WO2023143350A1 - 吩噻嗪类化合物的晶型、盐、制备方法及用途 - Google Patents

吩噻嗪类化合物的晶型、盐、制备方法及用途 Download PDF

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WO2023143350A1
WO2023143350A1 PCT/CN2023/073055 CN2023073055W WO2023143350A1 WO 2023143350 A1 WO2023143350 A1 WO 2023143350A1 CN 2023073055 W CN2023073055 W CN 2023073055W WO 2023143350 A1 WO2023143350 A1 WO 2023143350A1
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ethyl
phenyl
methylpiperazin
phenothiazine
acid
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PCT/CN2023/073055
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English (en)
French (fr)
Inventor
于舟
何鹏
董光新
李毅
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Chengdu Henghao Innovative Science And Technology Co Ltd
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Chengdu Henghao Innovative Science And Technology Co Ltd
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Priority to KR1020247027914A priority Critical patent/KR20240134998A/ko
Priority to CN202380019090.6A priority patent/CN118613475A/zh
Priority to AU2023213780A priority patent/AU2023213780B2/en
Priority to JP2024544862A priority patent/JP2025502542A/ja
Priority to US18/833,411 priority patent/US20250145605A1/en
Priority to EP23746231.2A priority patent/EP4471016A4/en
Priority to CA3249374A priority patent/CA3249374A1/en
Publication of WO2023143350A1 publication Critical patent/WO2023143350A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a crystal form, a salt, a preparation method and an application of a medicinal phenothiazine compound.
  • Ferroptosis is an iron-dependent and lipid peroxidation-driven programmed cell death.
  • the morphological features of ferroptosis are mainly manifested by reduced mitochondrial volume, increased mitochondrial membrane density, decreased or disappeared mitochondrial cristae, ruptured mitochondrial outer membrane, and normal nucleus size, which is the difference between ferroptosis and apoptosis, necrosis and autophagy.
  • the biochemical features of ferroptosis are mainly the accumulation of intracellular iron and ROS, activation of the mitogen-activated protein kinase (MAPK) signaling system, inhibition of the cystine/glutamate transporter system, and increased NADPH oxidation.
  • MAPK mitogen-activated protein kinase
  • ferroptosis is closely related to many conditions, disorders and diseases. This mode of cell death was first discovered by Dixon et al. in 2012 to be associated with small molecule-induced RAS tumor cell death (Scott J Dixon et al., Cell. 2012 May 25;149(5):1060-72.). Recent studies have further implicated the role of ferroptosis in cancer, organ damage, and degenerative diseases (Xuejun Jiang et al., Nat Rev Mol Cell Biol. 2021 Apr;22(4):266-282). Specifically, it involves the occurrence and development of various cancers, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, immune-related diseases, liver and kidney failure, inflammation, metabolic diseases, etc.
  • ferroptosis inhibitors are considered as potential drugs for the treatment of these diseases.
  • the polymorphism of drugs is a common phenomenon in drug research and development, and is an important factor affecting the quality of drugs.
  • Different crystal forms often have different solubility, stability, hygroscopicity and bioavailability, thus directly affecting the quality of the pharmaceutical preparation of the drug, the absorption behavior in the human body, and ultimately affect the therapeutic effect of the preparation in the human body.
  • One of the objects of the present invention is to provide various crystal forms of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine, especially its Various crystal forms of hydrochloride improve the druggability of the drug, such as stability, solubility, hygroscopicity, and bioavailability.
  • Another object of the present invention is to provide the pharmaceutical composition, preparation method and application of the above-mentioned crystal form.
  • the present invention adopts the following technical solutions:
  • the X-ray powder diffraction pattern of the Form A has the following characteristic peaks: 10.68 ⁇ 0.2°, 14.36 ⁇ 0.2°, 17.84 ⁇ 0.2°, 18.57 ⁇ 0.2°, 21.08 ⁇ 0.2°, 22.14 ⁇ 0.2°, 23.40 ⁇ 0.2°, 27.50 ⁇ 0.2°, 29.03 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form A has the following characteristic peaks: 10.68 ⁇ 0.2°, 14.36 ⁇ 0.2°, 16.54 ⁇ 0.2°, 17.84 ⁇ 0.2°, 18.57 ⁇ 0.2°, 20.89 ⁇ 0.2°, 21.08 ⁇ 0.2°, 22.14 ⁇ 0.2°, 22.92 ⁇ 0.2°, 23.40 ⁇ 0.2°, 25.88 ⁇ 0.2°, 27.50 ⁇ 0.2°, 29.03 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the Form A has the following characteristic peaks: 10.68 ⁇ 0.2°, 12.63 ⁇ 0.2°, 14.36 ⁇ 0.2°, 16.06 ⁇ 0.2°, 16.54 ⁇ 0.2°, 17.84 ⁇ 0.2°, 18.57 ⁇ 0.2°, 20.89 ⁇ 0.2°, 21.08 ⁇ 0.2°, 22.14 ⁇ 0.2°, 22.92 ⁇ 0.2°, 23.40 ⁇ 0.2°, 25.11 ⁇ 0.2°, 25.51 ⁇ 0.2°, 25.88 ⁇ 0.2°, 27.50 ⁇ 0.2°, 28.54 ⁇ 0.2°, 29.03 ⁇ 0.2°, 33.55 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A is shown in FIG. 1 using Cu—Ka radiation and expressed in 2 ⁇ angles.
  • One or more embodiments provide crystals of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride having the crystalline form FormB, using Cu-Ka radiation and expressed in 2 ⁇ angle, the X-ray powder diffraction pattern of the crystal form FormB has the following characteristic peaks: 16.46 ⁇ 0.2°, 22.01 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B has the following characteristic peaks: 16.46 ⁇ 0.2°, 22.01 ⁇ 0.2°, 27.62 ⁇ 0.2°, 28.91 ⁇ 0.2°, 33.41 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B has the following characteristic peaks: 5.41 ⁇ 0.2°, 10.92 ⁇ 0.2°, 16.46 ⁇ 0.2°, 22.01 ⁇ 0.2°, 27.62 ⁇ 0.2°, 28.91 ⁇ 0.2°, 33.41 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B is shown in FIG. 3 .
  • One or more embodiments provide a pharmaceutical composition, comprising the hydrochloride salt form Form A or the hydrochloride salt form Form B, and a pharmaceutically acceptable carrier.
  • One or more embodiments provide that the crystalline form FormA of the hydrochloride, or the crystalline form B of the hydrochloride, or its pharmaceutical composition is used for preventing and/or treating cancer, organ damage, and degenerative diseases. use in .
  • One or more embodiments provide that the crystalline Form A of the hydrochloride, or the crystalline Form B of the hydrochloride, or its pharmaceutical composition is used for the prevention and/or treatment of cancer, neurodegenerative diseases, heart and brain Use in vascular diseases, immune-related diseases, liver and kidney failure, inflammation, and metabolic diseases;
  • the disease may be selected from but not limited to cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, brain Stroke, ischemia-reperfusion injury, atherosclerosis, immune-related diseases, liver and kidney failure, inflammation, diabetes, and complications of diabetes;
  • the stroke is hemorrhagic stroke and/or ischemic stroke; the ischemic stroke is also known as cerebral infarction or cerebral infarction.
  • One or more embodiments provide the crystalline form FormA of hydrochloride, or the crystalline form B of hydrochloride, or the use of a pharmaceutical composition thereof in the preparation of a ferroptosis inhibitor.
  • One or more embodiments provide a method for preparing the crystalline form FormA of the hydrochloride salt of the present application, which includes compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl )-10H-phenothiazine was dispersed in methanol at 10-40°C, then a mixed solution of concentrated hydrochloric acid and methanol was added dropwise, stirred and crystallized, filtered, the filter cake was washed with methanol, and then the filter cake was vacuum-dried to obtain crystalline substances;
  • the weight ratio of the solvent methanol to the compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine is 5:1-15 :1, such as 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, 10.46: 1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1, or 15:1;
  • the weight ratio of the compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine to concentrated hydrochloric acid is 1:1-8 :1, such as 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.15:1, 4.5:1, 5:1, 5.5:1, 6: 1, 6.5:1, 7:1, 7.5:1, 8:1;
  • the stirring and crystallization time is 1-8h, such as 1h, 2h, 3h, 4h, 5h, 6h, 7h or 8h.
  • a method for preparing the crystalline form FormA of the hydrochloride salt of the present application includes compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl) Ethyl)-10H-phenothiazine is dispersed in acetone and water at 10-40°C, then a mixed solution of concentrated hydrochloric acid, acetone and water is added dropwise, stirred and crystallized, filtered, the filter cake is washed with acetone, and then filtered The cake was vacuum dried to obtain a crystalline substance;
  • the weight ratio between the solvent acetone, water and the compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine is ( 1-8):(0.5-3):(0.5-3), preferably (4-6):(0.5-1):(0.5-1), such as 4:1:1, 4.74:1:1, 5 :1:1;
  • the weight ratio of the compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine to concentrated hydrochloric acid is 1:1-8 :1, such as 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.66:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5: 1, 7:1, 7.5:1, 8:1.
  • the stirring crystallization time is 1-8h, preferably 2-5h;
  • the mass fraction of concentrated hydrochloric acid in the above preparation method is not less than 20%, such as 20%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%.
  • Organ damage in the present invention refers to any damage, injury, reduction or loss of one or more functions of an organ or tissues related to the organ.
  • Injury may include, but is not limited to, changes in the tissue or structure of an organ in the form of damage or changes relative to normal conditions, such as the development of areas of tissue necrosis, or disruption or loss of cellular or tissue structural integrity, or from, for example, cellular inflammatory processes or abnormal accumulation of apoptotic cellular material or debris. It should be recognized that different organs and tissue types may present different injury pathologies. Organ damage can also lead to the pathogenesis of a disorder or disease associated with the damage (ie, a disorder associated with organ damage).
  • the molar ratio of compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine to hydrochloric acid is about 1:(1 ⁇ 0.5), for example 1:(1 ⁇ 0.4), for example 1:(1 ⁇ 0.2), for example 1:(1 ⁇ 0.1), for example 1:1.
  • crystal form FormA of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride of the present invention is also called crystal form A ;
  • the present invention has the following beneficial effects:
  • the present invention has obtained two brand-new compound crystal forms through a large number of experimental studies, and its physical and chemical properties are significantly improved compared with free state compounds:
  • Hydrochloride crystal form A has a very high purity, for example, the purity reaches 99.76% in one embodiment of the present invention; the solubility in water is 10,000 times higher than that of the free compound, and it is also Good stability is maintained.
  • the crystal form A still maintains the same crystal form under grinding conditions, and has good mechanical stability.
  • the crystal form The melting point of A is about 265.31°C, indicating that the crystal form has good thermal stability.
  • the crystal form A still maintains the same crystal form under accelerated and stable conditions, and the purity remains basically unchanged.
  • the crystal form A was dissolved in different solvents, and the crystal transformation did not occur after magnetic stirring; in addition, the bioavailability of the crystal form A was also significantly improved compared with the free state compound.
  • the hydrochloride crystal form B has also achieved unexpected beneficial effects on the solubility compared with the free state compound.
  • the solubility of the crystal form B in water is 1000 times higher than that of the free state compound.
  • hydrochloride crystal form A has better physical and chemical properties:
  • hydrochloride form A In terms of hygroscopicity, the moisture absorption of hydrochloride form A at 25°C/80%RH is only 0.36%, indicating that it has only slightly hygroscopicity, which is better than that of crystal form B; in terms of solubility, hydrochloride form A is in The solubility in water and hydrochloric acid is better than crystal form B. For example, in water and hydrochloric acid solution with a pH value of 1.0, the solubility of hydrochloride crystal form A is more than 10 times that of hydrochloride crystal form B.
  • the hydrochloride crystal form A with better solubility has better stability, for example: in one embodiment of the present invention, the crystal form A remains unchanged under accelerated and stable conditions, while Crystal form B began to transform into crystal form A at room temperature for 2 days; in terms of stability, the purity of hydrochloride crystal form A remained basically unchanged after being placed under the conditions of long-term 25°C/60%RH and accelerated 40°C/75%RH for a week , good chemical stability, no crystal form change was observed in the sample; hydrochloride salt form A was placed under the conditions of RT-75%RH and RT-97%RH for a week, no crystal form change was observed in the sample; hydrochloride salt form After A is ground, its crystal form remains unchanged. And, under accelerated conditions (40°C ⁇ 2°C, 75%RH ⁇ 10%RH, 6 months), the total impurity content of FormA is significantly lower than that of FormB, and the stability of FormA is better than that of FormB.
  • Another object of the present invention is also to provide a variety of pharmaceutical compounds of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine Acceptable salts, which have significantly improved solubility and stability compared to compounds;
  • Another object of the present invention is to provide the preparation method and application of the salt of the above compound.
  • the moles of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine and hydrochloric acid in the hydrochloride The ratio is about 1:(0.5-2), for example 1:1, for example 1:2.
  • the mol ratio of compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine to acid is acceptable Appropriate fluctuations within the range, for example:
  • the molar ratio of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine to acid can be 1 :(2 ⁇ 0.4), for example 1:(2 ⁇ 0.3), for example 1:(2 ⁇ 0.2), for example 1:(2 ⁇ 0.1), for example 1:2;
  • the acid is optionally selected from hydrochloric acid , methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, tartaric acid, hydrobromic acid, oxalic acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid, perchloric acid, malic acid, water citric acid, mandelic acid, lactic acid and succinic acid.
  • the molar ratio of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine to acid can be 1 :(1 ⁇ 0.2), for example 1:(1 ⁇ 0.15), for example 1:(1 ⁇ 0.1), for example 1:(1 ⁇ 0.05), for example 1:1;
  • the acid is optionally selected from hydrochloric acid , methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, tartaric acid, hydrobromic acid, oxalic acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid, perchloric acid, malic acid, water citric acid, mandelic acid, lactic acid and succinic acid.
  • a method for preparing a salt of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine comprising 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine reacts with acid to obtain a salt;
  • the reaction is carried out in water and/or an organic solvent, and the solvent is optionally selected from one or more of ketones with 2 to 6 carbon atoms, ethyl acetate, lower aliphatic alcohols, and tetrahydrofuran Mixture; said lower aliphatic alcohol refers to the alcohols containing 1-8 carbon atoms;
  • ketones with 2 to 6 carbon atoms are preferably acetone
  • the lower fatty alcohol is optionally selected from methanol, ethanol, propanol and isopropanol;
  • the reaction is carried out in a solvent or more than one mixed solvent in acetone, methanol or ethanol;
  • the acid is selected from hydrochloric acid, HCl, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, tartaric acid, more preferably hydrochloric acid;
  • HCl refers to HCl gas.
  • a method for preparing 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride comprising Reaction of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine and hydrochloric acid in acetone, or ethanol, or isopropanol, or tetrahydrofuran , stir and filter.
  • a pharmaceutical composition comprising 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine salt and one or more pharmaceutically acceptable carriers and/or diluents; preferably, the salt is hydrochloride.
  • a salt of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine or a salt comprising 2-(
  • the pharmaceutical composition of the salt of 1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine is used in the preparation for the prevention and/or treatment of cancer, organ damage and degeneration use in disease.
  • a salt of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine or a salt comprising 2-(
  • the pharmaceutical composition of the salt of 1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine is used in the preparation for the prevention and/or treatment of cancer and neurodegenerative diseases , cardiovascular and cerebrovascular diseases, immune-related diseases, liver and kidney failure, inflammation, and metabolic diseases.
  • the disease is cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, stroke, ischemia-reperfusion Injury, immune-related disease, liver and kidney Failure, inflammation, atherosclerosis, diabetes, or complications of diabetes.
  • the stroke is hemorrhagic stroke and/or ischemic stroke; the ischemic stroke is also known as cerebral infarction or cerebral infarction.
  • the present invention is:
  • the solubility of hydrochloride is significantly improved compared with free compound.
  • the solubility of hydrochloride in water is increased by about 7700 times compared with free compound; in addition, other salts such as citrate are also more soluble than free compound.
  • the stability of the hydrochloride is greatly improved compared with the free compound.
  • the stability of the hydrochloride is better than that of the free compound under high temperature, high humidity and light conditions, and the total The impurity content is significantly lower; in addition, the hygroscopicity of the hydrochloride is also lower than that of the free compound.
  • hydrochloride has better dissolving properties than other salts.
  • hydrochloride is also improved by 7 times compared to citrate with better solubility, and compared with maleate And fumarate has also improved more than 35 times;
  • hydrochloride also has better effect than other salts, for example in one embodiment of the present invention, hydrochloride is in high temperature, high humidity, light condition The stability of the hydrochloride is higher than that of other salts, and the total impurity content is significantly lower than that of other salts.
  • the color of the hydrochloride solution remains unchanged in a hydrochloric acid solution with a pH of 1.0, while other salts such as lemon Salt, fumarate, and maleate have all undergone significant changes, indicating that the stability of hydrochloride is better; in terms of hygroscopicity, hydrochloride is also lower than other salts; in addition, hydrochloride It has good solidity during the preparation process, while other salts such as methanesulfonate and p-toluenesulfonate become sticky.
  • Fig. 1 is the XRPD collection of illustrative plates of crystal form FormA obtained in embodiment 1;
  • Fig. 2 is the XRPD spectrum of the crystal form FormA obtained in Example 2;
  • Figure 3 is the XRPD spectrum of Form B
  • Fig. 4 is the purity detection spectrum of crystalline form FormA
  • Fig. 5 is the 1HNMR spectrum of crystal form FormA
  • Figure 6 is the TGA spectrum of Form A
  • Fig. 7 is the collection of diagrams of the DSC of crystalline form FormA
  • Figure 8 is the XRPD spectrum of the stability study of the crystalline form FormA
  • Figure 9 is the XRPD spectrum of the stability study of the Form B form
  • Figure 10 is the 1 HNMR spectrum of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride;
  • Fig. 11 is the 13 CNMR spectrum of 2-(1-(4-(4-methylpiperazin-1-yl) phenyl) ethyl)-10H-phenothiazine hydrochloride;
  • Figure 12 is the 1 HNMR spectrum of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine citrate;
  • Fig. 13 is the 1 HNMR spectrum of 2-(1-(4-(4-methylpiperazin-1-yl) phenyl) ethyl)-10H-phenothiazine fumarate;
  • Fig. 14 is a 1 H NMR spectrum of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine maleate.
  • Example 1 Preparation method 1 of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride crystal form FormA
  • the obtained crystalline form FormA has a purity of 99.76%, a maximum single impurity content of 0.068%, and the total impurity and single impurity are less than or equal to 0.15% (
  • the daily maximum daily dose of this product is ⁇ 2 g/day) (see Figure 4 for the purity detection spectrum, the name of the main peak in the spectrum is DA414, which is 2-(1-(4-(4-methylpiperazin-1-yl)phenyl) Ethyl)-10H-phenothiazine hydrochloride crystal form FormA);
  • Example 4 XRPD determination of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride crystal form FormA:
  • Example 5 XRPD determination of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride crystal Form B:
  • Embodiment 6 TGA determination of crystal form FormA
  • Embodiment 7 the DSC determination of crystal form FormA
  • the DSC detection spectrum of the crystalline form FormA is shown in FIG. 7 .
  • the DSC spectrum shows that the crystalline FormA has a single endothermic peak, and the melting point is about 265.31°C, indicating that the crystalline FormA has good thermal stability.
  • Embodiment 9 Other preparation methods of crystalline form FormA
  • N/A means that not enough samples were obtained for detection.
  • N/A means that not enough samples were obtained for detection.
  • Example 10 Other preparation methods of Form B
  • Embodiment 11 Moisture-absorbing research
  • the hygroscopicity was evaluated by dynamic moisture adsorption (DVS). The results showed that the moisture adsorption of Form A hydrochloride was about 0.36% at 25°C/80%RH, indicating that it was slightly hygroscopic, and the crystal form remained unchanged before and after the hygroscopicity test.
  • Embodiment 12 Solubility comparative study
  • the inventors found in their research that other salt forms of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine, such as citrate Compared with their salts, the crystal forms obtained by crystallization of fumarate and maleate have basically the same solubility in water and hydrochloric acid solution at pH 1.0, and have not been significantly improved.
  • Embodiment 13 crystal form stability test
  • Test operation 1 Take the hydrochloride crystal form A sample and place it for a week under the conditions of long-term 25°C/60%RH and accelerated 40°C/75%RH respectively, and test the change of the crystal form.
  • the test results show that the hydrochloride crystal form After the Form A sample was placed for a week under the two test conditions, the purity remained basically unchanged, the chemical stability was good, and no crystal form change was observed in the sample.
  • the XRPD comparison chart before and after the stability of the sample is placed is shown in Figure 8.
  • Test operation 2 Weigh about 10 mg of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride form FormA in a 5mL vial , after placing the 5 mL vial open in the corresponding hygrostat, seal the hygrostat. After standing at room temperature for about a week, the solid was collected and subjected to XRPD test, and no crystal form change was observed in the sample. The test results are shown in Table 17.
  • Test operation 1 Weigh about 10 mg of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride form FormA into a 5mL vial 1 mL of a single solvent or a mixed solvent listed in Table 19 was added respectively, and the resulting suspension was placed under magnetic stirring at 5°C for about 3 days, and the solid was collected by centrifugation and subjected to XRPD test. The sample did not undergo crystallization. The test results are shown in Table 19.
  • Experimental operation 2 Weigh about 10 mg of starting material 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride crystal Type FormA into a 5mL vial, add 0.5mL of a single solvent or a mixed solvent listed in Table 20 to obtain a cloudy solution. After the turbid solution was magnetically stirred at room temperature for about 3 days, the solid was collected by centrifugation and subjected to XRPD test, and no crystallization occurred in the sample. The test results are shown in Table 20.
  • Test operation 3 Weigh about 10 mg of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride crystal form FormA to Into a 5mL vial, add 0.5mL of a single solvent or a mixed solvent listed in Table 21, and place the resulting suspension at 50°C for about 3 days under magnetic stirring, then collect the solid by centrifugation and conduct an XRPD test. The sample did not undergo crystallization. The test results are shown in Table 21.
  • Test operation Weigh a certain amount of hydrochloride crystal Form B sample into a sample bottle, then place the sample bottle closed at room temperature, and after 2 days and 5 days of closing at room temperature, take a certain amount of sample in the sample bottle to test XRPD, The test results show that the hydrochloride crystal form Form B sample was placed closed at room temperature for 2 days and began to crystallize to the hydrochloride crystal form Form A, and after 5 days of storage, the crystal form B partially transformed into the hydrochloride crystal form
  • the crystal form FormB is an unstable crystal form, and the XRPD pattern of the stability study of the crystal form FormB is shown in FIG. 9 . It can be seen that the crystal form A has better crystal stability than the crystal form B.
  • crystal form A has good compressibility, fluidity and other properties, and its specific surface area, bulk density, porosity and particle size and other characteristics are very suitable for the development and preparation of pharmaceutical preparations.
  • Form B does not have these characteristics.
  • the hydrochloride salt form A has better stability, and the measured total impurity content is lower.
  • the crystal forms FormA and FormB were placed under accelerated conditions (40°C ⁇ 2°C, 75%RH ⁇ 10%RH) for 6 months to detect the stability of the crystal forms FormA and FormB
  • Table 22 shows the stability experiments of different crystal forms. The results showed that the crystal form FormA was placed under accelerated conditions for 6 months, and the total impurities increased from 0.25% to 0.41%, while the crystal form FormB was placed under accelerated conditions for 6 months, and the total impurities increased from 0.28% to 0.88%.
  • the stability of FormB is very poor, and the crystal form FormA is more stable than the crystal form FormB.
  • Embodiment 14 Pharmacokinetic comparative study
  • Experimental method select 3 healthy male SD rats, and after fasting overnight, give 10 mg/kg of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl )-10H-phenothiazine (free state) or 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride Form A suspension (vehicle is 0.5% CMC-Na), the administration volume is 10ml/kg.
  • Embodiment 15 The research of the inhibitory rate of the compound of the present invention to Ferroptosis
  • the Ferroptosis screening model mainly uses the CCK8 cell viability detection method. First, culture mouse hippocampal neuron cells HT22 and human neuroblastoma cells SH-SY5Y in a dish, inoculate the cells in the logarithmic growth phase in a specific number of 96-well plates (5000 cells/well), 80 ⁇ L per well , and then cultured in an incubator at 37°C and 5% CO 2 to allow the cells to adhere to the wall.
  • each group also set 3 replicate wells to ensure the accuracy of the results. After dosing, put them into the incubator and cultivate for 24 hours.
  • Inhibition rate % [1-(A experimental group-A blank)/(A solvent-A blank)]*100%
  • the specific synthesis method of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine refers to the preparation method in the international application WO2019205854A1.
  • the impurities in the product were determined, and the total impurity content was 1.36%.
  • the impurities of the above hydrochloride products were measured, and the total impurity content was 0.10% to 0.25%.
  • the impurities of the above citrate products were measured, and the total impurity content was 0.64% to 0.80%.
  • the impurities in the above fumarate products were measured, and the total impurity content was 0.76% to 0.84%.
  • hydrochloric acid was replaced by hydrobromic acid to prepare 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrobromide.
  • fumaric acid was replaced by propionic acid to prepare 2-(1-(4-(4-methylpiperazin-1-yl) Phenyl)ethyl)-10H-phenothiazine propionate.
  • Solubility test result shows: 2-(1-(4-(4-methylpiperazin-1-yl) phenyl) ethyl) -10H-phenothiazine hydrochloride in water and pH1.0 hydrochloric acid solution
  • the solubility is better than 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine, especially the solubility in water;
  • 2-(1- The solubility of (4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine citrate in water was higher than that of 2-(1-(4-(4-methylpiperazine) -1-yl)phenyl)ethyl)-10H-phenothiazine is 1000 times higher.
  • solubility of hydrochloride is also significantly better than that of other salts of this compound, and the solubility of citrate is 7 times higher than that of maleate and fumarate. more than double.
  • Embodiment 32 Stability Test 1
  • the high-temperature test results show that after 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine is salified, its stability at high temperature is higher than that of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine in free state; wherein the hydrochloride has the best stability under high temperature conditions, No change in properties, low total impurity generation.
  • test product is placed in a constant humidity airtight container at 25°C and the relative humidity is 90% ⁇ 5%. Stand for 30 days, and take samples on the 5th, 10th and 30th days.
  • the results of the high-humidity test show that the stability of 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine under high-humidity conditions after salification Higher than free 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine; wherein hydrochloride has excellent stability under high humidity conditions Compared with other salt types, the properties remain unchanged, and the amount of total impurities generated is low.
  • the test product is placed in the stability test box, and the illuminance is 45001x ⁇ 5001x, and the total illuminance of the light source is not lower than 1.2 x10 6 lux ⁇ hr, and the energy of the near-ultraviolet lamp is not lower than 200W ⁇ hr/ m2 for 30 days, and samples are taken on the 5th, 10th and 30th days.
  • the light test results show that: after 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine is salt-formed, in the light bar
  • the stability under the conditions is higher than that of the free state 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine;
  • the appearance changed from light yellow to gray in 5 days, and dark gray in 10 days; the stability of hydrochloride under light conditions was better than that of other salt types, the properties did not change, and the amount of total impurities produced was low.
  • the results of the stability experiment show that 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine hydrochloride is stable under high temperature, high humidity, The stability under light conditions is higher than that of free compounds and other salts, and the total impurity content is significantly lower than other salts and free compounds.
  • Embodiment 33 Stability test 2
  • Embodiment 34 Contrastive experiment of hygroscopicity
  • Deliquescence absorption of sufficient water to form a liquid
  • the weight gain of moisture is not less than 15%;
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15% but not less than 2%;

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Abstract

提供了一种吩噻嗪类化合物的晶型、盐、及其制备方法和用途，该吩噻嗪类化合物的盐酸盐及其晶体可用作铁死亡抑制剂，并且该盐酸盐及其晶体有较好的溶解性、稳定性、口服吸收生物利用度和成药性。

Description

吩噻嗪类化合物的晶型、盐、制备方法及用途
本申请要求于2022年1月28日提交中国国家知识产权局、申请号为202210108728.0和202210108746.9的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药化学领域，具体涉及一种药用吩噻嗪类化合物的晶型、盐、其制备方法及用途。
背景技术
铁死亡(Ferroptosis)是一种铁依赖性和脂质过氧化驱动的程序性细胞死亡方式。铁死亡在形态学上的特征主要表现为线粒体体积变小，线粒体膜密度增加，线粒体嵴减少或消失，线粒体外膜破裂，而细胞核大小正常，这是铁死亡区别于凋亡、坏死和自噬的主要形态学特征。铁死亡的生化特点主要表现为细胞内铁和ROS的积累、丝裂原活化蛋白激酶(MAPK)信号传导系统的激活、胱氨酸/谷氨酸转运蛋白系统的抑制以及NADPH氧化增加等。
越来越多的研究证实细胞铁死亡与许多病症、障碍和疾病都密切相关。Dixon等人最早在2012年发现这种细胞死亡模式与小分子诱导的RAS肿瘤细胞死亡有关(Scott J Dixon等人，Cell.2012 May 25；149(5):1060-72.)。最近的研究进一步表明了铁死亡在癌症、器官损伤和退行性疾病中的作用(Xuejun Jiang等人，Nat Rev Mol Cell Biol.2021 Apr；22(4):266-282)。具体地，涉及到多种癌症、神经退行性疾病、心脑血管疾病、免疫相关疾病、肝肾衰竭、炎症、代谢性疾病等的发生和发展。尤其是在阿尔茨海默病、帕金森病、肿瘤、脑卒中、缺血再灌注损伤、动脉粥样硬化、肝肾衰竭、炎症以及糖尿病并发症等疾病中都发挥了重要作用。通过刺激或抑制铁死亡的发生，可以耐受相关疾病的发生和发展，因此，铁死亡抑制剂被认为可能是治疗这些疾病的潜在药物。
国际申请WO2019205854A1公开了化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪及其制备方法，其具有优异的铁死亡抑制活性。但现有技术并没有关于其晶型的研究。
药物的多晶型是药品研发中的常见现象，是影响药品质量的重要因素。不同晶型之间往往具有不同的溶解性、稳定性、引湿性和生物利用度，因而直接影响药物的药用制剂的质量、在人体的吸收行为，并最终影响该制剂在人体中产生的治疗效果和副作用的获益比。因此，有必要对该化合物进行晶型研究，以找到纯度高、溶解度好、稳定性好以及生物利用度高的晶型，从而使药物的有效性最大化，这对于药物开发具有重要的意义。
发明内容
本发明的目的之一在于，提供2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的多种晶型，尤其是其盐酸盐的多种晶型，改善了药物的成药性，如稳定性、溶解性、吸湿性、生物利用度等。
本发明的另一目的在于提供上述晶型的药物组合物、制备方法及用途。
为实现以上目的，本发明采用以下技术方案：
在一个或多个实施方式提供了2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的晶体，其具有晶型FormA，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、14.36±0.2°、18.57±0.2°、21.08±0.2°、22.14±0.2°、23.40±0.2°、29.03±0.2°。
一个或多个实施方式，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、14.36±0.2°、17.84±0.2°、18.57±0.2°、21.08±0.2°、22.14±0.2°、23.40±0.2°、27.50±0.2°、29.03±0.2°。
一个或多个实施方式，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、14.36±0.2°、16.54±0.2°、17.84±0.2°、18.57±0.2°、20.89±0.2°、21.08±0.2°、22.14±0.2°、22.92±0.2°、23.40±0.2°、25.88±0.2°、27.50±0.2°、29.03±0.2。
一个或多个实施方式，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、12.63±0.2°、14.36±0.2°、16.06±0.2°、16.54±0.2°、17.84±0.2°、18.57±0.2°、20.89±0.2°、21.08±0.2°、22.14±0.2°、22.92±0.2°、23.40±0.2°、25.11±0.2°、25.51±0.2°、25.88±0.2°、27.50±0.2°、28.54±0.2°、29.03±0.2°、33.55±0.2°。
在一个或多个实施方式中，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱如图1所示。
一个或多个实施方式提供了2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的晶体，其具有晶型FormB，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱具有以下特征峰：16.46±0.2°、22.01±0.2°。
一个或多个实施方式，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱具有以下特征峰：16.46±0.2°、22.01±0.2°、27.62±0.2°、28.91±0.2°、33.41±0.2°。
一个或多个实施方式，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱具有以下特征峰：5.41±0.2°、10.92±0.2°、16.46±0.2°、22.01±0.2°、27.62±0.2°、28.91±0.2°、33.41±0.2°。
一个或多个实施方式中，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱如图3所示。
一个或多个实施方式提供了药物组合物，包含如上所述的盐酸盐的晶型FormA、或盐酸盐的晶型FormB，以及药学上可接受的载体。
一个或多个实施方式提供了所述的盐酸盐的晶型FormA、或盐酸盐的晶型FormB、或其药物组合物在制备用于预防和/或治疗癌症、器官损伤和退行性疾病中的用途。
一个或多个实施方式提供了所述盐酸盐的晶型FormA、或盐酸盐的晶型FormB、或其药物组合物在制备用于预防和/或治疗癌症、神经退行性疾病、心脑血管疾病、免疫相关疾病、肝肾衰竭、炎症、代谢性疾病中的用途；
在一个或多个实施方式中，所述疾病可以选自但不限于癌症、阿尔茨海默病、帕金森病、多发性硬化症、亨廷顿氏舞蹈病、肌萎缩性脊髓侧索硬化症、脑卒中、缺血再灌注损伤、动脉粥样硬化、免疫相关疾病、肝肾衰竭、炎症、糖尿病、以及糖尿病并发症；
在一个或多个实施方式中，所述脑卒中为出血性脑卒中和/或缺血性脑卒中；所述缺血性脑卒中又名脑梗塞、脑梗死。
一个或多个实施方式提供了盐酸盐的晶型FormA、或盐酸盐的晶型FormB、或其药物组合物在制备用于铁死亡抑制剂中的用途。
一个或多个实施方式提供了制备本申请盐酸盐的晶型FormA的方法，其包括将化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪在10-40℃下分散于甲醇中，随后滴加浓盐酸与甲醇的混合溶液，搅拌析晶，过滤，将滤饼用甲醇洗涤，随后将滤饼真空干燥，得到结晶状物质；
优选地，所述溶剂甲醇与化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的重量比为5:1-15:1，例如5:1、5.5:1、6:1、6.5:1、7:1、7.5:1、8:1、8.5:1、9:1、9.5:1、10:1、10.46:1、11:1、11.5:1、12:1、12.5:1、13:1、13.5:1、14:1、14.5:1、或15:1；
优选地，所述化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与浓盐酸的重量比为1:1-8:1，例如1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4:1、4.15:1、4.5:1、5:1、5.5:1、6:1、6.5:1、7:1、7.5:1、8:1；
优选地，所述搅拌析晶时间为1-8h，例如1h、2h、3h、4h、5h、6h、7h或8h。
一个或多个实施方式中，提供了制备本申请盐酸盐的晶型FormA的方法，其包括将化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪在10-40℃下分散于丙酮和水中，随后滴加浓盐酸、丙酮和水的混合溶液，搅拌析晶，过滤，将滤饼用丙酮洗涤，随后将滤饼真空干燥，得到结晶状物质；
优选地，所述溶剂丙酮、水与化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪之间的重量比为(1-8):(0.5-3):(0.5-3)，优选(4-6):(0.5-1):(0.5-1)，例如4:1:1、4.74:1:1、5:1:1；
优选地，所述化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与浓盐酸的重量比为1:1-8:1，例如1:1、1.5:1、2:1、2.5:1、3:1、3.66:1、4:1、4.5:1、5:1、5.5:1、6:1、6.5:1、7:1、7.5:1、8:1。
优选地，所述搅拌析晶时间为1-8h，优选2-5h；
上述制备方法中的浓盐酸的质量分数不低于20％，如20％、25％、30％、35％、36％、37％、38％、39％、40％。
本发明所述器官损伤是指器官或与所述器官相关的组织的一种或多种功能的任何损害、伤害、降低或丧失。损伤可以包括但不限于器官组织或结构的变化，其形式为相对于正常情况的损害或变化，例如组织坏死区域的发展、或细胞或组织结构完整性的破坏或丧失、或来自例如细胞炎症过程或细胞凋亡的细胞物质或碎片的异常聚集。应认识到，不同的器官和组织类型可能呈现不同的损伤病理。器官损伤还可以导致与所述损伤相关的病症或疾病(即与器官损伤相关的病症)的发病机理。
本发明所述盐酸盐晶体中，化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与盐酸的摩尔比约为1:(1±0.5)、例如为1:(1±0.4)、例如为1:(1±0.2)、例如为1:(1±0.1)，例如为1:1。
本发明所述2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的晶型FormA，也称为晶型A；所述2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的晶型FormB，也称为晶型B。
本发明与现有技术相比，取得的有益效果如下：
1、本发明通过大量实验研究得到了两种全新的化合物晶型，其物理化学性质相较于游离态化合物有显著提高：
①盐酸盐晶型A具有很高的纯度，例如在本发明的一个实施例中该纯度达到了99.76％；在水中的溶解度较游离态化合物提高了10000倍，并且在溶解度显著提高的情况下还保持了很好的稳定性，例如在本发明的一个实施例中晶型A在研磨条件下依然保持晶型不变，具备良好的机械稳定性，在本发明的另一个实施例中，晶型A熔点约为265.31℃，表明晶型具有很好的热稳定性，在本发明的又一实施例中，晶型A在加速和稳定的条件下依然保持晶型不变，以及纯度基本不变，在本发明的又一实施例中，晶型A在不同溶剂中溶解，磁力搅拌后均未发生转晶；此外，晶型A在生物利用度上也较游离态化合物取得了显著的提高。
②盐酸盐晶型B较游离态化合物在溶解度上也取得了预料不到的有益效果，例如在本发明的一个实施例中晶型B在水中的溶解度较游离态化合物提高了1000倍。
2、本发明的盐酸盐晶型A和盐酸盐晶型B相比具有更好的物理化学性质：
在引湿性上，盐酸盐晶型A在25℃/80％RH下水分吸附仅为0.36％，表明其仅略有引湿性，优于晶型B；溶解度上，盐酸盐晶型A在水中和盐酸中的溶解度均优于晶型B，例如在水和pH值为1.0的盐酸溶液中，盐酸盐晶型A的溶解度为盐酸盐晶型B溶解度的10倍以上。然而在稳定性方面，溶解度更好的盐酸盐晶型A反而具有更好的稳定性，例如：在本发明的一个实施例中晶型A在加速和稳定条件下保持晶型不变，而晶型B在室温2天开始向晶型A转变；在稳定性方面，盐酸盐晶型A在长期25℃/60％RH和加速40℃/75％RH条件下放置一周，纯度基本不变，化学稳定性良好，样品未观察到晶型变化；盐酸盐晶型A在RT-75％RH和RT-97％RH条件下放置一周，样品未观察到晶型变化；盐酸盐晶型A经过研磨，其晶型保持不变等。以及，在加速(40℃±2℃,75％RH±10％RH，6个月)条件，晶型FormA的总杂含量明显低于FormB，晶型FormA稳定性优于晶型FormB。
本发明的另一目的之一还在于，提供化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的多种药学上可接受的盐，在溶解度和稳定性上较化合物都有显著的提高；
本发明的另一目的在于，提供上述化合物的盐的制备方法及用途。
对此，本发明的具体技术方案如下：
在本发明的一个或多个实施例中，提供了2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪甲磺酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乙磺酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪对甲苯磺酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪酒石酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪氢溴酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪草酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪磷酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪硫酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乙酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丙酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪高氯酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪苹果酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪水杨酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪扁桃 酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乳酸盐和2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丁二酸盐等。
一个或多个实施例中，提供了2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐。
一个或多个实施例中，所述盐酸盐中2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与盐酸的摩尔比约为1:(0.5～2)，例如为1:1，例如为1:2。
本发明所述盐中，化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与酸的摩尔比均在可接受的范围内适当波动，例如：
一个或多个实施例中，所述2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与酸的摩尔比可以为1:(2±0.4)、例如为1:(2±0.3)、例如为1:(2±0.2)、例如为1:(2±0.1)，例如为1:2；所述酸任选自盐酸、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、富马酸、马来酸、酒石酸、氢溴酸、草酸、磷酸、硫酸、乙酸、丙酸、高氯酸、苹果酸、水杨酸、扁桃酸、乳酸和丁二酸。
一个或多个实施例中，所述2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与酸的摩尔比可以为1:(1±0.2)、例如为1:(1±0.15)、例如为1:(1±0.1)、例如为1:(1±0.05)，例如为1:1；所述酸任选自盐酸、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、富马酸、马来酸、酒石酸、氢溴酸、草酸、磷酸、硫酸、乙酸、丙酸、高氯酸、苹果酸、水杨酸、扁桃酸、乳酸和丁二酸。
一个或多个实施例中，提供了制备2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的盐的方法，包括将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪和酸反应得到盐；
优选地，所述反应在水和/或有机溶剂中进行，所述溶剂任选自2～6个碳原子数的酮类、乙酸乙酯、低级脂肪醇、四氢呋喃中的一种或一种以上的混合；所述低级脂肪醇指含1-8个碳原子的醇类；
进一步的，所述2～6个碳原子数的酮类优选为丙酮；
更进一步的，所述低级脂肪醇任选自甲醇、乙醇、丙醇和异丙醇；
优选地，所述反应在丙酮、甲醇或乙醇中的一种溶剂或一种以上的混合溶剂中进行；
优选地，所述酸任选自盐酸、HCl、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、富马酸、马来酸、酒石酸的一种，更优选为盐酸；所述盐酸指HCl的水溶液，HCl指HCl气体。
一个或多个实施例中，提供了制备2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的方法，包括将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪和盐酸在丙酮、或乙醇、或异丙醇、或四氢呋喃中反应，搅拌，过滤即得。
一个或多个实施例中，提供了一种药物组合物，包括2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的盐和一种或多种药学上可接受载体和/或稀释剂；优选的，所述盐为盐酸盐。
一个或多个实施例中，提供了2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的盐、或包含2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的盐的药物组合物在制备用于预防和/或治疗癌症、器官损伤和退行性疾病中的用途。
一个或多个实施例中，提供了2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的盐、或包含2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的盐的药物组合物在制备用于预防和/或治疗癌症、神经退行性疾病、心脑血管疾病、免疫相关疾病、肝肾衰竭、炎症、代谢性疾病中的用途。
一个或多个实施例中，所述疾病为癌症、阿尔茨海默病、帕金森病、多发性硬化症、亨廷顿氏舞蹈病、肌萎缩性脊髓侧索硬化症、脑卒中、缺血再灌注损伤、免疫相关疾病、肝肾 衰竭、炎症、动脉粥样硬化、糖尿病、或糖尿病并发症。
一个或多个实施例中，所述脑卒中为出血性脑卒中和/或缺血性脑卒中；所述缺血性脑卒中又名脑梗塞、脑梗死。
本发明相较于现有技术取得的有益效果为：
1、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪成盐酸盐之后，在溶解度、稳定性以及引湿性上都得到了改善。
盐酸盐溶解度较游离化合物有显著的提高，例如在本发明的一个实施例中，盐酸盐较游离化合物在水中的溶解度提高了约7700倍；此外其他盐如柠檬酸盐也较游离化合物溶解度显著提高。盐酸盐稳定性较游离化合物有较大的提高，例如在本发明的一个实施例中，盐酸盐的稳定性较游离化合物在高温、高湿、光照条件下的稳定性更优，并且总杂含量明显更低；此外，盐酸盐的引湿性也较游离化合物更低。
2、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐较其他盐有显著的性能改善：
溶解度上，盐酸盐相较于其他盐溶解性能更优，例如在本发明的一个实施例中，盐酸盐相较于溶解度较好的柠檬酸盐也提高了7倍，较马来酸盐及富马酸盐也提高了35倍以上；在稳定性上，盐酸盐较其他盐也有更好的效果，例如在本发明的一个实施例中，盐酸盐在高温、高湿、光照条件下的稳定性高于其他盐，总杂含量相较于其它盐均明显更低，另一个实施例中，盐酸盐在pH为1.0的盐酸溶液中溶液颜色保持不变，而其他盐如柠檬酸盐、富马酸盐、马来酸盐均发生了显著性变化，说明盐酸盐的稳定性更好；引湿性上，盐酸盐也较其他盐引湿性更低；此外，盐酸盐在制备过程中成固性好，而其他盐如甲磺酸盐、对甲苯磺酸盐则成黏糊状。
附图说明
图1为实施例1所得晶型FormA的XRPD图谱；
图2为实施例2所得晶型FormA的XRPD图谱；
图3为晶型FormB的XRPD图谱；
图4为晶型FormA的纯度检测图谱；
图5为晶型FormA的1HNMR图谱；
图6为晶型FormA的TGA图谱；
图7为晶型FormA的DSC的图谱；
图8为晶型FormA的稳定性研究XRPD图谱；
图9为晶型FormB的稳定性研究XRPD图谱；
图10为2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的1HNMR图谱；
图11为2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的13CNMR图谱；
图12为2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐的1HNMR图谱；
图13为2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐的1HNMR图谱；
图14为2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐的1HNMR图谱。
具体实施方式
2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)的具体合成方法参照国际申请 WO2019205854A1中的制备方法。
实施例1：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA的制备方法一
50L反应釜中通入氮气置换反应釜中气体，随后在氮气氛围条件下向反应釜中加入1.70Kg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)及17.78Kg甲醇，开启搅拌，25±5℃条件下向反应釜中滴加0.41Kg浓盐酸(质量分数为36％)与0.82Kg甲醇的混合溶液，约1h左右滴加完毕，滴毕，反应混合液在25±5℃条件下保温搅拌2-4h析晶，随后反应混合液过滤，滤饼用1.50Kg甲醇洗涤，并将滤饼在40℃～50℃真空条件下(压力-0.08MPa～-0.10MPa)烘干12～16h，收料得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA共1.64Kg，结晶收率：88.3％，XRPD检测显示为晶型FormA(XRPD图谱见图1)；
制得的晶型FormA纯度为99.76％，最大单个杂质含量0.068％，总杂和单杂小于国家药监局公布的《化学药物杂质研究的技术指导原则》及ICHQ3A规定的控制限度≤0.15％(本品每日最大日剂量≤2克/天)(纯度检测图谱见图4，图谱中主峰名称DA414即2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA)；
核磁数据：1H NMR(400MHz,DMSO)δ＝11.27(s,1H),8.64(s,1H),7.09(d,J＝8.6Hz,2H),6.92(m,4H),6.80(d,J＝7.9Hz,1H),6.71(t,J＝8.6Hz,2H),6.64(d,J＝7.9Hz,1H),6.56(d,J＝1.2Hz,1H),3.90(m,1H),3.60(d,J＝73.7Hz,2H),3.39(s,2H),3.16(d,J＝9.1Hz,4H),2.77(s,3H),1.45(d,J＝7.2Hz,3H)，(1H NMR谱图见图5)。
实施例2：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA的制备方法二
50L反应釜中通入氮气置换反应釜中气体，随后在氮气氛围条件下向反应釜中加入1.50Kg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)、7.11Kg丙酮和1.50Kg水，开启搅拌，25±5℃条件下向反应釜中滴加0.41Kg浓盐酸(质量分数为36％)与0.68Kg丙酮和0.15Kg水的混合溶液，约1h左右滴加完毕，滴毕，反应混合液在25±5℃条件下保温搅拌2-4h析晶，随后反应混合液过滤，滤饼用1.50Kg丙酮洗涤，并将滤饼在40℃～50℃真空条件下(压力-0.08MPa～-0.10MPa)烘干12～16h，收料得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙 基)-10H-吩噻嗪盐酸盐晶型FormA共1.30Kg，结晶收率：79.5％，XRPD检测显示为晶型FormA(XRPD图谱见图2)。
实施例3：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormB的制备方法
称取约5mg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA，向其中加入0.2mL N,N-二甲基甲酰胺，超声溶解，溶液过滤至5mL小瓶，加入搅拌子。室温搅拌条件下，滴加4mL乙酸乙酯，大量沉淀析出，过滤，滤饼室温真空干燥过夜，XRPD检测显示为晶型FormB(晶型FormB的XRPD图谱见图3)。
实施例4：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA的XRPD测定：
按照《中国药典》(2020版)——第四部——通则0451——X-射线衍射法——第二法——粉末X-射线衍射法进行测定：
表1.晶型FormA粉末XRPD测试参数
2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型的XRPD图谱如图1所示，XRPD数据如表2，该晶型命名为晶型FormA。
表2.晶型FormA的XRPD数据
实施例5：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormB的XRPD测定：
按照《中国药典》(2020版)——第四部——通则0451——X-射线衍射法——第二法——粉末X-射线衍射法进行测定：
表3.晶型FormB粉末XRPD测试参数
2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型的XRPD图谱如图3所示，XRPD数据如表4，该晶型命名为晶型FormB。
表4.晶型FormB的XRPD数据
实施例6：晶型FormA的TGA测定
表5.TGA测试参数
晶型FormA的TGA检测图谱如图6所示。
TGA测试结果显示：晶型FormA在升温至120℃时，样品失重约0.1586％，表明晶型FormA是无水物。
实施例7：晶型FormA的DSC测定
表6.DSC测试参数
晶型FormA的DSC检测图谱如图7所示。
DSC图谱显示晶型FormA具有单一吸热峰，熔点约为265.31℃，表明晶型FormA具有很好的热稳定性。
实施例8：晶型FormA的离子色谱(IC)
表7.离子色谱IC测试参数
离子色谱(IC)测试结果显示，成盐比例为1:1，表明2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与HCl为1:1结合。
实施例9：晶型FormA的其他制备方法
(1)挥发结晶法
实验操作：称取约10mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA至5mL小瓶中，分别加入一定体积的表8中的混合溶剂溶解，使用0.45μm的PTFE滤头过滤至另一5mL小瓶，敞口放置在不同温度下挥发。收集所得固体并进行XRPD测试。试验结果如表8所示，得到盐酸盐晶型FormA产品。
表8.挥发实验结果汇总
(2)反溶剂添加法
称取约5mg每份的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA加至5mL的小瓶内，分别用表9中对应的第一溶剂将固体完全溶解，并使用0.45μm的PTFE滤头过滤至另一5mL小瓶。向该澄清溶液中边搅拌边滴加表9中的第二溶剂，直至有固体析 出，若当溶剂总体积加至5mL仍无固体析出，则转至5℃下磁力搅拌，搅拌过夜后，仍然澄清的样品则转至室温挥发或旋干。离心收集固体并进行XRPD测试。试验结果见表9，得到盐酸盐晶型FormA产品。
表9.反溶剂添加实验结果汇总
(3)反反溶剂添加法
称取约5mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA加至5mL的小瓶内，分别用表10中对应第一溶剂将固体完全溶解，并使用0.45μm的PTFE滤头过滤至另一5mL小瓶。搅拌条件下，将该澄清溶液滴加至表10中的第二溶剂中，第二溶剂体积为3mL，若无固体析出，则转至5℃下磁力搅拌，搅拌过夜后，仍然澄清的样品转至室温挥发或者旋干。离心收集固体并进行XRPD测试。试验结果见表10，只得到盐酸盐晶型FormA。
表10.反反溶剂添加实验结果汇总
注：N/A指未获得足够样品用于检测。
(4)冷却结晶法
称取约10mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA加至5mL的小瓶内，分别加入一定体积的表11中的对应单一溶剂或混合溶剂，在50℃超声条件下溶清后使用0.45μm的PTFE滤头过滤至另一5mL小瓶。将该澄清滤液放置在生化培养箱中，在50℃条件下恒温120min，再以0.1℃/min的速度降温至5℃，变温过程始终保持搅拌，若有固体析出，离心收集固体并进行XRPD测试。试验结果见表11。
表11.冷却结晶实验结果汇总
(5)气液扩散法
称取约10mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA至5mL小瓶中，分别加入一定体积的表12中的第一溶剂(单一溶剂或混合溶剂)溶解并使用0.45μm的PTFE滤头过滤至另一5mL小瓶，另取20mL的小瓶向其中加入约3mL的第二溶剂，将装有清液的5mL小瓶敞口置于20mL小瓶后，密封并于室温下静置约一周。收集得到的固体并进行XRPD测试。试验结果如表12所示。
表12.气液扩散实验结果汇总
(6)高聚物诱导法
称取约10mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA于5mL小瓶中，分别加入一定体积的混合溶剂溶解(使用0.45μm的PTFE滤头过滤)，加入1～2mg聚合物，用封口膜封住小瓶，并在上面扎孔，放置在室温下缓慢挥发。试验结果如表13所示，得到盐酸盐晶型FormA产品。
表13.高聚物诱导实验结果汇总
注：N/A指未获得足够样品用于检测。
XRPD结果显示实施例9制备得到的样品晶型均为晶型Form A(XRPD图谱未示出)。
实施例10：晶型FormB的其他制备方法
(1)反溶剂添加法
称取约5mg每份的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA加至5mL的小瓶内，分别用表14中对应的第一溶剂将固体完全溶解，并使用0.45μm的PTFE滤头过滤至另一5mL小瓶。向该澄清溶液中边搅拌边滴加表14中的第二溶剂，直至有固体析出。离心收集固体并进行XRPD测试。试验结果见表14，得到盐酸盐晶型FormB产品。
表14.反溶剂添加实验结果汇总
(2)高聚物诱导法
称取约10mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA于5mL小瓶中，分别加入一定体积的混合溶剂溶解(使用0.45μm的PTFE滤头过滤)，加入1～2mg聚合物，用封口膜封住小瓶，并在上面扎孔，放置在室温下缓慢挥发。试验结果如表15所示，得到盐酸盐晶型FormB产品。
表15.高聚物诱导实验结果汇总
XRPD结果显示实施例10制备得到的样品晶型均为晶型Form B(XRPD图谱未示出)。
实施例11：引湿性研究
通过动态水分吸附(DVS)评估引湿性，结果显示盐酸盐Form A在25℃/80％RH下水分吸附约为0.36％，表明其略有引湿性，引湿性实验前后晶型不变。
引湿性研究结果显示盐酸盐Form A的引湿性低于盐酸盐Form B，成药性更好。
实施例12：溶解度对比研究
根据《中国药典》(2020版)凡例溶解度试验方法，称取2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormB于25℃±2℃条件下加入到一定容量的溶剂中，每隔5分钟强力振摇30秒，观察30分钟内的溶解情况，并测试溶解度。
表16.溶解度对比数据
其中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐为实施例17方法一得到。
结果表明，在水溶液体系中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA的溶解度都要绝对优于2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐和2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormB；在pH 1.0盐酸溶液(大致人体胃液pH)体系中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA的溶解度都要绝对优于2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐和2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormB，表明晶型FormA理化性质更优，成药性更好。2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormB在水中的溶解度优于游离态1000倍，取得了预料不到的效果。
另外，发明人在研究中发现，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的其他盐型，例如柠檬酸盐、富马酸盐和马来酸盐经过析晶得到的晶型与其盐相比，在水中和pH1.0的盐酸溶液中的溶解度基本相同，并未得到明显提升。
实施例13：晶型稳定性试验
(1)晶型FormA的稳定性实验
实验1：温度、湿度稳定性实验
试验操作1：取盐酸盐晶型Form A样品分别在长期25℃/60％RH和加速40℃/75％RH条件下放置一周，测试晶型变化情况，测试结果显示，盐酸盐晶型Form A样品在两种测试条件下放置一周后，纯度基本不变，化学稳定性良好，样品未观察到晶型变化。样品稳定性放置前后的XRPD对比图如图8所示。
试验操作2：称取约10mg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA于5mL小瓶中，将5mL小瓶敞口置于相应的恒湿器中后，将恒湿器密封。室温下静置约一周后收集固体并进行XRPD测试，样品未观察到晶型变化。试验结果如表17所示。
表17.温湿度实验结果
实验2：机械稳定性实验
称取约10mg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA于研钵中，分三次加入0.05mL润湿剂进行研磨，每次研磨5min，收集固体测试XRPD，样品晶型保持不变。试验结果如表18所示。
表18.机械稳定性实验
实验3：其它稳定性实验
试验操作1：称取约10mg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA至5mL小瓶中，分别加入1mL的表19中所列的单一溶剂或混合溶剂，得到的悬浊液置于5℃下磁力搅拌约3天后，离心收集固体并进行XRPD测试，样品未发生转晶。试验结果见表19。
表19.低温浆料转化实验结果
试验操作2：称取约10mg每份的起始物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA至5mL小瓶中，分别加入0.5mL的表20中所列的单一溶剂或混合溶剂，得到混浊液。将混浊液置于室温下磁力搅拌约3天后，离心收集固体并进行XRPD测试，样品未发生转晶。试验结果见表20。
表20.室温浆料转化实验结果
试验操作3：称取约10mg每份的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型FormA至5mL小瓶中，分别加入0.5mL表21中所列的单一溶剂或混合溶剂，得到的悬浊液置于50℃下磁力搅拌约3天后，离心收集固体并进行XRPD测试，样品未发生转晶。试验结果见表21。
表21.高温浆料转化实验结果
(2)晶型FormB的稳定性试验
试验操作：称取一定量的盐酸盐晶型FormB样品于样品瓶中，随后将样品瓶室温闭口放置，分别于室温闭口2天和5天后，取一定量的样品瓶中的样品测试XRPD，测试结果显示，盐酸盐晶型FormB样品室温闭口放置2天即向盐酸盐晶型Form A开始转晶，放置5天后晶型B部分转晶为盐酸盐晶型Form A，盐酸盐晶型FormB为不稳定晶型，晶型FormB的稳定性研究XRPD图谱见图9。可见，晶型A比晶型B具有更好的晶型稳定性。
另外，晶型A具有良好的可压性、流动性等性质，其比表面积、堆密度、孔隙率和粒径等特性，非常适合于开发制备为药物制剂。而晶型B则不具有这些特点。
此外，对盐酸盐晶型A和盐酸盐晶型B进行影响因素试验研究，发现在高温(温度为60℃)、高湿(25℃/90％±5％RH)、光照(45001x±5001x)条件下放置30天的情况下，晶型A的稳定性优于晶型B，且杂质生成量更低。
同时，跟游离化合物相比，盐酸盐晶型A的稳定性更优，且测得总杂质含量更低。
(3)晶型FormA及FormB的稳定性对比试验
根据中国药典2020版及ICHQ1A稳定性研究指导原则，将晶型FormA及FormB放置于加速(40℃±2℃,75％RH±10％RH)条件下6个月，检测晶型FormA及FormB的总杂变化情况，，结果参见表22，表22为不同晶型稳定性实验。结果表明，晶型FormA在加速条件下放置6个月，总杂由0.25％增长到0.41％，而晶型FormB在加速条件下放置6个月，总杂由0.28％增长到0.88％，晶型FormB的稳定性很差，晶型FormA稳定性优于晶型FormB。
表22.不同晶型稳定性实验
实施例14：药代动力学对比研究
实验方法：选择健康雄性SD大鼠3只，禁食过夜后，分别灌胃给予10mg/kg的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)或2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐晶型Form A的混悬液(溶媒为0.5％CMC-Na)，给药体积为10ml/kg。在给药前及给药后0.25，0.5，1，2，4，8，12，24h于大鼠眼眶静脉丛采集全血约200μL，置于含 有EDTA-K2抗凝的离心管中，然后在3000-4000rpm条件下离心10min，将上层血浆全部转移到另一干净离心管内，使用LC-MS/MS的方法检测血浆样品中2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的血药浓度，并用非房室模型计算药代参数。
表23.大鼠灌胃给药药代动力学参数
注：表格中t为24h。
结果表明，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐Form A在大鼠经口服给药后，吸收良好，血液暴露量及生物利用度都要优于2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(游离态)，说明盐酸盐Form A较游离态的成药性得到了显著提升。
实施例15：本发明化合物对Ferroptosis的抑制率的研究
实验方法：本实施例为了研究铁死亡的抑制剂，构建了铁死亡的筛选模型，具体如下：Ferroptosis筛选模型主要是采用CCK8细胞活力检测法。首先在皿中培养小鼠海马神经元细胞HT22和人神经母细胞瘤细胞SH-SY5Y，将处于对数生长期的细胞按特定数量接种于96孔板中(5000个/孔)，每孔80μL，然后放入37℃、5％CO2环境的孵箱中培养，让细胞贴壁。24h后，加入10μL使用指定的培养基配制好的各种浓度的本发明化合物和终浓度为10μM的10μL Ferroptosis诱导剂Erastin，每个化合物设置3个复孔，保证结果的准确性。并设置阳性对照组(按照上述加入10μL相同培养基配制好的一定浓度的化合物Ferrostain-1和10μLFerroptosis诱导剂Erastin)、空白对照组(加入上述指定的等体积培养基以及和培养基等体积DMSO，不含细胞)和溶剂对照组(加入上述指定的等体积培养基以及和培养基等体积的DMSO，含细胞)，每组同样设置3个复孔，保证结果的准确性。加药之后放入孵箱，培养24h。每孔加入10μL CCK8溶液，放入孵箱继续培养2-4h，然后用酶标仪检测450nm处吸光度值，以计算药物对Ferroptosis的抑制率。采用如下公式计算抑制率：
抑制率％(inhibitionrate，IR)＝[1-(A实验组-A空白)/(A溶剂-A空白)]*100％
使用GraphPadPrism6软件拟合抑制率变化曲线并算出IC50。
实验结果：
表24.本发明化合物的IC50值
由表24所示的试验结果可知：本发明化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐FormA在多个细胞系上对于Ferroptosis均有抑制作用，抑制活性与阳性对照组Ferrostain-1相比显著更优。
实施例16：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的制备
2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的具体合成方法参照国际申请WO2019205854A1中的制备方法。测定产物杂质，总杂含量为1.36％。
实施例17：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的制备
方法一：
20～25℃条件下将5.0g的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪(12.45mmol，1.0eq)溶于50mL的丙酮中。将1.14mL质量分数为36％的浓盐酸(13.70mmol，1.1eq)用丙酮稀释至4.5mL，随后缓慢滴加入反应液中反应，继续搅拌1h后过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐4.4g，收率80.7％，1H NMR(400MHz,DMSO-d6)δ＝11.27(s,1H),8.65(s,1H),7.10(d,J＝8.6Hz,2H),6.93(m,4H),6.81(d,J＝7.9Hz,1H),6.72(t,J＝8.6Hz,2H),6.65(d,J＝7.9Hz,1H),6.56(d,J＝1.2Hz,1H),3.91(m,1H),3.70(s,2H),3.35(s,4H),3.17(d,J＝9.1Hz,2H),2.77(s,3H),1.46(d,J＝7.2Hz,3H)，(1H NMR谱图见图10)；13C NMR(101MHz,DMSO-d6)δ＝148.29,146.87,142.56,138.00,128.37,127.87,126.54,122.09,121.26,116.89,116.57,114.91,113.98,52.47,46.11,43.12,42.35,21.91，(13C NMR谱图见图11)。经结构确证，所得盐酸盐中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与盐酸为1:1结合。
方法二：
参考方法一的操作步骤，只是将其中的溶剂丙酮替换为乙醇，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐产品，经结构确证与方法一得到的产品一致。
方法三：
参考方法一的操作步骤，只是将其中的溶剂丙酮替换为异丙醇，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐产品，经结构确证与方法一得到的产品一致。
方法四：
参考方法一的操作步骤，只是将其中的溶剂丙酮替换为四氢呋喃，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐产品，经结构确证与方法一得到的产品一致。
测定以上盐酸盐产品的杂质，总杂含量为0.10％～0.25％。
实施例18：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪甲磺酸盐的制备
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL乙酸乙酯中，搅拌溶清。然后向反应液中滴加2mL乙酸乙酯与甲磺酸(36.0mg，0.374mmol，1.0eq)的混合溶液，滴加过程中，有大量的絮状固体物析出，继续于20～25℃条件下搅拌1h后过滤，滤饼成黏糊状，收集滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪甲磺酸盐90.15mg，收率48.4％。
实施例19：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪对甲苯磺酸盐的制备
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL乙酸乙酯中，搅拌溶清。然后向反应液中加入65mg对甲苯磺酸(0.374mmol，1.0eq)，有少量固体物析出，继续于20～25℃条件下搅拌1h后过滤，滤饼成黏糊状，收集滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪对甲苯磺酸盐100.20mg，收率46.5％。
实施例20：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐的制备
方法一：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于4mL甲醇中，搅拌溶清(溶清后有固体缓慢析出)。随后向反应液中加入72mg柠檬酸(0.374mmol，1.0eq)，由浑浊溶清，随后逐渐析出固体物，20～25℃条件下搅拌4h后过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐183.10mg。
方法二：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于4mL丙酮中，搅拌溶清。然后向反应液中加入72mg柠檬酸(0.374mmol，1.0eq)，搅拌过程中逐渐析出固体，20～25℃条件下继续搅拌2h后过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐179.63mg，1H NMR(400MHz,DMSO-d6)δ＝10.88 (s,2H),8.51(s,1H),7.09(d,J＝8.6Hz,2H),6.99–6.93(m,1H),6.89(d,J＝8.4Hz,3H),6.82(d,J＝7.6Hz,1H),6.73(m,1H),6.66(m,2H),6.52(d,J＝1.6Hz,1H),3.91(m,1H),3.22(s,4H),2.92(d,J＝4.4Hz,4H),2.65(d,J＝15.2Hz,2H),2.57(m,4H),2.53(s,2H),2.09(s,3H),1.47(d,J＝7.2Hz,3H)，(1H NMR谱图见图12)。经结构确证，所得柠檬酸盐中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与柠檬酸为1:2结合。
方法三：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL乙酸乙脂中，搅拌溶清。然后向反应液中加入72mg柠檬酸(0.374mmol，1.0eq)，搅拌过程中逐渐析出固体，20～25℃条件下继续搅拌4h后过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐189.4mg。
测定以上柠檬酸盐产物杂质，总杂含量为0.64％～0.80％。
实施例21：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐的制备
方法一：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL乙酸乙脂中，搅拌溶清。然后向反应液中加入43.41mg富马酸(反丁烯二酸；0.374mmol，1.0eq)，搅拌下逐渐固体析出。20～25℃条件下继续搅拌4h-5h后，大量固体物析出。过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐146.3mg，收率75.8％，1H NMR(400MHz,DMSO-d6)δ＝8.51(s,1H),7.06(d,J＝8.6Hz,2H),6.99–6.93(m,1H),6.91–6.84(m,3H),6.81(d,J＝8.0Hz,1H),6.73(m,1H),6.65(m,2H),6.59(s,2H),6.51(d,J＝1.6Hz,1H),3.90(m,1H),3.22–3.08(m,4H),2.70–2.58(m,4H),2.35(s,3H),1.46(d,J＝7.2Hz,3H)，(1H NMR谱图见图13)。经结构确证，所得富马酸盐中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与富马酸为1:1结合。
方法二：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL丙酮中，搅拌溶清。然后向反应液中加入43.41mg富马酸(反丁烯二酸；0.374mmol，1.0eq)，开始反应瓶底部有少量固体析出，随后逐渐成油状物。20～25℃条件下继续搅拌4h-5h后，则有大量固体物析出。过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐121mg，收率62.5％。
测定以上富马酸盐产物杂质，总杂含量为0.76％～0.84％。
实施例22：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪酒石酸盐的制备
方法一：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL丙酮中，搅拌溶清。然后向反应液中加入56mg酒石酸(DL型；0.374mmol，1.0eq)，搅拌过程中反应瓶底部有少量固体析出，随后20～25℃继续搅拌2h，固体物析出。过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪酒石酸盐155.3mg。
方法二：
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于2mL乙酸乙酯中，搅拌溶清。然后向反应液中加入56mg酒石酸(DL型；0.374mmol，1.0eq)，搅拌过程中反应瓶底部有少量固体析出，随后20～25℃继续搅拌2h，大量固体物析出。过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪酒石酸盐166.5mg。
实施例23：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐的制备
20～25℃条件下将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪150mg(0.374mmol)溶于3mL乙酸乙酯中，搅拌溶清。然后向反应液中加入43.41mg马来酸(顺丁烯二酸；0.374mmol，1.0eq)，搅拌下过程中反应瓶底部有少量固体析出，随后逐渐成油状物。20～25℃继续搅拌4h-5h后，则有大量固体物析出。过滤，滤饼干燥，可得2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐132.8mg，收率68.6％，总杂含量0.42％。1H NMR(400MHz,DMSO-d6)δ＝8.51(s,1H),7.11(d,J＝8.8Hz,2H),7.00–6.87(m,4H),6.82(d,J＝8.0Hz,1H),6.73(m,1H),6.66(dd,J＝8.0,2.0Hz,2H),6.54(d,J＝1.6Hz,1H),6.05(s,2H),3.92(m,1H),3.28(s,8H),2.83(s,3H),1.47(d,J＝7.2Hz,3H)，(1H NMR谱图见图14)。经结构确证，所得马来酸盐中，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与马来酸为1:1结合。
实施例24：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪氢溴酸盐的制备
参照实施例17的制备方法，将盐酸替换为氢溴酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪氢溴酸盐。
实施例25：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪磷酸盐的制备
参照实施例17的制备方法，将盐酸替换为磷酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪磷酸盐。
实施例26：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪草酸盐的制备
参照实施例17的制备方法，将盐酸替换为草酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪草酸盐。
实施例27：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乙磺酸盐的制备
参照实施例21的制备方法，将富马酸替换为乙磺酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乙磺酸盐。
实施例28：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪苹果酸盐的制备
参照实施例21的制备方法，将富马酸替换为苹果酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪苹果酸盐。
实施例29：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丁二酸盐的制备
参照实施例21的制备方法，将富马酸替换为丁二酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丁二酸盐。
实施例30：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丙酸盐的制备
参照实施例21的制备方法，将富马酸替换为丙酸，制备得到2-(1-(4-(4-甲基哌嗪-1-基) 苯基)乙基)-10H-吩噻嗪丙酸盐。
实施例31：溶解度对比研究
根据《中国药典》(2020版)凡例溶解度试验方法，称取2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐于25℃±2℃条件下加入到一定容量的溶剂中，每隔5分钟强力振摇30秒，观察30分钟内的溶解情况，并测试溶解度。
表25.溶解度对比数据
NA：代表未检测
溶解度实验结果表明：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐在水和pH1.0盐酸溶液中的溶解度均要优于2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪，尤其是在水中的溶解度；2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐在水中的溶解度比2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪高1000倍。
此外，盐酸盐的溶解度相较于该化合物的其他盐溶解度也显著更优，其中较溶解度较好的柠檬酸盐也提高了7倍，较马来酸盐及富马酸盐也提高了35倍以上。
实施例32：稳定性试验1
试验(1)：高温试验
根据《中国药典》(2020版)9001《原料药物与制剂稳定性试验指导原则》方法，将试验供试品开口置适宜的恒温设备中，在温度为60℃条件下放置30天，于第5天、10天和第30天取样。
高温试验结果表明：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪成盐后，在高温条件下的稳定性高于游离态的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪；其中盐酸盐的在高温条件下的稳定性最佳，性状无变化，总杂质生成量低。
表26.高温稳定性对比数据
试验(2)：高湿试验
根据《中国药典》(2020版)9001《原料药物与制剂稳定性试验指导原则》方法，将试验供试品开口置恒湿密闭容器中，在25℃分别于相对湿度90％±5％条件下放置30天，于第5天、10天和第30天取样。
高湿试验结果表明：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪成盐后，在高湿条件下的稳定性高于游离态的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪；其中盐酸盐在高湿条件下的稳定性优于其他盐型，性状无变化，总杂质生成量低。
表27.高湿稳定性对比数据
试验(3)：光照试验
根据《中国药典》(2020版)9001《原料药物与制剂稳定性试验指导原则》方法，将试验供试品置于稳定性试验箱中，在照度为45001x±5001x，且光源总照度不低1.2x106lux·hr、近紫外灯能量不低于200W·hr/m2条件下放置30天,于第5天、10天和第30天取样。
光照试验结果表明：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪成盐后，在光照条 件下的稳定性高于游离态的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪；其中，柠檬酸盐在光照条件下，5天外观由浅黄色变灰色，10天深灰色；盐酸盐在光照条件下的稳定性优于其他盐型，性状无变化，总杂质生成量低。
表28.光照稳定性对比数据
综上，稳定性实验结果显示，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐在高温、高湿、光照条件下的稳定性高于游离化合物以及其他盐，总杂含量相较于其它盐和游离化合物均明显更低。
实施例33：稳定性试验2
称取相同质量的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐于25℃±2℃条件下加入到一定容量的pH为1.0盐酸溶液中(近似人体胃液酸性)，每隔5分钟强力振摇30秒，观察0.5h及24h内的溶液颜色状态。
表29.稳定性试验2数据
实验结果表明：2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐样品在pH为1.0盐酸溶液中溶液颜色发生了显著性变化，稳定性较2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐差。
实施例34：引湿性对比实验
根据《中国药典》(2020版)第四部的《药物引湿性指导原则》，对上述实施例中所得的2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐、2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐等进行引湿性试验。
引湿性特征描述与引湿性增重的界定如下：
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
实验结果表明，2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的引湿性低，其理化性质优，成药性最好。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (18)

  1. 2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的晶体，其具有晶型FormA，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、14.36±0.2°、18.57±0.2°、21.08±0.2°、22.14±0.2°、23.40±0.2°、29.03±0.2°；
    优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、14.36±0.2°、17.84±0.2°、18.57±0.2°、21.08±0.2°、22.14±0.2°、23.40±0.2°、27.50±0.2°、29.03±0.2°；
    优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、14.36±0.2°、16.54±0.2°、17.84±0.2°、18.57±0.2°、20.89±0.2°、21.08±0.2°、22.14±0.2°、22.92±0.2°、23.40±0.2°、25.88±0.2°、27.50±0.2°、29.03±0.2°；
    优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱具有以下特征峰：10.68±0.2°、12.63±0.2°、14.36±0.2°、16.06±0.2°、16.54±0.2°、17.84±0.2°、18.57±0.2°、20.89±0.2°、21.08±0.2°、22.14±0.2°、22.92±0.2°、23.40±0.2°、25.11±0.2°、25.51±0.2°、25.88±0.2°、27.50±0.2°、28.54±0.2°、29.03±0.2°、33.55±0.2°；
    更优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormA的X-射线粉末衍射图谱如图1所示。
  2. 2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐的晶体，其具有晶型FormB，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱具有以下特征峰：16.46±0.2°、22.01±0.2°；
    优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱具有以下特征峰：16.46±0.2°、22.01±0.2°、27.62±0.2°、28.91±0.2°、33.41±0.2°；
    优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱具有以下特征峰：5.41±0.2°、10.92±0.2°、16.46±0.2°、22.01±0.2°、27.62±0.2°、28.91±0.2°、33.41±0.2°；
    更优选地，使用Cu-Ka辐射且以2θ角度表示，所述晶型FormB的X-射线粉末衍射图谱如图3所示。
  3. 药物组合物，包含权利要求1所述的盐酸盐的晶型FormA、或权利要求2所述的盐酸盐的晶型FormB，以及药学上可接受的载体。
  4. 权利要求1所述的盐酸盐的晶型FormA、或权利要求2所述的盐酸盐的晶型FormB、或者权利要求3所述的药物组合物在制备用于预防和/或治疗癌症、器官损伤和退行性疾病中的用途。
  5. 权利要求1所述的盐酸盐的晶型FormA、或权利要求2所述的盐酸盐的晶型FormB、或者权利要求3所述的药物组合物在制备用于预防和/或治疗癌症、神经退行性疾病、心脑血管疾病、免疫相关疾病、肝肾衰竭、炎症、代谢性疾病中的用途；
    优选地，所述疾病为癌症、阿尔茨海默病、帕金森病、多发性硬化症、亨廷顿氏舞蹈病、肌萎缩性脊髓侧索硬化症、脑卒中、缺血再灌注损伤、动脉粥样硬化、免疫相关疾病、肝肾衰竭、炎症、糖尿病、以及糖尿病并发症；
    优选地，所述脑卒中为出血性脑卒中和/或缺血性脑卒中。
  6. 权利要求1所述的盐酸盐的晶型FormA、或权利要求2所述的盐酸盐的晶型FormB、或者权利要求3所述的药物组合物在制备用于铁死亡抑制剂中的用途。
  7. 制备权利要求1所述的盐酸盐的晶型FormA的方法，其包括将化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪在10-40℃下分散于甲醇中，随后滴加浓盐酸与甲醇的混合溶液，搅拌析晶，过滤，将滤饼用甲醇洗涤，随后将滤饼真空干燥，得到结晶状物质；
    优选地，所述溶剂甲醇与化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪的重量比为5:1-15:1，优选8:1-12:1；
    优选地，所述化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与浓盐酸的重量比为1:1-8:1，优选3:1-5:1；
    优选地，所述搅拌析晶时间为1-8h，优选2-5h。
  8. 制备权利要求1所述的盐酸盐的晶型FormA的方法，其包括将化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪在10-40℃下分散于丙酮和水中，随后滴加浓盐酸、丙酮和水的混合溶液，搅拌析晶，过滤，将滤饼用丙酮洗涤，随后将滤饼真空干燥，得到结晶状物质；
    优选地，所述溶剂丙酮、水与化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪之间的重量比为(1-8):(0.5-3):(0.5-3)，优选(4-6):(0.5-1):(0.5-1)；
    优选地，所述化合物2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与浓盐酸的重量比为1:1-8:1，优选3:1-5:1；
    优选地，所述搅拌析晶时间为1-8h，优选2-5h。
  9. 一种2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐，所述盐任选自：
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪甲磺酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乙磺酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪对甲苯磺酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪柠檬酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪富马酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪马来酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪酒石酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪氢溴酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪草酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪磷酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪硫酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乙酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丙酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪高氯酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪苹果酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪水杨酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪扁桃酸盐；
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪乳酸盐；和
    2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪丁二酸盐。
  10. 根据权利要求9所述的盐，其特征在于，所述盐为2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪盐酸盐。
  11. 根据权利要求9所述的盐，其特征在于，所述盐酸盐中2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪与盐酸的摩尔比为1:(0.5～2)；优选的，所述摩尔比为1:1或1:2。
  12. 制备如权利要求9所述的盐的方法，其特征在于，将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪和酸反应生成盐；
    优选地，所述反应在水和/或有机溶剂中进行，所述有机溶剂任选自2～6个碳原子数的酮类、乙酸乙酯、低级脂肪醇和四氢呋喃中的一种或一种以上的混合；进一步的，所述2～6个碳原子数的酮类优选为丙酮；更进一步的，所述低级脂肪醇任选自甲醇、乙醇、丙醇和异丙醇；
    优选地，所述反应在任选自丙酮、甲醇和乙醇中的一种溶剂或一种以上的混合溶剂中进行；
    优选地，所述酸任选自盐酸、HCl、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、富马酸、马来酸、酒石酸、氢溴酸、草酸、磷酸、硫酸、乙酸、丙酸、高氯酸、苹果酸、水杨酸、扁桃酸、乳酸和丁二酸的一种，更优选为盐酸。
  13. 根据权利要求12所述的方法，其特征在于，将2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10H-吩噻嗪和盐酸在丙酮、乙醇、异丙醇、或四氢呋喃中反应，搅拌，过滤即得。
  14. 药物组合物，其特征在于，包括权利要求9～12任一项所述的盐和一种或多种药学上可接受载体和/或稀释剂；优选的，所述盐为盐酸盐。
  15. 权利要求9～12任意一项所述的盐、或权利要求14所述的药物组合物在制备用于预防和/或治疗癌症、器官损伤和退行性疾病中的用途。
  16. 权利要求9～12所述的盐、或权利要求14所述的药物组合物在制备用于预防和/或治疗癌症、神经退行性疾病、心脑血管疾病、免疫相关疾病、肝肾衰竭、炎症、代谢性疾病中的用途。
  17. 根据权利要求15所述的用途，其特征在于，所述疾病为癌症、阿尔茨海默病、帕金森病、多发性硬化症、亨廷顿氏舞蹈病、肌萎缩性脊髓侧索硬化症、脑卒中、缺血再灌注损伤、免疫相关疾病、肝肾衰竭、炎症、动脉粥样硬化、糖尿病、或糖尿病并发症。
  18. 根据权利要求17所述的用途，其特征在于，所述脑卒中为出血性脑卒中和/或缺血性脑卒中。
PCT/CN2023/073055 2022-01-28 2023-01-19 吩噻嗪类化合物的晶型、盐、制备方法及用途 Ceased WO2023143350A1 (zh)

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