WO2023082055A1 - 包含β-内酰胺类化合物的药物组合物及其用途 - Google Patents

包含β-内酰胺类化合物的药物组合物及其用途 Download PDF

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WO2023082055A1
WO2023082055A1 PCT/CN2021/129609 CN2021129609W WO2023082055A1 WO 2023082055 A1 WO2023082055 A1 WO 2023082055A1 CN 2021129609 W CN2021129609 W CN 2021129609W WO 2023082055 A1 WO2023082055 A1 WO 2023082055A1
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compound
formula
pharmaceutical composition
butyl
optionally substituted
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PCT/CN2021/129609
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English (en)
French (fr)
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宋丹青
蒋建东
汪燕翔
游雪甫
冯胜昔
李迎红
卢曦
林立东
范田运
庞晶
郭志浩
李志文
刘永华
王秀坤
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中国医学科学院医药生物技术研究所
广州艾奇西新药研究有限公司
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Priority to AU2021473165A priority Critical patent/AU2021473165A1/en
Priority to PCT/CN2021/129609 priority patent/WO2023082055A1/zh
Publication of WO2023082055A1 publication Critical patent/WO2023082055A1/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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 pharmaceutical compositions comprising ⁇ -lactam compounds and their use against microorganisms, especially bacteria, especially Gram-negative bacteria.
  • ⁇ -lactam antibiotics refer to a large class of antibiotics with a ⁇ -lactam ring in their chemical structure.
  • beta-lactam antibiotics are known. Such antibiotics have the advantages of strong bactericidal activity, low toxicity, wide indications and good clinical curative effect.
  • the present invention is made in order to overcome the above-mentioned deficiencies in the prior art.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • R and R each independently represent hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkylacyloxyalkyl or alkoxyacyloxy Alkyl, heterocyclyl, heteroaryl, or R 1 and R 2 together form a cycloalkyl group; all of the above groups are optionally substituted;
  • R and R each independently represent hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkylacyloxyalkyl or alkoxyacyloxy Alkyl, heterocyclyl, heteroaryl, or R 3 and R 4 together form a cycloalkyl group; all of the above groups are optionally substituted;
  • Y represents an optionally substituted alkenyl or alkynyl group, or represents a carboxyl or ester group
  • composition of the present invention can be used as it is, or together with pharmaceutically acceptable carriers, excipients or other auxiliary agents.
  • the present invention also provides the use of the pharmaceutical composition of the present invention as an antimicrobial agent.
  • the present invention also provides the use of the pharmaceutical composition of the present invention in the production of medicines for treating infectious diseases.
  • the present invention also provides a method for treating infectious diseases, comprising administering the pharmaceutical composition of the present invention to humans or animals.
  • the “pharmaceutical composition of the present invention” comprises the compound of the present invention and a lactamase inhibitor or efflux pump inhibitor, and optionally a pharmaceutically acceptable carrier, excipient and/or other auxiliaries.
  • the term "optional”, “optional” or “optionally” means that the event, circumstance or substance described thereafter may or may not occur or exist and that such description includes said event The occurrence or presence of a situation or substance and the absence or absence of said event, situation or substance.
  • microorganism has a well-known meaning in the art, including bacteria, viruses and fungi, especially bacteria, such as Gram-positive bacteria, Gram-negative bacteria and the like.
  • alkyl by itself or in combination with other terms such as arylalkyl - is understood to mean a saturated aliphatic hydrocarbon radical, which may be branched or unbranched.
  • Examples of (C 1 -C 12 )-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl , neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.
  • (C 1 -C 6 )-alkyl groups are particularly preferred. Particular preference is given to (C 1 -C 4 )-alkyl groups.
  • cycloalkyl by itself or in combination with other terms such as arylcycloalkyl - is understood to mean a saturated aliphatic cyclohydrocarbyl radical having 3 to 8 carbon ring atoms and may be optionally substituted.
  • Examples of (C 3 -C 8 )-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 7 -cycloalkyl and C 8 -cycloalkyl. The above groups may be optionally substituted.
  • alkoxy by itself or in combination with other terms such as carboxyalkoxyimino - is understood to mean alkyl-O-, wherein the term “alkyl” is as defined above.
  • alkyl groups here may be straight-chain or branched.
  • the number of carbon atoms refers to the alkyl group in the alkylcarbonyl group.
  • Alkyl group attached to the backbone for example (C 1 -C 10 )-, (C 1 -C 6 )- or (C 1 -C 4 )-alkylacyloxy.
  • the number of carbon atoms refers to the alkyl group in the alkylacyloxy group.
  • the number of carbon atoms refers to the alkyl group in the alkoxyacyloxy group.
  • alkenyl is understood to mean a hydrocarbyl group having at least one carbon-carbon double bond.
  • alkenyl are vinyl, propenyl, isopropenyl, allyl, n-butenyl, isobutenyl, 2-methylpropenyl, and the like.
  • alkynyl is understood to mean a hydrocarbyl group having at least one carbon-carbon triple bond.
  • the alkynyl group are ethynyl, propynyl, isopropynyl, propargyl, n-butynyl, isobutynyl, 2-methylpropynyl, and the like.
  • ester group is understood to mean a group having the structure -COOR 5 , wherein R 5 is an alkyl group as defined above.
  • R 5 is preferably (C 1 -C 12 )-alkyl, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, n-heptyl , n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. More preferably, R 5 is (C 1 -
  • heterocyclyl means a saturated or partially saturated monocyclic ring of carbon atoms and at least one heteroatom in the ring.
  • the heterocyclyl group contains 3, 4, 5, 6 or 7 carbon atoms and 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen.
  • heterocyclyl groups are azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxolyl, oxanyl, dioxanyl, thiacyclo Butyl (thietanyl), thietanyl, thiacyclohexyl and tetrahydrofuranyl.
  • aryl is understood to mean an aromatic group having 6 to 14 carbon atoms, preferably phenyl, naphthyl, anthracenyl or phenanthrenyl, more preferably phenyl .
  • arylalkyl is understood to mean a combination of the radicals "aryl” and “alkyl” as defined according to the present invention, wherein said radicals are usually attached via an alkyl group. Examples thereof are benzyl, phenethyl or ⁇ -methylbenzyl, benzyl being particularly preferred.
  • heteroaryl means a monocyclic, bicyclic or tricyclic heterocyclic group of carbon atoms and at least one heteroatom, wherein at least one ring is aromatic.
  • heteroaryl contains 3, 4, 5 or 6 carbon atoms and is selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2 , 4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl,
  • solvate refers to a form of a compound, or a salt thereof, which is associated with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • the compounds of formula (I) may exist as stereoisomers.
  • Possible stereoisomers defined by their specific three-dimensional forms, such as enantiomers, diastereomers, Z and E isomers, are included in formula (I).
  • enantiomers, diastereomers, Z and E isomers are included in formula (I).
  • diastereoisomers Z and E isomers
  • enantiomers and diastereomers may occur.
  • Stereoisomers can be obtained from the mixture obtained in the preparation by conventional separation methods.
  • Chromatographic separations can be performed on an analytical scale to find enantiomeric or diastereomeric excesses, or on a preparative scale to generate test samples for biological assays.
  • Stereoisomers can likewise be prepared selectively by employing stereoselective reactions using optically active starting materials and/or auxiliaries.
  • the present invention therefore also relates to all stereoisomers encompassed by formula (I) or intermediates thereof but not shown in their specific stereoisomeric form, and mixtures thereof.
  • the compounds of formula (I) may, if appropriate, exist in various polymorphic forms or as mixtures of various polymorphic forms. Pure polymorphs and polymorph mixtures are provided by the invention and can be used in accordance with the invention.
  • the term "synergy” has the meaning generally understood by those skilled in the art, eg an interaction in which the combination of two components achieves a total effect greater than the sum of the effects of the individual components.
  • the ratio of each component in the composition and mixture is based on weight.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • R and R each independently represent hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkylacyloxyalkyl or alkoxyacyloxy Alkyl, heterocyclyl, heteroaryl, or R 1 and R 2 together form a cycloalkyl group; all of the above groups are optionally substituted;
  • R and R each independently represent hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkylacyloxyalkyl or alkoxyacyloxy Alkyl, heterocyclyl, heteroaryl, or R 3 and R 4 together form a cycloalkyl group; all of the above groups are optionally substituted;
  • Y represents an optionally substituted alkenyl or alkynyl group, or represents a carboxyl or ester group
  • the pharmaceutical composition of the present invention comprises component (a) a compound of formula (I), or its stereoisomers, solvates and pharmaceutically acceptable salts or esters.
  • component (a) a compound of formula (I), or its stereoisomers, solvates and pharmaceutically acceptable salts or esters.
  • the compounds of formula (I) described above provide a broad definition of the compounds of the invention. Preferred, more preferred, particularly preferred and most preferred substituents or ranges of the groups listed in formula (I) of the present invention will be described below.
  • R 1 and R 2 each independently represent hydrogen, and optionally substituted the following groups: (C 1 -C 12 )-alkyl, (C 6 -C 14 )-aryl, (C 1 -C 12 )-alkoxy, (C 1 -C 12 )-alkylcarbonyl-(C 1 -C 12 )-alkyl, (C 1 -C 12 )-alkylacyloxy-(C 1 -C 12 )-alkyl or (C 1 -C 12 )-alkoxyacyloxy-(C 1 -C 12 )-alkyl, or R 1 and R 2 together form (C 3 -C 8 )cycloalkyl;
  • R 1 and R 2 each independently represent hydrogen, optionally substituted (C 1 -C 10 )-alkyl, for example, optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethyl Propyl, 1,2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl; or R 1 and R 2 together form (C 3 -C 6 )cycloalkyl;
  • R and R each independently represent hydrogen, optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; or R 1 and R 2 together form (C 3 -C 6 )cycloalkyl;
  • R 1 and R 2 each independently represent hydrogen, optionally substituted methyl, ethyl.
  • R 3 and R 4 each independently represent hydrogen, and optionally substituted the following groups: (C 1 -C 12 )-alkyl, (C 6 -C 14 )-aryl, (C 1 -C 12 )-alkoxy, (C 1 -C 12 )-alkylcarbonyl-(C 1 -C 12 )-alkyl, (C 1 -C 12 )-alkylacyloxy-(C 1 -C 12 )-alkyl or (C 1 -C 12 )-alkoxyacyloxy-(C 1 -C 12 )-alkyl, or R 3 and R 4 together form (C 3 -C 8 )cycloalkyl;
  • R 3 and R 4 each independently represent hydrogen, optionally substituted (C 1 -C 10 )-alkyl, for example, optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethyl Propyl, 1,2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl; optionally substituted (C 6 -C 12 )-aryl; or R 3 and R 4 together form (C 3 -C 6 )cycloalkyl;
  • R and R independently represent hydrogen, optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; any Optionally substituted (C 6 -C 12 )-aryl; or R 3 and R 4 together form (C 3 -C 6 )cycloalkyl;
  • R3 and R4 each independently represent hydrogen, optionally substituted methyl, ethyl, n-propyl, isopropyl, or R3 and R4 together form a ( C3 - C6 )cycloalkane base.
  • Y represents an optionally substituted alkenyl or alkynyl group, or represents a carboxyl or ester group.
  • Y represents vinyl, propenyl, isopropenyl, allyl, n-butenyl, isobutenyl, 2-methylpropenyl, ethynyl, propynyl, isopropynyl, propargyl , n-butynyl, isobutynyl, 2-methylpropynyl, carboxyl, and -COOR 5 , wherein R 5 is (C 1 -C 12 )-alkyl, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methyl butyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, n-h
  • Y represents vinyl, propenyl, isopropenyl, allyl, n-butenyl, isobutenyl, 2-methylpropenyl, ethynyl, propynyl, isopropynyl, propargyl , n-butynyl, isobutynyl, 2-methylpropynyl, carboxyl, and -COOR 5 , wherein R 5 is (C 1 -C 12 )-alkyl, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methyl butyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl.
  • Y represents vinyl, propenyl, ethynyl, propynyl, carboxyl, and -COOR 5 , wherein R 5 is methyl, ethyl, n-propyl, isopropyl.
  • Preferred compounds of the formula (I) according to the invention comprise combinations of the abovementioned preferred meanings.
  • More preferred compounds of formula (I) according to the invention comprise combinations of the abovementioned more preferred meanings.
  • Particularly preferred compounds of the formula (I) according to the invention comprise combinations of the abovementioned particularly preferred meanings.
  • the compound of formula (I) of the present invention is wherein R 1 represents H, and R 2 represents H, R 3 and R 4 together form a cyclopropyl group, and Y is a carboxyl group of the formula (I-1 ) compound:
  • the compound of formula (I) of the present invention is the formula ( I- 2) Compound:
  • the compound of formula (I) of the present invention is a compound selected from the group consisting of:
  • stereoisomers, solvates and pharmaceutically acceptable salts or esters of compounds of formula (I) can be obtained by conventional means known to those skilled in the art.
  • the present invention also provides the method for preparing aforementioned compound:
  • PG 1 and PG 2 represent protecting groups; R 1 , R 2 , R 3 , R 4 and Y have the same meanings as above.
  • the carboxyl protecting group PG 1 is a carboxyl protecting group commonly used in the art.
  • the "carboxyl protecting group” is not particularly limited as long as it is a protecting group having this function, and examples thereof include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl, such as 2,2 , 2-trichloroethyl and other halogenated lower alkyl groups, such as allyl and other lower alkenyl groups, such as benzyl, p-methoxybenzyl, p-nitrosobenzyl, benzhydryl, trityl etc.
  • aralkyl etc., particularly preferably methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl, benzhydryl and the like.
  • PG 1 is -CHPh 2 (benzhydryl).
  • the amino protecting group PG 2 is an amino protecting group commonly used in the art.
  • the “amino protecting group” is not particularly limited as long as it is a protecting group having this function, and examples thereof include -Boc (tert-butoxycarbonyl), -Cbz (benzyloxycarbonyl), -Teoc (trimethylsilylethyl) oxycarbonyl), -Tos (p-toluenesulfonyl), -Trt (trityl) and -Bn (benzyl).
  • PG 2 is -Boc(tert-butoxycarbonyl).
  • the reaction condition of described reaction is conventional deprotection group condition, and it changes according to the difference of PG 1 and PG 2 , as AGMyers, J.Gleason, T.Yoon, DWKung, J.Am.Chem.Soc., 1997, 119, 656; and in M. Frankel, D. Ladkany, C. Gilon, Y. Wolman, Tetrahedron Lett., 1966, 7, 4765.
  • step 1a the compound 7a was dissolved in a solvent, triethylamine was added, triphenylchloromethane was added in batches, and the reaction was carried out at room temperature. After the reaction is complete, the intermediate compound 7b is obtained.
  • organic solvent used in the reaction of the above step 1a for example: dichloromethane, chloroform, toluene, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol and their mixture.
  • step 1b the compound 7b was dissolved in 1,4-dioxane/water (50:50), and sodium hydroxide was added, and the stirring reaction was continued until the raw materials disappeared.
  • the 1,4-dioxane was evaporated under reduced pressure, the pH was adjusted to 2-3, stirred, filtered, and the filter cake was washed with water until the filtrate was neutral, and the filter cake was collected and dried to obtain compound 7c.
  • step 1 compound 1 and diphenyl bromide were dispersed in an organic solvent, and stirred at room temperature, DBU (1,8-diazabicyclo-undec-7-ene ), heat up to 70-80°C, stir the reaction until the raw materials are no longer reduced, then cool down to room temperature.
  • the reaction solution was extracted, the organic phases were combined, dried, and concentrated to obtain a residue, which was separated by column chromatography to obtain compound 2.
  • Examples of the organic solvent used in the reaction in the above step 1 include dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide and the like.
  • step 2 compound 2 and diphenylphosphoryl hydroxylamine were dispersed in an organic solvent, nitrogen pumped 3-4 times, stirred at 0°C, then sodium tert-butoxide was added, and the reaction was stirred at a constant temperature until After the conversion of the reactant was complete, a saturated sodium chloride solution was added to the reaction solution, stirred and filtered to remove insoluble matter to obtain compound 3.
  • Examples of the organic solvent used in the reaction in Step 2 include dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide and the like.
  • step 3 the compound 7c was dispersed in an organic solvent, and the methanol solution of the compound 3 was added under stirring at room temperature, and the reaction was stirred at a constant temperature until the conversion of the raw materials was complete, and the compound 4 was obtained by column chromatography.
  • Examples of the organic solvent used in the reaction in Step 3 include methanol, ethanol, isopropanol, N,N-dimethylformamide and the like.
  • step 4 compound 4 was dispersed in an organic solvent, and HATU (2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate), NaHCO3, compound 8, stirred at room temperature until the conversion of raw materials was complete, and column chromatography obtained compound 5.
  • Examples of the organic solvent used in the reaction in Step 4 include dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide and the like.
  • step 5 the compound 5 is dissolved in an organic solvent, stirred at -5 ⁇ -10 ° C, triethylsilane and trifluoroacetic acid are added thereto, and the reaction is carried out at a constant temperature until the reaction is complete, and evaporated at room temperature under reduced pressure. After removing the solvent, the target product, the compound of general formula (I), is isolated.
  • Examples of the organic solvent used in the reaction in Step 5 include anhydrous dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide and the like.
  • the pharmaceutical composition of the present invention comprises component (b) a lactamase inhibitor or an efflux pump inhibitor.
  • the lactamase inhibitor is a diazabicyclooctone beta-lactamase inhibitor.
  • the diazabicyclooctone-type ⁇ -lactamase inhibitor is selected especially from avibactam, farborbactam and relebactam.
  • the efflux pump inhibitor is selected from the group consisting of berberine, treberine and Pa ⁇ N:
  • the pharmaceutical composition of the present invention has an excellent antimicrobial effect, which is more active than known antimicrobial agents in the prior art, and can be used in a lower amount against the same microorganisms .
  • the side effects on humans or animals are less, the tolerance is better, and drug resistance can be less developed.
  • the pharmaceutical composition of the present invention has excellent antimicrobial effect, especially for Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Enterobacter aerogenes, Salmonella typhi, Serratia marcescens, Citrobacter freundii, Prufidenbacterium legiti, Proteus vulgaris, Proteus mirabilis, Pseudomonas maltophilia, Chi flexneri Heliconia, etc. have excellent antibacterial activity and low drug resistance.
  • Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Enterobacter aerogenes, Salmonella typhi, Serratia marcescens, Citrobacter freundii
  • the bacteria are eg Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae. In another embodiment, the bacteria are Acinetobacter baumannii, Pseudomonas aeruginosa. However, those skilled in the art should understand that these bacteria are only exemplary and in no way limit the present invention.
  • the bacterium is, for example, Klebsiella pneumoniae ATCC2146, ATCC700603, CCPM(A)-0814R18, CCPM(A)-0814R33, CCPM(A)-081301, CCPM(A)-081705, CCPM( A)-081715, CCPM(A)-081729, CCPM(A)-081716 and CCPM(A)-0817R61, Escherichia coli ATCC2469 and CCPM(A)-P-071301, Enterobacter cloacae CCPM(A)-P -111729 and ATCC2468.
  • the bacterium is Acinetobacter baumannii ATCC 19606, ATCC 17978, CCPM(A)-P-101633 (CRAB), Pseudomonas aeruginosa ATCC27853, PAO1 (CCPM(A)-P-09000032) , CCPM(A)-P-091626(CRPA).
  • the pharmaceutical composition according to the invention comprises at least one compound of formula (I), at least one beta-lactamase inhibitor and/or at least one efflux pump inhibitor.
  • the pharmaceutical composition of the present invention comprises at least one compound of formula (I), at least one beta-lactamase inhibitor selected from the group consisting of avibactam, farborbactam and relebactam and /or at least one efflux pump inhibitor selected from berberine, treberine and Pa ⁇ N.
  • the pharmaceutical composition of the present invention comprises at least one compound selected from formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I- 5) and a compound of formula (I-6), at least one ⁇ -lactamase inhibitor selected from avibactam, farborbactam and relebactam and/or at least one selected from berberine , an efflux pump inhibitor of conespinine and Pa ⁇ N.
  • the pharmaceutical composition of the present invention comprises at least one compound selected from formula (I-1) and formula (I-2), at least one compound selected from avibactam, farborbactam and radium A beta-lactamase inhibitor of lebactam and/or at least one efflux pump inhibitor selected from berberine, trycanine and Pa ⁇ N.
  • the pharmaceutical composition according to the invention comprises a compound of formula (I-1) and at least one beta-lactamase inhibitor selected from avibactam, farborbactam and relebactam.
  • the pharmaceutical composition of the present invention comprises the compound of formula (I-1) and at least one efflux pump inhibitor selected from the group consisting of berberine, trycanine and Pa ⁇ N.
  • the pharmaceutical composition according to the invention comprises a compound of formula (I-2) and at least one ⁇ -lactamase inhibitor selected from the group consisting of avibactam, farborbactam and relebactam.
  • the pharmaceutical composition of the present invention comprises the compound of formula (I-2) and at least one efflux pump inhibitor selected from berberine, conesinine and Pa ⁇ N.
  • the pharmaceutical composition of the present invention comprises a compound of formula (I-1), at least one beta-lactamase inhibitor selected from avibactam, farborbactam and relebactam and At least one efflux pump inhibitor selected from the group consisting of berberine, trepanine and Pa ⁇ N.
  • the pharmaceutical composition of the present invention comprises a compound of formula (I-2), at least one ⁇ -lactamase inhibitor selected from avibactam, farborbactam and relebactam and At least one efflux pump inhibitor selected from the group consisting of berberine, trepanine and Pa ⁇ N.
  • the compounds of formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5) and formula (I-6) have the above-mentioned meaning of the above.
  • the compound of the present invention and a lactamase inhibitor or an efflux pump inhibitor exhibit a synergistic effect.
  • the compound of the present invention is used in combination with a lactamase inhibitor or an efflux pump inhibitor, and simultaneously reduces the minimum inhibitory concentration of the compound of the present invention and a lactamase inhibitor or an efflux pump inhibitor; and the partial inhibitory concentration index (fractional inhibitory concentration index, FICI) ⁇ 0.5, indicating that the two have a synergistic effect.
  • component (a) and component (b) are 1:0.3 to 1:10, preferably 1:0.5 to 1:7, more preferably 1:0.8 to 1:6, most preferably Preferably 1:1 to 1:5.
  • the optimal dosage and interval of the compound of the present invention or the pharmaceutical composition of the present invention are determined by the properties of the compound and external conditions such as the form, route and site of administration and the specific mammals to be treated. Dosages can be determined by conventional techniques.
  • the optimal course of treatment that is, the daily dose of the compound of the present invention or the pharmaceutical composition of the present invention within a rated period of time, can be determined by methods known in the art.
  • the single administration amount of the pharmaceutical composition of the present invention is 1-5000mg active ingredient/kg body weight, preferably 2-4000mg compound/kg body weight, more preferably 5-3000mg active ingredient/kg body weight, particularly preferably 10 - 1000 mg active ingredient/kg body weight, also preferably 13-500 mg active ingredient/kg body weight, eg 14-300 mg active ingredient/kg body weight, 15-200 mg active ingredient/kg body weight, most preferably 15-100 mg active ingredient/kg body weight.
  • the compound of the invention is administered at least once a day, for example 1, 2, 3, 4 or 5 times a day.
  • the compounds of the invention are administered 1, 2 or 3 times daily.
  • active ingredient refers to a compound of the invention as well as a lactamase inhibitor or an efflux pump inhibitor.
  • the pharmaceutical composition of the present invention also optionally includes pharmaceutically acceptable carriers, excipients and/or other adjuvants.
  • pharmaceutically acceptable carriers, excipients and/or other adjuvants When pharmaceutically acceptable carriers, excipients and/or other adjuvants are included, an effective dose of the pharmaceutical composition of the present invention and one or more pharmaceutically acceptable carriers, excipients and/or other adjuvants are usually combined Proper administration or dosage forms are prepared by this procedure comprising mixing, granulating, compressing or dissolving the components by suitable means.
  • the content of the carrier in the pharmaceutical composition can be 1 to 98% by weight, usually about 80% by weight.
  • the present invention provides a pharmaceutical composition, comprising the compound of formula (I) of the present invention, or its stereoisomer, solvate or pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier, excipient and/or other Auxiliary.
  • the present invention also provides the use of the pharmaceutical composition of the present invention as an antimicrobial agent.
  • the term "microorganism” has the same meaning as in the description about the pharmaceutical composition.
  • the present invention also provides the use of the pharmaceutical composition of the present invention in the production of medicines for treating infectious diseases.
  • the present invention also provides a method for treating infectious diseases, which comprises administering component (a) and component (b) to humans or animals.
  • component (a) and component (b) have the meanings described above.
  • component (a) and component (b) are separately prepared pharmaceutical forms.
  • the time interval between administration of method component (a) and component (b) of the present invention is no more than 4 hours, preferably no more than 3 hours, more preferably no more than 2 hours, even more preferably no more than 1 hour. hours, particularly preferably no more than 30 minutes, most preferably simultaneously administering component (a) and component (b), for example in the form of a pharmaceutical composition comprising both components, ie in the form of a composition according to the invention.
  • the method for treating infectious diseases of the present invention comprises administering the pharmaceutical composition of the present invention to humans or animals.
  • composition of the present invention can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal cavity administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, peritoneal administration Intrathecal, intraventricular, intrasternal or intracranial injection or transfusion, or by means of an explanted reservoir, wherein oral, intramuscular injection, intraperitoneal or intravenous administration is preferred.
  • the pharmaceutical compositions of the present invention may be administered in unit dosage form.
  • the dosage forms for administration may be liquid dosage forms or solid dosage forms.
  • the liquid dosage forms can be true solutions, colloids, particulate dosage forms, and suspension dosage forms.
  • Other dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, clathrates, implants, patches, wipes Agents, sustained-release agents.
  • Oral tablets and capsules can be prepared by pharmaceutically known methods, and the tablets can also be coated.
  • Oral solutions can be made into water and oil suspensions, solutions, emulsions, syrups, and can also be made into dry products, and water or other suitable media should be added before use. Flavoring or coloring agents may be added if desired.
  • Suppositories may contain conventional suppository bases, such as cocoa butter or other glycerides.
  • liquid dosage forms are usually made up of the pharmaceutical composition of this invention and a sterile carrier.
  • the preferred carrier is water.
  • the pharmaceutical composition can be dissolved in the carrier or made into a suspension solution.
  • the pharmaceutical composition is first dissolved in water, filtered and sterilized, and then put into a sealed bottle or ampoule. middle.
  • compositions of this invention When applied topically to the skin, the pharmaceutical compositions of this invention may be in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers.
  • Step 1a Dissolve compound 7a (1.0mmol) in DMF (10.0v/g), add triethylamine (2.0mmol), add triphenylchloromethane (1.2mmol) in batches, and stir the reaction at room temperature After 6 hours, TLC monitoring, after the reaction was complete, water/ethyl acetate was added for extraction, the organic phases were combined, dried and concentrated, and separated by column chromatography to obtain the target compound 7b.
  • Step 1b Dissolve compound 7b (1.0mmol) in 1,4-dioxane (5v/g)/water (5v/g), stir at room temperature, add sodium hydroxide (5.0mmol), Continue to stir the reaction, monitor by TLC, the raw material disappears, distill out 1,4-dioxane under reduced pressure, adjust the pH to 2-3, stir for 10 minutes, filter, wash the filter cake with water until the filtrate is neutral, collect and dry the filter cake to obtain compound 7c.
  • Step 1 (Step 1): compound 1a (1.0mmol), diphenylbromomethane (1.1mmol) were dispersed in toluene solution (10.0v/g), and stirred at room temperature, DBU (1.5mmol) was added, the temperature was raised to 70-80°C, and the reaction was stirred 12-16 Hours, after TLC monitors that the raw material no longer decreases, cool down to room temperature, add water (10.0v/g x 2) to extract the reaction solution, backwash the aqueous layer with ethyl acetate (10v/g x 2), combine the organic phases, dry, and concentrate to obtain a residue
  • Step 2 Disperse compound 2a (1.0mmol) and diphenylphosphoryl hydroxylamine (1.1mmol) in anhydrous tetrahydrofuran solution (10.0v/g), pump nitrogen 3-4 times, and store at 0°C Stir, then add sodium tert-butoxide (1.5mmol), stir and react at constant temperature for 1-2 hours, TLC monitoring, the reactant has completely converted, add saturated sodium chloride solution (5.0v/g) to the reaction solution, and stir for 30 minutes , filter out the insoluble matter, wash the filter cake with ethyl acetate, add ethyl acetate (10.0v/g) and water (5.0v/g) to the filtrate, separate liquids, wash the organic phase once with water, combine the aqueous phase, and add ethyl acetate (10.0v/g) to the filtrate.
  • Step 3 compound 7c is dispersed in methanol (10.0v/g), under stirring at room temperature, add the methanol solution of compound 3a, stir and react at constant temperature for 30 minutes, TLC monitoring, the conversion of raw materials is complete, and the solvent is evaporated under reduced pressure,
  • the off-white solid compound 4a separated by column chromatography [1H NMR (600MHz, DMSO) ⁇ (ppm) 8.84 (s, 1H), 7.51-7.15 (m, 25H), 6.86 (s, 2H), 1.48-1.28 (m , 4H)].
  • Step 4 Dissolve compound 4a (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), and continue The reaction was stirred at constant temperature for 12 hours, and the reaction was monitored until the raw materials disappeared.
  • Step 5 Dissolve the above white solid 5a (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, and add triethylsilane (2.0mmol) to it and trifluoroacetic acid (100.0mmol), react at constant temperature for 5-6 hours, TLC monitors until the reaction is complete, evaporate the solvent under reduced pressure at room temperature, add ethyl acetate to the residue, stir at room temperature for 1 hour, filter, wash and filter with ethyl acetate Cake 3 times, collect the filter cake, dry, dissolve the above solid in methanol/water, pre-HPLC (YMC ODS-A, 5um, 10*250mm, 2.5mL/min, 2%-50% acetonitrile/0.1% formic acid water) to prepare and isolate the target product (I-1).
  • Test samples compounds I-1, I-2, avibactam, farborbactam and relebactam, as well as berberine, trycanine and Pa ⁇ N;
  • Avibactam and berberine were purchased from Enoch Technology Co., Ltd., Faborbactam and Relebactam were purchased from Shanghai Macklin Biochemical Technology Co., Ltd., conestinine was purchased from Bailingwei Technology Co., Ltd., and Pa ⁇ N was purchased from MedChemExpress .
  • Tested strains from the American Type Culture Collection (ATCC), and the Chinese Academy of Medical Sciences Pathogenic Microbial Bacteria (Virus) Species Preservation Center-Medicinal Microbial Related Bacteria (Virus) Species Preservation Sub-Center (CAMS- CCPM-A), the public can obtain these bacterial strains from the collection center (see Table 1 to Table 5 for details);
  • Test method according to CLSI/NCCLS standard, micro-dilution method and antibacterial activity determination.
  • test samples 4 mg of each sample, the drug is prepared into a 1024 ⁇ g/mL test solution with MH broth, diluted in a 96-well plate, and prepared into a series of gradient concentrations, and the volume of each well is 90 ⁇ L .
  • Test method Determination by checkerboard dilution method.
  • test samples 4 mg of each sample, the drug was prepared into a 2048 ⁇ g/mL test solution with MH broth, and diluted in a 96-well plate to prepare a series of gradient concentrations.
  • Tables 2A to 2C show the antibacterial spectrum data of the compound of formula (I-1) combined with avibactam, farborbactam and relebactam respectively.
  • Table 3 shows the antibacterial spectrum data of the compound of formula (I-2) combined with avibactam.
  • the MIC values of the compound of formula (I-1) against the 12 tested drug-resistant Enterobacteriaceae strains were all significantly reduced, and showed a synergistic effect (FICI ⁇ 0.5).
  • the MIC value of the compound of formula (I-1) to certain drug-resistant Enterobacteriaceae strains is reduced, and both show synergistic effect with borbactam and relebactam (FICI ⁇ 0.5).
  • the MIC value of the compound of formula (I-1) is between 16-32 ⁇ g/mL.
  • the efflux pump inhibitors berberine, conespinine and Pa ⁇ N showed weak activities against the above-mentioned strains of A. baumannii and resistant Pseudomonas aeruginosa.
  • the MIC value of the compound of formula (I-1) to 2 drug-resistant Acinetobacter baumannii strains ATCC19606 and ATCC17978 was reduced by 4 times, and the compound of formula (I-1) and berberine showed There was a synergistic effect (FICI ⁇ 0.5).
  • the MIC value of the compound of formula (I-1) to drug-resistant Acinetobacter baumannii strain ATCC19606 was reduced by 4 times, and the compound of formula (I-1) and trycanine showed a synergistic effect ( FICI ⁇ 0.5).
  • the MIC values of the compound of formula (I-1) against two drug-resistant Pseudomonas aeruginosa strains ATCC27853 and PAO1 were all reduced by 8 times, and showed a synergistic effect (FICI ⁇ 0.5);
  • the MIC value to drug-resistant Pseudomonas aeruginosa CCPM (A)-P-091626 (CRPA) was reduced by 4 times, and the same formula (I-1) compound and PA ⁇ N showed a synergistic antibacterial effect (FICI ⁇ 0.5).
  • ICR mice were used, which were healthy in appearance and weighed 18 to 22 g, half female and half male. The mice were randomly divided into groups, 5 in each dose group, regardless of gender.
  • the test bacterial solution containing NDM-1-producing Klebsiella pneumoniae was diluted with 5% highly active dry yeast, and the mice were intraperitoneally injected with 0.5% bacterial solution of 100% minimum lethal dose (100% MLD, 3.0 ⁇ 10 6 CFU/mouse). mL.
  • mice For intraperitoneal infection of NDM-1-producing Klebsiella pneumoniae (infection bacteria amount: 3.0 ⁇ 10 6 CFU) mice, a certain dose (see Table 5) was administered once in the tail vein at 1 hour and 6 hours after infection, and a total of The drug was administered twice, and the administration volume was 10 mL/kg. The survival of animals in each group was observed within 7 days, and the survival rate of the mice was calculated. In the control group, no drugs were administered, only physiological saline was administered, and the seven-day survival rate of the mice was 0.
  • Table 5 shows the protective effects of the compound of formula (I-1) alone and in combination with the compound of formula (I-1) and avibactam on Klebsiella pneumoniae ATCC BAA2146 (NDM-1) systemically infected mice. It is well known to those skilled in the art that avibactam itself has no antibacterial effect on the test strain in vivo.
  • Avibactam itself has no in vivo antibacterial effect on the test strain, but it can greatly enhance the latter's in vivo antibacterial activity after being administered in combination with the compound of formula (I-1).
  • the compound of formula (I-1) Under the dosage of 32mg/kg and 16mg/kg, the compound of formula (I-1) is administered in combination with avibactam of 1 times amount, 2 times amount and 3 times amount respectively, and the seven-day survival rate of mice All reached 100%. This shows that the combined use of the compound of formula (I-1) and avibactam in vivo can show a significant synergistic antibacterial effect.

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Abstract

本发明涉及包含一种式（I）的β-内酰胺类化合物，或其立体异构体、溶剂合物和可药用盐或酯，以及一种内酰胺酶抑制剂或外排泵抑制剂的药物组合物，及其用于抗微生物、特别是细菌、尤其是革兰阴性菌的用途，其中式（I）中各代号如说明书定义。

Description

包含β-内酰胺类化合物的药物组合物及其用途 技术领域
本发明涉及包含β-内酰胺类化合物的药物组合物，及其用于抗微生物、特别是细菌、尤其是革兰阴性菌的用途。
背景技术
β-内酰胺类抗生素(β-lactams)是指化学结构中具有β-内酰胺环的一大类抗生素。多种β-内酰胺类抗生素是已知的。此类抗生素具有杀菌活性强、毒性低、适应症广及临床疗效好的优点。
然而，随着抗生素在临床上的广泛使用，出现了一些耐药性，并且在一些方面的抗微生物效果并不总是令人满意。因此，需要开发新的抗微生物药物，其具有优异的抗微生物效果。
发明内容
为了克服现有技术中的上述不足而作出本发明。
本发明提供一种药物组合物，其包含
(a)一种式(I)化合物，或其立体异构体、溶剂合物和可药用盐或酯，
Figure PCTCN2021129609-appb-000001
其中
R 1和R 2各自独立地表示氢、烷基、芳基、烷氧基、芳氧基、芳基烷基、烷基羰基烷基、烷基酰氧基烷基或烷氧基酰氧基烷基、杂环基、杂芳基，或者R 1和R 2一起形成环烷基；所有上述基团任选地被取代；
R 3和R 4各自独立地表示氢、烷基、芳基、烷氧基、芳氧基、芳基烷基、烷基羰基烷基、烷基酰氧基烷基或烷氧基酰氧基烷基、杂环基、杂芳基，或者R 3和R 4一起形成环烷基；所有上述基团任选地被取代；
Y表示任选取代的烯基或炔基，或表示羧基或酯基；和
(b)一种内酰胺酶抑制剂或外排泵抑制剂。
本发明的药物组合物可原样使用，也可与可药用的载体、赋形剂或其他助剂一起使用。
本发明还提供本发明的药物组合物用作抗微生物剂的用途。
此外，本发明还提供本发明的药物组合物在生产用于治疗感染性疾病的药物中的用途。
另外，本发明还提供一种治疗感染性疾病的方法，包括对人或动物给药本发明的药物组合物。
出乎意料地已发现，本发明药物组合物中的式(I)化合物或其立体异构体、溶剂合物及可药用盐或酯与内酰胺酶抑制剂或外排泵抑制剂在抗微生物方面具有协同作用。
具体实施方式
一般定义
本发明的式(I)化合物，及其立体异构体、溶剂合物和可药用盐或酯有时也通称为“本发明的化合物”。
“本发明的药物组合物”包含本发明的化合物和内酰胺酶抑制剂或外排泵抑制剂，以及任选地可药用载体、赋形剂和/或其他助剂。
本文所用术语“任选”、“任选的”或“任选地”意为后面描述的事件、情况或物质可能出现或存在，也可能不出现或不存在，并且这样的描述包括所述事件、情况或物质出现或存在的情形和所述事件、情况或物质不出现或不存在的情形。
本文所用术语“包括”及其同义词“包含”和“含有”的含义为“包括但不限于”，其并不意在排除例如其它的添加物、组分、整数或步骤。
本发明中，“微生物”具有本领域公知的含义，包括细菌、病毒和真菌，特别是指细菌，例如革兰阳性菌、革兰阴性菌等。
在本发明的上下文中，除非另有不同定义，术语“烷基”——本身或与其他术语组合例如芳基烷基——应理解为是指饱和脂族烃基基团，其可以是支链的或非支链的。(C 1-C 12)-烷基的实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔 戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基、正庚基、正辛基、正壬基、正癸基、正十一烷基和正十二烷基。在这些烷基中，特别优选(C 1-C 6)-烷基。特别优选(C 1-C 4)-烷基。
在本发明的上下文中，除非另有不同定义，术语“环烷基”——本身或与其他术语组合例如芳基环烷基——应理解为是指饱和脂族环烃基基团，其具有3至8个碳环原子并且可以任选地被取代。(C 3-C 8)-环烷基的实例为环丙基、环丁基、环戊基、环己基、C 7-环烷基和C 8-环烷基。上述基团可以任选地被取代。
在本发明中，术语“烷氧基”——本身或与其他术语组合例如羧基烷氧基亚氨基——应理解为是指烷基-O-，其中术语“烷基”如上文所定义。特别是这里的烷基可以为直链或支链。
根据本发明，除非另有不同定义，“烷基羰基”(烷基-C(＝O)-)代表通过-C(＝O)-与骨架连接的烷基，例如(C 1-C 10)-、(C 1-C 6)-或(C 1-C 4)-烷基羰基。此处，碳原子数目涉及烷基羰基中的烷基。
根据本发明，术语“烷基酰氧基”(烷基-C(＝O)-O-)，除非另有不同定义，代表通过酰氧基(-C(＝O)-O-)的氧与骨架连接的烷基，例如(C 1-C 10)-、(C 1-C 6)-或(C 1-C 4)-烷基酰氧基。此处，碳原子的数目涉及烷基酰氧基中的烷基。
根据本发明，术语“烷氧基酰氧基”(烷氧基-C(＝O)-O-)，除非另有不同定义，代表通过酰氧基(-C(＝O)-O-)的氧与骨架连接的烷氧基，例如(C 1-C 10)-、(C 1-C 6)-或(C 1-C 4)-烷氧基酰氧基。此处，碳原子的数目涉及烷氧基酰氧基中的烷基。
根据本发明，除非另有不同定义，术语“烯基”应理解为是指具有至少一个碳碳双键的烃基基团。优选地，烯基的实例为乙烯基、丙烯基、异丙烯基、烯丙基、正丁烯基、异丁烯基、2-甲基丙烯基，等。
根据本发明，除非另有不同定义，术语“炔基”应理解为是指具有至少一个碳碳三键的烃基基团。优选地，炔基的实例为乙炔基、丙炔基、异丙炔基、炔丙基、正丁炔基、异丁炔基、2-甲基丙炔基，等。
根据本发明，除非另有不同定义，术语“酯基”应理解为是指具有-COOR 5结构的基团，其中R 5为如上文所定义的烷基。R 5优选为(C 1-C 12)-烷基，其实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁 基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基、正庚基、正辛基、正壬基、正癸基、正十一烷基和正十二烷基。更优选地，R 5为(C 1-C 6)-烷基。特别优选地，R 5为(C 1-C 4)-烷基。
除非另有不同定义，“杂环基”表示碳原子和至少一个在环中的杂原子的饱和或部分饱和的单环。优选地，杂环基含有3、4、5、6或7个碳原子和1或2个选自氧、硫和氮的杂原子。杂环基的实例为氮杂环丁烷基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、二氧杂环己基、硫杂环丁基(thietanyl)、硫杂环戊基、硫杂环己基和四氢呋喃基。
根据本发明，除非另有不同定义，术语“芳基”应理解为是指具有6至14个碳原子的芳族基团，优选苯基、萘基、蒽基或菲基，更优选苯基。
除非另有不同定义，术语“芳基烷基”应理解为是指根据本发明定义的基团“芳基”和“烷基”的结合，其中所述基团通常通过烷基连接。其实例为苄基、苯乙基或α-甲基苄基，特别优选苄基。
除非另有不同定义，“杂芳基”表示碳原子和至少一个杂原子的单环、双环或三环杂环基团，其中至少一个环为芳族的。优选地，杂芳基含有3、4、5或6个碳原子，其选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、1，2，3-三唑基、1，2，4-三唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、1，2，3-噁二唑基、1，2，4-噁二唑基、1，3，4-噁二唑基、1，2，5-噁二唑基、1，2，3-噻二唑基、1，2，4-噻二唑基、1，3，4-噻二唑基、1，2，5-噻二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1，2，3-三嗪基、1，2，4-三嗪基、1，3，5-三嗪基、四唑基、苯并呋喃基、苯并异呋喃基、苯并噻吩基、苯并异噻吩基、吲哚基、异吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、2，1，3-苯并噁二唑、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、苯并三嗪基、嘌呤基、蝶啶基和吲嗪基(indolizinyl)。
当基础结构“被取代”时，这在每种情况下包括被一个或多个相同的和/或结构不同的基团同时取代。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂缔合的化合物或其盐的形式。这种物理缔合可包括氢键键合。常规溶剂包括水、甲 醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
如果化合物可通过氢转移形成其中结构未被式(I)形式上涵盖的互变异构体，则这些互变异构体仍被本发明式(I)的化合物的定义所涵盖，除非另有考虑的特定的互变异构体。例如，许多羰基化合物既可以以酮形式也可以以烯醇形式存在，两种形式都包括在式(I)的化合物的定义中。
取决于取代基的性质和它们连接的方式，式(I)的化合物可以作为立体异构体存在。由其特定三维形式定义的可能的立体异构体，例如对映异构体、非对映异构体、Z和E异构体，均包括在式(I)中。例如，如果存在一个或多个链烯基，则可能出现非对映异构体(Z和E异构体)。例如，如果存在一个或多个不对称碳原子，则可能出现对映异构体和非对映异构体。立体异构体可以通过常规分离方法从在制备中获得的混合物中获得。色谱分离可以在分析规模上进行以发现对映体过量或非对映体过量，或者在制备规模上进行以产生用于生物测试的测试样品。同样可以通过在使用光学活性起始材料和/或助剂的情况下使用立体选择性反应选择性地制备立体异构体。因此，本发明还涉及被式(I)或其中间体所包括但未以其特定的立体异构形式示出的所有立体异构体，及其混合物。
如果合适的话，式(I)化合物可以以各种多晶型形式或作为各种多晶型形式的混合物存在。纯的多晶型物和多晶型物混合物由本发明提供并且可以根据本发明使用。
在本发明的上下文中，术语“协同”具有本领域技术人员通常理解的含义，例如两种组分的组合获得的总效果优于单独组分的效果之和的相互作用。
在本发明中，如无相反说明，则所有操作均在室温、常压条件下实施。
在本发明中，如无相反说明，则组合物、混合物中各成分的比例基于重量计。
药物组合物
在一个方面，本发明提供一种药物组合物，其包含
(a)一种式(I)化合物，或其立体异构体、溶剂合物和可药用盐或酯，
Figure PCTCN2021129609-appb-000002
其中
R 1和R 2各自独立地表示氢、烷基、芳基、烷氧基、芳氧基、芳基烷基、烷基羰基烷基、烷基酰氧基烷基或烷氧基酰氧基烷基、杂环基、杂芳基，或者R 1和R 2一起形成环烷基；所有上述基团任选地被取代；
R 3和R 4各自独立地表示氢、烷基、芳基、烷氧基、芳氧基、芳基烷基、烷基羰基烷基、烷基酰氧基烷基或烷氧基酰氧基烷基、杂环基、杂芳基，或者R 3和R 4一起形成环烷基；所有上述基团任选地被取代；
Y表示任选取代的烯基或炔基，或表示羧基或酯基；和
(b)一种内酰胺酶抑制剂或外排泵抑制剂。
组分(a)
本发明的药物组合物中包含组分(a)式(I)化合物，或其立体异构体、溶剂合物和可药用盐或酯。上文所述的式(I)化合物提供了本发明化合物的宽泛定义。以下将说明本发明式(I)中所列基团的优选、更优选、特别优选和最优选的取代基或范围。
优选地，R 1和R 2各自独立地表示氢，以及任选取代的以下基团：(C 1-C 12)-烷基、(C 6-C 14)-芳基、(C 1-C 12)-烷氧基、(C 1-C 12)-烷基羰基-(C 1-C 12)-烷基、(C 1-C 12)-烷基酰氧基-(C 1-C 12)-烷基或(C 1-C 12)-烷氧基酰氧基-(C 1-C 12)-烷基，或者R 1和R 2一起形成(C 3-C 8)环烷基；
更优选地，R 1和R 2各自独立地表示氢、任选取代的(C 1-C 10)-烷基，例如，任选取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基、正庚基、正辛基、正壬基、 正癸基；或者R 1和R 2一起形成(C 3-C 6)环烷基；
特别优选地，R 1和R 2各自独立地表示氢、任选取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基；或者R 1和R 2一起形成(C 3-C 6)环烷基；
最优选地，R 1和R 2各自独立地表示氢、任选取代的甲基、乙基。
优选地，R 3和R 4各自独立地表示氢，以及任选取代的以下基团：(C 1-C 12)-烷基、(C 6-C 14)-芳基、(C 1-C 12)-烷氧基、(C 1-C 12)-烷基羰基-(C 1-C 12)-烷基、(C 1-C 12)-烷基酰氧基-(C 1-C 12)-烷基或(C 1-C 12)-烷氧基酰氧基-(C 1-C 12)-烷基，或者R 3和R 4一起形成(C 3-C 8)环烷基；
更优选地，R 3和R 4各自独立地表示氢、任选取代的(C 1-C 10)-烷基，例如，任选取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基、正庚基、正辛基、正壬基、正癸基；任选取代的(C 6-C 12)-芳基；或者R 3和R 4一起形成(C 3-C 6)环烷基；
特别优选地，R 3和R 4各自独立地表示氢、任选取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基；任选取代的(C 6-C 12)-芳基；或者R 3和R 4一起形成(C 3-C 6)环烷基；
最优选地，R 3和R 4各自独立地表示氢、任选取代的甲基、乙基、正丙基、异丙基，或者R 3和R 4一起形成(C 3-C 6)环烷基。
优选地，Y表示任选取代的烯基或炔基，或表示羧基或酯基。
更优选地，Y表示乙烯基、丙烯基、异丙烯基、烯丙基、正丁烯基、异丁烯基、2-甲基丙烯基、乙炔基、丙炔基、异丙炔基、炔丙基、正丁炔基、异丁炔基、2-甲基丙炔基、羧基，以及-COOR 5，其中R 5为(C 1-C 12)-烷基，其实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基、正庚基、正辛基、正壬基、正癸基、正十一烷基和正十二烷基。
特别优选地，Y表示乙烯基、丙烯基、异丙烯基、烯丙基、正丁烯基、异丁烯基、2-甲基丙烯基、乙炔基、丙炔基、异丙炔基、炔丙基、正丁炔基、异丁炔基、2-甲基丙炔基、羧基，以及-COOR 5，其中R 5为(C 1-C 12)-烷基，其实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁 基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1，2-二甲基丙基、己基。
最优选地，Y表示乙烯基、丙烯基、乙炔基、丙炔基、羧基，以及-COOR 5，其中R 5为甲基、乙基、正丙基、异丙基。
上述基团各自宽泛的或各种优选的基团定义或说明可按需彼此组合，即可包括各自宽泛范围和各种优选范围之间的组合。它们既适用于式(I)化合物，也相应地适用于其立体异构体、溶剂合物和可药用盐或酯。
本发明优选的式(I)化合物包含上述优选含义的组合。
本发明更优选的式(I)化合物包含上述更优选含义的组合。
本发明特别优选的式(I)化合物包含上述特别优选含义的组合。
本发明最优选的式(I)化合物包含上述最优选含义的组合。
在一个优选的实施方案中，本发明的式(I)化合物为其中R 1代表H，且R 2代表H，R 3和R 4一起形成环丙基，并且Y为羧基的式(I-1)化合物：
Figure PCTCN2021129609-appb-000003
在另一个优选的实施方案中，本发明的式(I)化合物为其中R 1代表H，且R 2代表H，R 3和R 4一起形成环丁基，并且Y为羧基的式(I-2)化合物：
Figure PCTCN2021129609-appb-000004
在另一个优选的实施方案中，本发明的式(I)化合物为选自以下的化合物：
Figure PCTCN2021129609-appb-000005
此外，式(I)化合物的立体异构体、溶剂合物和可药用盐或酯可通过本领域技术人员已知的常规方式获得。
虽然本文示例性地描述了式(I)化合物及其立体异构体、溶剂合物和 可药用盐或酯，但对于本领域技术人员明显的是，这些化合物仅以示例的方式提供，绝不限制本发明。
式(I)化合物的制备
本发明还提供制备前述化合物的方法：
式(I)化合物通过方案制备：
Figure PCTCN2021129609-appb-000006
上述各式中，PG 1和PG 2表示保护基；R 1、R 2、R 3、R 4和Y具有与上文相同的含义。
所述羧基保护基PG 1为本领域常用的羧基保护基团。作为“羧基保护基”，若为具有该功能的保护基团则不特别限定，可以举出例如甲基、乙基、丙基、异丙基、叔丁基等低级烷基，例如2，2，2-三氯乙基等卤代低 级烷基，例如烯丙基等低级烯基，例如苄基、对甲氧基苄基、对亚硝基苄基、二苯甲基、三苯甲基等芳烷基等，特别优选甲基、乙基、叔丁基、烯丙基、苄基、对甲氧基苄基、二苯甲基等。本领域技术人员能够根据实际需要合理地进行选择。优选地，PG 1为-CHPh 2(二苯甲基)。
所述氨基保护基PG 2为本领域常用的氨基保护基团。作为“氨基保护基”，若为具有该功能的保护基团则不特别限定，可以举出例如-Boc(叔丁氧羰基)、-Cbz(苄氧羰基)、-Teoc(三甲基硅乙氧羰基)、-Tos(对甲苯磺酰基)、-Trt(三苯甲基)和-Bn(苄基)。本领域技术人员能够根据实际需要合理地进行选择。优选地，PG 2为-Boc(叔丁氧羰酰基)。
所述反应的反应条件为常规的去保护基条件，其根据PG 1和PG 2的不同而变化，如A.G.Myers，J.Gleason，T.Yoon，D.W.Kung，J.Am.Chem.Soc.，1997，119，656；和M.Frankel，D.Ladkany，C.Gilon，Y.Wolman，Tetrahedron Lett.，1966，7，4765中所述。
在上述步骤1a(step 1a)中，将化合物7a溶解在溶剂中，并加入三乙胺、分批加入三苯基氯甲烷，在室温下进行反应。反应完全后，获得中间化合物7b。
作为在上述步骤1a的反应中使用的有机溶剂，可列举出例如：二氯甲烷、氯仿、甲苯、四氢呋喃、N，N-二甲基甲酰胺、乙腈、甲醇、乙醇、异丙醇以及它们的混合物。
在上述步骤1b(step 1b)中，将化合物7b溶解在1，4-二氧六环/水(50∶50)中，并加入氢氧化钠，继续搅拌反应直至原料消失。减压蒸出1，4-二氧六环，调节pH至2-3，搅拌、过滤，水洗滤饼，至滤液中性，收集并干燥滤饼，得到化合物7c。
在上述步骤1(step 1)中，将化合物1、二苯基溴甲烷分散于有机溶剂中，并于室温下搅拌，加入DBU(1，8-二氮杂二环-十一碳-7-烯)，升温至70-80℃，搅拌反应直至原料不再减少后，降温至室温。萃取反应液，合并有机相，干燥，浓缩得残余物，柱层析分离得化合物2。
作为在上述步骤1的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N，N-二甲基甲酰胺等。
在上述步骤2(step 2)中，将化合物2、二苯基磷酰羟胺分散于有机溶剂中，氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠，恒温搅拌反应 直至反应物转化完全，向反应液中加入饱和氯化钠溶液，搅拌并滤除不溶物，得到化合物3。
作为在上述步骤2的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N，N-二甲基甲酰胺等。
在上述步骤3(step 3)中，将化合物7c分散于有机溶剂中，室温搅拌下，加入化合物3的甲醇溶液，恒温搅拌反应直至原料转化完全，柱层析得到化合物4。
作为在上述步骤3的反应中使用的有机溶剂，可列举出例如：甲醇、乙醇、异丙醇、N，N-二甲基甲酰胺等。
在上述步骤4(step 4)中，将化合物4分散于有机溶剂中，分别加入HATU(2-(7-氧化苯并三氮唑)-N，N，N’，N’-四甲基脲六氟磷酸酯)、NaHCO3、化合物8，室温搅拌反应直至原料转化完全，柱层析得到化合物5。
作为在上述步骤4的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N，N-二甲基甲酰胺等。
在上述步骤5(step 5)中，将化合物5溶解于有机溶剂中，于-5～-10℃搅拌，向其中加入三乙基硅烷及三氟乙酸，恒温反应至反应完全，室温减压蒸除溶剂，分离得到目标产物、即通式(I)化合物。
作为在上述步骤5的反应中使用的有机溶剂，可列举出例如：无水二氯甲烷、甲苯、四氢呋喃、N，N-二甲基甲酰胺等。
虽然本文示例性地描述了式(I)化合物的制备方法，但对于本领域技术人员明显的是，该制备方法仅以示例的方式提供，绝不限制本发明。
组分(b)
本发明的药物组合物中包含组分(b)内酰胺酶抑制剂或外排泵抑制剂。
在一个实施方案中，内酰胺酶抑制剂为二氮杂双环辛酮类β-内酰胺酶抑制剂。在一个实施方案中，二氮杂双环辛酮类β-内酰胺酶抑制剂特别是选自阿维巴坦、法硼巴坦和瑞莱巴坦。
Figure PCTCN2021129609-appb-000007
在一个实施方案中，所述外排泵抑制剂选自小檗碱、锥丝碱和PaβN：
Figure PCTCN2021129609-appb-000008
虽然本文示例性地描述了组分(b)的化合物，但对于本领域技术人员明显的是，这些化合物仅以示例的方式提供，绝不限制本发明。
出乎意料地发现，本发明的药物组合物具有优异的抗微生物效果，其与现有技术已知的抗微生物剂相比，活性更强，并且针对同样的微生物，能够以更少的用量使用。如此，通过施用本发明的药物组合物，对人或动物产生的副作用更小，耐受性更好，并且可更少地产生耐药性。
本发明的药物组合物具有优异的抗微生物效果，尤其是对于革兰氏阴性菌，诸如大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、阴沟肠杆菌、产气肠杆菌、伤寒沙门菌、粘质沙雷氏菌、弗劳地枸橼酸菌、雷极普鲁菲登杆菌、普通变形杆菌、奇异变形杆菌、嗜麦芽假单胞菌、福氏志贺菌等具有优异的抗菌活性，且耐药性低。
在一个实施方案中，细菌为例如肺炎克雷伯菌、大肠埃希菌、阴沟肠杆菌。在另一个实施方案中，细菌为鲍曼不动杆菌、铜绿假单胞菌。但是本领域技术人员应理解，这些细菌仅为示例性的，绝不限制本发明。
在一个具体的实施方案中，细菌为例如肺炎克雷伯菌ATCC2146、ATCC700603、CCPM(A)-0814R18、CCPM(A)-0814R33、CCPM(A)-081301、CCPM(A)-081705、CCPM(A)-081715、 CCPM(A)-081729、CCPM(A)-081716和CCPM(A)-0817R61，大肠埃希菌ATCC2469和CCPM(A)-P-071301，阴沟肠杆菌CCPM(A)-P-111729和ATCC2468。在另一个实施方案中，细菌为鲍曼不动杆菌ATCC 19606、ATCC 17978、CCPM(A)-P-101633(CRAB)，铜绿假单胞菌ATCC27853、PAO1(CCPM(A)-P-09000032)、CCPM(A)-P-091626(CRPA)。
在一个实施方案中，本发明的药物组合物包含至少一种式(I)化合物、至少一种β-内酰胺酶抑制剂和/或至少一种外排泵抑制剂。在一个实施方案中，本发明的药物组合物包含至少一种式(I)化合物、至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂和/或至少一种选自小檗碱、锥丝碱和PaβN的外排泵抑制剂。
在一个实施方案中，本发明的药物组合物包含至少一种选自式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)和式(I-6)的化合物、至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂和/或至少一种选自小檗碱、锥丝碱和PaβN的外排泵抑制剂。在一个实施方案中，本发明的药物组合物包含至少一种选自式(I-1)和式(I-2)的化合物、至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂和/或至少一种选自小檗碱、锥丝碱和PaβN的外排泵抑制剂。在一个实施方案中，本发明的药物组合物包含式(I-1)化合物以及至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂。在另一个实施方案中，本发明的药物组合物包含式(I-1)化合物以及至少一种选自小檗碱、锥丝碱和PaβN的外排泵抑制剂。在另一个实施方案中，本发明的药物组合物包含式(I-2)化合物以及至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂。在另一个实施方案中，本发明的药物组合物包含式(I-2)化合物以及至少一种选自小檗碱、锥丝碱和PaβN的外排泵抑制剂。
在另一个实施方案中，本发明的药物组合物包含式(I-1)化合物、至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂以及至少一种选自小檗碱、锥丝碱和PaβN的外排泵抑制剂。在另一个实施方案中，本发明的药物组合物包含式(I-2)化合物、至少一种选自阿维巴坦、法硼巴坦和瑞莱巴坦的β-内酰胺酶抑制剂以及至少一种选自小檗 碱、锥丝碱和PaβN的外排泵抑制剂。此处，式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)和式(I-6)的化合物具有上文所述的含义。
在本发明的药物组合物中，本发明的化合物和内酰胺酶抑制剂或外排泵抑制剂表现出协同作用。本发明的化合物与内酰胺酶抑制剂或外排泵抑制剂联用，同时降低了本发明的化合物和内酰胺酶抑制剂或外排泵抑制剂的最低抑菌浓度；并且部分抑菌浓度指数(fractional inhibitory concentration index，FICI)≤0.5，表明两者具有协同作用。
在一个实施方案中，其中组分(a)和组分(b)的重量比例为1∶0.3至1∶10，优选1∶0.5至1∶7，更优选1∶0.8至1∶6，最优选1∶1至1∶5。
本发明的化合物或本发明的药物组合物的最佳给药剂量和间隔是由化合物性质和诸如给药的形式、路径和部位以及治疗的特定哺乳动物等外部条件决定的，这一最佳给药剂量可用常规的技术确定。最佳的疗程，即本发明的化合物或本发明的药物组合物在额定的时间内每日的剂量，可用本领域内公知的方法确定。
在一个实施方案中，本发明的药物组合物的单次施用量为1-5000mg活性成分/kg体重，优选2-4000mg化合物/kg体重，更优选5-3000mg活性成分/kg体重，特别优选10-1000mg活性成分/kg体重，还优选13-500mg活性成分/kg体重，例如14-300mg活性成分/kg体重、15-200mg活性成分/kg体重，最优选15-100mg活性成分/kg体重。在一个实施方案中，本发明的化合物每日施用至少一次，例如每日1、2、3、4或每日5次。优选地，本发明的化合物每日施用1、2或3次。此处，术语“活性成分”是指本发明的化合物以及内酰胺酶抑制剂或外排泵抑制剂。
本发明的药物组合物还任选地包含可药用载体、赋形剂和/或其他助剂。当包含可药用载体、赋形剂和/或其他助剂时，通常将有效剂量的本发明的药物组合物以及一种或多种可药用载体、赋形剂和/或其他助剂结合制成适当的施用形式或剂量形式，这一程序包括通过合适的方法将组分混合、粒化、压缩或溶解。载体在药物组合物中的含量可以是1至98重量％，通常大约占到80重量％。为方便起见，局部麻醉剂、防腐剂、缓冲剂等其他助剂可直接溶于载体中。因此，本发明提供了药物组合物，包括本发明的式(I)化合物、或其立体异构体、溶剂合物或可药用盐或酯以及可药用载体、赋形剂和/或其他助剂。
本发明还提供本发明的药物组合物用作抗微生物剂的用途。在用途发明中，术语“微生物”具有与关于药物组合物的描述中相同的含义。
此外，本发明还提供本发明的药物组合物在生产用于治疗感染性疾病的药物中的用途。
另外，本发明还提供一种治疗感染性疾病的方法，其包括对人或动物给药组分(a)和组分(b)。此处，组分(a)和组分(b)具有上文描述的含义。在一个实施方案中，组分(a)和组分(b)为分开制备的药物形式。在一个实施方案中，本发明的方法组分(a)和组分(b)的给药间隔时间不超过4小时，优选不超过3小时，更优选不超过2小时，还更优选不超过1小时，特别优选不超过30分钟，最优选同时给药组分(a)和组分(b)，例如以包括两种组分的药物组合物形式，即如本发明的组合物形式。
在一个实施方案中，本发明的治疗感染性疾病的方法包括对人或动物给药本发明的药物组合物。
给药
本发明的药物组合物可以以下面的任意方式给药：口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入，或借助一种外植的储器用药，其中优选口服、肌注、腹膜内或静脉内用药方式。
本发明的药物组合物可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂、缓释剂。
口服片剂和胶囊可以用制药学上公知的方法制备，片剂还可以包衣。
口服液可以制成水和油的悬浮液、溶液、乳浊液、糖浆，也可以制成干品，用前补充水或其他合适的媒质。如需要可添加调味剂或着色剂。
栓剂可包含常规的栓剂基质，如可可黄油或其他甘油酯。
对胃外给药，液态剂型通常由本发明的药物组合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同，药物组合物既可溶于载体也可制成悬浮溶液，在制成注射用溶液时先将药物组合物溶于 水中，过滤消毒后装入封口瓶或安培中。
还可以制成注射用无菌制剂，包括结晶粉针、冻干粉针等。
当皮肤局部施用时，本发明的药物组合物可以制成适当的软膏、洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的载体中。
以下通过实施例更详细地描述本发明。
制备实施例
制备实施例1：式(I-1)化合物的合成
Figure PCTCN2021129609-appb-000009
步骤1a(Step 1a)：将化合物7a(1.0mmol)溶于DMF(10.0v/g)中，加入三乙胺(2.0mmol)，分批加入三苯基氯甲烷(1.2mmol)，室温搅拌反应6小时，TLC监测，反应完全后，加入水/乙酸乙酯萃取，合并有机相，干燥浓缩，柱层析分离得目标化合物7b。
步骤1b(Step 1b)：将化合物7b(1.0mmol)溶于1，4-二氧六环(5v/g)/水(5v/g)，于室温搅拌，加入氢氧化钠(5.0mmol)，继续搅拌反应，TLC监测，原料消失，减压蒸出1，4-二氧六环，将pH调至2-3，搅拌10分钟，过滤，水洗滤饼，至滤液中性，收集并干燥滤饼，得化合物7c。
步骤1(Step 1)：将化合物1a
Figure PCTCN2021129609-appb-000010
(1.0mmol)、二苯基溴甲烷(1.1mmol)分散于甲苯溶液(10.0v/g)中，并于室温下搅拌，加入DBU(1.5mmol)，升温至70-80℃，搅拌反应12-16小时，TLC监控原料不再减少后，降温至室温，加入水(10.0v/g x 2)萃取反应液，乙酸乙酯(10v/g x 2)反洗水层，合并有机相，干燥，浓缩得残余物，柱层析分离得透明油状化合物2a(后固化)[1H NMR(400MHz，CDCl3)δ(ppm)7.42-7.31(m，10H)，6.96(s，1H)，1.44(dd，J＝8.1，4.9Hz，2H)，1.25(dd，J＝8.1，4.9Hz，2H)]。
步骤2(Step 2)：将化合物2a(1.0mmol)、二苯基磷酰羟胺(1.1mmol)分散于无水四氢呋喃溶液(10.0v/g)中，氮气抽排3-4次，于0℃搅拌，然后 加入叔丁醇钠(1.5mmol)，恒温搅拌反应1-2小时，TLC监控，反应物转化完全，向反应液中加入饱和氯化钠溶液(5.0v/g)，搅拌30分钟后，滤除不溶物，乙酸乙酯洗涤滤饼，向滤液中加入乙酸乙酯(10.0v/g)，水(5.0v/g)，分液，水洗有机相一次，合并水相，乙酸乙酯反洗水相，合并有机相，干燥，浓缩得油状物3a[1H NMR(600MHz，DMSO)δ(ppm)7.46-7.27(m，10H)，6.84(s，1H)，6.36(s，2H)，1.30-1.22(m，4H)]。
步骤3(Step 3)：化合物7c分散于甲醇(10.0v/g)中，室温搅拌下，加入化合物3a的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，柱层析分离的类白色固体化合物4a[1H NMR(600MHz，DMSO)δ(ppm)8.84(s，1H)，7.51-7.15(m，25H)，6.86(s，2H)，1.48-1.28(m，4H)]。
步骤4(Step 4)：将化合物4a(1.0mmol)溶于DMF(10.0v/g)，室温搅拌，分别加入HATU(1.2mmol)，NaHCO 3(2.0mmol)，化合物8(1.3mmol)，继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，柱层析分离得类白色泡状固体化合物5a[1H NMR(600MHz，DMSO)δ(ppm)9.29(d，J＝7.9Hz，1H)，8.91(s，1H)，7.45-7.43(m，3H)，7.36-7.33(m，6H)，7.32-7.22(m，15H)，6.86(s，1H)，6.76(d，J＝0.5Hz，1H)，4.56(d，J＝7.9Hz，1H)，1.50-1.40(m，5H)，1.30(m，2H)，1.20(s，2H)]。
步骤5(Step 5)：将上述白色固体5a(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A，5um，10＊250mm，2.5mL/min，2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(I-1)。
1H NMR(600MHz，DMSO)δ(ppm)9.40(d，J＝7.9Hz，1H)，6.89(s，1H)，4.62(d，J＝8.0Hz，1H)，1.44(s，3H)，1.36(m，4H)，1.25(s，3H).13C NMR(151MHz，DMSO)δ(ppm)173.7，169.8，161.9，111.6，68.3，63.3，61.3，60.2，23.8，21.0，16.2. 13C NMR(151MHz，DMSO)δ173.7，169.8，161.9，111.6，68.3，63.3，61.3，60.2，23.8，21.0，16.2.HRMS：calculated for  C 14H 17N 5O 9S 2[M-H]462.0396，found 462.0394
制备实施例2：化合物(I-2)的合成
Figure PCTCN2021129609-appb-000011
化合物(I-2)的合成方法，参见(I-1)。
2b： 1H NMR(600MHz，DMSO)δ(ppm)7.44(d，J＝7.4Hz，4H)，7.37(t，J＝7.6Hz，4H)，7.29(t，J＝7.3Hz，2H)，6.83(s，1H)，5.87(s，1H)，2.47-2.40(m，2H)，2.16-2.07(m，2H)，1.89-1.74(m，2H).；
3b： 1H NMR(600MHz，DMSO)δ(ppm)7.35(ddd，J＝46.9，31.4，7.3Hz，10H)，6.85(s，1H)，6.11(s，2H)，2.35(ddd，J＝13.4，7.2，3.7Hz，2H)，2.22-2.09(m，2H)，1.92-1.74(m，2H).；
4b： 1H NMR(600MHz，DMSO)δ(ppm)8.58(s，1H)，7.50-7.15(m，25H)，6.78(s，1H)，6.12(s，1H)，2.42(s，2H)，2.25-2.22(m，2H)，1.96-1.69(m，2H).(含有50％杂质，参考z21e)；
式(I-2)化合物： 1H NMR(600MHz，DMSO)δ(ppm)9.56(d，J＝7.3Hz，1H)，6.89(s，1H)，4.66(d，J＝7.8Hz，1H)，2.45(s，2H)，2.35-2.19(m，2H)，1.99-1.79(m，2H)，1.46(s，3H)，1.32(s，3H). 13C NMR(151MHz，DMSO)δ(ppm)173.6，170.3，161.8，129.5，128.8，126.7，111.5，83.7，68.4，61.4，30.6，30.5，23.7，21.0，13.9.HRMS：calculated for C 15H 19N 5O 9S 2[M+Na]500.0516，found 500.0500.
参照制备实施例1的方法，并采用适当原料，制备式(I-3)至式(I-6)化合物。
式(I-3)化合物：1H NMR(600MHz，DMSO)δ(ppm)9.51(d，J＝7.6Hz，1H)，6.86(s，1H)，4.63(d，J＝7.7Hz，1H)，2.09-1.97(m，4H)，1.73-1.64(m，4H)，1.46(s，3H)，1.29(s，3H).13C NMR(151MHz，DMSO)δ(ppm)174.83，163.48，161.82，149.85，140.60，110.92，92.84，68.28，61.44， 35.83，24.64，24.51，23.75，20.91.HRMS：calculated for C 16H 21N 5O 9S 2[M-H]490.0708，found 490.0700.
式(I-4)化合物：1H NMR(600MHz，DMSO)δ(ppm)9.58(d，J＝7.5Hz，1H)，6.89(s，1H)，4.65(d，J＝7.6Hz，1H)，4.37(d，J＝5.2Hz，1H)，2.13-2.07(m，1H)，1.45(s，3H)，1.30(s，3H)，1.00-0.86(m，6H)。13C NMR(151MHz，DMSO)δ172.2，170.2，164.4，163.5，161.8，11.7，111.4，87.6，68.1，61.4，30.1，23.8，21.1，18.8，18.2.HRMS：calculated for C 15H 21N 5O 9S 2[M+Na]502.0673，found 502.0677
式(I-5)化合物：1H NMR(600MHz，DMSO)δ9.53(d，J＝7.4Hz，1H)，6.87(s，1H)，4.62(d，J＝7.5Hz，1H)，4.31(d，J＝5.7Hz，1H)，2.08(dd，J＝13.1，6.6Hz，1H)，1.45(s，3H)，1.30(s，3H)，0.96(dd，J＝15.5，6.7Hz，6H).13C NMR(151MHz，DMSO)δ172.4，169.9，166.0，163.6，161.8，111.2，110.1，87.6，68.2，61.4，30.2，23.9，20.9，19.0，18.3.HRMS：calculated for C 15H 21N 5O 9S 2[M+Na]502.0673，found 502.0661
式(I-6)化合物：1H NMR(600MHz，DMSO)δ9.37(s，1H)，6.72(s，1H)，4.60(d，1H)，4.22(s，1H)，2.02(s，1H)，1.43(s，3H)，1.29(s，3H)，0.93(s，6H).HRMS：calculated for C 17H23N 5O 9S2[M-H]504.0864，found 504.0850。
效果实施例
供试样品：化合物I-1、I-2、阿维巴坦、法硼巴坦和瑞莱巴坦，以及小檗碱、锥丝碱和PaβN；
阿维巴坦和小檗碱购自伊诺凯科技有限公司，法硼巴坦和瑞莱巴坦购自上海麦克林生化科技有限公司，锥丝碱购自百灵威科技有限公司，PaβN购自MedChemExpress。
供试菌株：来源于美国模式菌种收集中心(American Type Culture Collection；ATCC)，以及中国医学科学院病原微生物菌(毒)种保藏中心-药用微生物相关菌(毒)种保藏分中心(CAMS-CCPM-A)，公众可从该保藏中心获得这些菌株(详见表1至表5)；
单独的化合物的抗微生物活性评价方法(MIC测定)
水解酪蛋白胨肉汤(Mueller-Hinton broth，MH肉汤)培养基、胰酪大豆胨肉汤(TSB肉汤)培养基：购自BD Difco，Cockeysville，MD，USA；
96孔板：Corning Costar，Cambridge，MA，USA；
测试方法：按照CLSI/NCCLS标准，采用微稀释法及进行抑菌活性测定。
(1)供试样品配制：每种样品4mg，将药物用MH肉汤配制成1024μg/mL的供试溶液，在96孔板中经对倍稀释，配制成系列梯度浓度，各孔体积为90μL。
(2)菌液的制作：按照CLSI/NCCLS标准，胰酪大豆胨肉汤(TSB肉汤)扩增试验菌株。
(3)加样：配制6×10 5cfu/mL浓度的菌液，吸取10μL至96孔板各孔。每个浓度设三个平行试验，取其平均值。阴性对照组加入10μl菌液以及90μL MH肉汤。
(4)培养：将96孔板置于37℃恒温培养箱18小时；观察菌株生长情况，无菌生长的孔中所含药物浓度即为测得的MIC。
体外联合用药研究方法
水解酪蛋白肉汤(Mueller-Hinton broth，MH肉汤)培养基、胰酪大豆胨肉汤(TSB肉汤)培养基：购自BD Difco，Cockeysville，MD，USA；
96孔板：Corning Costar，Cambridge，MA，USA；
测试方法：棋盘稀释法测定。
(1)供试样品配制：每种样品4mg，将药物用MH肉汤配制成2048μg/mL的供试溶液，在96孔板中经对倍稀释，配制成系列梯度浓度。
(2)菌液的制作：按照CLSI/NCCLS标准，胰酪大豆胨肉汤(TSB肉汤)扩增试验菌株。
(3)加样：吸取10μL6×10 5CFU/mL的菌液加入到96微孔板的每个孔中，每个孔中含有用肉汤两倍稀释浓度的抗菌药物式(I-1)化合物、式(I-2)化合物以及上述内酰胺酶抑制剂或外排泵抑制剂。使得式(I-1)化合物、式(I-2)化合物样品的实际浓度分别为64.0、32.0、16.0、8.0、4.0、2.0、1.0、和0.0μg/mL，内酰胺酶抑制剂或外排泵抑制剂样品的实际浓度分别为256、128、64、32.0、16.0、8.0、4.0、2.0、1.0、0.5、0.25和0.0μg/mL， 充分混匀，每个浓度设三个平行试验，取其平均值。阴性对照组加入10μl菌液以及90μL水解酪蛋白肉汤。
(4)培养：将96孔板置于37℃恒温培养箱18小时；观察菌株生长情况。
(5)计算：每种药物与抑制剂的体外联合使用效果通过计算FICI值进行分析，FICI＝(联合用药中的A药的MIC/A药单独使用的MIC)+(联合用药中的B药的MIC/B药单独使用的MIC)。当FICI≤0.5时，两种药物具有良好的协同效应；0.5＜FICI＜4时，说明两种药物无协同效应；FICI≥4时，说明两种药物具有拮抗效应。
为保证数据可靠，分别在不同日期进行三次重复试验，取其平均值。
效果实施例1
根据上文描述的测定方法，对式(I-1)化合物和式(I-2)化合物以及β-内酰胺酶抑制剂单独的抗肠杆菌的MIC进行了测定，测试结果见表1。
Figure PCTCN2021129609-appb-000012
由表1可见，对于某些耐药肠杆菌，如肺炎克雷伯菌ATCC 2146、ATCC700603、CCPM(A)-0814R18、CCPM(A)-0814R33、CCPM(A)-081705、CCPM(A)-081715和CCPM(A)-081729，大肠埃希菌ATCC2469和CCPM(A)-P-071301，阴沟肠杆菌17-19和ATCC2468，式(I-1)化合物和式(I-2)化合物的MIC值介于0.5-4μg/mL之间；对于肺炎克雷伯菌CCPM(A)-081716和CCPM(A)-0817R61，式(I-1)化合物和式(I-2)化合物的MIC值分别介于32-128μg/mL之间。β-内酰胺酶抑制剂阿维巴坦、法硼巴坦和瑞莱巴坦本身对上述肠杆菌表现出较弱的活性。
效果实施例2
根据上文描述的棋盘法测定方法，对式(I-1)化合物和式(I-2)化合物与β-内酰胺酶抑制剂的联合用药的抗肠杆菌的MIC进行了测定，测试结果见表2A至2C和表3。其中，表2A至2C示出了式(I-1)化合物分别与阿维巴坦、法硼巴坦和瑞莱巴坦联用后的抗菌谱数据。表3示出了式(I-2)化合物与阿维巴坦联用后的抗菌谱数据。
表2A式(I-1)化合物与阿维巴坦联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000013
表2B式(I-1)化合物与法硼巴坦联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000014
表2C式(I-1)化合物与瑞莱巴坦联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000015
表3式(I-2)化合物与阿维巴坦联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000016
与阿维巴坦联用后，式(I-1)化合物对所测的12株耐药肠杆菌菌株的MIC值均显著降低，并显示出协同作用(FICI＜0.5)。与法硼巴坦和瑞莱巴坦联用后，式(I-1)化合物对某些耐药肠杆菌菌株的MIC值降低，并且与法硼巴坦和瑞莱巴坦均显示出协同作用(FICI＜0.5)。这表明式(I-1)化合物与二氮杂双环辛酮类β-内酰胺酶抑制剂，如阿维巴坦、法硼巴坦和瑞莱巴坦的复方制剂具有开发成为临床治疗多药耐药革兰氏阴性肠杆菌感染药物的巨大潜力。
与阿维巴坦联用后，式(I-2)化合物对所测的4株耐药肠杆菌菌株的MIC值均显著降低，并显示出协同作用(FICI＜0.5)。这表明式(I-2)化合物与β-内酰胺酶抑制剂，如阿维巴坦的复方制剂也具有开发成为临床治疗多药耐药革兰氏阴性肠杆菌感染药物的巨大潜力。
效果实施例3
根据上文描述的测定方法，对式(I-1)化合物和外排泵抑制剂单独的抗鲍曼不动杆菌或绿脓不动杆菌的MIC进行了测定，测试结果见表4。
表4单独的化合物的抗鲍曼不动杆菌和绿脓不动杆菌的MIC数据
Figure PCTCN2021129609-appb-000017
Figure PCTCN2021129609-appb-000018
由表4可见，对于多种鲍曼不动杆菌和抗铜绿假单胞菌的菌株，化合物式(I-1)化合物的MIC值介于16-32μg/mL之间。外排泵抑制剂小檗碱、锥丝碱和PaβN对上述多种鲍曼不动杆菌和抗铜绿假单胞菌的菌株表现出较弱的活性。
效果实施例4
根据上文描述的测定方法，对化合物式(I-1)化合物与外排泵抑制剂小檗碱、锥丝碱和PaβN的联合用药的抗菌的MIC进行了测定，测试结果见表5A至表5C。
表5A化合物式(I-1)化合物与小檗碱联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000019
＊表示在所测的浓度范围内均未观察到协同作用
表5B化合物式(I-1)化合物与锥丝碱联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000020
NT：未测试。
表5C化合物式(I-1)化合物与PAβN联用的MIC值和协同作用
Figure PCTCN2021129609-appb-000021
＊表示在所测的浓度范围内均未观察到协同作用
与小檗碱联用后，式(I-1)化合物对2株耐药鲍曼不动杆菌菌株ATCC19606和ATCC17978的MIC值降低了4倍，并且式(I-1)化合物和小檗碱显示出协同作用(FICI＜0.5)。与锥丝碱联用后，式(I-1)化合物对耐药鲍曼不动杆菌菌株ATCC19606的MIC值降低了4倍，并且式(I-1)化合物和锥丝碱显示出协同作用(FICI＜0.5)。
与PAβN联用后，式(I-1)化合物对2株耐药铜绿假单胞菌株ATCC27853和PAO1(CCPM(A)-P-09000032)的MIC值均降低了8倍，并显示出协同作用(FICI＜0.5)；对耐药铜绿假单胞菌CCPM(A)-P-091626(CRPA)的MIC值降低了4倍，同样式(I-1)化合物和PAβN显示出协同抗菌作用(FICI≤0.5)。
以上结果表明，式(I-1)化合物与小檗碱或锥丝碱的复方制剂具有开发成为临床治疗鲍曼不动杆菌感染药物的潜力，式(I-1)化合物与PAβN的复方制剂具有开发成为临床治疗铜绿假单胞菌感染药物的巨大潜力。
效果实施例5：体内联合用药研究
使用ICR小鼠，外观健康，体重为18至22g，雌、雄各半。小鼠随机分组，每个剂量组5只，性别不限。包含产NDM-1的肺炎克雷伯菌的试验菌液用5％高活性干酵母稀释，小鼠腹腔注入100％最小致死量(100％MLD，3.0×10 6CFU/鼠)的菌液0.5mL。
对腹腔感染产NDM-1的肺炎克雷伯菌(感染菌量：3.0×10 6CFU)小鼠，分别于感染后1h和6h以一定剂量(参见表5)尾静脉给药一次，共 给药2次，给药体积为10mL/kg，观察7天内各组动物存活情况，并计算小鼠的存活率。对照组不施用任何药物，仅施用生理盐水，小鼠的七天存活率为0。
式(I-1)化合物单独和式(I-1)化合物与阿维巴坦联合用药对肺炎克雷伯菌ATCC BAA2146(NDM-1)全身感染小鼠的保护作用见表5。本领域技术人员公知的是，阿维巴坦本身对该试验菌株无体内抗菌作用。
表5式(I-1)化合物和阿维巴坦静脉注射对肺炎克雷伯菌ATCC BAA2146(NDM-1)腹腔感染小鼠的作用的体内试验
Figure PCTCN2021129609-appb-000022
由表5可见，对腹腔感染产NDM-1的肺炎克雷伯菌(感染菌量：3.0×10 6CFU)小鼠，分别于感染后1小时和6小时以32mg/kg的剂量尾静脉给药注射式(I-1)化合物，小鼠七天存活率为60％；分别于感染后1小时和6小时以16mg/kg的剂量尾静脉注射式(I-1)化合物，小鼠七天存活率为20％。
阿维巴坦本身对该试验菌株无体内抗菌作用，但是其与式(I-1)化合物联合给药后可大大增强后者的体内抗菌活性。在式(I-1)化合物以32mg/kg和16mg/kg的给药剂量下，分别与一倍量、二倍量和三倍量的阿维巴坦联合给药，小鼠的七天存活率均达到100％。这表明式(I-1)化合物与阿维巴坦在体内的联用可表现出显著的协同抗菌作用。
虽然本文已经示出并描述了本发明的优选实施方案，但对于本领域技术人员明显的是，这些实施方案仅以示例的方式提供。在不脱离本发明的情况下，本领域技术人员将会想到许多变化、改变和替换。应当理解，可采用本文所述的本发明的实施方案的各种替换方案来实践本发明。旨在由以下权利要求限定本发明的范围，并且由其涵盖这些权利要求范围内的方法和结构及其等同物。

Claims (14)

  1. 一种药物组合物，其包含：
    (a)一种式(I)化合物，或其立体异构体、溶剂合物和可药用盐或酯，
    Figure PCTCN2021129609-appb-100001
    其中
    R 1和R 2各自独立地表示氢、烷基、芳基、烷氧基、芳氧基、芳基烷基、烷基羰基烷基、烷基酰氧基烷基或烷氧基酰氧基烷基、杂环基、杂芳基，或者R 1和R 2一起形成环烷基；所有上述基团任选地被取代；
    R 3和R 4各自独立地表示氢、烷基、芳基、烷氧基、芳氧基、芳基烷基、烷基羰基烷基、烷基酰氧基烷基或烷氧基酰氧基烷基、杂环基、杂芳基，或者R 3和R 4一起形成环烷基；所有上述基团任选地被取代；
    Y表示任选取代的烯基或炔基，或表示羧基或酯基；和
    (b)一种内酰胺酶抑制剂或外排泵抑制剂。
  2. 根据权利要求1所述的药物组合物，其中，在所述式(I)化合物中，
    R 1和R 2各自独立地表示氢、任选取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基；或者R 1和R 2一起形成(C 3-C 6)环烷基；
    R 3和R 4各自独立地表示氢、任选取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基；任选取代的(C 6-C 12)-芳基；或者R 3和R 4一起形成(C 3-C 6)环烷基；并且
    Y表示乙烯基、丙烯基、异丙烯基、烯丙基、正丁烯基、异丁烯基、2-甲基丙烯基、乙炔基、丙炔基、异丙炔基、炔丙基、正丁炔基、异丁炔基、2-甲基丙炔基、羧基，以及-COOR 5，其中R 5为(C 1-C 12)-烷基，其实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1,2-二甲基丙基、己基。
  3. 根据权利要求1或2所述的药物组合物，其中，在所述式(I)化合 物中，
    R 1和R 2各自独立地表示氢、任选取代的甲基、乙基；
    R 3和R 4各自独立地表示氢、任选取代的甲基、乙基、正丙基、异丙基，或者R 3和R 4一起形成(C 3-C 6)环烷基；并且
    Y表示乙烯基、丙烯基、乙炔基、丙炔基、羧基，以及-COOR 5，其中R 5为甲基、乙基、正丙基、异丙基。
  4. 根据前述权利要求任一项所述的药物组合物，其中所述式(I)化合物选自：
    Figure PCTCN2021129609-appb-100002
    Figure PCTCN2021129609-appb-100003
  5. 根据前述权利要求中任一项所述的药物组合物，其中所述内酰胺酶抑制剂选自阿维巴坦、法硼巴坦和瑞莱巴坦，
    Figure PCTCN2021129609-appb-100004
  6. 根据前述权利要求中任一项所述的药物组合物，其中所述外排泵抑制剂为小檗碱、锥丝碱和PaβN，
    Figure PCTCN2021129609-appb-100005
  7. 根据前述权利要求中任一项所述的药物组合物，其中组分(a)和组分(b)的重量比例为1:0.3至1:10，优选1:0.5至1:7，更优选1:0.8至1:6，最优选1:1至1:5。
  8. 根据前述权利要求中任一项所述的药物组合物，其还包含可药用 载体、赋形剂和/或其他助剂。
  9. 根据前述权利要求中任一项所述的药物组合物用作抗微生物剂的用途。
  10. 根据权利要求9所述的用途，其中所述微生物为细菌，尤其是革兰氏阴性菌，诸如大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、阴沟肠杆菌、产气肠杆菌、伤寒沙门菌、粘质沙雷氏菌、弗劳地枸橼酸菌、雷极普鲁菲登杆菌、普通变形杆菌、奇异变形杆菌、嗜麦芽假单胞菌和福氏志贺菌。
  11. 根据权利要求9或10所述的用途，其中所述微生物为肺炎克雷伯菌、大肠埃希菌、阴沟肠杆菌、鲍曼不动杆菌和铜绿假单胞菌。
  12. 根据权利要求9-11中任一项所述的用途，其中组分(b)为选自阿维巴坦、法硼巴坦和瑞莱巴坦的二氮杂双环辛酮类β-内酰胺酶抑制剂，
    Figure PCTCN2021129609-appb-100006
    ；并且
    所述微生物选自肺炎克雷伯菌、大肠埃希菌和阴沟肠杆菌。
  13. 根据权利要求9-12中任一项所述的用途，其中组分(b)为选自小檗碱、锥丝碱和PaβN的外排泵抑制剂：
    Figure PCTCN2021129609-appb-100007
    并且
    所述微生物选自鲍曼不动杆菌和铜绿假单胞菌。
  14. 根据权利要求1-8中任一项所述的药物组合物在生产用于治疗感染性疾病的药物中的用途。
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