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WO2023236877A1 - 苯并[c]色满化合物的可药用盐、其多晶型及用途 - Google Patents

苯并[c]色满化合物的可药用盐、其多晶型及用途 Download PDF

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WO2023236877A1
WO2023236877A1 PCT/CN2023/098204 CN2023098204W WO2023236877A1 WO 2023236877 A1 WO2023236877 A1 WO 2023236877A1 CN 2023098204 W CN2023098204 W CN 2023098204W WO 2023236877 A1 WO2023236877 A1 WO 2023236877A1
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formula
compound represented
characteristic peaks
angle
crystal form
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English (en)
French (fr)
Inventor
孙龙伟
侯延婷
朱嘉俊
杨光
郝欣
罗志阳
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Reistone Biopharma Co Ltd
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Reistone Biopharma Co Ltd
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Priority to US18/872,180 priority Critical patent/US20250361226A1/en
Priority to EP23819042.5A priority patent/EP4538277A4/en
Priority to JP2024571417A priority patent/JP2025518345A/ja
Priority to CN202380039466.XA priority patent/CN119156391A/zh
Priority to CA3255979A priority patent/CA3255979A1/en
Priority to KR1020247043328A priority patent/KR20250023398A/ko
Priority to AU2023285191A priority patent/AU2023285191A1/en
Publication of WO2023236877A1 publication Critical patent/WO2023236877A1/zh
Priority to MX2024015035A priority patent/MX2024015035A/es
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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 present disclosure belongs to the field of medical technology and relates to a pharmaceutically acceptable salt of a benzo[c]chroman compound, its polymorphic form and uses.
  • Cathepsins are a type of proteolytic enzymes that widely exist in the lysosomes of various tissue cells. According to their structures and catalytic types, cathepsins are divided into serine proteases (cathepsin A and G) and aspartic proteases (cathepsin A and G). D and E) and caspase class 3. Among them, cysteine proteases are the largest cathepsin family, including 11 proteases: cathepsins B, C, F, H, K, L, O, S, W, V and Z.
  • Cathepsin C is also known as dipeptidyl peptidase I or "DPP1".
  • DPP1 is constitutively expressed in many tissues, with the highest levels in the lungs, kidneys, liver and spleen.
  • Several recently published studies have begun to describe the role of cathepsin C in certain inflammatory processes. For example: J Clin Invest.2002 Feb;109(3):363-71 published by Adkison et al.; Archives of Biochemistry and Biophysics.2002 403:160-170 published by Tinh et al.
  • cathepsin C is closely related to a certain Several serine proteases are co-expressed in granules and function to process the precursor forms of these proteases into active forms that are then released from inflammatory cell granules recruited to sites of inflammation. Once activated, these proteases have many functions, including the degradation of various extracellular matrix components, which together can propagate tissue damage and chronic inflammation.
  • WO 2004/110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.
  • WO 2009/074829 relates to peptidyl nitriles and their use as DPP1 inhibitors.
  • WO 2010/128324 relates to ⁇ -aminoamide nitriles and their use as DPP1 inhibitors.
  • WO 2012/119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors.
  • WO 2013/041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as a DPP1 inhibitor.
  • WO 2001/096285 and WO 2003/048123 relate to ⁇ -aminocarbamide nitriles having inhibitory activity against cysteine proteases.
  • WO 2015/110826 relates to ⁇ -aminoamide nitriles and their use as DPP1 inhibitors.
  • WO 2022/117059 provides a cathepsin C inhibitor whose chemical name is (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[ c] chroman-3-yl)ethyl)-1,4-oxazepane-2-carboxamide, having the structure shown in formula I,
  • the crystal form of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystal forms.
  • amorphous pharmaceutical products do not have regular crystal structures and often have other defects, such as poor product stability, fine crystallization, difficulty in filtration, easy agglomeration, and poor fluidity.
  • Polymorphic forms of drugs have different requirements for product storage, production and scale-up. Therefore, it is necessary to conduct in-depth research on the crystal forms of the above-mentioned compounds and improve various properties of the above-mentioned compounds.
  • the present disclosure provides a pharmaceutically acceptable salt of the compound represented by Formula I, wherein the pharmaceutically acceptable salt is an acid addition salt, selected from the group consisting of hydrochloride, methanesulfonate, phosphate, L-tartrate, Maleates, p-toluenesulfonates, sulfates, fumarates, succinates, citrates, malates and hydrobromides, preferably the pharmaceutically acceptable salts are in crystalline form,
  • the pharmaceutically acceptable salt of the compound represented by Formula I wherein the chemical ratio of the compound represented by Formula I to acid molecules or acid radicals is 1:0.5 to 1:3, preferably 1:0.5, 1:1 , 1:1.2, 1:2 or 1:3; more preferably 1:1.
  • the pharmaceutically acceptable salt of the compound represented by Formula I wherein the pharmaceutically acceptable salt of the compound represented by Formula I is the hydrochloride, and the chemical ratio of the compound represented by Formula I and hydrochloride is 1:1.
  • the present disclosure also provides a method for preparing the above-mentioned pharmaceutically acceptable salt, which includes the step of forming a salt of the compound represented by formula I and an acid.
  • the step of forming a salt between the compound represented by formula I and an acid is carried out in a solvent, and the solvent is selected from the group consisting of dichloromethane, N,N-dimethylformamide, acetonitrile, methanol, ethanol, One or more of propanol, tetrahydrofuran, acetone, 1,4-dioxane, water, dimethyl sulfoxide and ethyl acetate, preferably acetone, methanol, ethanol, ethanol/water, isopropyl alcohol/ Water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide/water, 1,4-dioxane, methanol/water, N,N-dimethylformamide and
  • the present disclosure also provides a hydrochloride crystal form A of the compound represented by formula I, in which the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ angle has characteristic peaks at 7.043, 12.430, 14.356, 14.840 and 15.250, The 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250 and 17.686 There is a characteristic peak at , and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250, 17.686 There are characteristic peaks at , 21.697, 22.305, 25.635 and 27.433, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ as shown in Figure 1 .
  • the hydrochloride salt form A of the compound represented by formula I has an endothermic peak at 268°C in the DSC spectrum, and the error range of the endothermic peak is ⁇ 2°C.
  • the present disclosure also provides a method for preparing the hydrochloride crystal form A of the compound represented by Formula I, including:
  • the preparation method further includes centrifugation, washing and/or drying steps.
  • the preparation method of the hydrochloride crystal form A of the compound represented by formula I is selected from water, C 1-4 ketone solvents, C 1-4 alcohol solvents, water and C 1 - A mixed solvent of 4 alcohol solvents, a C 1-4 ester solvent, a C 1-4 nitrile solvent, a mixed solvent of tetrahydrofuran, dimethyl sulfoxide and water, and 1,4-dioxane;
  • the alcohol Preferred solvents include acetone, methanol, ethanol, ethanol/water, isopropanol/water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide/water, 1,4-dioxane and methanol/water.
  • the method for preparing the hydrochloride crystal form A of the compound represented by formula I is that every milligram of the compound represented by formula I is dissolved in 0.01-0.05 ml of solvent A; more preferably, every milligram of the compound represented by formula I is dissolved in 0.01-0.05 ml of solvent A. In 0.01-0.03ml of solvent A.
  • the mixed solvent of water and alcoholic solvent is a mixed solvent of water and methanol, wherein the molar ratio of water and methanol is 0.10 -0.95, preferably 0.14, 0.26, 0.37, 0.47, 0.57, 0.66, 0.74, 0.82, 0.90.
  • the present disclosure also provides a hydrochloride crystal form A' of the compound represented by the above formula I, wherein the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ angle is at 8.452, 12.476, 15.884, 17.037, 17.227, 22.328 and 23.566 There are characteristic peaks, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A' of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 8.452, 10.537, 12.476, 15.884, 17.037, 17.227, 20.784, 22.328 There are characteristic peaks at , 23.566 and 27.567, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A' of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 8.452, 10.537, 12.476, 13.296, 14.332, 15.884, 17.037, 17.227 There are characteristic peaks at , 20.784, 22.328, 23.566 and 27.567, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A' of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 8.452, 10.537, 12.476, 13.296, 14.332, 15.884, 17.037, 17.227 There are characteristic peaks at , 20.784, 21.329, 22.328, 23.566, 24.497, 25.221 and 27.567, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrochloride salt form A' of the compound represented by formula I has an endothermic peak at 161°C in the DSC spectrum, and the error range of the endothermic peak is ⁇ 2°C.
  • the present disclosure also provides a methanesulfonate salt form B of the compound represented by the above formula I, in which the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ angle is at 6.717, 8.783, 13.969, 15.902, 16.647 and 17.515. Characteristic peak, the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form B of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647 and 17.515 There are characteristic peaks, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form B of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647, 17.515, There are characteristic peaks at 20.446, 21.069, 21.645 and 24.665, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form B of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647, 17.515, There are characteristic peaks at 20.446, 21.069, 21.645, 23.549, 24.665, 26.284, 27.289 and 27.667, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ of the mesylate salt form B of the compound represented by Formula I is as shown in Figure 6 .
  • the methanesulfonate salt form B of the compound represented by Formula I has an endothermic peak at 161°C in the DSC spectrum, and the error range of the endothermic peak is ⁇ 2°C.
  • the present disclosure also provides a methanesulfonate salt form C of the compound represented by the above formula I, in which the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ angle is at 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759 There is a characteristic peak at , and the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and There is a characteristic peak at 19.759, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549, There are characteristic peaks at 19.759, 21.460, 24.637 and 25.497, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549, There are characteristic peaks at 19.759, 21.460, 22.539, 24.637 and 25.497, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the methanesulfonate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ as shown in Figure 9.
  • the methanesulfonate salt form C of the compound represented by Formula I has an endothermic peak at 194°C in the DSC spectrum, and the error range of the endothermic peak is ⁇ 2°C.
  • the present disclosure also provides a phosphate D crystal form of the compound represented by the above formula I, in which the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 9.593, 12.831, 13.464, 15.666, 18.161 and 19.245 , the 2 ⁇ angle error range is ⁇ 0.20.
  • a phosphate crystal form D of the compound of Formula I wherein the X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle, is at 8.491, 9.593, 12.831, 13.464, 13.954, 14.943, 15.666, There are characteristic peaks at 16.616, 17.259, 18.161 and 19.245, and the 2 ⁇ angle error range is ⁇ 0.20.
  • a phosphate crystal form D of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 4.213, 6.650, 8.491, 9.593, 10.897, 12.831, 13.464, There are characteristic peaks at 13.954, 14.943, 15.666, 16.616, 17.259, 18.161 and 19.245, and the 2 ⁇ angle error range is ⁇ 0.20.
  • a phosphate crystal form D of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 4.213, 6.650, 8.491, 9.593, 10.897, 12.831, 13.464, There are characteristic peaks at 13.954, 14.943, 15.666, 16.616, 17.259, 18.161, 19.245, 24.822, 25.665 and 26.618, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ of the phosphate crystal form D of the compound represented by Formula I is as shown in Figure 12.
  • the DSC spectrum of the phosphate crystal form D of the compound represented by Formula I has endothermic peaks at 130°C and 143°C, and the error range of the endothermic peak is ⁇ 2°C.
  • the present disclosure also provides an L-tartrate crystal form E of the compound represented by the above formula I, in which the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ has characteristic peaks at 6.383, 9.081, 12.936, 16.161 and 18.397 , the 2 ⁇ angle error range is ⁇ 0.20.
  • the L-tartrate salt form E of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.383, 9.081, 12.936, 14.400, 16.161, 18.397 and 19.489 There are characteristic peaks, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the L-tartrate crystal form E of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.383, 9.081, 12.936, 14.400, 16.161, 18.397, 19.489, There are characteristic peaks at 23.786, 24.536 and 26.203, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the L-tartrate crystal form E of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ as shown in Figure 15.
  • the L-tartrate crystal form E of the compound represented by Formula I has an endothermic peak at 132°C in the DSC spectrum, and the error range of the endothermic peak is ⁇ 2°C.
  • the present disclosure also provides a hydrobromide crystal form F of the compound represented by the above formula I, wherein the diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern represented by the angle has characteristic peaks at 7.133, 12.485, 14.422, 17.721 and 18.823, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrobromide salt form F of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721 and 18.823 There are characteristic peaks, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrobromide salt form F of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721, 18.823, There are characteristic peaks at 20.738, 21.656, 22.309, 23.238, 25.116, 25.672 and 27.416, and the 2 ⁇ angle error range is ⁇ 0.20.
  • the hydrobromide salt form F of the compound represented by Formula I has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ as shown in Figure 18.
  • the hydrobromide salt form F of the compound represented by Formula I has endothermic peaks at 99°C and 216°C in the DSC spectrum, and the error range of the endothermic peak is ⁇ 2°C.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in this disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including numbers exceeding 1 decimal place after rounding situation), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17 ,0.18,0.19,0.20.
  • the present disclosure also provides a pharmaceutical composition containing a pharmaceutically acceptable salt of the compound represented by the above formula I, the hydrochloride crystal form A of the compound represented by formula I, and the crystal form B of the mesylate salt of the compound represented by formula I. , the C crystal form of the methanesulfonate salt of the compound represented by the formula I, the D crystal form of the phosphate salt of the compound represented by the formula I, the L-salt E crystal form of the compound represented by the formula I, the hydrogen bromide of the compound represented by the formula I Salt Form F and pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, which includes preparing the hydrochloride crystal form A of the compound represented by formula I, the mesylate crystal form B of the compound represented by formula I, and the formazan form of the compound represented by formula I.
  • the present disclosure also relates to pharmaceutically acceptable salts of the compound represented by the above formula I, crystal form A of the hydrochloride salt of the compound represented by the formula I, crystal form B of the mesylate salt of the compound represented by the formula I, and crystal form B of the compound represented by the formula I.
  • the above composition is prepared for the prevention and/or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, ⁇ 1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, Use in medicines for rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.
  • the present disclosure also relates to a method for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, ⁇ 1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease
  • a method for treating diseases, rheumatoid arthritis, sinusitis, hidradenitis suppurativa or cancer which includes administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound represented by the above formula I, a compound represented by the formula I Crystal form A of the hydrochloride salt, crystal form B of the mesylate salt of the compound represented by formula I, crystal form C of the mesylate salt of the compound represented by formula I, and crystal form D of the phosphate salt of the compound represented by formula I.
  • L-tartrate crystal form E of the compound represented by formula I hydrobromide crystal form
  • the present disclosure also relates to pharmaceutically acceptable salts of the compound represented by the above formula I, crystal form A of the hydrochloride salt of the compound represented by the formula I, crystal form B of the mesylate salt of the compound represented by the formula I, and crystal form B of the compound represented by the formula I.
  • the above composition is used for preventing and/or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, ⁇ 1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, Rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.
  • Excipients include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock animals. , preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents or emulsifiers.
  • the starting materials used in the crystal form preparation method of the present disclosure can be compounds in any form. Specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.
  • Differential scanning calorimetry or DSC refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the process of heating or constant temperature of the sample to characterize all physical phenomena related to thermal effects. changes and chemical changes to obtain phase change information of the sample.
  • the numerical values in this disclosure are measured and calculated data, and there is inevitably a certain degree of error. Generally speaking, ⁇ 10% is within the reasonable error range. There is a certain degree of error variation depending on the context where it is used. The error variation does not exceed ⁇ 10% and can be ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2% or ⁇ 1%, preferably ⁇ 5%.
  • Figure 1 is an XRPD pattern of the hydrochloride form A of the compound represented by formula I;
  • Figure 2 is a DSC chart of the hydrochloride form A of the compound represented by formula I;
  • FIG. 3 is a TGA diagram of the hydrochloride form A of the compound represented by formula I;
  • FIG. 4 is a DVS diagram of the hydrochloride form A of the compound represented by formula I;
  • Figure 5 is the XRPD pattern before and after DVS of the hydrochloride form A of the compound represented by formula I (the upper one is the XRPD spectrum before DVS, and the lower one is the XRPD spectrum after DVS);
  • Figure 6 is an XRPD pattern of the mesylate crystal form B of the compound represented by formula I;
  • Figure 7 is a DSC chart of the mesylate crystal form B of the compound represented by formula I;
  • Figure 8 is a TGA diagram of the mesylate crystal form B of the compound represented by Formula I;
  • Figure 9 is an XRPD pattern of the mesylate crystal form C of the compound represented by formula I;
  • Figure 10 is a DSC chart of the mesylate crystal form C of the compound represented by formula I;
  • Figure 11 is a TGA diagram of the mesylate crystal form C of the compound represented by formula I;
  • Figure 12 is an XRPD pattern of the phosphate crystal form D of the compound represented by formula I;
  • Figure 13 is a DSC chart of the phosphate crystal form D of the compound represented by formula I;
  • Figure 14 is a TGA diagram of the phosphate crystal form D of the compound represented by formula I;
  • Figure 15 is an XRPD pattern of the L-tartrate crystal form E of the compound represented by formula I;
  • Figure 16 is a DSC chart of the L-tartrate crystal form E of the compound represented by formula I;
  • Figure 17 is a TGA diagram of the L-tartrate crystal form E of the compound represented by formula I;
  • Figure 18 is the XRPD spectrum of the hydrobromide crystal form F of the compound represented by formula I;
  • Figure 19 is a DSC spectrum of the hydrobromide crystal form F of the compound represented by formula I;
  • Figure 20 is a TGA spectrum of the hydrobromide crystal form F of the compound represented by formula I;
  • Figure 21 is the NMR spectrum of the hydrobromide crystal form F of the compound represented by formula I;
  • Figure 22 is an XRPD pattern of the hydrochloride form A’ of the compound represented by formula I;
  • Figure 23 is a DSC chart of the hydrochloride form A' of the compound represented by formula I;
  • Figure 24 is a TGA diagram of the hydrochloride form A' of the compound represented by formula I.
  • the detection uses SMS Intrinsic PLUS, at 25°C, the humidity is from 50%-0%-90%, the step is 10%, the judgment standard is that the change in dM/dT of each gradient is less than 0.002%, TMAX 360min, two cycles.
  • HPLC conditions in the content detection method of high performance liquid chromatography described in the present disclosure Chromatographic column: Agilent Eclipse Plus C18 4.6mm*150mm, 3.5 ⁇ m; mobile phase: A: 10mmol/L sodium dihydrogen phosphate solution (pH8.0 ), B-ACN; flow rate: 1.0ml/min; wavelength: 210nm.
  • HPLC conditions chromatographic column: Agilent Eclipse Plus C18 4.6mm*150mm, 3.5 ⁇ m; mobile phase: A: 10mmol/L ammonium acetate solution, B-ACN ;Flow rate: 1.0ml/min;Wavelength: 210nm.
  • compound I-2 (2.90g, 6.37mmol), palladium acetate (0.14g, 0.64mmol), potassium carbonate (1.76g, 12.73mmol) and tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.64 mmol) was dissolved in N,N-dimethylformamide (30 mL), and the reaction mixture was heated to 120°C and stirred for 1.5 hours. After the reaction was completed, cool to room temperature, add water (200 mL), and extract with ethyl acetate (200 mL ⁇ 2). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate.
  • compound I-7 (220mg, 0.68mmol), compound a (170mg, 0.69mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole- 1-yl)urea hexafluorophosphate (360 mg, 0.95 mmol) and N, N-diisopropylethylamine (250 mg, 1.93 mmol) were dissolved in N, N-dimethylformamide (5 mL), and the reaction mixture was Stir at room temperature for 3 hours. After the reaction was completed, compound I-8 was separated by preparative liquid chromatography (C18, acetonitrile/water system). MS-ESI: m/z 465.1[M-56+1] + .
  • Example 2 Biological evaluation of the compound represented by formula I - in vitro CatC cell activity detection experiment
  • the compound was prepared as a 10mM solution in DMSO, the compound was diluted into a 1mM solution in DMSO, and half-log diluted with DMSO for 10 points using HPD300.
  • Gly-Phe-AFC was prepared into a 35mM solution in DMSO, aliquoted, and Gly-Phe-AFC was prepared in serum-free medium to 1.75mM. After adding the drug, incubate in the incubator for 1 hour, add substrate-AFC, and add 12.5 ⁇ l to the plate. After incubating for 30 minutes, test the plate.
  • Inhibition rate (%) (1-(RFU compound-RFU Blank)/(RFU DMSO–RFU Blank)) ⁇ 100%.
  • Use a 4-parameter model [fitting (A+((BA)/(1+((C/x) ⁇ D)))).
  • the compound represented by Formula I of the present disclosure inhibited the activity of CatC cells in vitro and was measured by the above test.
  • the measured IC 50 value was 6.1 nM, indicating a significant inhibitory effect on the activity of CatC cells.
  • the product is defined as the hydrochloride crystal form A of the compound represented by Formula I.
  • the XRPD pattern is shown in Figure 1, and its characteristic peak positions are shown in Table 1.
  • the DSC spectrum is shown in Figure 2.
  • the endothermic peak peak is around 268°C.
  • the TGA spectrum is shown in Figure 3, which begins to lose weight rapidly above 200°C.
  • the DVS test is shown in Figure 4. Under accelerated experimental conditions (i.e. 80% RH), the moisture absorption weight gain is approximately 1.1%. During the humidity change process from 0% to 90%RH, the desorption and adsorption process of this sample were consistent. And the crystal form was re-measured after DVS detection. The XRPD spectrum is shown in Figure 5, which shows that the crystal form has not changed before and after DVS detection.

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Abstract

一种苯并[c]色满化合物I的可药用盐、其多晶型及用途。所述可药用盐选自盐酸盐、甲磺酸盐、磷酸盐、L-酒石酸盐、马来酸盐、对甲苯磺酸盐、硫酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、苹果酸盐和氢溴酸盐。所述可药用盐及其多晶型提高了生物利用度和稳定性，可作为组织蛋白酶C 抑制剂用于治疗气喘、阻塞性肺病、支气管扩张、ANCA 相关性血管炎、银屑病、α1-抗胰蛋白酶缺乏症、狼疮性肾炎、糖尿病、炎症性肠病、风湿性关节炎、鼻窦炎、化脓性汗腺炎或癌症。

Description

苯并[c]色满化合物的可药用盐、其多晶型及用途 技术领域
本公开属于医药技术领域，涉及一种苯并[c]色满化合物的可药用盐、其多晶型及用途。
背景技术
组织蛋白酶是广泛存在于多种组织细胞溶酶体内的一类蛋白水解酶，根据其结构和催化型，组织蛋白酶被分为丝氨酸蛋白酶(组织蛋白酶A和G)、天冬氨酸蛋白酶(组织蛋白酶D和E)和半胱氨酸蛋白酶3类。其中，半胱氨酸蛋白酶是最大的组织蛋白酶家族，包括11种蛋白酶：组织蛋白酶B、C、F、H、K、L、O、S、W、V和Z。
组织蛋白酶C(cathepsin C)也已知为二肽基肽酶Ⅰ或“DPP1”，DPP1组成性地表达于许多组织中，其中在肺、肾、肝和脾中水平最高。最近公布的一些研究已经开始描述组织蛋白酶C在某些炎症过程中起到的作用。例如：Adkison等发表的J Clin Invest.2002 Feb；109(3):363-71；Tinh等发表的Archives of Biochemistry and Biophysics.2002 403:160-170；从这些研究看来，组织蛋白酶C与某些丝氨酸蛋白酶在颗粒中共表达，并起到将这些蛋白酶的前体形式加工成活性形式的作用，然后从募集到炎症部位的炎性细胞颗粒中释放出来。一旦被激活，这些蛋白酶具有许多功能，包括各种细胞外基质组分的降解，它们一起可以传播组织损伤和慢性炎症。
WO 2004/110988涉及某些腈衍生物及其作为DPP1抑制剂的用途。
WO 2009/074829涉及肽基腈及其作为DPP1抑制剂的用途。
WO 2010/128324涉及α-氨基酰胺腈及其作为DPP1抑制剂的用途。
WO 2012/119941涉及肽基腈化合物及其作为DPP1抑制剂的用途。
WO 2013/041497涉及N-[1-氰基-2-(苯基)乙基]-2-氮杂双环[2.2.1]庚烷-3-甲酰胺及其作为DPP1抑制剂的用途。
WO 2001/096285和WO 2003/048123涉及对半胱氨酸蛋白酶具有抑制性活性的β-氨基酰胺腈。
WO 2015/110826涉及α-氨基酰胺腈及其作为DPP1抑制剂的用途。
WO 2022/117059提供一种组织蛋白酶C抑制剂，其化学名为(S)-N-((S)-1-氰基-2-(8-氰基-2-氟-6H-苯并[c]色满-3-基)乙基)-1,4-恶氮杂环庚烷-2-甲酰胺，具有式I所示的结构，
作为药用活性成分的晶型往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。药物的多晶型对产品储存、生产及放大有不同的要求。因此，深入研究上述化合物的晶型，改善上述化合物的各方面性质是很有必要的。
发明内容
本公开提供了一种式I所示化合物的可药用盐，其中所述可药用盐为酸式加成盐，选自盐酸盐、甲磺酸盐、磷酸盐、L-酒石酸盐、马来酸盐、对甲苯磺酸盐、硫酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、苹果酸盐和氢溴酸盐，优选地，所述可药用盐为结晶形式，
在一些实施方案中，式I所示化合物的可药用盐，其中所述式I所示化合物与酸分子或酸根的化学配比1:0.5至1:3，优选1:0.5、1:1、1:1.2、1:2或1:3；更优选1:1。
在一些实施方案中，式I所示化合物的可药用盐，其中所述式I所示化合物的可药用盐为盐酸盐，所述式I所示化合物与盐酸根的化学配比为1:1。
本公开还提供一种上述可药用盐的制备方法，其包括将式I所示化合物与酸成盐的步骤。在某些实施方案中，式I所示化合物与酸成盐的步骤在溶剂中进行，所述溶剂选自二氯甲烷、N,N-二甲基甲酰胺、乙腈、甲醇、乙醇、、异丙醇、四氢呋喃、丙酮、1,4-二氧六环、水、二甲基亚砜和乙酸乙酯中的一种或多种，优选丙酮、甲醇、乙醇、乙醇/水、异丙醇/水、乙酸乙酯、乙腈、四氢呋喃、二甲基亚砜/水、1,4-二氧六环、甲醇/水、N,N-二甲基甲酰胺和二氯甲烷。
本公开还提供一种式I所示化合物的盐酸盐A晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在7.043、12.430、14.356、14.840和15.250处有特征峰， 所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在7.043、8.719、10.737、12.430、14.356、14.840、15.250和17.686处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在7.043、8.719、10.737、12.430、14.356、14.840、15.250、17.686、21.697、22.305、25.635和27.433处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
在一些实施方案中，式I所示化合物的盐酸盐A晶型，其中DSC谱图在268℃处有吸热峰，所述吸热峰的误差范围为±2℃。
本公开还提供一种上述的式I所示化合物的盐酸盐A晶型的制备方法，包括：
a)将式I所示化合物的盐酸盐溶于溶剂A；
b)搅拌；
在一些实施方案中，所述的制备方法还包括离心、洗涤和/或干燥步骤。
在一些实施方案中，式I所示化合物的盐酸盐A晶型的制备方法，所述溶剂A选自水、C1-4酮类溶剂、C1-4醇类溶剂、水和C1-4醇类溶剂的混合溶剂、C1-4酯类溶剂、C1-4腈类溶剂、四氢呋喃、二甲基亚砜和水的混合溶剂以及1,4-二氧六环；所述醇类溶剂优选丙酮、甲醇、乙醇、乙醇/水、异丙醇/水、乙酸乙酯、乙腈、四氢呋喃、二甲基亚砜/水、1,4-二氧六环以及甲醇/水。
在一些实施方案中，式I所示化合物的盐酸盐A晶型的制备方法，每毫克式I所示化合物溶于0.01-0.05ml的溶剂A中；更优选每毫克式I所示化合物溶于0.01-0.03ml的溶剂A中。
在一些实施方案中，式I所示化合物的盐酸盐A晶型的制备方法中，水和醇类溶剂的混合溶剂为水和甲醇的混合溶剂，其中水和所述甲醇的摩尔比为0.10-0.95，优选0.14、0.26、0.37、0.47、0.57、0.66、0.74、0.82、0.90。
本公开还提供一种上述式I所示化合物的盐酸盐A’晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图在8.452、12.476、15.884、17.037、17.227、22.328和23.566处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A’晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图在8.452、10.537、12.476、15.884、17.037、17.227、20.784、22.328、23.566和27.567处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A’晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图在8.452、10.537、12.476、13.296、14.332、15.884、17.037、17.227、20.784、22.328、23.566和27.567处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A’晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图在8.452、10.537、12.476、13.296、14.332、15.884、17.037、17.227、20.784、21.329、22.328、23.566、24.497、25.221和27.567处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的盐酸盐A’晶型，其中DSC谱图在161℃处有吸热峰，所述吸热峰的误差范围为±2℃。
本公开还提供一种上述式I所示化合物的甲磺酸盐B晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.717、8.783、13.969、15.902、16.647和17.515处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐B晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.717、8.105、8.783、13.969、15.902、16.647和17.515处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐B晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.717、8.105、8.783、13.969、15.902、16.647、17.515、20.446、21.069、21.645和24.665处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐B晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.717、8.105、8.783、13.969、15.902、16.647、17.515、20.446、21.069、21.645、23.549、24.665、26.284、27.289和27.667处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
在一些实施方案中，式I所示化合物的甲磺酸盐B晶型，其中DSC谱图在161℃处有吸热峰，所述吸热峰的误差范围为±2℃。
本公开还提供一种上述式I所示化合物的甲磺酸盐C晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在7.747、11.163、12.676、15.268、16.824、18.549和19.759处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐C晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在4.522、7.747、11.163、12.676、15.268、16.824、18.549和19.759处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐C晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在4.522、7.747、11.163、12.676、15.268、16.824、18.549、19.759、21.460、24.637和25.497处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐C晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在4.522、7.747、11.163、12.676、15.268、16.824、18.549、19.759、21.460、22.539、24.637和25.497处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的甲磺酸盐C晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
在一些实施方案中，式I所示化合物的甲磺酸盐C晶型，其中DSC谱图在194℃处有吸热峰，所述吸热峰的误差范围为±2℃。
本公开还提供一种上述式I所示化合物的磷酸盐D晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在9.593、12.831、13.464、15.666、18.161和19.245处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，一种式I所示化合物的磷酸盐D晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在8.491、9.593、12.831、13.464、13.954、14.943、15.666、16.616、17.259、18.161和19.245处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，一种式I所示化合物的磷酸盐D晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在4.213、6.650、8.491、9.593、10.897、12.831、13.464、13.954、14.943、15.666、16.616、17.259、18.161和19.245处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，一种式I所示化合物的磷酸盐D晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在4.213、6.650、8.491、9.593、10.897、12.831、13.464、13.954、14.943、15.666、16.616、17.259、18.161、19.245、24.822、25.665和26.618处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的磷酸盐D晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
在一些实施方案中，式I所示化合物的磷酸盐D晶型，其中DSC谱图在130℃和143℃有吸热峰，所述吸热峰的误差范围为±2℃。
本公开还提供一种上述式I所示化合物的L-酒石酸盐E晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.383、9.081、12.936、16.161和18.397处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的L-酒石酸盐E晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.383、9.081、12.936、14.400、16.161、18.397和19.489处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的L-酒石酸盐E晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.383、9.081、12.936、14.400、16.161、18.397、19.489、23.786、24.536和26.203处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的L-酒石酸盐E晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
在一些实施方案中，式I所示化合物的L-酒石酸盐E晶型，其中DSC谱图在132℃处有吸热峰，所述吸热峰的误差范围为±2℃。
本公开还提供一种上述式I所示化合物的氢溴酸盐F晶型，其中以衍射角2θ 角度表示的X-射线粉末衍射图，在7.133、12.485、14.422、17.721和18.823处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的氢溴酸盐F晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.152、7.133、10.827、12.485、14.422、17.721和18.823处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的氢溴酸盐F晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.152、7.133、10.827、12.485、14.422、17.721、18.823、20.738、21.656、22.309、23.238、25.116、25.672和27.416处有特征峰，所述2θ角度误差范围为±0.20。
在一些实施方案中，式I所示化合物的氢溴酸盐F晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
在一些实施方案中，式I所示化合物的氢溴酸盐F晶型，其中DSC谱图在99℃和216℃处有吸热峰，所述吸热峰的误差范围为±2℃。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开还提供一种药物组合物，含有上述式I所示化合物的可药用盐、式I所示化合物的盐酸盐A晶型、式I所示化合物的甲磺酸盐的B晶型、式I所示化合物的甲磺酸盐的C晶型、式I所示化合物的磷酸盐的D晶型、式I所示化合物的L-盐E晶型、式I所示化合物的氢溴酸盐F晶型和药学上可接受的赋形剂。
本公开还提供一种药物组合物的制备方法，包括将式I所示化合物的盐酸盐A晶型、式I所示化合物的甲磺酸盐的B晶型、式I所示化合物的甲磺酸盐的C晶型、式I所示化合物的磷酸盐的D晶型、式I所示化合物的L-酒石酸盐E晶型、式I所示化合物的氢溴酸盐F晶型与药学上可接受的赋形剂混合的步骤。
本公开还涉及上述式I所示化合物的可药用盐、式I所示化合物的盐酸盐A晶型、式I所示化合物的甲磺酸盐的B晶型、式I所示化合物的甲磺酸盐的C晶型、式I所示化合物的磷酸盐的D晶型、式I所示化合物的L-酒石酸盐E晶型、式I所示化合物的氢溴酸盐F晶型或上述组合物在制备用于预防和/或治疗气喘、阻塞性肺病、支气管扩张、ANCA相关性血管炎、银屑病、α1-抗胰蛋白酶缺乏症、狼疮性肾炎、糖尿病、炎症性肠病、风湿性关节炎、鼻窦炎、化脓性汗腺炎或癌症的药物中的用途。
本公开还涉及一种用于预防和/或治疗气喘、阻塞性肺病、支气管扩张、ANCA相关性血管炎、银屑病、α1-抗胰蛋白酶缺乏症、狼疮性肾炎、糖尿病、炎症性肠 病、风湿性关节炎、鼻窦炎、化脓性汗腺炎或癌症的方法，其包括向需要其的受试者施用治疗有效量的上述式I所示化合物的可药用盐、式I所示化合物的盐酸盐A晶型、式I所示化合物的甲磺酸盐的B晶型、式I所示化合物的甲磺酸盐的C晶型、式I所示化合物的磷酸盐的D晶型、式I所示化合物的L-酒石酸盐E晶型、式I所示化合物的氢溴酸盐F晶型或上述组合物。
本公开还涉及上述式I所示化合物的可药用盐、式I所示化合物的盐酸盐A晶型、式I所示化合物的甲磺酸盐的B晶型、式I所示化合物的甲磺酸盐的C晶型、式I所示化合物的磷酸盐的D晶型、式I所示化合物的L-酒石酸盐E晶型、式I所示化合物的氢溴酸盐F晶型或上述组合物，其用于预防和/或治疗气喘、阻塞性肺病、支气管扩张、ANCA相关性血管炎、银屑病、α1-抗胰蛋白酶缺乏症、狼疮性肾炎、糖尿病、炎症性肠病、风湿性关节炎、鼻窦炎、化脓性汗腺炎或癌症。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开晶型制备方法中所用的起始原料可以是任意形式的化合物，具体形式包括但不限于：无定形、任意晶型、水合物、溶剂合物等。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参a考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开中数值如有关物质含量为测定计算的数据，不可避免存在一定程度的误差。一般而言，±10％均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化，该误差变化不超过±10％，可以为±9％、±8％、±7％、±6％、±5％、±4％、±3％、±2％或±1％，优选±5％。
附图说明
图1为式I所示化合物盐酸盐A晶型的XRPD图；
图2为式I所示化合物盐酸盐A晶型的DSC图；
图3为式I所示化合物盐酸盐A晶型的TGA图；
图4为式I所示化合物盐酸盐A晶型的DVS图；
图5为式I所示化合物盐酸盐A晶型的DVS前后的XRPD图(其中，上方的是DVS前的XRPD谱图，下方的是DVS后的XRPD谱图)；
图6为式I所示化合物甲磺酸盐B晶型的XRPD图；
图7为式I所示化合物甲磺酸盐B晶型的DSC图；
图8为式I所示化合物甲磺酸盐B晶型的TGA图；
图9为式I所示化合物甲磺酸盐C晶型的XRPD图；
图10为式I所示化合物甲磺酸盐C晶型的DSC图；
图11为式I所示化合物甲磺酸盐C晶型的TGA图；
图12为式I所示化合物磷酸盐D晶型的XRPD图；
图13为式I所示化合物磷酸盐D晶型的DSC图；
图14为式I所示化合物磷酸盐D晶型的TGA图；
图15为式I所示化合物L-酒石酸盐E晶型的XRPD图；
图16为式I所示化合物L-酒石酸盐E晶型的DSC图；
图17为式I所示化合物L-酒石酸盐E晶型的TGA图；
图18为式I所示化合物氢溴酸盐F晶型的XRPD谱图；
图19为式I所示化合物氢溴酸盐F晶型的DSC谱图；
图20为式I所示化合物氢溴酸盐F晶型的TGA谱图；
图21为式I所示化合物氢溴酸盐F晶型的NMR谱图；
图22为式I所示化合物盐酸盐A’晶型的XRPD图；
图23为式I所示化合物盐酸盐A’晶型的DSC图；
图24为式I所示化合物盐酸盐A’晶型的TGA图。
具体实施方式
以下将结合实施例或实验例更详细地解释本公开，本公开中的实施例或实验例仅用于说明本公开中的技术方案，并非限定本公开中的实质和范围。
本公开所用到的缩写的解释如下：
XRPD         X-射线粉末衍射
DSC          示差扫描量热法
TGA          热重分析
DVS          动态水分吸附
1H-NMR        液态核磁氢谱
DMF          N,N-二甲基甲酰胺
MEK          丁酮
MTBE         甲基叔丁基醚
THF          四氢呋喃
IPA          异丙醇
ACN          乙腈
MeOH         甲醇
EOH          乙醇
ACT          丙酮
PA           磷酸
TA           酒石酸
HBr            氢溴酸
HCl            盐酸
DCM            二氯甲烷
本公开中实验所用仪器的测试条件：
1、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：Malver Panalytical Aeris X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.54188)
扫描方式：θ/2θ，扫描范围(2θ范围)：3.5～50°
电压：40kV，电流：15mA
2、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：TA DSC250
吹扫气：氮气；氮气吹扫速度：50mL/min
升温速率：10℃/min
温度范围：25℃-250℃
3、热重分析仪(Thermogravimetric Analysis，TGA)
仪器型号：TA TGA550
吹扫气：氮气；氮气吹扫速度：20ml/min
扫描速率：10℃/min
温度范围：30℃-350℃
4、动态水分吸附(DVS)
检测采用SMS Intrinsic PLUS，在25℃，湿度从50％-0％-90％，步进为10％，判断标准为每个梯度质量变化dM/dT小于0.002％，TMAX 360min，循环两圈。
5、本公开A晶型稳定性测试中所述的高效液相色谱法(HPLC)图在Agilent1260Infinity II上采集。
本公开所述的高效液相色谱法的含量检测方法中HPLC条件：色谱柱：Agilent Eclipse Plus C18 4.6mm*150mm,3.5μm；流动相：A:10mmol/L磷酸二氢钠溶液(pH8.0)，B-ACN；流速：1.0ml/min；波长：210nm。
本公开所述的高效液相色谱法的有关物质检测方法如中HPLC条件：色谱柱：Agilent Eclipse Plus C18 4.6mm*150mm,3.5μm；流动相：A:10mmol/L乙酸铵溶液，B-ACN；流速：1.0ml/min；波长：210nm。
实施例1：(S)-N-((S)-1-氰基-2-(8-氰基-2-氟-6H-苯并[c]色满-3-基)乙基)-1,4-恶氮杂环庚烷-2-甲酰胺(式I所示化合物)的制备
化合物I-2的合成
室温下，将2-氟-5-羟基苯甲酸甲酯(4.30g,25.29mmol)，4-溴-3-(溴甲基)苯腈(化合物I-1)(7.72g,25.30mmol)和碳酸钾(6.99g,50.58mmol)溶于N,N-二甲基甲酰胺(50mL)中，反应混合物加热至40℃搅拌12小时。加水(300mL)，用乙酸乙酯(100mL×2)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物经柱层析(SiO2,石油醚/乙酸乙酯＝9/1)分离得到化合物I-2。1H NMR(400MHz,CDCl3)δ7.87(d,1H),7.73(d,1H),7.55-7.48(m,2H),7.18-7.09(m,2H),5.11(s,2H),3.95(s,3H)。
化合物I-3的合成
室温及氮气保护下，将化合物I-2(2.90g,6.37mmol)，醋酸钯(0.14g,0.64mmol)，碳酸钾(1.76g,12.73mmol)和三环己基膦四氟硼酸盐(0.23g,0.64mmol)溶于N,N-二甲基甲酰胺(30mL)中，反应混合物加热至120℃搅拌1.5小时。反应完毕后，冷却至室温，加入水(200mL)，用乙酸乙酯(200mL×2)萃取。合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物经柱层析(SiO2,石油醚/乙酸乙酯＝4/1)分离得到化合物I-3。1H NMR(400MHz,CDCl3)δ7.80-7.72(m,2H),7.60(d,1H),7.52-7.49(m,2H),5.18(s,2H),3.98(s,3H)。
化合物I-4的合成
室温下，将化合物I-3(1.20g,3.81mmol)和硼氢化锂(0.25g,11.47mmol)溶于四氢呋喃(25mL)中，反应混合物加热至55℃搅拌2小时。反应完毕后，反应混合物冷却至室温，加入水(200mL)，用乙酸乙酯(200mL×2)萃取。合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物经柱层析(SiO2,石油醚/乙酸乙酯＝9/1)分离得到化合物I-4。1H NMR(400MHz,CDCl3)δ7.67(s,2H),7.47(s,1H),7.38(d,1H),7.12(d,1H),5.11(s,2H),4.77(s,2H)。
化合物I-5的合成
室温下，将化合物I-3(450mg,1.59mmol)溶于二氯甲烷(15mL)中，随后滴加三溴化磷(520mg,1.92mmol)，反应混合物室温搅拌20分钟。反应完毕后，加入水(100mL)，用乙酸乙酯(100mL×2)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物经柱层析(SiO2,石油醚/乙酸乙酯＝9/1)分离得到化合物I-5。1H NMR(300MHz,CDCl3)δ7.73(s,2H),7.52(s,1H),7.45(d,1H),7.10(d,1H),5.17(s,2H),4.53(s,2H)。
化合物I-6的合成
室温下，将二苯基亚甲基氨基乙腈(250mg,1.14mmol)，化合物I-5(470mg,1.26mmol)，苄基三甲基氯化铵(22mg,0.12mmol)和氢氧化钠(91mg,2.3mmol)溶于二氯甲烷(6mL)和水(6mL)的混合溶剂中，反应混合物加热至35℃搅拌24小时。加入水(30mL)，用二氯甲烷(30mL×2)萃取。合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物经柱层析(SiO2,石油醚/乙酸乙酯＝4/1)分离得到化合物I-6。MS-ESI:m/z 458.4[M+1]+。
化合物I-7的合成
室温下，将化合物I-6(520mg,0.90mmol)溶于四氢呋喃(10mL)中，随后滴加1M盐酸水溶液(4mL)，反应混合物在室温下搅拌1小时。反应完毕后，加入饱和碳酸氢钠水溶液(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，所得残余物经柱层析(SiO2,石油醚/乙酸乙酯＝2/1)分离得到化合物I-7。MS-ESI:m/z 293.9[M+1]+。
化合物I-8的合成
室温下，将化合物I-7(220mg,0.68mmol)，化合物a(170mg,0.69mmol)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(360mg,0.95mmol)和N,N-二异丙基乙胺(250mg,1.93mmol)溶于N,N-二甲基甲酰胺(5mL)中，反应混合物在室温下搅拌3小时。反应完毕后，经制备级液相色谱(C18，乙腈/水体系)分离得到化合物I-8。MS-ESI:m/z 465.1[M-56+1]+。
化合物I-9的合成
化合物I-8(280mg,0.51mmol)经手性拆分(色谱柱：chiralpak IE,250*25mm,5μm；流动相：正己烷，乙醇；梯度配比：正己烷相30％；流速：15mL/min；柱温：30℃)得到化合物I-9(共两个非对映异构体峰，化合物I-9为第一个洗脱的峰)。1H NMR(300MHz,DMSO-d6)δ8.89(d,1H),8.08(d,1H),7.94-7.89(m,2H),7.83(s,1H),7.07(d,1H),5.24-5.14(m,2H),5.09-5.07(m,1H),4.15-4.12(m,1H),3.99-3.87(m,2H),3.63-3.56(m,2H),3.29-3.02(m,4H),1.89-1.79(m,2H),1.41-1.36(m,9H)。
化合物I的合成
室温下，将化合物I-9(85mg,0.16mmol)溶于甲酸(1mL)中，反应混合物加热至40℃搅拌1小时。反应完毕后，经制备级液相色谱(C18，碳酸氢铵/乙腈/水体系)得到化合物I。所得化合物经XRPD检测为无定型。MS-ESI:m/z 421.2[M+1]+。1H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.05(d,1H),7.89-7.86(m,2H),7.80(s,1H),7.03(d,1H),5.20-5.12(m,2H),5.09-5.02(m,1H),4.00-3.97(m,1H),3.88-3.83(m,1H),3.77-3.68(m,1H),3.25-3.14(m,2H),3.05-2.98(m,1H),2.82-2.72(m,1H),2.62-2.53(m,2H),1.80-1.66(m,2H)。
实施例2：式I所示化合物的生物学评价——体外CatC细胞活性检测实验
1、实验材料
2、实验步骤
配制完全培养基RPMI1640+10％FBS，充分混匀。复苏U937细胞系，传两代左右选择生长状态良好的细胞株。吸取细胞悬液并移入离心管中，800-1000rpm的转速离心3-5分钟。弃上清。向离心管中加适当体积的培养基，轻柔吹打使细胞重悬均匀。使用Vi-Cell XR细胞计数仪计数。将细胞悬液调至合适浓度。将细胞悬液加入384孔板中，25000μl/孔。化合物在DMSO中配制成10mM溶液,将化合物在DMSO中稀释成1mM溶液，并用HPD300以DMSO进行半对数稀释10个点。Gly-Phe-AFC在DMSO中配制成35mM溶液，分装，将Gly-Phe-AFC用无血清培养基配置到1.75mM。加完药后在培养箱中孵育1h后添加底物-AFC，取12.5μl加到板中。孵育30min后测板。将培养板放入EnSpire读板,在Ex 400nm,Em 505nm下记录荧光读值结果,按下列公式计算抑制率：抑制率(％)＝(1-(RFU化合物-RFU 空白)/(RFU DMSO–RFU空白))×100％。利用XLFit绘制药效抑制率曲线并计算IC50值。利用4参数模型[拟合＝(A+((B-A)/(1+((C/x)^D))))]。
本公开的式I所示化合物在体外对CatC细胞活性抑制通过以上的试验进行测定，测得的IC50值为6.1nM，对CatC细胞活性抑制效果显著。
实施例3：式I所示化合物的盐酸盐晶型A的制备
方法1：
将式I所示化合物(1.01g)，加入76mL丙酮，放置在60℃条件中搅拌，溶清后，加入586.0μL稀释后盐酸溶液(量取500μL盐酸，量取500μL纯化水，二者混匀备用)，现象：盐酸滴入后，有沉淀生成；关闭加热，过夜搅拌。次日将样品倒在滤纸上，在通风橱中风干后收集起来，得到式I所示化合物盐酸盐，密封保存960mg，(类白色固体，收率：95％)。
经X-射线粉末衍射检测，该产物定义为式I所示化合物盐酸盐A晶型，XRPD图谱如图1，其特征峰位置如表1所示。DSC谱图如图2所示，吸热峰峰值268℃左右。TGA谱图如图3所显示，其在200℃以上开始快速失重。
A晶型样品进行氯离子含量测试(离子色谱)，结果为7.64％，与1mol盐酸盐理论值7.7％基本一致，证实盐酸与式I所示化合物游离碱按摩尔比1:1成盐。
DVS检测如图4所示，加速实验条件(即80％RH)，吸湿增重约为1.1％。在0％-90％RH湿度变化过程中，该样品的解吸附与吸附过程一致。且DVS检测后复测晶型，XRPD谱图如图5所示，显示DVS检测前后晶型未转变。
表1盐酸盐A晶型的XRPD特征衍射峰数据

方法2：
将30mg的式I所示化合物游离碱加入0.3mL表2中溶剂，搅拌条件下得到混悬液，将4mol/L盐酸水溶液按照与游离碱摩尔比1.2:1的比例加入混悬液，补充液体体积到1.2mL，50℃搅拌3小时，随后降温至25℃，保温搅拌过夜，对体系析出的固体进行离心，60℃减压干燥6小时后，得到固体，所得固体经XRPD检测确定结晶形式为晶型A。
表2打浆制备盐酸盐A晶型

方法3：
将10mg的式I所示化合物盐酸盐加入到0.2mL表3所述的溶剂中，保持式I在溶剂中成浆，搅拌一周，迅速使用滤纸去除溶剂，所得固体经XRPD检测确定结晶形式为晶型A。
表3打浆制备盐酸盐A晶型
实施例4：式I所示化合物的甲磺酸盐B晶型的制备
将15mg式I所示化合物溶解于到1ml DMF中，加入甲磺酸(4.1mg)，将溶液升温至50℃，50℃恒温搅拌4小时后，降温至0℃，控温搅拌两天以上持续反应，真空干燥所得固体即为式I所示化合物甲磺酸盐B晶型，其XRPD谱图如图6所示，其特征峰位置如表4所示，其DSC谱图如图7，在161℃出现吸热峰，结晶度较低，其TGA谱图如图8。
表4式I所示化合物甲磺酸盐B晶型的XRPD特征衍射峰数据

实施例5：式I所示化合物的甲磺酸盐C晶型的制备
将15mg式I所示化合物溶解于到1ml DCM中，加入甲磺酸(4.1mg)，将溶液升温至50℃，50℃恒温搅拌4小时后，降温至0℃，控温搅拌两天以上持续反应，真空干燥所得固体经XRPD检测为式I所示化合物甲磺酸盐C晶型。式I所示化合物甲磺酸盐C晶型的XRPD检测数据如表5所示，其XRPD谱图如图9所示，其DSC谱图如图10，吸热峰峰值194℃左右，其TGA谱图如图11。
表5甲磺酸盐C晶型的XRPD特征衍射峰数据
实施例6：式I所示化合物的磷酸盐D晶型的制备
将15mg式I所示化合物溶解于到1ml DCM中，加入磷酸(4.2mg)，将溶液升温至50℃，50℃恒温搅拌4小时后，降温至0℃，控温搅拌两天以上持续反应，真空干燥所得固体经XRPD检测为式I所示化合物磷酸盐D晶型。式I所示化合 物磷酸盐D晶型的XRPD检测数据如表6所示，其XRPD谱图如图12所示，其DSC谱图如图13，在130℃和143℃出现吸热峰，其TGA谱图如图14。离子色谱检测结果显示磷酸根含量为24.18％，显示磷酸与游离碱近似1:1成盐。
表6式I所示化合物的磷酸盐D晶型的XRPD特征衍射峰数据
实施例7：式I所示化合物的L-酒石酸盐E晶型的制备
将15mg式I所示化合物溶解于到1ml DMF中，加入L-酒石酸(6.4mg)，将溶液升温至50℃，50℃恒温搅拌4小时后，降温至0℃，控温搅拌两天以上持续反应，真空干燥所得固体经XRPD检测为式I所示化合物L-酒石酸盐E晶型。式I所示化合物L-酒石酸盐E晶型的XRPD检测数据如表7所示，其XRPD谱图如图15所示，其DSC谱图如图16，在132℃出现吸热峰，其TGA谱图如图17。
表7式I所示化合物L-酒石酸盐E晶型的XRPD特征衍射峰数据
实施例8：式I所示化合物的氢溴酸盐F晶型的制备
将80mg式I所示化合物溶解于到1ml二氧六环中，按酸与API摩尔比1.2:1加入氢溴酸，有固体析出，室温搅拌12小时，真空干燥所得固体经XRPD检测为式I所示化合物氢溴酸盐F晶型，XRPD检测数据如表8所示，其XRPD谱图如图18所示，其DSC谱图如图19，在99℃和216℃出现吸热峰，其TGA谱图如图20。NMR结果(图21)显示化合物I与氢溴酸近似1:1成盐。
表8式I所示化合物氢溴酸盐F晶型的XRPD特征衍射峰数据

实施例9：式I所示化合物的盐酸盐A晶型的稳定性实验
测定光照、温度和湿度对式I所示化合物盐酸盐A晶型的稳定性是否有影响：将盐酸盐A晶型置于避光稳定箱中，使用一系列温湿度组合条件进行影响因素实验。在光照及各个温湿度条件下放置不同天数后取出样品，将所得固体与初始盐酸盐A晶型比较，高效液相色谱法测定式I所示化合物的异构体(如表9所示)均未有明显增长。在光照及各个温湿度条件下放置的最后一天取出的样品进行XRPD检测，显示盐酸盐A晶型无变化，具有良好的稳定性。
表9盐酸盐A晶型影响因素实验异构体测定结果

实施例10：式I所示化合物的盐酸盐A’晶型的制备
称取式I所示化合物0.42g(0.1mmol)，加入25ml乙醇，放置在70℃条件中搅拌，溶清后，过滤，滤液中析出白色固体；将滤液瓶移至70℃油浴中，溶清后加入2ml盐酸乙醇溶液(1:1)，析出大量固体，降至室温析晶4小时，过滤，滤饼50℃干燥12小时，得0.39g，收率85.5％，A’晶型。其XRPD谱图如图22所示，其特征峰位置如表10所示，其DSC谱图如图23，在161℃出现吸热峰，结晶度较低，其TGA谱图如图24。
表10式I所示化合物盐酸盐A’晶型的XRPD特征衍射峰数据

Claims (19)

  1. 一种式I所示化合物的可药用盐，其中所述可药用盐为酸式加成盐，选自盐酸盐、甲磺酸盐、磷酸盐、L-酒石酸盐、马来酸盐、对甲苯磺酸盐、硫酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、苹果酸盐和氢溴酸盐，优选地，所述可药用盐为结晶形式，
  2. 根据权利要求1所述的式I所示化合物的可药用盐，其中所述式I所示化合物与酸分子或酸根的化学配比为1:0.5至1:3，优选1:0.5、1:1、1:1.2、1:2或1:3；
    特别地，
    所述式I所示化合物的可药用盐为盐酸盐，所述式I所示化合物与盐酸根的化学配比为1:1。
  3. 一种根据权利要求1或2所述的式I所示化合物的可药用盐的制备方法，其包括将式I所示化合物与酸成盐的步骤；
    特别地，
    式I所示化合物与酸成盐的步骤在溶剂中进行，所述溶剂选自二氯甲烷、N,N-二甲基甲酰胺、乙腈、甲醇、乙醇、异丙醇、四氢呋喃、丙酮、1,4-二氧六环、水、二甲基亚砜和乙酸乙酯中的一种或多种，优选丙酮、甲醇、乙醇、乙醇/水、异丙醇/水、乙酸乙酯、乙腈、四氢呋喃、二甲基亚砜/水、1,4-二氧六环、甲醇/水、N,N-二甲基甲酰胺和二氯甲烷。
  4. 一种式I所示化合物的盐酸盐A晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图在7.043、12.430、14.356、14.840和15.250处有特征峰，优选在7.043、8.719、10.737、12.430、14.356、14.840、15.250和17.686处有特征峰，更优选在7.043、8.719、10.737、12.430、14.356、14.840、15.250、17.686、21.697、22.305、25.635和27.433处有特征峰，所述2θ角度误差范围为±0.20，
  5. 根据权利要求4所述的式I所示化合物的盐酸盐A晶型，其中DSC谱图在268℃处有吸热峰，所述吸热峰的误差范围为±2℃。
  6. 一种式I所示化合物的盐酸盐A’晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图在8.452、12.476、15.884、17.037、17.227、22.328和23.566处有特征峰，优选在8.452、10.537、12.476、15.884、17.037、17.227、20.784、22.328、23.566和27.567处有特征峰，更优选在8.452、10.537、12.476、13.296、14.332、15.884、17.037、17.227、20.784、22.328、23.566和27.567处有特征峰，最优选在8.452、10.537、12.476、13.296、14.332、15.884、17.037、17.227、20.784、21.329、22.328、23.566、24.497、25.221和27.567处有特征峰，所述2θ角度误差范围为±0.20，
  7. 根据权利要求6所述的式I所示化合物的盐酸盐A’晶型，其中DSC谱图在263℃处有吸热峰，所述吸热峰的误差范围为±2℃。
  8. 一种式I所示化合物的甲磺酸盐B晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.717、8.783、13.969、15.902、16.647和17.515处有特征峰，优选在6.717、8.105、8.783、13.969、15.902、16.647和17.515处有特征峰，更优选在6.717、8.105、8.783、13.969、15.902、16.647、17.515、20.446、21.069、21.645和24.665处有特征峰，最优选在6.717、8.105、8.783、13.969、15.902、16.647、17.515、20.446、21.069、21.645、23.549、24.665、26.284、27.289和27.667处有特征峰，所述2θ角度误差范围为±0.20，
  9. 根据权利要求8所述的式I所示化合物的甲磺酸盐B晶型，其中DSC谱图在161℃处有吸热峰，所述吸热峰的误差范围为±2℃。
  10. 一种式I所示化合物的甲磺酸盐C晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在7.747、11.163、12.676、15.268、16.824、18.549和19.759处有特征峰，优选在4.522、7.747、11.163、12.676、15.268、16.824、18.549和19.759处有特征峰，更优选在4.522、7.747、11.163、12.676、15.268、16.824、18.549、19.759、21.460、24.637和25.497处有特征峰，最优选在4.522、7.747、11.163、12.676、15.268、16.824、18.549、19.759、21.460、22.539、24.637和25.497处有特征峰，所述2θ角度误差范围为±0.20，
  11. 根据权利要求10所述的式I所示化合物的甲磺酸盐C晶型，其中DSC谱图在194℃处有吸热峰，所述吸热峰的误差范围为±2℃。
  12. 一种式I所示化合物的磷酸盐D晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在9.593、12.831、13.464、15.666、18.161和19.245处有特征峰，优选在8.491、9.593、12.831、13.464、13.954、14.943、15.666、16.616、17.259、18.161和19.245处有特征峰，更优选在4.213、6.650、8.491、9.593、10.897、12.831、13.464、13.954、14.943、15.666、16.616、17.259、18.161和19.245处有特征峰，最优选在4.213、6.650、8.491、9.593、10.897、12.831、13.464、13.954、14.943、15.666、16.616、17.259、18.161、19.245、24.822、25.665和26.618处有特征峰，所述2θ角度误差范围为±0.20，
  13. 根据权利要求12所述的式I所示化合物的磷酸盐D晶型，其中DSC谱图在130℃和143℃有吸热峰，所述吸热峰的误差范围为±2℃。
  14. 一种式I所示化合物的L-酒石酸盐E晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在6.383、9.081、12.936、16.161和18.397处有特征峰，优选在6.383、9.081、12.936、14.400、16.161、18.397和19.489处有特征峰，更优选在6.383、9.081、12.936、14.400、16.161、18.397、19.489、23.786、24.536和26.203处有特征峰，所述2θ角度误差范围为±0.20，
  15. 根据权利要求14所述的式I所示化合物的L-酒石酸盐E晶型，其中DSC谱图在132℃处有吸热峰，所述吸热峰的误差范围为±2℃。
  16. 一种式I所示化合物的氢溴酸盐F晶型，其中以衍射角2θ角度表示的X-射线粉末衍射图，在7.133、12.485、14.422、17.721和18.823处有特征峰，优选在6.152、7.133、10.827、12.485、14.422、17.721和18.823处有特征峰，更优选在6.152、7.133、10.827、12.485、14.422、17.721、18.823、20.738、21.656、22.309、23.238、25.116、25.672和27.416处有特征峰，所述2θ角度误差范围为±0.20，
  17. 根据权利要求16所述的式I所示化合物的氢溴酸盐F晶型，其中DSC谱图在99℃和216℃处有吸热峰，所述吸热峰的误差范围为±2℃。
  18. 一种药物组合物，其含有根据权利要求1或2所述的式I所示化合物的可药用盐或根据权利要求4-17中任一项所述的晶型，和药学上可接受的赋形剂。
  19. 根据权利要求1或2所述的式I所示化合物的可药用盐、根据权利要求4-17中任一项所述的晶型或根据权利要求18所述的药物组合物在制备用于预防和/或治疗气喘、阻塞性肺病、支气管扩张、ANCA相关性血管炎、银屑病、α1-抗胰蛋白酶缺乏症、狼疮性肾炎、糖尿病、炎症性肠病、风湿性关节炎、鼻窦炎、化脓性汗腺炎或癌症的药物中的用途。
PCT/CN2023/098204 2022-06-07 2023-06-05 苯并[c]色满化合物的可药用盐、其多晶型及用途 Ceased WO2023236877A1 (zh)

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US18/872,180 US20250361226A1 (en) 2022-06-07 2023-06-05 Pharmaceutically acceptable salt of benzo[c]chroman compound and polymorphic form and use of pharmaceutically acceptable salt
EP23819042.5A EP4538277A4 (en) 2022-06-07 2023-06-05 PHARMACEUTICALLY ACCEPTABLE SALT OF A BENZO[C]CHROMANE COMPOUND, POLYMORPHIC FORM AND USE OF A PHARMACEUTICALLY ACCEPTABLE SALT
JP2024571417A JP2025518345A (ja) 2022-06-07 2023-06-05 ベンゾ［ｃ］クロマン化合物の薬学的に許容される塩、ならびに薬学的に許容される塩の多形及び使用
CN202380039466.XA CN119156391A (zh) 2022-06-07 2023-06-05 苯并[c]色满化合物的可药用盐、其多晶型及用途
CA3255979A CA3255979A1 (en) 2022-06-07 2023-06-05 PHARMACEUTICALLY ACCEPTABLE SALT OF A BENZO[C]CHROMANE COMPOUND, POLYMORPHIC FORM AND USE OF A PHARMACEUTICALLY ACCEPTABLE SALT
KR1020247043328A KR20250023398A (ko) 2022-06-07 2023-06-05 벤조[c]크로만 화합물의 약학적으로 허용되는 염, 상기 약학적으로 허용되는 염의 다형체 형태 및 용도
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12479837B2 (en) 2023-01-06 2025-11-25 Insmed Incorporated Reversible DPP1 inhibitors and uses thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096285A1 (en) 2000-06-14 2001-12-20 F. Hoffmann-La Roche Ag Beta-amino acid nitrile derivatives
WO2003048123A1 (en) 2001-12-04 2003-06-12 F. Hoffmann-La Roche Ag Substituted 2-amino-cycloalkanecarboxamides and their use as cysteine protease inhibitors
WO2004110988A1 (en) 2003-06-18 2004-12-23 Prozymex A/S Protease inhibitors
WO2009074829A1 (en) 2007-12-12 2009-06-18 Astrazeneca Ab Peptidyl nitriles and use thereof as dipeptidyl peptidase i inhibitors
WO2010128324A1 (en) 2009-05-07 2010-11-11 Astrazeneca Ab Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750
WO2012119941A1 (en) 2011-03-04 2012-09-13 Prozymex A/S Peptidyl nitrilcompounds as peptidase inhibitors
WO2013041497A1 (en) 2011-09-19 2013-03-28 Boehringer Ingelheim International Gmbh Substituted n- [1-cyano-2- (phenyl) ethyl] -2-azabicyclo [2.2.1] heptane-3-carboxamide inhibitors of cathepsin c
WO2015110826A1 (en) 2014-01-24 2015-07-30 Astrazeneca Ab (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase i inhibitors
WO2022117059A1 (zh) 2020-12-04 2022-06-09 瑞石生物医药有限公司 组织蛋白酶c小分子抑制剂及其医药用途

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096285A1 (en) 2000-06-14 2001-12-20 F. Hoffmann-La Roche Ag Beta-amino acid nitrile derivatives
WO2003048123A1 (en) 2001-12-04 2003-06-12 F. Hoffmann-La Roche Ag Substituted 2-amino-cycloalkanecarboxamides and their use as cysteine protease inhibitors
WO2004110988A1 (en) 2003-06-18 2004-12-23 Prozymex A/S Protease inhibitors
WO2009074829A1 (en) 2007-12-12 2009-06-18 Astrazeneca Ab Peptidyl nitriles and use thereof as dipeptidyl peptidase i inhibitors
WO2010128324A1 (en) 2009-05-07 2010-11-11 Astrazeneca Ab Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750
WO2012119941A1 (en) 2011-03-04 2012-09-13 Prozymex A/S Peptidyl nitrilcompounds as peptidase inhibitors
WO2013041497A1 (en) 2011-09-19 2013-03-28 Boehringer Ingelheim International Gmbh Substituted n- [1-cyano-2- (phenyl) ethyl] -2-azabicyclo [2.2.1] heptane-3-carboxamide inhibitors of cathepsin c
CN103814028A (zh) * 2011-09-19 2014-05-21 勃林格殷格翰国际有限公司 组织蛋白酶c 抑制剂取代的n-[1-氰基-2-(苯基)乙基]-2-氮杂双环[2.2.1]庚烷-3-甲酰胺
WO2015110826A1 (en) 2014-01-24 2015-07-30 Astrazeneca Ab (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase i inhibitors
CN105980367A (zh) * 2014-01-24 2016-09-28 阿斯利康(瑞典)有限公司 (2s)-n-[(1s)-1-氰基-2-苯基乙基]-1，4-氧杂氮杂环庚烷-2-甲酰胺作为二肽基肽酶i抑制剂
WO2022117059A1 (zh) 2020-12-04 2022-06-09 瑞石生物医药有限公司 组织蛋白酶c小分子抑制剂及其医药用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ADKISON ET AL., J CLIN INVEST., vol. 109, no. 3, February 2002 (2002-02-01), pages 363 - 71
See also references of EP4538277A4
TINH ET AL., ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS., vol. 403, 2002, pages 160 - 170

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12479837B2 (en) 2023-01-06 2025-11-25 Insmed Incorporated Reversible DPP1 inhibitors and uses thereof

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