WO2021143841A1 - 三并环类pde3/pde4双重抑制剂化合物的药物组合物 - Google Patents

三并环类pde3/pde4双重抑制剂化合物的药物组合物 Download PDF

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WO2021143841A1
WO2021143841A1 PCT/CN2021/072145 CN2021072145W WO2021143841A1 WO 2021143841 A1 WO2021143841 A1 WO 2021143841A1 CN 2021072145 W CN2021072145 W CN 2021072145W WO 2021143841 A1 WO2021143841 A1 WO 2021143841A1
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compound
pharmaceutical composition
formula
surfactant
concentration
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PCT/CN2021/072145
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English (en)
French (fr)
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杨淼
孙源源
李婉婧
徐仲
鲍鹏悦
高静
董平
惠慧
季雄锋
罗云富
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正大天晴药业集团股份有限公司
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Priority to KR1020227026829A priority Critical patent/KR20220127845A/ko
Priority to EP21741236.0A priority patent/EP4092025A4/en
Priority to CN202180008484.2A priority patent/CN114929700A/zh
Priority to CA3167378A priority patent/CA3167378A1/en
Priority to US17/792,282 priority patent/US20230060174A1/en
Priority to JP2022543589A priority patent/JP2023512475A/ja
Priority to AU2021208129A priority patent/AU2021208129A1/en
Publication of WO2021143841A1 publication Critical patent/WO2021143841A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This application belongs to the technical field of medicine, and relates to a pharmaceutical composition of a triple-cyclic PDE3/PDE4 dual inhibitor compound, a preparation method and use thereof, and specifically relates to a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Its preparation method and its use.
  • Phosphodiesterase is a superfamily of enzymes, including 11 families, each of which participates in different signal transduction and regulates different physiological processes.
  • PDE3 is the main phosphodiesterase in airway smooth muscle (ASM). Inhibiting PDE3 will increase the concentration of intracellular cAMP and relax bronchial smooth muscle.
  • ASM airway smooth muscle
  • PDE4 plays a major regulatory role in the expression of pro-inflammatory mediators and anti-inflammatory mediators
  • PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.
  • an inhibitor that has inhibitory effects on PDE3 and PDE4 will have both the bronchodilation effect of ⁇ -adrenergic receptor agonists and the anti-inflammatory action of inhaled glucocorticoids.
  • the functional complementarity of dual targeting has the theoretical basis that it is more effective than single targeting.
  • the single drug achieves the therapeutic effect that can only be achieved through the combination of drugs, overcomes the defect that the physical and chemical properties of the drug components of the combined drug cannot be completely matched, and simplifies the treatment.
  • the way of medicine is convenient for quantitative administration.
  • the application provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant:
  • the above-mentioned pharmaceutical composition further comprises a metal chelating agent (or metal complexing agent).
  • the above-mentioned pharmaceutical composition further comprises a buffering agent.
  • the aforementioned pharmaceutical composition further comprises a diluent.
  • the aforementioned pharmaceutical composition further comprises an osmotic pressure regulator.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a surfactant and a buffer.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant, a buffer, and an osmotic pressure regulator.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant, a buffer, and a metal chelating agent.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as well as a surfactant, a buffer, an osmotic pressure regulator, and a metal chelating agent.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant, a buffer, an osmotic pressure regulator, a metal chelating agent, and a diluent.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a surfactant, and at least one of a buffer, an osmotic pressure regulator, a metal chelating agent, and a diluent .
  • the aforementioned pharmaceutically acceptable salt is selected from maleate, sulfate, methanesulfonate, or p-toluenesulfonate.
  • the above-mentioned pharmaceutically acceptable salt of the compound of formula (I), wherein the molar ratio of the compound of formula (I) to the acid radical ion forming the pharmaceutically acceptable salt may be (1:1) to (1:2), For example, 1:1 or 1:2.
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” can be replaced with a “compound of formula (I)".
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), a surfactant, a buffer, an osmotic pressure regulator, a metal chelating agent, and a diluent.
  • the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 0.001 to about 80 mg/mL, preferably 0.002-50 mg/mL, based on the compound of formula (I), It is more preferably from 0.1 to 20 mg/mL.
  • the surfactant of the present application is a pharmaceutically acceptable surfactant, such as a wetting agent.
  • the above-mentioned surfactant may be a nonionic surfactant, an anionic surfactant, a cationic surfactant or a zwitterionic surfactant.
  • the above-mentioned one or more surfactants are nonionic surfactants.
  • the above-mentioned surfactant is selected from ethylene glycol polyoxyethylene ether, polypropylene glycol alkyl ether, alkyl polyglucoside, octylphenol polyoxyethylene ether, alkylphenol polyoxyethylene ether, glycerin Alkyl ester, polyoxyethylene sorbitan fatty acid ester (polysorbate), sorbitan alkyl ester, sorbitan fatty acid ester, cocamide MEA, cocamide DEA, dodecane One or more of dimethyl amine oxide, a block copolymer of polyethylene ethylene glycol and polypropylene glycol (poloxamer) and polyethoxylated tallow amine (POEA).
  • ethylene glycol polyoxyethylene ether polypropylene glycol alkyl ether, alkyl polyglucoside
  • octylphenol polyoxyethylene ether alkylphenol polyoxyethylene ether
  • glycerin Alkyl ester polyoxyethylene
  • the above-mentioned surfactant is one or more selected from polyoxyethylene sorbitan fatty acid esters (for example, Tweens) and sorbitan fatty acid esters (for example, Spans).
  • polyoxyethylene sorbitan fatty acid esters for example, Tweens
  • sorbitan fatty acid esters for example, Spans
  • the above-mentioned polyoxyethylene sorbitan fatty acid ester is selected from polysorbate 20 (polyoxyethylene sorbitan laurate; Tween 20), polysorbate 40 (polyoxyethylene sorbitan Sugar alcohol monopalmitate), polysorbate 60 (polyoxyethylene sorbitan stearate) and polysorbate 80 (polyoxyethylene sorbitan monooleate; Tween 80) or one of Many kinds.
  • the above-mentioned sorbitan fatty acid ester is selected from sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate , One or more of sorbitan tristearate and sorbitan monooleate.
  • the above-mentioned surfactant is selected from one or more of Tweens and Spans.
  • the above-mentioned surfactant is selected from one or more of Tween 20, Tween 80 and Span 20.
  • the concentration of the aforementioned surfactant is about 0.01 to about 8 mg/mL. More typically, the concentration of the surfactant in the pharmaceutical composition is about 0.01 to 5 mg/mL, preferably about 0.02 to 3 mg/mL, further preferably about 0.05 to 2 mg/mL, and even more preferably about 0.1 to 1 mg/mL mL.
  • the mass ratio between the compound of formula (I) or a pharmaceutically acceptable salt thereof (calculated as the compound of formula (I)) and the surfactant is about 1: 200 to 100:1, preferably about 1:150 to 50:1, more preferably about 1:50 to 25:1, still more preferably about 1:1 to 15:1, for example, about 10:1.
  • the aforementioned buffer is a pharmaceutically acceptable buffer.
  • the buffer can be any buffer suitable for liquid pharmaceutical compositions suitable for inhalation.
  • the buffer is usually selected from sulfuric acid, hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, lactic acid, sodium lactate, acetic acid, sodium acetate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, tartaric acid, One or more of sodium tartrate, glycine, boric acid and phthalic acid.
  • the preferred number of buffers is 2 or more, and the type is citrate buffer or phosphate buffer, more preferably the sodium salt of both.
  • Citrate buffers include citric acid, sodium citrate and mixtures thereof.
  • Phosphate buffers include phosphoric acid, monosodium phosphate (ie, sodium dihydrogen phosphate), disodium hydrogen phosphate, and mixtures thereof.
  • the aforementioned buffer is selected from citric acid, citrate (e.g. sodium citrate), tartaric acid, tartrate (e.g. sodium tartrate), phosphoric acid or phosphate (e.g. sodium dihydrogen phosphate and disodium hydrogen phosphate) .
  • the aforementioned buffering agent is selected from citrate (e.g. sodium citrate), tartrate (e.g. sodium tartrate) or phosphate (e.g. sodium dihydrogen phosphate and disodium hydrogen phosphate).
  • citrate e.g. sodium citrate
  • tartrate e.g. sodium tartrate
  • phosphate e.g. sodium dihydrogen phosphate and disodium hydrogen phosphate
  • the concentration of the aforementioned buffer is about 0.01 to about 50 mg/mL, preferably about 0.05 to about 40 mg/mL, more preferably 0.1 to about 25 mg/mL; still more preferably 0.5 to about 6 mg/mL.
  • the above-mentioned buffering agent is used to control the pH value of the above-mentioned pharmaceutical composition between about 3.0 and about 8.5, preferably between about 5 and about 7.
  • the above-mentioned osmotic pressure regulator is usually selected from simple non-toxic salts, such as sodium chloride, potassium chloride, etc., or sugars, such as one or more of glucose, mannitol, xylitol, etc. kind.
  • the above-mentioned osmotic pressure regulator is sodium chloride.
  • the concentration of the above-mentioned osmotic pressure regulator depends on the amount required to achieve isotonicity, such as isotonicity with plasma or lung fluid.
  • concentration of the osmotic pressure regulator is generally about 0.01 mg/mL to about 10 mg/mL, and more generally about 5 mg/mL to 9 mg/mL.
  • the aforementioned metal chelating agent is selected from one or more of edetate salts such as edetate, disodium edetate, and calcium sodium edetate.
  • Edetic acid salts for example, calcium salt, sodium salt
  • EDTA-2Na edetic acid disodium
  • the concentration of the metal chelating agent depends on the amount of metal ions that can be introduced during the preparation of the above-mentioned pharmaceutical composition, and is generally about 0.01 to about 40 mg/mL, preferably about 0.01 to about 20 mg/mL, and more preferably about 0.01 to about 5 mg/mL. mL; further preferably about 0.01 to about 2 mg/mL.
  • the diluent in the above-mentioned pharmaceutical composition, may be any pharmaceutically acceptable diluent.
  • the diluent is suitable for inhalation administration.
  • the diluent is selected from one or more of water, ethanol and glycerin.
  • the preferred diluent is water, and the more preferred diluent is sterile water.
  • the amount of diluent used in the above-mentioned pharmaceutical composition may be an appropriate amount, so that the concentration of the compound of formula (I) or its pharmaceutically acceptable salt or excipient in the above-mentioned pharmaceutical composition is within a certain range.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I), and Tweens or Spans; further, the aforementioned Tweens or Spans are selected from Tween 20, Tween 80 and Span One or more of 20.
  • the above-mentioned pharmaceutical composition further includes a phosphate; further, the above-mentioned phosphate may be selected from sodium dihydrogen phosphate or its monohydrate and disodium hydrogen phosphate; in some embodiments, the above-mentioned pharmaceutical composition further includes Sodium citrate or sodium tartrate.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), a mixture of Span and Tween (such as Tween 80, Tween 20 or Span 20) and water.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), a mixture of Spans and Tweens (such as Tween 80, Tween 20 or Span 20), sodium citrate or sodium tartrate, and water.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I), Tweens (such as Tween 80 or Tween 20), sodium dihydrogen phosphate or its monohydrate, disodium hydrogen phosphate, and Disodium tertiary acid and water.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), Tweens (such as Tween 80 or Tween 20), sodium dihydrogen phosphate or its monohydrate, disodium hydrogen phosphate, chlorine Sodium chloride, disodium edetate and water.
  • the aforementioned pharmaceutical composition comprises a compound of formula (I), Tweens (such as Tween 80 or Tween 20), sodium citrate or sodium tartrate, sodium chloride, and water.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), a mixture of Spans and Tweens (such as Tween 80, Tween 20 or Span 20), sodium citrate or sodium tartrate, Sodium chloride and water.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), a surfactant, a buffer, an osmotic pressure regulator, a metal chelating agent, and a diluent, wherein the concentration of the compound of formula (I) is 0.002- 50mg/mL, the concentration of surfactant is 0.02 to 3mg/mL, the concentration of buffer is 0.1 to about 25mg/mL, the concentration of osmotic pressure regulator is 5mg/mL to 9mg/mL, the concentration of metal chelating agent is 0.01 To about 5mg/mL.
  • concentration of the compound of formula (I) is 0.002- 50mg/mL
  • the concentration of surfactant is 0.02 to 3mg/mL
  • the concentration of buffer is 0.1 to about 25mg/mL
  • the concentration of osmotic pressure regulator is 5mg/mL to 9mg/mL
  • the concentration of metal chelating agent is 0.01 To about 5m
  • the surfactant, buffer, osmotic pressure regulator, metal chelating agent, and diluent are as defined above, respectively.
  • the above-mentioned pharmaceutical composition comprises a compound of formula (I), a surfactant, a buffer, an osmotic pressure regulator, a metal chelating agent, and a diluent, wherein the concentration of the compound of formula (I) is 0.002- 50mg/mL, the concentration of surfactant is 0.02 to 3mg/mL, the concentration of buffer is 0.1 to about 25mg/mL, the concentration of osmotic pressure regulator is 5mg/mL to 9mg/mL, the concentration of metal chelating agent is 0.01 To about 5mg/mL; the surfactant is one or more of Tween 20, Tween 80 and Span 20, and the buffer is sodium dihydrogen phosphate or its monohydrate, disodium hydrogen phosphate , One or more of tartaric acid and citric acid, the osmotic pressure regulator is sodium chloride, and the metal chelating agent is one or more of edetate disodium and calcium sodium sodium
  • the aforementioned pharmaceutical composition comprises a compound of formula (I), Tween 80, sodium dihydrogen phosphate or its monohydrate, disodium hydrogen phosphate, sodium chloride, disodium edetate, and water
  • concentration of the compound of formula (I) is 0.002-50mg/mL
  • concentration of Tween 80 is 0.02-3mg/mL
  • concentration of sodium dihydrogen phosphate and disodium hydrogen phosphate is 0.1-25mg/mL
  • sodium chloride The concentration is 5 mg/mL to 9 mg/mL
  • the concentration of edetate disodium is 0.01 to about 5 mg/mL.
  • the crystal of the compound of formula (I) above has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern of Cu K ⁇ radiation: 5.81 ⁇ 0.2°, 13.96 ⁇ 0.2°, 15.01 ⁇ 0.2°, 17.95 ⁇ 0.2° and 24.73 ⁇ 0.2°.
  • the crystal of the compound of formula (I) above has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern of Cu K ⁇ radiation: 5.81 ⁇ 0.2°, 8.38 ⁇ 0.2°, 11.16 ⁇ 0.2 °, 13.96 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.01 ⁇ 0.2°, 17.95 ⁇ 0.2°, 24.73 ⁇ 0.2° and 26.13 ⁇ 0.2°.
  • the crystal of the compound of formula (I) above has a X-ray powder diffraction pattern of Cu K ⁇ radiation with diffraction peaks at the following 2 ⁇ angles: 5.81 ⁇ 0.2°, 8.38 ⁇ 0.2°, 11.16 ⁇ 0.2°, 13.96 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.01 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.95 ⁇ 0.2°, 20.83 ⁇ 0.2°, 24.73 ⁇ 0.2° and 26.13 ⁇ 0.2°.
  • the crystal of the compound of formula (I) above has diffraction peaks at the following 2 ⁇ angles in the X-ray powder diffraction pattern of Cu K ⁇ radiation: 5.81 ⁇ 0.2°, 8.38 ⁇ 0.2°, 9.13 ⁇ 0.2°, 11.16 ⁇ 0.2°, 11.60 ⁇ 0.2°, 12.82 ⁇ 0.2°, 13.96 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.01 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.91 ⁇ 0.2°, 20.83 ⁇ 0.2°, 24.36 ⁇ 0.2°, 24.73 ⁇ 0.2°, 25.78 ⁇ 0.2° and 26.13 ⁇ 0.2°.
  • the crystal of the compound of formula (I) mentioned above has an X-ray powder diffraction pattern using Cu K ⁇ radiation, which contains selected from the following 2 ⁇ angles 5, 6, 7, 8, 9, 10, 11 , 12 or more diffraction peaks: 5.81 ⁇ 0.2°, 8.38 ⁇ 0.2°, 9.13 ⁇ 0.2°, 11.16 ⁇ 0.2°, 11.60 ⁇ 0.2°, 12.82 ⁇ 0.2°, 13.96 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.01 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.91 ⁇ 0.2°, 20.83 ⁇ 0.2°, 24.36 ⁇ 0.2°, 24.73 ⁇ 0.2°, 25.78 ⁇ 0.2° and 26.13 ⁇ 0.2°.
  • the crystal of the compound of formula (I) described above includes an X-ray powder diffraction pattern of Cu K ⁇ radiation selected from 5, 6, 7, 8, 9, 10, or 11 at the following 2 ⁇ angles. Diffraction peaks: 5.81 ⁇ 0.2°, 8.38 ⁇ 0.2°, 11.16 ⁇ 0.2°, 13.96 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.01 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.95 ⁇ 0.2°, 20.83 ⁇ 0.2°, 24.73 ⁇ 0.2° and 26.13 ⁇ 0.2°.
  • the crystal of the compound of formula (I) mentioned above contains 5, 6, 7, 8 or 9 diffraction peaks selected from the following 2 ⁇ angles in the X-ray powder diffraction pattern of Cu K ⁇ radiation: 5.81 ⁇ 0.2°, 8.38 ⁇ 0.2°, 11.16 ⁇ 0.2°, 13.96 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.01 ⁇ 0.2°, 17.95 ⁇ 0.2°, 24.73 ⁇ 0.2° and 26.13 ⁇ 0.2°.
  • the crystal of the compound of formula (I) above has an XRPD pattern using Cu Ka radiation as shown in FIG. 1.
  • the crystal of the compound of formula (I) above has an exothermic peak at 247.70°C ⁇ 2°C in its differential scanning calorimetry curve.
  • the differential scanning calorimetry spectrum of the crystal of the compound of formula (I) is shown in FIG. 2.
  • thermogravimetric analysis curve of the crystal of the compound of formula (I) above has a weight loss of 0.4870% at 155.75 ⁇ 2°C; and a weight loss of 7.287% between 155.75 ⁇ 2°C and 262.18 ⁇ 2°C.
  • thermogravimetric analysis pattern of the crystal of the compound of formula (I) is shown in FIG. 3.
  • the particle size of the compound of formula (I) or a pharmaceutically acceptable salt thereof is X 50 ⁇ 10 ⁇ m, preferably between 0.1 ⁇ m and 8 ⁇ m.
  • the particle size of the compound of formula (I) or a pharmaceutically acceptable salt thereof is X 50 ⁇ 5 ⁇ m and X 90 ⁇ 10 ⁇ m.
  • compositions of the present application can be administered to humans in a variety of preparation forms, such as solutions, etc., which are intended to be suitable for oral or inhalation.
  • the pharmaceutical composition of the present application is administered by inhalation.
  • the pharmaceutical composition of the present application is administered via oral or nasal inhalation.
  • the pharmaceutical composition of the present application is a solution for inhalation.
  • the pharmaceutical composition of the application is in the form of a suspension.
  • the pharmaceutical composition of the present application is in the form of a suspension for inhalation.
  • this application provides a preparation method of the above-mentioned pharmaceutical composition, which includes the following process: mixing a surfactant with a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the preparation method includes mixing a surfactant, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of a metal chelating agent, a buffer, a diluent, and an osmotic pressure regulator.
  • this application provides a method for preparing the above-mentioned pharmaceutical composition, which includes the following processes: a wetting agent, a buffer, an osmotic pressure regulator, a metal chelating agent, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a diluent mix.
  • the preparation method of the above-mentioned pharmaceutical composition includes the following process:
  • the above preparation process further includes step 3): homogenizing the product obtained in step 2).
  • the particle size of the compound of formula (I) or a pharmaceutically acceptable salt thereof is X 50 ⁇ 5 ⁇ m and X 90 ⁇ 10 ⁇ m.
  • the above-mentioned preparation process further includes a filling step.
  • this application also provides a method for preventing or treating PDE3 and/or PDE4 related disorders in a mammal, including administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to a mammal in need of such prevention or treatment, preferably a human.
  • the application also provides the application of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating PDE3 and/or PDE4 related diseases.
  • the application also provides the use of the above-mentioned pharmaceutical composition for preventing or treating diseases related to PDE3 and/or PDE4.
  • this application also provides the above-mentioned pharmaceutical composition for preventing or treating PDE3 and/or PDE4 related diseases.
  • the PDE3 and/or PDE4 related disorder is selected from asthma or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compound of formula (I) of the present application and its pharmaceutical composition have significant dual PDE3 and PDE4 inhibitory effects, and have significant inhibitory effects on TNF- ⁇ in human peripheral blood mononuclear cells (hPBMC).
  • hPBMC peripheral blood mononuclear cells
  • the induced acute lung injury model in rats also shows excellent anti-inflammatory effects; it has high plasma clearance in vivo, low oral plasma system exposure and low oral bioavailability, and the safety of local route administration is good; It has low inhibitory effect on the five isoenzymes of human liver microsomal cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), and no risk of drug-drug interaction; reduces the total number of white blood cells in BALF, has a significant anti-inflammatory effect, and has The effective dose is low; reduce the airway resistance index Penh.
  • the crystals of the compound of formula (I) and the pharmaceutically acceptable salt thereof of the present application have advantages in drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, ease of preparation, etc., To meet the needs of pharmaceutical production, storage, transportation and preparation.
  • the crystal form of the compound of formula (I) is not very hygroscopic, which is conducive to the absorption of inhaled drugs.
  • the pharmaceutical composition of the compound of formula (I) of the present application has good stability, no growth of impurities, and exhibits pharmaceutically acceptable levels of impurities; good dispersibility, stable kinetics, including no obvious sedimentation of particles, no growth of particle size, in the approved
  • the inhalation product is within the range required for effective delivery.
  • the particle size of the composition is uniform and moderate, and the absorption speed is fast.
  • the delivery rate is good, the dosage is accurate, the proportion of aerosol particles that can be inhaled is high, and the dosage of fine particles is high.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or formulation described in this application to prevent a disease or one or more symptoms related to the disease, including: preventing the occurrence of a disease or disease state in a mammal, especially when this When mammals are susceptible to this disease state, but have not been diagnosed as having this disease state.
  • terapéuticaally effective amount means (i) treatment or prevention of a particular disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • the characteristic equivalent spherical diameter (called the volume diameter) is measured by laser diffraction to quantify the particle size of the particles, for example, by a laser particle size tester.
  • volume diameter (VD) is used to represent the particle size distribution.
  • X 10 refers to the particle size when the cumulative volume distribution percentage reaches 10%, and its physical meaning is that particles with a particle size smaller than it account for 10% of the total volume.
  • X 50 refers to the particle size corresponding to the volume cumulative distribution percentage reaching 50%, which is called the volume median diameter. Its physical meaning is that the particles with a particle size smaller than it account for 50% of the total volume. .
  • X 90 refers to the particle size corresponding to the volume cumulative distribution percentage reaching 90%, and its physical meaning is that particles with a particle size smaller than it account for 90% of the total volume.
  • each parameter value (including 2 ⁇ value, reaction conditions) is regarded as modified by the term "about" to reflect the measurement and other errors of each value, for example, relative to a given value, there is ⁇ 5% error.
  • Figure 1 is an XRPD spectrum of the crystal of the compound of formula (I);
  • Figure 2 is a DSC spectrum of the crystal of the compound of formula (I);
  • Figure 3 is a TGA spectrum of the crystal of the compound of formula (I);
  • Figure 4 is a DVS diagram of the crystal of the compound of formula (I);
  • Figure 5 shows the total number of white blood cells in BALF
  • Figure 6 shows the detection of lung function induced by methacholine Mch (airway resistance index Penh).
  • the particle size of the compound of formula (I) in the formulation is controlled to be X 50 ⁇ 5 ⁇ m and X 90 ⁇ 10 ⁇ m;
  • RRT/Norm% Total miscellaneous% 0 days 0.11 60°C_5 days 0.10 60°C_10 days 0.11 92.5%RH_5 days 0.11 92.5%RH_10 days 0.10 Protect from light 0.11 illumination 0.10 40°C+75%RH-10 days 0.10 60°C+75%RH-10 days 0.10 40°C+75%RH-1 month 0.10 60°C+75%RH-1 month 0.10 40°C+75%RH-2 months 0.08 40°C+75%RH-3 months 0.09
  • crystals of the compound of formula (I) of the present application have good stability under high temperature, high humidity or light conditions, and there is no growth of impurities during the test.
  • Test conditions Take a sample (10-20 mg, the crystal prepared in Example 3) and place it in the DVS sample pan for testing.
  • Experimental purpose Measure the expression of AMP/GMP according to fluorescence polarization, that is, to trace the binding of AMP/GMP antibody to indicate the activity of the enzyme.
  • Experimental buffer solution 10 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 0.01% Brij 35, 1 mM dithiothreitol (DTT), and 1% DMSO.
  • the fluorescence polarization signal is calculated according to the AMP/GMP standard curve and the percentage of enzyme activity relative to the DMSO control by Excel software, converted into nM. Curve fitting uses GraphPad Prism (drawing medical icons). The experimental results are shown in Table 4.
  • Experimental purpose Measure the expression of AMP/GMP according to fluorescence polarization, that is, to trace the binding of AMP/GMP antibody to indicate the activity of the enzyme.
  • Experimental buffer solution 10 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 0.01% Brij 35, 1 mM DTT, and 1% DMSO.
  • Enzyme Recombinant human PDE4B (gene accession number NM_002600; amino acid 305 end) is expressed in baculovirus with N-terminal GST tag in Sf9 insect cells, and its molecular weight is 78kDa.
  • the fluorescence polarization signal was calculated according to the AMP/GMP standard curve and the% enzyme activity relative to the DMSO control by Excel software, converted into nM. Curve fitting uses GraphPad Prism (drawing medical icons).
  • the active ingredients in the pharmaceutical composition of the present application have significant dual PDE3 and PDE4 inhibitory effects.
  • the clear solution of the compound of formula (I) was injected into two 10-12 kg beagle dogs via the cephalic vein or saphenous vein, and the clear solution of the compound of formula (I) was intragastrically administered to two 10-12 kg Dogl (fasting overnight).
  • the animals were all 0.0333, 0.0833, 0.25, 0.5, 1, 2, 4, 6 , 8 and 24 hours after administration, about 500 ⁇ L of blood was collected from the peripheral vein and transferred to the anticoagulant containing 0.85-1.15 mg of K 2 EDTA*2H 2 O In a commercial centrifuge tube, centrifuge at 3000g for 10 minutes at 4°C to collect plasma.
  • the LC-MS/MS method was used to determine the blood drug concentration, and the WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by the non-compartmental model linear logarithmic ladder method.
  • the active ingredient in the pharmaceutical composition of the present application has a high in vivo plasma clearance rate, a low oral plasma system exposure, and a low oral bioavailability.
  • a total of 5 specific probe substrates of CYP's 5 isoenzymes are phenacetin (Phenacetin, CYP1A2), diclofenac (Diclofenac, CYP2C9), (S)-Mephenytoin ((S)-Mephenytoin, CYP2C19), Dextromethorphan (CYP2D6) and Midazolam (Midazolam, CYP3A4) were incubated with human liver microsomes and the compound of formula (I), respectively, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added.
  • the active ingredients in the pharmaceutical composition of the present application have a low inhibitory effect on the five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450.
  • the animals are reared adaptively for one week after arriving at the facility, and are randomly divided into 6 groups according to their weight;
  • the whole body exposure nebulization device nebulizes the test compound and the reference compound at the maximum nebulization rate (about 12 mL) for 30 minutes.
  • Dosing frequency 30 minutes before smoking or solvent in the morning, and before LPS inhalation on the 4th day.
  • BALF alveolar lavage fluid
  • mice peripheral blood mononuclear cells
  • the active ingredients in the pharmaceutical composition of the present application can exhibit effective anti-inflammatory activity and have a significant inhibitory effect on TNF- ⁇ in human peripheral blood mononuclear cells (hPBMC).
  • hPBMC human peripheral blood mononuclear cells
  • Example 28 The product obtained in Example 28 was placed under accelerated conditions (40°C ⁇ 2°C/RH 25% ⁇ 5%) and long-term conditions (30°C ⁇ 2°C/RH 65% ⁇ 5%) for 6 months. The results are shown in Table 10.
  • the pharmaceutical composition of the present application exhibits good stability under accelerated conditions and long-term conditions, with no significant increase in impurities and no increase in particle size.

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Abstract

三并环类PDE3/PDE4双重抑制剂化合物的药物组合物及其制备方法，具体而言涉及式(I)化合物或其可药用盐的药物组合物、其制备方法及其用途。

Description

三并环类PDE3/PDE4双重抑制剂化合物的药物组合物
相关申请的交叉引用
本申请要求于2020年01月15日向中华人民共和国国家知识产权局提交的第202010042865.X号中国发明专利申请的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于医药技术领域，涉及三并环类PDE3/PDE4双重抑制剂化合物的药物组合物、其制备方法及用途，具体而言涉及式(I)化合物或其可药用盐的药物组合物、其制备方法及其用途。
背景技术
磷酸二酯酶(PDE)属超家族酶系，包含11个家族，每个家族参与不同的信号传导，调节不同的生理过程。其中，PDE3是人气道平滑肌(ASM)中主要的磷酸二酯酶，抑制PDE3会提高细胞内cAMP的浓度，使支气管平滑肌松弛。而PDE4在促炎介质和抗炎介质的表达中起主要调节作用，PDE4抑制剂能够抑制炎症细胞释放有害介质。因此，原则上一个对PDE3和PDE4都有抑制作用的抑制剂将会兼具β-肾上腺素受体激动剂的支气管扩张效果(bronchodilation)和吸入糖皮质激素的抗炎功效(anti-inflammatory action)。双重靶向功能性的互补具有比单独靶向更大功效的理论基础，通过单药达到目前只能通过联合用药才能达到的治疗效果，克服联合用药药物成分理化性质无法完全匹配的缺陷，简化给药方式，方便定量给药剂量。
Victoria Boswell et al,J.Pharmaco.Experi.Therap.2006,318,840-848和WO200005830报道了化合物RPL554和RPL565，具有长效支气管扩张和抗炎作用的药效，以及溶解度差、血浆清除率高等理化性质，适宜吸入给药，但是数据同时也显示其PDE4的抑制活性无法令人满意，抗炎效果不够理想，因此需要开发同时具备良好的PDE3/4的抑制活性的化合物。
Figure PCTCN2021072145-appb-000001
发明内容
一方面，本申请提供了药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂：
Figure PCTCN2021072145-appb-000002
在一些实施方案中，上述药物组合物还包含金属螯合剂(或称金属络合剂)。
在一些实施方案中，上述药物组合物还包含缓冲剂。
在一些实施方案中，上述药物组合物还包含稀释剂。
在一些实施方案中，上述药物组合物还包含渗透压调节剂。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂和缓冲剂。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂、缓冲剂和渗透压调节剂。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂、缓冲剂和金属螯合剂。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂、缓冲 剂、渗透压调节剂和金属螯合剂。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂、缓冲剂、渗透压调节剂、金属螯合剂和稀释剂。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物或其可药用盐、表面活性剂，以及缓冲剂、渗透压调节剂、金属螯合剂和稀释剂中的至少一种。
在一些实施方案中，上述可药用盐选自马来酸盐、硫酸盐、甲磺酸盐或对甲基苯磺酸盐。
在一些实施方案中，上述式(I)化合物的可药用盐，其中式(I)化合物与形成可药用盐的酸根离子的摩尔比可为(1:1)至(1:2)，例如1:1或1:2。
在一些实施方案中，上述的药物组合物中，所述的“式(I)化合物或其可药用盐”可替换为“式(I)化合物”。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、表面活性剂、缓冲剂、渗透压调节剂、金属螯合剂及稀释剂。
在一些实施方案中，上述的药物组合物中，其中式(I)化合物或其可药用盐的浓度以式(I)化合物计为约0.001至约80mg/mL、优选0.002～50mg/mL、进一步优选自0.1～20mg/mL。
本申请的表面活性剂是药学上可接受的表面活性剂，例如润湿剂。上述表面活性剂可以是非离子表面活性剂、阴离子表面活性剂、阳离子表面活性剂或两性离子表面活性剂。优选的上述一种或多种表面活性剂为非离子表面活性剂。
在一些实施方案中，上述表面活性剂为选自乙二醇聚氧乙烯醚、聚丙二醇烷基醚、烷基聚葡糖苷、辛基酚聚氧乙烯醚、烷基酚聚氧乙烯醚、甘油烷基酯、聚氧乙烯山梨糖醇酐脂肪酸酯(聚山梨酸酯)、脱水山梨糖醇烷基酯、失水山梨醇脂肪酸酯、椰油酰胺MEA、椰油酰胺DEA、十二烷基二甲基氧化胺、聚乙烯的嵌段共聚物乙二醇和聚丙二醇(泊洛沙姆)和聚乙氧基化牛脂胺(POEA)的一种或多种。
优选地，上述表面活性剂为选自聚氧乙烯山梨糖醇酐脂肪酸酯(例如吐温类)和失水山梨醇脂肪酸酯(例如司盘类)的一种或多种。
在一些实施方案中，上述聚氧乙烯山梨糖醇酐脂肪酸酯为选自聚山梨酯20(聚氧乙烯失水山梨醇月桂酸酯；吐温20)、聚山梨酯40(聚氧乙烯山梨糖醇酐单棕榈酸酯)、聚山梨酯60(聚氧乙烯山梨醇酐硬脂酸酯)和聚山梨酯80(聚氧乙烯脱水山梨醇单油酸酯；吐温80)的一种或多种。
在一些实施方案中，上述失水山梨醇脂肪酸酯为选自山梨糖醇酐单月桂酸酯(司盘20)、失水山梨糖醇单棕榈酸酯、山梨糖醇酐单硬脂酸酯、失水山梨糖醇三硬脂酸酯和失水山梨糖醇单油酸酯的一种或多种。
更优选地，上述表面活性剂选自吐温类和司盘类的一种或多种。
在一些具体的实施方案中，上述表面活性剂选自吐温20、吐温80和司盘20中的一种或多种。
在一些实施方案中，上述表面活性剂的浓度为约0.01至约8mg/mL。更典型地，该药物组合物中表面活性剂的浓度为约0.01至5mg/mL，优选为约0.02至3mg/mL，进一步优选为约0.05至2mg/mL，更进一步优选为约0.1至1mg/mL。
在一些实施方案中，在上述药物组合物中，所述式(I)化合物或其可药用盐(以式(I)化合物计)与所述表面活性剂之间的质量比为约1:200至100:1、优选约1:150至50:1、更优选约1:50至25:1、进一步更优选约1:1至15:1、例如可为约10:1。
在一些实施方案中，上述缓冲剂是药学上可接受的缓冲剂。该缓冲剂可以是适用于适合吸入的液体药物组合物的任何缓冲液。缓冲剂通常选自硫酸、盐酸、氢氧化钠、柠檬酸、柠檬酸钠、乳酸、乳酸钠、醋酸、醋酸钠、磷酸三钠、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、酒石酸、酒石酸钠、甘氨酸、硼酸、邻苯二甲酸中的一种或几种。优选的缓冲剂数量为2种及2种以上，类型为柠檬酸盐缓冲液或磷酸盐缓冲液，更优选为二者的钠盐。柠檬酸盐缓冲液包括柠檬酸、柠檬酸钠及其混合物。磷酸盐缓冲液包括磷酸、磷酸一钠(即，磷酸二氢钠)、磷酸氢二钠及其混合物。
在一些实施方案中，上述缓冲剂选自柠檬酸、柠檬酸盐(例如柠檬酸钠)、酒石酸、酒石酸盐(例如酒石酸钠)、磷酸或磷酸盐(例如磷酸二氢钠和磷酸氢二钠)。
在一些实施方案中，上述缓冲剂选自柠檬酸盐(例如柠檬酸钠)、酒石酸盐(例如酒石酸钠)或磷酸盐(例如磷酸二氢钠和磷酸氢二钠)。
在一些实施方案中，上述缓冲剂的浓度为约0.01至约50mg/mL，优选为约0.05至约40mg/mL，更优选0.1至约25mg/mL；更进一步优选0.5至约6mg/mL。
在一些实施方案中，上述缓冲剂用于使上述药物组合物的pH值控制在约3.0至约8.5之间，优选为约 5至约7之间。
在一些实施方案中，上述渗透压调节剂通常选自简单的无毒盐，如氯化钠、氯化钾等，或糖类，如葡萄糖、甘露醇、木糖醇等中的一种或多种。在一些实施方案中，上述渗透压调节剂为氯化钠。
上述渗透压调节剂的浓度取决于达到等渗所需要的量，例如与血浆或肺液等渗。渗透压调节剂的浓度通常为约0.01mg/mL至约10mg/mL，并且更通常为约5mg/mL至9mg/mL。
在一些实施方案中，上述金属螯合剂选自依地酸、依地酸二钠、依地酸钙钠等依地酸盐类中的一种或多种。优选依地酸盐(例如钙盐、钠盐)，尤其优选依地酸二钠(EDTA-2Na)。
金属螯合剂的浓度取决于上述药物组合物制备过程中可引入的金属离子的量，一般为约0.01至约40mg/mL，优选为约0.01至约20mg/mL，更优选约0.01至约5mg/mL；更进一步优先约0.01至约2mg/mL。
在一些实施方案中，上述药物组合物中，稀释剂可以是任何药学上可接受的稀释剂。该稀释剂适合吸入给药。通常，稀释剂选自水、乙醇和甘油中的一种或多种。优选的稀释剂为水，更优选的稀释剂是无菌的水。
在一些实施方案中，上述药物组合物中，稀释剂的使用量可以是适量的，以使上述药物组合物中式(I)化合物或其可药用盐或者辅料的浓度处在一定的范围内。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物，以及吐温类或司盘类；进一步上述吐温类或司盘类选自吐温20、吐温80和司盘20中的一种或多种。
在一些实施方案中，上述药物组合物还包括磷酸盐；进一步所述磷酸盐可以选自磷酸二氢钠或其一水合物和磷酸氢二钠；在一些实施方案中，上述药物组合物还包括柠檬酸钠或者酒石酸钠。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、司盘类与吐温类混合(如吐温80、吐温20或司盘20)和水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、司盘类与吐温类混合(如吐温80、吐温20或司盘20)、柠檬酸钠或者酒石酸钠和水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、吐温类(如吐温80或吐温20)、磷酸二氢钠或其一水合物、磷酸氢二钠、依地酸二钠和水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、吐温类(如吐温80或吐温20)、磷酸二氢钠或其一水合物、磷酸氢二钠、氯化钠、依地酸二钠和水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、吐温类(如吐温80或吐温20)、柠檬酸钠或者酒石酸钠、氯化钠和水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、司盘类与吐温类混合(如吐温80、吐温20或司盘20)、柠檬酸钠或者酒石酸钠、氯化钠和水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、表面活性剂、缓冲剂、渗透压调节剂、金属螯合剂及稀释剂，其中式(I)化合物的浓度为0.002～50mg/mL、表面活性剂的浓度为0.02至3mg/mL、缓冲剂的浓度为0.1至约25mg/mL、渗透压调节剂的浓度为5mg/mL至9mg/mL、金属螯合剂的浓度为0.01至约5mg/mL。
在一些实施方案中，上述药物组合物中，其中所述表面活性剂、缓冲剂、渗透压调节剂、金属螯合剂及稀释剂分别如上述定义。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、表面活性剂、缓冲剂、渗透压调节剂、金属螯合剂及稀释剂，其中式(I)化合物的浓度为0.002～50mg/mL、表面活性剂的浓度为0.02至3mg/mL、缓冲剂的浓度为0.1至约25mg/mL、渗透压调节剂的浓度为5mg/mL至9mg/mL、金属螯合剂的浓度为0.01至约5mg/mL；所述表面活性剂为吐温20、吐温80和司盘20中的一种或多种，所述缓冲剂为磷酸二氢钠或其一水合物、磷酸氢二钠、酒石酸和柠檬酸中的一种或多种，所述渗透压调节剂为氯化钠，所述金属螯合剂为依地酸二钠和依地酸钙钠中的一种或多种，所述稀释剂为水。
在一些实施方案中，上述的药物组合物，其包含式(I)化合物、吐温80、磷酸二氢钠或其一水合物、磷酸氢二钠、氯化钠、依地酸二钠和水；其中式(I)化合物的浓度为0.002～50mg/mL、吐温80的浓度为0.02至3mg/mL、磷酸二氢钠和磷酸氢二钠的浓度为0.1至25mg/mL、氯化钠的浓度为5mg/mL至9mg/mL、依地酸二钠的浓度为0.01至约5mg/mL。
在一些实施方案中，上述的式(I)化合物或其可药用盐的药物组合物，其中式(I)化合物为固体形式；在一些实施方案中，上述式(I)化合物为式(I)化合物的结晶。
在一些实施方案中，上述的式(I)化合物或其可药用盐的药物组合物，其中所述的式(I)化合物为 将式(I)化合物的结晶经过粒度控制后得到的产物。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.81±0.2°、13.96±0.2°、15.01±0.2°、17.95±0.2°和24.73±0.2°。
本申请的一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.81±0.2°、8.38±0.2°、11.16±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、17.95±0.2°、24.73±0.2°和26.13±0.2°。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.81±0.2°、8.38±0.2°、11.16±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、16.76±0.2°、17.95±0.2°、20.83±0.2°、24.73±0.2°和26.13±0.2°。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.81±0.2°、8.38±0.2°、9.13±0.2°、11.16±0.2°、11.60±0.2°、12.82±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、16.76±0.2°、17.95±0.2°、18.91±0.2°、20.83±0.2°、24.36±0.2°、24.73±0.2°、25.78±0.2°和26.13±0.2°。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的5、6、7、8、9、10、11、12或更多个衍射峰：5.81±0.2°、8.38±0.2°、9.13±0.2°、11.16±0.2°、11.60±0.2°、12.82±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、16.76±0.2°、17.95±0.2°、18.91±0.2°、20.83±0.2°、24.36±0.2°、24.73±0.2°、25.78±0.2°和26.13±0.2°。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的5、6、7、8、9、10或11个衍射峰：5.81±0.2°、8.38±0.2°、11.16±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、16.76±0.2°、17.95±0.2°、20.83±0.2°、24.73±0.2°和26.13±0.2°。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的5、6、7、8或9个衍射峰：5.81±0.2°、8.38±0.2°、11.16±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、17.95±0.2°、24.73±0.2°和26.13±0.2°。
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的XRPD图谱中，衍射峰的峰位置及相对强度由下表1表示：
表1
编号 2θ角(±0.2°) 相对强度(％) 编号 2θ角(±0.2°) 相对强度(％)
1 5.81 47.9 17 17.69 20.9
2 8.38 23.7 18 17.95 69.7
3 9.13 15.4 19 18.91 15.0
4 10.57 8.2 20 20.21 8.0
5 11.16 46.9 21 20.83 24.3
6 11.60 17.6 22 21.25 5.3
7 11.77 6.2 23 22.96 9.9
8 12.82 16.5 24 24.14 5.1
9 13.96 99.5 25 24.36 19.5
10 14.47 38.4 26 24.73 100.0
11 15.01 80.7 27 25.48 11.1
12 15.71 8.0 28 25.78 19.9
13 16.03 9.1 29 26.13 61.8
14 16.54 9.2 30 29.05 12.5
15 16.76 24.4 31 29.37 6.3
16 17.47 8.3      
在一些实施方案中，上述式(I)化合物的结晶，其使用Cu Kα辐射的XRPD图谱如图1所示。
在一些实施方案中，上述式(I)化合物的结晶，其差示扫描量热曲线在247.70℃±2℃处具有放热峰。
在一些实施方案中，上述式(I)化合物的结晶，其差示扫描量热图谱如图2所示。
在一些实施方案中，上述式(I)化合物的结晶的热重分析曲线在155.75±2℃处失重达0.4870％；在155.75±2℃至262.18±2℃之间失重达7.287％。
在一些实施方案中，上述式(I)化合物的结晶，其热重分析图谱如图3所示。
在一些实施方案中，上述药物组合物中，其中式(I)化合物或其可药用盐的粒度为X 50≤10μm，优选 0.1μm至8μm之间。
在一些实施方案中，上述药物组合物中，其中式(I)化合物或其可药用盐的粒度为X 50≤5μm且X 90≤10μm。
本申请的上述药物合物可以通过多种旨在形成为适合于口服或吸入的方式给药至人的制剂形式，例如溶液等。
在一些实施方案中，本申请的药物组合物通过吸入给药。
在一些实施方案中，本申请的药物组合物通过口腔或鼻腔吸入给药。
在一些实施方案中，本申请的药物组合物为吸入用溶液。
在一些实施方案中，本申请的药物组合物为混悬液形式。
在一些实施方案中，本申请的药物组合物为吸入用混悬液形式。
另一方面，本申请提供了上述药物组合物的制备方法，包括以下过程：将表面活性剂与式(I)化合物或其可药用盐混合。优选地，所述制备方法包括将表面活性剂、式(I)化合物或其可药用盐以及选自如下中的至少一种混合：金属螯合剂、缓冲剂、稀释剂和渗透压调节剂。更优选地，本申请提供了上述药物组合物的制备方法，包括以下过程：润湿剂、缓冲剂、渗透压调节剂、金属螯合剂、式(I)化合物或其可药用盐和稀释剂混合。
在一些实施方案中，上述药物组合物的制备方法包括以下过程：
1)润湿剂、缓冲剂、渗透压调节剂、金属螯合剂和稀释剂混合形成溶液，
2)式(I)化合物或其可药用盐与步骤1)的溶液混合。
在一些实施方案中，上述制备过程还包括步骤3)：将步骤2)得到的产物进行均质。
在一些实施方案中，上述均质过程后，式(I)化合物或其可药用盐的粒度为X 50≤5μm且X 90≤10μm。
在一些实施方案中，上述制备过程还包括灌装步骤。
另一方面，本申请还提供了预防或治疗哺乳动物中的与PDE3和/或PDE4相关病症的方法，包括对需要该预防或治疗的哺乳动物、优选人给予治疗有效量的上述药物组合物。
另一方面，本申请还提供了上述药物组合物在制备用于预防或治疗与PDE3和/或PDE4相关病症的药物中的应用。
另一方面，本申请还提供了上述药物组合物用于预防或治疗与PDE3和/或PDE4相关病症的用途。
另一方面，本申请还提供了用于预防或治疗与PDE3和/或PDE4相关病症的上述药物组合物。
本申请的一些实施方案中，所述与PDE3和/或PDE4相关病症选自哮喘或慢性阻塞性肺病(COPD)。
技术效果
本申请式(I)化合物及其药物组合物具有显著的双重PDE3和PDE4抑制作用，并且对人外周血单核细胞(hPBMC)中TNF-α有显著的抑制作用，在LPS(lipopolysaccharide，脂多糖)诱导的大鼠急性肺损伤模型中也显示出优异的抗炎作用；具有高的体内血浆清除率、低的口服血浆系统暴露量以及低的口服生物利用度，局部途径给药安全性好；对人肝微粒体细胞色素P450的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)抑制作用低，无药物-药物相互作用风险；降低BALF白细胞总数，具有显著抗炎效果，且起效剂量低；降低气道阻力指数Penh。
本申请式(I)化合物的结晶及其药学上可接受盐的结晶在药物活性、药代动力学、生物利用度、吸湿性、熔点、稳定性、溶解性、纯度、易制备等具备优势，以满足药物在生产、储存、运输和制剂等方面的需求。式(I)化合物的晶型吸湿性不大，利于吸入药物的吸收。
本申请式(I)化合物的药物组合物，稳定性良好，杂质无增长，表现出药学可接受水平的杂质；分散性良好，动力学稳定，包括颗粒无明显沉降，粒度无增长，在认可的吸入产品有效递送所需的范围内。另外，该组合物颗粒大小均匀适中，吸收速度快。递送速率良好、剂量准确，可被吸入的气溶胶粒子比例高、微细粒子剂量高。
术语解释
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”或“包含(comprise)”及其英文变体例如“comprises”和“comprising”或等同物应解释为开放式的、含括式的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定；换句话说，在本文中，单数术语涵盖复数术语，反之亦然。因此，例如提到的包括“催化剂”的反应包括一种催化剂、或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
一般的，通过激光衍射测量特征性的等价球体直径(称作体积直径)，从而定量颗粒的粒度，例如通过激光粒度测试仪测定。
本申请以体积直径(VD)表示粒度分布(particle size distribution)。
术语“X 10”是指体积累积分布百分数达到10％时所对应的粒径，它的物理意义是粒径小于它的颗粒占总体积的10％。
术语“X 50”是指体积累积分布百分数达到50％时所对应的粒径，称为体积中位直径(volum median diameter)，它的物理意义是粒径小于它的颗粒占总体积的50％。
术语“X 90”是指体积累积分布百分数达到90％时所对应的粒径，它的物理意义是粒径小于它的颗粒占总体积的90％。
在本文中，除非另有说明，各参数值(包括2θ值、反应条件)均被视为由术语“约”修饰，以反映各值存在的测量等误差，例如相对于给定值，存在±5％的误差。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
附图说明
图1为式(I)化合物的结晶的XRPD谱图；
图2为式(I)化合物的结晶的DSC谱图；
图3为式(I)化合物的结晶的TGA谱图；
图4为式(I)化合物的结晶的DVS图；
图5为BALF白细胞总数；
图6为乙酰甲胆碱Mch诱导下肺功能检测(气道阻力指数Penh)。
具体实施方式
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。
实施例
中间体BB-1的合成
Figure PCTCN2021072145-appb-000003
步骤1：化合物BB-1-2的合成
氮气氛围下，化合物BB-1-1(21.10g)和氰基乙酸乙酯(11.00g,10.38mL)的混合物在100℃下搅拌16小时。反应完毕后，将混合物冷却至70℃，慢慢滴加乙醇(30mL)，有大量固体析出。过滤，滤饼减压干燥得到产物BB-1-2。
1H NMR(400MHz,DMSO-d6)δ＝8.26(t,J＝5.2Hz,1H),6.86(d,J＝8.0Hz,1H),6.79(br s,1H),6.71(d,8.0Hz,1H),4.00(q,J＝6.8Hz,2H),3.72(s,3H),3.59(s,2H),3.31-3.23(m,2H),2.64(t,J＝7.2Hz,2H),1.32(t,J＝6.8Hz,3H).MS–ESI m/z:263.1[M+H] +.
步骤2：化合物BB-1-3的合成
氮气氛围下，将三氯氧磷(379.50g,230.00mL)升温至85℃，分批加入化合物BB-1-2(26.00g)。反应混合物在85℃下搅拌反应2小时。反应完毕后，减压蒸馏除去大部分三氯氧磷。向剩余物中加入二氯甲烷(200mL)，用水(100mL×2)洗涤。有机相用无水硫酸钠干燥后，过滤去除干燥剂，减压浓缩。所得粗品经乙酸乙酯(20mL)打浆纯化得到化合物BB-1-3。
1H NMR(400MHz,CD 3OD)δ＝7.16(s,1H),6.83(s,1H),4.62(s,1H),4.12(q,J＝6.8Hz,2H),3.86(s,3H),3.35(d,J＝6.4Hz,2H),2.84(t,J＝6.4Hz,2H),1.44(t,J＝6.8Hz,3H).MS–ESI m/z:245.1[M+H] +.
步骤3：化合物BB-1-4的合成
在0℃下，向98％浓硫酸(12.88g,128.69mmol,7.00mL)中分批加入化合物BB-1-3(1.00g)。反应混合物在27℃下搅拌3小时。反应完毕后，将混合物加入到冷水(15mL)中，然后滴加氢氧化钠水溶液(4mol/L,32mL)调节pH值至中性，再用乙酸乙酯(100mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤去除干燥剂，减压浓缩，得到化合物BB-1-4。
MS–ESI m/z:263.1[M+H] +.
步骤4：化合物BB-1-5的合成
在0℃下，将钠(2.42g)分批加入到乙醇(80mL)中。混合物在28℃搅拌0.5小时后，向溶液中分批加入化合物BB-1-4(6.90g)，在80℃下搅拌0.5小时。随后一次性加入碳酸二乙酯(9.32g,9.51mL)，该混合物继续在80℃下搅拌5小时。反应完毕后，混合物冷却至室温，慢慢加入冰水(30mL)，然后用稀盐酸(2mol/L,53mL)调节pH值至中性，有大量固体析出，过滤，所得滤饼经乙醇(10mL)打浆纯化得到化合物BB-1-5。
1H NMR(400MHz,DMSO-d 6)δ＝11.22(br s,1H),7.35(s,1H),6.95(s,1H),6.22(s,1H),4.09(q,J＝6.8Hz,2H),3.90(br s,2H),3.83(s,3H),2.89(br s,2H),1.35(t,J＝6.8Hz,3H).MS–ESI m/z:289.1[M+H] +.
步骤5：化合物BB-1-6的合成
室温下将化合物BB-1-5(5.00g)溶于三氯氧磷(30mL)中。氮气氛围下，反应混合物于100℃搅拌16小时。反应完毕后，减压蒸馏除去大部分溶剂。加入水(100mL)，用二氯甲烷(150mL×2)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到化合物BB-1-6。MS–ESI m/z:306.9[M+H] +.
步骤6：化合物BB-1的合成
室温下将化合物BB-1-6(925.67mg)溶于异丙醇(8mL)中，加入2,4,6-三甲基苯胺(2.10g)。氮气氛围下，反应混合物于90℃搅拌15小时。反应完毕后，混合物降至室温，减压浓缩，所得残留物经乙醇(6mL)打浆纯化得到化合物BB-1。
1H NMR(400MHz,DMSO-d 6)δ＝8.85(br s,1H),7.27(s,1H),6.97(s,1H),6.90(s,2H),6.45(s,1H),4.10(q,J＝6.8Hz,2H),3.90(t,J＝6.0Hz,2H),3.86(s,3H),2.87(t,J＝6.0Hz,2H),2.45(s,3H),2.11(s,6H),1.37(t,J＝6.8Hz,3H).MS–ESI m/z:406.2[M+H] +.
化合物BB-4的合成
Figure PCTCN2021072145-appb-000004
步骤1：化合物BB-4-1的合成
室温下将化合物BB-1(1.00g)溶于2-丁酮(35mL)中，依次加入2-(2-溴乙基)异吲哚啉-1,3-二酮(3.76g)、碳酸钾(3.07g)和碘化钠(2.22g)。氮气氛围下，反应混合物于85℃搅拌72小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(30mL)、乙酸乙酯(25mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝15:1～3:1)纯化得到化合物BB-4-1。
MS–ESI m/z:579.3[M+H] +.
步骤2：化合物BB-4的合成
室温下将化合物BB-4-1(500.00mg)溶于三氯甲烷(3mL)和乙醇(3mL)中，加入水合肼(152.67mg,85％纯度)。氮气氛围下，混合物于28℃搅拌16小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(15mL)、二氯甲烷(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩得到化合物BB-4。
1H NMR(400MHz,DMSO-d 6)δ＝6.95(s,1H),6.85(br s,2H),6.66(s,1H),5.31(s,1H),4.14(t,J＝6.8Hz,2H),4.05(q,J＝6.8Hz,2H),3.91(t,J＝6.4Hz,2H),3.62(s,3H),2.90-2.86(m,4H),2.22(s,3H),1.95(br s,6H),1.33(t,J＝6.8Hz,3H).MS–ESI m/z:449.2[M+H] +.
实施例1：式(Ⅰ)化合物的制备
20℃下将5-羟基-3-甲基-1,2,3-三氮唑-4-羧酸(18.50mg)溶于DCM(1mL)中，向其中加入HATU(8.80mg)和三乙胺(57.40μL)后搅拌2小时，随后向其中加入化合物BB-4(50mg)，保持该温度继续搅拌16小时。混合物用DCM稀释至10mL后用水(30mL*3)洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩蒸除溶剂得粗产品。粗产品经prep-HPLC分离纯化得黄色固体目标式(Ⅰ)化合物。
1H NMR(400MHz,CD 3OD)δ＝6.94(s,2H),6.87(s,1H),6.77(s,1H),5.52(s,1H),4.48(t,J＝6.0Hz,2H),4.15(s,3H),4.12-4.08(m,2H),4.01(t,J＝6.0Hz,2H),3.87(t,J＝6.0Hz,2H),3.69(s,3H),2.94(t,J＝6.0Hz,2H),2.29(s,3H),2.06(s,6H),1.41(t,J＝6.8Hz,3H).MS m/z[M+H] +574.1.
实施例2：式(Ⅰ)化合物的结晶的制备
将50mg式(Ⅰ)化合物加入到4mL玻璃瓶中，向其中加入1mL无水乙醇和0.2mL水后升温至40℃搅拌48小时。自然冷却至室温，离心分离出固体，真空干燥得46mg固体结晶。其XRPD谱图如图1所示，DSC谱图如图2所示，TGA谱图如图3所示。
实施例3-36
制备过程：
1)向配制罐中加入各辅料，搅拌溶清，得到辅料溶液；
2)向上述制备得到的辅料溶液中加入式(Ⅰ)化合物，搅拌使呈均匀混悬液；
3)进一步经高压均质机、微射流或砂磨机等设备，控制制剂中式(Ⅰ)化合物粒度为X 50≤5μm且X 90≤10μm；
4)得到产品。
具体辅料用量及产品如下表2所述。
表2
Figure PCTCN2021072145-appb-000005
*其中实施例35及36，在上述步骤1)中的各辅料混合溶清后，需要加入适量氢氧化钠，调节pH至5.0至7.0。
实验例1：式(Ⅰ)化合物的结晶固体稳定性研究
高效液相色谱分析方法(HPLC)
HPLC方法色谱条件参见下表：
色谱柱：Zorbax SB C-18,4.6mm×150mm，5μm(PDS-HPLC-007)
流动相A：0.1％TFA in water
流动相B：100％ACN
样品配制：采用乙腈与水的混合溶剂(乙腈:水＝50:50(v/v))溶解样品。
固体稳定性放样方法
考察化合物在以下条件放置的稳定性，并在不同的时间点取样检测含量。准确称重实施例2中制备的 式(Ⅰ)化合物的结晶约5mg置于干燥洁净的玻璃瓶中，一式两份，摊成薄薄一层，作为正式供试样品，放置于影响因素试验条件下((60℃)、(相对湿度92.5％)、光照(总照度1.2×10 6Lux·hr/近紫外200w·hr/m 2)、(40℃，相对湿度75％)、或(60℃，相对湿度75％))，其样品为完全暴露放样，用铝箔纸盖上，扎上小孔。在5天、10天、1月、2月、3月进行取样分析。光照(可见光1200000Lux，紫外200W)条件下放置的样品为室温完全暴露放样。实验结果见表3。
表3 固体稳定性样品含量分析结果(5天、10天、1月、2月、3月)
RRT/Norm％ 总杂％
0天 0.11
60℃_5天 0.10
60℃_10天 0.11
92.5％RH_5天 0.11
92.5％RH_10天 0.10
避光 0.11
光照 0.10
40℃+75％RH-10天 0.10
60℃+75％RH-10天 0.10
40℃+75％RH-1月 0.10
60℃+75％RH-1月 0.10
40℃+75％RH-2月 0.08
40℃+75％RH-3月 0.09
由此可见，本申请的式(I)化合物的结晶在高温、高湿或光照条件下均具有良好的稳定性，在测试期间杂质无增长。
实验例2：式(I)化合物的结晶的吸湿性研究
仪器型号：SMS DVS Advantage动态蒸汽吸附仪
测试条件：取样品(10～20mg，实施例3制备得到的结晶)置于DVS样品盘内进行测试。
详细的DVS参数如下：
温度：25℃
平衡：dm/dt＝0.01％/min(最短：10min，最长：180min)
干燥：0％RH下干燥120min
RH(％)测试梯级：10％
RH(％)测试梯级范围：0％-90％-0％。所得动态蒸汽吸附(DVS)图如图4所示。
由图4可以看出，本申请的式(I)化合物的结晶的吸湿性小。
实验例3：体外检测化合物对PDE 3A酶的抑制活性
实验目的：根据荧光偏振测定AMP/GMP表达，即示踪AMP/GMP抗体结合来表示酶的活性。
试剂：
实验缓冲溶液：10mM Tris-HCl(pH 7.5)，5mM MgCl 2，0.01％Brij 35，1mM二硫苏糖醇(DTT)，和1％DMSO。
酶：重组人源PDE3A(基因登录号NM_000921；氨基酸669端)用N端GST标签在Sf9昆虫细胞中的杆状病毒来表达，其分子量＝84kDa。
酶作用物：1μM cAMP
检测：
Figure PCTCN2021072145-appb-000006
GMP2抗体和AMP2/GMP2AlexaFluor633示踪。
操作步骤：
1.将重组人源PDE3A酶和酶作用物(1μM cAMP)分别溶解到新鲜制备的实验缓冲液中；
2.将上述PDE3A酶缓冲溶液转移到反应孔中；
3.通过声学技术(回声550；毫微升范围)将100％DMSO溶解的化合物加到PDE3A酶缓冲溶液反应孔中，并在室温下孵育10分钟；
4.将酶作用物缓冲溶液加到上述反应孔中以启动反应；
5.在室温下孵育1小时；
6.添加检测混合物(
Figure PCTCN2021072145-appb-000007
GMP2抗体和AMP2/GMP2 AlexaFluor633示踪)以终止反应，并在缓慢混合下孵育90分钟。荧光偏振测定范围是Ex/Em＝620/688。
数据分析：荧光偏振信号根据AMP/GMP标准曲线和通过Excel软件计算相对DMSO对照的酶活性百分比，换算成nM。曲线拟合使用GraphPad Prism(绘制医学图标)。实验结果见表4。
实验例4：体外检测化合物对PDE 4B酶的抑制活性
实验目的：根据荧光偏振测定AMP/GMP表达，即示踪AMP/GMP抗体结合来表示酶的活性。
试剂：
实验缓冲溶液：10mM Tris-HCl(pH 7.5)，5mM MgCl 2，0.01％Brij 35，1mM DTT，和1％DMSO。
酶：重组人源PDE4B(基因登录号NM_002600；氨基酸305端)用N端GST标签在Sf9昆虫细胞中的杆状病毒来表达，其分子量＝78kDa。
酶作用物：1μM cAMP
检测：
Figure PCTCN2021072145-appb-000008
GMP2抗体和AMP2/GMP2AlexaFluor633示踪。
操作步骤：
1.将重组人源PDE4B酶和酶作用物(1μM cAMP)分别溶解到新鲜制备的实验缓冲液中；
2.将上述PDE4B酶缓冲溶液转移到反应孔中；
3.通过声学技术(回声550；毫微升范围)将100％DMSO溶解的化合物加到PDE4B酶缓冲溶液反应孔中，并在室温下孵育10分钟
4.将酶作用物缓冲溶液加到上述反应孔中以启动反应
5.在室温下孵育1小时
6.添加检测混合物(
Figure PCTCN2021072145-appb-000009
GMP2抗体和AMP2/GMP2AlexaFluor633示踪)以终止反应，并在缓慢混合下孵育90分钟。荧光偏振测定范围是Ex/Em＝620/688。
数据分析：荧光偏振信号根据AMP/GMP标准曲线和通过Excel软件计算相对DMSO对照的％酶活性，换算成nM。曲线拟合使用GraphPad Prism(绘制医学图标)。
实验结果见表4：
表4 化合物体外筛选测试结果
Figure PCTCN2021072145-appb-000010
本申请的药物组合物中的活性成分具有显著的双重PDE3和PDE4抑制作用。
实验例5：比格犬药代动力学试验
本研究受试动物选用雄性比格犬，应用LC-MS/MS法定量测定比格犬经静脉注射或灌胃给予式(Ⅰ)化合物不同时间点的血浆中的药物浓度，以评价式(Ⅰ)化合物在比格犬体内的药代动力学特征。
将式(Ⅰ)化合物的澄清溶液经头静脉或隐静脉注射到两只10-12公斤的比格犬体内，并将式(Ⅰ)化合物的澄清溶液灌胃给予两只10-12公斤的比格犬(过夜禁食)。动物均于给药后0.0333、0.0833、0.25、0.5、1、2、4、6、8和24小时从外周静脉采血约500μL转移至含有0.85-1.15mg的K 2EDTA*2H 2O抗凝剂商品化离心管中，4℃、3000g离心10min取血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
表5 化合物在比格犬中的药代动力学参数
Figure PCTCN2021072145-appb-000011
本申请的药物组合物中的活性成分具有高的体内血浆清除率，低的口服血浆系统暴露量以及低的口服生物利用度。
实验例6：人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性 的抑制作用
将CYP的5种同工酶的一共5个特异性探针底物非那西丁(Phenacetin，CYP1A2)、双氯芬酸(Diclofenac，CYP2C9)、(S)-美芬妥英((S)-Mephenytoin，CYP2C19)、右美沙芬(Dextromethorphan，CYP2D6)和咪达唑仑(Midazolam，CYP3A4)分别与人肝微粒体以及式(Ⅰ)化合物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后对样品处理并采用液相色谱串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的5种代谢产物对乙酰氨基酚(Acetaminophen)、4’-羟基双氯芬酸(4’-Hydroxydiclofenac)、4’-羟基美芬妥英(4’-Hydroxymephenytoin)、右啡烷(Dextrorphan)、1’-羟基咪达唑仑(1’-Hydroxymidazolam)的浓度，以计算相应的半抑制浓度(IC 50)。
表6式(Ⅰ)化合物对于五种CYP酶的抑制作用参数
Figure PCTCN2021072145-appb-000012
本申请的药物组合物中的活性成分对人肝微粒体细胞色素P450的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)抑制作用低。
实验例7：烟熏诱导的大鼠急性肺损伤模型中的药效研究
实验动物
雄性Sprague-Dawley大鼠(上海斯莱克实验动物有限公司提供)，SPF级，体重约200g。
实验流程
1.动物到达设施后适应性饲养一周，按体重随机分为6组；
2.实验第1～3天，雾化各组对应的化合物30分钟，然后模型组及各化合物处理组的动物烟熏暴露1小时，间隔4小时后，再次烟熏暴露1小时。香烟烟雾每天暴露2次，连续3天暴露。对照组动物暴露于室内空气；
3.实验第4天，雾化各组对应的化合物30分钟，在模型组及各化合物处理组的动物雾化吸入暴露150μg/mL的LPS 15分钟、3小时后(距开始雾化的时间)烟熏暴露1小时，再检测动物肺功能(Penh和F)，CO2安乐死动物后收集肺泡灌洗液用于细胞计数。
4.给药处理
给药方式：全身暴露雾化装置以最大雾化率(约12mL)雾化待测化合物及参考化合物，30分钟。
给药频率：每天早上烟熏之前雾化给药或溶剂30分钟，第4天在LPS雾化吸入前给药。
5药效终点测量
(1)BALF(肺泡灌洗液)白细胞总数；
(2)乙酰甲胆碱Mch诱导下肺功能检测(气道阻力指数Penh)；
表7 实验分组
组别 动物数量 雾化溶液化合物浓度 给药时间
模型组 10 - 每天第一次烟熏前30min
式(Ⅰ)化合物低剂量组 10 0.05mg/mL 每天第一次烟熏前30min
式(Ⅰ)化合物高剂量组 10 0.15mg/mL 每天第一次烟熏前30min
实验结果见图5及图6。
由图5和图6可以看出，本申请的药物组合物中的活性成分可有效地降低肺泡灌洗液中的白细胞数量和气道阻力指数Penh。
实验例8：体外检测化合物对人外周血单核细胞TNF-α的抑制活性
实验目的：根据人外周血单核细胞(hPBMC)中TNF-α的水平来表达测试化合物细胞水平的抗炎活性。
操作步骤：
1.采集正常人全血，EDTA抗凝管抗凝；
2.Ficoll密度梯度离心分离PBMC，计数，调整细胞浓度为2x10 6/mL；
3.U底96孔板，每孔加入2×10 5个细胞、LPS 1ng/mL，将式(I)化合物分别制备成100μM、10μM、1μM、100nM、10nM、1nM、100pM、10pM浓度的DMSO溶液，每孔200μL体系；
4.培养24小时，收取上清；
5.ELISA检测上清中TNF-α的水平，Graphpad Prism软件拟合抑制曲线并计算IC 50。
实验结果见表8：
表8 化合物体外测试结果
Figure PCTCN2021072145-appb-000013
因此，本申请的药物组合物中的活性成分可表现出有效的抗炎活性，对人外周血单核细胞(hPBMC)中TNF-α有显著的抑制作用。
实验例9：稳定性试验
实施例28所得产品在加速条件(40℃±2℃/RH 25％±5％)和长期条件(30℃±2℃/RH 65％±5％)下放置6个月，结果见表10。
表9
Figure PCTCN2021072145-appb-000014
由此可见，本申请的药物组合物在加速条件和长期条件下表现出良好的稳定性，杂质无明显增长，粒度无增长。

Claims (20)

  1. 一种药物组合物，其包含式(I)化合物或其可药用盐、以及表面活性剂，
    Figure PCTCN2021072145-appb-100001
  2. 如权利要求1所述的药物组合物，其还包含金属螯合剂。
  3. 如权利要求1或2所述的药物组合物，其还包含缓冲剂。
  4. 如权利要求1-3中任一项所述的药物组合物，其还包含渗透压调节剂。
  5. 如权利要求1-4中任一项所述的药物组合物，其还包含稀释剂。
  6. 如权利要求1-5中任一项所述的药物组合物，其包含式(I)化合物或其可药用盐、表面活性剂，以及缓冲剂、渗透压调节剂、金属螯合剂和稀释剂中的至少一种。
  7. 如权利要求1-6中任一项所述的药物组合物，其中所述表面活性剂为非离子表面活性剂；
    或者，所述表面活性剂选自乙二醇聚氧乙烯醚、聚丙二醇烷基醚、烷基聚葡糖苷、辛基酚聚氧乙烯醚、烷基酚聚氧乙烯醚、甘油烷基酯、聚氧乙烯山梨糖醇酐脂肪酸酯、脱水山梨糖醇烷基酯、失水山梨醇脂肪酸酯、椰油酰胺MEA、椰油酰胺DEA、十二烷基二甲基氧化胺、聚乙烯的嵌段共聚物乙二醇和聚丙二醇和聚乙氧基化牛脂胺的一种或多种；
    或者，所述表面活性剂选自吐温类和司盘类的一种或多种；
    或者，所述表面活性剂选自吐温20、吐温80和司盘20中的一种或多种；
    或者，所述表面活性剂的浓度为约0.01至约8mg/mL。
  8. 如权利要求3所述的药物组合物，其中所述缓冲剂为选自硫酸、盐酸、氢氧化钠、柠檬酸、柠檬酸钠、乳酸、乳酸钠、醋酸、醋酸钠、磷酸三钠、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、酒石酸、酒石酸钠、甘氨酸、硼酸、邻苯二甲酸中的一种或多种；
    或者，所述缓冲剂选自柠檬酸、柠檬酸盐、酒石酸、酒石酸盐、磷酸或磷酸盐；
    或者，所述缓冲剂选自柠檬酸盐、酒石酸盐或磷酸盐；
    或者，所述缓冲剂的浓度为约0.01至约50mg/mL；
    或者，所述缓冲剂用于使所述药物组合物的pH值控制在约3.0至约8.5之间。
  9. 如权利要求4所述的药物组合物，所述渗透压调节剂为选自氯化钠、氯化钾、葡萄糖、甘露醇或木糖醇中的一种或多种。
  10. 如权利要求2所述的药物组合物，所述金属螯合剂为选自依地酸、依地酸二钠或依地酸钙钠中的一种或多种。
  11. 如权利要求5所述的药物组合物，所述稀释剂为选自水、乙醇和甘油中的一种或多种。
  12. 如权利要求1-11中任一项所述的药物组合物，其包含式(I)化合物、表面活性剂、缓冲剂、渗透压调节剂、金属螯合剂及稀释剂，其中式(I)化合物的浓度为0.002～50mg/mL、表面活性剂的浓度为0.02至3mg/mL、缓冲剂的浓度为0.1至约25mg/mL、渗透压调节剂的浓度为5mg/mL至9mg/mL、金属螯合剂的浓度为0.01至约5mg/mL。
  13. 如权利要求1-12中任一项所述的药物组合物，其包含式(I)化合物、吐温80、磷酸二氢钠或其一水合物、磷酸氢二钠、氯化钠、依地酸二钠和水；任选地，其中式(I)化合物的浓度为0.002～50mg/mL、吐温80的浓度为0.02至3mg/mL、磷酸二氢钠和磷酸氢二钠的浓度为0.1至25mg/mL、氯化钠的浓度为5mg/mL至9mg/mL、依地酸二钠的浓度为0.01至约5mg/mL。
  14. 如权利要求1-13中任一项所述的药物组合物，其中式(I)化合物为式(I)化合物的结晶，该结晶使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的5、6、7、8、9、10或11个衍射峰：5.81±0.2°、8.38±0.2°、11.16±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、16.76±0.2°、17.95±0.2°、20.83±0.2°、24.73±0.2°和26.13±0.2°；或者，使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.81±0.2°、13.96±0.2°、15.01±0.2°、17.95±0.2°和24.73±0.2°；或者，在下列2θ角处具有衍射峰：5.81±0.2°、8.38±0.2°、11.16±0.2°、13.96±0.2°、14.47±0.2°、15.01±0.2°、16.76±0.2°、17.95±0.2°、20.83±0.2°、24.73±0.2°和26.13±0.2°。
  15. 如权利要求1-14中任一项所述的药物组合物，其中所述式(I)化合物或其可药用盐的粒度为X 50≤10μm；或者，其中所述式(I)化合物或其可药用盐的粒度为X 50≤5μm且X 90≤10μm。
  16. 如权利要求1-15中任一项所述的药物组合物，其中所述式(I)化合物或其可药用盐与所述表面活性 剂之间的质量比为约1:200至100:1、优选约1:150至50:1、更优选约1:50至25:1、进一步更优选约1:1至15:1，所述式(I)化合物或其可药用盐的质量以式(I)化合物计。
  17. 如权利要求1-16中任一项所述的药物组合物，其中所述药物组合物为混悬液形式。
  18. 权利要求6的药物组合物的制备方法，包括：将表面活性剂、式(I)化合物或其可药用盐以及选自如下中的至少一种混合：金属螯合剂、缓冲剂、稀释剂和渗透压调节剂。
  19. 预防或治疗哺乳动物中的与PDE3和/或PDE4相关病症的方法，包括对需要该预防或治疗的哺乳动物、优选人给予治疗有效量的权利要求1-17中任一项所述的药物组合物；任选地，所述与PDE3和/或PDE4相关病症选自哮喘或慢性阻塞性肺病。
  20. 权利要求1-17中任一项所述的药物组合物在制备用于预防或治疗与PDE3和/或PDE4相关病症的药物中的应用；任选地，所述与PDE3和/或PDE4相关病症选自哮喘或慢性阻塞性肺病。
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