CN115463219A - 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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- 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
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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
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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
- A61K31/435—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
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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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
- A61K31/55—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
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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
- A61K31/56—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
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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
- A61K31/69—Boron compounds
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- 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
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- 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
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- 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
Abstract
Pharmaceutical compositions comprising beta-lactam compounds and uses thereof. The invention relates to beta-lactams of formula (I)The compounds, or stereoisomers, solvates and pharmaceutically acceptable salts or esters thereof, and a pharmaceutical composition of a lactamase inhibitor or an efflux pump inhibitor, and their use against microorganisms, particularly bacteria, especially gram-negative bacteria, wherein the symbols in formula (I) are as defined in the specification.
Description
The application is a divisional application of Chinese patent application named as 'pharmaceutical composition containing beta-lactam compound and application thereof' on 9/11/2021 with application number of 202111322162.3.
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 diseases and good clinical curative effect.
However, with the wide clinical use of antibiotics, some resistance has developed, 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 substitutedSubstitution;
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.
The pharmaceutical composition of the present invention may be used as such, or may be used together with a pharmaceutically acceptable carrier, excipient or other auxiliary agent.
The invention also provides the use of the pharmaceutical composition of the invention as an antimicrobial agent.
In addition to this, the present invention is, the invention also 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, comprising 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 a lactamase inhibitor or an efflux pump inhibitor.
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.
As used herein, the terms "comprising" and its synonyms "including" and "containing" mean "including but not limited to", and are 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, 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 cyclic hydrocarbon 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 carboxyalkoxyimino, 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 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 ) -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 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 radicals, examples being methyl, ethyl, n-propyl, isopropylN-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 group, 1,3,5-triazinyl group, tetrazolyl group, benzofuranyl group, benzoisofuranyl group, benzothiophenyl group, benzoisothiazolyl group, indolyl group, isoindolyl group, indazolyl group, benzothiazolyl group, benzoisothiazolyl group, benzoxazolyl group, benzoisoxazolyl group, benzimidazolyl group, 2,1,3-benzooxadiazole, quinolyl group, isoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, naphthyridinyl group, benzotriazinyl group, purinyl group, pteridinyl group, and indolizinyl group (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, 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 solvates in solution and isolatable solvates. 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 generally understood by a person skilled in the art, such as 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 R2 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 foregoing 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 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.
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 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.
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 in a conventional manner known to the person 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 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 include a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a tert-butyl group, a halogenated lower alkyl group such as 2,2,2-trichloroethyl group, a lower alkenyl group such as an allyl group, an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a p-nitrosobenzyl group, a benzhydryl group and a trityl group, and particularly preferably a methyl group, an ethyl group, a tert-butyl group, an allyl group, a benzyl group, a p-methoxybenzyl group and a benzhydryl group. 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 commonly used in the art as amino protecting groups. As "ammoniaThe group-protecting group "is not particularly limited as long as it is a protecting group having such a function, examples thereof include, for example, -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 (tert-butyloxycarbonyl).
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: 50) and sodium hydroxide was added and the reaction was continued with stirring until the starting material disappeared. Evaporating 1,4-dioxane under reduced pressure, adjusting pH to 2-3, stirring, filtering, washing filter cake with water until filtrate is neutral, collecting and drying filter cake to obtain compound 7c.
In the step 1, the compound 1 and the diphenyl bromomethane 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 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 present 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, less side effects are produced to humans or animals, the tolerance is better and the resistance can be less developed.
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, klebsiella citrate, lei Jipu Lu Feideng Bacillus, 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 specific 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) -P071301, 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 relibatan 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, 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 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, farbactam and releptian. 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 from 1: 0.3 to 1: 10, preferably from 1: 0.5 to 1: 7, more preferably from 1: 0.8 to 1: 6, most preferably from 1: 1 to 1: 5.
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, buffer 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 via 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 saline 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 if 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 different carrier and drug concentration, when making injection solution, the pharmaceutical composition is dissolved in water, filtered and sterilized, and then filled into sealed bottles or amperes.
Can also be made into aseptic preparation for injection, including crystalline powder for injection, lyophilized powder for injection, etc.
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 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 the compound 7c.
Step 1 (Step 1): reacting the compound 1a
(1.0 mmol) and diphenylbromomethane (1.1 mmol) were dispersed in toluene solution (10.0 v/g) and stirred at room temperature, DBU (1.5 mmol) was added, the temperature was raised to 70-80 deg.C, the reaction was stirred for 12-16 hours, TLC was monitored to prevent decrease of the starting material, the temperature was lowered to room temperature, water (10.0 v/g x 2) was added to extract the reaction solution, ethyl acetate (10 v/gx 2) was used to backwash the aqueous layer, the organic phase was combined, dried and concentrated to obtain a residue, and column chromatography was performed to obtain a clear oily compound 2a (post-solidified) [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)]。
Step 2 (Step 2): dispersing compound 2a (1.0 mmol) and diphenyl phosphoryl hydroxylamine (1.1 mmol) in anhydrous tetrahydrofuran solution (10.0 v/g), pumping nitrogen for 3-4 times, stirring at 0 ℃, then adding sodium tert-butoxide (1.5 mmol), stirring at constant temperature for 1-2 hours, monitoring by TLC, the reactant conversion is complete, adding saturated sodium chloride solution (5.0 v/g) into the reaction solution, stirring for 30 minutes, filtering off insoluble substances, washing filter cake with ethyl acetate, adding ethyl acetate (10.0 v/g), water (5.0 v/g), separating, washing organic phase once, combining aqueous phase, backwashing aqueous phase with ethyl acetate, combining organic phase, drying, and concentrating to obtain oily substance 3a 1H NMR (600MHz, DMSO) delta (ppm) 7.46-7.27 (m, 10H), 6.84 (s, 1H), 6.36 (s, 2H), 1.30-1.22 (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 for 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 [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) into the mixture, reacting at constant temperature for 5 to 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 ANG 250mm,2.5mL/min,2 to 50 percent acetonitrile/0.1 percent 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).13CNMR(151MHz，DMSO)δ(ppm)173.7，169.8，161.9，111.6，68.3，63.3，61.3，60.2，23.8，21.0，16.2.1 3 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 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 the 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: calculated 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) 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 NMR151MHz，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: calculated for 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，found504.0850。
Effects of the embodiment
A sample to be tested: compounds I-1, I-2, abamectin, faribatan and relibatan, as well as berberine, coniferine and Pa beta N;
abamebactam and berberine were purchased from Inokay technologies, inc., fabibatan and Relbutan were purchased from Shanghai Meclin Biochemical technologies, inc., conaspine was purchased from Bailingwei technologies, inc., and Pa beta N was purchased 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 (MH broth), tryptic casein 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: 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 6X10 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 bacterial broth 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 combined drug research method
Hydrolyzed casein broth (Mueller-Hinton broth, MH broth) medium, trypticase soy peptone broth (TSB broth) medium: purchased from BD Difco, cockaysville, 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 in trypticase Soy broth (TSB broth) according to the CLSI/NCCLS standard.
(3) Sample adding: aspirate 10. Mu.L of 6X10 5 CFU/mL of the inoculum was added to each well of a 96-well microplate, and each well was filled with the inoculumComprises the antibacterial drugs of the formula (I-1) compound and the formula (I-2) compound which are diluted by twice with bouillon, and the lactamase inhibitor or efflux pump inhibitor. Samples of the compound of formula (I-1), the compound of formula (I-2) were brought to actual concentrations of 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, and 0.0. Mu.g/mL, respectively, samples of the lactamase inhibitor or efflux pump inhibitor were brought to actual concentrations of 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, mixed well, with each concentration setting in triplicate, and the average taken. 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 FICI is more than 0.5 and less than 4, the two medicines have no synergistic effect; when the FICI is more than or equal to 4, indicating that the two drugs have antagonistic effect.
To ensure reliable data, three replicates were performed on different days and averaged.
Effect example 1
The MICs of the compound of formula (I-1) and the compound of formula (I-2) and the beta-lactamase inhibitor alone against Enterobacter were determined according to the determination methods described above, and the results of the tests are shown in Table 1.
TABLE 1 MIC data for anti-Enterobacter for Compounds alone
NT: not tested.
As can be seen from Table 1, for certain drug-resistant Enterobacter 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; for Klebsiella pneumoniae CCPM (A) -081716 and CCPM (A) -0817R61, the MIC values of the compound of formula (I-1) and the compound of formula (I-2) were 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 (FICI is less than 0.5) is shown. The MIC values of the compounds of formula (I-1) for certain drug-resistant Enterobacter strains are reduced in combination with faribatan and relibatan and show synergistic effects with both faribatan and relibatan (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 relibatan, has great potential for being developed into a medicament 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 (FICI is less than 0.5) is shown. 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 values of the compound of formula (I-1) were between 16-32. 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 MICs of the antibacterial agents of the compound of formula (I-1) in combination with the efflux pump inhibitors berberine, conradine and Pa β N were determined according to the assay described above and the results are shown in tables 5A to 5C.
TABLE 5A MIC values and synergism of Compounds of formula (I-1) in combination with Berberine
Means that no synergistic effect is observed in the concentration range measured
TABLE 5B Compounds MIC values and synergism of Compounds of formula (I-1) in combination with Coniferin
NT: not tested.
TABLE 5C Compounds MIC values and synergism of Compounds of formula (I-1) in combination with PA β N
Means that no synergistic effect is observed in the concentration range 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).
After combined with PA β N, the MIC values of the compound of formula (I-1) for both 2 drug-resistant P.aeruginosa strains ATCC27853 and PAO1 (CCPM (A) -P-09000032) were reduced by 8-fold 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 in the same form (I-1) and PA beta N 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. Mice were randomly grouped into 5 per dose group, with unlimited character. The test bacterial solution containing Klebsiella pneumoniae which produces NDM-1 was diluted with 5% of high activity dry yeast, and 100% of the minimum lethal dose (100% MLD, 3.0X 10) was injected into the abdominal cavity of the mouse 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 administered 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 at 1 hour and 6 hours after infection, respectively, and the survival rate of mice was 20% for seven days.
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 one time, two times and three times of abamectin for administration, and the seven-day survival rate of the mouse 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 (14)
1. 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.
2. The pharmaceutical composition according to claim 1, wherein, in the compound of formula (I),
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;
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; and is
Y represents vinyl, propenyl, isopropenyl, allyl, n-butenyl, isobutenyl, 2-methylpropenyl, ethynyl, propynyl, isopropynyl, propargyl, n-butynyl, isobutenyl, 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.
3. The pharmaceutical composition according to claim 1 or 2, wherein, in the compound of formula (I),
R 1 and R 2 Each independently represents hydrogen, optionally substituted methyl, ethyl;
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; and is
Y represents ethenyl, propenyl, ethynyl, propynyl, carboxyl, and-COOR 5 Wherein R is 5 Methyl, ethyl, n-propyl and isopropyl.
4. The pharmaceutical composition according to any one of the preceding claims, wherein the compound of formula (I) is selected from:
5. the pharmaceutical composition according to any one of the preceding claims, wherein the lactamase inhibitor is selected from avibactam, farbactam, and releptian,
6. the pharmaceutical composition according to any one of the preceding claims, wherein the efflux pump inhibitor is berberine, coniferine and Pa β N,
7. the pharmaceutical composition according to any of the preceding claims, wherein the weight ratio of component (a) to component (b) is from 1: 0.3 to 1: 10, preferably from 1: 0.5 to 1: 7, more preferably from 1: 0.8 to 1: 6, most preferably from 1: 1 to 1: 5.
8. The pharmaceutical composition according to any of the preceding claims, further comprising a pharmaceutically acceptable carrier, excipient and/or other auxiliary agent.
9. Use of a pharmaceutical composition according to any one of the preceding claims as an antimicrobial agent.
10. The use according to claim 9, wherein the microorganism is a bacterium, in particular a gram-negative bacterium, such as escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, enterobacter cloacae, enterobacter aerogenes, salmonella typhi, serratia marcescens, citrobacter fraudulans, lei Jipu Lu Feideng bacillus, proteus vulgaris, proteus mirabilis, pseudomonas maltophilia and shigella flexneri.
11. The use according to claim 9 or 10, wherein the microorganism is klebsiella pneumoniae, escherichia coli, enterobacter cloacae, acinetobacter baumannii and pseudomonas aeruginosa.
12. The use according to any one of claims 9 to 11, wherein component (b) is a diazabicyclooctanone beta-lactamase inhibitor selected from avibactam, farbactam and releptian,
The microorganism is selected from Klebsiella pneumoniae, escherichia coli and Enterobacter cloacae.
13. Use according to any one of claims 9 to 12, wherein component (b) is an efflux pump inhibitor selected from berberine, coniferine and Pa β N:
The microorganism is selected from Acinetobacter baumannii and Pseudomonas aeruginosa.
14. Use of a pharmaceutical composition according to any one of claims 1-8 in the manufacture of a medicament for the treatment of an infectious disease.
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