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WO2020239096A1 - 抗菌性氨基糖苷衍生物 - Google Patents

抗菌性氨基糖苷衍生物 Download PDF

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Publication number
WO2020239096A1
WO2020239096A1 PCT/CN2020/093436 CN2020093436W WO2020239096A1 WO 2020239096 A1 WO2020239096 A1 WO 2020239096A1 CN 2020093436 W CN2020093436 W CN 2020093436W WO 2020239096 A1 WO2020239096 A1 WO 2020239096A1
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Prior art keywords
compound
pharmaceutically acceptable
alkyl
isomer
acceptable salt
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PCT/CN2020/093436
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English (en)
French (fr)
Inventor
汤东东
黄志刚
李程
丁照中
陈曙辉
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南京明德新药研发有限公司
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Priority to KR1020217040773A priority Critical patent/KR102697956B1/ko
Priority to UAA202107603A priority patent/UA127070C2/uk
Priority to EA202193266A priority patent/EA202193266A1/ru
Priority to EP20815146.4A priority patent/EP3978506A4/en
Priority to US17/615,307 priority patent/US20220227802A1/en
Priority to JP2021571459A priority patent/JP7249438B2/ja
Priority to MX2021014544A priority patent/MX2021014544A/es
Priority to CN202080038437.8A priority patent/CN114026105B/zh
Priority to CA3142199A priority patent/CA3142199C/en
Priority to AU2020285280A priority patent/AU2020285280B2/en
Publication of WO2020239096A1 publication Critical patent/WO2020239096A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/224—Cyclohexane rings substituted by at least two nitrogen atoms with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicine, in particular to a new class of aminoglycoside derivatives, pharmaceutically acceptable salts or isomers thereof, and pharmaceutically acceptable compositions thereof, and their preparation for the treatment of bacterial infection-related diseases Drug application.
  • RNA has a competitive protein with a complex structure, rather than a simple sequence like DNA. Genome sequencing revealed the sequence of the protein and the mRNA encoding the protein. Since the protein is synthesized using an RNA template, the protein can be inhibited by first interfering with the translation of the mRNA to prevent the production of the protein. Since both protein and RNA are potential drug targeting sites, the number of targets revealed by genome sequencing effectively doubles.
  • Aminoglycoside drugs specifically bind to the A site of the 16S rRNA decoding region of the 30S subunit of the bacterial ribosome to cause mistranslation of mRNA, thereby interfering with protein synthesis and killing pathogenic bacteria.
  • Aminoglycoside drugs are highly effective broad-spectrum antibiotics and are the most commonly used anti-infective drugs. Most aminoglycoside drugs have expected pharmacokinetic properties and have synergistic effects with other anti-infective drugs, making them useful for the treatment of life-threatening infections. Excellent varieties. In the past few decades, many varieties of this type of antibiotics have been clinically popular.
  • aminoglycoside drugs originated from the discovery of streptomycin in 1944, and a series of landmark compounds (kanamycin, gentamicin, tobramycin) were successfully marketed afterwards, and aminoglycosides were established. The status of drugs in the treatment of gram-negative bacterial infections.
  • the semi-synthetic aminoglycoside antibiotics dibekacin, amikacin, netilmicin, isepamicin and etimicin appeared one after another, indicating that they can be successfully obtained through a semi-synthetic route Aminoglycoside antibiotics that are effective against early antibiotic-resistant bacteria and have low adverse reactions, but the pace of development of aminoglycoside antibiotics has slowed down.
  • Aminoglycoside drugs are glycosides formed by connecting amino sugars and amino cyclic alcohols through oxygen bridges. There are streptomycin from Streptomyces, natural aminoglycosides such as gentamicin from Micromonas, and semisynthetic aminoglycosides such as etimicin and amikacin, all of which are broad-spectrum Antibacterial drugs. Aminoglycoside drugs are mainly used for systemic infections caused by sensitive aerobic gram-negative bacilli.
  • cephalosporins and quinolones have been widely used in clinical practice in recent years, because aminoglycoside drugs have a longer PAE for common gram-negative bacilli such as Pseudomonas aeruginosa, pneumoniae, and E. So it is still used to treat serious infections caused by aerobic gram-negative bacteria.
  • the invention aims to solve the problems of serious resistance to inactivating enzymes and the existence of ototoxicity and nephrotoxicity of traditional antibiotics such as etimicin, amikacin, gentamicin and the like. Compared with the prior art, a simpler synthetic method is used to prepare novel aminoglycoside drugs with broader antibacterial spectrum and better activity.
  • the present invention provides a compound represented by formula (II), its pharmaceutically acceptable salt or its isomer:
  • L is -O-CH 2 -CH 2 -or -CH 2 -;
  • R 1 is H or C 1-3 alkyl
  • R 2 is H, C 1-3 alkyl or Wherein the C 1-3 alkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 or -NO 2 replace;
  • Each R is independently F, Cl, Br, I, -OH, -OCH 3 , -CN, or -NH 2 .
  • the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or isomer thereof:
  • R 1 is H or C 1-3 alkyl
  • R 2 is H, C 1-3 alkyl or Wherein the C 1-3 alkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 or -NO 2 replace;
  • Each R is independently F, Cl, Br, I, -OH, -OCH 3 , -CN, or -NH 2 .
  • the above-mentioned compound has a structure represented by formula (I-1):
  • R a , R b and R 1 are as defined in the present invention.
  • R 1 is H or -CH 3 , and other variables are as defined in the present invention.
  • R 1 is H, and other variables are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-2):
  • R a and R b are as defined in the present invention.
  • each R above is independently F or Cl, and other variables are as defined in the present invention.
  • each R above is independently F, and other variables are as defined in the present invention.
  • R a and R b are each independently H or Other variables are as defined in the present invention.
  • R 2 is H, -CH 3 , -CH 2 CH 3 or Wherein said -CH 3 and -CH 2 CH 3 are optionally selected by 1, 2 or 3 independently selected from F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 or -NO 2 substituents, R a and R b are as defined, and other variables of the present invention.
  • the above-mentioned compound is:
  • the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of the above-mentioned compound as an active ingredient, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above-mentioned compound, its pharmaceutically acceptable salt or its isomers, and the above-mentioned pharmaceutical composition in the preparation of drugs for the treatment of bacterial infection-related diseases; in some aspects of the present invention, the above-mentioned bacteria are resistant Carbapenem Enterobacteria.
  • the present invention synthesizes the compound of formula (II) and its isomers through a simpler preparation method to obtain a new class of aminoglycoside antibiotics, which are used to combat super bacteria such as CRE (Carbapenem-resistant Enterobacteria)
  • CRE Cell-resistant Enterobacteria
  • the drug-resistant bacterial infection caused by the solution solves the problems of traditional antibiotic inactivation enzyme resistance and the existence of ototoxicity and nephrotoxicity.
  • the compound of the invention has a wider antibacterial spectrum, better activity, and no cytotoxicity.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound 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 amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound 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, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, 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, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , Diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, All these mixtures fall within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • 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 you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary groups are cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium. The bond between deuterium and carbon is stronger than that of ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes the situation where the event or condition occurs and the situation where the event or condition does not occur.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that can effectively treat the target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group containing 1 to 6 carbon atoms.
  • the C 1- 6 alkyl includes C 1-5, C 1-4, C 1-3 , C 1-2, C 2-6, C 2-4, C 6 and C 5 alkyl groups like; which may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to denote a linear or branched saturated hydrocarbon group containing 1 to 3 carbon atoms.
  • the C 1- 3 alkyl includes C 1-2 alkyl and C 2-3 and the like; which may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl) and the like.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di (4'-Methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • CFU stands for the number of colonies
  • Boc stands for t-butoxycarbonyl
  • MIC stands for minimum inhibitory concentration.
  • Figure 1 shows the in vivo efficacy data of compound 1 (dose 30mpk) and Plazomicin (dose 30mpk) in a mouse thigh muscle model (Enterobacterium ATCC-25922);
  • Figure 2 shows the in vivo efficacy of compound 1 (dose 10mpk and 30mpk), Plazomicin (dose 10mpk and 30mpk), and meropenem (dose 100mpk) in a mouse pneumonia model (Klebsiella pneumonia ATCC-BAA-1705) data;
  • Figure 3 shows the change of the compound action potential amplitude: at a fixed frequency of 32kHz, the CAP amplitude of compound 1, gentamicin and Plazomicin changes at different intensities;
  • Figure 4 shows the changes in the amplitude of the compound action potential: at a fixed frequency of 16kHz, the changes in the CAP amplitude of compound 1, gentamicin and Plazomicin at different intensities;
  • Figure 5 shows the change in the amplitude of the compound action potential: the change in the CAP amplitude of compound 1, gentamicin and Plazomicin at different intensities during a short sound (Click);
  • Figure 6 shows the damage of cochlear hair cells: A is the damage of compound 1, gentamicin and Plazomicin to inner hair cells; B is the damage of compound 1, gentamicin and Plazomicin to outer hair cells;
  • Figure 7 shows the changes in spiral ganglion cell density caused by compound 1, gentamicin and Plazomicin;
  • Figure 8 shows the toxicity regression curve of Plazomicin on HK-2 cells
  • Figure 9 shows the toxicity regression curve of compound 1 on HK-2 cells
  • Figure 10 shows the toxicity regression curve of netilmicin on HK-2 cells
  • Figure 11 shows the toxicity regression curve of amikacin on HK-2 cells.
  • step 1
  • Dissolve compound 1-6 (15g, 33.52mmol, 1eq) in methanol (150mL), then add S-ethyl 2,2,2-trifluoroethyl thioester (4.24g, 26.82mmol, 0.8eq) in methanol (150mL) solution was added dropwise to the above methanol solution, the mixture was stirred at 20 °C for 16 hours, then zinc acetate (14.72g, 80.44mmol, 2.4eq) was added to the solution, and then (N-hydroxy- 5-Norbornene-2,3-Diformimido)-tert-butyl ester (16.85g, 60.33mmol, 1.8eq) and triethylamine (10.17g, 100.55mmol, 14.00mL, 3eq) in tetrahydrofuran (170mL ) The solution was added dropwise to the mixed solution, and the reaction solution was stirred at 20°C for 30 hours.
  • Dissolve compound 1-8 (16.40g, 17.35mmol, 1eq), di-tert-butyl dicarbonate (4.55g, 20.83mmol, 4.78mL, 1.2eq), DIEA (2.69g, 20.83mmol, 3.6mL, 1.2eq)
  • the reaction solution was stirred at 20°C for 16 hours.
  • the reaction solution was diluted with water (200mL), and then extracted with dichloromethane (100mL ⁇ 2) respectively.
  • the combined organic phase was washed with 0.1M hydrochloric acid (20mL) and saturated brine (60mL) successively, and dried with anhydrous sodium sulfate.
  • step 1
  • step 1
  • E.coli ATCC 25922, E.coli ATCC BAA-2523, K.pneumonia ATCC BAA-1705 were used to pass the micro-liquid dilution method according to the requirements of the Institute of Clinical and Laboratory Standard (CLSI) Determine the minimum inhibitory concentration ( M inimum I nhibitory C oncentration, MIC) of each compound.
  • CLSI Institute of Clinical and Laboratory Standard
  • M inimum I nhibitory C oncentration, MIC Minimum inhibitory concentration
  • BD BBL TM pick fresh bacterial single clones, suspended in sterile normal saline, adjust the concentration to 1 ⁇ 10 8 CFU/mL, and then use cation-adjusted Sinton Miller medium Cation-Adjusted Mueller Hinton II Broth (MHB, Catalog#212332, BD BBL TM ) was diluted to 5 ⁇ 10 5 CFU/mL, and 100 ⁇ L was added to the round bottom 96-well plate containing the drug. After incubating the plate at 37°C for 20-24 hours, read the MIC value, and set the lowest drug concentration that inhibits bacterial growth as the MIC. The results are shown in Table 1.
  • the compound of the present invention has good antibacterial activity in vitro.
  • the compound of the present invention has good pharmacokinetic properties in rats.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • the animals in the intravenous group were given a single injection of the corresponding compound through the tail vein, and the administration volume was 5 mL/kg; the animals were weighed before the administration, and the administration volume was calculated based on the body weight.
  • the sample collection time is: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24h.
  • Approximately 30 ⁇ L of whole blood was collected through the saphenous vein at each time point to prepare plasma for high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for concentration determination. All animals were euthanized by CO 2 anesthesia after collecting PK samples at the last time point.
  • the compound of the present invention has good pharmacokinetic properties in mice.
  • mice mouse thigh muscle model
  • mice in 48 cages were intraperitoneally injected again with the immunosuppressant cyclophosphamide (100mpk); the MHA plate resuscitated the strain E.coli ATCC-25922 (Enterobacterium ATCC-25922). Pick the recovered colonies and dissolve them in physiological saline to prepare E. coli ATCC-25922 bacterial solution with a concentration of 1.00E+07CFU/mL for use in mouse thigh muscle infection.
  • the amount of bacterial solution injected into the thigh muscle of experimental mice is 100 ⁇ L/mouse, that is, the inoculation amount is 1.00E+06CFU/mouse. 2h after infection, the mice in the control group took the thigh muscle tissue and placed it in 10 mL of normal saline, homogenized the thigh muscle tissue, and plated it with gradient dilution;
  • mice The specific administration of mice is as follows:
  • CD-1 female mice Twenty-one CD-1 female mice were divided into 7 cages, 3 in each cage; the immunosuppressive cyclophosphamide (150mpk) was injected intraperitoneally on the 4th day.
  • mice in 7 cages were injected intraperitoneally again with the immunosuppressant cyclophosphamide (100mpk); MHA plate resuscitation strain Kpn ATCC-BAA-1705 (Klebsiella pneumonia ATCC-BAA-1705). Pick the resuscitated colonies and dissolve them in physiological saline to prepare Kpn ATCC-BAA-1705 bacterial solution with a concentration of 4.00E+08CFU/mL for lung infection in mice.
  • the amount of bacterial infection in the lungs of the experimental mice was 50 ⁇ L/mouse, that is, the inoculation amount was 2.00E+07CFU/mouse.
  • the lung tissues of the mice in the control group were placed in 5mL saline, the lung tissues were homogenized, and the lung tissues were homogenized.
  • mice The specific administration of mice is as follows:
  • CAP animal compound action potential
  • the cochlea of the animals was taken out for fixation and staining.
  • One cochlea was laid on a basement membrane to count the loss of hair cells to make a cochlea map, and the other cochlea was decalcified and frozen sectioned. And count the density of spiral ganglion, compare between groups.
  • Gentamicin was purchased from Dalian Meilun Biotechnology Co., Ltd., and Plazomicin and compound 1 were provided by Wuhan WuXi Kangde New Drug Development Co., Ltd. Each time it is used, it is dissolved in normal saline, the concentration is 50mg/mL, and the injection dose is 100mg/kg body weight. Method: subcutaneous injection, after each injection, confirm that there is no liquid leakage.
  • CAP Compound Action Potential
  • the functional changes of different frequencies correspond to the different structural and functional changes of the cochlea from top to bottom gyrus.
  • the length of the incubation period is also related to the function of hair cells and auditory nerve response.
  • the increase of the threshold when the cochlea is injured will inevitably lead to the prolongation of the incubation period.
  • the prolongation of the incubation period when the threshold does not change significantly also reflects the discharge of the auditory nerve
  • the synchronicity is reduced, in other words, the incubation period is extended and the response function is reduced.
  • the ototoxicity of aminoglycoside antibiotics was mainly concentrated in the high-frequency area.
  • the gentamicin group was consistent with previous results, as summarized below.
  • Compound 1 only caused a decrease in the high frequency (32kHz) CAP amplitude of the experimental group, suggesting hearing damage in the high frequency area, but its amplitude was still higher than that of the gentamicin and Plazomicin groups; while the Plazomicin group had a larger damage range, 16kHz and 32kHz There are damages, and the 32kHz damage is greater than compound 1, but significantly lower than the gentamicin group; the damage of gentamicin to the experimental group is concentrated in the high frequency (32kHz) area, but its 32kHz threshold shift is obvious, and the damage is more than the other two Group drugs are larger (see Figures 3 to 5).
  • the CAP amplitude results proved that the hearing damage of compound 1 to experimental animals was significantly less than that of gentamicin and Plazomicin.
  • the compound group only had a slight loss of outer hair cells in the top gyrus, and the rest had its bottom gyrus and inner hair cells were preserved intact. Its hair cell toxicity was significantly lower than that of the gentamicin group and the Plazomicin group.
  • compound 1 was administered subcutaneously in animals (guinea pigs) for 14 consecutive days, and the ototoxicity was less than that in the Plazomicin and gentamicin groups after another 14 days. Based on the results of this study, it is confirmed that the auditory toxicity of compound 1 obtained by the present invention is better than that of Plazomicin and gentamicin.
  • test compound 50mg/mL
  • positive control 75 microliters of test compound (50mg/mL) and positive control to the second column of the 96-v well plate;

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Abstract

一类新的抗菌性氨基糖苷衍生物，和包含此类化合物的药物组合物，以及它们在制备治疗细菌感染相关疾病的药物中的应用。具体公开了式(II)所示化合物、其药学上可接受的盐及其异构体。

Description

抗菌性氨基糖苷衍生物
本申请主张如下优先权：
申请号：CN201910463155.1，申请日：2019年05月30日；
申请号：CN202010299506.2，申请日：2020年04月16日。
技术领域
本发明涉及药物领域，具体涉及一类新的氨基糖苷衍生物、其药学上可接受的盐或其异构体，及其药学上可接受的组合物，以及它们在制备治疗细菌感染相关病症的药物上的应用。
背景技术
在现代药物发现中，特别受到关注的是，开发通过结合RNA起作用的新颖小分子口服生物可利用药物。RNA作为DNA与蛋白质之间的信使，曾被认为是不具备显著结构的复杂性的完全柔性分子。近来的研究已显示，RNA的结构出人意料的复杂。RNA具有结构复杂的竞争性蛋白质，而不是像DNA一样的简单序列。基因组测序揭示出所述蛋白质与编码所述蛋白质的mRNA的序列。由于蛋白质是使用RNA模板合成，故可通过首先干扰mRNA的翻译以阻止所述蛋白质的产生，来抑制所述蛋白质。由于蛋白质和RNA都为潜在的药物靶向位点，故通过基因组测序揭示出的标靶的数目有效的翻倍。这些观察为制药工业开启了使用小分子靶向RNA的新篇章。
现代生物化学与分子生物学研究表明细菌核糖体30S亚基与tRNA的结合是蛋白质合成的关键步骤之一。至今，已有至少两种细菌(Thermus thermophiles和Escherichia coli)的核糖体30S亚基的晶体结构被成功报道，从其晶体结构中能清楚的分辨出与tRNA结合的3个位点：氨酰基位点A(Aminoacyl)，肽酰基位点P(Peptite)，E(Exit)位点。氨基糖苷类药物正是通过与细菌核糖体30S亚基的16S rRNA解码区A位点特异性结合来引起mRNA发生错译，从而干扰蛋白质的合成杀死病原菌。氨基糖苷类药物是高效广谱抗生素，是最常用的抗感染药物，大部分氨基糖苷类药物具有预期的药物动力学特性，而且与其他抗感染药物具有协同作用，使其成为治疗危及生命感染的优良品种，在过去几十年中，这一类抗生素中的许多品种在临床是深受欢迎。
氨基糖苷类药物的历史起源于1944年链霉素的发现，其后又成功上市了一系列具有里程碑意义的化合物(卡那霉素，庆大霉素，妥布霉素)，确立了氨基糖苷类药物在治疗革兰氏阴性菌感染中的地位。20世纪70-90年代，半合成氨基糖苷类抗生素地贝卡星，阿米卡星，奈替米星，异帕米星及依替米星相继出现，表明通过半合成的途径可成功的获得对早期抗生素耐药的细菌有效且不良反应较低的氨基糖苷类抗生素，但氨基糖苷类抗生素发展的步伐慢了下来。与此同时，人们对氨基糖苷类药物进行了广泛的基础与临床研究，特别是对其杀菌机制和耐药机制的研究，不仅使我们对该类抗生素有了更深入的了解，而且这些研究结果，为我们临床合理用药，减少耐药菌，设计新的抗耐药菌的氨基糖苷类药物提供了理论基础。
氨基糖苷类药物是由氨基糖与氨基环醇通过氧桥连接而成苷类。有来自链霉菌的链霉素等，来自小单胞菌的庆大霉素等天然氨基糖苷类药物，还有依替米星，阿米卡星等半合成氨基糖苷类药物，均属广谱抗菌药。氨基糖苷类药物主要用于敏感的需氧革兰氏阴性杆菌所致的全身感染。虽然近年来有多种头孢菌素和喹诺酮类药物在临床的广泛应用，但由于氨基糖苷类药物对铜绿假单胞菌，肺炎杆菌，大肠杆菌等常见 的革兰氏阴性杆菌的PAE较长，所以仍然被用于治疗需氧革兰氏阴性菌所致的严重感染。
随着氨基糖苷类药物在临床上长期而大量的使用，该类药物不可避免地出现了严重的耐药性问题，同时氨基糖苷类药物普遍存在的耳毒性和肾毒性等副作用也限制了氨基糖苷类药物的使用。近些年来的，出现了一些能解决传统抗生素耐药问题的药物分子，如Achaogen公司最新开发的Plazomicin(WO2009067692)，已完成临床三期研究。
本发明旨在解决传统抗生素如依替米星、阿米卡星、庆大霉素等对于钝化酶耐药严重以及存在耳毒性与肾毒性的问题。通过相对于现有技术更简单的合成方法制备得到抗菌谱更广，活性更好的新型氨基糖苷类药物。
发明内容
本发明提供了式(II)所示化合物、其药学上可接受的盐或其异构体：
Figure PCTCN2020093436-appb-000001
其中，
R'为
Figure PCTCN2020093436-appb-000002
L为-O-CH 2-CH 2-或-CH 2-；
R 1为H或C 1-3烷基；
R 2为H、C 1-3烷基或
Figure PCTCN2020093436-appb-000003
其中所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2或-NO 2的取代基所取代；
R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-C 1-3烷基或C 1-3烷基，其中所述-C(＝O)-C 1-3烷基和C 1-3烷基任选被1、2或3个R所取代；
各R独立地为F、Cl、Br、I、-OH、-OCH 3、-CN或-NH 2。
本发明提供了式(I)所示化合物、其药学上可接受的盐或其异构体：
Figure PCTCN2020093436-appb-000004
其中，R 1为H或C 1-3烷基；
R 2为H、C 1-3烷基或
Figure PCTCN2020093436-appb-000005
其中所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2或-NO 2的取代基所取代；
R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-C 1-3烷基或C 1-3烷基，其中所述-C(＝O)-C 1-3烷基和C 1-3烷基任选被1、2或3个R所取代；
各R独立地为F、Cl、Br、I、-OH、-OCH 3、-CN或-NH 2。
在本发明的一些方案中，上述化合物具有式(I-1)所示结构：
Figure PCTCN2020093436-appb-000006
其中，R a、R b和R 1如本发明所定义。
在本发明的一些方案中，上述R 1为H或-CH 3，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1为H，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-2)所示结构：
Figure PCTCN2020093436-appb-000007
其中，R a和R b如本发明所定义。
在本发明的一些方案中，上述各R独立地为F或Cl，其他变量如本发明所定义。
在本发明的一些方案中，上述各R独立地为F，其他变量如本发明所定义。
在本发明的一些方案中，上述R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-CH 3、-CH 3或-CH 2CH 3，其中所述-C(＝O)-CH 3、-CH 3和-CH 2CH 3任选被1、2或3个R所取代，R及其他变量如本发明所定义。
在本发明的一些方案中，上述R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-CH 3、-CH 3、-CH(R) 2、-CH 2CH 3或-CH 2CH(R) 2，R及其他变量如本发明所定义。
在本发明的一些方案中，上述R a和R b各自独立地为H或
Figure PCTCN2020093436-appb-000008
其他变量如本发明所定义。
在本发明的一些方案中，上述R 2为H、-CH 3、-CH 2CH 3或
Figure PCTCN2020093436-appb-000009
其中所述-CH 3和-CH 2CH 3任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2或-NO 2的取代基所取代，R a和R b 及其他变量如本发明所定义。
在本发明的一些方案中，上述R 2为
Figure PCTCN2020093436-appb-000010
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2020093436-appb-000011
为
Figure PCTCN2020093436-appb-000012
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2020093436-appb-000013
为
Figure PCTCN2020093436-appb-000014
其他变量如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
在本发明的一些方案中，上述化合物为：
Figure PCTCN2020093436-appb-000015
本发明还提供了一种药物组合物，其包括作为活性成分的治疗有效量的上述化合物、其药学上可接受的盐或其异构体以及药学上可接受的载体。
本发明还提供了上述化合物、其药学上可接受的盐或其异构体以及上述药物组合物在制备治疗细菌感染相关病症的药物上的应用；在本发明的一些方案中，上述细菌为耐碳青霉烯类肠科杆菌。
技术效果
本发明通过更简单的制备方法合成了式(II)化合物及其异构体，获得一类新的氨基糖苷类抗生素，用于对抗由CRE(耐碳青霉烯类肠科杆菌)等超级细菌引起的耐药性细菌感染，解决了传统抗生素钝化酶耐药以及存在耳毒性与肾毒性的问题。同时，本发明化合物的抗菌谱更广，活性更好，且无细胞毒性。
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、有机胺或镁盐或类似的盐。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。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。
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。
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，包括互变异构体、顺式和反式异构体、(-)-和(+)-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。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020093436-appb-000016
和楔形虚线键
Figure PCTCN2020093436-appb-000017
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020093436-appb-000018
和直形虚线键
Figure PCTCN2020093436-appb-000019
表示立体中心的相对构型，用波浪线
Figure PCTCN2020093436-appb-000020
表示楔形实线键
Figure PCTCN2020093436-appb-000021
或楔形虚线键
Figure PCTCN2020093436-appb-000022
或用波浪线
Figure PCTCN2020093436-appb-000023
表示直形实线键
Figure PCTCN2020093436-appb-000024
和直形虚线键
Figure PCTCN2020093436-appb-000025
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
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)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。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。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
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。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原 子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2020093436-appb-000026
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2020093436-appb-000027
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2020093436-appb-000028
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的包含1至6个碳原子的饱和碳氢基团。所述C 1- 6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的包含1至3个碳原子的饱和碳氢基团。所述C 1- 3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二(4'-甲氧基苯基)甲 基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
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：CFU代表菌落数；Boc代表叔丁氧羰基；MIC代表最小抑菌浓度。
附图说明
图1显示的为化合物1(剂量30mpk)和Plazomicin(剂量30mpk)在小鼠大腿肌肉模型(肠科杆菌ATCC-25922)中的体内药效数据；
图2显示的为化合物1(剂量10mpk和30mpk)、Plazomicin(剂量10mpk和30mpk)以及美罗培南(剂量100mpk)在小鼠肺炎模型(肺炎克雷伯菌ATCC-BAA-1705)中的体内药效数据；
图3为复合动作电位振幅改变：在固定频率32kHz时，化合物1、庆大霉素和Plazomicin的CAP幅值在不同强度的变化；
图4为复合动作电位振幅改变：在固定频率16kHz时，化合物1、庆大霉素和Plazomicin的CAP幅值在不同强度的变化；
图5为复合动作电位振幅改变：在短声(Click)时，化合物1、庆大霉素和Plazomicin的CAP幅值在不同强度的变化；
图6为耳蜗毛细胞损伤情况：A为化合物1、庆大霉素和Plazomicin对内毛细胞损伤情况；B为化合物1、庆大霉素和Plazomicin对外毛细胞损伤情况；
图7为化合物1、庆大霉素和Plazomicin导致螺旋神经节细胞密度的改变；
图8为Plazomicin对于HK-2细胞的毒性回归曲线；
图9为化合物1对于HK-2细胞的毒性回归曲线；
图10为奈替米星对于HK-2细胞的毒性回归曲线；
图11为阿米卡星对于HK-2细胞的毒性回归曲线。
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。
实施例1：化合物1
Figure PCTCN2020093436-appb-000029
步骤1：
将二苯基膦酰羟胺(10g,42.88mmol,1eq)和化合物1-1(13.65g,128.64mmol,12.19mL,3eq)与叔丁醇钠(4.95g,51.46mmol,1.2eq)溶解在四氢呋喃(100mL)中,在5-15℃条件下搅拌反应16小时。将反应液过滤，滤液浓缩得到化合物1-2。
步骤2：
将上一步得到的化合物1-2(5.19g,42.84mmol,1eq)的四氢呋喃(100mL)溶液与N,N-二-BOC-1H-吡唑-1-甲脒(13.30g,42.84mmol,1eq)在66℃下搅拌反应16小时。反应液冷却至室温,向反应液中加入水(300mL)并用乙酸乙酯(100mL×2)萃取。合并有机相并用硫酸钠干燥过滤,滤液浓缩得到粗品,并通过柱层析(二氧化硅，石油醚/乙酸乙酯＝20/1,1/1(v/v))得到化合物1-3。
步骤3：
将化合物1-3(1g,2.75mmol,1eq)与2-碘酰基苯甲酸(847.59mg,3.03mmol,1.1eq)溶解在二甲基亚砜(10mL)中,反应液在40℃下搅拌反应1小时。将反应液过滤,滤液加水(40mL)并用叔丁基甲基醚(20mL×2次)萃取。合并有机相用饱和硫代硫酸钠(10mL)洗涤,有机相用无水硫酸钠干燥,过滤浓缩得到化合物1-4。
步骤4：
把安伯来特(离子交换树脂)IRA-402(OH)(500g)加入到甲醇(500mL)中，将此溶液于20℃下搅拌1个小时，然后把混合物过滤，把滤饼加入到甲醇(500mL)中，再把化合物1-5入到此混合液中，混合物于20℃下搅拌11个小时，反应过程中，化合物1-5溶解。将反应液过滤，把滤液浓缩即得到化合物1-6。LCMS(ESI)m/z:448.4(M+1)。
步骤5：
把化合物1-6(15g,33.52mmol,1eq)溶解到甲醇中(150mL)，再把S-乙基2,2,2-三氟乙硫酯(4.24g,26.82mmol,0.8eq)的甲醇(150mL)溶液逐滴加到上述甲醇溶液中，将混合液于20℃下搅拌16小时，然后把醋酸锌(14.72g,80.44mmol,2.4eq)加入到溶液中，再把(N-羟基-5-降冰片烯-2,3-二甲酰亚氨基)-叔丁酯(16.85g,60.33mmol,1.8eq)和三乙胺(10.17g,100.55mmol,14.00mL,3eq)的四氢呋喃(170mL)溶液逐滴加入到混合液中，将反应液于20℃下搅拌30小时。把反应液用甘氨酸(7g)淬灭，然后浓缩，再用二氯甲烷(1000mL)稀释浓缩液，再分别用(300mL)(水：氨水＝7:3)洗涤两次，将有机相浓缩。粗品用柱层析法(二氧化硅，二氯甲烷/甲醇＝50/1～5/1(v/v)，含少量氨水)纯化得到化合物1-7。LCMS(ESI)m/z:744.3(M+1)。
步骤6：
把(2S)-4-(叔丁基氧羰基氨基)-2-羟基-丁酸(6.85g,31.26mmol,1.5eq)溶解到N,N-二甲基甲酰胺(150mL)里，向溶液中加入N-羟基-5-降冰片稀-2,3-二酰亚胺(5.60g,31.26mmol,1.5eq)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(4.85g,31.26mmol,5.53mL,1.5eq)，将反应液于20℃下搅拌2小时，再把化合物1-7(15.5g,20.84mmol,1eq)加入到反应液里，将反应液于20℃下搅拌16小时，然后用水(200mL)稀释，再分别用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水(100mL)洗涤，再用无水硫酸钠干燥，过滤，把滤液浓缩得到混合物。将混合物用柱层析(二氧化硅，二氯甲烷/甲醇＝50/1～10/1(v/v))纯化得到化合物1-8。LCMS(ESI)m/z:945.5(M+1)。
步骤7：
把化合物1-8(16.40g,17.35mmol,1eq)，二碳酸二叔丁酯(4.55g,20.83mmol,4.78mL,1.2eq)，DIEA(2.69g,20.83mmol,3.6mL,1.2eq)溶解到四氢呋喃(170mL)里，氮气置换三次后，将反应液于20℃下搅拌16小时。将反应液加水(200mL)稀释，然后分别用二氯甲烷(100mL×2)萃取，合并的有机相依次用0.1M盐酸(20mL)和饱和食盐水(60mL)洗涤，用无水硫酸钠干燥，过滤，把滤液浓缩，得到固体混合物，将混合物用柱层析进行纯化(二氧化硅，石油醚/乙酸乙酯＝15/1～0/1(v/v))得到目标化合物1-9。LCMS(ESI)m/z:1045.3(M+1)。
步骤8：
把化合物1-9(15.00g,14.35mmol,1eq)和氨水(63.70g,1.82mol,70mL,126.62eq)溶解到甲醇(80mL)里，将混合液于20℃下搅拌16小时。将反应液浓缩以除去溶剂，加入水(100mL)稀释，再用二氯甲烷(100mL×3次)萃取，合并的有机相用饱和食盐水(200mL)洗涤,再用无水硫酸钠干燥，过滤，将滤液浓缩。将浓缩后的混合物用柱层析纯化(二氧化硅，先用石油醚/乙酸乙酯＝10/1～0/1(v/v)后续用二氯甲烷/甲醇＝6/1(v/v)，洗脱剂中含少量氨水)得到化合物1-10。LCMS(ESI)m/z:949.3(M+1)。
步骤9：
将化合物1-4(50.63mg,0.15mmol)和化合物1-10(145.00mg,0.15mmol)溶解在甲醇(5.00mL)中，加入4A分子筛(0.5g)，氮气氛围于18℃搅拌0.5小时，然后加入氰基硼氢化钠(19.20mg,0.30mmol)搅拌1小时，LCMS检测反应完全，过滤浓缩，用制备型-HPLC:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:60％-90％,10min分离得到化合物1-11。LCMS(ESI)m/z:1294.7(M+1)。
步骤10：
将化合物1-11(91.00mg,71.97μmol)溶解在无水二氯甲烷(2.00mL)中，氮气氛围保护下冷却到0℃加入三氟乙酸(1.54g,13.51mmol)，并于0-19℃搅拌9小时，常温浓缩，用乙腈/甲基叔丁基醚(4mL,1/3)打浆，过滤并浓缩得到化合物1。
1H NMR(400MHz,D 2O)δ(ppm):5.62(s,1H),5.24(s,1H),5.08(s,1H),4.09-4.06(m,1H),3.98-3.96(m,2H),3.94-3.93(m,5H),3.77-3.73(m,4H),3.24(s,1H),3.22-3.10(m,6H),2.83(s,3H),2.61-2.14(m,2H),2.04-2.14(m,6H),1.26(s,3H)；LCMS(ESI)m/z:664.5(M+1)。
实施例2：化合物2
Figure PCTCN2020093436-appb-000030
步骤1：
将化合物2-1(1g,12.19mmol,71.94μL,1.2eq)，N,N-二-BOC-1H-吡唑-1-甲脒(3.15g,10.16mmol,1eq)和三苯基膦(3.20g,12.19mmol,1.2eq)溶解在四氢呋喃(40mL)中，在0℃下滴加DIAD(2.46g,12.19mmol,2.37mL,1.2eq)，然后升温到20℃搅拌12小时。在反应液中加入水(100mL)后用乙酸乙酯(50mL,3次)萃 取，合并后的有机相经水(30mL,3次)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，粗品经色谱层析柱纯化(二氧化硅，石油醚/乙酸乙酯＝50/1到20/1(v/v))得到化合物2-2。
步骤2：
将化合物1-2(2.1g,17.34mmol,1eq)溶解在四氢呋喃(50mL)中，在20℃加入化合物2-2(3.25g,8.67mmol,0.5eq)，反应液在67℃下搅拌12小时。在反应液中加入水(100mL)，用乙酸乙酯(50mL×3)萃取，合并后的有机相经水(30mL,3次)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，粗品经色谱层析柱纯化(二氧化硅，石油醚/乙酸乙酯＝10/1到1/1(v/v))得到化合物2-3。
步骤3：
将化合物2-3(150mg,350.93μmol,1eq)溶解在二甲基亚砜(3mL)中，在40℃下加入2-碘酰基苯甲酸(108.09mg,386.02μmol,1.1eq)，反应液在40℃下搅拌2小时。在反应液中加入饱和碳酸氢钠/硫代硫酸钠(30mL,(v/v))，用乙酸乙酯(20mL×2)萃取，合并后的有机相经饱和碳酸氢钠/硫代硫酸钠(10mL×3次(1/1,v/v))，无水硫酸钠干燥，过滤浓缩得到化合物2-4。
步骤4：
将化合物1-10(239.32mg,252.16μmol,1eq)溶解在1,2-二氯乙烷(2mL)中，在20℃下加入化合物2-5(118mg,277.37μmol,1.1eq)和4A分子筛(300mg)搅拌1小时后加入醋酸硼氢化钠(64.13mg,302.59μmol,1.2eq)，反应液在20℃下搅拌12小时。反应液加水(20mL)，用二氯甲烷(20mL×3)萃取，合并后的有机相经水(10mL×3)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，经过制备HPLC(柱子:Phenomenex Synergi C18150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:35％-56％,7min)纯化得到化合物2-6。LCMS(ESI)m/z:1358.7(M+1)。
步骤5：
将化合物2-8(40mg,29.44μmol,1eq)溶解在二氯甲烷(1mL)中，在0℃下加入三氟乙酸(1.54g,13.51mmol,1mL,458.70eq)后升温到20℃搅拌2小时。反应液冷却到0℃加入甲基叔丁基醚(15mL)，过滤，用甲基叔丁基醚(2mL×3)洗涤后油泵40℃干燥得到化合物2。
1H NMR(400MHz,D 2O)δ＝6.18-5.87(m,1H),5.63(s,1H),5.28-5.22(m,1H),5.08(d,J＝3.8Hz,1H),4.23-4.16(m,1H),4.09-4.03(m,3H),3.98-3.89(m,2H),3.83(br t,J＝5.2Hz,1H),3.79-3.68(m,8H),3.46-3.38(m,1H),3.33(br d,J＝13.0Hz,1H),3.26-3.22(m,2H),3.16-3.07(m,2H),2.83(s,3H),2.69-2.55(m,1H),2.42-2.28(m,1H),2.19-2.06(m,2H),1.95-1.85(m,1H),1.83-1.71(m,1H),1.29-1.23(m,3H)。LCMS(ESI)m/z:758.3(M+1)。
实施例3：化合物3
Figure PCTCN2020093436-appb-000031
Figure PCTCN2020093436-appb-000032
步骤1：
将化合物3-1(16.00g，115.12mmol)溶解在乙腈中(200.00mL)，并依次向其中加入N-BOC-羟胺(15.33g,115.12mmol)和DBU(19.28g,126.63mmol)，将此混合物在11℃-25℃反应16小时，然后浓缩，残留物用乙酸乙酯(350mL)稀释，用水(100mL×3)洗涤，用饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥并浓缩，剩余物用柱层析(填充物硅胶粉，淋洗剂乙酸乙酯/石油醚＝0-1/1(v/v))分离得产物3-2。
步骤2：
将化合物3-2(1.00g，5.23mmol)和氯化氢的二氧六环溶液(10mL,4mmol)混合在一起并在20℃搅拌16小时，然后减压浓缩得化合物3-3。
步骤3：
将化合物3-3(581.27mg,6.38mmol)和双Boc吡唑胍(1.80g，5.8mmol)溶解在四氢呋喃(20mL)并加入三乙胺(1mL)，将溶液于80℃搅拌16小时，LCMS检测反应，将此混合物倒入水(100mL)中，用乙酸乙酯稀释(100mL×3)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥并浓缩，剩余物用柱层析(填充物硅胶粉，淋洗剂乙酸乙酯/石油醚＝50/1-20/1(v/v))分离得到化合物3-4。
步骤4：
将化合物3-4(0.40g,1.50mmol)溶解在二甲基亚砜(5.00mL)中，加入2-碘酰基苯甲酸(0.34g,1.2mmol)，氮气氛围于40℃搅拌3小时，用乙酸乙酯(100mL)稀释，水(50mL×2)和饱和食盐水(50mL)洗涤并浓缩，剩余物用柱层析(填充物硅胶粉，淋洗剂乙酸乙酯/石油醚＝0-1/1)分离得到化合物3-5。
步骤5：
将化合物3-5(50.63mg,0.15mmol)和化合物1-10(145.00mg,0.15mmol)溶解在甲醇(5.00mL)中， 加入4A分子筛(0.5g)，氮气氛围于18℃搅拌0.5小时，然后加入氰基硼氢化钠(19.20mg,0.30mmol)搅拌1小时，LCMS检测反应完全，过滤浓缩，用制备型-HPLC:Phenomenex Synergi C18 150×25×10μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:60％-90％,10min分离得到化合物3-7。
步骤6：
将化合物3-7(91.00mg,71.97μmol)溶解在无水二氯甲烷(2.00mL)中，氮气氛围保护下冷却到0℃加入三氟乙酸(1.54g,13.51mmol)，并于0-19℃搅拌9小时，常温浓缩，剩余物用乙腈/甲基叔丁基醚(4mL,1/3)洗涤得到化合物3。
1H NMR(400MHz,D 2O)δ(ppm):5.62(s,1H),5.24(s,1H),5.08(s,1H),4.09-4.06(m,1H),3.98-3.96(m,2H),3.94-3.93(m,5H),3.77-3.73(m,4H),3.24(s,1H),3.22-3.10(m,6H),2.83(s,3H),2.61-2.14(m,2H),2.04-2.14(m,6H),1.26(s,3H)；LCMS(ESI)m/z:664.5(M+1)。
生物活性测试
实验例1：化合物抑菌作用检测(MIC)
用3株肠科杆菌E.coli ATCC 25922，E.coli ATCC BAA-2523，K.pneumonia ATCC BAA-1705按照临床和实验室标准协会(Institute of clinical and laboratory standard,CLSI)要求通过微量液体稀释法测定各化合物的最低抑菌浓度( Minimum  Inhibitory  Concentration，MIC)。在圆底96-孔板(Catalog#3788，Corning)中加入2倍系列梯度稀释化合物(终浓度范围0.125μg/mL-128μg/mL)，从过夜辛顿米勒琼脂培养基Mueller Hinton II Agar(MHA,Cat.No.211438，BD BBL TM)平板上挑取新鲜细菌单克隆，悬浮于灭菌生理盐水，调节浓度为1×10 8CFU/mL，再用阳离子调节的辛顿米勒培养基Cation-Adjusted Mueller Hinton II Broth(MHB,Catalog#212332，BD BBL TM)稀释到5×10 5CFU/mL，取100μL加入到含有药物的圆底96-孔板。平板倒置于37℃培养20-24h后读取MIC值，将抑制细菌生长的最低药物浓度定为MIC。结果见表1。
表1本发明化合物的抑菌作用检测(MIC)数据
Figure PCTCN2020093436-appb-000033
结论：本发明化合物具有良好的体外抑菌活性。
实验例2：大鼠体内药代动力学评价
实验目的：
检测本发明化合物在大鼠体内的药代动力学参数
实验方案：
1)实验药品：化合物1；
2)实验动物：3只7-9周龄的雄性SD大鼠；
3)药物配制：称取适量药物，溶于生理盐水中，配置成60mg/mL的溶液；
实验操作：
动物通过尾静脉单次静脉滴注30min给予剂量为150mg/kg、浓度为60mg/mL的药物。动物于给药后0、0.0333、0.0833、0.25、0.5、1、2、4、6、8和24小时采集血浆样品。使用LC-MS/MS方法测定血浆样品中的药物浓度，得出测试药物的动力学参数见表2：
表2本发明化合物在大鼠体内的药代动力学评价结果
Figure PCTCN2020093436-appb-000034
结论：本发明化合物在大鼠体内具有良好的药代动力学性质。
实验例3：小鼠体内药代动力学研究
实验目的：
本实验目的是评价化合物单次静脉注射和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度。
实验操作：
选取7至10周龄的CD-1雄性小鼠，静脉给药的剂量1毫克每公斤。小鼠在给药前禁食至少12小时，给药4小时后恢复供食，整个试验期间自由饮水。
实验当天静脉组动物通过尾静脉单次注射给予相应化合物，给药体积为5mL/kg；在给药前称量动物体重，根据体重计算给药体积。样品采集时间为：0.083，0.25，0.5，1，2，4，8，24h。每个时间点通过隐静脉采集大约30μL全血用于制备血浆供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。所有动物在采集完最后一个时间点的PK样品后进行CO 2麻醉安乐死。采用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。实验结果：小鼠PK性质评价结果见表3。
表3本发明化合物在小鼠体内的药代动力学性质评价结果
Figure PCTCN2020093436-appb-000035
结论：本发明化合物在小鼠体内具有良好的药代动力学性质。
实验例4：小鼠体内药效实验评估(小鼠大腿肌肉模型)
12只CD-1雌鼠分成4笼，每笼3只；腹腔注射免疫抑制剂环磷酰胺(150mpk)。
24小时后，48笼小鼠再次腹腔注射免疫抑制剂环磷酰胺(100mpk)；MHA平板复苏菌株E.coli ATCC-25922(肠科杆菌ATCC-25922)。挑取复苏的菌落溶于生理盐水中，制备浓度为1.00E+07CFU/mL的E.coli ATCC-25922菌液，用于小鼠大腿肌肉感染。实验小鼠的大腿肌肉注射菌液量为100μL/只，即接种量为1.00E+06CFU/鼠。感染后2h，对照组小鼠取大腿肌肉组织置于10mL生理盐水中，大腿肌肉组织匀浆，梯度稀释点板；
小鼠具体给药情况如下：
(1)感染后2h：第1笼小鼠感染2h终点，取大腿肌肉组织置于10mL生理盐水中，大腿肌肉组织匀浆，梯度稀释点板，每只小鼠两个重复。对小鼠大腿肌肉组织载菌量进行计数，第3、4笼分别皮下注射30mpk的Plazomicin和化合物1。
(2)感染后10h：第3、4笼分别皮下注射30mpk的Plazomicin和化合物1。第2～4笼小鼠感染24h终点，取大腿肌肉组织置于10mL生理盐水中，大腿肌肉组织匀浆，梯度稀释点板，每只小鼠两个重复。对小鼠大腿肌肉组织载菌量进行计数，整理实验结果，实验结果见图1。
结论：图1结果显示化合物1在30mpk下体内药效优于Plazomicin。
实验例5：小鼠体内药效实验评估(小鼠肺炎模型)
21只CD-1雌鼠分成7笼，每笼3只；于第4天腹腔注射免疫抑制剂环磷酰胺(150mpk)。
于第一天，7笼小鼠再次腹腔注射免疫抑制剂环磷酰胺(100mpk)；MHA平板复苏菌株Kpn ATCC-BAA-1705(肺炎克雷伯菌ATCC-BAA-1705)。挑取复苏的菌落溶于生理盐水中，制备浓度为4.00E+08CFU/mL的Kpn ATCC-BAA-1705菌液，用于小鼠肺部感染。实验小鼠的肺部感染菌液量为50μL/只，即接种量为2.00E+07CFU/小鼠。感染后2h和24h，对照组小鼠取肺部组织置于5mL生理盐水中，肺部组织匀浆，梯度稀释点板；
小鼠具体给药情况如下：
(1)感染后2h：第1笼小鼠感染2h终点，取肺部组织置于5mL生理盐水中，肺部组织匀浆，梯度稀释点板，每只小鼠两个重复。对小鼠肺部组织载菌量进行计数，第3、4笼分别皮下注射剂量为30mpk和10mpk的化合物Plazomicin，第5、6笼分别皮下注射剂量为30mpk和10mpk的化合物1；第7笼皮下注射100mpk的美罗培南。
(2)感染后10h：第3、4笼分别皮下注射剂量为30mpk和10mpk的Plazomicin，第5、6笼分别皮下注射剂量为30mpk和10mpk的化合物1；第7笼皮下注射100mpk的美罗培南。第2～7笼小鼠感染24h终点，取肺部组织置于5mL生理盐水中，肺部组织匀浆，梯度稀释点板，每只小鼠两个重复。对小鼠肺部组织载菌量进行计数，整理实验结果，实验结果见图2。
结论：图2结果显示Plazomicin和化合物1在肺炎克雷伯菌株1705肺部感染模型中显示出良好的体内活性。同时化合物1的药效优于Plazomicin，10mpk剂量的化合物1的药效相当于30mpk剂量的Plazomicin的药效。
实验例6：新型氨基糖苷类抗生素药物听觉安全性研究报告
研究目的：
评估化合物1与已有抗生素plazomicin在豚鼠体内对于听功能的影响，评估化合物1的听觉毒性作用。
研究方法：
以健康成年豚鼠(150-250g)作为研究对象，随机分为生理盐水对照组，庆大霉素组，化合物Plazomicin组及化合物1组，每组8只动物。采用皮下给药方式，连续给药14天期间及给药结束后进行如下检测：
1.为分析不同药物对于豚鼠听功能的影响，分别在用药结束后第14天(29天，即4周)记录动物复合动作电位(Compound Action Potential,CAP)，对所得结果进行分析，并比较不同处理组间阈移及幅值、潜伏期等指标变化。
2.不同组动物进行处理并采集好听觉功能数据后，取出动物耳蜗进行固定、染色，一侧耳蜗行基底膜铺片计数毛细胞损失制作耳蜗图，另一侧耳蜗脱钙后进行冰冻切片，并计数螺旋神经节密度，进行组间比较。
研究结果：
1.给药方法及处理
药物庆大霉素(Gentamicin)、Plazomicin、以及化合物1，庆大霉素购于大连美仑生物技术有限公司，Plazomicin及化合物1由武汉药明康德新药开发有限公司提供。每次现用现配，使用生理盐水溶解，浓度为50mg/mL，注射剂量为100mg/kg体重。方法：皮下注射，每次注射后确认无药液渗出。
2.复合动作电位结果(Compound action potential,CAP)分析
我们检测记录了给予各组动物短声(Click)及不同频率纯音(1KHz-32kHz)时的复合动作电位(Compound action potential,CAP)，主要比较给予短声及中高频纯音(16、32kHz)时振幅及潜伏期的变化。振幅的大小反应毛细胞及听神经的响应能力，振幅越大，I/O曲线斜率越大，反应性越好，功能也越好。此外，耳蜗从顶回到底回分别对低频到高频的声音有响应性，即为耳蜗基底膜的频率对应性，不同频率的功能变化相对应的是耳蜗从顶回到底回不同的结构功能改变。潜伏期的长短也同毛细胞及听神经响应的功能相关，一般来讲，耳蜗受损伤时阈值升高势必会引起潜伏期的延长，除此之外，阈值无明显变化时潜伏期的延长也反应听神经放电的同步性降低，换言之，潜伏期延长反应功能下降。而既往氨基糖苷类抗生素的耳毒性主要集中在高频区域，本次研究中庆大霉素组与以往结果一致，概括如下。
化合物1仅造成实验组高频(32kHz)CAP幅值下降，提示高频区域听力损伤，但其幅值仍高于庆大霉素与Plazomicin组；而Plazomicin组的损伤范围较大，16kHz及32kHz均有损伤，且32kHz损伤大于化合物1，但显著低于庆大霉素组；庆大霉素对于实验组的损伤集中在高频(32kHz)区域，但其32kHz阈移明显，损伤比另两组药物更大(见图3～5)。
1)16kHz振幅结果显示，化合物1与对照组(Control)无差异，Plazomicin组产生了25.9％的损伤。
2)在32kHz，CAP振幅结果显示化合物1，Plazomicin及Gentamicin分别对32kHz造成了34.7％，48.2％及74.3％的听力损伤，即化合物1仍然导致了32kHz的听力损伤，但相比Plazomicin及Gentamicin损伤分别减少了13.5％及39.6％；
3)短声(Click)CAP振幅提示化合物1及Gentamicin均与对照组(Control)一致，而Plazomicin造成了听力损伤。
具体数值如下：
1)16kHz CAP振幅：双因素方差分析(Holm-Sidak method)显示，四组动物组间存在差异，F3，570＝7.858，p<0.001。其中化合物1动物组与对照组(Control)及Gentamicin组动物听力没有统计学差异。Plazomicin组动物听力分别低于Ctrl组(t＝4.566,p<0.001)，Gentamicin组(t＝4.099，p<0.001)和化合物1组(t＝2.799,p＝0.021)。*：p<0.05。在90dB处各组响应均为最大，此时化合物1动物听力(381.646±20.895uv)显著高于Plazomicin组(282.058±22.569uv，t＝2.799，p＝0.021)，与对照组(Control)(383.130±19.545)组和Gentamicin组(373.329±15.332uv)没有明显差异。
2)32kHz CAP振幅：双因素方差分析(Holm-Sidak method)显示，四组动物组间存在差异， F3,570＝100.611，p<0.001。化合物1动物听力低于对照组(Control)(t＝5.019，p<0.001)，高于Plazomicin组(t＝3.128，p＝0.002)及Gentamicin组(t＝10.484，p<0.001)。在90dB处各组响应均为最大，此时化合物1组动物听力(79.420±7.000uv)低于对照组(Control)(121.608±6.548uv，t＝4.401，p<0.001)，高于Gentamicin组(31.272±5.137uv，t＝5.545，p<0.001)与Plazomicin组(62.982±7.561uv，t＝1.595，p＝0.111)。
3)短声(Click)CAP振幅：双因素方差分析(Holm-Sidak method)显示，四组动物组间存在差异，F3,570＝6.751，p<0.001。化合物1动物组听力显著优于Plazomicin组(t＝3.493，p＝0.003)，与对照组(Control)和Gentamicin组之间无显著差异。
总体来说，由CAP振幅结果证明化合物1对于实验动物的听功能损伤明显小于庆大霉素以及Plazomicin。
3.毛细胞数目改变
为比较不同药物对于毛细胞的影响，我们对于耳蜗基底膜全场进行毛细胞染色及计数，结果提示庆大霉素组在中高频区域(自顶回起60-100％)有12-67.7％的外毛细胞丢失，且高频更明显，Plazomicin组在高频(自顶回起70～100％处)有11.2-28.1％的外毛细胞丢失以及顶回起始端(10-20％处)16.7-24.2％的外毛细胞丢失，但是在化合物1组，外毛细胞丢失仅发生于顶回起的低频区域(自顶回起-40％)，外毛细胞损失率在此范围内约2.5-11％，高频区域外毛细胞较完整(见图6中B)。具体数值见表4。
化合物1组内毛细胞几乎无损伤，Plazomicin及庆大霉素组均在近底回末端处(从顶回起100％)分别有3.5±3.0％及9.3±4.1％的内毛细胞丢失(见图6中A)。具体数值见表5。
综上，化合物组仅在顶回存在轻微外毛细胞丢失，其余部分有其底回以及内毛细胞保存较完整，其毛细胞毒性明显低于庆大霉素组以及Plazomicin组。
4.螺旋神经节改变
我们将豚鼠耳蜗从底回到顶回，分别列为回(Turn)1、回2、回3和回4，并在对螺旋神经元(Spiral ganglion neurons,SGNs)在冰冻切片上进行TuJ标记染色后，计数SGNs在特定面积内的密度，并进行组间比较。化合物1组各回SGN密度与对照组无明显差异，即无螺旋神经节损伤，庆大霉素组各回均有明显损伤，Plazomicin组在近顶回处有SGN密度降低，但优于庆大霉素组。通过双因素方差分析可得组间有显著性差异，F(3,74)＝35.43，p<0.0001(见图7)。具体数值见表6。
结论：基于对不同组间复合动作电位分析，证实化合物1组仅在高频(32kHz)存在听力损伤，优于Plazomicin以及庆大霉素组；通过对毛细胞以及螺旋神经节的观察，证实除近顶回2.5-11％的外毛细胞损伤外，化合物1未造成明显其他区域外毛细胞的损伤，内毛细胞数目以及螺旋神经节数目也未受影响，明显优于庆大霉素以及Plazomicin组。因此，化合物1在动物(豚鼠)皮下连续应用14天，再恢复14天耳毒性小于Plazomicin以及庆大霉素组。综合本研究各项结果证实，本发明得到的化合物1的听毒性优于Plazomicin与庆大霉素。
表4第29天外耳毛细胞损伤情况(％，百分数)
损伤百分比(％) 化合物1 Plazomicin 庆大霉素
10 11.0±1.3 24.4±13.5 9.5±2.9
20 6.3±0.9 16.7±13.4 4.1±0.7
损伤百分比(％) 化合物1 Plazomicin 庆大霉素
30 6.2±1.1 10.5±6.5 2.7±0.7
40 2.5±1.4 7.8±4.0 3.2±1.0
50 1.1±0.8 7.2±2.0 3.2±1.5
60 1.4±1.5 5.7±5.1 12.6±5.6
70 0.7±0.3 11.2±11.8 13.6±6.1
80 0.5±0.3 19.9±15.7 12.0±5.4
90 0.2±0.3 20.7±7.9 42.8±8.2
100 0.9±0.7 28.1±10.1 67.7±9.8
表5第29天内耳毛细胞损伤情况(％，百分数)
损伤百分比(％) 化合物1 Plazomicin 庆大霉素
10 0.3±0.3 0.5±0.4 0
20 0 0.3±0.3 0
30 0 0.5±0.5 0
40 0.1±0.1 0.2±0.2 0
50 0 0 0
60 0 0.8±0.8 0.4±0.4
70 0.3±0.3 1.3±1.3 0.6±0.6
80 0 0 0.2±0.2
90 0 0 2.5±1.7
100 0.7±0.5 3.5±3.0 9.3±4.1
表6第29天螺旋神经节密度变化(n/10000μm 2)
回(turn) 庆大霉素 Plazomicin 化合物1 对照
回1 4.407±0.517 6.816±0.852 8.230±0.500 7.548±0.534
回2 5.540±0.757 5.876±0.536 8.282±0.254 7.695±0.298
回3 4.604±0.598 5.553±0.793 8.136±0.247 7.935±0.292
回4 5.259±0.280 5.641±0.767 7.469±0.772 6.936±0.205
实验例7：本发明化合物对细胞HK-2的毒性实验
准备细胞：
实验当天，当培养瓶细胞HK-2汇合率达到80％-90％时，弃去培养基，用杜氏磷酸缓冲液(DPBS)清洗2次，加入3mL的胰酶(T150型号细胞培养瓶)进行消化1～2分钟，立即加入9毫升完全培养基(RPMI1640+10％FBS)终止消化，终止后，用移液枪轻轻吹打均匀，形成单个细胞悬液。每秒1000转，离心5分钟。弃去上清，加入新鲜的完全培养基，吹打均匀。根据细胞计数仪测定实际的细胞密度，将细胞悬液调整为2.5×10 5细胞/毫升。用排枪吸取80μL细胞悬液，加入到96孔黑底板内(2×10 4细胞/孔)。随后，将96孔板放在二氧化碳培养箱内孵育4.5小时。此为细胞板。
配置化合物：
a.按如下表格配置化合物母液，溶剂为完全培养基；
表7化合物信息
化合物 质量(mg) 纯度(％) 浓度(mg/mL) 体积(μL)
Plazomicin 5.88 99.65 50 117.19
化合物1 5.51 95 50 104.69
奈替米星 5.00 - 50 100.00
阿米卡星 5.74 - 50 114.80
b.往96-v孔板内第3-11列加50微升完全培养基；
c.96-v孔板的第2列加75微升待测化合物(50mg/mL)和阳性对照；
d.从第2列取出25微升化合物加到第3列中，用排枪吹吸几次，再从第3列取25微升加入到第4列，以此3倍梯度稀释，直至第10列，从第2列至第11列，化合物浓度分别为：50,16.67,5.56,1.85,0.62,0.21,0.07,0.02,0.008,0mg/mL；
e.用排枪转移20μL配置好各种浓度的化合物溶液到细胞板对应的孔内。此为测试板。
测试板培养：
将所有的板子放置37℃，5％CO 2培养箱中培养43小时。
读数：
培养到相应的时间后，往测试板内加入10微升阿尔马蓝，立即将测试板置于37℃，5％CO 2培养箱中培养3小时。然后用酶标仪读取测试板的每孔的荧光值(波长Ex 540nm/Em 585nm)。然后用prism软件模拟曲线计算CC 50值。
研究结果：
表8实验结果及预测CC 50
Figure PCTCN2020093436-appb-000036
结论：化合物1与Plazomicin对于HK-2细胞的毒性明显低于奈替米星和阿米卡星，结合毒性回归曲线与软件预测(如图8～11)，化合物1对HK-2细胞的毒性低于Plazomicin。

Claims (17)

  1. 式(II)所示化合物、其药学上可接受的盐或其异构体：
    Figure PCTCN2020093436-appb-100001
    其中，
    R'为
    Figure PCTCN2020093436-appb-100002
    L为-O-CH 2-CH 2-或-CH 2-；
    R 1为H或C 1-3烷基；
    R 2为H、C 1-3烷基或
    Figure PCTCN2020093436-appb-100003
    其中所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2或-NO 2的取代基所取代；
    R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-C 1-3烷基或C 1-3烷基，其中所述-C(＝O)-C 1-3烷基和C 1-3烷基任选被1、2或3个R所取代；
    各R独立地为F、Cl、Br、I、-OH、-OCH 3、-CN或-NH 2。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其化合物具有式(I)所示结构：
    Figure PCTCN2020093436-appb-100004
    其中，R 1为H或C 1-3烷基；
    R 2为H、C 1-3烷基或
    Figure PCTCN2020093436-appb-100005
    其中所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2或-NO 2的取代基所取代；
    R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-C 1-3烷基或C 1-3烷基，其中所述-C(＝O)-C 1-3烷基和C 1-3烷基任选被1、2或3个R所取代；
    各R独立地为F、Cl、Br、I、-OH、-OCH 3、-CN或-NH 2。
  3. 根据权利要求2所述的化合物、其药学上可接受的盐或其异构体，其化合物具有式(I-1)所示结构：
    Figure PCTCN2020093436-appb-100006
    其中，R a、R b和R 1如权利要求2所定义。
  4. 根据权利要求1～3任一项所述的化合物、其药学上可接受的盐或其异构体，其中R 1为H或-CH 3。
  5. 根据权利要求4所述的化合物、其药学上可接受的盐或其异构体，其化合物具有式(I-2)所示结构：
    Figure PCTCN2020093436-appb-100007
    其中，R a和R b如权利要求4所定义。
  6. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中各R独立地为F或Cl。
  7. 根据权利要求1～3或5任一项所述的化合物、其药学上可接受的盐或其异构体，其中R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-CH 3、-CH 3或-CH 2CH 3，其中所述-C(＝O)-CH 3、-CH 3和-CH 2CH 3任选被1、2或3个R所取代。
  8. 根据权利要求7所述的化合物、其药学上可接受的盐或其异构体，其中R a和R b各自独立地为H、-C(＝O)-NH 2、-C(＝O)-CH 3、-CH 3、-CH(R) 2、-CH 2CH 3或-CH 2CH(R) 2。
  9. 根据权利要求8所述的化合物、其药学上可接受的盐或其异构体，其中R a和R b各自独立地为H或
    Figure PCTCN2020093436-appb-100008
  10. 根据权利要求1、2、8或9任一项所述的化合物、其药学上可接受的盐或其异构体，其中R 2为H、-CH 3、-CH 2CH 3或
    Figure PCTCN2020093436-appb-100009
    其中所述-CH 3和-CH 2CH 3任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2或-NO 2的取代基所取代。
  11. 根据权利要求10所述的化合物、其药学上可接受的盐或其异构体，其中R 2为
    Figure PCTCN2020093436-appb-100010
    Figure PCTCN2020093436-appb-100011
  12. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其异构体，其中结构单元
    Figure PCTCN2020093436-appb-100012
    为
    Figure PCTCN2020093436-appb-100013
  13. 根据权利要求12所述的化合物、其药学上可接受的盐或其异构体，其中结构单元
    Figure PCTCN2020093436-appb-100014
    为
    Figure PCTCN2020093436-appb-100015
  14. 下式化合物、其药学上可接受的盐或其异构体：
    Figure PCTCN2020093436-appb-100016
  15. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～14任一项所述化合物、其药学上可接受的盐或其异构体以及药学上可接受的载体。
  16. 根据权利要求1～14任一项所述化合物、其药学上可接受的盐或其异构体或根据权利要求15所述的药物组合物在制备治疗细菌感染相关病症的药物上的应用。
  17. 根据权利要求16所述的应用，其中，所述细菌为耐碳青霉烯类肠科杆菌。
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