CN109568323A - Bactericidal composition and application thereof - Google Patents

Bactericidal composition and application thereof Download PDF

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CN109568323A
CN109568323A CN201710912114.7A CN201710912114A CN109568323A CN 109568323 A CN109568323 A CN 109568323A CN 201710912114 A CN201710912114 A CN 201710912114A CN 109568323 A CN109568323 A CN 109568323A
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alkyl
beta
compound
base
amino
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CN109568323B (en
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史澂空
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Beijing Tianxinyuan Pharmaceutical Science And Technology Development Co ltd
Beijing Sihuan Pharmaceutical Co Ltd
Beijing Ao He Research Institute Co Ltd
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Sihuan Pharmaceutical Holdings Group Ltd
Shandong Xuanzhu Pharma Co Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention relates to pharmaceutical technology fields, a kind of specific drug products, it includes compound (a) or its pharmaceutically acceptable salts, ester or solvated compounds or its stereoisomer, and at least one beta-lactam antibiotic or derivatives thereof, wherein, the compound (a) has structure shown in formula (I).It also relates to the drug products be used to prepare treatment and/or preventing the purposes in bacterial infection disease drug, it is preferable that the bacterium has the drug resistance as caused by beta-lactamase.

Description

Bactericidal composition and application thereof
Technical field
The invention belongs to pharmaceutical technology fields.Particularly, the present invention relates to a kind of drug products, in particular to one kind includes The antibacterial combination of diazabicyclo octanone compound and beta-lactam antibiotic, and its in preparation prevention and/or control Treat the purposes in infectious disease medicament caused by bacterium.
Background technique
The fast development of antibiotic is of great significance in modern medical service history.First β-being successfully applied to clinically Lactam drugs are benzyl penicillins, specify direction for the clinical application of subsequent beta-lactam antibiotic.Beta-lactam Antibiotic means the major class antibiotic in chemical structure with beta-lactam nucleus, including clinical most common penicillin, cephalo Bacteriums, Carbapenems, monobactams etc..The several drugs, which are still fallen within, can be used for the most wide of bacterial-infection resisting General, safe and effective drug continues on and researches and develops gradually deep, the beta-lactam antibiosis however as antibiotic Element easily generates the drug resistance got worse by the β-lactamase hydrolysis of pathogenic bacteria generation.Solve drug resistance approach first is that Using beta-lactamase inhibitor, the activity of beta-lactamase is reduced or inhibited, restore the original antibacterial activity of antibiotic and is resisted Bacterium spectrum, improves its clinical efficacy.
According to amino acid sequence differences in molecular structure, beta-lactamase is broadly divided into two major classes: one kind is with serine For A, C, D class of active site, the second class is with metal ion (especially Zn2+Ion) be active site metal enzyme.Face The beta-lactamase inhibitor of bed application has clavulanic acid (Clavulanic acid), Sulbactam (Sulbactam) and his azoles bar Smooth (Tazobactam).
Clavulanic acid, Sulbactam and Tazobactam Sodium are Structure of Penicillin analog, for irreversible " Suicide enzyme inhibition Agent ", maintenance effect time are shorter.The main zymogram of clavulanic acid be part A class beta-lactamase (such as CTX-M, TEM-1, SHV-1), and for newly generated A class beta-lactamase (such as KPC), B metalloid enzyme (such as IMP, NDM-1, VIM), C class The drug resistance of the initiations such as enzyme (such as AmpC) or D fermentoid (such as OXA), combination effect are bad.Sulbactam and Tazobactam Sodium are main The inhibiting effect of the enzymes such as part C class (such as AmpC), D class (such as OXA) is improved, but for newly generated A class β-interior acyl Amine enzyme (such as KPC) and B metalloid enzyme (such as IMP, NDM-1, VIM) are still without good inhibitory activity.AVM hereinafter Batan (Avibactam, AVI) and MK-7655 are diazabicyclo octanone compound, and structure is as follows.With clavulanic acid, Shu Ba Smooth to compare with Tazobactam Sodium, AVM hereinafter Batan has long-acting enzyme inhibition, and solves part by A class beta-lactamase (example Such as KPC) resistance problems that mediate, but still it not can effectively solve drug resistance caused by B metalloid enzyme, clinical application is limited System.The antimicrobial spectrum of MK-7655 is wider, but does not equally show good drug effect to the bacterial strain for producing B metalloid enzyme.In addition, Ah Tie up the half-life period (T of Batan and MK-76551/2) shorter, it cannot effectively coincide with the half-life period of antibiotic, limit it clinically Using.
The novel phenodiazine by Xuan Zhu Shandong Medicine Technology Co's independent research is disclosed in patent WO2017045510 Miscellaneous bicyclic octanone compound has preferable activity of inhibiting beta-lactamase, and has certain antibacterial action, such drug can Effectively solve the problems, such as that bacterial drug resistance caused by one or more beta-lactamases, especially B metalloid enzyme are mediated resistance to Pharmacological property problem effectively compensates for the deficiency of similar drugs, has very urgent and real clinical demand.
Summary of the invention
One of the technical problem to be solved in the present invention is to solve the problems, such as the bacterial drug resistance as caused by beta-lactamase, especially It is bacterial drug resistance problem caused by B metalloid beta-lactamase.It include diazabicyclo octanone this application provides one kind The drug products of compound and beta-lactam antibiotic can be used for preventing and/or treating bacterial infection disease.
In one aspect, this application provides a kind of drug products, it includes compound (a) or its is pharmaceutically acceptable Salt, ester or solvated compounds or its stereoisomer, and at least one beta-Lactam antibiotic or derivatives thereof, wherein The compound (a) has structure shown in formula (I),
Wherein,
R1For-SO3M ,-OSO3M ,-SO2NH2,-PO3M ,-OPO3M ,-CH2CO2M ,-CF2CO2M or-CF3；
M is selected from H or pharmaceutically acceptable cation；
Ring A is selected from the following groups being optionally substituted with a substituent: 5-15 member bridged ring base, 5-15 member loop coil base, 5-15 member bridge Heterocycle or 5-15 member spiro heterocyclic radical, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-6Alkyl, halogenated C1-6 Alkyl, C1-6Alkoxy, C1-6Alkyl amino or C1-6Alkyl-carbonyl；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, halogenated C1-6Alkoxy C1-6Alkyl, C1-6Alkyl Amino, two (C1-6Alkyl) amino, C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl-carbonyl, halogenated C1-6Alkyl-carbonyl, halogenated C1-6Alkane Base carbonyl C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkoxy carbonyl, C1-6Alkyl carbonyl epoxide C1-6Alkyl, C1-6Alkyl acyl Amino, C1-6Alkyl amino-carbonyl, two (C1-6Alkyl) amino carbonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C1-6Alkane Base sulfonyl C1-6Alkyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-6Alkenyl, C2-6Alkynyl, 3-8 member naphthenic base, 3-8 member naphthenic base-C1-6Alkyl, 6-8 member aryl, the thick aryl of 6-15 member, 4-15 member condensed ring radical, 5-15 member bridged ring base, 5-15 member spiral shell Ring group, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base-C1-6Alkyl, 5-8 unit's heteroaryl, the thick heteroaryl of 5-15 member, 4-15 member condensed hetero ring Base, 5-15 member bridge heterocycle or 5-15 member spiro heterocyclic radical.
In certain embodiments, ring A is the 5-15 member bridged ring base being optionally substituted with a substituent.In certain embodiments In, ring A is the 5-15 member loop coil base being optionally substituted with a substituent.In certain embodiments, ring A is optionally to be substituted with a substituent 5-15 member bridge heterocycle.In certain embodiments, ring A is the 5-15 member spiro heterocyclic radical being optionally substituted with a substituent.
In certain embodiments, the compound (a) has structure shown in formula (II),
Wherein, R1、R2, ring A it is as defined above.
In certain embodiments, the compound (a) has structure shown in formula (III),
Wherein,
Ring A is selected from the following groups being optionally substituted with a substituent: 5-15 member loop coil base, the nitrogenous bridge heterocycle of 5-15 member or 5- 15 yuan of nitrogenous spiro heterocyclic radicals, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino or C1-6Alkyl-carbonyl；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, halogenated C1-6Alkoxy C1-6Alkyl, C1-6Alkyl Amino, two (C1-6Alkyl) amino, C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl-carbonyl, halogenated C1-6Alkyl-carbonyl, halogenated C1-6Alkane Base carbonyl C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkoxy carbonyl, C1-6Alkyl carbonyl epoxide C1-6Alkyl, C1-6Alkyl acyl Amino, C1-6Alkyl amino-carbonyl, two (C1-6Alkyl) amino carbonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C1-6Alkane Base sulfonyl C1-6Alkyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-6Alkenyl, C2-6Alkynyl, 3-8 member naphthenic base, 3-8 member naphthenic base-C1-6Alkyl, 4-10 member condensed ring radical, 5-10 member bridged ring base, 5-10 member loop coil base, 3-8 circle heterocyclic ring base, 3-8 member Heterocycle-C1-6Alkyl, 4-10 member condensed hetero ring base, 5-10 member bridge heterocycle or 5-10 member spiro heterocyclic radical；
M is selected from H, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, ammonium ion or four (C1-6Alkyl) quaternary ammonium Ion.
In certain embodiments, ring A is the nitrogenous bridge heterocycle of 5-15 member being optionally substituted with a substituent.In certain implementations In scheme, ring A is the nitrogenous spiro heterocyclic radical of 5-15 member being optionally substituted with a substituent.
In certain embodiments, in the compound (a),
Ring A is selected from the following groups being optionally substituted with a substituent: 7-9 member loop coil base, the nitrogenous bridge heterocycle of 7-9 member or 7-9 The nitrogenous spiro heterocyclic radical of member, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-6Alkyl, halogenated C1-6Alkyl or C1-6Alkoxy；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkyl-carbonyl, it is halogenated C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl amido, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C1-6Alkane Ylsulfonylamino, 3-8 member naphthenic base, 3-8 member naphthenic base-C1-6Alkyl, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base-C1-6Alkyl, 5- 9 yuan of condensed hetero ring bases, 6-9 member bridge heterocycle or 6-9 member spiro heterocyclic radical；
M is selected from H, sodium ion, potassium ion, zinc ion or potassium ion.
In certain embodiments, ring A is the 7-9 member loop coil base being optionally substituted with a substituent.In certain embodiments, Ring A is the nitrogenous bridge heterocycle of 7-9 member being optionally substituted with a substituent.In certain embodiments, ring A is that optionally substituted base takes The nitrogenous spiro heterocyclic radical of 7-9 member in generation.
In certain embodiments, in the compound (a),
Ring A is selected from the following groups being optionally substituted with a substituent: 7-9 member loop coil base, the nitrogenous bridge heterocycle of 7-9 member or 7-9 The nitrogenous spiro heterocyclic radical of member, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-4Alkyl, halogenated C1-4Alkyl or C1-4Alkoxy；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-4Alkyl, halogenated C1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy, C1-4Alkyl amino, two (C1-4Alkyl) amino, C1-4Alkyl-carbonyl, it is halogenated C1-4Alkyl-carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl amido, C1-4Alkyl sulphinyl, C1-4Alkyl sulphonyl, C1-4Alkane Ylsulfonylamino, 3-6 member naphthenic base, 3-6 member naphthenic base-C1-4Alkyl, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base-C1-4Alkyl；
M is selected from H, sodium ion, potassium ion, zinc ion or potassium ion.
In certain embodiments, the ring A is connected by ring carbon atom with the nitrogen-atoms of amide group in compound (a) It connects.
In certain embodiments, in the compound (a),
Ring A is selected from 2- azabicyclo [2.2.1] the heptane base being optionally substituted with a substituent, 7- azabicyclo [2.2.1] heptan Alkyl, 3- azabicyclo [3.2.1] octyl, 8- azabicyclo [3.2.1] octyl, 2- azabicyclo [3.2.1] octyl, 2- azabicyclo [2.2.2] octyl, 2,5- diazabicyclos [2.2.1] heptane base, 3,8- diazabicyclos [3.2.1] octane Base, 2- oxa- -5- azabicyclo [2.2.1] heptane base, 8- oxa- -3- azabicyclo [3.2.1] octyl, 3,8- diazas are double Ring [3.2.1] oct-6-ene base, 3,9- diazabicyclos [3.3.1] nonyl, 5- azaspiro [2.4] heptane base, 2- azaspiro [3.3] heptane base, 2- azaspiro [3.5] nonyl, 7- azaspiro [3.5] nonyl, 2,6- diaza spiroheptane bases, 2- oxa- -6- azepine spiroheptane base, 6- oxa- -2- azaspiro [3.4] octyl, 2- azaspiro [3.4] octyl, 6- Azaspiro [3.4] octyl, 2- azaspiro [4.4] nonyl, 2- oxa- -7- azaspiro [4.4] nonyl, 6- azaspiro [3.4] octyl- 7- alkenyl, 2- oxa- -6- azaspiro [3.4] octyl- 7- alkenyl, 2- azaspiro [4.4] nonyl- 7- alkenyl or spiral shell [3.3] Heptane base, the substituent group are selected from fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl or propyl；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, Trifluoromethoxy, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopenta Methyl, cyclohexyl, cyclohexyl methyl, pyrrolidinyl, tetrahydrofuran base, piperidyl or morpholinyl.
In certain embodiments, in the compound (a),
Ring A is selected from 3- azabicyclo [3.2.1] octyl being optionally substituted with a substituent, and 8- azabicyclo [3.2.1] is pungent Alkyl, 3,9- diazabicyclos [3.3.1] nonyl, 2- azepine spiroheptane base, 2- azaspiro [3.5] nonyl, 7- nitrogen Miscellaneous spiral shell [3.5] nonyl or spiral shell [3.3] heptane base；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, Trifluoromethoxy, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopenta Methyl, cyclohexyl, cyclohexyl methyl, pyrrolidinyl, piperidyl or morpholinyl.
In certain embodiments, in the compound (a),
Ring A is selected from the 2- azepine spiroheptane base being optionally substituted with a substituent, and the substituent group is selected from fluorine atom, chlorine Atom, amino, hydroxyl, methyl, ethyl or propyl；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, Trifluoromethoxy, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopenta Methyl, cyclohexyl, cyclohexyl methyl, pyrrolidinyl, piperidyl or morpholinyl.
In certain embodiments, the compound (a) has structure shown in formula (IV):
Wherein, R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, first Oxygroup, trifluoromethoxy, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, ring Phenyl-methyl, cyclohexyl, cyclohexyl methyl, pyrrolidinyl, piperidyl or morpholinyl；
M is selected from H, sodium ion, potassium ion, zinc ion or potassium ion.
In certain embodiments, the compound (a) is selected from following compounds 1 to compound 15-2:
In certain embodiments, the compound (a) is selected from
In certain embodiments, the beta-lactam antibiotic includes penicillins, cephalosporins, carbon mould Alkenes, monobactams；
The penicillin antibiotics are selected from: benzyl penicillin, scotcil, novocillin, ospen, long-acting west Woods, oxacillin, Cloxacillin, methicillin, oxacillin, naphthlazole, flucloxacillin, dicloxacillin, ampicillin, Ah Amdinocillin, hetacillin, metampicillin, Talampicillin, Pivampicillin, Bacampicillin, Carbenicillin, Piperacillin, sulphur benzyl west Woods, Furbenicillin, Ticarcillin, azlocillin, mezlocillin, apalcillin, Mecillinam, Pivmecillinam, temocillin or its Any combination；
The cephalosporin analog antibiotic is selected from: cephazoline, Ceftiolene, Cefedrolor, Cefaparole, cefrotil, head Spore sulphur miaow, Cefaclor, cefaloglycin, cephalo pyrrole quinoline, cefatrizine, ceftezole, Cefcanel, Cefazedone cefadroxil Benzyl, cefalexin, cefaloram, Cefacetrile, cefroxadine, Cefradine, cephalo trifluoro azoles, Cefetrizole, cefoxitin, Cefuroxime, Loracarbef, Cefcanel, Cefprozil, Cefaclor, Cefdaloxime, cefmetazole, cefbuperazone, cephalo For smooth, Cefotiam, cephalo amine azoles, cefonicid, Cefamandole, Cefoxitin, Cefuracetime, ceftriaxone, cefotaxime, Cefotaxime, Cefixime, Cefpodoxime, Ceftiofur, Cefminox, cefoperazone, cephalo tie up star, Cefuzonam, cephalo Thiophene oxygen, Ceftiolene, Cefsumide, cefpiramide, ceforanide, cefivitril, Cefetrizole, Cefetecol, latamoxef, Ceftibuten, Cefpimizole, Cefsulodin, Cefdinir, Cefodizime, Cefmenoxime, Ceftizoxime, Cefcapene, cephalo He is beautiful, Cefteram, cefoperon, Cefepime, Cefclidin, Cefquinome, cephalo quinoline ketone, Cefozopran, Cefpirome, Flomoxef, cefluprenam, Cefoselis, Cefempidone, Ceftaroline Fosamil, Ceftobiprole or any combination thereof；
The carbapenem antibiotic is selected from: hundred Na Peinan, Imipenem, Meropenem, ertapenem, comparing A Pei South, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof.
The monocycle beta-lactam class antibiotic is selected from: aztreonam, carumonan or combinations thereof.
In certain embodiments, the preferred cephalosporin analog antibiotic of beta-lactam class antibiotic, the cephalosporin analog antibiotic It is preferred that: cefotaxime, ceftriaxone, Cefepime, Cefozopran, cefotaxime, cefoperazone, Ceftaroline Fosamil or it is any Combination.
In certain embodiments, the derivative of the beta-lactam antibiotic is selected from the beta-lactam antibiotic Ester, pharmaceutically acceptable salt, stereoisomer, prodrug, solvated compounds, compound or metabolin.
In certain embodiments, the beta-lactam antibiotic is its clinically common form, such as can be with trip Form from alkali is formed combination product or is formed combination product in the form of sodium salt etc..For example, combination product signified in the present invention In ceftriaxone, can refer to its free alkali compound, may also mean that its sodium salt.
In certain embodiments, in the drug products, compound (a) is The beta-lactam antibiotic is cephalosporin analog antibiotic, such as: cefotaxime, ceftriaxone, Cefepime, Cefozopran, Cefotaxime, cefoperazone, Ceftaroline Fosamil or any combination thereof or carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, the training of head cyclopentadienyl is southern, safe pyrrole training is southern or it Meaning combination or monocycle beta-lactam antibiotics, such as aztreonam.
In certain embodiments, in the drug products, compound (a) is The beta-lactam antibiotic is cephalosporin analog antibiotic, such as: cefotaxime, ceftriaxone, Cefepime, Cefozopran, Cefotaxime, cefoperazone, Ceftaroline Fosamil or any combination thereof or carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, the training of head cyclopentadienyl is southern, safe pyrrole training is southern or it Meaning combination or monocycle beta-lactam antibiotics, such as aztreonam.
In certain embodiments, in the composition, compound (a) is In certain embodiments, the beta-lactam antibiotic is cephalosporin analog antibiotic, such as: cefotaxime, ceftriaxone, head Spore pyrrole oxime, Cefozopran, cefotaxime, cefoperazone, Ceftaroline Fosamil or any combination thereof or Carbapenems antibiosis Element, such as: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, the training of head cyclopentadienyl South, safe pyrrole training south or any combination thereof or monocycle beta-lactam antibiotics, such as aztreonam.
In certain embodiments, in the drug products, compound (a) or its pharmaceutically acceptable salt, ester or molten Immunomodulator compounds or its stereoisomer and the beta-lactam antibiotic or derivatives thereof are with prevention and/or therapeutically effective amount Or unit dose exists.
In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or The weight ratio of its stereoisomer and beta-lactam antibiotic or derivatives thereof are as follows: 0.5~50:0.5~50, such as 0.5~ 10:0.5~50,10~20:0.5~50,20~30:0.5~50,30~40:0.5~50,40~50:0.5~50,0.5~ 50:0.5~10,0.5~50:10~20,0.5~50:20~30,0.5~50:30~40,0.5~50:40~50,0.5~ 10:0.5~10,10~20:10~20,0.5~20:0.5~20,20~30:20~30,30~40:30~40,40~50: 40~50,1~10:1~10,1~10:1~20,1~20:1~10,1:0.5~50,1:1~32,1:0.5~16,1:1~ 20,0.5~20:1 or 0.5~16:1；Such as 0.5:0.5,0.5:1,0.5:1.5,0.5:2,0.5:2.5,0.5:3,0.5: 3.5、0.5:4、0.5:4.5、0.5:5、0.5:5.5、0.5:6、0.5:6.5、0.5:7、0.5:7.5、0.5:8、0.5:8.5、 0.5:9、0.5:9.5、0.5:10、0.5:10.5、0.5:11、0.5:11.5、0.5:12、0.5:12.5、0.5:13、0.5: 13.5、0.5:14、0.5:14.5、0.5:15、0.5:15.5、0.5:16、0.5:16.5、0.5:17、0.5:17.5、0.5:18、 0.5:18.5、0.5:19、0.5:19.5、0.5:20、0.5:20.5、0.5:21、0.5:21.5、0.5:22、0.5:22.5、0.5: 23、0.5:23.5、0.5:24、0.5:24.5、0.5:25、0.5:25.5、0.5:26、0.5:26.5、0.5:27、0.5:27.5、 0.5:28、0.5:28.5、0.5:29、0.5:29.5、0.5:30、0.5:30.5、0.5:31、0.5:31.5、0.5:32、0.5: 32.5、0.5:33、0.5:33.5、0.5:34、0.5:34.5、0.5:35、0.5:35.5、0.5:36、0.5:36.5、0.5:37、 0.5:37.5、0.5:38、0.5:38.5、0.5:39、0.5:39.5、0.5:40、0.5:40.5、0.5:41、0.5:41.5、0.5: 42、0.5:42.5、0.5:43、0.5:43.5、0.5:44、0.5:44.5、0.5:45、0.5:45.5、0.5:46、0.5:46.5、 0.5:47、0.5:47.5、0.5:48、0.5:48.5、0.5:49、0.5:50、1:0.5、1.5:0.5、2:0.5、2.5:0.5、3: 0.5、3.5:0.5、4:0.5、4.5:0.5、5:0.5、5.5:0.5、6:0.5、6.5:0.5、7:0.5、7.5:0.5、8:0.5、 8.5:0.5、9:0.5、9.5:0.5、10:0.5、10.5:0.5、11:0.5、11.5:0.5、12:0.5、12.5:0.5、13:0.5、 13.5:0.5、14:0.5、14.5:0.5、15:0.5、15.5:0.5、16:0.5、16.5:0.5、17:0.5、17.5:0.5、18: 0.5、18.5:0.5、19:0.5、19.5:0.5、20:0.5、20.5:0.5、21:0.5、21.5:0.5、22:0.5、22.5:0.5、 23:0.5、23.5:0.5、24:0.5、24.5:0.5、25:0.5、25.5:0.5、26:0.5、26.5:0.5、27:0.5、27.5: 0.5、28:0.5、28.5:0.5、29:0.5、29.5:0.5、30:0.5、30.5:0.5、31:0.5、31.5:0.5、32:0.5、 32.5:0.5、33:0.5、33.5:0.5、34:0.5、34.5:0.5、35:0.5、35.5:0.5、36:0.5、36.5:0.5、37: 0.5、37.5:0.5、38:0.5、38.5:0.5、39:0.5、39.5:0.5、40:0.5、40.5:0.5、41:0.5、41.5:0.5、 42:0.5、42.5:0.5、43:0.5、43.5:0.5、44:0.5、44.5:0.5、45:0.5、45.5:0.5、46:0.5、46.5: 0.5,47:0.5,47.5:0.5,48:0.5,48.5:0.5,49:0.5,49.5:0.5 or 50:0.5.Optionally, the β-is interior Amides antibiotic is selected from cefotaxime, ceftriaxone, Cefepime, Cefozopran, cefotaxime, cefoperazone, cephalo Lorraine ester or combinations thereof object.Optionally, the beta-lactam antibiotic is selected from: hundred Na Peinan, Imipenem, Metro training South, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof.Optionally, The beta-lactam antibiotic is selected from aztreonam.
In certain embodiments, in the drug products, every 1 gram of beta-lactam antibiotic, compound (a) or its Pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer with 0.02g~50g (such as 0.02g~0.1g, 0.1g~10g, 0.125g~8g, 0.25g~4g, 0.5g~2g, 1g~2g, 1g~10g, 10g~20g, 20g~30g, 30g ~40g or 40g~50g, for example, 0.02g, 0.03g, 0.04g, 0.05g, 0.06g, 0.07g, 0.08g, 0.09g, 0.1g, 0.11g、0.12g、0.13g、0.14g、0.15g、0.16g、0.17g、0.18g、0.19g、0.2g、0.21g、0.22g、0.23g、 0.24g、0.25g、0.26g、0.27g、0.28g、0.29g、0.3g、0.31g、0.32g、0.33g、0.34g、0.35g、0.36g、 0.37g、0.38g、0.39g、0.4g、0.41g、0.42g、0.43g、0.44g、0.45g、0.46g、0.47g、0.48g、0.49g、 0.5g、0.51g、0.52g、0.53g、0.54g、0.55g、0.56g、0.57g、0.58g、0.59g、0.6g、0.61g、0.62g、 0.63g、0.64g、0.65g、0.66g、0.67g、0.68g、0.69g、0.7g、0.71g、0.72g、0.73g、0.74g、0.75g、 0.76g、0.77g、0.78g、0.79g、0.8g、0.81g、0.82g、0.83g、0.84g、0.85g、0.86g、0.87g、0.88g、 0.89g、0.9g、0.91g、0.92g、0.93g、0.94g、0.95g、0.96g、0.97g、0.98g、0.99g、1g、2g、3g、4g、 5g、6g、7g、8g、9g、10g、11g、12g、13g、14g、15g、16g、17g、18g、19g、20g、21g、22g、23g、24g、 25g、26g、27g、28g、29g、30g、31g、32g、33g、34g、35g、36g、37g、38g、39g、40g、41g、42g、43g、 44g, 45g, 46g, 47g, 48g, 49g or 50g) amount exist.Optionally, the beta-lactam antibiotic is selected from head His pyridine of spore, ceftriaxone, Cefepime, Cefozopran, cefotaxime, cefoperazone, Ceftaroline Fosamil or combinations thereof object.It is optional , the beta-lactam antibiotic be selected from: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof.Optionally, the beta-lactam antibiotic is It is selected from: aztreonam.
In certain embodiments, the drug products include:
(1) 0.0625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(2) 0.125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(3) 0.25g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, With 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo thiophene Oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；Example Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(4) 0.33g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, And 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(5) 0.5g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, With 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo thiophene Oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；Example Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(6) 1g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, for example, cefotaxime, ceftriaxone, cefotaxime, Cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Metro Train south, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；Such as it is single Ring beta-lactam antibiotic, such as aztreonam)；Or
(7) 2g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 2g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, for example, cefotaxime, ceftriaxone, cefotaxime, Cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Metro Train south, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；Such as it is single Ring beta-lactam antibiotic, such as aztreonam；Or
(8) 0.03125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(9) 0.0625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(10) 0.125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(11) 0.167g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, head Spore thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(12) 0.25g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(13) 0.5g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, With 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo thiophene Oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；Example Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(14) 1g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 1g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, for example, cefotaxime, ceftriaxone, cefotaxime, Cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, Imipenem, Metro Train south, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；Such as it is single Ring beta-lactam antibiotic, such as aztreonam)；Or
(15) 0.015625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its solid are different Structure body and 0.5g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, for example, cefotaxime, ceftriaxone, Cefotaxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines It is southern or its any group to train south, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, the training of safe pyrrole It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(16) 0.03125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its solid are different Structure body and 0.5g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, for example, cefotaxime, ceftriaxone, Cefotaxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines It is southern or its any group to train south, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, the training of safe pyrrole It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(17) 0.0625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 0.5g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, head Spore thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(18) 0.125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 0.5g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, head Spore thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(19) 0.25g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 0.5g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, head Spore thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam)；Or
(20) 0.5g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, With 0.5g beta-lactam antibiotic or derivatives thereof (such as cephalosporin analog antibiotic, such as cefotaxime, ceftriaxone, cephalo Thiophene oxime, cefoperazone, Cefepime, Ceftaroline Fosamil；Such as carbapenem antibiotic, such as: hundred Na Peinan, imines training South, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or its any group It closes；Such as monocycle beta-lactam antibiotics, such as aztreonam).
Optionally, the drug products further include one or more therapeutically active agents, and the therapeutically active agent is selected from anti-thin Microbial inoculum, beta-lactamase inhibitor, anaerobe resistant agent, antifungal agent, anti-inflammatory agent, Matrix Metalloproteinase Inhibitors, rouge oxygen close Enzyme inhibitor, cytokine antagonist, immunosuppressor, anticancer agent, antivirotic, cell factor, growth factor, immunological regulation Agent, prostaglandin, anti-angiogenic anti-hyperproliferative compound or any combination thereof.
In certain embodiments, the antibacterial agent be selected from tobramycin, lavo-ofloxacin, vancomycin, benefit how azoles Amine, tigecycline, tigecycline or any combination thereof.
In certain embodiments, the beta-lactamase inhibitor be selected from clavulanic acid, Tazobactam Sodium, Sulbactam or its Any combination.
In certain embodiments, the anaerobe resistant agent is metronidazole, and the antifungal agent is colistin.
In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or Its stereoisomer, described beta-lactam antibiotic or derivatives thereof and optional therapeutically active agent are separately present in the medicine In produce product, such as it is present in different preparations.In certain embodiments, the different preparation has identical or different Dosage form.
In certain embodiments, the dosage form is selected from powder, tablet, granule, capsule, solution, emulsion, mixes Suspension, injection, spray, aerosol, powder spray, lotion, liniment, ointment, emplastrum, paste, patch, gargle or bolt Agent.
In certain embodiments, the different preparation respectively contains a kind of active constituent.For example, the drug products Comprising the first preparation and the second preparation, the active constituent of first preparation is the compound (a) or its is pharmaceutically acceptable Salt, ester, solvated compounds or its stereoisomer, the active constituent of second preparation is the beta-lactam antibiosis Element or derivatives thereof.For example, the drug products include the first preparation, the second preparation and third group preparation, first preparation Active constituent be the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer, The active constituent of second preparation is described beta-lactam antibiotic or derivatives thereof, the active constituent of the third preparation For the therapeutically active agent.
In certain embodiments, the preparation can be such as oral, parenteral, straight with any suitable administration mode The modes such as intestines, transpulmonary or local administration are applied to the patient or subject for needing to prevent and/or treat.When for being administered orally When, the preparation is oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or, oral solution Body preparation, such as oral solution, oral suspensions, syrup.The oral preparation also may include suitable filler, bonding Agent, disintegrating agent, lubricant etc..When being used for parenteral administration, the preparation can be injection, including injection, note It penetrates with aseptic powdery and concentrated solution for injection.For injection, the conventional method in existing pharmaceutical field can be used to be given birth to It produces.When preparing injection, additives can be added without in the preparation, suitable add can also be added according to the property of drug Agent.When being used for rectally, the preparation can be suppository etc..When for transpulmonary administration, the preparation can be inhalant Or spray etc..In this application, preferred administration mode is intravenously administrable, intramuscular delivery or oral administration.
In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or Its stereoisomer and the beta-lactam antibiotic or derivatives thereof are present in the drug in the form of pharmaceutical composition In product.In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its Stereoisomer and the therapeutically active agent are present in the drug products in the form of pharmaceutical composition.In certain embodiment party In case, described beta-lactam antibiotic or derivatives thereof is present in institute with the therapeutically active agent in the form of pharmaceutical composition It states in drug products.In certain embodiments, the compound (a) or pharmaceutically acceptable salt, ester, solvated compounds, Or its stereoisomer, described beta-lactam antibiotic or derivatives thereof with the therapeutically active agent with the shape of pharmaceutical composition Formula is present in the drug products.
In certain embodiments, described pharmaceutical composition is made into pharmaceutically acceptable any dosage form, such as powder, Tablet, granule, capsule, solution, emulsion, suspension, injection, spray, aerosol, powder spray, lotion, liniment, Ointment, emplastrum, paste, patch, gargle or suppository, such as powder, tablet, granule, capsule, solution, injection Agent, ointment, gargle or suppository.
In certain embodiments, described pharmaceutical composition can be with any suitable administration mode, such as takes orally, stomach Outside, the modes such as rectum, transpulmonary or local administration are applied to the patient or subject for needing to prevent and/or treat.When for taking orally When administration, described pharmaceutical composition can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, particle Agent etc.；Or, oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, the medicine Compositions also may include suitable filler, adhesive, disintegrating agent, lubricant etc..When being used for parenteral administration, the medicine Compositions can be made into injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, The conventional method in existing pharmaceutical field can be used to be produced in described pharmaceutical composition.When preparing injection, the medicine It can be added without additives in compositions, suitable additives can also be added according to the property of drug.When for rectally When, described pharmaceutical composition can be made into suppository etc..When for transpulmonary administration, described pharmaceutical composition can be made into inhalant or spraying Agent etc..In this application, preferred administration mode is intravenously administrable, intramuscular delivery or oral administration.
In certain embodiments, the drug products further include one or more pharmaceutical carriers.
In one aspect, this application involves compound (a) as defined above or its pharmaceutically acceptable salt, ester, solvents Compound or its stereoisomer and beta-lactam antibiotic or derivatives thereof are in preparation prevention and/or treatment subject Purposes in the drug products of the infectious diseases as caused by bacterium.
In certain embodiments, the bacterium has the drug resistance as caused by beta-lactamase.
In certain embodiments, the beta-lactamase is selected from: A class beta-lactamase, B metalloid beta-lactamase, C Class beta-lactamase, D class beta-lactamase or any combination thereof.
In certain embodiments, the beta-lactamase is B metalloid beta-lactamase.
In certain embodiments, the beta-lactamase is selected from: CTX-M, TEM, SHV, KPC, NDM, IMP, VIM, AmpC, OXA, extended spectrumβ-lactamase (ESBLs) or any combination thereof.
In certain embodiments, the beta-lactam antibiotic is selected from cephalosporin analog antibiotic or monobactams Antibiotic.
In certain embodiments, the bacterium is selected from gram-positive bacteria, Gram-negative bacteria or any combination thereof.
In certain embodiments, the bacterium is Gram-negative bacteria.
In certain embodiments, the gram-positive bacteria is selected from: Staphylococcus aureus, staphylococcus epidermis, agalasisa Streptococcus, enterococcus faecalis, streptococcus pneumonia, micrococcus scarlatinae, enterococcus, clostridium difficile or any combination thereof.
In certain embodiments, the Gram-negative bacteria is selected from: citrobacter category, citrobacter freundii, yin Enterobacter cloacae, Klebsiella Pneumoniae, Escherichia coli, proteus vulgaris, salmonella, serratia marcescens, will congratulate formula bacillus, Pseudomonas aeruginosa, mucositis Moraxella, neisseria gonorrhoeae, Neisseria meningitidis, Neisseria gonorrhoeae, acinetobacter calcoaceticus Category, Burkholderia category, campylobacter, helicobacter pylori, comma bacillus, klebsiella spp, haemophilus influenzae, the compound branch of bird Bacillus, mycobacterium abscessus, mycobacterium kansasii, mycobacterium buruli, Chlamydophila pneumoniae, chlamydia trachomatis, influenza are thermophilic It is blood bacillus, micrococcus scarlatinae, beta hemolytic streptococcus, Acinetobacter bauamnnii, Pseudomonas aeruginosa, bacteroides fragilis, waxy Bacillus, stenotrophomonas maltophilia, Huo Shi enterobacteria, Klebsiella oxytoca or any combination thereof.
In certain embodiments, the infectious diseases as caused by bacterium is selected from: the infection of the upper respiratory tract, lower respiratory tract Infection, complexity urinary tract infection and other urinary tract infections, central nervous system infection, ear infection, pleura lung and bronchus sense Dye, pulmonary tuberculosis, concurrent or non-concurrent urinary tract infection, intraperitoneal infection, cardiovascular infections, bloodstream infection, septicemia, bacterium blood Disease, CNS infection, skin or soft tissue infection, GI infection, Arthropyosis infection, genital infection, ocular infection, granuloma sense Dye, concurrent or non-concurrent skin and skin structure infection, catheter infections, pharyngitis, sinusitis, otitis externa, tympanitis, bronchus Inflammation, pyothorax, pneumonia, Community-acquired bacterial pneumonia, Nosocomial Pneumonia, Nosocomial bacterial pneumonia, respirator Pneumonia, infection in diabetic foot, Vancomycin resistant enterococcal infection, cystitis and pyelonephritis, kidney stone, prostate Infection, dialysis Related peritonitis, visceral abscesses, the internal membrane of heart in inflammation, peritonitis, complexity intraperitoneal infection and other peritonaeums Inflammation, myocarditis, pericarditis, be transfused related septicemia, meningitis, encephalitis, brain abscess, osteomyelitis, arthritis, genital ulcer, Urethritis, vaginitis, cervicitis, gingivitis, conjunctivitis, keratitis, entophthamia, the infection in cystic fibrosis patient, heat Property neutrophil cell reduce patient infection or any combination thereof.
In certain embodiments, the subject be mammal, such as bovid, equid, caprid, Porcine animals, canid, felid, rodent, primate；It is wherein, particularly preferred that subject is a human.
In one aspect, this application involves the infectious diseases as caused by bacterium in a kind of prevention and/or treatment subject Method, including to subject apply prevention and/or therapeutically effective amount compound (a) as defined above or its pharmaceutically may be used Salt, ester, solvated compounds or its stereoisomer of receiving, and at least one beta-lactam antibiotic or derivatives thereof.
In certain embodiments, the bacterium has the drug resistance as caused by beta-lactamase.
In certain embodiments, the beta-lactamase is selected from: A class beta-lactamase, B metalloid beta-lactamase, C Class beta-lactamase, D class beta-lactamase or any combination thereof.
In certain embodiments, the beta-lactamase is B metalloid beta-lactamase.
In certain embodiments, the beta-lactam antibiotic is selected from cephalosporin analog antibiotic or monocycle-lactams Class antibiotic.
In certain embodiments, the compound (a), its pharmaceutically acceptable salt, its ester, its solvated compounds or Its stereoisomer, described beta-lactam antibiotic or derivatives thereof and optional therapeutically active agent are simultaneously or sequentially applied For subject, for example, can apply the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or Prior to, concurrently with, or after its stereoisomer, therapeutically active agent is applied.For example, the beta-lactam antibiosis can applied Prior to, concurrently with, or after element or derivatives thereof, therapeutically active agent is applied.
In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or Its stereoisomer and the beta-lactam antibiotic or derivatives thereof be administered simultaneously in the form of pharmaceutical composition in by Examination person.In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or it is vertical Body isomers and therapeutically active agent are administered simultaneously in the form of pharmaceutical composition in subject.In certain embodiments, institute Beta-lactam antibiotic or derivatives thereof and therapeutically active agent is stated to be administered simultaneously in the form of pharmaceutical composition in subject. In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its solid are different Structure body, described beta-lactam antibiotic or derivatives thereof and therapeutically active agent be administered simultaneously in the form of pharmaceutical composition in Subject.
In certain embodiments, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or Its stereoisomer is applied to subject by intravenously administrable, intramuscular delivery or oral administration.In certain embodiments, institute State compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer according to daily administration 1,2, 3 or 4 modes are applied to subject.
In certain embodiments, described beta-lactam antibiotic or derivatives thereof passes through intravenously administrable, intramuscular delivery Or oral administration is applied to subject.In certain embodiments, described beta-lactam antibiotic or derivatives thereof according to The mode that daily administration is 1,2,3 or 4 time is applied to subject.
In certain embodiments, the therapeutically active agent is administered by intravenously administrable, intramuscular delivery or oral administration In subject.In certain embodiments, the therapeutically active agent is applied in the way of daily administration 1,2,3 or 4 time Subject.
In certain embodiments, the subject be mammal, such as bovid, equid, caprid, Porcine animals, canid, felid, rodent, primate；It is wherein, particularly preferred that subject is a human.
On the other hand, the application further relate to it is a kind of prepare the compound (a), its pharmaceutically acceptable salt, ester, The method of solvated compounds or its stereoisomer comprising following steps:
Step (1): the preparation of intermediate 1
Raw material 1 and raw material 2 are dissolved in organic solvent, preferably polar organic solvent, organic base, carboxyl group activating reagents is added And dehydrating agent, or organic base and polypeptide condensing agent is added, it is under nitrogen protection, 10-80 DEG C of reaction a few hours, preferred to react Temperature is 25 DEG C, and the preferred reaction time is 12-20h, after reaction, purified to handle to obtain intermediate 1.
Step (2): the preparation of compound (a)
Intermediate 1 is dissolved in the in the mixed solvent of organic solvent and/or water, organic base, SO is added3M complex compound (such as three Sulfur oxide trimethylamine complex) and palladium charcoal, under hydrogen environment, a few hours are reacted at room temperature, preferably reaction 1-20h, after reaction, It adds organic acid and/or acylate is acidified, react at room temperature a few hours, after reaction, purification process obtains compound (a)。
The organic solvent is selected from one of the following or a variety of: halogenated hydrocarbon solvent, is selected from methylene chloride, three chloromethanes Alkane etc.；Amide solvent, selected from n,N-Dimethylformamide, n,N-dimethylacetamide etc.；Alcohols solvent is selected from methanol, second Alcohol, propyl alcohol, isopropanol, butanol, the tert-butyl alcohol, ethylene glycol and glycerine etc.；Ketones solvent is selected from acetone, methyl butyl ketone and first Base isobutyl ketone etc.；Esters solvent is selected from methyl acetate, ethyl acetate, repefral and propyl acetate etc..
The organic base is selected from: organic amine alkali, as dimethylamine, diethylamine, triethylamine, n,N-diisopropylethylamine, Isopropylamine, hexamethylene diamine etc.；The alkaline metal salt of alcohol, selected from tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, Sodium ethoxide and potassium ethoxide etc..
The carboxyl group activating reagents are selected from: 1- hydroxy benzo triazole (HOBt), 1- hydroxyl -7- azo benzotriazole (HOAt)。
The dehydrating agent is selected from: 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl), N, N- dicyclohexylcarbodiimide (DCC).
Polypeptide condensing agent is selected from: O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester (HBTU)；2- (7- azo benzo three Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU).
In the description and claims of this application, compound is in accordance with chemical structural formula and names, if It indicates that the name of compound is not inconsistent with chemical structural formula when same compound, is subject to chemical structural formula or chemical equation.
In this application, unless otherwise stated, Science and Technology noun used herein has art technology The normally understood meaning of personnel institute.However, for a better understanding of the present invention, be provided below part relational language definition and It explains.In addition, working as the definition of term provided herein and explaining with the normally understood meaning of those skilled in the art not When consistent, with the definition of term provided herein and it is construed to quasi-.
It is of the present invention it is " halogenated " refer to replaced by " halogen atom ", " halogen atom " refers to that fluorine atom, chlorine atom, bromine are former Son or iodine atom.
" C of the present invention1-6Alkyl " indicates the alkyl containing 1-6 carbon atom of linear chain or branched chain, including such as " C1-5 Alkyl ", " C1-4Alkyl ", " C1-3Alkyl ", " C1-2Alkyl ", " C2-6Alkyl ", " C2-5Alkyl ", " C2-4Alkyl ", " C2-3Alkyl ", “C3-6Alkyl ", " C3-5Alkyl ", " C3-4Alkyl ", " C4-6Alkyl ", " C4-5Alkyl ", " C5-6Alkyl " etc., specific example include but It is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2- first Base butyl, neopentyl, 1- ethyl propyl, n-hexyl, isohesyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3,3- Dimethylbutyl, 2,2- dimethylbutyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 1,3- dimethylbutyl, 2,3- bis- Methyl butyl, 2- ethyl-butyl, 1,2- dimethyl propyl etc.." C of the present invention1-4Alkyl " refers to C1-6Contain 1- in alkyl The specific example of 4 carbon atoms.
" halogenated C of the present invention1-6Alkyl " refers to that one or more halogen atoms replace C1-6One or more on alkyl Group derived from a hydrogen atom, " halogen atom " and " C1-6Alkyl " is as defined hereinabove.It is of the present invention " halogenated C1-4Alkyl " refers to halogenated C1-6The specific example containing 1-4 carbon atom in alkyl.
" hydroxyl C of the present invention1-6Alkyl " refers to that one or more hydroxyls replace C1-6One or more hydrogen on alkyl Group derived from the atom, " C1-6Alkyl " is as defined hereinabove." hydroxyl C of the present invention1-4Alkyl " refers to hydroxyl C1-6 The specific example containing 1-4 carbon atom in alkyl.
" amino C of the present invention1-6Alkyl " refers to that one or more amino replace C1-6One or more hydrogen on alkyl Group derived from the atom, " C1-6Alkyl " is as defined hereinabove." amino C of the present invention1-4Alkyl " refers to amino C1-6 The specific example containing 1-4 carbon atom in alkyl.
" C of the present invention2-6Alkenyl " refer to the straight chain that containing at least one double bond and carbon atom number is 2-6, branch or Cricoid alkenyl, including such as " C2-5Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl ", " C3-6Alkenyl ", " C3-5Alkenyl ", " C3-4Alkene Base ", " C4-6Alkenyl ", " C4-5Alkenyl ", " C5-6Alkenyl " etc..The example includes but is not limited to: vinyl, 1- acrylic, 2- propylene Base, 1- cyclobutenyl, 2- cyclobutenyl, 1,3- butadienyl, 1- pentenyl, 2- pentenyl, 3- pentenyl, 1,3- pentadienyl, 1, 4- pentadienyl, 1- hexenyl, 2- hexenyl, 3- hexenyl, 1,4- hexadienyl, cyclopentenyl, 1,3- cyclopentadienyl group, ring Hexenyl, 1,4- cyclohexadienyl etc..
" C of the present invention2-6Alkynyl " refers to the linear chain or branched chain that containing at least one three key and carbon atom number is 2-6 Alkynyl, including such as " C2-5Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl ", " C3-6Alkynyl ", " C3-5Alkynyl ", " C3-4Alkynyl ", “C4-6Alkynyl ", " C4-5Alkynyl ", " C5-6Alkynyl " etc..The example includes but is not limited to: acetenyl, propinyl, 2- butynyl, 2- Pentynyl, 3- pentynyl, 4- methyl-valerylene base, 2- hexin base, 3- hexin base, 5- methyl -2- hexin base etc..
" four (C of the present invention1-6Alkyl) quaternary ammonium ion " refer to multiple identical or different C1-6Alkyl replaces quaternary ammonium Ion (H4N+) on four hydrogen atoms derived from group, " the C1-6Alkyl " is as defined hereinabove.
" C of the present invention1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, halogenated C1-6Alkoxy C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkoxy carbonyl, C1-6Alkyl carbonyl epoxide C1-6Alkyl, C1-6 Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkyl amino C1-6Alkyl, halogenated C1-6Alkyl-carbonyl, halogenated C1-6Alkyl-carbonyl C1-6Alkyl, C1-6Alkyl amido, C1-6Alkyl amino-carbonyl, two (C1-6Alkyl) amino carbonyl, C1-6Alkyl sulphinyl, C1-6 Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C1-6Alkyl sulphonyl C1-6Alkyl, C1-6Alkyl sulphonyl " refers to C1-6Alkane Base-O-, C1-6Alkyl-O-C1-6Alkyl-, halogenated C1-6Alkyl-O-, halogenated C1-6Alkyl-O-C1-6Alkyl-, C1-6Alkyl-C (O)-, C1-6Alkyl-C (O)-O-, C1-6Alkyl-O-C (O)-, C1-6Alkyl-C (O)-O-C1-6Alkyl-, C1-6Alkyl-NH-, (C1-6Alkane Base)2- N-, C1-6Alkyl-NH-C1-6Alkyl-, halogenated C1-6Alkyl-C (O)-, halogenated C1-6Alkyl-C (O)-C1-6Alkyl-, C1-6Alkane Base-C (O)-NH-, C1-6Alkyl-NH-C (O)-, (C1-6Alkyl)2- NH-C (O)-, C1-6Alkyl-SO-, C1-6Alkyl-SO2- NH-, C1-6Alkyl-SO2- O-, C1-6Alkyl-SO2-C1-6Alkyl-, C1-6Alkyl-SO2The group that mode connects, wherein " C1-6Alkyl, halogen For C1-6Alkyl " is as defined hereinabove." C of the present invention1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, halogenated C1-4Alkoxy, Halogenated C1-4Alkoxy C1-4Alkyl, C1-4Alkyl-carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkoxy carbonyl, C1-4Alkyl-carbonyl oxygen Base C1-4Alkyl, C1-4Alkyl amino, two (C1-4Alkyl) amino, C1-4Alkyl amino C1-4Alkyl, halogenated C1-4Alkyl-carbonyl, it is halogenated C1-4Alkyl-carbonyl C1-4Alkyl, C1-4Alkyl amido, C1-4Alkyl amino-carbonyl, two (C1-4Alkyl) amino carbonyl, C1-4Alkyl Sulfinyl, C1-4Alkyl sulfonyl amino, C1-4Alkylsulfonyloxy, C1-4Alkyl sulphonyl C1-4Alkyl, C1-4Alkyl sulphonyl " Refer to the specific example containing 1-4 carbon atom in the alkyl in examples detailed above.
" pharmaceutically acceptable cation " of the present invention can be the chemical valence in the periodic table of elements be monovalence or Divalent metal, such as Na+、K+、Ca2+、Mg2+、Zn2+、Fe2+；It can also be ammonium ion or nitrogenous organic cation, The nitrogenous organic cation includes following several: (1) multiple C1-6Alkyl replaces the hydrogen of ammonium ion to be formed by (C1-6Alkane Base)4N+, multiple C1-6Alkyl can be the same or different, described in text as defined above, preferably (C1-4Alkyl)4N+； (2) nitrogenous organic heterocyclic or hetero-aromatic ring are formed by organic cation, and preferably 3-8 member heterocyclic ring containing nitrogen cation and 5-6 member contains Nitrogen heteroaromatic rings cation, such as can be Deng.
" 3-8 member naphthenic base " of the present invention refers to the cyclic alkyl of the saturation containing 3-8 carbon atom, including for example " 3-4 member naphthenic base ", " 3-5 member naphthenic base ", " 3-6 member naphthenic base ", " 3-7 member naphthenic base ", " 4-5 member naphthenic base ", " 4-6 member Naphthenic base ", " 4-7 member naphthenic base ", " 4-8 member naphthenic base ", " 5-6 member naphthenic base ", " 5-7 member naphthenic base ", " 5-8 member cycloalkanes Base ", " 6-7 member naphthenic base ", " 6-8 member naphthenic base ", " 7-8 member naphthenic base " etc..Specific example includes but is not limited to: cyclopropane Base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base etc.." 5-6 member naphthenic base " refers to containing 5-6 The cyclic alkyl of the saturation of carbon atom.
" 6-8 member aryl " of the present invention refers to the monocyclic aryl containing 6-8 ring carbon atom, and the example includes but not It is limited to: phenyl, cyclooctatetraenyl etc..
" the thick aryl of 6-15 member " of the present invention refers to shares two phases by two or more cyclic structures each other Adjacent atom is formed by, containing 6-15 ring carbon atom, unsaturated, with armaticity cyclic group.Specific example It includes but are not limited to: naphthalene, anthryl, phenanthryl etc.." the thick aryl of 6-10 member " refers to annular atom in the thick aryl of 6-15 member The specific example that number is 6-10.
" 4-15 member condensed ring radical " of the present invention refers to shares two phases by two or more cyclic structures each other Adjacent atom is formed by, the cyclic structure containing 4-15 ring carbon atom, including such as " 4-12 member condensed ring radical ", " 4-11 is first Condensed ring radical ", " 5-10 member condensed ring radical ", " 6-11 member condensed ring radical ", " 5-9 member condensed ring radical ", " 7-10 member condensed ring radical ", " 4-12 member is thick Ring group ", " 8-9 member condensed ring radical ", " 9-10 member condensed ring radical " etc., optionally, the carbon atom in cyclic structure can be by oxo.In fact Example includes but is not limited to:
Deng.The 4-10 member condensed ring radical " refers to the specific example containing 4-10 annular atom in 4-15 member condensed ring radical.
" 5-15 member loop coil base " of the present invention refers to shares a carbon by two or more cyclic structures each other Atom is formed by, the cyclic structure containing 5-15 ring carbon atom.Optionally, the carbon atom in cyclic structure can be by oxygen Generation." 5-15 member loop coil base " includes such as " 4-11 member loop coil base ", " 6-11 member loop coil base ", " 5-10 member loop coil base ", " 7-10 member Loop coil base ", " 6-9 member loop coil base ", " 7-9 member loop coil base ", " 7-8 member loop coil base ", " 9-10 member loop coil base " etc..Specific example packet It includes but is not limited only to:
Deng." the 7-9 member spiral shell Ring group " or " 5-10 member loop coil base " refer to the specific example in 5-15 member loop coil base containing 7-9 or 5-10 annular atom.
" 5-15 member bridged ring base " of the present invention refer to by two or more cyclic structures each other share two it is non- Adjacent carbon atom is formed by, the cyclic structure containing 5-15 ring carbon atom.Optionally, the carbon atom in cyclic structure can be with By oxo." 5-15 member bridged ring base " includes such as " 5-11 member bridged ring base ", " 6-11 member bridged ring base ", " 5-10 member bridged ring base ", " 7- 10 yuan of bridged ring bases ", " 6-9 member bridged ring base ", " 7-9 member bridged ring base ", " 7-8 member bridged ring base ", " 9-10 member bridged ring base " etc..It is specific real Example includes but are not limited to:
Deng." the 5-10 member bridged ring Base " refers to the specific example containing 5-10 annular atom in 5-15 member bridged ring base.
It is 3-8 ring containing a heteroatomic and annular atom number that " 3-8 circle heterocyclic ring base " of the present invention, which refers at least, The saturation of atom or the cyclic group of fractional saturation, the hetero atom are nitrogen-atoms, oxygen atom and/or sulphur atom.Optionally, ring Annular atom (such as carbon atom, nitrogen-atoms or sulphur atom) in shape structure can be by oxo." 3-8 circle heterocyclic ring base " includes for example " 3-7 circle heterocyclic ring base ", " 3-6 circle heterocyclic ring base ", " 4-7 circle heterocyclic ring base ", " 4-6 circle heterocyclic ring base ", " 6-8 circle heterocyclic ring base ", " 5-7 member Heterocycle ", " 5-6 circle heterocyclic ring base ", " 3-8 member oxygen-containing heterocycle ", " 3-6 member oxygen-containing heterocycle ", " 5-6 member oxygen-containing heterocycle ", " 5-6 member is saturated oxygen-containing heterocycle ", " 3-8 member heterocyclic ring containing nitrogen base ", " 5-6 member heterocyclic ring containing nitrogen base ", " 5-6 member is saturated nitrogen-containing heterocycle Base " etc., preferably " 5-6 circle heterocyclic ring base ".Specific example includes but are not limited to: aziridine base, 2H- aziridine Base, diazacyclo propyl, 3H- diazacyclo acrylic, azetidinyl, 1,4- dioxane base, 1,3- dioxy Azacyclohexane base, 1,3- dioxolane base, 1,4- Dioxin base, tetrahydrofuran base, pyrrolin base, pyrroles Alkyl, imidazolidinyl, 4,5- glyoxalidine base, pyrazolidinyl, 4,5- pyrazoline base, 2,5- dihydrothiophene, thiophane Base, 4,5- dihydro-thiazolyl, thiazolidinyl, piperidyl, tetrahydro pyridyl, piperidone base, tetrahydropyridine ketone group, dihydro piperidones Base, piperazinyl, morpholinyl, 4,5- dihydro-oxazole base, 4,5- dihydro-isoxazole base, 2,3- dihydro-isoxazole base, oxazolidinyl, 2H-1,2- oxazines base, 4H-1,2- oxazines base, 6H-1,2- oxazines base, 4H-1,3- oxazines base, 6H-1,3- oxazines base, 4H-1,4- Oxazines base, 4H-1,3- thiazinyl, 6H-1,3- thiazinyl, 2H- pyranose, 2H- pyran-2-one base, 3,4- dihydro -2H- pyrans Base etc.." the 5-6 circle heterocyclic ring base " refers to the specific example containing 5-6 annular atom in 3-8 circle heterocyclic ring base.
" 4-15 member condensed hetero ring base " of the present invention refers to shares two by two or more cyclic structures each other Adjacent atom is formed by, containing 4-15 annular atom, (wherein at least one annular atom is hetero atom, such as nitrogen-atoms, oxygen Atom or sulphur atom) cyclic structure.Optionally, the annular atom in cyclic structure (such as carbon atom, nitrogen-atoms or sulphur atom) It can be by oxo." 4-15 member condensed hetero ring base " includes such as " 4-12 member condensed hetero ring base ", " 4-10 member condensed hetero ring base ", " 5-10 member Condensed hetero ring base ", " 5-9 member condensed hetero ring base ", " 6-11 member condensed hetero ring base ", " 7-9 member condensed hetero ring base ", " 9-10 member condensed hetero ring base ", " the nitrogenous condensed hetero ring base of 4-15 member ", " the nitrogenous condensed hetero ring base of 4-10 member ", " the nitrogenous condensed hetero ring base of 5-12 member ", " 5-10 member is nitrogenous thick Heterocycle ", " the nitrogenous condensed hetero ring base of 6-10 member ", " the nitrogenous condensed hetero ring base of 7-9 member " etc..Specific example includes but are not limited to: pyrrole Cough up alkyl and cyclopropyl, cyclopenta and aziridinyl, pyrrolidinyl and cyclobutyl, pyrrolidinyl pyrrolizine base, pyrrolidines Base and piperidyl, pyrrolidinyl and piperazinyl, pyrrolidinyl and morpholinyl, piperidyl and morpholinyl, benzopyrrolodinyl, tetrahydro Imidazo [4,5-c] pyridyl group, 3,4- dihydroquinazoline base, 1,2- dihydro-quinoxaline base, benzo [d] [1,3] dioxane penta Alkenyl, 1,3- dihydroisobenzofuran base, 2H- chromogen alkenyl, 2H- chromogen alkene -2- ketone group, 4H- chromene base, 4H- chromene -4- ketone Base, Chromanyl, 4H-1,3- benzoxazinyl-, 4,6- dihydro -1H- furans simultaneously [3,4-d] imidazole radicals, 3a, 4,6,6a- tetrahydro - 1H- furans simultaneously [3,4-d] imidazole radicals, 4,6- dihydro -1H- thieno [3,4-d] imidazole radicals, 4,6- dihydro -1H- pyrrolo- [3, 4-d] imidazole radicals, benzimidazole alkyl, octahydro-benzo [d] imidazole radicals, decahydroquinolyl, hexahydro Thienoimidazole base, hexahydro furan It mutters and imidazole radicals, 4,5,6,7- tetrahydro -1H- benzo [d] imidazole radicals, octahydro cyclopenta [c] pyrrole radicals, indolinyl, two Hydrogen isoindolyl, benzoxazoles alkyl, benzothiazole alkyl, 1,2,3,4- tetrahydro isoquinolyl, 1,2,3,4- tetrahydric quinoline group, 4H-1,3- benzoxazinyl- etc..
" 5-15 member spiro heterocyclic radical " of the present invention refers to shares one by two or more cyclic structures each other Annular atom is formed by, containing 5-15 annular atom, (wherein at least one annular atom is hetero atom, such as nitrogen-atoms, oxygen atom Or sulphur atom) saturation or fractional saturation cyclic structure.Optionally, (such as the carbon atom, nitrogen-atoms of the annular atom in cyclic structure Or sulphur atom) can be by oxo." 5-15 member spiro heterocyclic radical " includes such as " 5-11 member spiro heterocyclic radical ", " 6-11 member spiroheterocyclic Base ", " 5-10 member spiro heterocyclic radical ", " 6-9 member spiro heterocyclic radical ", " 7-9 member spiro heterocyclic radical ", " 9-10 member spiro heterocyclic radical ", " 7-9 member Be saturated spiro heterocyclic radical ", " 5-15 member nitrogenous loop coil base ", " the nitrogenous spiro heterocyclic radical of 5-10 member ", " the nitrogenous spiro heterocyclic radical of 7-11 member ", " the nitrogenous spiro heterocyclic radical of 7-9 member ", " 7-9 member is saturated nitrogenous spiro heterocyclic radical " etc..Specific example includes but are not limited to:
Deng." the 5-10 member spiro heterocyclic radical " refers to the specific reality containing 5-10 annular atom in 5-15 member spiro heterocyclic radical Example." the nitrogenous spiro heterocyclic radical of 7-9 member " refers to and contains 7-9 annular atom and wherein at least one in 5-15 member spiro heterocyclic radical A annular atom is the specific example of nitrogen-atoms.
" 5-15 member bridge heterocycle " of the present invention refers to shares two by two or more cyclic structures each other Non-adjacent annular atom is formed by, containing 5-15 annular atom, (wherein at least one annular atom is hetero atom, such as nitrogen original Son, oxygen atom or sulphur atom) saturation or fractional saturation cyclic structure.Optionally, (such as carbon is former for the annular atom in cyclic structure Son, nitrogen-atoms or sulphur atom) it can be by oxo." 5-15 member bridge heterocycle " includes such as " 5-10 member bridge heterocycle ", " 6-11 member Bridge heterocycle ", " 6-10 member bridge heterocycle ", " 6-9 member bridge heterocycle ", " 7-10 member bridge heterocycle ", " 7-9 member bridge heterocycle ", " 7-9 member is saturated bridge heterocycle ", " the nitrogenous bridge heterocycle of 5-15 member ", " the nitrogenous bridge heterocycle of 5-9 member ", " the nitrogenous bridge heterocycle of 7-9 member Base ", " the nitrogenous bridge heterocycle of 7-8 member ", " 7-9 member is saturated nitrogenous bridge heterocycle " etc..Specific example includes but are not limited to:
Deng." the 5-10 member bridge heterocycle " refers to the specific example containing 5-10 annular atom in 5-15 member bridge heterocycle." the 7- 9 yuan of nitrogenous bridge heterocycles " refer in 5-15 member bridge heterocycle containing 7-9 annular atom and wherein at least one annular atom is The specific example of nitrogen-atoms.
" 5-8 unit's heteroaryl " of the present invention refers to that (wherein at least one annular atom is miscellaneous original containing 5-8 annular atom Son, such as nitrogen-atoms, oxygen atom or sulphur atom) the monocycle cyclic group with armaticity.Optionally, the ring in cyclic structure Atom (such as carbon atom, nitrogen-atoms or sulphur atom) can be by oxo." 5-8 unit's heteroaryl " include such as " 5-7 unit's heteroaryl ", " 5-6 unit's heteroaryl " etc..Specific example includes but are not limited to furyl, thienyl, pyrrole radicals, thiazolyl, isothiazolyl, thiophene Di azoly, oxazolyl, isoxazolyl, oxadiazoles base, imidazole radicals, pyrazolyl, 1,2,3- triazolyl, 1,2,4- triazolyl, 1,2, 3- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles base, 1,3,4- oxadiazoles base, pyridyl group, 2- pyriconyl, 4- Pyriconyl, pyrimidine radicals, pyridazinyl, pyrazinyl, 1,2,3- triazine radical, cyanuro 1,3,5,1,2,4,5- tetrazine base, azacyclo- Heptantriene base, 1,3- diaza cycloheptatriene base, azepine cyclooctatetraenyl etc.." the 5-6 unit's heteroaryl " refers to 5-8 member heteroaryl Specific example containing 5-6 annular atom in base.
" the thick heteroaryl of 5-15 member " of the present invention refers to shares two by two or more cyclic structures each other Adjacent atom is formed by, containing 5-15 annular atom, (wherein at least one annular atom is hetero atom, such as nitrogen-atoms, oxygen Atom or sulphur atom), the unsaturated cyclic structure with armaticity.Optionally, (such as the carbon of the annular atom in cyclic structure Atom, nitrogen-atoms or sulphur atom) it can be by oxo." the thick heteroaryl of 5-15 member " includes such as " the thick heteroaryl of 5-10 member ", " 7-10 The thick heteroaryl of member ", " the thick heteroaryl of 9-10 member " etc..Specific example includes but is not limited to: benzofuranyl, benzisoxa furyl, Benzothienyl, indyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazole base, quinolyl, 2- Quinoline ketone group, 4- quinoline ketone group, 1- isoquinolin ketone group, isoquinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinoline Oxazoline base, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridines base, phenazinyl, phenothiazinyl etc..It is described that " 5-10 member is thick miscellaneous Aryl " refers to the specific example containing 5-10 annular atom in the thick heteroaryl of 5-14 member.
" carbon atom, nitrogen-atoms or sulphur atom are by oxo " of the present invention refers to form C=O, N=O, S=O or SO2 Structure.
" being optionally substituted with a substituent " of the present invention refer to be substituted with a substituent or unsubstituted base replace.
" pharmaceutically acceptable salt " of the compounds of this invention (a) refers to acidic functionality (example present in compound (a) Such as-COOH ,-OH ,-SO3H etc.) with appropriate inorganic or organic cation (alkali) formed salt, including with alkali metal or alkaline earth Salt, the ammonium salt of metal formation, and the salt formed with nitrogenous organic base；And basic functionality (example present in compound (a) Such as-NH2Deng) salt with appropriate inorganic or organic anion (acid) formation, including with inorganic acid or organic acid (such as carboxylic acid Deng) formed salt.
" ester " of the compounds of this invention (a) indicates that compound (a) there are when carboxyl, can occur esterification with alcohol and be formed Ester esterification can occur with organic acid, inorganic acid, acylate etc. and be formed when compound (a) is there are when hydroxyl Ester.Under the conditions of ester is existing for the acid or alkali, hydrolysis can occur and generate corresponding acid or alcohol.
" alloisomerism " of the compounds of this invention is divided into conformational isomerism and configuration isomery, and configuration isomery is also divided into along anteiso- Structure and optical isomerism (enantiomerism).Conformational isomerism refers to the organic molecule with certain configuration due to the rotation of carbon, carbon single bond Turn or distortion and make each atom of molecule or atomic group generate a kind of stereo-isomerism of different arrangement modes in space, often That sees has the structure of alkane and naphthene-based compounds, such as the chair conformation and boat conformation occurred in cyclohexane structure." optically-active Isomers (enantiomter) " refers to when the compounds of this invention contains one or more asymmetric centers, thus can be used as racemic Body and racemic mixture, single enantiomter, non-enantiomer mixture and single diastereoisomer.Of the present inventionization Closing object has asymmetric center, and this kind of asymmetric center respectively will independently generate two optical isomers, the scope of the present invention packet Include all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.It is of the present invention If compound contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomer and transisomer.It is of the present invention Compound can exist with tautomeric forms, pass through the connections that one or more double-bond shifts have different hydrogen Point.For example, ketone and its Enol forms are ketone-enol tautomers.Each tautomer and its mixture are included in this In the compound of invention.The enantiomters of all compounds (a), diastereoisomer, racemic modification, mesomer, along anti- Isomers, tautomer, geometric isomer, epimer and its mixture etc. are claimed range, include In the scope of the invention.
" solvated compounds " of the present invention refer to compound (such as beta-lactam antibiotic) and water or organic solvent Complex is formed by by the interaction of non-covalent bond；The organic solvent includes understood by one of ordinary skill in the art All categories, such as alcohols, ethers, esters, arene or fat hydrocarbon etc..
" compound " of the present invention refers to compound (such as beta-lactam antibiotic) and another or a variety of medicines It is be combined with each other the aggregate with certain (physiology, chemistry) or obvious (materialization) characteristic of composition with accessory molecule；Such as benefit The substance obtained with crystallographic property, preparation nature etc. that molecule of pharmaceutical improves compound.
" metabolin " of the present invention refers to by compound (such as beta-lactam antibiotic) in vivo metabolic process Generated substance may have bioactivity more higher than former compound, it is also possible to lower than the bioactivity of former compound, May also not have bioactivity.
" dosage form " of the present invention, which refers to, is made form suitable for clinical use for drug, including but not limited to powder, Tablet, granule, capsule, solution, emulsion, suspension, injection (including injection, injection sterile powder and injection With concentrated solution), spray, aerosol, powder spray, lotion, liniment, ointment, emplastrum, paste, patch, gargle or bolt Agent, more preferable powder, tablet, granule, capsule, solution, injection, ointment, gargle or suppository.
" carrier " of the present invention includes but is not limited to filler, diluent, adhesive, wetting agent, disintegrating agent, lubrication It is agent, surfactant, preservative, colorant, corrigent, aromatic, effervescent agent, emulsifier, flocculant, deflocculant, antibacterial Agent, solubilizer；Such as: ion-exchanger, aluminium oxide, aluminum stearate, lecithin, haemocyanin such as human albumin, cushion Matter such as phosphate, glycerol, sorbic acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolysis Matter, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, cabosil, magnesium trisilicate, polyethylene Pyrrolidones, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, polyethylene-polyoxypropylene are embedding Section polymer, lanolin or any combination thereof.
" compound preparation " of the present invention refers to the preparation containing two or more main component, that is, several differences The preparation that the drug of classification mixes.
" beta-lactamase " of the present invention is the protein for referring to inactivation beta-lactam antibiotic.Beta-lactam Enzyme is the enzyme that can be catalyzed the beta-lactam cyclizing hydrolysis of beta-lactam antibiotic.The invention mainly relates to be that microorganism β-is interior Amidase can be divided into " A class ", " B class ", " C class ", " D class " beta-lactamase.Referring specifically to Waley, The Chemistry of The type of enzyme described in β-lactamase, Page Ed., Chapman&Hall, London, (1992) 198-228.This hair The beta-lactamase that bright emphasis is related to includes Pseudomonas aeruginosa (Pesudomonas pyocyaneum), citrobacter freundii Or the C class beta-lactamase that enterobacter cloacae (Eenterbacter cloacae) generates；Bacteroides fragilis (CcrA), pneumonia gram The primary bacterium of thunder, escherichia coli (Escherichia coli), enterobacter cloacae, citrobacter freundii, bacillus cereus (Bc II) or thermophilic The B metalloid beta-lactamase that Stenotrophomonas maltophilia (L1) generates；Klebsiella oxytoca, Klebsiella Pneumoniae, large intestine angstrom are uncommon The A class beta-lactamase that bacterium, enterobacter cloacae, citrobacter freundii or Huo Shi enterobacteria generate；And Klebsiella Pneumoniae Or the D class beta-lactamase that escherichia coli generates.
" beta-lactamase inhibitor " of the present invention, which refers to, can reduce or inhibit the active chemical combination of beta-lactamase Object.Beta-lactam enzymatic activity refers to the activity of A, B, C and/or D class beta-lactamase.For antimicrobial application, preferably Half effective inhibition concentration be not higher than 100 μ g/mL, perhaps not higher than 50 μ g/mL or be not higher than 25 μ g/mL, it is preferably not high In 8 μ g/mL, more preferably no higher than 4 μ g/mL.
" antibiotic " of the present invention refers to the change for reducing microorganism viablity or suppressing growth of microorganism or being proliferated Object or composition are closed, term " inhibiting growth or proliferation " refers to the generation time for increasing at least about 2 times (that is, bacterial cell division Or the population double required time).Preferred antibiotic is can to increase at least about 10 times or more (for example, dead in total cell In dying, at least about 100 times or even unlimited) antibiotic in generation time.Antibiotic used in the present invention further include resist it is micro- Biological agent, bacteriostatic agent or fungicide.Example suitable for antibiotic of the invention includes beta-lactam, preferably penicillin Class, cephalo-type, Carbapenems, monobactams.
" effective quantity " of the present invention refers to the amount for being enough to obtain or at least partly obtaining desired effect.For example, pre- Anti- disease (such as disease relevant to bacterial infection) effective quantity refers to, it is sufficient to prevent, prevent or postpone disease (such as with carefully Bacterium sexuality contaminates relevant disease) generation amount；Treatment condition effective amount refers to, it is sufficient to cure or at least partly prevent patient's The amount of disease and its complication.Such effective quantity is measured completely within the limit of power of those skilled in the art, it such as can be with Judged by clinical test results, animal pattern infection research and/or in vitro test.Therapeutical uses, which will effectively be measured, to be taken Certainly in the severity of disease to be treated, the overall status of the immune system of patient oneself, the personal characteristics of patient (such as year Age, weight and gender), the method for application of drug and the other treatment being administered simultaneously etc..For prophylactic treatment, prevention has Effect amount is by the amount of effective prevention bacterium infection.
" collaboration " of the present invention or " synergistic function " refer to two or more drug interactions, make theirs Combined effect is better than their own effect.
" drug products " of the present invention, it includes two or more main components, such as the compounds of this invention (a) or its pharmaceutically acceptable salt, its ester, its solvated compounds or its stereoisomer and beta-lactam antibiotic Or derivatives thereof), described two or two or more main components can be separately present, such as discretely be packed individually to make Agent exists, or is mutually mixed, and exists in the form of pharmaceutical composition.
Technical solution in the application in cited reference paper, is all contained within the scope of disclosure of the invention, can be with Content for explaining the present invention.
Advantageous effect of the invention
Compared with prior art, the drug products of the application have one or more of the following advantages:
(1) drug products of the application have excellent antibacterial activity, effectively reduce the suppression of beta-lactam antibiotic Bacteria concentration reduces because of toxic side effect caused by drug high dose, and to caused by the bacterium of resistance to beta-lactam antibiotic Infectious diseases have excellent therapeutic effect；
(2) drug products of the application can effectively inhibit the activity of one or more beta-lactamases, can be used in controlling The disease for treating the drug resistant bacterial infections as caused by the bacterium that can generate beta-lactamase, especially by B metalloid can be generated Bacterium (such as bacteroides fragilis (CcrA), Klebsiella Pneumoniae, escherichia coli or the enterobacter cloacae, not of beta-lactamase Family name's citric acid bacillus, bacillus cereus (Bc II) or stenotrophomonas maltophilia (L1) etc.) caused by drug resistance disease, subtract Stop, the higher death rate and the more medical expenses of longer time caused by being infected by caused by drug tolerant bacteria less；
(3) each component of the drug products of the application has good medicine in pharmacokinetics and/or pharmacodynamics Learn property, such as good inside and outside antibacterial effect, higher exposed amount, better bioavilability and/or longer half-life period Deng, and the pharmaceutical properties of each component can coincide well, the drug products of the application have good clinical value；
(4) in the drug products of the application, compound (a), its pharmaceutically acceptable salt, ester, solvated compounds or its Stereoisomer can be used as beta-lactamase inhibitor and/or antibiotic and play therapeutic effect, with beta-lactam antibiosis Element combination has synergistic function.When it is as beta-lactamase inhibitor, all or part of beta-lactam can be inhibited Enzyme effectively improves the antimicrobial concentration of beta-lactam antibiotic, enhances its drug activity；When it is as antibiotic, has and kill Dead bacterium or the effect for inhibiting bacterial growth, can cooperate with enhancing antibacterial activity with beta-lactam antibiotic.Compound (a), The technical effect that its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer have is on different bacterial strains It can exist simultaneously or individualism.
Specific embodiment
Below by way of specific embodiment, the invention will be further described, but this is not a limitation of the present invention.This Field technical staff is in accordance with the teachings of the present invention, it is possible to make various modifications or improvements, without departing from basic thought of the invention And range.
The synthesis of the compounds of this invention (a) can be found in the method disclosed in patent WO2017045510, all the application Cited technology contents, are all contained in the scope of the disclosure of the present application.
Experimental program
Exemplary partial experimental program of the invention presented below, to show the beneficial activity of drug products of the present invention and have Beneficial technical effect.It is understood that following experimental programs are only the example to the content of present invention, rather than to model of the present invention The limitation enclosed.Those skilled in the art can carry out appropriate repair to technical solution of the present invention under the introduction of this specification Change or change, without departing from the spirit and scope of the invention.
The antibacterial activity in vitro of 1 compound (a) of experimental example
For trying strain: experiment producing enzyme reference culture is purchased from ATCC, is clinically separated CRE bacterial strain and is purchased from medical university, third army Learn southwestern hospital.
Test sample: the salt of part of compounds (a) or compound (a), chemical name and preparation method are shown in each compound Prepare embodiment.
Comparison medicine: AVM hereinafter Batan (AVI) sodium salt, MK-7655 are made by oneself by Xuan Zhu Shandong Medicine Technology Co, knot Structure formula is as stated in the background art.
Experimental method: agar dilution, with reference to M100-S23:Performance Standards for Antimicrobial Susceptibility Testing；Twenty-Third Informational Supplement (Clinical And Laboratory Standards Institute, 2013), calculate minimal inhibitory concentration (MIC, minimum inhibitory concentration,μg/mL)。
Experimental result:
Table 1, compound (a) are to the antibacterial activity in vitro (μ g/mL) of ATCC producing enzyme reference culture
Note: oblique line "/" indicates undetermined.
(a is to the antibacterial activity in vitro (μ g/mL) for being clinically separated CRE bacterial strain for table 2, compound
Note: ESBLs represents " extended spectrumβ-lactamase；Oblique line "/" indicates undetermined.
Table 3, compound (a) are to the antibacterial activity in vitro (μ g/mL) of bacterium producing multi enzyme preparation
Experiment conclusion:
It can determine whether by the experimental result of table 1, table 2, table 3, suppression of the compound (a) to drug-resistant bacteria caused by beta-lactamase Production is with comparison medicine AVM hereinafter Batan (AVI) sodium salt or MK-7655 is substantially better than, and especially the bacterium as caused by B metalloid enzyme is resistance to Pharmacological property problem illustrates that compound (a) can solve the antibiotics resistance problem as caused by beta-lactamase；For above for trying bacterium Strain has preferable antibacterial activity, illustrates compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its solid Isomers has preferable clinical application potentiality.
The external zymetology activity experiment of 2 compound (a) of experimental example
Test sample: the salt of part of compounds (a) or compound (a), chemical name and preparation method are shown in each compound Prepare embodiment.
Comparison medicine: AVM hereinafter Batan (AVI) sodium salt, MK-7655 are made by oneself by Xuan Zhu Shandong Medicine Technology Co, knot Structure formula is as stated in the background art.
Experimental method:
Nitrocefin (Nitrocefin, cephalosporins) is sensitive to most of beta-lactamase, after being hydrolyzed Color change can occur.By the rate for recording corresponding absorbance measurement Nitrocefin hydrolysis in reaction system in real time. Beta-lactamase inhibitor can inhibit enzyme to reduce the rate of hydrolysis to the hydrolysis of Nitrocefin.By measuring different suppressions Reaction rate under formulation concentrations in same reaction system calculates the IC of inhibitor50(half maximal inhibitory concentration)。
1. preparation of reagents:
Nitrocefin is dissolved in DMSO, compound concentration 2mM, packing deposits in -20 DEG C.Purchased beta-lactamase is female Liquid is 1mg/mL, and mother liquor is dissolved in 50% glycerol.Partial mother liquid is taken to dilute 1000 times of reaction solutions, packing deposits in -20 DEG C.
2. compound solution is prepared:
Untested compound is dissolved in DMSO, compound concentration is the mother liquor of 10mM.If the same day does not use, mother liquor storage In -20 DEG C.Its test is final concentration of: 100 μM, 25 μM, and 6.25 μM, 1.563 μM, 390.6nM, 97.66nM, 24.41nM, 6.10nM, 1.53nM, 0.381nM, 0.095nM.(EDTA-Na2Control as NDM-1 test originates final concentration of 20mM).
3. reaction system:
Test 1 result:
Table 4, compound (a) are to the inhibitory activity (IC of beta-lactamase50)
Note: oblique line "/" indicates undetermined.
Test 2 results:
Table 5, compound (a) are to the inhibitory activity (IC of beta-lactamase50,nM)
Test 3 results
Table 6, compound (a) are to the inhibitory activity (IC of beta-lactamase50)
Experiment conclusion:
It can determine whether by upper table, compound (a) or its salt have good inhibiting effect to beta-lactamase, and are better than or quite In the inhibitory activity of comparison medicine AVM hereinafter Batan (AVI) sodium salt or MK-7655.
Antibacterial activity in vitro associated with 3 compound (a) of experimental example and cefotaxime
Test sample: the salt of part of compounds (a) or compound (a), chemical name and preparation method are as described above.
Comparison medicine: AVM hereinafter Batan (Avibactam, AVI) sodium salt is bought from Jinan Xin Zheng Pharmaceutical Technology Co., Ltd；MK- 7655, self-control, referring to the preparation method of (publication date 2009-07-23) in WO2009091856A2；Cefotaxime (ceftazidime, CAZ), purchase are made profits moral Biotechnology Co., Ltd from Nanjing.
For trying strain: experiment producing enzyme reference culture is purchased from ATCC, is clinically separated CRE bacterial strain and is purchased from medical university, third army
Learn southwestern hospital.
Experimental method: agar dilution, with reference to M100-S23:Performance Standards for Antimicrobial Susceptibility Testing；Twenty-Third Informational Supplement (Clinical And Laboratory Standards Institute, 2013), the concentration of fixed compound calculate minimum Mlc (MIC, minimum inhibitory concentration, μ g/mL).
Experimental result:
Table 7, the present composition are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Note: the expression of short-term "-" is not tested.
Table 8, the present composition are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Table 9, the present composition are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Note: the expression of short-term "-" is not tested.
Table 10, the present composition are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Note: the expression of short-term "-" is not tested.
Table 11, the present composition are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Note: the expression of short-term "-" is not tested.
Table 12, the present composition are to the antibacterial activity in vitro MIC (μ g/mL) for being clinically separated CRE bacterial strain
Note: the expression of short-term "-" is not tested.
Experiment conclusion:
As the experimental result in table 7-13 it is found that composition of the invention is to the drug resistance as caused by beta-lactamase above Bacterium have good antibacterial activity, and inhibiting effect better than cefotaxime one pack system, AVM hereinafter Batan (AVI) sodium salt and cephalo he The composition, and/or MK-7655 of pyridine and the composition of cefotaxime can make cephalo especially to the bacterium for producing B metalloid enzyme The effective concentration of his pyridine is reduced up to more than 1000 times.
As the experimental result in table 14-15 it is found that the composition of different proportion of the present invention is to resistance to caused by beta-lactamase Pharmacological property bacterium has good antibacterial effect, is better than the combination of cefotaxime one-component, AVM hereinafter Batan (AVI) sodium salt and cefotaxime The antibacterial effect of the composition of object, and/or MK-7655 and cefotaxime is effectively reduced especially to the bacterium for producing B metalloid enzyme The effective concentration of cefotaxime.In the composition of different proportion of the present invention, when the ratio of compound and cefotaxime is 1:1, Antibacterial effect is best, i.e. the effective concentration of cefotaxime is lower.
It can be seen from the above result that the present composition can be effectively used for the bacterium as caused by one or more beta-lactamases Drug resistance disease；Particularly, to the bacterial drug resistance disease as caused by B class beta-lactam metalloenzyme, the present composition has Preferable clinical application potentiality.
4 compound (a) of experimental example and Ceftriaxone Sodium, Cefotaxime Sodium, cefoperazone, Cefepime, Ceftaroline Fosamil Associated with antibacterial activity in vitro
Test sample part of compounds of the present invention, chemical name and preparation method are as described above；Ceftriaxone Sodium, cephalo thiophene Oxime sodium, cefoperazone sodium, Cefepime, Ceftaroline Fosamil, are derived from commercially available.
Reference substance: AVM hereinafter Batan (Avibactam, AVI) sodium salt；
For trying strain: experiment producing enzyme reference culture is purchased from ATCC, and totally 11 plants；
Concentration setting:
1, antibiotic concentration is arranged
Ceftriaxone Sodium, Cefotaxime Sodium, cefoperazone sodium, Cefepime and Ceftaroline Fosamil, concentration range when being applied alone For 0.03~128 μ g/ml, totally 13 gradients, cefoperazone sodium are 0.03~64 μ g/ml with concentration range when enzyme inhibitor combination Outside totally 12 gradients, concentration range is 0.03~32 μ g/ml, tetra- antibiotic when other four antibiotic and enzyme inhibitor are combined, Totally 11 gradients.
2, enzyme inhibitor concentration is arranged
Maximum concentration is that 64 μ g/ml used times are most highly concentrated when compound 2, compound 6, AVM hereinafter Batan sodium salt are applied alone, minimum dense Degree is 0.03 μ g/ml, totally 12 gradients；
Five kinds of antibiotic are combined with compound 2, compound 6 or AVM hereinafter Batan sodium salt with fixed mixing ratio, and ratio is 1: 1,2:1,4:1,6:1 and 8:1.
3, group
This experiment is divided into antibiotic group, enzyme inhibitor group, antibiotic-enzyme inhibitor group, vehicle control group and blank Control group.
Experimental method
1, the dilution process of drug:
Antibiotic or enzyme inhibitor are configured to the mother liquor that concentration is 1280 μ g/ml.
Group is applied alone in antibiotic group and enzyme inhibitor: different concentration gradients is diluted to coubling dilution, steps are as follows:
The sterilized water for injection of 2ml is first respectively added to the 12nd test tube for second test tube, is added in first test tube The medical fluid 2ml (the 1280 μ g/ml+2ml sterilizeds water for injection that enzyme inhibitor is then 2ml) of 1280 μ g/ml.Add in second test tube Enter the medical fluid 2ml (the 2ml medical fluid in the first pipe is then added in enzyme inhibitor) of 1280 μ g/ml, mixing takes 2ml to place third test tube In, doubling dilution is carried out with this, after the last one pipe mixes, 2ml is taken out and discards, minimum concentration is 0.3 μ g/ml；
Antibiotic group and enzyme inhibitor fixed mixing ratio combination group, then it is the mother liquor of concentration needed for prepared two compound is each After taking 2ml, volume ratio 1:1 to mix, doubling dilution is carried out to required minimum concentration.
2, the preparation of drug containing plate
Group is applied alone in drug: prepared compound solution 2ml being sequentially added into corresponding plate first.Finally exist (55 DEG C) MH agar medium 18ml that water-bath has balanced is added in each plate, side edged mixes.Each plate Chinese medicine liquid quilt 10 times of dilution, it is to be followed successively by 64,32,16,8,4,2,1,0.5 from high to low that wherein the ultimate density of group, which is applied alone, in enzyme inhibitor, 0.25,0.125,0.06,0.03 μ g/ml, it is to be followed successively by 128,64,32,16 from high to low that the ultimate density of group, which is applied alone, in antibiotic, 8,4,2,1,0.5,0.25,0.125,0.06,0.03 μ g/ml.
Drug combination group: fixed mixing ratio combination group first respectively takes the mother liquor of concentration needed for prepared two compound 2ml after mixing, carries out doubling dilution, is sequentially added into corresponding plate.Water-bath balance is finally added in each plate Good (55 DEG C) MH agar medium 18ml, side edged mix.Each plate Chinese medicine liquid is diluted 10 times, such as with ceftriaxone Sodium/compound 6 is by taking fixed mixing ratio 2:1 combination as an example, and the ultimate density of compound is to be followed successively by 32 (16) from high to low, 16 (8), 8 (4), 4 (2), 2 (1), 1 (0.5), 0.5 (0.25), 0.25 (0.125), 0.125 (0.06), 0.06 (0.03), 0.03 (0.015)μg/ml。
3, the preparation of bacterium solution is tested
From the fresh colony for growing 18-20 hours on Nonsele ctive culture media, choose single bacterium colony, directly with sterile life Reason salt water is adjusted to the Maxwell 0.5# turbidity (about 108cfu/ml), 10 times of normal saline dilution, spare.
4, inoculated and cultured
On the drug containing plate prepared, it is inoculated with configured good 5 μ l of bacterium solution with bacterium instrument is connect automatically, each plate at most connects 27 plants of bacterium of kind, carry out the position mark of each bacterium.
It will be inoculated with the plate of bacterium, sets in biochemical cultivation case 35 DEG C of cultures 16~for 24 hours.
This experiment selects 11 plants of bacterial strains altogether, as shown in the table:
Strain number Strain name Producing enzyme information
BAA-2452TM Klebsiella Pneumoniae NDM-1
BAA-2524TM Klebsiella Pneumoniae OXA-48
BAA-2523TM Klebsiella Pneumoniae OXA-48
BAA-2340TM Escherichia coli KPC
BAA-196TM Escherichia coli TEM-10
BAA-2146TM Escherichia coli NDM-1
BAA-2341TM Escherichia coli KPC
BAA-1900TM Enterobacter cloacae KPC
BAA-2468TM Enterobacter cloacae NDM-1
ATCC-51983TM Huo Shi enterobacteria SHV-5
BAA-2082TM Klebsiella oxytoca KPC
Experimental result
When compound (a) is used alone in the present invention, to the MIC concentration of above-mentioned bacterial strains in 1~8 μ g/ml, especially to production The MIC concentration of the bacterium of B metalloid enzyme can be down to 1 μ g/ml；AVM hereinafter Batan is to the MIC concentration of above-mentioned bacterial strains in 8~64 μ g/ml More than, and MIC concentration > 8 μ g/mls of the AVM hereinafter Batan to the bacterium for producing B metalloid enzyme.
When Ceftriaxone Sodium, Cefotaxime Sodium, cefoperazone sodium, Cefepime, Ceftaroline Fosamil are used alone, to production A The bacterial strain such as BAA-2524 of class and D class beta-lactamaseTM、BAA-2523TMBAA-2340TM、BAA-196TM、BAA-2341TM、 BAA-1900TM、ATCC-51983TM、BAA-2082TM, have certain inhibitory effect or inhibitory effect weaker or unrestraint effect； After being combined respectively with compound (a) with the proportional manner of such as 1:1,2:1,4:1,6:1 and 8:1, MIC is significantly reduced, and is better than The effect being applied alone is up to 64 times or more, such as Ceftriaxone Sodium and compound 2 or compound 6 are directed to BAA- with the combination of 1:1 ratio 2523TMMIC value be reduced to 0.5 μ g/ml, the MIC being applied alone compared to Ceftriaxone Sodium (128 μ g/ml) improves about 256 times；Cephalo Qusong sodium and compound 2 or compound 6 are combined with 1:1 ratio is directed to BAA-2341TMMIC value be reduced to 1 μ g/ml, compare head The MIC (64 μ g/ml) that spore Qusong sodium is applied alone improves about 64 times；The connection of above-mentioned each cephalosporin analog antibiotic and the application compound (a) It is more excellent or suitable with the antibacterial effect after the combination of AVM hereinafter Batan respectively with the more above-mentioned each cephalosporin analog antibiotic of effect.
When Ceftriaxone Sodium, Cefotaxime Sodium, cefoperazone sodium, Cefepime, Ceftaroline Fosamil are used alone, to production B The bacterial strain of metalloid beta-lactamase such as BAA-2452TM、BAA-2146TM、BAA-2468TM, almost without inhibitory effect；Respectively with After compound (a) is with the proportional manner combination of such as 1:1,2:1,4:1,6:1 and 8:1, MIC is significantly reduced, better than what is be applied alone About 4~128 times of effect, and it is better than the antibacterial effect about 2~8 after above-mentioned each cephalosporin analog antibiotic is combined with AVM hereinafter Batan respectively Times, especially in low proportional region (cephalosporin analog antibiotic is than compound (a) 1:1~4:1), the antibacterial effect of the present composition Most preferably.
Experiment conclusion
The present composition can significantly reduce the effective concentration of cephalosporin analog antibiotic, solve thin as caused by beta-lactamase Drug resistance problems caused by bacterium drug resistance problems, especially B metalloid enzyme.
Internal sterilization of 5 present composition of experimental example in Neutropenia mouse thigh infection model is made With experiment
Test sample: part of compounds of the present invention, chemical name and preparation method are as described above；Antibacterial agent: cefotaxime (ceftazidime, CAZ), it is commercially available.
Comparison medicine: AVM hereinafter Batan (Avibactam, AVI) sodium salt is bought from Jinan Xin Zheng Pharmaceutical Technology Co., Ltd；MK- 7655, self-control, referring to the preparation method of (publication date 2009-07-23) in WO2009091856A2.
Experimental method:
1. antibacterial activity in vitro is tested
Referring to experimental example 1 method, the concentration of fixed compound, calculate antibiotic (CAZ) minimal inhibitory concentration (MIC, Minimum inhibitory concentration, μ g/mL), as a result as shown in table 16.
2. animal experiment in vivo
Animal
SPF grades of mouse of female CD-1 (ICR) of 25 ± 2g of weight are used in an experiment.Pass through the cyclophosphamide of two kinds of dosage Intraperitoneal injection: one kind 4 days (150mg/kg) before infection experiment, and another kind lures for 1 day (100mg/kg) before infection experiment Granulocyte is sent out to reduce.
Animal is raised under SPF grades of environment, grain of not restricting water supply.
Bacterial strain
Infection
It is about 10 by bacterial concentration5-107The bacterial suspension of cfu/mL is small to neutropenic through intramuscular inoculation In the thigh of mouse two sides, often flanking kind of volume is 0.1mL.
The preparation of one pack system or composition medical fluid
With 5% glucose injection or 1%Na2CO3Aqueous solution dissolves corresponding drug, and being vortexed to mix is configured to Then highly concentrated solution is successively diluted to other strength solutions.For being combined medical fluid, two drug solutions are pressed into 1:1 before administration (V/V) mixing uses after mixing, and specific compound concentration is as shown in the table:
Administration
T=0h, i.e., 2h starts administration after initiation infection or solvent (control) is treated, and dosage 10mL/kg gives Medicine approach be intravenously administrable or subcutaneous administration, administration frequency be every 2,4,8 or 12 hours (q2h, q4h, q8h or q12h) (for 24 hours It is interior).Thigh is harvested from all animals within 24 hours after treatment starts, the mouse for failing to survive 24 hours harvest when dying.Institute There is the equal cervical dislocation of the harvest of Study Mouse to put to death.After execution, thigh is taken out, removes thigh bone, and every leg muscle individually exists Homogenate is made in physiological saline.Leg muscle is homogenized and carries out gradient dilution, required dilution is then taken to carry out on nutrient agar Bed board is measured for CFU.In addition to treatment group mentioned above and vehicle control group, another group 3 are harvested when being administered and starting The untreated mouse of infection puts to death 3 mouse in t=0h humanly, to measure the preceding initial inoculation object at once for the treatment of. Difference (average value of 3 mouse) when effect of drugs is measured as t=24h and t=0h between log10 [cfu/thigh] value indicates For " Mean (logCFU/thigh)change".As a result as shown in table 17-19.
Experimental result:
The MIC (μ g/mL) of table 16, one pack system or composition for bacterial strain in drug efficacy study
Table 17, one pack system or composition in neutropenic thigh infection model to produce A class beta-lactamase, The in vivo efficacy research of the bacterium of super wide spectrum enzyme
Note: oblique line "/" indicates no specific value ,-indicate that data do not count.
Table 18, one pack system or composition are in neutropenic thigh infection model to production B class or C class β-interior acyl The in vivo efficacy research of the bacterium of amine enzyme, super wide spectrum enzyme
Note: oblique line "/" indicates no specific value.
Table 19, one pack system or composition in neutropenic thigh infection model to produce D class beta-lactamase, The in vivo efficacy research of the bacterium of super wide spectrum enzyme
Note: oblique line "/" indicates no specific number.
Experiment conclusion:
It can determine whether by the experimental result of table 16, the present composition makees the inhibition of drug-resistant bacteria caused by beta-lactamase With the combination for being substantially better than cefotaxime one pack system, compound one pack system, and/or AVM hereinafter Batan (AVI) sodium salt and cefotaxime Object is especially significantly better than AVM hereinafter Batan (AVI) sodium salt to the bacteriostasis for producing B metalloid enzyme (NDM-1, IMP, VIM) With cefotaxime composition.
It can determine whether by the experimental result of table 17, in neutropenic thigh infection model, for producing, A class β-is interior The internal drug activity of the reference culture and clinical strains of amidase (KPC, SHV), super wide spectrum enzyme, the present composition is better than head His pyridine one pack system, compound one pack system, and/or cefotaxime-AVM hereinafter Batan sodium salt composition of spore；Wherein, cefotaxime+chemical combination The internal drug activity of object 2 increases in proportion dependence, is infected and is more had to caused by treatment above-mentioned bacterial strains with 4:1 or more combination Advantage；Though cefotaxime+compound 6 is relatively weaker than the cefotaxime+compound 2 matched on an equal basis with drug activity associated with 4:1 Activity, but it is substantially better than the drug activity that cefotaxime is applied alone.
It can determine whether by the experimental result of table 18, in neutropenic thigh infection model, for B metalloid β- Lactamase (IMP, NDM-1), C class beta-lactamase (AmpC), super wide spectrum enzyme reference culture and clinical strains, of the present invention group The drug activity for closing object is better than cefotaxime one pack system, compound one pack system, and/or cefotaxime-AVM hereinafter Batan sodium salt group Close object；Wherein the internal drug activity of cefotaxime+compound 2 increases in proportion dependence, and with the increasing of administration frequency Add and enhance, is infected advantageously with 4:1 or more combination caused by treatment above-mentioned bacterial strains；The medicine of cefotaxime+compound 6 Effect activity is substantially better than the drug activity that cefotaxime is applied alone.
It can determine whether by the experimental result of table 19, in neutropenic thigh infection model, for D class β-interior acyl The drug activity of the clinical strains of amine enzyme (OXA), super wide spectrum enzyme, the present composition is better than cefotaxime one pack system, compound One pack system, and/or cefotaxime-AVM hereinafter Batan sodium salt composition；Wherein cefotaxime+compound 2 is combined with 2:1 to treatment Infection caused by above-mentioned bacterial strains is advantageously.
Therefore, the present composition can solve the bacterial drug resistance problem as caused by one or more beta-lactamases, The especially bacterial drug resistance problem as caused by B metalloid enzyme.
6 present composition of experimental example causes the internal sterilization test in mouse septicemia model in BAA-1705
Test sample: compound 6, chemical name and preparation method are as described above；Cefotaxime (ceftazidime, CAZ) It is provided by Xuan Zhu Shandong Medicine Technology Co.
6 preparation method of compound:
Solvent: 5% glucose injection
It prepares: taking compound that the dissolution of 5% glucose injection is added, through 0.22 μm of membrane filtration degerming, then again with molten Agent is diluted to required concentration.
CAZ preparation method
Solvent: 1%Na2CO3 aqueous solution
It prepares: taking compound that 1%Na2CO3 aqueous dissolution is added, through 0.22 μm of membrane filtration degerming, then again with molten Agent is diluted to required concentration.
It is combined medical fluid, two drug solutions is mixed before administration after mixing by 1:1 (V/V), is used.
Experimental animal
SPF Kunming mice with the animal quality certification, 18~22g of weight, half male and half female.
Animal feeding is in SPF grades of environment.
Test strain
Strain name: Klebsiella Pneumoniae；
Strain number: BAA-1705；
Producing enzyme information: KPC；
Source: ATCC.
Compound 6 and CAZ see the table below the external minimum inhibitory concentration situation of the BAA-1705.
The MIC value of compound 6 and CAZ to BAA-1705
Infection
The bacterial concentration of 100% minimum lethal dose (MLD) is about 107CFU/ml, i.e., uses the Maxwell 2.0# turbidity bacterium solution 0.5% dry ferment solution dilutes 5 times as injection bacterium solution, through intraperitoneal injection bacterium solution infecting mouse (0.5ml/ is only).
Dosage setting and administration
Test 2 model control groups (100%MLD and 1/10MLD group) of setting, 1 solvent group set 10 for reagent and give Pharmaceutical quantities group.It by weight after fasting in 18~22g Kunming mouse, is grouped at random, every group 8, half male and half female, experimental animal is total Divide 18 groups.
Dosage setting
After animal subject bacterial infection 1h and 4h, each subcutaneous administration is primary, and every mouse administered volume is 10mL/kg.Knot Fruit observation
It after administration, observes, is observed continuously 7 days day by day.The 7th day after administration, count each group dead mouse number, and with compare Group compares carry out statistical disposition, and using survival rate as the index of evaluation drug effect.
Experimental result
Table 20, compound 6 and CAZ cause mouse septicemia Protective effect test result to BAA-1705
ED50: refer to and sepsis is treated with fixed mixing ratio (cefotaxime: compound 6=2:1) in cefotaxime and compound 6 In the dose-effect reaction of the test model of disease, dose that 50% experimental animal can be protected to survive.
This test model control group as can be seen from Table 20: 100%MLD the and 1/10MLD group death rate is 100%, Illustrate this test modeling success, infection dosage is slightly bigger than normal.
In summary vivo bacteria corrosion action test result analysis is as follows:
When 1.CAZ is applied alone, when dosage is 512mg/kg, infecting mouse unprotect is acted on；
ED50 associated with 2.CAZ and compound 6 is 25.13/12.56mg/kg, be in dosage≤16/8mg/kg when, It is poor to the protective effect of infecting mouse, only 12.5%, when dosage is 256/128mg/kg, to the guarantor of infecting mouse Shield effect can reach 100%.
Experiment conclusion
Compared with CAZ is applied alone, composition of the invention significantly improves the survival rate that BAA-1705 causes the mouse of septicemia, And the effective concentration of cefotaxime is reduced, there is good protective effect to infecting mouse.The above present composition is to animal Testing program and effect can effectively instruct the clinical trial protocol of the composition and predict clinical trial result.
The antibacterial activity in vitro of 7 the compounds of this invention of experimental example
For trying strain: experiment producing enzyme reference culture is purchased from ATCC, is clinically separated CRE bacterial strain and is purchased from medical university, third army Learn southwestern hospital.
Test sample: part of compounds of the present invention, chemical name and preparation method are as described above.
Comparison medicine: AVI is made by oneself by Xuan Zhu Shandong Medicine Technology Co, and structural formula is as stated in the background art.
Experimental method: agar dilution, with reference to M100-S23:Performance Standards for Antimicrobial Susceptibility Testing；Twenty-Third Informational Supplement (Clinical And Laboratory Standards Institute,2013)
Experimental result and conclusion:
Table 21, the compounds of this invention are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Annotation: when measuring the antimicrobial concentration of composition, the concentration of fixed compound measures the MIC of Meropenem, similarly hereinafter.
"-" indicates undetermined, similarly hereinafter.
Table 22, the compounds of this invention are to the antibacterial activity in vitro MIC (μ g/mL) of ATCC producing enzyme reference culture
Table 23, the compounds of this invention are to the antibacterial activity in vitro MIC (μ g/mL) for being clinically separated CRE bacterial strain
Table 24, Meropenem and the combination of the compounds of this invention fixed mixing ratio are living to the in-vitro antibacterial of ATCC producing enzyme reference culture Property MIC (μ g/mL)
[annotation]: the 2:1 and 4:1 each mean Meropenem than compound 6 or compound 2, it is the same below to be.
Table 25, Meropenem and the combination of the compounds of this invention fixed mixing ratio are living to the in-vitro antibacterial for being clinically separated CRE bacterial strain Property MIC (μ g/mL)
By table 21-25 experimental result as it can be seen that the compounds of this invention and Meropenem are combined to the bacterium for producing beta-lactamase There is preferable antibacterial activity and be substantially better than the fungistatic effect of Meropenem one-component, particularly, to production KPC enzyme and B eka-gold The bacterium for belonging to enzyme achieves good fungistatic effect, effectively reduces the MIC concentration of Meropenem, illustrates that the compounds of this invention has There are the potentiality for solving carbapenem antibiotic resistance problems.
The antibacterial activity in vitro of experimental example 8 the compounds of this invention and aztreonam composition
For trying strain: experiment producing enzyme reference culture is purchased from ATCC, is clinically separated CRE bacterial strain and is purchased from medical university, third army Learn southwestern hospital.
Test sample: compound 6, chemical name, structural formula and preparation method are shown in patent PCT/CN2016/095837.
Comparison medicine: OP-0595 is made by oneself by Xuan Zhu Shandong Medicine Technology Co, and structural formula is as stated in the background art.
Experimental method: agar dilution, with reference to M100-S23:Performance Standards for Antimicrobial Susceptibility Testing；Twenty-Third Informational Supplement (Clinical And Laboratory Standards Institute,2013)
Experimental result and conclusion:
Table 26, the compounds of this invention are to the antibacterial activity in vitro (μ g/mL) of ATCC producing enzyme reference culture
Table 27, the compounds of this invention are to the antibacterial activity in vitro (μ g/mL) for being clinically separated CRE bacterial strain
The antibacterial activity in vitro of table 28, aztreonam and the combination of the compounds of this invention fixed mixing ratio to ATCC producing enzyme reference culture (μg/mL)
[annotation]: the 2:1 and 4:1 each mean aztreonam than compound 6 or compound 2, it is the same below to be.
Table 29, aztreonam and the combination of the compounds of this invention fixed mixing ratio are to the antibacterial activity in vitro for being clinically separated CRE bacterial strain (μg/mL)
By table 26-29 experimental result as it can be seen that the compounds of this invention and aztreonam combination are equal to the bacterium for producing beta-lactamase There is preferable antibacterial activity and be substantially better than the fungistatic effect of aztreonam one-component, particularly, to production KPC enzyme and B metalloid enzyme Bacterium achieve good fungistatic effect, effectively reduce the MIC concentration of aztreonam, and the compounds of this invention and aztreonam join Used time has better bacteriostatic activity at low ratio (such as the compounds of this invention: aztreonam=1:1~2), illustrates of the present inventionization Closing object has the potentiality for solving the problems, such as such antibiotics resistance.
Above by experimental example form, the contents of the present invention are described in further detail.But this should not be interpreted as The range of the above-mentioned theme of the present invention is only limitted to above-described embodiment.All technologies realized based on above content of the present invention belong to this The range of invention.

Claims (13)

1. a kind of drug products, it includes compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or it is vertical Body isomers, and at least one beta-lactam antibiotic or derivatives thereof, wherein the compound (a) has formula (I) institute The structure shown,
Wherein,
R1For-SO3M ,-OSO3M ,-SO2NH2,-PO3M ,-OPO3M ,-CH2CO2M ,-CF2CO2M or-CF3；
M is selected from H or pharmaceutically acceptable cation；
Ring A is selected from the following groups being optionally substituted with a substituent: 5-15 member bridged ring base, 5-15 member loop coil base, 5-15 member bridge heterocycle Base or 5-15 member spiro heterocyclic radical, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-6Alkyl, halogenated C1-6Alkane Base, C1-6Alkoxy, C1-6Alkyl amino or C1-6Alkyl-carbonyl；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkane Base, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, halogenated C1-6Alkoxy C1-6Alkyl, C1-6Alkyl amino, Two (C1-6Alkyl) amino, C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl-carbonyl, halogenated C1-6Alkyl-carbonyl, halogenated C1-6Alkyl oxycarbonyl Base C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkoxy carbonyl, C1-6Alkyl carbonyl epoxide C1-6Alkyl, C1-6Alkyl amido, C1-6Alkyl amino-carbonyl, two (C1-6Alkyl) amino carbonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl Base C1-6Alkyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-6Alkenyl, C2-6Alkynyl, 3-8 member naphthenic base, 3-8 member ring Alkyl-C1-6Alkyl, 6-8 member aryl, the thick aryl of 6-15 member, 4-15 member condensed ring radical, 5-15 member bridged ring base, 5-15 member loop coil base, 3- 8 circle heterocyclic ring bases, 3-8 circle heterocyclic ring base-C1-6Alkyl, 5-8 unit's heteroaryl, the thick heteroaryl of 5-15 member, 4-15 member condensed hetero ring base, 5-15 First bridge heterocycle or 5-15 member spiro heterocyclic radical.
2. the drug products of claim 1, the compound (a) has structure shown in formula (II),
Wherein, R1、R2, ring A it is as defined in claim 1.
3. the drug products of claims 1 or 2, the compound (a) has structure shown in formula (III),
Wherein,
Ring A is selected from the following groups being optionally substituted with a substituent: 5-15 member loop coil base, the nitrogenous bridge heterocycle of 5-15 member or 5-15 member Nitrogenous spiro heterocyclic radical, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkane Oxygroup, C1-6Alkyl amino or C1-6Alkyl-carbonyl；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkane Base, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, halogenated C1-6Alkoxy C1-6Alkyl, C1-6Alkyl amino, Two (C1-6Alkyl) amino, C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl-carbonyl, halogenated C1-6Alkyl-carbonyl, halogenated C1-6Alkyl oxycarbonyl Base C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkoxy carbonyl, C1-6Alkyl carbonyl epoxide C1-6Alkyl, C1-6Alkyl amido, C1-6Alkyl amino-carbonyl, two (C1-6Alkyl) amino carbonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl Base C1-6Alkyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-6Alkenyl, C2-6Alkynyl, 3-8 member naphthenic base, 3-8 member ring Alkyl-C1-6Alkyl, 4-10 member condensed ring radical, 5-10 member bridged ring base, 5-10 member loop coil base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base- C1-6Alkyl, 4-10 member condensed hetero ring base, 5-10 member bridge heterocycle or 5-10 member spiro heterocyclic radical；
M is selected from H, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, ammonium ion or four (C1-6Alkyl) quaternary ammonium ion.
4. the drug products of any one of claim 1-3, in the compound (a),
Ring A is selected from the following groups being optionally substituted with a substituent: 7-9 member loop coil base, and the nitrogenous bridge heterocycle of 7-9 member or 7-9 member contain Nitrogen spiro heterocyclic radical, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-6Alkyl, halogenated C1-6Alkyl or C1-6Alkane Oxygroup；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkane Base, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkyl-carbonyl, halogenated C1-6Alkane Base carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl amido, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C1-6Alkyl sulphur Acylamino-, 3-8 member naphthenic base, 3-8 member naphthenic base-C1-6Alkyl, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base-C1-6Alkyl, 5-9 member Condensed hetero ring base, 6-9 member bridge heterocycle or 6-9 member spiro heterocyclic radical；
M is selected from H, sodium ion, potassium ion, zinc ion or potassium ion.
5. the drug products of any one of claim 1-4, in the compound (a),
Ring A is selected from the following groups being optionally substituted with a substituent: 7-9 member loop coil base, and the nitrogenous bridge heterocycle of 7-9 member or 7-9 member contain Nitrogen spiro heterocyclic radical, the substituent group are selected from halogen, amino, carboxyl, hydroxyl, cyano, C1-4Alkyl, halogenated C1-4Alkyl or C1-4Alkane Oxygroup；
R2Selected from hydrogen atom, halogen, amino, carboxyl, hydroxyl, C1-4Alkyl, halogenated C1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkane Base, C1-4Alkoxy, halogenated C1-4Alkoxy, C1-4Alkyl amino, two (C1-4Alkyl) amino, C1-4Alkyl-carbonyl, halogenated C1-4Alkane Base carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl amido, C1-4Alkyl sulphinyl, C1-4Alkyl sulphonyl, C1-4Alkyl sulphur Acylamino-, 3-6 member naphthenic base, 3-6 member naphthenic base-C1-4Alkyl, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base-C1-4Alkyl；
M is selected from H, sodium ion, potassium ion, zinc ion or potassium ion；
Preferably, the ring A is connected by ring carbon atom with the nitrogen-atoms of amide group in compound (a).
6. the drug products of any one of claim 1-5, in the compound (a),
Ring A is selected from 2- azabicyclo [2.2.1] heptane base for being optionally substituted with a substituent, 7- azabicyclo [2.2.1] heptane base, 3- azabicyclo [3.2.1] octyl, 8- azabicyclo [3.2.1] octyl, 2- azabicyclo [3.2.1] octyl, 2- nitrogen Miscellaneous bicyclic [2.2.2] octyl, 2,5- diazabicyclos [2.2.1] heptane base, 3,8- diazabicyclos [3.2.1] octyl, 2- oxa- -5- azabicyclo [2.2.1] heptane base, 8- oxa- -3- azabicyclo [3.2.1] octyl, 3,8- diazabicyclos [3.2.1] oct-6-ene base, 3,9- diazabicyclos [3.3.1] nonyl, 5- azaspiro [2.4] heptane base, 2- azaspiro [3.3] heptane base, 2- azaspiro [3.5] nonyl, 7- azaspiro [3.5] nonyl, 2,6- diaza spiroheptane bases, 2- oxa- -6- azepine spiroheptane base, 6- oxa- -2- azaspiro [3.4] octyl, 2- azaspiro [3.4] octyl, 6- Azaspiro [3.4] octyl, 2- azaspiro [4.4] nonyl, 2- oxa- -7- azaspiro [4.4] nonyl, 6- azaspiro [3.4] octyl- 7- alkenyl, 2- oxa- -6- azaspiro [3.4] octyl- 7- alkenyl, 2- azaspiro [4.4] nonyl- 7- alkenyl or spiral shell [3.3] Heptane base, the substituent group are selected from fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl or propyl；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, fluoroform Oxygroup, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopentyl-methyl, ring Hexyl, cyclohexyl methyl, pyrrolidinyl, tetrahydrofuran base, piperidyl or morpholinyl.
7. the drug products of any one of claim 1-6, in the compound (a),
Ring A is selected from 3- azabicyclo [3.2.1] octyl for being optionally substituted with a substituent, 8- azabicyclo [3.2.1] octyl, 3,9- diazabicyclos [3.3.1] nonyl, 2- azepine spiroheptane base, 2- azaspiro [3.5] nonyl, 7- azaspiro [3.5] nonyl or spiral shell [3.3] heptane base；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, fluoroform Oxygroup, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopentyl-methyl, ring Hexyl, cyclohexyl methyl, pyrrolidinyl, piperidyl or morpholinyl；
Preferably, R2Selected from hydrogen atom, amino, methyl, ethyl, butyl, acetyl group, mesyl, cyclopropyl or cyclopropyl first Base；
Preferably, M is selected from H, sodium ion, potassium ion.
8. the drug products of any one of claim 1-7, in the compound (a),
Ring A is selected from the 2- azepine spiroheptane base that is optionally substituted with a substituent, and the substituent group is selected from fluorine atom, chlorine atom, Amino, hydroxyl, methyl, ethyl or propyl；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, fluoroform Oxygroup, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopentyl-methyl, ring Hexyl, cyclohexyl methyl, pyrrolidinyl, piperidyl or morpholinyl；
Preferably, R2Selected from hydrogen atom, amino, methyl, ethyl, butyl, acetyl group, mesyl, cyclopropyl or cyclopropyl first Base；
Preferably, M is selected from H, sodium ion, potassium ion.
9. the drug products of any one of claim 1-8, the compound (a) has structure shown in formula (IV):
Wherein, R2Selected from hydrogen atom, fluorine atom, chlorine atom, amino, hydroxyl, methyl, ethyl, butyl, trifluoromethyl, methoxyl group, Trifluoromethoxy, acetyl group, mesyl, cyclopropyl, Cvclopropvlmethvl, cyclobutyl, cyclobutylmethyl, cyclopenta, cyclopenta Methyl, cyclohexyl, cyclohexyl methyl, pyrrolidinyl, piperidyl or morpholinyl；
M is selected from H, sodium ion, potassium ion, zinc ion or potassium ion；
Preferably, R2Selected from hydrogen atom, amino, methyl, ethyl, butyl, acetyl group, mesyl, cyclopropyl or cyclopropyl first Base；
Preferably, M is selected from H, sodium ion, potassium ion.
10. the drug products of any one of claim 1-9, the compound (a) is selected from:
Preferably, the compound (a) is selected from
11. the drug products of any one of claim 1-10, the beta-lactam antibiotic includes penicillins, cephalo bacterium Plain class, Carbapenems, monobactams；
The penicillin antibiotics are selected from benzyl penicillin, scotcil, novocillin, ospen, tardocillin, benzene azoles XiLin, Cloxacillin, methicillin, oxacillin, naphthlazole, flucloxacillin, dicloxacillin, ampicillin, Amoxicillin, Hetacillin, metampicillin, Talampicillin, Pivampicillin, Bacampicillin, Carbenicillin, Piperacillin, sulbenicillin, furan benzyl XiLin, Ticarcillin, azlocillin, mezlocillin, apalcillin, Mecillinam, Pivmecillinam, temocillin or its any group It closes；
The cephalosporin analog antibiotic is selected from: cephazoline, Ceftiolene, Cefedrolor, Cefaparole, cefrotil, cephalo sulphur Miaow, Cefaclor, cefaloglycin, cephalo pyrrole quinoline, cefatrizine, ceftezole, Cefcanel, Cefazedone cefadroxil, Cefalexin, cefaloram, Cefacetrile, cefroxadine, Cefradine, cephalo trifluoro azoles, Cefetrizole, cefoxitin, head Spore cefuroxime, Loracarbef, Cefcanel, Cefprozil, Cefaclor, Cefdaloxime, cefmetazole, cefbuperazone, cephalo replace It is smooth, Cefotiam, cephalo amine azoles, cefonicid, Cefamandole, Cefoxitin, Cefuracetime, ceftriaxone, cefotaxime, head His pyridine of spore, Cefixime, Cefpodoxime, Ceftiofur, Cefminox, cefoperazone, cephalo tie up star, Cefuzonam, cephalo thiophene Oxygen, Ceftiolene, Cefsumide, cefpiramide, ceforanide, cefivitril, Cefetrizole, Cefetecol, latamoxef, head Spore cloth alkene, Cefpimizole, Cefsulodin, Cefdinir, Cefodizime, Cefmenoxime, Ceftizoxime, Cefcapene, cephalo he Beauty, Cefteram, cefoperon, Cefepime, Cefclidin, Cefquinome, cephalo quinoline ketone, Cefozopran, Cefpirome, fluorine Oxygen cephalo, cefluprenam, Cefoselis, Cefempidone, Ceftaroline Fosamil, Ceftobiprole or any combination thereof；
The carbapenem antibiotic is selected from: hundred Na Peinan, Imipenem, Meropenem, ertapenem, Biapenem, Panipenem, donipenem, head cyclopentadienyl training south, safe pyrrole training south or any combination thereof；
The monocycle beta-lactam antibiotics are selected from: aztreonam, carumonan or combinations thereof；
Preferably, the derivative of the beta-lactam antibiotic is selected from the ester of the beta-lactam antibiotic, pharmaceutically may be used Salt, stereoisomer, prodrug, solvated compounds, compound or the metabolin of receiving.
12. the drug products of any one of claim 1-11, the compound (a) or its pharmaceutically acceptable salt, ester or molten The weight ratio of immunomodulator compounds or its stereoisomer and beta-lactam antibiotic or derivatives thereof are as follows: 0.5~50:0.5~ 50；Such as 0.5~10:0.5~50,10~20:0.5~50,20~30:0.5~50,30~40:0.5~50,40~50: 0.5~50,0.5~50:0.5~10,0.5~50:10~20,0.5~50:20~30,0.5~50:30~40,0.5~50: 40~50,0.5~10:0.5~10,10~20:10~20,0.5~20:0.5~20,20~30:20~30,30~40:30 ~40,40~50:40~50,1~10:1~10,1~10:1~20,1~20:1~10,1:0.5~50,1:1~32,1: 0.5~16,1:1~20,0.5~20:1 or 0.5~16:1；Such as 0.5:0.5,0.5:1,0.5:1.5,0.5:2,0.5:2.5, 0.5:3、0.5:3.5、0.5:4、0.5:4.5、0.5:5、0.5:5.5、0.5:6、0.5:6.5、0.5:7、0.5:7.5、0.5:8、 0.5:8.5、0.5:9、0.5:9.5、0.5:10、0.5:10.5、0.5:11、0.5:11.5、0.5:12、0.5:12.5、0.5:13、 0.5:13.5、0.5:14、0.5:14.5、0.5:15、0.5:15.5、0.5:16、0.5:16.5、0.5:17、0.5:17.5、0.5: 18、0.5:18.5、0.5:19、0.5:19.5、0.5:20、0.5:20.5、0.5:21、0.5:21.5、0.5:22、0.5:22.5、 0.5:23、0.5:23.5、0.5:24、0.5:24.5、0.5:25、0.5:25.5、0.5:26、0.5:26.5、0.5:27、0.5: 27.5、0.5:28、0.5:28.5、0.5:29、0.5:29.5、0.5:30、0.5:30.5、0.5:31、0.5:31.5、0.5:32、 0.5:32.5、0.5:33、0.5:33.5、0.5:34、0.5:34.5、0.5:35、0.5:35.5、0.5:36、0.5:36.5、0.5: 37、0.5:37.5、0.5:38、0.5:38.5、0.5:39、0.5:39.5、0.5:40、0.5:40.5、0.5:41、0.5:41.5、 0.5:42、0.5:42.5、0.5:43、0.5:43.5、0.5:44、0.5:44.5、0.5:45、0.5:45.5、0.5:46、0.5: 46.5、0.5:47、0.5:47.5、0.5:48、0.5:48.5、0.5:49、0.5:50、1:0.5、1.5:0.5、2:0.5、2.5: 0.5、3:0.5、3.5:0.5、4:0.5、4.5:0.5、5:0.5、5.5:0.5、6:0.5、6.5:0.5、7:0.5、7.5:0.5、8: 0.5、8.5:0.5、9:0.5、9.5:0.5、10:0.5、10.5:0.5、11:0.5、11.5:0.5、12:0.5、12.5:0.5、13: 0.5、13.5:0.5、14:0.5、14.5:0.5、15:0.5、15.5:0.5、16:0.5、16.5:0.5、17:0.5、17.5:0.5、 18:0.5、18.5:0.5、19:0.5、19.5:0.5、20:0.5、20.5:0.5、21:0.5、21.5:0.5、22:0.5、22.5: 0.5、23:0.5、23.5:0.5、24:0.5、24.5:0.5、25:0.5、25.5:0.5、26:0.5、26.5:0.5、27:0.5、 27.5:0.5、28:0.5、28.5:0.5、29:0.5、29.5:0.5、30:0.5、30.5:0.5、31:0.5、31.5:0.5、32: 0.5、32.5:0.5、33:0.5、33.5:0.5、34:0.5、34.5:0.5、35:0.5、35.5:0.5、36:0.5、36.5:0.5、 37:0.5、37.5:0.5、38:0.5、38.5:0.5、39:0.5、39.5:0.5、40:0.5、40.5:0.5、41:0.5、41.5: 0.5、42:0.5、42.5:0.5、43:0.5、43.5:0.5、44:0.5、44.5:0.5、45:0.5、45.5:0.5、46:0.5、 46.5:0.5,47:0.5,47.5:0.5,48:0.5,48.5:0.5,49:0.5,49.5:0.5 or 50:0.5；
Preferably, in the drug products, every 1 gram of beta-lactam antibiotic, compound (a) or its is pharmaceutically acceptable Salt, ester or solvated compounds or its stereoisomer are with 0.02g~50g (such as 0.02g~0.1g, 0.1g~10g, 0.125g ~8g, 0.25g~4g, 0.5g~2g, 1g~2g, 1g~10g, 10g~20g, 20g~30g, 30g~40g or 40g~50g, Such as 0.02g, 0.03g, 0.04g, 0.05g, 0.06g, 0.07g, 0.08g, 0.09g, 0.1g, 0.11g, 0.12g, 0.13g, 0.14g、0.15g、0.16g、0.17g、0.18g、0.19g、0.2g、0.21g、0.22g、0.23g、0.24g、0.25g、0.26g、 0.27g、0.28g、0.29g、0.3g、0.31g、0.32g、0.33g、0.34g、0.35g、0.36g、0.37g、0.38g、0.39g、 0.4g、0.41g、0.42g、0.43g、0.44g、0.45g、0.46g、0.47g、0.48g、0.49g、0.5g、0.51g、0.52g、 0.53g、0.54g、0.55g、0.56g、0.57g、0.58g、0.59g、0.6g、0.61g、0.62g、0.63g、0.64g、0.65g、 0.66g、0.67g、0.68g、0.69g、0.7g、0.71g、0.72g、0.73g、0.74g、0.75g、0.76g、0.77g、0.78g、 0.79g、0.8g、0.81g、0.82g、0.83g、0.84g、0.85g、0.86g、0.87g、0.88g、0.89g、0.9g、0.91g、 0.92g、0.93g、0.94g、0.95g、0.96g、0.97g、0.98g、0.99g、1g、2g、3g、4g、5g、6g、7g、8g、9g、 10g、11g、12g、13g、14g、15g、16g、17g、18g、19g、20g、21g、22g、23g、24g、25g、26g、27g、28g、 29g、30g、31g、32g、33g、34g、35g、36g、37g、38g、39g、40g、41g、42g、43g、44g、45g、46g、47g、 48g, 49g or 50g) amount exist；
Such as, the drug products include:
(1) 0.0625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 2g beta-lactam antibiotic or derivatives thereof；Or
(2) 0.125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 2g beta-lactam antibiotic or derivatives thereof；Or
(3) 0.25g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 2g beta-lactam antibiotic or derivatives thereof；Or
(4) 0.33g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 2g beta-lactam antibiotic or derivatives thereof；Or
(5) 0.5g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 2g beta-lactam antibiotic or derivatives thereof；Or
(6) 1g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer and 2g Beta-lactam antibiotic or derivatives thereof；Or
(7) 2g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer and 2g β Lactam antibiotics or derivatives thereof；Or
(8) 0.03125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, And 1g beta-lactam antibiotic or derivatives thereof；Or
(9) 0.0625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 1g beta-lactam antibiotic or derivatives thereof；Or
(10) 0.125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 1g beta-lactam antibiotic or derivatives thereof；Or
(11) 0.167g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 1g beta-lactam antibiotic or derivatives thereof；Or
(12) 0.25g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 1g beta-lactam antibiotic or derivatives thereof；Or
(13) 0.5g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 1g beta-lactam antibiotic or derivatives thereof；Or
(14) 1g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer and 1g Beta-lactam antibiotic or derivatives thereof；Or
(15) 0.015625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its alloisomerism Body and 0.5g beta-lactam antibiotic or derivatives thereof；Or
(16) 0.03125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, And 0.5g beta-lactam antibiotic or derivatives thereof；Or
(17) 0.0625g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, And 0.5g beta-lactam class antibiotic or derivatives thereof；Or
(18) 0.125g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 0.5g beta-lactam antibiotic or derivatives thereof；Or
(19) 0.25g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, with And 0.5g beta-lactam antibiotic or derivatives thereof；Or
(20) 0.5g compound (a) or its pharmaceutically acceptable salt, ester or solvated compounds or its stereoisomer, and 0.5g beta-lactam antibiotic or derivatives thereof；
Optionally, the drug products further include one or more therapeutically active agents, the therapeutically active agent be selected from antibacterial agent, Beta-lactamase inhibitor, anaerobe resistant agent, antifungal agent, anti-inflammatory agent, Matrix Metalloproteinase Inhibitors, lipoxygenase inhibit It is agent, cytokine antagonist, immunosuppressor, anticancer agent, antivirotic, cell factor, growth factor, immunomodulator, preceding Column parathyrine, anti-angiogenic anti-hyperproliferative compound or any combination thereof；
Preferably, the antibacterial agent is selected from tobramycin, lavo-ofloxacin, vancomycin, Linezolid, tigecycline, replaces Ji Huansu or any combination thereof；
Preferably, the beta-lactamase inhibitor is selected from clavulanic acid, Tazobactam Sodium, Sulbactam or any combination thereof；
Preferably, the anaerobe resistant agent is metronidazole, and the antifungal agent is colistin；
Preferably, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer, institute It states beta-lactam antibiotic or derivatives thereof and optional therapeutically active agent is separately present in the drug products, such as deposit It is in different preparations；
Preferably, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer and Described beta-lactam antibiotic or derivatives thereof is present in the drug products in the form of pharmaceutical composition；
Preferably, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer with The therapeutically active agent is present in the drug products in the form of pharmaceutical composition；
Preferably, described beta-lactam antibiotic or derivatives thereof is deposited in the form of pharmaceutical composition with the therapeutically active agent It is in the drug products；
Preferably, the compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds or its stereoisomer, institute It states beta-lactam antibiotic or derivatives thereof and is present in the drug in the form of pharmaceutical composition with the therapeutically active agent In product；
Preferably, the drug products further include one or more pharmaceutical carriers.
13. any one of claim 1-10 definition compound (a) or its pharmaceutically acceptable salt, ester, solvated compounds, Or its stereoisomer and beta-lactam antibiotic or derivatives thereof are drawn in preparation prevention and/or treatment subject by bacterium Purposes in the drug products of the infectious diseases risen；
Preferably, the bacterium has the drug resistance as caused by beta-lactamase；
Preferably, the beta-lactamase is selected from: A class beta-lactamase, B metalloid beta-lactamase, C class beta-lactamase, D Class beta-lactamase or any combination thereof；
Preferably, the beta-lactamase is B metalloid beta-lactamase；
Preferably, the beta-lactamase is selected from: CTX-M, TEM, SHV, KPC, NDM, IMP, VIM, AmpC, OXA, super wide spectrum β- Lactamase (ESBLs) or any combination thereof；
Preferably, the bacterium is selected from gram-positive bacteria, Gram-negative bacteria or any combination thereof；
Preferably, the bacterium is Gram-negative bacteria；
Preferably, the gram-positive bacteria is selected from: Staphylococcus aureus, staphylococcus epidermis, Streptococcusagalactiae, excrement intestines ball Bacterium, streptococcus pneumonia, micrococcus scarlatinae, enterococcus, clostridium difficile or any combination thereof；
Preferably, the Gram-negative bacteria is selected from: citrobacter category, citrobacter freundii, enterobacter cloacae, pneumonia gram The primary bacterium of thunder, Escherichia coli, proteus vulgaris, salmonella, serratia marcescens, will are congratulated formula bacillus, pseudomonas aeruginosa, are sticked It is film inflammation Moraxella, neisseria gonorrhoeae, Neisseria meningitidis, Neisseria gonorrhoeae, acinetobacter, Burkholderia category, curved Curved bar bacterium, helicobacter pylori, comma bacillus, klebsiella spp, haemophilus influenzae, Mycobacterium avium complex, abscess branch bar Bacterium, mycobacterium kansasii, mycobacterium buruli, Chlamydophila pneumoniae, chlamydia trachomatis, haemophilus influenzae, suppurative chain Coccus, beta hemolytic streptococcus, Acinetobacter bauamnnii, Pseudomonas aeruginosa, bacteroides fragilis, bacillus cereus, thermophilic malt Narrow food monad, Huo Shi enterobacteria, Klebsiella oxytoca or any combination thereof；
Preferably, the infectious diseases as caused by bacterium is selected from: the infection of the upper respiratory tract, lower respiratory tract infection, complexity urine It is road infection and other urinary tract infections, central nervous system infection, ear infection, pleura lung and bronchial infection, pulmonary tuberculosis, concurrent Or non-concurrent urinary tract infection, intraperitoneal infection, cardiovascular infections, bloodstream infection, septicemia, bacteremia, CNS infection, skin Or it is soft tissue infection, GI infection, Arthropyosis infection, genital infection, ocular infection, granulomatous infections, concurrent or non-concurrent Skin and skin structure infection, catheter infections, pharyngitis, sinusitis, otitis externa, tympanitis, bronchitis, pyothorax, pneumonia, community Acquired bacterial pneumonia, Nosocomial Pneumonia, Nosocomial bacterial pneumonia, ventilator associated pneumonia, diabetes Foot infection, Vancomycin resistant enterococcal infection, cystitis and pyelonephritis, kidney stone, prostatitis, peritonitis, complexity Infection in intraperitoneal infection and other peritonaeums, dialysis Related peritonitis, visceral abscesses, endocarditis, myocarditis, pericarditis, It is transfused related septicemia, meningitis, encephalitis, brain abscess, osteomyelitis, arthritis, genital ulcer, urethritis, vaginitis, uterus Neck inflammation, gingivitis, conjunctivitis, keratitis, entophthamia, the infection in cystic fibrosis patient, hot neutrophil cell are reduced Infection of patient or any combination thereof；
Preferably, the subject is mammal, such as bovid, equid, caprid, porcine animals, Canidae Animal, felid, rodent, primate；It is wherein, particularly preferred that subject is a human.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101918407A (en) * 2008-01-18 2010-12-15 默沙东公司 Beta-lactamase inhibitors
WO2017045510A1 (en) * 2015-09-16 2017-03-23 山东轩竹医药科技有限公司 Β-lactamase inhibitor and application thereof
CN108619141A (en) * 2017-03-16 2018-10-09 山东轩竹医药科技有限公司 A kind of bactericidal composition and application thereof
CN108778270A (en) * 2016-03-31 2018-11-09 山东轩竹医药科技有限公司 A kind of bactericidal composition and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101918407A (en) * 2008-01-18 2010-12-15 默沙东公司 Beta-lactamase inhibitors
WO2017045510A1 (en) * 2015-09-16 2017-03-23 山东轩竹医药科技有限公司 Β-lactamase inhibitor and application thereof
CN108778270A (en) * 2016-03-31 2018-11-09 山东轩竹医药科技有限公司 A kind of bactericidal composition and application thereof
CN108619141A (en) * 2017-03-16 2018-10-09 山东轩竹医药科技有限公司 A kind of bactericidal composition and application thereof

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