WO2020125670A1 - 单环β-内酰胺化合物在制药中的应用 - Google Patents

单环β-内酰胺化合物在制药中的应用 Download PDF

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WO2020125670A1
WO2020125670A1 PCT/CN2019/126261 CN2019126261W WO2020125670A1 WO 2020125670 A1 WO2020125670 A1 WO 2020125670A1 CN 2019126261 W CN2019126261 W CN 2019126261W WO 2020125670 A1 WO2020125670 A1 WO 2020125670A1
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acid
compound
reduced pressure
under reduced
pharmaceutically acceptable
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French (fr)
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魏霞蔚
丁照中
黎健
陈曙辉
魏于全
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南京明德新药研发有限公司
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Priority to CN201980084589.9A priority Critical patent/CN113227088B/zh
Priority to EP19897972.6A priority patent/EP3901150A4/en
Priority to JP2021535115A priority patent/JP7179185B2/ja
Priority to US17/414,491 priority patent/US20220062244A1/en
Publication of WO2020125670A1 publication Critical patent/WO2020125670A1/zh

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to the use of compounds represented by formula (I) and pharmaceutically acceptable salts thereof in the pharmaceutical field.
  • Aztreonam is the only monocyclic ⁇ -lactam approved by the FDA worldwide and the second analogue (tigemonam) sold only in the Japanese market.
  • the value of monocyclic ⁇ -lactam antibiotics is far from being Excavated (Rev. Infect. Dis., 1985, 7, 579-593).
  • the resistance of bacteria makes the permeability of aztreonam worse, the efflux effect is enhanced, and the bacteriostatic spectrum is reduced.
  • AiCuris (WO2013110643) and Novartis (WO2015148379) respectively reported the modification of the aztreonam (Aztreonam) molecule to improve the activity of the compound, the compound structural formula is shown below, wherein the group A is connected with amidino and guanidine Aromatic ring structure.
  • Novartis (WO2017050218) also reported a salt patent for one of these compounds, which are currently in the preclinical or clinical development stage.
  • the present invention provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pneumonia.
  • the pneumonia is caused by infection with Pseudomonas aeruginosa.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and /Or a pharmaceutically acceptable carrier.
  • the above composition wherein the excipient is a surface stabilizer, solubilizer, buffer, opacifier, binder, disintegrant, or lubricant.
  • the above composition wherein the surface stabilizer includes an amphoteric surfactant, a nonionic surfactant, a cationic surfactant or an anionic surfactant, or a combination thereof.
  • the above composition wherein the pharmaceutical composition is for oral use.
  • the above composition wherein the pharmaceutical composition is a tablet or capsule.
  • the above composition, wherein the pharmaceutical combination is in the form of an injection preparation or an inhalation preparation.
  • the invention also provides the application of the above composition in the preparation of medicine for treating pneumonia.
  • the use of the above composition, wherein the pneumonia is caused by infection with Pseudomonas aeruginosa is caused by infection with Pseudomonas aeruginosa.
  • the compound of the present invention has good antibacterial activity against Gram-negative bacteria, especially significant antibacterial activity against Pseudomonas aeruginosa.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal
  • the salt is contacted with a base or an acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • pharmaceutically acceptable salts belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic acids or organic acid salts of bases such as amines, alkali metals or organic salts of acid radicals such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include but are not limited to those derived from inorganic acids and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalact
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the compounds provided by the invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • wedge-shaped solid line key And wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, with wavy lines Represents a solid wedge key Or wedge-shaped dashed key Use straight solid keys And straight dotted keys Represents the relative configuration of the three-dimensional center.
  • the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and mixtures thereof are included in the scope of the present invention.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer.
  • a diastereomer salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography that uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like.
  • Remington The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the contents of this document are incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or medicament that is non-toxic but achieves the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine tests.
  • active ingredient refers to a chemical entity that can effectively treat a target disorder, disease or disorder.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations:
  • aq stands for water; min stands for minutes; FA stands for formic acid; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; DCC stands for N,N′-dicyclohexylcarbodiimide; DCM stands for dichloro Methane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; BH 3 ⁇ SMe 2 stands for borane dimethyl sulfide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; Cbz stands for benzyloxycarbonyl, which is an amine protecting group; Boc stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; ACN stands for acetonitrile ; BH 3 represents sodium cyano
  • Figure 1 shows the results of the lung load of immunosuppressed mice with pyocyanin infection in the lungs.
  • Step 1 Compound A1_1 (100.00g, 642.76mmol, 1.00eq) was added to THF (1.50L), then triethylamine (136.59g, 1.35mol, 187.10mL, 2.10eq), the resulting mixture was cooled to 0 °C Then, at this temperature, a solution of Boc 2 O (154.31g, 707.03mmol, 162.43mL, 1.10eq) in THF (500.00mL) was added dropwise, and the temperature was raised to 10°C and stirred at this temperature for 10 hours, then filtered, and the filtrate Concentrate under reduced pressure, add saturated sodium bicarbonate solution (300 mL) to the resulting crude product, and extract with ethyl acetate (500 mL*2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound A1_2.
  • Step 2 Dissolve A1_2 in THF (2000 mL) and cool to -50°C with stirring for 10 minutes, then add MeMgBr (3M, 638.59mL, 6.00eq) dropwise at -50°C for 20 minutes. After the resulting mixture was stirred at 25°C for 60 minutes, dilute hydrochloric acid (2000 mL, 0.5 M) was added at 0°C to quench the reaction mixture, and then the resulting mixture was extracted with ethyl acetate (500 mL*2). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • MeMgBr 3M, 638.59mL, 6.00eq
  • Step 3 Dissolve A1_3 (30g, 136.81mmol, 1.00eq) in a mixed solution of sodium phosphate buffer (540.00mL, 0.7M, 2.76eq) and acetonitrile (300mL), then add TEMPO (2.15g, 13.68mmol, 0.10eq), added dropwise with stirring at 35 °C NaClO (81.47g, 5.47mmol, 67.33mL, purity of 0.5%, 0.04eq) and NaClO 2 (98.99g, 1.09mol, 8.00eq ) in water (300 mL) was added. The resulting mixture was stirred at 35°C for 12 hours, then cooled to room temperature and citric acid (10 g) was added.
  • Step 4 Dissolve A1_4 (48g, 205.78mmol, 1.00eq) in DMF (700mL), then add DCC (84.92g, 411.56mmol, 83.25mL, 2.00eq) and HOBt (55.61g, 411.56mmol, 2eq), in After stirring at 10°C for 0.5 hour, O-benzylhydroxylamine hydrochloride (39.41 g, 246.93 mmol, 1.20 eq) and aqueous sodium bicarbonate solution (69.15 g, 823.11 mmol, 32.01 mL, 4 eq) were added.
  • Step 5 Dissolve A1_5 (57g, 168.44mmol, 1eq) in pyridine (600mL), stir at 55°C for 12 hours and add sulfur trioxide pyridine (187.67g, 1.18mol, 7eq). The reaction mixture was then concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate (800 mL). An aqueous potassium carbonate solution (816.94 mL, 2M, 9.7 eq) was added dropwise to the solid at 0°C, and the resulting mixture was stirred at 100°C for 2 hours. The reaction was then cooled to room temperature and extracted with ethyl acetate (400 mL*3).
  • Step 6 Dissolve A1_6 (31g, 96.76mmol, 1.00eq) in methanol (620mL), and add Pd/C (3g, 10%) under a nitrogen atmosphere, then replace the reaction flask with nitrogen three times. Then, hydrogen gas was charged at 20° C. and reacted for 1 hour in a 50 psi atmosphere, and then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain compound A1_7.
  • Step seven (220mL) was added DMF ⁇ SO 3 (17.56g, 114.65mmol , 1.2eq) to A1_7 (22g, 95.54mmol, 1.00eq) in DMF. The mixture was stirred at 0°C for 1 hour and then diluted with saturated KH 2 PO 4 (200 mL). The resulting mixture was extracted with ethyl acetate (100 mL), Bu 4 HSO 4 (38.93 g, 114.65 mmol, 1.20 eq) was added to the combined aqueous layer at 10° C. for 20 minutes, and the resulting aqueous phase was extracted with EtOAc (350 mL*4) )extraction. The organic phases were combined and the filtrate was concentrated under reduced pressure to obtain compound A1_8.
  • Step 8 A1_8 (68g, 123.24mmol, 1.00eq) was added to trifluoroacetic acid (300mL), and then the mixture was stirred at 15°C under nitrogen for 4 hours. The reaction mixture was diluted with dichloromethane (350 mL) and filtered, and the filtrate was concentrated under reduced pressure to obtain compound A1.
  • Step three Compound A2_3 (4.2g, 11.78mmol, 1eq) and pyrazole hydrochloride (1.23g, 11.78mmol, 1eq) were added to THF (40mL) and replaced with nitrogen three times, then the mixture was at 75 °C The reaction was stirred for 12 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered, and the filter cake was collected. After drying, compound A2_4 was obtained.
  • Step 4 To DCM (20mL) solution of compound 0°C (2.1g, 4.56mmol, 1eq) at 0°C, add TFAA (765.41mg, 3.64mmol, 506.89 ⁇ L, 0.8eq) and triethylamine (1.01g, 10.02) mmol, 1.39 mL, 2.2 eq), the mixture was stirred at 0° C. for 20 minutes, and then diluted with water (20 mL). The resulting mixture was extracted with DCM (50 mL*2), and the organic layers were combined and concentrated under reduced pressure to obtain compound A2.
  • Step 1 Add compound A3_1 to 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol (10.16g, 43.06mmol, 10eq) and DCM (20mL) In the mixed solution, the reaction was stirred at room temperature for 45 minutes (20-25°C) and concentrated under reduced pressure to obtain compound A3.
  • Step one To a solution of compound 1_1 (29 g, 128.30 mmol, 1 eq) in THF (300 mL) was added BH 3 ⁇ SMe 2 (10M, 38.49 mL, 3 eq). The mixture was reacted at 80°C for 12 hours, then cooled to 0°C, and quenched with methanol (100 mL). Dilute hydrochloric acid (90 mL, 1M) was then added, and stirred at 80°C for 1 hour, and concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL*2).
  • Step 3 To compound 1_3 (9g, 30.18mmol, 1eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3, 2- dioxaborolane) (15.33g, 60.37mmol, 2eq) in DMSO was added (150 mL) solution of 2.46g, 3.02mmol, 0.1eq) and potassium acetate Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 (( 11.85g, 120.73mmol, 4eq). After the mixture was replaced with nitrogen three times, it was stirred at 90°C for 12 hours.
  • reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL*3).
  • Step 4 To a solution of compound 1-4 (11 g, 31.86 mmol, 1 eq) in THF (100 mL) was added H 2 O 2 (86.69 g, 764.69 mmol, 73.47 mL, 30% purity, 24 eq) and acetic acid (9.95 g, 165.68 mmol , 9.48 mL, 5.2 eq). After the mixture was stirred at 20°C for 12 hours, it was quenched with saturated sodium carbonate (30 mL), and the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL*2).
  • Step 5 To intermediate 1_5 (6.8g, 26.69mmol, 1eq), ethylene oxide-2-carboxylic acid ethyl ester (7.75g, 66.72mmol, 2.5eq), To a solution of molecular sieve (8 g) in MTBE (10 mL) was added catalyst A3 (673.34 mg, 800.64 ⁇ mol, 0.03 eq), and the mixture was replaced with nitrogen three times and stirred at 20° C. for 12 hours.
  • Step 6 To TCM (14.88g, 130.51mmol, 9.66mL, 7.53eq) was added TCA (14.88g, 130.51mmol, 9.66mL, 7.53eq) to compound 1-6 (6.3g, 17.32mmol, 1eq) in DCM (20mL) at 0°C, and the mixture was stirred at 20°C for 1 hour Concentrate under reduced pressure to obtain the trifluoroacetate salt of compound 1-7.
  • Step 7 To a solution of Intermediate A2 (3.8g, 7.30mmol, 1eq) in DMF (30mL) was added triethylamine (2.95g, 29.20mmol, 4.06mL, 4eq) and the trifluoroacetate salt of compound 1-7 (5.33 g, 14.60 mmol, 2eq). The mixture was stirred at 45°C for 2 hours and concentrated under reduced pressure to remove DMF, and the residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL).
  • Step eleven To a solution of compound 1-11 (1 g, 1.10 mmol, 1 eq) in EtOH (10 mL) was added NH 2 NH 2 .H 2 O (77.95 mg, 1.32 mmol, 75.68 ⁇ L, 85% purity, 1.2 eq). The mixture was stirred at 20°C for 30 minutes, then filtered and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with DCM (20 mL). The combined organic layers were dried over anhydrous ammonium sulfate, filtered and concentrated under reduced pressure to give compound 1-12. LCMS (ESI) m/z: 761.5 (M+1).
  • Step 13 To a solution of compound 1_13 (200 mg, 163.39 ⁇ mol, 1 eq) in DMF (2 mL) was added N,N′-diisopropylcarbodiimide (41.24 mg, 326.77 ⁇ mol, 2 eq) and HOBt (44.15 mg , 326.77 ⁇ mol, 2eq). After the mixture was stirred at 20°C for 1 hour, Intermediate Al (48.08 mg, 228.74 ⁇ mol, 1.4 eq) and NaHCO 3 (54.90 mg, 653.55 ⁇ mol, 25.42 ⁇ L, 4 eq) were added and stirred at 20 °C for 11 hours. The reaction mixture was diluted with water (8 mL), and then the solid was collected by filtration to obtain compound 1-14. LCMS (ESI) m/z: 1350.2 (M+1).
  • Step 14 To a solution of Compound 1-14 (220 mg, 163.01 ⁇ mol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 82.85 eq) at 0°C and stirred for 1 hour.
  • the reaction solution was diluted with petroleum ether/ethyl acetate (10 mL, 4/1), and the solid was collected by filtration and passed preparative HPLC (TFA, column: Phenomenex Synergi C18 150 mm ⁇ 25 mm ⁇ 10 ⁇ m; mobile phase: [water (0.1% TFA)- Acetonitrile]; Acetonitrile%: 1%-30%, 9 minutes) Purified to obtain compound (I).
  • Pseudomonas aeruginosa PA14 Pseudomonas aeruginosa PA14.
  • Test compound compound of formula (I)
  • Reference compound AiCuris patent WO2018065636 Reference compound I-g, aztreonam (product of Dalian Meilun Biotechnology Co., Ltd.).
  • MHA Mueller-Hinton agar
  • TSA medium purchased from BD.
  • CD-1 mice provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., weighed 23 to 27g, 7 weeks old, female, a total of 46 mice.
  • mice Intraperitoneal injection of cyclophosphamide to form immunosuppressed mice
  • mice were intraperitoneally injected with cyclophosphamide 150 mg/kg on day 1 and day 4 to form immunosuppressed mice.
  • mice were injected with 50 ⁇ L of bacterial solution (2 ⁇ 10 3 CFU) in the airway.
  • Four models of mice were sacrificed by cervical spondylectomy 2 hours after infection.
  • the drugs were administered in groups, and they were administered intraperitoneally once every 2 hours, 4 hours, 6 hours, and 8 hours, a total of 4 times.
  • the cervical vertebrae were sacrificed and the mice were sacrificed.
  • Lung and kidney tissues were taken aseptically, put into a sterilized tissue homogenate tube, weighed, and an appropriate amount of normal saline (NS) was added.
  • the homogenizer homogenized for 1 min.
  • the lung tissue of the animals in the group was diluted 10 4 , 10 5 , 10 6 times, the lung tissue of the animals in each administration group was diluted 10, 100 times, and the kidney tissue of the model group was diluted 10 2 , 10 3 , 10 4 times, The tissue was diluted 10 times, the TSA plate was coated with a screw coater, cultured at 37°C overnight, and the CFU was counted with a colony counter.
  • Graphpad Prism mapping software was used to make scatter plots of lung tissue CFU.
  • SPSS19.0 software was used to count CFU and average body weight, and analysis of variance was used to analyze differences between groups.
  • mice infected with cyclophosphamide twice intraperitoneally were infected with Pseudomonas aeruginosa PA14 in the lungs of about 1.06 ⁇ 10 4 CFU. After 2 hours, the lung tissue homogenate was taken to count the bacteria and calculate the bacterial load of the mice. Its range lies in the average load of 5.10 ⁇ 10 3 CFU.
  • the compound of formula (I), compound Ig and aztreonam were injected intraperitoneally at 2h, 4h, 6h and 8h after infection.
  • the animals were sacrificed at 24h.
  • Lung tissues were taken aseptically, soaked with physiological saline (NS), and homogenized after appropriate dilution Spread 50 ⁇ L on TSA plate and incubate overnight in a 37°C incubator. Count the number of colonies and convert it to CFU per milliliter according to the dilution ratio. Then take the amount of bacteria as a logarithm based on 10 and compare the average of each group. And standard deviation, the results are shown in Table 3 and Figure 1.
  • the 24h bacterial load in the model group increased from an infection volume of 1.06 ⁇ 10 4 CFU to 3.34 ⁇ 10 8 CFU (LOG 10 of the bacterial load was 8.14), and the bacterial load of each administration group was significantly lower than that of the model group, which was basically cleared.
  • the compound of formula (I) has an in vivo therapeutic effect on the lung infection of Pseudomonas aeruginosa caused by cyclophosphamide-induced immunosuppression in mice, which can significantly reduce the bacterial load of lung tissues and remove Pseudomonas aeruginosa infections on the lungs.
  • the compound of formula (I) can completely eliminate the bacteria infected by the lungs.
  • the body weight of the animals in the administration group did not change significantly, indicating that the compound of formula (I) is safe.

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Abstract

式(I)化合物及其药学上可接受的盐在制备治疗肺炎药物中的应用。

Description

单环β-内酰胺化合物在制药中的应用
本申请主张如下优先权：
CN201811549551.8，申请日2018年12月18日。
技术领域
本发明涉及式(I)所示化合物及其药学上可接受的盐在制药领域中的用途。
背景技术
公共卫生专家和官员普遍认为耐药菌的出现和传播是21世纪的主要公共卫生问题之一。抗菌药物耐药的频率及其与严重传染病的关系以惊人的速度增加。院内病原体耐药性日益普遍，特别令人不安。在美国每年出现的超过200万例院内感染中，50％至60％是由抗菌素耐药细菌引起的。对常用抗菌药物的高耐药率增加了与院内感染有关的发病率，死亡率和成本。死于不可治愈的院内感染的患者人数持续增长，现在每年全球因耐药菌死亡的人数达到70万人，如果不开发新的治疗药物或者治疗方案，到2050年这一数字将会增加到1000万(Nature,2017,543,15)。对于由耐多药革兰氏阴性菌(包括肠杆菌科和非发酵菌)引起的感染可以选择的治疗方式特别有限，更为严重的是医药工业的研发管线中包含能够突破细菌耐药性的化合物很少(Clin.Inf.Dis.,2009,48,1-12)。
过去几十年来，非常成功和耐受良好的一类β-内酰胺抗生素一直是治疗由革兰氏阴性病原体引起的感染的主要依据。其中特别是第三代头孢菌素，碳青霉烯类和单环内酰胺被广泛用于治疗革兰氏阴性菌引起的感染。但是越来越多的内酰胺酶和其他耐药机制的出现严重危及当前化合物在这些亚类中的中期可用性，特别是超广谱内酰胺酶(ESBLs)和碳青霉烯酶是产生耐药性的重要动力，因此迫切需要能够突破耐药性的新型β-内酰胺类抗生素来填补空白。
氨曲南作为世界范围内使用的FDA唯一批准的单环β-内酰胺以及仅在日本市场销售的第二种类似物(tigemonam)，单环β-内酰胺类抗生素的价值还远远没有被发掘出来(Rev.Infect.Dis.,1985,7,579-593)。另一方面细菌的耐药性使氨曲南的渗透性变差，外排作用增强，抑菌谱缩小。为了提高单环β-内酰胺对细菌的渗透性，Basilea(WO 2007065288)，Naeja Pharmaceuticals(WO 2002022613)和Squibb&Sons(ΜS 5290929，EP 531976，EP 484881)在单环β-内酰胺分子上引入铁载体摄取系统。最近，辉瑞公司重新研究了在N1-位携带磺酰氨基羰基活化基团的单环β-内酰胺(WO 2010070523)。另外，在WO 2008116813中，Basilea描述了使用单环β-内酰胺与碳青霉烯类的联合治疗方法。AiCuris(WO 2013110643)和Novartis(WO 2015148379)分别报道了通过修饰氨曲南(Aztreonam)分子上的取代基来提高活性的研究，化合物结构式如下所示，其中基团A为连接有脒基和胍基的芳香环结构。Novartis(WO 2017050218)还报道了其中一个化合物的盐型专利，目前这些化合物都处在临床前或临床开发阶段。
Figure PCTCN2019126261-appb-000001
发明内容
本发明提供式(I)所示化合物或其药学上可接受的盐在制备治疗肺炎药物中的应用。
Figure PCTCN2019126261-appb-000002
在本发明的一些方案中，上述的应用，其中，所述肺炎是由感染铜绿假单胞菌引起的。
本发明还提供一种药物组合物，其包含作为活性成分的治疗有效量的式(I)所示化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂和/或药学上可接受的载体。
在本发明的一些方案中，上述组合物，其中所述赋形剂为表面稳定剂、增溶剂、缓冲剂、遮光剂、粘合剂、崩解剂或润滑剂。
在本发明的一些方案中，上述组合物，其中所述表面稳定剂包括两性表面活性剂、非离子表面活性剂、阳离子表面活性剂或阴离子表面活性剂，或其组合。
在本发明的一些方案中，上述组合物，其中所述药物组合物用于口服使用。
在本发明的一些方案中，上述组合物，其中所述药物组合物为片剂、胶囊剂。
在本发明的一些方案中，上述组合物，其中所述药物组合为注射制剂或吸入制剂的形式。
本发明还提供上述组合物在制备治疗肺炎药物中的应用。
在本发明的一些方案中，上述组合物的应用，其中，所述肺炎是由感染革兰氏阴性菌引起的。
在本发明的一些方案中，上述组合物的应用，其中，所述肺炎是由感染铜绿假单胞菌引起的。
技术效果
本发明化合物对革兰氏阴性菌的抑菌活性较好，尤其是对绿脓杆菌抑菌活性显著。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使 用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，除非另有说明，用楔形实线键
Figure PCTCN2019126261-appb-000003
和楔形虚线键
Figure PCTCN2019126261-appb-000004
表示一个立体中心的 绝对构型，用波浪线
Figure PCTCN2019126261-appb-000005
表示楔形实线键
Figure PCTCN2019126261-appb-000006
或楔形虚线键
Figure PCTCN2019126261-appb-000007
用直形实线键
Figure PCTCN2019126261-appb-000008
和直形虚线键
Figure PCTCN2019126261-appb-000009
表示立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：
aq代表水；min代表分钟；FA代表甲酸；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；DCC代表N,N′-二环己基碳二亚胺；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二甲酸二异丙酯；DMF代表N,N-二甲基甲酰胺；BH 3·SMe 2代表硼烷二甲硫醚；DMSO代表二甲亚砜；EtOAc代表乙酸 乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，是一种胺保护基团；Boc代表叔丁氧羰基，是一种胺保护基团；HOAc代表乙酸；ACN代表乙腈；BH 3代表氰基硼氢化钠；r.t.代表室温；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基氨基锂；TEMPO代表2,2,6,6-四甲基哌啶-1-氧自由基或2,2,6,6-四甲基哌啶氧化物；NaClO代表次氯酸钠；NaClO 2代表亚氯酸钠；HOBt代表1-羟基苯并三氮唑；psi代表磅/平方英寸；DMF·SO 3代表N，N-二甲基甲酰胺三氧化硫；KH 2PO 4代表磷酸二氢钾；Bu 4HSO 4代表四丁基硫酸氢铵；PPh 3代表三苯基膦；NH 2NH 2·H 2O代表水合肼；DPPF代表1,1'-双(二苯基膦基)二茂铁；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯(0)；MIC代表最小抑菌溶度；DMAP代表4-二甲基氨基吡啶；BnBr代表卞溴；H 2O 2代表双氧水。
附图说明
图1为给药治疗免疫抑制小鼠肺部绿脓感染的肺荷菌量结果。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
中间体A1的合成：
Figure PCTCN2019126261-appb-000010
步骤一：将化合物A1_1(100.00g，642.76mmol，1.00eq)加入到THF(1.50L)中，然后加入三乙胺(136.59g，1.35mol，187.10mL，2.10eq)，所得混合物冷却至0℃，然后在此温度下滴加Boc 2O(154.31g，707.03mmol，162.43mL，1.10eq)的THF(500.00mL)溶液，升温至10℃并在此温度下搅拌10小时， 然后过滤，将滤液减压浓缩，向所得的粗产品中加入饱和碳酸氢钠溶液(300mL)，并用乙酸乙酯(500mL*2)萃取。将合并的有机层用无水硫酸钠干燥，过滤并减压浓缩得到化合物A1_2。
1H NMR(400MHz,CDCl 3)δ(ppm):5.51(br s,1H),4.46-4.31(m,1H),4.03-3.86(m,2H),3.83-3.72(m,3H),2.64(br s,1H),1.46(s,9H)。
步骤二：将A1_2溶解于THF(2000mL)中，并降温至-50℃下搅拌10分钟，然后在-50℃下经20分钟滴加MeMgBr(3M，638.59mL，6.00eq)。将所得混合物在25℃下搅拌60分钟后在0℃下加入稀盐酸(2000mL，0.5M)淬灭反应混合物，然后将所得混合物用乙酸乙酯(500mL*2)萃取。合并的有机层用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，所得到粗产品其用石油醚/乙酸乙酯(70mL，10/1)搅拌洗涤后通过柱色谱(SiO 2，石油醚/乙酸乙酯＝10/1至1/1(v/v))纯化得到化合物A1_3。
1H NMR(400MHz,CDCl 3)δ(ppm):5.41-5.23(m,1H),3.96(br d,J＝11.2Hz,1H),3.79-3.70(m,1H),3.40(br d,J＝8.3Hz,1H),2.53-2.39(m,2H),1.39(s,9H),1.28(s,3H),1.18(s,3H)。
步骤三：将A1_3(30g，136.81mmol，1.00eq)溶解于磷酸钠缓冲液(540.00mL，0.7M，2.76eq)和乙腈(300mL)的混合溶液中，然后加入TEMPO(2.15g，13.68mmol，0.10eq)，在35℃搅拌下滴加NaClO(81.47g，5.47mmol，67.33mL，纯度为0.5％，0.04eq)和NaClO 2(98.99g，1.09mol，8.00eq)的水(300mL)溶液。将所得混合物在35℃下搅拌12小时，然后冷却至室温并加入柠檬酸(10g)。所得混合物用乙酸乙酯(500mL*4)萃取，将合并的有机层用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，过滤并将滤液减压浓缩。向所得粗产品中加入碳酸钠水溶液(300mL，2M)后用乙酸乙酯(200mL*2)洗涤。将水层冷却至0℃后用稀盐酸(1M)将pH调节至3.0。然后向水溶液中加入氯化钠至饱和，所得混合物用乙酸乙酯(500mL*4)萃取。合并的有机层用饱和氯化钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤并将滤液减压浓缩得到化合物A1_4。
1H NMR(400MHz,CDCl 3)δ(ppm):5.42(br d,J＝7.8Hz,1H),4.18(br d,J＝8.4Hz,1H),1.39(s,9H),1.30(s,3H),1.22(s,3H)。
步骤四：将A1_4(48g，205.78mmol，1.00eq)溶于DMF(700mL)，然后加入DCC(84.92g，411.56mmol，83.25mL，2.00eq)和HOBt(55.61g，411.56mmol，2eq)，在10℃下搅拌0.5小时，然后加入O-苄基羟胺盐酸盐(39.41g，246.93mmol，1.20eq)和碳酸氢钠水溶液(69.15g，823.11mmol，32.01mL，4eq)。将所得混合物在10℃下搅拌1.5小时，然后将反应混合物过滤并将滤液减压浓缩。将粗产品用水(400mL)稀释，并用乙酸乙酯(500mL*2)萃取。合并的有机层用饱和氯化钠水溶液洗涤，无水硫酸钠干燥并过滤。将滤液减压浓缩，所得残留物通过柱色谱(SiO 2，石油醚/乙酸乙酯＝6/1至3/1(v/v))纯化得到化合物A1_5。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.06(s,1H),7.45-7.32(m,5H),6.45(br d,J＝9.2Hz,1H),4.80(d,J＝2.6Hz,2H),4.65(s,1H),4.04(d,J＝7.0Hz,1H),3.77(br d,J＝9.2Hz,1H),1.40(s,9H),1.11(s,3H),1.08(s,3H)；
LC-MS(ESI)m/z:283(M-56+1)。
步骤五：将A1_5(57g，168.44mmol，1eq)溶解于吡啶(600mL)中，在55℃下搅拌12小时后加入三氧化硫吡啶(187.67g，1.18mol，7eq)。然后将反应混合物减压浓缩，所得固体溶于乙酸乙酯(800mL) 中。在0℃下向固体中滴加碳酸钾水溶液(816.94mL，2M，9.7eq)，所得混合物在100℃下搅拌2小时。然后将反应冷却至室温，并用乙酸乙酯(400mL*3)萃取。合并的有机层用无水硫酸钠干燥，过滤并减压浓缩滤液。所得粗产品通过柱色谱(SiO 2，石油醚/乙酸乙酯＝12/1至9/1(v/v))纯化得到化合物A1_6。 1H NMR(400MHz,CDCl 3)δ(ppm):7.41(br d,J＝1.0Hz,5H),5.02-4.97(m,2H),4.32(d,J＝6.7Hz,1H),1.50-1.43(m,9H),1.34(s,3H),1.11(s,3H)；
LC-MS(ESI)m/z:321.1(M+1)。
步骤六：将A1_6(31g，96.76mmol，1.00eq)溶于甲醇(620mL)中，并在氮气气氛下加入Pd/C(3g，10％)，然后将反应瓶用氮气置换三次。然后在20℃充入氢气并在50psi气氛下反应1小时，然后将反应混合物过滤并减压浓缩滤液得到化合物A1_7。
步骤七：向A1_7(22g，95.54mmol，1.00eq)的DMF(220mL)溶液中加入DMF·SO 3(17.56g，114.65mmol，1.2eq)。将混合物在0℃下搅拌1小时，然后用饱和KH 2PO 4(200mL)稀释。所得混合物用乙酸乙酯(100mL)萃取，在10℃下经20分钟向合并的水层中加入Bu 4HSO 4(38.93g，114.65mmol，1.20eq)，所得的水相用EtOAc(350mL*4)萃取。合并有机相并减压浓缩滤液得到化合物A1_8。
步骤八：将A1_8(68g，123.24mmol，1.00eq)加入到三氟乙酸(300mL)中，然后将混合物在15℃氮气下搅拌4小时。将反应混合物用二氯甲烷(350mL)稀释并过滤，将滤液减压浓缩得到化合物A1。 1H NMR(400MHz,DMSO-d 6)δ(ppm):8.79(br s,3H),4.18(br s,1H),1.46-1.38(m,6H)。
中间体A2的合成：
Figure PCTCN2019126261-appb-000011
步骤一：在20℃下向A2_1(7g，53.35mmol，7.54mL，1eq)的THF(70mL)溶液中缓慢滴加BOC-ONB(29.80g，106.69mmol，2eq)和Et 3N(11.34g，112.03mmol，15.59mL，2.1eq)的THF(330mL)溶液，将所得混合物在20℃下搅拌11小时。将反应混合物过滤后并减压浓缩滤液，所得残余物用碳酸钾溶液(100mL，2M)稀释，并用乙酸乙酯(100mL*2)萃取，合并有机相并减压浓缩得化合物A2_2。
步骤二：在0℃下向A2_2(15g，45.26mmol，1eq)的MeOH(150mL)溶液中加入BrCN(7.86g，74.21mmol，5.46mL，1.64eq)和醋酸钠(7.43g，90.51mmol，2eq)，混合物在室温下搅拌2小时后用饱和碳酸钠溶液的饱和水溶液(300mL)稀释并用乙酸乙酯(100mL)萃取。将有机相减压浓缩，残余物通过柱色谱法(SiO 2，石油醚/乙酸乙酯＝5/1至1/1)纯化得化合物A2_3。
步骤三：将化合物A2_3(4.2g，11.78mmol，1eq)和吡唑盐酸盐(1.23g，11.78mmol，1eq)分别加入到THF(40mL)中并用氮气置换三次，然后将混合物在在75℃下搅拌反应12小时。将反应冷却至室温后用乙酸乙酯(100mL)稀释后过滤并收集滤饼，干燥后得化合物A2_4。
LCMS(ESI)m/z：425.4(M+1)。
步骤四：在0℃下向化合物0℃(2.1g，4.56mmol，1eq)的DCM(20mL)溶液加入TFAA(765.41mg，3.64mmol，506.89μL，0.8eq)和三乙胺(1.01g，10.02mmol，1.39mL，2.2eq)，混合物在0℃下搅拌20分钟后用水(20mL)稀释，所得混合物用DCM(50mL*2)萃取，合并有机层并减压浓缩得化合物A2。
中间体A3的合成：
Figure PCTCN2019126261-appb-000012
步骤一：将化合物A3_1加入到1,1,1,3,3,3-六氟-2-(三氟甲基)丙-2-醇(10.16g，43.06mmol，10eq)和DCM(20mL)的混合溶液中，将反应物在室温下搅拌45分钟(20-25℃)后减压浓缩得化合物A3。
实施例1式(I)化合物的制备
Figure PCTCN2019126261-appb-000013
Figure PCTCN2019126261-appb-000014
步骤一：向化合物1_1(29g，128.30mmol，1eq)的THF(300mL)溶液中加入BH 3·SMe 2(10M，38.49mL，3eq)。混合物在80℃反应12小时后冷却至0℃，用甲醇(100mL)淬灭。然后加入稀盐酸(90mL，1M)，并在80℃下搅拌1小时，减压浓缩以除去溶剂。残余物用水(100mL)稀释，乙酸乙酯(150mL*2)萃取。然后水层用氢氧化钠水溶液(1M)调节至pH＝10～11，所得水相再用乙酸乙酯(150mL*2)萃取。合并有机层用无水硫酸钠干燥，过滤并减压浓缩得到化合物1_2。
步骤二：向化合物1_2(6g，30.29mmol，1eq)的二氯甲烷(50mL)溶液中加入Boc 2O(6.61g，30.29mmol，6.96mL，1eq)和三乙胺(6.13g，60.59mmol，8.43mL，2eq)。混合物在20℃下搅拌12小时减压浓缩以除去溶剂。将残余物用水(100mL)稀释并用乙酸乙酯(50mL*3)萃取。合并有机层减压浓缩，得到残余物通过柱色谱法(SiO 2，石油醚/乙酸乙酯＝1/0至10/1(v/v))纯化得化合物1_3。
步骤三：向化合物1_3(9g，30.18mmol，1eq)和4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼烷)(15.33g，60.37mmol，2eq)的DMSO(150mL)溶液中加入Pd(dppf)Cl 2·CH 2Cl 2(2.46g，3.02mmol，0.1eq)和乙酸钾(11.85g，120.73mmol，4eq)。混合物用氮气置换3次后在90℃下搅拌12小时。将反应混合物用水(200mL)稀释并用乙酸乙酯(150mL*3)萃取。合并的有机层过滤并减压浓缩滤液，残余物通过柱色谱法(SiO 2，石油醚/乙酸乙酯＝100/1至20/1(v/v))纯化得到化合物1_4。
步骤四：向化合物1_4(11g，31.86mmol，1eq)的THF(100mL)溶液中加入H 2O 2(86.69g，764.69mmol，73.47mL，30％纯度，24eq)和乙酸(9.95g，165.68mmol，9.48mL，5.2eq)。混合物在20℃下搅拌12小时后用饱和碳酸钠(30mL)淬灭，所得混合物用水(10mL)稀释后用乙酸乙酯(20mL*2)萃取。合并有机层减压浓缩，残余物通过柱色谱法(SiO 2，石油醚/乙酸乙酯＝15/1至7/1(v/v))纯化得到化合物1_5。LC-MS(ESI)m/z：180(M-56+1)。 1H NMR(400MHz,DMSO-d 6)δ(ppm):7.09(t,J＝6.3Hz,1H),6.72-6.65(m,2H),4.47(br t,J＝12.7Hz,4H),1.45(s,9H)。
步骤五：向中间体1_5(6.8g，26.69mmol，1eq)，环氧乙烷-2-羧酸乙酯(7.75g，66.72mmol，2.5eq)，
Figure PCTCN2019126261-appb-000015
分子筛(8g)的MTBE(10mL)溶液中加入催化剂A3(673.34mg，800.64μmol，0.03eq)，混合物用氮气置换3次后在20℃下搅拌12小时。将反应混合物用乙酸乙酯(30mL)稀释并过滤，将滤液减压浓缩后通过柱色谱(SiO 2，石油醚/乙酸乙酯＝6/1至3/1(v/v))纯化得到化合物1_6。
步骤六：在0℃下向化合物1_6(6.3g，17.32mmol，1eq)的DCM(20mL)溶液加入TFA(14.88g，130.51mmol，9.66mL，7.53eq)，混合物在20℃下搅拌1小时后减压浓缩得到化合物1_7的三氟乙酸盐。
步骤七：向中间体A2(3.8g，7.30mmol，1eq)的DMF(30mL)溶液中加入三乙胺(2.95g，29.20mmol，4.06mL，4eq)和化合物1_7的三氟乙酸盐(5.33g，14.60mmol，2eq)。混合物在45℃下搅拌2小时后减压浓缩除去DMF，将残余物用水(50mL)稀释并用乙酸乙酯(50mL)萃取。合并有机层用饱和氯化钠水溶液(25mL)洗涤，用无水硫酸钠干燥，过滤并减压浓缩得残余物通过柱色谱(SiO 2，石油醚/乙酸乙酯＝1/1至0/1)纯化得化合物1_8。LCMS(ESI)m/z:704.4(M+1)。
步骤八：向化合物1_8(3.3g，4.50mmol，1eq)的MeOH(20mL)溶液中加入NaOH(378.39mg，9.46mmol，2.1eq)。混合物在20℃下搅拌17小时后用稀盐酸(2M)将反应混合物调节pH＝3-4，减压浓缩后残余物用甲醇(20mL)稀释溶解，然后过滤并减压浓缩，得到化合物1_9。LCMS(ESI)m/z:580.5(M+1)。
步骤九：化合物1_9(2g，3.45mmol，1eq)的MeOH(20mL)溶液中加入二苯基重氮甲烷(1.34g，6.90mmol，2eq)。混合物在20℃下搅拌12小时后将减压浓缩，残余物用水(20mL)稀释后再用DCM(40mL)萃取。将合并的有机层用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，然后过滤并减压浓缩，残余物通过柱色谱法(SiO 2，DCM/MeOH＝20/1至10/1(v/v))纯化得化合物1_10。LCMS(ESI)m/z:746.5(M+1)。
步骤十：在0℃向化合物1_10(1.2g，1.42mmol，1eq)和2-羟基异吲哚啉-1,3-二酮(278.65mg，1.71mmol，1.2eq)的THF(12mL)溶液中加入PPh 3(560.04mg，2.14mmol，1.5eq)和DIAD(431.75mg，2.14mmol，415.15μL，1.5当量)。混合物在20℃下搅拌1小时后减压浓缩除去THF，残余物通过柱色谱(SiO 2，DCM/EtOH＝20/1至10/1(v/v))纯化得化合物1_11。LCMS(ESI)m/z:891.5(M+1)。
步骤十一：向化合物1_11(1g，1.10mmol，1eq)的EtOH(10mL)溶液中加入NH 2NH 2·H 2O(77.95mg，1.32mmol，75.68μL，85％纯度，1.2eq)。混合物在20℃下搅拌30分钟后过滤并减压浓缩，残余物用水(10mL)稀释并用DCM(20mL)萃取，合并有机层用无水硫酸铵干燥，过滤并减压浓缩得化合物1_12。LCMS(ESI)m/z:761.5(M+1)。
步骤十二：向化合物1_12(900mg，1.00mmol，1eq)的DCM(5mL)和EtOH(5mL)溶液中加入中间体A2(416.01mg，1.00mmol，1eq)，在20℃下将混合物在氮气下搅拌1小时，然后将反应混合物减压浓缩，残余物通过柱色谱法(SiO 2，DCM/MeOH＝20/1至10/1(v/v))纯化得化合物1_13。LCMS(ESI)m/z:1157.7(M+1)。
步骤十三：向化合物1_13(200mg，163.39μmol，1eq)的DMF(2mL)溶液中加入N,N'-二异丙基碳二亚胺(41.24mg，326.77μmol，2eq)和HOBt(44.15mg，326.77μmol，2eq)。混合物在20℃下搅拌1小时后加入中间体A1(48.08mg，228.74μmol，1.4eq)和NaHCO 3(54.90mg，653.55μmol，25.42μL，4eq) 并在20℃搅拌11小时。反应混合物用水(8mL)稀释，然后过滤收集固体得化合物1_14。LCMS(ESI)m/z:1350.2(M+1)。
步骤十四：在0℃下向化合物1_14(220mg，163.01μmol，1eq)的DCM(1mL)溶液中加入TFA(1.54g，13.51mmol，1mL，82.85eq)并搅拌1小时。反应液用石油醚/乙酸乙酯(10mL，4/1)稀释后过滤收集固体并通过制备HPLC(TFA，柱：Phenomenex Synergi C18 150mm×25mm×10μm；流动相：[水(0.1％TFA)-乙腈]；乙腈％：1％-30％，9分钟)纯化得化合物(I)。
1H NMR(400MHz,D 2O)δ＝7.23(d,J＝8.4Hz,1H),7.10(s,1H),6.93-6.85(m,2H),5.19(dd,J＝2.0,5.7Hz,1H),4.87-4.76(m,4H),4.64(s,1H),4.54-4.48(m,1H),4.44-4.37(m,1H),3.43(br t,J＝7.3Hz,4H),3.04-2.91(m,4H),1.98(quin,J＝7.6Hz,4H),1.41(s,3H),0.97(s,3H)ppm；LCMS(ESI)m/z:741.3(M+1)。
实验例1：式(I)化合物对小鼠肺部感染铜绿假单胞菌的实验
1.实验菌株
铜绿假单胞菌PA14。
2.受试药物
(1)测试化合物：式(I)化合物
(2)参考化合物：AiCuris专利WO2018065636参考化合物I-g，氨曲南(大连美仑生物技术有限公司产品)。
Figure PCTCN2019126261-appb-000016
3.培养基
Mueller-Hinton琼脂(MHA)和TSA培养基，均购自BD公司。
4.实验动物
CD-1(ICR)小鼠，北京维通利华实验动物技术有限公司提供，体重23～27g，7周龄，雌性，共计46只。
5.实验方法
(1)腹腔注射环磷酰胺形成免疫抑制小鼠
将46只小鼠于第1天、第4天腹腔注射环磷酰胺150mg/kg，即形成免疫抑制小鼠。
(2)实验分组
本实验设7组，分别为式(I)化合物高、中、低剂量组，化合物I-g高、中剂量组，氨曲南组和模型组，每组6只动物，另余4只动物为肺部感染2h后取肺组织计细菌数。具体的分组情况见下表。
表1小鼠肺部感染铜绿假单胞菌实验分组表
Figure PCTCN2019126261-appb-000017
(3)肺部感染铜绿假单胞菌
小鼠气道注射50μL菌液(2×10 3CFU)。感染后2小时脱颈椎处死4只模型组小鼠。
(4)给药
感染2小时后开始按组别给药，均于2h、4h、6h和8h各腹腔注射给药1次，共4次。
(5)细菌计数
感染后24小时脱颈椎处死各组小鼠，无菌操作取肺和肾组织，放入灭菌组织匀浆管中，称重，加入适量生理盐水(NS)，匀浆器匀浆1min，模型组动物肺组织稀释10 4、10 5、10 6倍，各给药组动物肺组织稀释10、100倍，模型组动物肾组织稀释10 2、10 3、10 4倍，各给药组动物肺组织稀释10倍，用螺旋涂布仪涂TSA板，37℃培养过夜，用菌落计数仪计数CFU。
(6)体重
试验开始后每天称重，记录体重变化。
(7)数据处理
采用Graphpad Prism作图软件制作肺组织CFU散点图。采用SPSS19.0软件统计CFU、体重平均值，采用方差分析分析组间差异。
6.实验结果
(1)免疫抑制小鼠肺部感染铜绿假单胞菌后的细菌荷载量
经腹腔注射2次环磷酰胺的4只免疫抑制小鼠肺部感染铜绿假单胞菌PA14约1.06×10 4CFU，2小时后取肺组织匀浆，计数细菌，计算小鼠细菌荷载量，其范围在，平均荷载量为5.10×10 3CFU。
(2)体重变化：各组动物体重见表2。
表2新单环β内酰胺抗生素体内保护试验的动物体重变化
Figure PCTCN2019126261-appb-000018
Figure PCTCN2019126261-appb-000019
(3)给药治疗后小鼠的肺组织细菌荷载量
于感染后2h、4h、6h和8h腹腔注射式(I)化合物、化合物I-g及氨曲南，24h处死动物，无菌取肺组织，用生理盐水(NS)浸泡，组织匀浆，适当稀释后取50μL均匀涂布于TSA平板上，37℃孵箱中孵育过夜，计数菌落数，按稀释比例换算成每毫升的CFU，再将荷菌量以10为底作对数值，每组比较其均数和标准差，结果见表3、图1。模型组24h荷菌量由感染量1.06×10 4CFU增长为3.34×10 8CFU(荷菌量的LOG 10为8.14)，各给药组荷菌量显著低于模型组，基本得到清除，式(I)化合物高、中、低剂量组得到完全清除。
结论：
式(I)化合物对环磷酰胺所致免疫抑制小鼠肺部感染铜绿假单胞菌具有体内疗效，能显著降低肺组织荷菌量，清除肺上感染的绿脓杆菌。其中，式(I)化合物在最低给药剂量下，能完全清除肺部感染的细菌。且给药组动物体重没有显著变化，表明式(I)化合物安全性好。
表3给药治疗免疫抑制小鼠肺部绿脓感染后的肺荷菌量
Figure PCTCN2019126261-appb-000020
注：**与模型组比，p<0.01，有非常显著性差异

Claims (10)

  1. 式(I)所示化合物或其药学上可接受的盐在制备治疗肺炎药物中的应用。
    Figure PCTCN2019126261-appb-100001
  2. 根据权利要求1所述的应用，其中，所述肺炎是由感染铜绿假单胞菌引起的。
  3. 一种药物组合物，其包含作为活性成分的治疗有效量的式(I)所示化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂和/或药学上可接受的载体。
  4. 根据权利要求3所述的组合物，其中所述赋形剂为表面稳定剂、增溶剂、缓冲剂、遮光剂、粘合剂、崩解剂或润滑剂。
  5. 根据权利要求4所述的组合物，其中所述表面稳定剂包括两性表面活性剂、非离子表面活性剂、阳离子表面活性剂或阴离子表面活性剂，或其组合。
  6. 根据权利要求3-5任意一项所述的组合物，其中所述药物组合物用于口服使用。
  7. 根据权利要求6所述的组合物，其中所述药物组合物为片剂、胶囊剂。
  8. 根据权利要求3-5任意一项所述的组合物，其中所述药物组合为注射制剂或吸入制剂的形式。
  9. 根据权利要求3-8任意一项所述的组合物在制备治疗肺炎药物中的应用。
  10. 根据权利要求9所述的应用，其中，所述肺炎是由感染铜绿假单胞菌引起的。
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