CN1419560A - Anti-infective actatm - Google Patents

Anti-infective actatm Download PDF

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Publication number
CN1419560A
CN1419560A CN01806912A CN01806912A CN1419560A CN 1419560 A CN1419560 A CN 1419560A CN 01806912 A CN01806912 A CN 01806912A CN 01806912 A CN01806912 A CN 01806912A CN 1419560 A CN1419560 A CN 1419560A
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microorganism
compound
beta
antibiotics resistance
group
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Inventor
H·M·谢帕德
M·F·钱
V·R·德帕拉普迪
B·E·卡瑟
M·S·希克松
T·J·洛伯尔
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Celmed Oncology USA Inc
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Celmed Oncology USA Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides compositions and methods for targeting toxic anti-metabolites to inhibit the growth of antibiotic resistant microbial infections. It provides a means of taking advantage of a key disease resistance mechanism to activate these drugs locally, and to overcome the resistance phenotype of the microbes. In addition, the invention provides methods for treating a subject infected with an antibiotic resistant microorganism by administering the compounds or compositions of the invention.

Description

Anti-infectious ECTA TM
The cross reference of related application
The application requires the U.S. Provisional Application No.60/185 that proposed on February 28th, 2000 according to 35U.S.C. § 119 (e), 479 right of priority, and it is for referencial use that the content of this provisional application is incorporated the disclosure into.
Technical field
The present invention relates to enzymatic treatment activation (ECTA TM) therapy, relate in particular to substrate, the effectiveness of present obtainable medicine so they are blockaded by the enzyme of infectious agent expression.
Background
In the disclosure, each publication of reference is author and date (in the bracket), the patent No. or publication number in regular turn.At the application end, just before claims, provided complete reference list.It is for referencial use so that describe the state of the art that the application is correlated with more fully that therefore these documents open incorporate the disclosure into.
Resistance for biocide is medical care problem (Schaechter etc., 1993 that people generally acknowledge; Murray etc., 1997).Recognize that in early days this problem is the penicillin resistance in the Staphylococcus (Staphylococci), the problem of recognizing now comprises (hospital obtains) infectation of bacteria (Bush, 1988 of nearly all hospital then about the treatment of a lot of infectation of bacteria; Steinberg etc., 1996; Murray, 1997).Hospital infection takes place in 5% among the patient who is admitted to hospital (annual about 2,000,000 patients of the U.S.); They cause that annual about 20,000 examples are dead, and have influence on the death of other 60,000 routine hospitals.According to estimates, increase about 7,500,000 hospital's days (hospital day) and 1,000,000,000 dollars of health subsidies usefulness (Wilson etc., 1991) because of hospital infection every year.The importance of antibiotic-resistant bacteria has increased day by day, because a lot of biological [for example, streptococcus aureuses (Staphylococcus aureus)] have formed several different antibiotic resistances (" multiresistance phenotype ").The enzyme that relates to drug resistance comprises: penicillinase, β-Nei Xiananmei, cephalosporinase and other enzyme.These enzymes make the microbiotic deactivation by microbiotic being become inactive compound.The resistance that is caused by enzyme also comprises the antibiotics modification (Murray, 1997) that is caused by E.C. 2.3.1.28 and other aminoglycoside modifying enzyme.Cause other mechanism of antibiotics resistance to comprise, drug permeability sudden change, the expression of the translocator that microbiotic is extruded from the target organism, and the sudden change of medicine target self (Murray, 1997) energetically.Antibiotic sign
Microbiotic is that the target organism is had the medicine that suppresses cell effect or cytotoxic effect.The key of microbiotic success is the selectivity to the disease target, and lacks the toxicity to host or patient.A lot of microbiotic are that other then is the antibiotic synthesis of derivatives of natural generation (Wilson etc., 1991) from the culture purifying of microorganism self.The most useful anti-infective microbiotic is those of attack micro organisms specific target.For example, beta-lactam antibiotics is by being attached on the cell walls precursor and the interference cell wall is synthetic.Because mammalian cell lacks the cell walls of bacterium, so these medicines have great safety margin to the patient.The most common form of anti-beta-lactam antibiotics is the production of the β-Nei Xiananmei of degraded antibiotic molecule.β-Nei Xiananmei is by plasmid or chromogene coding.
Though antibiotic inactivation may be the most common mechanism of drug resistance, also because the sudden change of medicine target self causes producing resistance.These tools that suddenly change are distinctive to be sudden change in the penicillin-binding protein (PBPs), and they cause the reduction of these protein bound microbiotic abilities or the corresponding reduction or the loss of loss and antibiotic activity.Beta-lactam antibiotics comprises: penicillin, Ampicillin Trihydrate, Gepcillin, and cynnematin (comprising Cephalexin Monohydrate Micro/Compacted, cefaclor, cefoxitin, cefotaxime and cefoperazone).Because the production of high-level β-Nei Xiananmei makes above-mentioned resistance very common, so, develop a lot of novel drugs and suppressed these enzymes, so, the effectiveness of increase beta-lactam antibiotics.The example of beta-lactamase inhibitor comprises: Clavulanic Potassium, Ticarcillin/Clavulanate Acid and Sulbactam (Bush, 1988; Wilson etc., 1991; Schaechter etc., 1993).The combination of beta-lactam antibiotics and beta-lactamase inhibitor has prolonged these antibiotic suitable medicine time limits (Bush, 1988).The shortcoming of existing biocide
Existing agent has the effect target that has characterized well.It is as follows to provide several examples:
??? Microbiotic family ???????? Example ?????????? Target
Beta-lactam antibiotics Penicillin, cynnematin The cell walls biosynthesizing
Sulphonamide Sulfanilamide (SN) Stop the synthetic of tetrahydrofolic acid (THFA)
Aminoglycoside Streptomycin sulphate Protein synthesis
Trimethoprim ??--- Folic acid metabolism
Paraxin ??--- Protein synthesis
Vancomycin ??--- Cell walls is synthetic
Other microbiotic is by stoping the production of dna replication dna, cell RNA, perhaps by modifying many cells target work (Schaechter etc., 1993).Generation to antibiotic resistance is common phenomenon, and people have described a lot of mechanism (Schaechter etc., 1993; Murray, 1997).These mechanism comprise: the overexpression of target enzyme, the expression of microbiotic inactivator, the perhaps sudden change of target (so it is no longer discerned by microbiotic).These machine-processed examples have:
Microbiotic The principle mechanisms of resistance
Penicillin and other beta-lactam antibiotics By the beta-lactam enzyme-deactivating
Sulfanilamide (SN) The sudden change of dihydropteroic acid salt synthase target enzyme
Aminoglycoside By the deactivation of aminoglycoside modifying enzyme, perhaps by the target mutation deactivation
Trimethoprim The sudden change of Tetrahydrofolate dehydrogenase target enzyme
Paraxin By the deactivation of paraxin transacetylase
The X-1497 The sudden change of penicillin-binding protein
Vancomycin The sudden change of target cell wall peptide
In the document detail record infectation of bacteria for the increase resistance of antibiotic therapy (for example, referring to Steinberg etc., 1996), and now become universally recognized problem (Murray, 1997).Each " new " microbiotic (for example, from the cynnematin of penicillin) beginning of former generation from it time all is successful, but has increased about the report of resistance afterwards.Series β-Nei Xiananmei microbiotic is exactly typical case's representative of this area.The more degraded of anti-beta-lactamase of each follow-up microbiotic is so organism produces more substantial β-Nei Xiananmei.Especially true (Wilson etc., 1991 concerning hospital's (hospital obtains) infection; Murray, 1997).The most common mechanism of transmitting the drug resistance phenotype is by plasmid, although the regulon of some antibiotics resistances is positioned at (Schaechter etc., 1993) on the bacterial chromosome.The production of beta-lactamase inhibitor has solved the disappointment of medical profession.Regrettably, though β-Nei Xiananmei has covered substrate specificity, they develop into with having nothing in common with each other has each other (still being correlated with) aminoacid sequence.By changing each beta-lactamase inhibitor widely the effectiveness of different enzymes has been expressed this problem.
Vancomycin suppresses the synthetic and assembling of the subordinate phase of whole cell peptidoglycan polymkeric substance, promptly, by with their D-alanyl-D-L-Ala before volume recombination, its vancomycin molecule " pocket " of packing into, so, prevent that it is attached to the peptidoglycan end, this end is the target that changes glycolase and transpeptidase enzyme.In addition, vancomycin may destroy the synthetic and damage protoplastis of RNA by the tenuigenin membrane permeability that changes them.The faecalis of anti-vancocin (enterococci) is to occur as important nosocomial pathogens in the U.S. (VRE).Measured the bacterial strain (VIRSA) of the streptococcus aureus of medium ground anti-vancocin in 1997 in the U.S..VRE and VIRSA have caused the great concern about the continuation effect of vancomycin in these infection of treatment.The faecalis of anti-vancocin produces two kinds of new enzymes: ligase enzyme and desaturase form the terminal D-ala-D-lactate of new depsipeptide at pentapeptide (pentapeptide).This replacement can be proceeded cell walls in the presence of vancomycin synthetic.
The precursor toxicity than them is bigger usually for a new generation's microbiotic, so, can not use the patient according to a conventional method.Formed a resistance circulation, it needs novel method to solve.Therefore, require such microbiotic of new generation, that is, they are insensitive to the medicine escape mechanism of determining.The present invention has satisfied this requirement and relevant advantage is provided.
Disclosure of the present invention
Described a lot of enzymes-prodrug combination in the document in detail.Application comprises antiviral, for example, and expression (Melton and Sherwood, 1996 of the bacterial enzyme of the treatment cancer that ganciclovir (Straus, 1993) and antibody or gene instruct; Stosor etc., 1996).The present invention has changed the technology that antibiotic therapy is had the transmissible disease of resistance for the treatment of.
Therefore, the invention provides the prodrug and the method for the propagation that optionally suppresses the antibiotics resistance microorganism, this method contacts with these prodrugs of significant quantity by making the sample that contains this microorganism.In addition, the present invention provides treatment to be subjected to the patient's of antibiotics resistance infected by microbes method by using composition of the present invention.
Prodrug of the present invention has general structure as follows:
The beta-lactam prodrug
Figure A0180691200121
X, Y, Z and R ' have clearly been defined in this application.
Implement mode of the present invention
Some term that is used for this paper has following definition.
Unless clearly explanation in addition in the literary composition, singulative " " and " this " comprise plural implication.For example, term " cell " comprises a lot of cells, comprises their mixture.
Term " comprise " be intended to the expression, composition and method comprise the part of citation but do not get rid of other.When being used for definitions section compound and method, " substantially by ... form " will represent to have got rid of other composition that any essential meaning is arranged concerning composition.So the basic composition that is grouped into by the one-tenth of this paper definition should not get rid of to come the contaminant trace species of self-separation and purification process and pharmaceutically acceptable carrier, for example, the salt solution of phosphate buffered, sanitas etc." by ... form " what will represent eliminating is not other component of trace constituent and the essence method steps of using the present composition.Embodiment by each definition of these transitional term all belongs to this
Scope of invention.
As term " prodrug " expression that this paper uses, compare with drug metabolite, to the cytotoxicity of target cell littler and can or be converted into the parent or the derivative form of the pharmaceutically active agents or the material of more active form by the enzymatic activatory.
A kind of " composition " is intended to represent the combination of promoting agent and another kind of inert compound or composition (for example, detectable agent or marker or pharmaceutically acceptable carrier) or active compound or composition (for example, assistant agent).
A kind of " pharmaceutical composition " is intended to comprise the combination of a kind of promoting agent and a kind of inert or active carrier, makes described composition be fit in external, the body or ex vivo diagnosis or treatment are used.
The term of using as this paper " pharmaceutically acceptable carrier " comprises any standard drug carrier (for example, phosphate buffered salt solution), water, emulsion (for example, oil-in-water or water-in-oil emulsion), and various wetting agent.Described composition also can comprise stablizer and sanitas.The example of carrier, stablizer and assistant agent is referring to Martin, REMINGTON ' S PHARM.SCI., the 15th edition (Mack Publ.Co., Easton (1975)).
" significant quantity " is the amount that is enough to realize useful or required result.Significant quantity can be by in single or divided doses, coating or dosage are used.
" contrast " is alternative testee or the sample that is used for testing for relatively.A contrast can be " male " or " feminine gender ".
A kind of antibiotics resistance microorganism is a kind ofly can weaken or suppress microbiotic and suppress microorganism growth or kill and wound the microorganism of the ability of microorganism.
A kind of " beta-lactam resistant microorganism " is during a kind of energy synthesizes and the proteinic microorganism of beta-lactam antibiotics.
Microorganism " suppressing growth " represented to compare with the contrast microorganism of the same race that does not contact with described agent by contacting the rate of propagation that reduces this microorganism with a kind of agent.
" testee " is a kind of plant or a kind of vertebrates, fish for example, bird or Mammals (and preferably people).Fish includes but not limited to pet and feeding animals.Bird includes but not limited to pet, sports animal (sport animal) and feeding animals.Mammals includes but not limited to mouse, monkey, people, feeding animals, sports usefulness animal and pet.
The invention provides composition and the method for target for the deleterious metabolic antagonist of antibiotics resistance infected by microbes.In one embodiment, the invention provides a kind of method, this method is utilized crucial disease resistance mechanism (for example, the excess production of β-Nei Xiananmei) to come local these medicines of activation and is overcome resistant phenotype and the inhibition microbial growth.The present invention further provides by using the method that significant quantity compound of the present invention or composition are treated the testee who is subjected to the antibiotics resistance infected by microbes.
On the one hand, the invention provides a kind of prodrug compound with following structure:
Figure A0180691200141
Wherein, R ' is selected from down group: hydrogen, alkyl, aryl, halogenated aryl, phenol, nitro aryl, ammonium, methylamine, dimethylamine, low-grade alkylamine, two low-grade alkylamines, ethylene glycol, glycerine, Sorbitol Powder, polyoxyethylene glycol (PEG), salt form (sodium, potassium, lithium), THAM (2-amino-2-methylol-1, ammediol), and pharmaceutically acceptable salt;
Wherein, X does not exist or is selected from down group: carbonyl, methylene radical, oxygen, sulphur and nitrogen;
Wherein, Y is selected from down group: methylene radical, methyl thiazolinyl, methylene radical alkynyl, methylene oxygen carbonyl, vinyl, and C1～C6 alkynyl; And wherein, Z is a toxophoric group.
On the one hand, described toxophoric group Z is selected from 1-fluoro-1-carbonyl methyl and 1-nitro-2-carbonyl ethyl.On the other hand, Z is selected from down group: Zorubicin, two (2-chloroethyl) amine, mitomycin, triclocarban (trichlorcarban), trichlorine carbanilide, the tribromo salicylamide, Sulfamethoxazole, paraxin, seromycin, trimethoprim, chlorhexidine, Hexachlorophene, the 2-mercapto-pyridine-n-oxide, camptothecine, A Piao meat poison alkene (apoptolidene), cis-platinum, anthracene nucleus (anthracycline), according to pool thioketones (epothilone), halichondrins (halichondrin), half chrysanthemin (hemiasterlin), Methioprim, thapsigargin and D25.Further, described toxophoric group Z is a chlorinated phenol.These chlorinated phenols include but not limited to down group: 5-chloro-2-(2,4 dichloro benzene oxygen base) phenol, 4-chloro-2-(2, the 4-dichlorophenoxy) phenol, 3-chloro-2-(2,4 dichloro benzene oxygen base) phenol, 6-chloro-2-(2, the 4-dichlorophenoxy) phenol, 5-chloro-2-(3, the 4-dichlorophenoxy) phenol, 5-chloro-2-(2, the 5-dichlorophenoxy) phenol and 5-chloro-2-(3, the 5-dichlorophenoxy) phenol.Alternatively, described toxophoric group Z be 2,2 '-dihydroxydiphenyl ether.In another embodiment, described toxophoric group Z is a halo 2-hydroxy benzophenone.
In further embodiment, Y and X constitute one and have the substituting group that is selected from following structure:
Figure A0180691200151
With
Figure A0180691200152
, wherein, T is selected from oxygen, nitrogen, sulphur and carbon.
Specific embodiments of the present invention includes but not limited to the above following modification of the structure of note: 1.Z does not exist; 2.Y be C2～C3 alkynyl.3.X be carbonyl or methylene radical.4.X be methylene radical; And 5. prodrug with following array structure:
Figure A0180691200153
Any compound described herein all can with a kind of carrier (for example, pharmaceutically acceptable carrier) combination.The present invention also provides a kind of composition, and it comprises: above-mentioned prodrug compound, separately with or with other compound known or to be found or other agent combination usefulness, and a kind of carrier.In one embodiment, described carrier is pharmaceutically acceptable carrier.
The present invention also provides a kind of in vitro method that suppresses or kill and wound the medicine of antibiotics resistance microorganism of analyzing, this method comprises the steps: to make described medicine to contact with the antibiotics resistance microorganism, and described antibiotics resistance microorganism is contacted and the comparison microbial growth with prodrug compound of the present invention, so analyze the medicine that suppresses or kill and wound the antibiotics resistance microorganism.Have with similar inhibition of compound of the present invention or the medicine that kills and wounds the antibiotics resistance microbic activity be considered to treat relevant, for further test and exploitation.
Present method is particularly suitable for analyzing effectively the medicine at beta-lactam or vancomycin resistant microorganism.The beta-lactam resistant microorganism is Gram-negative bacteria or gram-positive microorganism.The example of this bacterioid includes but not limited to be selected from down the Gram-negative bacteria of group: naphthalene Se Shi Coccus (Neisseria), moraxella (Moraxella), campylobacter (Campylobacter), enterobacteriaceae (Ehterobacteriaceae), Rhodopseudomonas (Pseudomonas), acinetobacter (Acinetobacter), Haemophilus spp (Haemophilus) and Bacteroides (Bacteroides) and the gram-positive microorganism that is selected from down group: streptococcus aureus, staphylococcus epidermidis (Staphylococcus epidermis), and other coagulase negative staphylococcus, streptococcus pyogenes (Streptococcuspyogenes), streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus agalactiae (Streptococcus agalactiae) and enterococcus spp.
The present invention also provides a kind of method that suppresses the antibiotics resistance microorganism growth, and it contacts by making described microorganism and significant quantity prodrug compound of the present invention.Contact can be carried out in external or body.When in external contact, present method provides a kind of control antibiotics resistance microorganism in epontic measure, and uses a kind of sterilizing agent.In vivo, present method provides a kind of positive control with test potential novel drugs for animal model.
The latent effect agent of different concns is contacted with sample to measure the suitableeest effective concentration of this agent.So, on the one hand, the present invention relates to the discovery and the application thereof of agent, this agent is a selective substrate of giving the drug-fast enzyme of microorganism.
The present invention also provides test kit, and they comprise prodrug described herein and screen required indication.
The sample of the cell or tissue that this paper uses comprises the cell or tissue that exists for feature with drug-fast, and described resistance is the result of infective micro-organisms to the overexpression of enzyme.Described cell can be eukaryotic cell (that is, mammalian cell), for example, and mouse cell, rat cell, hamster cell or people's cell.Described cell also can be a prokaryotic cell prokaryocyte, for example, and bacterial cell.Described cell can be cultivated continuously or be separated from infected animals or people testee.
Present method can be implemented in external, ex vivo or body.Implement an animal model system easily is provided in the body of the present invention in the such animal of for example rat or mouse, can before clinical trial therapeutical agent or prodrug, use said system.In this system, if the microbial inoculant amount has reduced or the sx that infects (each is compared with untreated infection animal), the potential prodrug will be successful.Have independent, also not have the negative control group of infected cells or animal also be useful, it provides comparison basis.
When implementing in vivo, animal is used the alternative prodrug of significant quantity.The term of using as this paper is in the body and ex vivo and " using " or " send and pass " (returning same (from body) or another patient (allogenic) if require targeted cell population) expression, offer the alternative prodrug of testee's significant quantity, this medicine can reduce bacterial load effectively.In these cases, described agent or prodrug can be used with pharmaceutically acceptable carrier.Agent of the present invention, prodrug and composition can be used to produce medicament and be used for using (for example, being in the active ingredient in the pharmaceutical composition) and treatment people and other animal by program routinely.
The drug administration method for compositions is that those of ordinary skills know, and they include but not limited to, micro-injection, intravenously or parenteral dispenser.Described composition is intended to by surface, per os or local dispenser, and intravenously, subcutaneous or intramuscular dispenser.In therapeutic process, can be continuously or carry out dispenser off and on.The method of determining the most effective drug delivery route and dosage is well known by persons skilled in the art, and will change with following factors: the prodrug that is used for the treatment of, therapeutic purpose, processed microorganism, the severity and the subject main body of infection.Can carry out the one or many dispenser, dosage level and form are selected by the treatment doctor.For example, can be to suffering from testee's applying said compositions that antibiotic-resistant bacteria infects.In the case, the composition of using effectively " therapeutic dose " with prevent to continue and stop microorganism growth and propagation at least in part, thereby alleviate the symptom relevant with infection.
Yet, can commute testee or individuality infected or that be in the danger of infecting that shows effect use described prodrug.In these embodiments, use the composition of " prevention significant quantity " and cell viability and function are remained on the approaching level that infects preceding level.
Should understand that by undesirable necrocytosis in prevention or inhibition testee or the individuality, prodrug composition of the present invention and method also provide treatment, prevent or alleviated and be characterised in that the symptom of the disease-related of undesirable infection.Such disease includes but not limited to that the Gram-negative shown in the following table infects and Gram-positive infects.
Biological Disease
Gram-positive
Streptococcus aureus Main human pathogen, microbemia, pneumonia
Staphylococcus epidermidis and other coagulase negative staphylococcus Urinary tract infection, osteomyelitis, microbemia
Streptococcus pyogenes Microbemia, lymphangitis, pneumonia
Streptococcus pneumoniae Pneumonia, otitis media, sinusitis paranasal sinusitis
Streptococcus agalactiae The primary microbemia, pneumonia, endocarditis, osteomyelitis
The enterococcus spp bacterium Urinary tract infection, microbemia, endocarditis infects and pelvic infection newborn infant's sepsis in the abdomen
Gram-negative
Diplococcus gonorrhoeae (Neisseria gonorrhoeae) Genital infection, serohepatitis
Morazella catarrhalis (Moraxella catarrhalis) Otitis media, lower digestive tract infects, pneumonia, microbemia
Campylobacter jejuni jejunum subspecies (Campylobacter jejuni) Acute enteritis, acute colitis, microbemia
Enterobacteriaceae (comprising Escherichia (Escherichia), salmonella (Salmonella), Shigella (Shigella), Klebsiella (Klebsiella), enterobacter (Enterobacter)) Intestines infect, urinary tract infection, respiratory infection, microbemia, bacillary dysentery
Pseudomonas aeruginosa (Pseudomonas aeruginosa) Endocarditis, respiratory infection, microbemia, central nervous system infection
The acinetobacter bacterium Respiratory tract infection, microbemia, genitourinary infection
Haemophilus influenzae (Haemophilus influenzae) Pneumonia, meningitis, epiglottitis, microbemia
Bacteroides (Bacteroides) Peritonitis
Can pass through as U.S. Patent No. 5,085, the polymerase chain reaction of modifying described in 983 (PCR) detects the amplification of the gene relevant with microbial resistance with monitoring.Optionally analytical procedure comprises enzyme activity assay (Miller, 1992; Spector etc., 1997) and by polymerase chain reaction analysis (Spector etc., 1997; Maher etc., 1995).
Present method is particularly suitable for analyzing effectively the medicine at beta-lactam or vancomycin resistant microorganism.The beta-lactam resistant microorganism is Gram-negative bacteria or gram-positive microorganism.The example of this bacterioid includes but not limited to: naphthalene Se Shi Coccus, moraxella, campylobacter, enterobacteriaceae, Rhodopseudomonas, acinetobacter, Haemophilus spp such as Bacteroides, and the gram-positive microorganism that is selected from down group: streptococcus aureus, staphylococcus epidermidis, and other coagulase negative staphylococcus, streptococcus pyogenes, streptococcus pneumoniae, streptococcus agalactiae and enterococcus spp.
In addition, the present invention's anti-vancocin resistance biology effectively.Compound of the present invention kills and wounds bacterium by different mechanism of action.These prodrug compounds are designed to have the dual-use function pattern.They can the formation bactericide kills and wounds bacterium in the bacterial strain by producing at β-Nei Xiananmei.They also may have by suppressing the fungicidal activity of the biosynthetic mechanism of cell walls to non-β-Nei Xiananmei bacterial strain.These compounds have strengthened the activity that anti-beta-lactamase is produced bacterial strain, also have the anti-potential that lacks the bacterial strain of β-Nei Xiananmei.When handling these compounds with the bacterial strain that lacks β-Nei Xiananmei, they are expected to suppress penicillin-binding protein (PBP), and are similar to conventional beta-lactam antibiotics.Simultaneously, form equimolar bactericide, kill bacterial activity so produce.Therefore, infect for β-Nei Xiananmei is negative, compound of the present invention is by forming bactericide and bringing into play their antibacterial activity by suppressing PBP.
The present invention further provides and a kind ofly passed significant quantity compound of the present invention and treat by the testee's of antibiotics resistance infected by microbes method by the testee is sent.Can send like this and pass or send and pass described compound as containing on the medicine composition of acceptable carrier." testee " who uses as this paper includes but not limited to plant and the vertebrates (for example, fish, Mammals or bird) as the preamble definition.Present method is particularly suitable for analyzing effectively the medicine at beta-lactam or vancomycin resistant microorganism.The beta-lactam resistant microorganism is Gram-negative bacteria or gram-positive microorganism.The example of this bacterioid includes but not limited to be selected from down the Gram-negative bacteria of group: Neisseria, moraxella, campylobacter, enterobacteriaceae, Rhodopseudomonas, acinetobacter, Haemophilus spp and Bacteroides, and the gram-positive microorganism of organizing under advancing certainly: streptococcus aureus, staphylococcus epidermidis, and other coagulase negative staphylococcus, streptococcus pyogenes, streptococcus pneumoniae, streptococcus agalactiae and enterococcus spp.
When using significant quantity compound of the present invention or composition, treating or preventing infection to testee's (for example, a kind of plant, animal or human patient).
Prodrug compound of the present invention also is applicable to produce and is used for treating the medicament that antibiotics resistance microorganism (for example, beta-lactam or vancomycin resistant microorganism) infects.The beta-lactam resistant microorganism can be Gram-negative bacteria or gram-positive microorganism.The example of this bacterioid includes but not limited to be selected from down the Gram-negative bacteria of group: naphthalene Se Shi Coccus, not at Bordetella, campylobacter, enterobacteriaceae, Rhodopseudomonas, acinetobacter, Haemophilus spp and Bacteroides, and the gram-positive microorganism that is selected from down group: streptococcus aureus, staphylococcus epidermidis, and other coagulase negative staphylococcus, streptococcus pyogenes, streptococcus pneumoniae, streptococcus agalactiae and enterococcus spp.
In addition, (for example the invention provides a kind of selected antibiotics sensitivity, the beta-lactam activity) method is because biological a kind of of resistance who obtains prodrug may mechanism be through the active loss of β-Nei Xiananmei, so it makes bacterium once more to the beta-lactam antibiotics sensitivity.So, the invention provides the method that a kind of loss by selected resistance enzymic activity reverses antibiotics resistance in the microorganism.This method requires microorganism is contacted with prodrug of the present invention, thereby kills and wounds the microorganism of expressing this enzyme.Only use beta-lactam as an example, the biology that has lost β-Nei Xiananmei will be survived.The biology of now selected these survivals is because they are to original antibiotic susceptibility, so can be by they being contacted with this microbiotic and killing and wounding them effectively.Therefore, the present invention also provides a kind of combination treatment for the treatment of infected by microbes, wherein, and the antibiotics resistance that described microorganism can produce as hereinafter define.Described combination treatment requirement at first with beta-lactam antibiotics treatment, again with the beta-lactam prodrugs therapy of this paper definition, and is treated with original beta-lactam antibiotics at last.Also disclose a kind of method that reverses antibiotics resistance in the microorganism, this method contacts by making described microorganism and significant quantity prodrug of the present invention.
With former work (Melton ﹠amp; Sherwood, 1996) difference, prodrug of the present invention does not need to combine with directed agents.Therefore, described prodrug can be by direct usefulness, the surface with or whole body use.
The present invention also provides a kind of method that optionally suppresses the antibiotics resistance microbial growth, and this method contacts by making described microorganism and significant quantity prodrug of the present invention.As mentioned above, this contact can be carried out to resist ex vivo or sample that cultivate in vivo or sampling in animal system external.But method of the present invention also ex vivo is implemented, and uses U.S. Patent No. 5,399, the modifying method of method described in 346.
Prodrug of the present invention is applicable to the propagation of the microorganism that suppresses anti-beta-lactam antibiotics (for example, penicillin or cynnematin).In addition, prodrug of the present invention also is applicable to the propagation of the microorganism that suppresses anti-vancocin.
Can find β-Nei Xiananmei outside microbial cell or in the periplasmic space.May carry on the plasmid or may in bacterial chromosome, exist about β-Nei Xiananmei synthetic genetic information; Any of both of these case all may cause the generation of the enzyme of anti-common beta-lactam antibiotics.
Plasmid-mediated β-Nei Xiananmei is latent especially, because these extra-chromosomal genetic elements are transferred to another kind from a kind of bacterial strain easily.Initial some β-Nei Xiananmei of encoding on plasmid may have this genetic information, and this information finally is incorporated into karyomit(e) to be become in the permanent thymus nucleic acid that adds cell to.The plasmid that bacterium is carried the multiple antibiotics modification enzyme of a lot of codings is common.Also may on a kind of plasmid, carry a lot of antibiotics resistance factors.So it is more prevalent to show anti-two classes or the antibiotic bacterium of three classes.
One of the most worried aspect of karyomit(e) β-Nei Xiananmei production is that these enzymes are induced easily, causes the β-Nei Xiananmei of high density.Known best inductor is a beta-lactam antibiotics, normally passes through those of inducible enzyme hydrolysis subsequently.In some cases, can select the mutant of stably being prevented, total β-Nei Xiananmei content is equivalent to reach 4% of the interior gross protein of bacterial cell.
One of purpose of the present invention provides can be by any β-Nei Xiananmei activated prodrug, thereby avoids the problem of selected suitable beta-lactamase inhibitor.Since the beta-lactam adducts of described prodrug will be widely β-Nei Xiananmei by a variety of bacteriums activate (referring to for example, Vrudhula etc., 1995), a kind of prodrug will be applicable to that the difference of a lot of treatment-resistants in the past of treatment (being because the cause of the high-caliber β-Nei Xiananmei of target biological production) infects.This method has been avoided the problem (Bush, 1988) of the sudden change resistance of beta-lactamase inhibitor experience.It is because the resistance of these prodrugs might occur because of the active forfeiture of β-Nei Xiananmei that this method also is suitable for.This will cause bacterium to regain susceptibility to penicillin.Therefore, the also claimed a kind of method of the present invention, this method is by becoming to the beta-lactam antibiotics sensitivity described biology biological the contact with significant quantity prodrug of the present invention or the agent by aforementioned Screening and Identification of beta-lactam antibiotics resistance.
Some present obtainable potential antibiotic another limitation are that their lack specificity.Example comprises and Zorubicin that the two is all from streptomyces (Streptomyces).One of main difficulty is the effective target disease mechanisms of medicine in the discovery of medicine and exploitation, and anosis organ or host's organ are lacked effect.Because a lot of microbiotic of finding can not well be distinguished bacterium target and host's target so far, so they also are not used as anti-infection agent.Yet some of these compounds has been used to treat other disease, for example, and cancer.The invention provides a kind of method, this method make these toxic chemicals (form that is prodrug) target infectious biological and inferior limit make the host be exposed to described toxin.
Relevant with invention also have very important prior art, designed these antibiotic prodrug structures in the prior art, and wherein, they are activated by bacterium specific enzymes (for example, β-Nei Xiananmei).In this class technology of the prodrug therapy (GDEPT) that is called as antibody targeted prodrug therapy (ADEPT) or gene targeting, a kind of bacterial enzyme is navigated to (Melton on the tumour by a specific specificity target-seeking agent (for example, a kind of antibody); Sherwood, 1996).Then, the patient is used described prodrug, and preferably in tumor sites activation (enzyme is positioned with engaging of antibody by it) herein.The location that this provides antitumor antibiotics makes the active medicine that greater concn is arranged on the tumor sites, and to active medicine and toxicity system's contact still less thereof.Prepared several prodrugs, they are activated by β-Nei Xiananmei widely.These comprise the beta-lactam derivatives of following material: Zorubicin (Vrudhula etc., 1995), taxol (Rodrigues etc., 1995), nitrogen mustard (Kerr etc., 1995), vinca alkaloids (Meyer etc., 1992) and mitomycin (Vrudhula etc., 1995).Confirmed that these compounds quilts are from the not wide spectrum β-Nei Xiananmei activation (Vrudhula etc., 1995) of bacterium of the same race.The effect of these medicines depends on the suitable location of activating enzymes, and this location is by the antibodies on the tumour, perhaps by the preferred expression of activating enzymes in tumour cell.The author of above-mentioned publication does not disclose the application of prodrug as anti-infection agent.The present invention does not need this location by antibody or other method, because have only infectious biological just to express activating enzymes.
The objective of the invention is to utilize this prodrug technology to treat transmissible disease rather than cancer.Be usually directed to antibiotic therapy resistance, by β-Nei Xiananmei or the similar prodrug of other microbial enzyme (dose overexpression only infected dose expression and/or infected) activatory, to be used to activate the prodrug form of the medicine that is host toxicity usually, be particularly useful for treating transmissible disease.This " biochemical target-seeking " technology has overcome the effect specificity that said medicine lacks by the activated form that only produces high density in the transmissible disease position or on the position.This is a kind of novel method, is used for the too strong medicine of anti-infection toxicity before it can utilize.In the past, as if Mobashery and his colleague (Mobashery and Johnson, 1986) had described a kind of by β-Nei Xiananmei activated peptide antibiotics.Their work can not be explained several important issues: (1) activity not only depends on the beta-lactam expression of enzymes, also depends on the transhipment that described peptide enters bacterial cell by the peptide permease, is activated in other cellular enzymes born of the same parents subsequently; (2) peptide of Ying Yonging does not have activity (Boisvert etc., 1986) in " nourishing " substratum.Earlier near medicine, follow by first method for limiting of efficient restricted because of the ability that it enters cell.Secondly, described peptide lacks active in enriched medium, and this may be a situation about running in using in any body.Aforementioned authors do not have prediction to make by this " target-seeking " method can use the bigger microbiotic of toxicity (for example, mitomycin or Zorubicin).Equally, research ADEPT, recognize that the Study on Value group that the beta-lactam prodrug is used for the treatment of cancer does not consider their application in transmissible disease simultaneously.
In therapeutic process, can be by applied once, use continuously or off and on and carry out pesticide application in vivo.The method of determining the most effective application method and dosage is well known to those skilled in the art, and will change with following factors: the composition that is used for the treatment of, therapeutic purpose, subject target cell and the testee who is treated.Can carry out the one or many dispenser, dosage level and form are selected by the treatment doctor.The proper dosage prescription and the application process of therapeutical agent see below.
Described pharmaceutical composition can by in per os, the nose, parenteral or use by anapnotherapy, and can be tablet, lozenge, particle, capsule, pill, ampoule, suppository or aerocolloidal form.They also can be following form: suspension, solution and emulsion, syrup, granulate or the powder of active ingredient in water-based or non-diluent water.Except agent of the present invention, described pharmaceutical composition also can comprise the perhaps multiple compound of the present invention of other medicines active compound.
More particularly, agent of the present invention (also being called as active ingredient at this paper) can be by the dispenser for treatment of any suitable way, these drug delivery routes comprise: per os, per rectum, intranasal, local (comprising through skin, aerosol, through cheek and hypogloeeis), transvaginal is in parenteral (comprising subcutaneous, intramuscular, intravenously and intracutaneous) and the lung.Should understand that also preferred approach will become with receptor's condition and age and subject disease.
It is desirable to, should use described agent and reach the peak concentration of active compound at disease location.This can realize by for example following method, that is, by the described agent of intravenous injection (optional being dissolved in the salt solution), perhaps per os dispenser, for example, as tablet, capsule or contain the syrup of described active ingredient.Can keep the desired blood level of agent by continuous infusion, thereby the therapeutic dose of active ingredient in diseased tissue is provided.Estimate to adopt effectively combination so that this therapeutic combination (therapeutic combinations) to be provided, promptly, the total dose that requires each composition agent is than using may need when each treats compound or medicine lower separately, so reduce side effect.
Though might use described agent separately, preferably provide with pharmaceutical preparation, it comprises the active ingredient of at least a preamble definition, with one or more pharmaceutically acceptable carriers and optional other therapeutical agent.Each carrier with the implication of other component compatibility of described preparation on must be " acceptable " and harmless to the patient.
Preparation comprises suitable per os, per rectum, intranasal, local (comprising through skin, through cheek and hypogloeeis), transvaginal, those of parenteral (comprising subcutaneous, intramuscular, intravenously and intracutaneous) and the interior dispenser of lung.Described preparation can be conveniently that unit dosage form provides and can prepare by any means that the medicament field is known.Such method comprises active ingredient is combined this step with the carrier that constitutes one or more ancillary components.Usually, be to prepare preparation like this: with active ingredient and liquid vehicle or finely divided solid carrier or the two evenly, fully mix, then, if necessary with product machine-shaping.
The preparation of the present invention that is fit to the per os dispenser can be used as following discrete unit to be provided: for example, capsule, cachet or tablet, each unit contains the active ingredient of predetermined amount; As powder or particle; As solution in water-based or on-aqueous liquid or suspension; Perhaps as oil-in-water liquid emulsion or water-in-oil liquid emulsion.Described active ingredient also can be used as bolus, electuary or paste and provides.
Tablet can be by compacting or molded the preparation, optional one or more ancillary components that add.The sheet of compacting can prepare like this, promptly, in suitable machinery, will choose wantonly with following component blended, the active ingredient (for example, powder or particle) that is free-flowing form and compress: tackiness agent (for example, polyvidone, gelatin, Vltra tears), lubricant, inert diluent, sanitas, disintegrating agent are (for example, sodium starch glycollate, polyvinylpolypyrrolidone, croscarmellose sodium), tensio-active agent or dispersion agent.Molded tablet can prepare by the mixture of mold pressing in suitable machinery with the wetting powder compound of inertia liquid diluent.Can choose wantonly tablet coating or impression, also can be mixed with the form that slow release or sustained release active ingredient wherein is provided, the Vltra tears of application examples such as different ratios provides the release profile of requirement.Tablet can be chosen wantonly and have enteric coating, thereby is provided in the partial enteral rather than release under one's belt.
Be adapted at that the preparation of local dispenser comprises in the oral cavity: lozenge comprises the active ingredient that is in the flavouring base material (normally sucrose and gum arabic or tragacanth gum); Pastille comprises the active ingredient that is in the inertia base-material (for example, gelatin and glycerine, perhaps sucrose and gum arabic); And mouth wash shua, comprise the active ingredient that is in the suitable liquid carrier.
The pharmaceutical composition of the local dispenser of the present invention can be used as ointment, emulsifiable paste, suspension, lotion, powder, solution, paste, gel, sprays, aerosol or oil preparation.Alternatively, a kind of preparation can comprise diaphragm or dressing, for example, and with active ingredient with choose any one kind of them or the bandage or the binding property plaster of multiple vehicle or thinner dipping.
If necessary, the water of emulsifiable paste base-material can comprise, for example, and at least about 30%w/w polyvalent alcohol (that is, having the alcohol of two or more hydroxyls), for example, propylene glycol, 1,3 butylene glycol, mannitol, Sorbitol Powder, glycerine and polyoxyethylene glycol and composition thereof.Local dispenser preparation can desirably comprise the compound that the enhancement agent absorbs and permeates by skin or other infected position.Such skin penetration enhancer example comprises methyl-sulphoxide and relevant analogue.
The oil phase of emulsion of the present invention can constitute from known composition by currently known methods.Though this may only comprise emulsifying agent mutually, it desirably comprise at least a emulsifying agent and a kind of fat or a kind of oil or with the mixture of a kind of fat and a kind of oil.Preferably, the lipophilic emulsifier that comprises a kind of hydrophilic emulsifier and a kind of stabilizer function.It also preferably comprise a kind of oil and a kind of fat the two.Simultaneously, the emulsifying agent that contains or do not contain stablizer constitutes so-called emulsifying wax, and this wax constitutes so-called emulsification ointment base with oil and/or fat, and it forms the oily disperse phase of cream formulation.
Be applicable to that emulsifying agent and emulsion stabilizer in the preparation of the present invention comprise: Tween 60, Span80, cetostearyl alcohol, tetradecyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
The suitable oily or fatty selection that is used for described preparation is based on reaching desired performance attractive in appearance, because the solvability of described active compound in most of oil that may be used in the pharmaceutical emulsion is very low.So described emulsifiable paste should preferably not have greasy, non-staining and rinsable product, it have suitable denseness in case from the pipe or other container in seepage.Can use alkyl ester straight or branched, monobasic or binary, for example, propylene glycol diesters, Isopropyl myristate, decyl oleate, Wickenol 111, butyl stearate, the palmitinic acid-2-ethylhexyl of two dissidents, two acid esters, the different hexadecanol ester of stearic acid, coco-nut oil fatty acid or be called as the mixture of the branched ester of CrodamolCAP, last three kinds is preferred ester.These esters can use separately according to desired performance or combination is used.Alternatively, can use the high-melting-point lipid, for example, white soft wax and/or whiteruss or other mineral oil.
Be fit to the preparation of the local dispenser of eye is also comprised eye drops, wherein, described active ingredient is dissolved in or is suspended in the suitable carriers (especially for the aqueous solvent of this agent).
The preparation that is fit to the per rectum dispenser can be used as the suppository that contains suitable base-material to be provided, and it comprises, for example, and theobroma oil or salicylate.
The preparation that is fit to the vagina dispenser can be used as vaginal suppository, tampon, emulsifiable paste, gel, paste, foam or sprays to be provided, and except described agent, it also comprises suitable carriers known in the art.
The preparation of suitable intranasal dispenser (wherein, carrier is a solid) comprise a kind of coarse meal, it has for example particle diameter in about 20～about 500 micrometer ranges, and it is pressed the mode dispenser of snuff tobacco, that is, suck rapidly by nasal cavity from the container that fills described powder near the nostril.Wherein, carrier be the liquid used of dispenser suitable formulation example if any, nasal spray, nasal drop, the atomizer that perhaps utilizes the aqueous solution that fills agent or oil solution is by the aerosol dispenser.
The preparation that is fit to the parenteral dispenser comprises the isotonic sterile injection liquid of water-based or non-water, and they may comprise antioxidant, buffer reagent, fungistat and solute, and this solute oozes the testee's of preparation and expection blood etc.; And the sterile suspensions of water-based and non-water, they may comprise suspension agent and thickening material, and liposome or other microgranular system, and they are designed to targeting compounds blood ingredient or one or more organ.The container that described preparation can be dosage unit or multiple doses sealing provides, for example, and ampoule and phial, and can under cryodesiccated (freeze dried) condition, store, only need just to add before use aseptic liquid carrier (for example, water for injection).The injection liquid of interim allotment and suspension can be from the sort of tablet formulation of sterilized powder, particle and preamble description.
Preferred dosage unit preparation is those, that is, contain agent as the aforementioned per daily dose of this paper or unit, day divided dose (subdose) or its suitable part again.
Should understand, except the component of above mentioning especially, preparation of the present invention also can comprise this area other conventional agent relevant with described preparation classification, and for example, those of suitable per os dispenser can comprise for example such agent of sweetener, thickening material and seasonings.Wish that also composition and therapy that agent of the present invention, composition and method and other are suitable combine.
These agents of the present invention and above-claimed cpd and derivative thereof can be used to prepare the medicament of using in method described herein.
During the described prodrug of clinical application, microbiotic may will be followed the criterion of good formulation.Dosage may with to great majority other microbiotic adopted similar.According to estimates, the dosage of prodrug will be in 100mg～1gm scope, and dispenser in per eight hours once perhaps once a day, continues to use a week or two weeks, perhaps checks infection biological to be negative until the patient.
On the one hand, the present invention includes a kind of processing or protective plant in case the method that antibiotic-resistant bacteria infects, it comprises, applies the described prodrug of significant quantity.
In order to realize the good dispersion and bonding when being used to handle plant of described compound, maybe advantageously, with helping to disperse and the adherent component is prepared described compound.Appropriate formulation will be well known by persons skilled in the art.
A kind of processing or protective plant also are provided in the present invention in case the method that antibiotic-resistant bacteria infects, and it comprises, to the described prodrug compound of the soil application significant quantity around leaf, root or plant or the root.Can be with these isolated compound and known agricultural chemicals or sterilant combination.
In case antibiotic-resistant bacteria when infecting, compound of the present invention can be used as preparations such as wettable powder, particle when being used for processing or protective plant, and perhaps available suitable medium etc. carries out microencapsulation.Other examples of formulations includes but not limited to: formulation, water-based flowable formulation, wettable particle dispersion, emulsifiable concentrate and waterborne suspension are moved in soluble powder, wettable particle, master stream.Other appropriate formulation will be well known by persons skilled in the art.
The present invention further provides and a kind of fish has been used the method that the described prodrug compound of significant quantity infects with prevention or treatment antibiotic-resistant bacteria.Can use this compound by described compound is mixed fish meal.Alternatively, this compound can be added in the water that sashimi (raw fish) lives or be equipped with in the water of fish.At last, as suitable pharmaceutical preparation fish is used described compound.Other appropriate formulation will be well known by persons skilled in the art.Raw material and method are produced the method for described prodrug compound
The method of producing prodrug of the present invention further is provided.Usually, this method needs the following step:
7-α-bromine cephalosporinic acid (7-α-Bromocephalosporanic acid) (2)
Press Rosati (U.S. Patent No. 4,429, issue on January 31st, 128,1984) and prepared this compound, obtain the cream-coloured foam of 80% productive rate.In step subsequently, do not have purifying and directly use it.
3-acetoxyl methyl cephalo-3-alkene-4-formic acid (3)
Adopt Chern etc., 1988 working method, with tributylphosphine in MeOH with 7-α-bromine cephalosporinic acid debrominate.Obtain a kind of yellow foam with quantitative productive rate.
4-nitrobenzyl 3-acetoxyl methyl cephalo-3-alkene-4-manthanoate (4)
Thick cephalo-3-alkene-4-the carboxylic acid that derives from previous step is dissolved in dimethyl formamide (DMF).Under water cooling, drip diisopropylethylamine (1 equivalent).Be divided into small portion ground and add 4-nitrobenzyl bromine (1 equivalent).Remove water-bath, at room temperature reaction mixture is stirred 4h.Solvent removed in vacuo and volatile constituent are dissolved in EtOAc with resistates.Water, 0.5N HCl and saturated NaHCO 3This organic solution of solution washing.At anhydrous MgSO 4After the last drying, provide thick product except that desolvating, handle and provide cream-coloured froth product in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.
4-nitrobenzyl 3-(iodomethyl) cephalo-3-alkene-4-manthanoate (6)
Adopted Bonjouklian, 1981 method.In the nitrogen atmosphere under 20 ℃, toward the CH of 4-nitrobenzyl cephalosporinic acid ester 4 2Cl 2Drip the iodo trimethyl silane in the solution.At room temperature reactant is stirred 3h.Use CH 2Cl 2Diluted reaction mixture is used 10% Na 2S 2O 3, salt solution and water washing, at MgSO 4Go up dry final vacuum evaporation and provide light brown oily title compound.
4-nitrobenzyl 3-((5-chloro-2-(2,4 dichloro benzene oxygen base) phenoxy group) methyl) cephalo-3-alkene-4-manthanoate (7)
At room temperature stir iodo-methyl compound 6 (1 equivalent), triclosan (2,4,4 '-three chloro-2 '-hydroxy diphenyl ether, 1 equivalent), NaHCO 3(1 equivalent) mixture in DMF is exhausted until monitor whole raw materials 6 by tlc.Vacuum-evaporation DMF distributes resistates between EtOAc and water.Separate organic layer and use the salt water washing, at MgSO 4Last dry back concentrates and provides thick product.Produce white solid by the column chromatography purifying.
3-((5-chloro-2-(2,4 dichloro benzene oxygen base) phenoxy group) methyl)-cephalo-3-alkene-4-formic acid (8)
4-nitrobenzyl ester 7 is dissolved in MeOH.Add the 5%Pd/C catalyzer, in nitrogen atmosphere, sway mixture.Reaction finishes, and removes by filter catalyzer.Under reduced pressure concentrated filtrate is dissolved in EtOAc.Use saturated NaHCO 3Twice of solution extraction organic phase.With the NaHCO that merges 3Extraction liquid is cooled to 0 ℃ also with 1N HCl acidifying (pH＜2).The crystal of collecting precipitation is used CH 2Cl 2Washing, vacuum-drying and provide desired product.Be further purified by recrystallization.
Compound 10
3-(pyridine-2-base-N-oxide compound) thiomethyl cephalo-3-alkene-4-manthanoate (10)
At room temperature stir iodo-methyl compound 6 (1.0 equivalent), 2-mercapto-pyridine-n-oxide (1.0 equivalent) and NaHCO 3(1.1 equivalent) mixture in DMF is exhausted until monitor whole raw materials 6 by tlc.Vacuum-evaporation DMF distributes resistates between EtOAc and water.Separate organic layer and use the salt water washing, at MgSO 4Last dry back concentrates and provides thick product.Provide solids by the column chromatography purifying.Compound 10 is provided by like that right-nitrobenzyl is gone protection about compound 8 described operations.
Figure A0180691200322
Compound 11
3-(N, two (2-chloroethyl) carbamyls of N-) methyl cephalo-3-alkene-4-manthanoate (11)
The anhydrous CH of cooling methylol compound 3 (1.0 equivalent) and pyridine (1.0 equivalent) in ice bath 2Cl 2Solution injects N lentamente by syringe, two (2-chloroethyl) carbamyl chlorides of N-.After 30 minutes, water, salt solution washing reaction mixture are at MgSO 4Last dry back concentrates and provides thick product.Provide solids by the column chromatography purifying.Compound 11 is provided by like that right-nitrobenzyl is gone protection about compound 8 described operations.
Compound 12
3-(4-amino-3-oxygen-isoxazole alkyls-2-yl) methyl cephalo-3-alkene-4-manthanoate (12)
At room temperature stir methylol compound 3 (1.0 equivalent), triphenyl phosphine (1.0 equivalent), ethyl azodicaboxylate (1.0 equivalent) and the mixture of (3-oxo-isoxazole alkyls-4-yl) carboxylamine tertiary butyl ester (1.0 equivalent) in anhydrous THF and reach 4 hours.
Add EtOAc then, water, salt solution washing reaction mixture are at MgSO 4Last dry.Concentrate and provide solids by the column chromatography purifying.Compound 12 is provided by like that right-nitrobenzyl is gone protection about compound 8 described operations.
Compound 13
3-[(4-amino-benzenesulfonyl)-and (5-methyl-isoxazole-3-bases)-amino] methyl cephalo-3-alkene-4-manthanoate (13)
At room temperature methylol compound 3 (1.0 equivalent), triphenyl phosphine (1.0 equivalent), diethylazodicarboxylate's (1.0 equivalent) and the mixture of Sulfamethoxazole (1.0 equivalent) in anhydrous THF are reached 1 hour.
Add EtOAc then, water, salt solution washing reaction mixture are at MgSO 4Last dry.Concentrate and provide solids by the column chromatography purifying.Compound 13 is provided by like that right-nitrobenzyl is gone protection about compound 8 described operations.
Compound 14
3-(mitomycin carbamyl oxygen base) methyl cephalo-3-alkene-4-manthanoate (14)
Cooling methylol compound 3 (1.0 equivalent), 2 in ice bath, the solution of 6-lutidine (1.0 equivalent) in anhydrous THF adds the 4-chloroformate nitrophenyl ester lentamente.After 30 minutes, in argon atmospher, add the anhydrous THF solution of N-BOC ametycin.Remove ice bath then, at room temperature continue stirring and finish until monitor reaction by tlc.Then, water, salt solution washing reaction mixture are at MgSO 4Last dry.Concentrate and provide solids by the column chromatography purifying.Compound 14 is provided by like that right-nitrobenzyl is gone protection about compound 8 described operations.
Analyzed in vitro
Sensitivity tests is to be undertaken by the NCCLS of the MIC ' s that use to measure Antimicrobe compound (national clinical trial standard committee) method (screening has been modified about high throughput).MIC is defined as, under the required proper temperature of bacterial growth, be incubated 16～18 hours after the minimum concentration of bacterial growth (being equivalent to visible growth) when being suppressed.The storing solution of all test compounds all is water or DMSO preparation, and this depends on solubleness.Under the highest experimental concentration, DMSO content should not surpass 0.5%.Briefly, in 384 hole droplet plates preparation from the test compound concentration of 20 2 times of serial dilutions below the maximum concentration.Inoculate every hole to about 1～1.5 * 10 with the nutrient solution of test bacterium 6The ultimate density of individual cells/ml.Measure bacterial growth by the optical density(OD) increase of adopting small plate reader (Tecan SpectraFluor Plus) to measure the 600nm place.
Oxicity analysis
The toxicity of ECTA compound is to measure by several groups of ICR-CD1 male mices of intravenous injection (about 22～25 grammes per square metres) with the prodrug compound of different concns.With compound carrier with comparing.After the inoculation, observed animal and reach 14 days for twice, the record death toll in one day.Measure MTD (maximum tolerated dose).
The body inner analysis
By rendeing a service in the body of having assessed described compound with 0.5ml bacterium intraperitoneal inoculation ECR-CD1 mouse under 100 times of MLD.With Saliva Orthana with comparing.After the inoculation, one or many is used prodrug compound (perhaps intravenously, subcutaneous, intramuscular or per os).With compound carrier with comparing.After the inoculation, observed animal and reach 14 days for twice, the record death toll in one day.Measured the ED50 (median effective dose) of compound.
Should understand that though described the present invention in conjunction with above-mentioned embodiment, the description of preamble and embodiment subsequently are intended to set forth rather than limit the scope of the invention.It will be appreciated by one of skill in the art that the others, advantage and the modification that belong to the scope of the invention.
ReferenceAnderson etc., U.S. Patent No. 5,399,346, issue on March 21 nineteen ninety-five.Boisvert etc. (1986), journal of biological chemistry (J.Biol.Chem.) 261:7871～7878.Bonjouklian (1981), tetrahedron communication (Tetrahedron Lett.), 22:3915～3918.Bush (1988), clinical microbiology comment (Clinical Microbial Rev.), 1:109～123.Chem etc. (1988), heterocycle (Heterocycles), 27:1349～1351.(1995) such as Kerr D.E., cancer research (Cancer Research), 55:3558～3563.Maher etc. (1995), molecular probe and cell probe (Mol.Cell Probes), 9:265～276.Martin, REMINGTON ' S PHARM.SCI., the 15th edition (Mack Publ.Co., Easton (1975)).Melton and Sherwood, National Cancer Institute magazine (J.Natl.Cancer Inst.), 88:153～65 (1996).(1992) such as Meyer D.L., biconjugate chemistry (Biconjugate Chem.) 3:42～48.Miller, J.H., bacterial genetics short-term study course: about the laboratory operation guide and handbook (A Short Course In Bacterial Genetics:ALaboratory Manual And Handbook For E.Coli And RelatedBacteria) the .Cold Spring Harbor Press (1992) of colon bacillus and Related Bacteria.Mobashery etc. (1986), journal of biological chemistry, 261 (17): 7879～7887.Murray (1997), antibiotics resistance, internal medicine progress (Adv.Int.Med.), 42:339～367.Physicians Desk Reference, 50 ThEdition (1996), Publ.MedicalEconomics Co., Montvale, NJ.Rodrigues etc. (1995), chemistry and biology (Chemistry And Biology), 2:223～227.Rosati, U.S. Patent No. 4,429, issue on January 31st, 128,1984.Scanlon, U.S. Patent No. 5,085, issue on February 4th, 983,1992.Schaechter etc., microbial diseases mechanism (Mechanisms of microbialdisease) (the 2nd edition).Publ.Williams?&?Wilkins，pp.973(1993)。(1996) such as Steinberg J.P., clinical transmissible disease (Clinical InfectiousDiseases) 23:255～259.(1996) such as Stosor V. infect and medicine (Infect.Med.) 13:487～488 (1996) Opit.Pp.493～498 (1996).Straus, S.E., the measure of anti-virus infection, the mechanism of microbial diseases (Strategies ToCombat Viral Infections, In Mechanisms Of Microbial Disease) (the 2nd edition).T.S.Satterfield edits, Publ.Williams ﹠amp; Williams, Baltimore, Md pp.537～550,973 (1993).Vrudhula etc. (1995), medicochemistry magazine (J.Med.Chem.), 38:1380～1385.Wilson J.D., Braunwald E, Isselbacher KJ etc., Harrison internal medicine principle (Harrison ' s Principles of Internal Medicine), (the 12nd edition), McGraw-Hill publishes, pp.2208 (1991).(1997) such as Young Y., biotechnology (Biotechniques), 22:1032～1038.

Claims (57)

1. prodrug compound with following structure: Wherein, R ' is selected from down group: hydrogen, alkyl, aryl, halogenated aryl, phenol, nitro aryl, ammonium, methylamine, dimethylamine, low-grade alkylamine, two low-grade alkylamines, ethylene glycol, glycerine, Sorbitol Powder, polyoxyethylene glycol (PEG), salt form (sodium, potassium, lithium), THAM (2-amino-2-methylol-1, ammediol), and pharmaceutically acceptable salt; Wherein, X does not exist or is selected from down group: carbonyl, methylene radical, oxygen, sulphur and nitrogen; Wherein, Y is selected from down group: methylene radical, methyl thiazolinyl, methylene radical alkynyl, methylene oxygen carbonyl, vinyl, and C1～C6 alkynyl; And wherein, Z is a toxophoric group.
2. the compound of claim 1, wherein, toxophoric group Z is selected from 1-fluoro-1-carbonyl methyl and 1-nitro-2-carbonyl ethyl.
3. the compound of claim 1, wherein, described toxophoric group Z is selected from down group: Zorubicin, two (2-chloroethyl) amine, mitomycin, triclocarban, trichlorine carbanilide, tribromo salicylamide, Sulfamethoxazole, paraxin, seromycin, trimethoprim, chlorhexidine, Hexachlorophene, 2-mercapto-pyridine-n-oxide, camptothecine, A Piao meat poison alkene, cis-platinum, anthracene nucleus is according to the pool thioketones, halichondrins, half chrysanthemin, Methioprim, thapsigargin and D25.
4. the compound of claim 1, wherein, described toxophoric group Z is a chlorinated phenol.
5. the compound of claim 4, wherein, described chlorinated phenol is selected from down group: 5-chloro-2-(2, the 4-dichlorophenoxy) phenol, 4-chloro-2-(2,4 dichloro benzene oxygen base) phenol, 3-chloro-2-(2,4 dichloro benzene oxygen base) phenol, 6-chloro-2-(2, the 4-dichlorophenoxy) phenol, 5-chloro-2-(3, the 4-dichlorophenoxy) phenol, 5-chloro-2-(2, the 5-dichlorophenoxy) phenol and 5-chloro-2-(3, the 5-dichlorophenoxy) phenol.
6. the compound of claim 1, wherein, described toxophoric group Z is 2,2 '-dihydroxydiphenyl ether.
7. the compound of claim 1, wherein, described toxophoric group Z is a halo 2-hydroxy benzophenone.
8. the compound of claim 1, wherein, Y and X constitute one and have the substituting group that is selected from following structure:
Figure A0180691200031
With , wherein, T is selected from oxygen, nitrogen, sulphur and carbon.
9. each compound of claim 1～8, wherein, Z does not exist.
10. each compound of claim 1～8, wherein, Y is C2～C3 alkynyl.
11. the compound of claim 1, wherein, X is carbonyl or methylene radical.
12. the compound of claim 1, wherein, X is a methylene radical.
13. prodrug compound with following structure:
14. prodrug compound with following structure:
Figure A0180691200034
15. prodrug compound with following structure:
Figure A0180691200041
16. prodrug compound with following structure:
17. prodrug compound with following structure:
18. a composition, it comprises claim 1～8 or 11～17 each compound and a kind of carriers.
19. a composition, it comprises compound and a kind of carrier of claim 9.
20. a composition, it comprises compound and a kind of carrier of claim 10.
21. the composition of claim 18, wherein, described carrier is pharmaceutically acceptable carrier.
22. the composition of claim 19, wherein, described carrier is pharmaceutically acceptable carrier.
23. the composition of claim 20, wherein, described carrier is pharmaceutically acceptable carrier.
24. analyze the in vitro method that suppresses or kill and wound the medicine of antibiotics resistance microorganism for one kind, this method comprises the steps:
A) described medicine being contacted also with the antibiotics resistance microorganism makes described antibiotics resistance microorganism contact with the compound of claim 1 independently; And
B) compare microbial growth, so analyze the medicine that suppresses or kill and wound the antibiotics resistance microorganism.
25. the method for claim 24, wherein, described antibiotics resistance microorganism is the beta-lactam resistant microorganism.
26. the method for claim 24, wherein, described antibiotics resistance microorganism is the vancomycin resistant microorganism.
27. the method for claim 25, wherein, described beta-lactam resistant microorganism is a Gram-negative bacteria.
28. the method for claim 27, wherein, described Gram-negative bacteria is selected from down the group bacterium: Neisseria, moraxella, campylobacter, enterobacteriaceae, Rhodopseudomonas, acinetobacter, Haemophilus spp and Bacteroides.
29. the method for claim 25, wherein, described beta-lactam resistant microorganism is a gram-positive microorganism.
30. the method for claim 29, wherein, described gram-positive microorganism is selected from down the group bacterium: streptococcus aureus, staphylococcus epidermidis, coagulase negative staphylococcus, streptococcus pyogenes, streptococcus pneumoniae, streptococcus agalactiae and enterococcus spp.
31. a method that suppresses the antibiotics resistance microorganism growth, it comprises makes described microorganism contact with the compound of significant quantity claim 1.
32. the method for claim 31, wherein, described antibiotics resistance microorganism is the beta-lactam resistant microorganism.
33. the method for claim 31, wherein, described antibiotics resistance microorganism is the vancomycin resistant microorganism.
34. the method for claim 32, wherein, described beta-lactam resistant microorganism is a Gram-negative bacteria.
35. the method for claim 34, wherein, described Gram-negative bacteria is selected from down the group bacterium: Neisseria, moraxella, campylobacter, enterobacteriaceae, Rhodopseudomonas, acinetobacter, Haemophilus spp and Bacteroides.
36. the method for claim 32, wherein, described beta-lactam resistant microorganism is a gram-positive microorganism.
37. the method for claim 36, wherein, described gram-positive microorganism is selected from down the group bacterium: streptococcus aureus, staphylococcus epidermidis, coagulase negative staphylococcus, streptococcus pyogenes, streptococcus pneumoniae, streptococcus agalactiae and enterococcus spp.
38. a treatment is by the testee's of antibiotics resistance infected by microbes method, it comprises send the compound of passing significant quantity claim 1 to described testee.
39. the method for claim 38, wherein, described antibiotics resistance microorganism is the beta-lactam resistant microorganism.
40. the method for claim 38, wherein, described beta-lactam resistant microorganism is the vancomycin resistant microorganism.
41. the method for claim 39, wherein, described beta-lactam resistant microorganism is a Gram-negative bacteria.
42. the method for claim 41, wherein, described Gram-negative bacteria is selected from down the group bacterium: Neisseria, moraxella, campylobacter, enterobacteriaceae, Rhodopseudomonas, acinetobacter, Haemophilus spp and Bacteroides.
43. the method for claim 39, wherein, described beta-lactam resistant microorganism is a gram-positive microorganism.
44. the method for claim 43, wherein, described gram-positive microorganism is selected from down the group bacterium: streptococcus aureus, staphylococcus epidermidis, coagulase negative staphylococcus, streptococcus pyogenes, streptococcus pneumoniae, streptococcus agalactiae and enterococcus spp.
45. the method for claim 38, wherein, described testee is a kind of plant.
46. the method for claim 38, wherein, described testee is a kind of vertebrates.
47. the method for claim 46, wherein, described vertebrates is a kind of fish, Mammals or a kind of bird.
48. claim 1～8 or 11～17 each compounds are used for the treatment of application in the medicament that antibiotics resistance infects in production.
49. the compound of claim 10 is used for the treatment of application in the medicament that antibiotics resistance infects in production.
50. the compound of claim 11 is used for the treatment of application in the medicament that antibiotics resistance infects in production.
51. the application of claim 48, wherein, described antibiotics resistance microorganism is beta-lactam resistant microorganism or vancomycin resistant microorganism.
52. the application of claim 49, wherein, described antibiotics resistance microorganism is beta-lactam resistant microorganism or vancomycin resistant microorganism.
53. the application of claim 50, wherein, described antibiotics resistance microorganism is beta-lactam resistant microorganism or vancomycin resistant microorganism.
54. method of selecting antibiotics sensitivity in order to reverse antibiotics resistance in the microorganism, a kind of enzyme of giving this microbial antibiotic resistance of described microbial expression, described method comprises, described microorganism is contacted, so kill and wound the microorganism of expressing this kind of enzyme with the compound of claim 1.
55. the method for claim 54, wherein, described enzyme is a β-Nei Xiananmei.
56. one kind is suppressed microorganism growth or kills and wounds method of microorganism, it comprises, described microorganism is contacted with a kind of microbiotic, and described microorganism is contacted with the compound of claim 1.
57. one kind by making microorganism contact the method that reverses antibiotics resistance in the microorganism with the compound of significant quantity claim 1.
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