936646000014.tif200170

[0107] Table 6 summarizes the effectiveness comparison of the two purification methods. Compared with the HPLC results of the crude compound of formula (I), purifying amorphous samples by slurrying them using various solvent mixtures basically had no effect on removing impurities. In contrast, the purification effect of crystalline form A was remarkable, not only improving the purity of the crude product from 92.95% before purification to 98.2%, but also completely removing impurities such as RRT0.54, RRT0.92, RRT0.97, and RRT1.08. For impurities that are difficult to remove by amorphous slurrying, such as RRT0.63, RRT0.85, RRT0.92, RRT0.95, RRT0.97, and RRT1.21, the crystallization purification method of crystalline form A has a more significant purification effect than amorphous form.

[0108] Furthermore, Table 7 shows the results of a comparative study of the removal capabilities of a purification method involving slurrying with ethanol / water after column chromatography and a crystallization method using crystalline form A, regarding impurities that are difficult to remove. The results showed that crystalline form A had a superior removal effect against impurities RRT0.83 and RRT0.98, which are difficult to remove by column chromatography. In particular, for impurity RRT0.98 (structural formula shown in Figure 14), the crystallization method using crystalline form A could control it to below the detection limit. On the other hand, the purification method using column chromatography is time-consuming and labor-intensive, has high production costs, high demands on processes and equipment, and makes it difficult to control impurities, whereas the crystallization purification method using crystalline form A is environmentally friendly and advantageous in reducing production costs.

[0109] TIFF0007936646000015.tif66170

Claims

1. Crystalline form A of the free base of the compound represented by formula (I), Crystal form A exhibits characteristic peaks at diffraction angle 2θ values ​​of 5.28°±0.2°, 7.17°±0.2°, 8.50°±0.2°, 10.66°±0.2°, 14.33°±0.2°, 15.84°±0.2°, and 18.60°±0.2°, as determined by X-ray powder diffraction.

2. Crystal form A according to claim 1, wherein the diffraction angle 2θ has one or more characteristic peaks at 12.61°±0.2°, 14.83°±0.2°, 15.26°±0.2°, 16.57°±0.2°, 19.97°±0.2°, and 21.97°±0.2°.

3. Crystal form A according to claim 1, having characteristic peaks at diffraction angle 2θ values ​​of 12.61°±0.2°, 14.83°±0.2°, 15.26°±0.2°, 16.57°±0.2°, 19.97°±0.2°, and 21.97°±0.2°.

4. Crystalline form A according to claim 1, which is an anhydrous and / or solvate.

5. A pharmaceutical composition comprising crystalline form A as described in any one of claims 1 to 4, and a optionally pharmaceutically acceptable carrier.

6. A pharmaceutical composition for treating or alleviating a disease caused by bacterial infection or a related pathological condition, comprising crystalline form A as described in any one of claims 1 to 4.

7. The pharmaceutical composition according to claim 6, wherein the bacteria are selected from Helicobacter pylori, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Acinetobacter baumannii, Bacteroides fragilis, Bifidobacterium longum, Ruminococcus, Prevotella, Clostridium perfringens, Clostridioides difficile, Lactobacillus acidophilus, Egasella lenta, Fusobacterium nucleatum, Gardnerella vaginalis, Mobiluncus murielis, Peptostreptococcus, Porphyromonas asaccharoritica, Prevotella vivia, Cutibacterium acnes, and Veillonella parbra.

8. The pharmaceutical composition according to claim 6, wherein the disease or related pathological condition is selected from gastritis, gastric ulcer, bacterial vaginosis, diarrhea, pneumonia, appendicitis, cholecystitis, otitis media, endocarditis, endometritis, brain abscess, myocardial necrosis, osteomyelitis, peritonitis, empyema, salpingitis, suppurative arthritis, liver abscess, sinusitis, pelvic inflammatory disease and bacteremia, as well as upper respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, lung infections, intra-abdominal infections, eye infections, ear infections, oral infections and surgical infections.

9. A method for producing crystalline form A according to any one of claims 1 to 4, comprising crystallizing a compound represented by formula (I) in a solvent containing an alcohol-based solvent.

10. The method according to claim 9, wherein the alcohol-based solvent is selected from one or more combinations selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.

11. The method according to claim 9, wherein the alcohol-based solvent is methanol, ethanol, or a combination thereof.

12. The method according to claim 9, further comprising crystallization in an alcohol-based solvent.

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