CN113975396B - Pharmaceutical composition containing beta-lactam compound and application thereof - Google Patents
Pharmaceutical composition containing beta-lactam compound and application thereof Download PDFInfo
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Abstract
The invention relates to pharmaceutical compositions comprising a beta-lactam compound of formula (I), wherein the indices are as defined in the description, or stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof, and a lactamase inhibitor or efflux pump inhibitor, and to the use thereof against microorganisms, in particular bacteria, especially gram-negative bacteria.
Description
Technical Field
The present invention relates to pharmaceutical compositions comprising beta-lactams, and their use for combating microorganisms, in particular bacteria, especially gram-negative bacteria.
Background
Beta-lactam antibiotics (beta-lactams) refer to a large class of antibiotics with a beta-lactam ring in the chemical structure. Various beta-lactam antibiotics are known. The antibiotic has the advantages of strong bactericidal activity, low toxicity, wide adaptation and good clinical curative effect.
However, with the wide clinical use of antibiotics, some resistance has emerged, and the antimicrobial effect is not always satisfactory in some aspects. Therefore, there is a need to develop a new antimicrobial drug, which has an excellent antimicrobial effect.
Disclosure of Invention
The present invention has been made to overcome the above-mentioned disadvantages of the prior art.
The present invention provides a pharmaceutical composition comprising
(a) A compound of formula (I), or stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof,
wherein
R 1 And R 2 Each independently represents hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkanoyloxyalkyl or alkoxyacyloxyalkyl, heterocyclyl, heteroaryl, or R 1 And R 2 Together form a cycloalkyl group; all of the above groups are optionally substituted;
R 3 and R 4 Each independently represents hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkanoyloxyalkyl or alkoxyacyloxyalkyl, 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 group or an ester group; and
(b) A lactamase inhibitor or efflux pump inhibitor.
The pharmaceutical compositions of the present invention may be used as such or together with pharmaceutically acceptable carriers, excipients or other adjuvants.
The invention also provides the use of the pharmaceutical composition of the invention as an antimicrobial agent.
Furthermore, the present invention provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of an infectious disease.
In addition, the present invention provides a method for treating infectious diseases, which comprises administering the pharmaceutical composition of the present invention to a human or an animal.
It has unexpectedly been found that the compounds of formula (I) or stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof in the pharmaceutical compositions of the present invention have a synergistic effect with respect to antimicrobial activity with respect to lactamase inhibitors or efflux pump inhibitors.
Detailed Description
General definitions
The compounds of formula (I) of the present invention, and stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof, are sometimes also referred to generally as "compounds of the invention".
The "pharmaceutical composition of the invention" comprises a compound of the invention and a lactamase inhibitor or an efflux pump inhibitor, and optionally a pharmaceutically acceptable carrier, excipient and/or other auxiliary agent.
The terms "optional," "optional," or "optionally" as used herein mean that the subsequently described event, circumstance, or substance may or may not be present, and that the description includes instances where the event, circumstance, or substance is present, and instances where the event, circumstance, or substance is not present, or is not present.
The terms "comprising" and its synonyms "including" and "containing" as used herein mean "including but not limited to", which is not intended to exclude, for example, other additives, components, integers or steps.
In the present invention, "microorganism" has a meaning well known in the art, and includes bacteria, viruses and fungi, and particularly means bacteria such as gram-positive bacteria, gram-negative bacteria and the like.
In the context of the present invention, unless otherwise defined differently, the term "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. (C) 1 -C 12 ) Examples of-alkyl 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. Among these alkyl groups, (C) is particularly preferred 1 -C 6 ) -an alkyl group. Particularly preferred is (C) 1 -C 4 ) -an alkyl group.
In the context of the present invention it is,unless otherwise defined differently, the term "cycloalkyl", by itself or in combination with other terms such as arylcycloalkyl, is understood to mean a saturated aliphatic cycloalkyl group having from 3 to 8 carbon ring atoms and which may be optionally substituted. (C) 3 -C 8 ) Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 7 -cycloalkyl and C 8 -a cycloalkyl group. The above groups may be optionally substituted.
In the present invention, the term "alkoxy", by itself or in combination with other terms such as carboxyalkylimino, is understood to mean alkyl-O-, wherein the term "alkyl" is as defined above. In particular, the alkyl group herein may be straight or branched.
According to the invention, unless defined otherwise, "alkylcarbonyl" (alkyl-C (= O) -) represents an alkyl group attached to the backbone via-C (= O) -, for example (C) 1 -C 10 )-、(C 1 -C 6 ) -or (C) 1 -C 4 ) -an alkylcarbonyl group. Here, the number of carbon atoms refers to the alkyl group in the alkylcarbonyl group.
According to the invention, the term "alkanoyloxy" (alkyl-C (= O) -O-), unless otherwise defined differently, represents an alkyl group attached to the backbone via the oxygen of an acyloxy (-C (= O) -O-), e.g. (C) 1 -C 10 )-、(C 1 -C 6 ) -or (C) 1 -C 4 ) -an alkanoyloxy group. Here, the number of carbon atoms refers to the alkyl group in the alkanoyloxy group.
According to the invention, the term "alkoxyacyloxy" (alkoxy-C (= O) -O-), unless otherwise defined differently, represents an alkoxy group which is bound to the backbone via the oxygen of an acyloxy (-C (= O) -O-), for example (C) 1 -C 10 )-、(C 1 -C 6 ) -or (C) 1 -C 4 ) -alkoxyacyloxy. Here, the number of carbon atoms refers to the alkyl group in the alkoxyacyloxy group.
According to the present invention, unless defined differently, the term "alkenyl" is understood to mean a hydrocarbon radical having at least one carbon-carbon double bond. Preferably, examples of alkenyl groups are ethenyl, propenyl, isopropenyl, allyl, n-butenyl, isobutenyl, 2-methylpropenyl, and the like.
According to the present invention, unless otherwise defined differently, the term "alkynyl" is understood to mean a hydrocarbyl group having at least one carbon-carbon triple bond. Preferably, examples of alkynyl groups are ethynyl, propynyl, isopropynyl, propargyl, n-butynyl, isobutynyl, 2-methylpropynyl, and the like.
According to the invention, unless defined differently, the term "ester group" is understood to mean having a-COOR group 5 A group of the structure (I) 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, 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 -C 6 ) -an alkyl group. Particularly preferably, R 5 Is (C) 1 -C 4 ) -an alkyl group.
Unless otherwise defined, "heterocyclyl" means a saturated or partially saturated monocyclic ring of carbon atoms and at least one heteroatom in the ring. Preferably, the heterocyclyl contains 3,4, 5,6 or 7 carbon atoms and 1 or 2 heteroatoms selected from oxygen, sulphur and nitrogen. Examples of heterocyclyl groups are azetidinyl, azacyclohexyl, oxetanyl, oxocyclopentyl, oxocyclohexyl, dioxanyl, thietanyl, and tetrahydrofuranyl.
According to the invention, unless defined differently otherwise, the term "aryl" is understood to mean an aromatic radical having from 6 to 14 carbon atoms, preferably phenyl, naphthyl, anthryl or phenanthryl, more preferably phenyl.
Unless otherwise defined differently, the term "arylalkyl" is understood to mean a combination of the groups "aryl" and "alkyl" defined according to the invention, wherein said groups are usually linked by an alkyl group. Examples thereof are benzyl, phenethyl or α -methylbenzyl, particularly preferably benzyl.
Unless otherwise defined differently, "heteroaryl" denotes a monocyclic, bicyclic or tricyclic heterocyclic group of carbon atoms and at least one heteroatom, wherein at least one ring is aromatic. Preferably, heteroaryl contains 3,4, 5 or 6 carbon atoms, selected from the group consisting of 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, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl 1,3,5-triazinyl, tetrazolyl, benzofuranyl, benzisothiafuranyl, benzothienyl, benzisothiathiophenyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, 2,1,3-benzoxadiazole, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl, and indolizinyl (indolizinyl).
When the basic structure is "substituted", this includes in each case simultaneous substitution by one or more identical and/or structurally different radicals.
The term "solvate" refers to a form of a compound or salt thereof associated with a solvent, typically formed by a solvolysis reaction. Such physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes a solvate in a solution state and a solvate which can be isolated. Representative solvates include hydrates, ethanolates, and methanolates.
If the compounds can form tautomers by hydrogen transfer in which the structure is not formally encompassed by formula (I), then these tautomers are still encompassed by the definition of compounds of formula (I) of the present invention, unless a specific tautomer is considered otherwise. For example, many carbonyl compounds may exist in both keto and enol forms, both of which are included in the definition of compounds of formula (I).
Depending on the nature of the substituents and the manner in which they are attached, the compounds of formula (I) may exist as stereoisomers. Possible stereoisomers, such as enantiomers, diastereomers, Z and E isomers, defined by their particular three-dimensional forms are included in formula (I). For example, if one or more alkenyl groups are present, diastereomers (Z and E isomers) may occur. For example, if one or more asymmetric carbon atoms are present, enantiomers and diastereomers may occur. Stereoisomers may be obtained from the mixtures obtained in the preparation by customary separation methods. Chromatographic separations can be performed on an analytical scale to find enantiomeric or diastereomeric excesses, or on a preparative scale to produce test samples for biological testing. Stereoisomers can likewise be prepared selectively by using stereoselective reactions with the use of 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 forms, and mixtures thereof.
The compounds of the formula (I) may, if appropriate, be present in various polymorphic forms or as a mixture of various polymorphic forms. Pure polymorphs and polymorph mixtures are provided by the present invention and may be used according to the present invention.
In the context of the present invention, the term "synergistic" has the meaning commonly understood by a person skilled in the art, e.g. an interaction in which the total effect obtained by the combination of two components is better than the sum of the effects of the individual components.
In the present invention, unless otherwise stated, all operations are carried out at room temperature under normal pressure.
In the present invention, the proportions of the individual components in the compositions, mixtures are based on weight, unless stated to the contrary.
Pharmaceutical composition
In one aspect, the present invention provides a pharmaceutical composition comprising
(a) A compound of formula (I), or stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof,
wherein
R 1 And R 2 Each independently represents hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkanoyloxyalkyl or alkoxyacyloxyalkyl, heterocyclyl, heteroaryl, or R 1 And R 2 Together form a cycloalkyl group; all of the above groups are optionally substituted;
R 3 and R 4 Each independently represents hydrogen, alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylcarbonylalkyl, alkanoyloxyalkyl or alkoxyacyloxyalkyl, 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 group or an ester group; and
(b) A lactamase inhibitor or an efflux pump inhibitor.
Component (a)
The pharmaceutical compositions of the present invention comprise component (a) a compound of formula (I), or stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof. The compounds of formula (I) as hereinbefore described provide a broad definition of the compounds of the invention. Preferred, more preferred, particularly preferred and most preferred substituents or ranges for the groups listed in formula (I) of the present invention will be described below.
Preferably, R 1 And R 2 Each independently represents hydrogen, and optionally substituted: (C) 1 -C 12 ) Alkyl radicals, (C) 6 -C 14 ) -aryl, (C) 1 -C 12 ) -alkoxy, (C) 1 -C 12 ) -alkylcarbonyl- (C) 1 -C 12 ) Alkyl radicals, (C) 1 -C 12 ) -alkanoyloxy- (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 ) A cycloalkyl group;
more preferably, R 1 And R 2 Each independently represents 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-ethylpropyl, 1, 2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl; or R 1 And R 2 Together form (C) 3 -C 6 ) A cycloalkyl group;
particularly preferably, R 1 And R 2 Each independently represents 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 ) A cycloalkyl group;
most preferably, R 1 And R 2 Each independently represents hydrogen, an optionally substituted methyl group, or an ethyl group.
Preferably, R 3 And R 4 Each independently represents hydrogen, and optionally substituted: (C) 1 -C 12 ) Alkyl radicals, (C) 6 -C 14 ) -aryl, (C) 1 -C 12 ) -alkoxy, (C) 1 -C 12 ) -alkylcarbonyl- (C) 1 -C 12 ) Alkyl radicals, (C) 1 -C 12 ) -alkanoyloxy- (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 ) A cycloalkyl group;
more preferably, R 3 And R 4 Each independently represents 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-ethylpropyl, 1, 2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl; optionally substituted (C) 6 -C 12 ) -an aryl group; or R 3 And R 4 Together form (C) 3 -C 6 ) A cycloalkyl group;
particularly preferably, R 3 And R 4 Each independently represents hydrogen, optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; optionally substituted (C) 6 -C 12 ) -an aryl group; or R 3 And R 4 Together form (C) 3 -C 6 ) A cycloalkyl group;
most preferably, R 3 And R 4 Each independently represents hydrogen, optionally substituted methyl, ethyl, n-propyl, isopropyl, or R 3 And R 4 Together form (C) 3 -C 6 ) A cycloalkyl group.
Preferably, Y represents an optionally substituted alkenyl or alkynyl group, or represents a carboxyl group or an ester group.
More preferably, 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 is 5 Is (C) 1 -C 12 ) Alkyl, examples being 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-nonylN-decyl, n-undecyl and n-dodecyl.
Particularly preferably, 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 is 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-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, hexyl.
Most preferably, Y represents ethenyl, propenyl, ethynyl, propynyl, carboxyl, and-COOR 5 Wherein R is 5 Methyl, ethyl, n-propyl and isopropyl.
The definitions or explanations of the individual broad or preferred groups of the abovementioned radicals can be combined with one another as desired, i.e. combinations between the respective broad ranges and the preferred ranges can be included. They apply both to the compounds of formula (I) and, correspondingly, to the stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof.
Preferred compounds of formula (I) according to the invention comprise combinations of the above preferred meanings.
More preferred compounds of formula (I) according to the invention comprise combinations of the above more preferred meanings.
Particularly preferred compounds of the formula (I) according to the invention comprise combinations of the abovementioned particularly preferred meanings.
The most preferred compounds of formula (I) according to the invention comprise combinations of the above most preferred meanings.
In a preferred embodiment, the compounds of formula (I) according to the invention are those wherein R is 1 Represents H, and R 2 Represents H, R 3 And R 4 A compound of formula (I-1) wherein cyclopropyl is taken together and Y is carboxy:
in another preferred embodiment, the compounds of formula (I) according to the invention are those wherein R is 1 Represents H, and R 2 Represents H, R 3 And R 4 A compound of formula (I-2) wherein R is cyclobutyl and Y is carboxy:
in another preferred embodiment, the compounds of formula (I) of the present invention are compounds selected from the group consisting of:
furthermore, stereoisomers, solvates and pharmaceutically acceptable salts or esters of the compounds of formula (I) may be obtained by conventional means known to those skilled in the art.
Although the compounds of formula (I) and stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof are described herein by way of example, it will be apparent to those skilled in the art that these compounds are provided by way of example only and are in no way limiting of the present invention.
Preparation of Compounds of formula (I)
The present invention also provides a process for preparing the aforementioned compounds:
the compounds of formula (I) were prepared by the scheme:
in the above formulas, PG 1 And PG 2 Represents a protecting group; r is 1 、R 2 、R 3 、R 4 And Y has the same meaning as above.
The carboxyl protecting group PG 1 Are carboxyl protecting groups commonly used in the art. The "carboxyl-protecting group" is not particularly limited as long as it is a protecting group having such a function, and examples thereof includeLower alkyl groups such as methyl, ethyl, propyl, isopropyl and tert-butyl, for example, halogenated lower alkyl groups such as 2, 2-trichloroethyl, for example, lower alkenyl groups such as allyl, for example, aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrosobenzyl, benzhydryl and trityl, and particularly, methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl and benzhydryl are preferred. The person skilled in the art can make a reasonable choice according to the actual needs. Preferably, PG 1 is-CHPh 2 (benzhydryl).
The amino protecting group PG 2 Are amino protecting groups commonly used in the art. The "amino-protecting group" is not particularly limited as long as it is a protecting group having such a function, and examples thereof include-Boc (t-butyloxycarbonyl), -Cbz (benzyloxycarbonyl), -Teoc (trimethylsilethoxycarbonyl), -Tos (p-toluenesulfonyl), -Trt (trityl) and-Bn (benzyl). The person skilled in the art can make a reasonable choice according to the actual needs. Preferably, PG 2 is-Boc (t-butyloxycarbonyloxy).
The reaction conditions of the reaction are conventional deprotection conditions, according to PG 1 And PG 2 E.g., a.g. myers, j.gleason, t.yoon, d.w.kung, j.am.chem.soc.,1997,119,656; and m.frankel, d.ladkany, c.gilon, y.wolman, tetrahedron lett, 1966,7, 4765.
In the above step 1a (step 1 a), the compound 7a is dissolved in a solvent, triethylamine is added thereto, triphenylchloromethane is added in portions, and the reaction is carried out at room temperature. After completion of the reaction, intermediate compound 7b was obtained.
Examples of the organic solvent used in the reaction of step 1a include: dichloromethane, chloroform, toluene, tetrahydrofuran, N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, and mixtures thereof.
In step 1b (step 1 b) above, compound 7b was dissolved in 1, 4-dioxane/water (50) and sodium hydroxide was added and the reaction was continued with stirring until the starting material disappeared. And (3) distilling the 1, 4-dioxane under reduced pressure, adjusting the pH to 2-3, stirring, filtering, washing a filter cake with water until the filtrate is neutral, collecting and drying the filter cake to obtain a compound 7c.
In the step 1, the compound 1 and the diphenylbromomethane are dispersed in the organic solvent, stirred at room temperature, added with DBU (1, 8-diazabicyclo-undec-7-ene), heated to 70-80 ℃, stirred for reaction until the raw materials are not reduced any more, and then cooled to room temperature. Extracting the reaction solution, combining organic phases, drying, concentrating to obtain a residue, and performing column chromatography separation to obtain a compound 2.
Examples of the organic solvent used in the reaction of step 1 include: dichloromethane, toluene, tetrahydrofuran, N-dimethylformamide, and the like.
In the step 2 (step 2), the compound 2 and diphenylphosphoryl hydroxylamine are dispersed in an organic solvent, nitrogen is pumped out for 3-4 times, the mixture is stirred at 0 ℃, sodium tert-butoxide is added, the mixture is stirred at a constant temperature for reaction until the reaction product is completely converted, a saturated sodium chloride solution is added into the reaction solution, and the mixture is stirred and insoluble substances are filtered out to obtain the compound 3.
Examples of the organic solvent used in the reaction of step 2 include: dichloromethane, toluene, tetrahydrofuran, N-dimethylformamide, and the like.
In the step 3 (step 3), the compound 7c is dispersed in an organic solvent, a methanol solution of the compound 3 is added while stirring at room temperature, the reaction is stirred at a constant temperature until the conversion of the raw material is completed, and column chromatography is performed to obtain the compound 4.
Examples of the organic solvent used in the reaction of step 3 include: methanol, ethanol, isopropanol, N-dimethylformamide, and the like.
In the step 4 (step 4), the compound 4 is dispersed in an organic solvent, HATU (2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate), naHCO3 and the compound 8 are respectively added, stirred at room temperature for reaction until the raw materials are completely converted, and the compound 5 is obtained by column chromatography.
Examples of the organic solvent used in the reaction of step 4 include: dichloromethane, toluene, tetrahydrofuran, N-dimethylformamide, and the like.
In the step 5 (step 5), the compound 5 is dissolved in an organic solvent, stirred at-5 to-10 ℃, added with triethylsilane and trifluoroacetic acid, reacted at constant temperature until the reaction is completed, and the solvent is removed by evaporation at room temperature under reduced pressure, and the target product, namely the compound of the general formula (I), is obtained by separation.
Examples of the organic solvent used in the reaction of step 5 include: anhydrous dichloromethane, toluene, tetrahydrofuran, N-dimethylformamide, and the like.
Although the preparation of the compounds of formula (I) is described herein by way of example, it will be apparent to those skilled in the art that this preparation is provided by way of example only and is in no way limiting of the invention.
Component (b)
The pharmaceutical composition of the present invention comprises component (b) a lactamase inhibitor or an efflux pump inhibitor.
In one embodiment, the lactamase inhibitor is a diazabicyclooctanone beta-lactamase inhibitor. In one embodiment, the diazabicyclooctanone beta-lactamase inhibitor is in particular selected from abamectin, faribatan and relibatan,
in one embodiment, the efflux pump inhibitor is selected from berberine, conosidine and Pa β N:
although the compounds of component (b) are described herein by way of example, it will be apparent to those skilled in the art that these compounds are provided by way of example only and in no way limit the invention.
It has surprisingly been found that the pharmaceutical composition of the invention has an excellent antimicrobial effect, is more active than antimicrobial agents known from the prior art and can be used in a smaller amount against the same microorganism. Thus, by administering the pharmaceutical composition of the present invention, fewer side effects are produced on humans or animals, better tolerability is achieved, and fewer resistance can be produced.
The pharmaceutical composition of the present invention has an excellent antimicrobial effect, particularly has excellent antimicrobial activity against gram-negative bacteria such as Escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, enterobacter cloacae, enterobacter aerogenes, salmonella typhi, serratia marcescens, kloelandica, klebsiella pneumoniae, proteus peru, proteus vulgaris, proteus mirabilis, pseudomonas maltophilia, shigella flexneri, etc., and has low drug resistance.
In one embodiment, the bacteria are, for example, klebsiella pneumoniae, escherichia coli, enterobacter cloacae. In another embodiment, the bacterium is acinetobacter baumannii, pseudomonas aeruginosa. It will be understood by those skilled in the art that these bacteria are merely exemplary and in no way limit the present invention.
In a particular embodiment, the bacteria are, 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. In another embodiment, the bacteria are Acinetobacter baumannii ATCC19606, ATCC17978, CCPM (A) -P-101633 (CRAB), pseudomonas aeruginosa ATCC27853, PAO1 (CCPM (A) -P-09000032), CCPM (A) -P-091626 (CRPA).
In one embodiment, the pharmaceutical composition of the invention comprises at least one compound of formula (I), at least one beta-lactamase inhibitor and/or at least one efflux pump inhibitor. In one embodiment, the pharmaceutical composition of the invention comprises at least one compound of formula (I), at least one beta-lactamase inhibitor selected from abamectin, faribatan and relibatan and/or at least one efflux pump inhibitor selected from berberine, conserpine and Pa β N.
In one embodiment, the pharmaceutical composition of the invention comprises at least one compound selected from the group consisting of formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5) and formula (I-6), at least one beta-lactamase inhibitor selected from abamectin, farobatan and relebatan and/or at least one efflux pump inhibitor selected from berberine, conosine and Pa β N. In one embodiment, the pharmaceutical composition of the invention comprises at least one compound selected from the group consisting of formula (I-1) and formula (I-2), at least one beta-lactamase inhibitor selected from abamectin, farabiptan and relebaptan, and/or at least one efflux pump inhibitor selected from berberine, conatine and Pa β N. In one embodiment, the pharmaceutical composition of the invention comprises a compound of formula (I-1) and at least one beta-lactamase inhibitor selected from avibactam, farbactam and releptian. In another embodiment, the pharmaceutical composition of the invention comprises a compound of formula (I-1) and at least one efflux pump inhibitor selected from berberine, conradine and Pa β N. In another embodiment, the pharmaceutical composition of the invention comprises a compound of formula (I-2) and at least one beta-lactamase inhibitor selected from avibactam, farebaptan and relebaptan. In another embodiment, the pharmaceutical composition of the invention comprises a compound of formula (I-2) and at least one efflux pump inhibitor selected from berberine, conradine and Pa β N.
In another embodiment, the pharmaceutical composition of the invention comprises a compound of formula (I-1), at least one beta-lactamase inhibitor selected from abamectin, faribatan and relibatan, and at least one efflux pump inhibitor selected from berberine, conoidine and Pa β N. In another embodiment, the pharmaceutical composition of the invention comprises a compound of formula (I-2), at least one beta-lactamase inhibitor selected from abamectin, faribatan and relibatan, and at least one efflux pump inhibitor selected from berberine, conoidine and Pa β N. Here, the compounds of the formula (I-1), the formula (I-2), the formula (I-3), the formula (I-4), the formula (I-5) and the formula (I-6) have the meanings indicated above.
In the pharmaceutical composition of the present invention, the compound of the present invention and the lactamase inhibitor or the efflux pump inhibitor show a synergistic effect. The compound is combined with a lactamase inhibitor or an efflux pump inhibitor, and simultaneously the minimum inhibitory concentration of the compound and the lactamase inhibitor or the efflux pump inhibitor is reduced; and partial bacteriostatic concentration index (FICI) is less than or equal to 0.5, which indicates that the two have synergistic action.
In one embodiment, wherein the weight ratio of component (a) to component (b) is 1.
The optimal dosage and interval of administration of a compound of the invention or a pharmaceutical composition of the invention will be determined by the nature of the compound and external conditions such as the form, route and site of administration and the particular mammal being treated, and such optimal dosage can be determined by conventional techniques. The optimal course of treatment, i.e., the daily dosage of a compound of the invention or a pharmaceutical composition of the invention over a nominal period of time, can be determined by methods well known in the art.
In one embodiment, the pharmaceutical composition of the invention is administered in a single dose of 1 to 5000mg of active ingredient per kg body weight, preferably 2 to 4000mg of compound per kg body weight, more preferably 5 to 3000mg of active ingredient per kg body weight, particularly preferably 10 to 1000mg of active ingredient per kg body weight, and still preferably 13 to 500mg of active ingredient per kg body weight, for example 14 to 300mg of active ingredient per kg body weight, 15 to 200mg of active ingredient per kg body weight, most preferably 15 to 100mg of active ingredient per kg body weight. In one embodiment, the compounds of the invention are administered at least once daily, for example 1,2,3, 4 or 5 times daily. Preferably, the compounds of the invention are administered 1,2 or 3 times daily. Herein, the term "active ingredient" refers to a compound of the invention as well as a lactamase inhibitor or an efflux pump inhibitor.
The pharmaceutical compositions of the present invention also optionally comprise 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 invention will generally be combined with one or more pharmaceutically acceptable carriers, excipients and/or other adjuvants and formulated into a suitable administration form or dosage form, which procedure comprises mixing, granulating, compressing or dissolving the components by suitable means. The carrier may be present in the pharmaceutical composition in an amount of from 1 to 98% by weight, typically about 80% by weight. For convenience, the local anesthetic, preservative, buffering agent, and other adjuvants may be dissolved directly in the vehicle. Accordingly, the present invention provides pharmaceutical compositions comprising a compound of formula (I) of the present invention, or a stereoisomer, solvate, or pharmaceutically acceptable salt or ester thereof, together with a pharmaceutically acceptable carrier, excipient, and/or other adjuvant.
The invention also provides the use of the pharmaceutical composition of the invention as an antimicrobial agent. In the use invention, the term "microorganism" has the same meaning as in the description about the pharmaceutical composition.
Furthermore, the present invention provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of an infectious disease.
In addition, the present invention provides a method for treating infectious diseases, which comprises administering the component (a) and the component (b) to a human or an animal. Here, component (a) and component (b) have the meanings described above. In one embodiment, component (a) and component (b) are in separately prepared pharmaceutical forms. In one embodiment, the method of the invention is such that component (a) and component (b) are administered with a time interval of not more than 4 hours, preferably not more than 3 hours, more preferably not more than 2 hours, still more preferably not more than 1 hour, particularly preferably not more than 30 minutes, most preferably component (a) and component (b) are administered simultaneously, e.g. in the form of a pharmaceutical composition comprising both components, i.e. as a composition of the invention.
In one embodiment, the method of treating infectious diseases of the present invention comprises administering the pharmaceutical composition of the present invention to a human or animal.
Administration of drugs
The pharmaceutical composition of the present invention may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous administration being preferred.
The pharmaceutical compositions of the present invention may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, and delayed release agent.
Tablets and capsules for oral administration may be prepared by methods well known in the art of pharmacy, and tablets may be coated.
The oral liquid can be made into water and oil suspension, solution, emulsion, syrup, or dried product, and supplemented with water or other suitable medium before use. Flavoring or coloring agents may be added as desired.
Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
For parenteral administration, liquid dosage forms are generally prepared from the pharmaceutical compositions of the present invention and a sterile vehicle. The carrier is preferably water. The pharmaceutical composition can be dissolved in the carrier or made into suspension solution according to the difference of the carrier and the drug concentration, and the pharmaceutical composition is firstly dissolved in water when being made into the solution for injection, filtered and sterilized and then filled into a sealed bottle or an ampere.
Can also be made into sterile injectable preparation such as crystalline powder for injection and lyophilized powder for injection.
When applied topically to the skin, the pharmaceutical compositions of the present invention may be formulated in the form of a suitable ointment, lotion, or cream, in which the active ingredient is suspended or dissolved in one or more carriers.
The present invention is described in more detail below by way of examples.
Preparation examples
Preparation example 1: synthesis of Compound of formula (I-1)
Step 1a (Step 1 a): dissolving the compound 7a (1.0 mmol) in DMF (10.0 v/g), adding triethylamine (2.0 mmol), adding triphenylchloromethane (1.2 mmol) in batches, stirring at room temperature for 6 hours, monitoring by TLC, adding water/ethyl acetate for extraction after complete reaction, combining organic phases, drying, concentrating, and separating by column chromatography to obtain the target compound 7b.
Step 1b (Step 1 b): dissolving the compound 7b (1.0 mmol) in 1, 4-dioxane (5 v/g)/water (5 v/g), stirring at room temperature, adding sodium hydroxide (5.0 mmol), continuing stirring for reaction, monitoring by TLC, allowing the raw materials to disappear, evaporating the 1, 4-dioxane under reduced pressure, adjusting the pH to 2-3, stirring for 10 minutes, filtering, washing the filter cake with water until the filtrate is neutral, collecting and drying the filter cake to obtain a compound 7c.
Step 1 (Step 1): reacting the compound 1a
(1.0 mmol) and diphenylbromomethane (1.1 mmol) are dispersed in toluene solution (10.0 v/g) and stirred at room temperature, DBU (1.5 mmol) is added, the temperature is raised to 70-80 ℃, the reaction is stirred for 12-16 hours, TLC is used for monitoring that the raw material is not reduced any more, the temperature is reduced to room temperature, water (10.0 v/g x 2) is added for extracting the reaction solution, ethyl acetate (10 v/g x 2) is used for back washing the water layer, the organic phase is combined, dried and concentrated to obtain a residue, and the transparent oily compound 2a (post-solidification) [1H NMR (400MHz, CDCl3) delta (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) is obtained by column chromatography]。
Step 2 (Step 2) dispersing Compound 2a (1.0 mmol), diphenylhydroxylamine phosphate (1.1 mmol) in anhydrous tetrahydrofuran solution (10.0 v/g), evacuating with nitrogen for 3-4 times, stirring at 0 deg.C, then adding sodium t-butoxide (1.5 mmol), stirring at constant temperature for 1-2 hours, monitoring by TLC, the conversion of the reaction is complete, adding saturated sodium chloride solution (5.0 v/g) to the reaction solution, stirring for 30 minutes, filtering off insoluble matter, washing the filter cake with ethyl acetate, adding ethyl acetate (10.0 v/g), water (5.0 v/g), separating, washing the organic phase once, combining the aqueous phases, backwashing the aqueous phases with ethyl acetate, combining the organic phases, drying, and concentrating to obtain an oily substance a [ a ], [1H NMR (MHz, DMSO) delta (ppm) 7.46-7.27 (m, 10H), 6.84 (s, 1H), 6.36 (s, 2H), 1.30-1.22 m (m, 4H) ].
Step 3 (Step 3): compound 7c was dispersed in methanol (10.0 v/g), a methanol solution of Compound 3a was added with stirring at room temperature, the reaction was stirred at a constant temperature for 30 minutes, monitoring by TLC, completion of conversion of the starting material, the solvent was distilled off under reduced pressure, and the off-white solid Compound (4a, [1H NMR (600MHz, DMSO). Delta. (ppm) 8.84 (s, 1H), 7.51-7.15 (m, 25H), 6.86 (s, 2H), 1.48-1.28 (m, 4H) ] was isolated by column chromatography.
Step 4 (Step 4): compound 4a (1.0 mmol) was dissolved in DMF (10.0 v/g), stirred at room temperature and HATU (1.2 mmol), naHCO were added separately 3 (2.0 mmol) and Compound 8 (1.3 mmol) were stirred at constant temperature for 12 hours and the reaction was monitored until the starting material disappeared. Diluting with ethyl acetate (10.0 v/g), washing with water 2 times, backwashing with ethyl acetate once, combining the organic phases, drying, concentrating, and separating by column chromatography to obtain off-white foamy solid compound 5a [ 2 ], [1H NMR (600MHz, DMSO) delta (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)]。
Step 5 (Step 5): dissolving the white solid 5 se:Sup>A (1.0 mmol) in anhydrous dichloromethane (10.0 v/g), stirring at-5 to-10 ℃, adding triethylsilane (2.0 mmol) and trifluoroacetic acid (100.0 mmol), reacting at constant temperature for 5-6 hours, monitoring by TLC until the reaction is complete, evaporating the solvent at room temperature under reduced pressure, adding ethyl acetate into the residue, stirring at room temperature for 1 hour, filtering, washing the filter cake with ethyl acetate for 3 times, collecting the filter cake, drying, dissolving the solid in methanol/water, and preparing and separating by pre-HPLC (YMC ODS-A,5um,10 x 250mm,2.5mL/min,2% -50% acetonitrile/0.1% formic acid water) to obtain the target product (I-1).
1 H 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. 13 C 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 14 H 17 N 5 O 9 S 2 [M-H]462.0396,found 462.0394
Preparation example 2: synthesis of Compound (I-2)
A method for synthesizing the compound (I-2) is described in (I-1).
2b: 1 H 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: 1 H 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: 1 H NMR (600MHz, DMSO) delta (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) (contains 50% impurities, ref. Z21 e);
a compound of the formula (I-2): 1 H 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). 13 C 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 15 H 19 N 5 O 9 S 2 [M+Na]500.0516,found 500.0500.
with reference to the procedure for the preparation of example 1 and using the appropriate starting materials, compounds of formulae (I-3) to (I-6) were prepared.
A compound of formula (I-3): 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 calulated for C 16 H 21 N 5 O 9 S 2 [M-H]490.0708,found 490.0700.
A compound of formula (I-4): 1H NMR (600MHz, DMSO) delta (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 15 H 21 N 5 O 9 S 2 [M+Na]502.0673,found 502.0677
a compound of formula (I-5): 1H NMR (600mhz, dmso) δ 9.53 (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) δ 172.4,169.9,166.0,163.6,161.8,111.2,110.1,87.6,68.2,61.4,30.2,23.9,20.9,19.0,18.3 hrms calcaultedfor C 15 H 21 N 5 O 9 S 2 [M+Na]502.0673,found 502.0661
A compound of formula (I-6): 1H NMR (600MHz, DMSO). Delta.9.37 (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 17H 23N 5 O 9 S2[M-H]504.0864,found 504.0850。
Effects of the embodiment
A test sample: compounds I-1, I-2, abamectin, faribatan and relibatan, as well as berberine, coniferine and Pa beta N;
avermebactam and berberine were purchased from Inokay technologies, inc., fababatan and Relbutant from Mecang Biochemical technologies, inc., nemacitene from Bailingwei technologies, inc., pa.beta.N from MedChemExpress.
Test strains: from American Type Culture Collection (ATCC), and the Collection of pathogenic microorganism (virus) species of the Chinese academy of medical sciences-medicinal microorganism-associated species Collection center (CAMS-CCPM-A), from which the strains are publicly available (see tables 1 to 5 for details);
method for evaluating antimicrobial Activity of Individual Compounds (MIC assay)
Hydrolyzed casein peptone broth (Mueller-Hinton broth, MH broth) medium, trypticase soy peptone broth (TSB broth) medium: from BD Difco, cockeysville, md., USA;
96-well plate: corning Costar, cambridge, MA, USA;
the test method comprises the following steps: according to CLSI/NCCLS standard, micro-dilution method and antibacterial activity determination are adopted.
(1) Preparing a test sample: 4mg of each sample, drug was formulated in test solution 1024. Mu.g/mL in MH broth, diluted two-fold in 96-well plates to serial gradient concentrations, each well volume 90. Mu.L.
(2) Preparing a bacterial liquid: the test strains were amplified in trypticase Soy broth (TSB broth) according to the CLSI/NCCLS standard.
(3) Sample adding: preparation of 6X 10 5 10. Mu.L of the bacterial solution was pipetted into each well of a 96-well plate at cfu/mL. Three replicates were set for each concentration and averaged. The negative control group was added with 10. Mu.l of the inoculum and 90. Mu.l of MH broth.
(4) Culturing: placing the 96-well plate in a constant-temperature incubator at 37 ℃ for 18 hours; and observing the growth condition of the strain, wherein the concentration of the medicament contained in the bacteria-free growing hole is the measured MIC.
In-vitro drug combination research method
Hydrolyzed casein broth (Mueller-Hinton broth, MH broth) medium, trypticase soytone broth (TSB broth) medium: from BD Difco, cockeysville, md., USA;
96-well plate: corning Costar, cambridge, MA, USA;
the test method comprises the following steps: and (4) measuring by a chessboard dilution method.
(1) Preparing a test sample: 4mg of each sample was prepared as 2048. Mu.g/mL test solution in MH broth and serially graded in 96-well plates by double dilution.
(2) Preparing a bacterial liquid: the test strains were amplified from trypticase Soytone broth (TSB broth) according to the CLSI/NCCLS standard.
(3) Sample adding: aspirate 10. Mu.L of 6X 10 5 CFU/mL of the broth was added to each well of a 96-well plate containing the antibacterial drug of formula (I-1), formula (I-2) and the above lactam in a concentration twice as diluted with the brothAn enzyme inhibitor or an efflux pump inhibitor. So that the actual concentrations of the compound of formula (I-1), the compound of formula (I-2) samples were 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, and 0.0. Mu.g/mL, respectively, and the actual concentrations of the lactamase inhibitor or efflux pump inhibitor samples were 256, 128, 64, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, and 0.0. Mu.g/mL, respectively, were mixed well, and each concentration was averaged over three replicates. The negative control group was added with 10. Mu.l of the bacterial solution and 90. Mu.l of hydrolyzed casein broth.
(4) Culturing: placing the 96-well plate in a constant-temperature incubator at 37 ℃ for 18 hours; and observing the growth condition of the strain.
(5) And (3) calculating: the effect of each drug in combination with the inhibitor in vitro was analyzed by calculating the FICI value, FICI = (MIC of drug A in combination/MIC of drug A alone) + (MIC of drug B in combination/MIC of drug B alone). When the FICI is less than or equal to 0.5, the two medicines have good synergistic effect; when 0.5-woven FICI woven fabrics 4, no synergistic effect of the two medicines is shown; when the FICI is more than or equal to 4, the two medicines have antagonistic effect.
To ensure reliable data, three replicates were performed on different days, and the average was taken.
Effect example 1
MICs of the compound of formula (I-1) and the compound of formula (I-2) and beta-lactamase inhibitor alone against Enterobacter were determined according to the above-described determination methods, and the results are shown in Table 1.
As can be seen from Table 1, for certain drug-resistant Enterobacter bacteria, such as Klebsiella pneumoniae ATCC2146, ATCC700603, CCPM (A) -0814R18, CCPM (A) -0814R33, CCPM (A) -081705, CCPM (A) -081715 and CCPM (A) -081729, escherichia coli ATCC2469 and CCPM (A) -P-071301, enterobacter cloacae 17-19 and ATCC2468, the MIC values of the compound of formula (I-1) and the compound of formula (I-2) are between 0.5 and 4. Mu.g/mL; MIC values for the compound of formula (I-1) and the compound of formula (I-2) for Klebsiella pneumoniae CCPM (A) -081716 and CCPM (A) -0817R61 are between 32-128. Mu.g/mL, respectively. The beta-lactamase inhibitors avibactam, faribatan and relibatan show weaker activity on the enterobacter.
Effect example 2
MIC's against Enterobacter were determined for the compound of formula (I-1) and the compound of formula (I-2) in combination with a beta-lactamase inhibitor according to the checkerboard assay described above, and the results are shown in tables 2A to 2C and Table 3. Wherein tables 2A to 2C show the antibiogram data of the compound of formula (I-1) in combination with avibactam, farbactam and relibatan, respectively. Table 3 shows the antibiogram data of the compound of formula (I-2) in combination with avibactam.
TABLE 2 MIC values and synergism of the Compound of formula (I-1) in combination with Avermentan
TABLE 2 MIC values and synergism of the Compound of formula (I-1) in combination with Falbobactam
TABLE 2C MIC values and synergism in combination with Riebatan for Compounds of formula (I-1)
TABLE 3 MIC values and synergism of the Compound of formula (I-2) in combination with Avermentan
After the compound shown in the formula (I-1) is combined with abamectin, the MIC values of the tested 12 drug-resistant Enterobacter strains are obviously reduced, and a synergistic effect is shown (FICI < 0.5). The MIC values of the compounds of formula (I-1) for certain drug-resistant Enterobacter strains are reduced after combination with farbactam and releptin, and show synergistic effects with both farbactam and releptin (FICI < 0.5). The results show that the compound preparation of the compound shown in the formula (I-1) and diazabicyclooctanone beta-lactamase inhibitor, such as abamectin, faribatan and relebatan, has great potential to be developed into the medicine for clinically treating multidrug-resistant gram-negative enterobacter infection.
After the compound shown in the formula (I-2) is combined with abamectin, the MIC values of the tested 4 drug-resistant Enterobacter strains are obviously reduced, and a synergistic effect is shown (FICI < 0.5). The results show that the compound preparation of the compound shown in the formula (I-2) and a beta-lactamase inhibitor, such as avibactam, also has great potential for being developed into a medicament for clinically treating multi-drug resistant gram-negative enterobacter infection.
Effect example 3
MIC of the compound of formula (I-1) and an efflux pump inhibitor against Acinetobacter baumannii or Acinetobacter aeruginosa alone were determined according to the determination methods described above, and the results of the tests are shown in Table 4.
TABLE 4 MIC data for Acinetobacter baumannii and Acinetobacter aeruginosa for individual compounds
As can be seen from Table 4, the MIC value of the compound of formula (I-1) is between 16 and 32. Mu.g/mL for various Acinetobacter baumannii and Pseudomonas aeruginosa-resistant strains. The efflux pump inhibitors berberine, conradine and Pa β N show weaker activity against the above mentioned various acinetobacter baumannii and pseudomonas aeruginosa resistant strains.
Effect example 4
The MIC of the antibacterial activity of the combination of the compound of formula (I-1) with the efflux pump inhibitor berberine, conoidine and Pa.beta.N was determined according to the assay described above and the results are shown in tables 5A to 5C.
TABLE 5A Compounds MIC values and synergistic effects of the Compounds of formula (I-1) in combination with Berberine
* Indicating that no synergistic effect was observed in any of the concentration ranges measured
TABLE 5B Compounds MIC values and synergism of Compounds of formula (I-1) in combination with Coniferin
NT: not tested.
TABLE 5C MIC values and synergism of Compounds of formula (I-1) in combination with PA β N
* Indicating that no synergistic effect was observed in any of the concentration ranges measured
The MIC values of the compound of formula (I-1) were reduced 4-fold for 2 drug-resistant Acinetobacter baumannii strains ATCC19606 and ATCC17978 in combination with berberine, and the compound of formula (I-1) and berberine showed a synergistic effect (FICI < 0.5). The MIC value of the compound of formula (I-1) against the drug-resistant A.baumannii strain ATCC19606 was reduced 4-fold after combination with coniferine, and the compound of formula (I-1) and coniferine showed a synergistic effect (FICI < 0.5).
The MIC values of the compound of formula (I-1) were reduced 8-fold for both 2 drug-resistant P.aeruginosa strains ATCC27853 and PAO1 (CCPM (A) -P-09000032) when combined with PA β N and showed a synergistic effect (FICI < 0.5); the MIC value of the drug-resistant pseudomonas aeruginosa CCPM (A) -P-091626 (CRPA) is reduced by 4 times, and the compound and PA beta N in the same mode (I-1) show synergistic antibacterial effect (FICI is less than or equal to 0.5).
The results show that the compound preparation of the compound shown in the formula (I-1) and berberine or conoidine has the potential of being developed into a medicament for clinically treating the infection of the acinetobacter baumannii, and the compound preparation of the compound shown in the formula (I-1) and PA beta N has great potential of being developed into a medicament for clinically treating the infection of the pseudomonas aeruginosa.
Effect example 5: in vivo drug combination study
ICR mice were used and were healthy in appearance, 18 to 22g in weight, and male and female halves. The mice were randomly grouped, 5 mice per dose group, with no restriction. The test bacterial solution containing NDM-1-producing Klebsiella pneumoniae was diluted with 5% of high activity dry yeast, and the mouse was intraperitoneally injected with 100% of the minimum lethal dose (100% MLD, 3.0X 10) 6 CFU/mouse) 0.5mL.
Klebsiella pneumoniae which produces NDM-1 when infected in the abdominal cavity (infectious bacteria amount: 3.0X 10) 6 CFU) mice were administered with a dose (see table 5) of one tail vein at 1h and 6h after infection for 2 times in total, at a dose volume of 10mL/kg, and survival of each group of animals was observed for 7 days and survival rate of the mice was calculated. The control group was administered with no drug, only with physiological saline, and the seven-day survival rate of the mice was 0.
The protective effect of the compound of formula (I-1) alone and the compound of formula (I-1) in combination with abamectin on mice systemically infected with Klebsiella pneumoniae ATCC BAA2146 (NDM-1) is shown in Table 5. It is well known to those skilled in the art that avibactam itself has no in vivo antibacterial effect on the test strain.
TABLE 5 in vivo test of the Effect of Compounds of formula (I-1) and Abamebactam intravenous injection on Klebsiella pneumoniae ATCC BAA2146 (NDM-1) Abdominal infection in mice
As can be seen from Table 5, the infection of the abdominal cavity with Klebsiella pneumoniae which produces NDM-1 (infectious bacterial load: 3.0X 10) 6 CFU) mice injected with the compound of formula (I-1) at a dose of 32mg/kg tail vein at 1 hour and 6 hours after infection, respectively, with a 60% survival rate of the mice for seven days; the compound of formula (I-1) was injected tail vein at a dose of 16mg/kg 1 hour and 6 hours after infection, respectively,the seven-day survival rate of mice was 20%.
The abamectin has no in vivo antibacterial effect on the test strain, but the abamectin and the compound shown in the formula (I-1) can greatly enhance the in vivo antibacterial activity of the latter after being co-administered. Under the administration dosage of 32mg/kg and 16mg/kg of the compound shown in the formula (I-1), the compound is respectively combined with abamectin which is twice, twice and three times, and the seven-day survival rate of the mice reaches 100 percent. This shows that the combination of the compound of formula (I-1) and avibactam in vivo can show significant synergistic antibacterial effect.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention herein. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Claims (11)
1. A pharmaceutical composition for combating gram-negative bacteria, comprising:
(a) 
(I-1); and
(b) A lactamase inhibitor or an efflux pump inhibitor,
wherein the lactamase inhibitor is selected from avibactam, farbactam and releptian,
wherein the efflux pump inhibitor is selected from the group consisting of berberine, conoidine and Pa beta N,
2. a pharmaceutical composition for combating gram-negative bacteria, comprising:
(a) 
(I-2); and
(b) Abamebactam.
3. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of component (a) to component (b) is from 1.3 to 1.
4. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of component (a) to component (b) is 1.
5. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of component (a) to component (b) is 1.
6. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of component (a) to component (b) is 1 to 1.
7. The pharmaceutical composition of claim 1 or 2, further comprising a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 1 or 2, further comprising an excipient.
9. The pharmaceutical composition according to claim 1 or 2, further comprising other adjuvants.
10. Use of a pharmaceutical composition according to any one of claims 1-9, wherein the microorganism is escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, enterobacter cloacae, for the preparation of an antimicrobial agent.
11. Use of a pharmaceutical composition according to any one of claims 1-9 in the manufacture of a medicament for the treatment of an infectious disease, wherein the infectious disease is an infectious disease caused by a microorganism selected from the group consisting of escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, enterobacter cloacae.
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