CN107629023A - A kind of new fragrant imido grpup thiazole compound, preparation method and use - Google Patents
A kind of new fragrant imido grpup thiazole compound, preparation method and use Download PDFInfo
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- CN107629023A CN107629023A CN201610570776.6A CN201610570776A CN107629023A CN 107629023 A CN107629023 A CN 107629023A CN 201610570776 A CN201610570776 A CN 201610570776A CN 107629023 A CN107629023 A CN 107629023A
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- 0 **1C=CC(c2c[s]c(Nc3ccccc3)n2)=CCC1 Chemical compound **1C=CC(c2c[s]c(Nc3ccccc3)n2)=CCC1 0.000 description 6
- QEWHNJPLPZOEKU-UHFFFAOYSA-N CC(c(c(F)c1)ccc1F)=O Chemical compound CC(c(c(F)c1)ccc1F)=O QEWHNJPLPZOEKU-UHFFFAOYSA-N 0.000 description 1
- PFFFYUUCYZSKRI-UHFFFAOYSA-N Cc1ccc(C(CBr)O)cc1 Chemical compound Cc1ccc(C(CBr)O)cc1 PFFFYUUCYZSKRI-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to a kind of compound and its preparation method and purposes with antibacterial synergistic activity, more particularly to a kind of new fragrant imido grpup thiazole compound, preparation method and use.More specifically, the invention discloses a kind of compound or its optical isomer shown in formula (I), cis-trans-isomer or pharmaceutically acceptable salt, and its production and use, the invention also discloses the pharmaceutical composition comprising above-claimed cpd.The compound of the present invention can effectively strengthen the antibacterial activity of antibiotic, and can be applied to the treatment to the germ with antibiotic resistance.
Description
Technical field
The present invention relates to field of medicaments, more particularly to a kind of compound that can strengthen antibiotic antibacterial activity, its system
Preparation Method and purposes.
Background technology
It is resulting " super because antibiotic clinical causes bacterial resistance sexploitation and sprawling with non-clinical abuse
Level bacterium " is as one of chief threat of global public health.At present, in world wide wide-scale distribution and diffusion it is " super
Bacterium " is main：ESKAPE, i.e. Enterococcus faecium (drug resistance of vancomycin enterococcus faecalis), Staphylococcus
Aureus (methicillin-resistant staphylococcus aureus), Klebsiella pneumoniae (Nosocomial infection kerekou pneumonia
Primary bacterium), Acinetobacter baumanii (general resistance Acinetobacter bauamnnii), Pseudomonas aeruginosa (multiple medicines
Tolerant Pseudomonas aeruginosa), and Enterobacter species (multidrug resistance enterobacteria), serious threat the life of the mankind
Life health.
Polymyxins is used for clinic since the nineteen fifty-two, is the anti-infectious agent to Gram-negative bacteria with excellent activity
Thing.But on the one hand due to its larger renal toxicity and neurotoxicity, on the other hand due to the appearance of carbapenem antibiotic
And the effect of to gram positive bacterial infection, the medicine are terminated in last century late nineteen seventies early eighties and used.With facing
A large amount of uses of carbapenem antibiotic on bed, in beginning of this century last century end, it is blue or green to occur substantial amounts of carbon in the world
Mould alkene resistance Gram-negative bacteria.Then, people have to reinstate polymyxins again, as 21st century anti-gram-negative
Property bacterium infection " the last item defence line " return to clinic, Acinetobacter bauamnnii, kerekou pneumonia primary particularly for extensive resistance
Bacterium and the infection of pseudomonas aeruginosa, because these bacteriums are only sensitive to polymyxins at present.
The content of the invention
It is an object of the invention to provide a kind of new fragrant imido grpup thiazole compound, preparation method and use.
Another object of the present invention is to provide a kind of pharmaceutical composition containing with good grounds compound of the invention.
The first aspect of the present invention, there is provided a kind of compound with structure shown in logical formula (I), or its optical siomerism
Body, cis-trans-isomer or pharmaceutically acceptable salt:
In formula,
X represents the substituent on any one or more positions on the phenyl ring where it, and each X is under
Group：Substituted or unsubstituted C1-6Alkyl, halogen；
Y represents the substituent on any one or more positions on the phenyl ring where it, and each Y is under
Group：Halogen, cyano group, nitro, substituted or unsubstituted C1-4Alkyl.
In another preference, the quantity of substituent X is 1,2 or 3.
In another preference, substituent Y quantity is 1,2 or 3.
In another preference, each X is independently selected from the following group：Halogen, C1-2Haloalkyl (is preferably the C of F substitutions1-2Halogen
Substituted alkyl).
In another preference, each X is independently selected from the following group：Halogen (is preferably F, Cl or Br；More preferably F or
Cl)、CF3(trifluoromethyl).
In another preference, X CF3, preferably the position of substitution is contraposition.
In another preference, Y Br, preferably the position of substitution include contraposition and/or ortho position.
In another preference, when X is CF3When, at least one Y is Br.
In another preference, when X is CF3When, and when at least one Y is F, substituent Y numbers are 2, are preferably taken
Include contraposition and ortho position for base Y the position of substitution.
In another preference, when X is CF3When, and when at least one Y is Cl, substituent Y numbers are 2, are preferably taken
Include contraposition for base Y the position of substitution.
In another preference, each Y is independently selected from the following group：F, Cl, Br or I, F and Br are preferably chosen from.
In another preference, the position of substitution of the substituent X includes contraposition.
In another preference, the position of substitution of the substituent X also includes meta and/or ortho position.
In another preference, the position of substitution of the substituent Y includes contraposition.
In another preference, the position of substitution of the substituent Y also includes meta and/or ortho position.
The second aspect of the present invention, there is provided a kind of pharmaceutical composition, described pharmaceutical composition include：(i) effective dose
First aspect present invention described in compound of formula I, or its pharmaceutically acceptable salt；(ii) pharmaceutically acceptable carrier
And/or excipient.
In another preference, described pharmaceutical composition also includes antibiotic.
In another preference, the antibiotic is anti-Gram-negative bacteria antibiotic.
In another preference, one or more that the antibiotic is selected from the group：Polymyxin class antibiotic, carbon mould
Carbapenem antibiotic, aminoglycoside antibiotics, cephalo-type (such as 2 generations, 3 generations or 4 generation cephalosporin analog antibiotics) antibiotic, quinolone
Class antibiotic.
In another preference, the antibiotic is polymyxin class antibiotic；Preferably polymyxin B.
In another preference, the valid density of the compound of formula I is 0.01-150mg/L.
In another preference, the weight ratio that the compound of formula I mixes with the antibiotic is 1：50~200：1, it is excellent
Elect 1 as：10~100：1.
In another preference, the dosage form of the composition is selected from the group：It is tablet, lozenge, beans shape capsule, scattered
Agent, suspending agent, solution, capsule, diaphragm, or its combination.
The third aspect of the present invention, there is provided the purposes of the compound described in first aspect present invention, for preparing antibiosis
The synergist of element.
Described in another preference in another preference, the antibiotic is anti-Gram-negative bacteria antibiotic.
In another preference, one or more that the antibiotic is selected from the group：Polymyxin class antibiotic, carbon mould
Carbapenem antibiotic, aminoglycoside antibiotics, cephalo-type (such as 2 generations, 3 generations or 4 generation cephalosporin analog antibiotics) antibiotic, quinolone
Class antibiotic.
In another preference, the antibiotic is polymyxin class antibiotic；Preferably polymyxin B.
The fourth aspect of the present invention, there is provided the preparation method of the compound described in first aspect present invention, methods described
Including step：
(1) in atent solvent, formula A compounds are reacted with formula B compounds, obtain formula C compounds, formula C compounds and alkali
Reaction, acid adding neutralizes after the completion of reaction, is filtrated to get formula D compounds.
(2) in atent solvent, formula E compounds are reacted with NBS, obtain formula F compounds.
(3) in atent solvent, formula D compounds are reacted with formula F compounds, obtain compound of formula I.
It is above-mentioned it is various in, X, Y are as defined above.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical scheme.As space is limited, exist
This no longer tires out one by one states.
Embodiment
The present inventor's in-depth study by long-term, it has unexpectedly been found that and having synthesized a series of there is good synergy to resist
The fragrant imido grpup thiazole compound of raw element (such as polymyxin B) antibacterial activity.On this basis, inventor completes this hair
It is bright.
Definition
Unless otherwise defined, the present invention used in technology and scientific term, with the present invention belonging to field it is general
The general understanding of technology has identical meaning.
Term " C1-6Alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, for example, methyl, ethyl, propyl group,
Isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.Term " halo " refers to by identical or different one or more above-mentioned
The group of halogen atom substitution, such as trifluoromethyl, pentafluoroethyl group, seven fluorine isopropyls or similar group.
Term " alkyl " refers to minus the group that a hydrogen atom forms in alkane molecule；Term " alkylidene " refers to alkane
The group that two hydrogen atoms form is minused in molecule.Similarly, " alkenylene ", " alkynylene ", " cycloalkylidene ", " sub- cyclenes
Base ", " phenylene ", " naphthylene ", the definition of " sub- heterocyclic radical " or " the sub- ring of heteroaryl two or three ring ring systems " are similar.
Group of the present invention is " substituted or unsubstituted " unless stated otherwise, and otherwise group of the invention can quilt
The substituent being selected from the group is substituted：Halogen, cyano group, nitro, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Haloalkene
Base, C2-6Alkynyl, C2-6Halo alkynyl, hydroxyl, hydroxyl C1-4Alkyl.
Atent solvent refers to the various solvents not reacted with raw material, includes the alcohol of various straight chains, side chain or ring-type,
Ether or ketone, alkyl halide, Isosorbide-5-Nitrae-dioxane, acetonitrile, tetrahydrofuran, DMF (DMF), dimethyl sulfoxide (DMSO)
(DMSO) etc..
The compound of the present invention can contain one or more asymmetric centers, and therefore be mixed with raceme, racemic
Thing, single enantiomer, the form of diastereomeric compound and single diastereomer occur.In the asymmetry that there may be
The heart, the property depending on various substituents on molecule.Each this asymmetric center will independently produce two optical isomers,
And all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound are included in the model of the present invention
Within enclosing.The present invention includes all isomeric forms of compound.
As used herein, term " respiratory tract infection " is divided into the infection of the upper respiratory tract and ALRI.Upper respiratory tract sense
Dye refers to the general name from nasal cavity to the acute inflammation between throat, and ALRI refers to acute tracheae --- bronchitis,
Chronic bronchitis, pneumonia, bronchiectasis etc..
As used herein, term " bacteremia " refers to the illness for occurring microorganism in blood.
As used herein, term " urinary infection " refer to urothelium to bacterium invade caused by inflammatory reaction, generally
With bacteruria and pyuria, also known as urinary tract infections.
As used herein, term " meningitis " means that the diffusivity inflammation of pia mater sexually revises.
As used herein, term " surgical site infection " refers to when the microorganism pollution of operative incision reaches to a certain degree
When, the infection of the operative site of initiation, including infection of incisional wound and the infection of the perform the operation organ or lacuna that are related to.
As used herein, term " pneumonia " refers to the inflammation of last air flue, alveolar and interstitial lung eventually.
As used herein, term " infection of biliary tract " refers to there is bacterium infection in biliary tract, can individualism, but more and cholelithiasis
Simultaneously and deposit, reciprocal causation.
As used herein, term " septicemia " refers to pathogenic bacteria or conditioned pathogen intrusion blood circulation, and is grown in blood
Breeding, the acute systemic infection for producing toxin and occurring.
As used herein, term " antibiotic " (antibiotic) refers to the compound with resisting pathogenic microbes activity.
It is preferably carried out in the present invention in mode, the antibiotic is preferably the antibiotic of anti-Gram-negative bacteria, such as polymyxin class
Antibiotic, carbapenem antibiotic, aminoglycoside antibiotics, cephalo-type (such as 2 generations, 3 generations or 4 generation cephalosporin analog antibiotics)
Antibiotic, carbostyril antibiotic.
In the preferred embodiment of the present invention, the antibiotic is polymyxin class antibiotic, it is therefore preferable to
Polymyxin B.
Polymyxin B is a kind of polypeptide antibiotics as caused by aerobacillus polymyxa Donker (bacilluspolymyxa).Its
Antimicrobial spectrum and clinical practice are similar to polymyxin e, to gram negative bacilli, such as Escherichia coli, Pseudomonas aeruginosa, secondary large intestine bar
Bacterium, bacillus canalis capsulatus, bacillus acidophilus, Bordetella pertussis and shigella dysenteriae etc. have suppression or bactericidal action.It is clinically main
For urinary system infection contamination and eye, tracheae, meningitis, septicemia, burning caused by infection caused by sensitive bacteria and Pseudomonas aeruginosa
Sentiment dye and mucocutaneous infections etc., because its toxicity is big, almost stop in 1970-1980 clinical practice.In recent years,
There is the resistant Gram negative bacterial strain of multiple antibody in CICU, can be effective in not new antiseptic
In the case of resisting these pathogen, people restart to use polymyxin B, and are mainly used in urgent patient, as treatment
Last one of barrier of the microbial infectious diseases of Gram-negative, therefore, Novel synergistic agent is developed, reduce polymyxins and use
Amount, alleviates its toxic effect, tool is of great significance.
As used herein, the term effective dose of a certain specified disease " be used for treat " refers to and improved enough or to a certain extent
Mitigate the amount of the symptom associated with this disease.This dose can be administered with single dose, can also be administered according to therapeutic scheme.This
Dosage can cure disease, but be typically administered to improve symptom；In some preferred embodiments, to improve symptom,
Repeatedly patient can be administered.
As used herein, term " pharmaceutically acceptable salt, ester or other derivatives " is used including those skilled in the art
Any salt, ester or derivatives thereof of the compounds of this invention prepared by known method.Described salt, ester or derivative can be used for dynamic
Thing and/or people's administration, and do not have toxicity.The compound or there is pharmaceutical activity, or pro-drug.
Used herein, " treatment " refers to mitigation, prevention or the reverse of disease or illness or its at least one distinguishable symptom, with
Improvement, prevention or the reverse of the related at least one measurable body parameter of treated disease or illness, suppress or slow down disease
Or the progress of illness, or the breaking-out of delay disease or illness.
Used herein, the symptom for giving a certain specified disease of a certain certain drug composition " improvement " refers to any mitigation,
It is either permanent, interim, long-term, mitigation, the prevention of of short duration disease or illness or its at least one distinguishable symptom
Or reverse.
Used herein, " prodrug " or " pro-drug " refers to a kind of compound of vivo medicine-feeding, and the compound can be in vivo
It is metabolized, or is converted into activity form biologically, pharmaceutically or therapeutically in vivo.In order to manufacture pro-drug,
Described active medical compounds is modified, the medical compounds is turned in vivo by internal metabolic process
Turn to required medical compounds.Prodrug is designed to change its metabolic stability, or the precursor of transportation characterization, to change
It is apt to its side effect or toxicity, improves the sense of taste of medicine, or change other characteristics.By medicine for power mechanics and drug metabolism in vivo
Knowledge, once reactive compound is, it is known that those skilled in the art can be according to above-mentioned knowledge, with reference to the public affairs of this area on medicine
Know that knowledge designs go out the prodrug of formula I.
" composition " used herein refers to any mixture.Can be solution, mixed liquor, liquid, powder, ointment, water-based
, non-aqueous or their any combinations.
As used herein, term " joint " refers to any joint between two or more medicines or drug component.
Terms used herein " object " includes human or animal, for example, dog, cat, ox, pig, rodent etc..This area
Technical staff is, it is to be appreciated that the object of the present invention should be adapted to and be ready to respiratory tract infection, bacteremia, urinary infection, brain
The diseases such as film inflammation, surgical site infection, pneumonia, infection of biliary tract, septicemia or symptom are treated and prevented.
Any protectiveness group used herein, the abbreviation of amino acid and other compounds, and they are general, generally acknowledge
The Biochemical Nomenclature that abbreviation or the IUPAC-IUB committees promulgate is consistent, unless stated otherwise.
Active component
Because formula I has the excellent synergistic effect to polypeptide antibiotics, therefore formula Iization
Compound and its various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, prodrug, and contain this
Invention compound of formula I and antibiotic can be used for treating, prevent and alleviating by bacterium for the pharmaceutical composition of main active
Infect related disease.
It is preferably carried out in of the invention in mode, shown in the representational following Table A of compound structure：
Table A
Pharmaceutically acceptable salt, stereoisomer, dynamic isomer
As used herein, term " pharmaceutically acceptable salt " refers to this according to the compound of formula I of the present invention and pharmaceutically may be used
The salt that the inorganic acid and organic acid of receiving are formed, wherein, preferable inorganic acid includes (but being not limited to)：Hydrochloric acid, hydrobromic acid,
Phosphoric acid, nitric acid, sulfuric acid；Preferable organic acid includes (but being not limited to)：Formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,
5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethacetic acid, malonic acid, butanedioic acid, rich horse
Acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, benzenpropanoic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, first
Sulfonic acid, p-methyl benzenesulfonic acid, citric acid, and amino acid.
As used herein, it can be R configurations that term " optical isomer ", which refers to asymmetric carbon atom involved by the compounds of this invention,
Can also be S configurations, or its combination.
Pharmaceutical composition and application process
The present invention pharmaceutical composition include safe and effective amount in the range of formula I or its pharmacologically may be used
The salt of receiving and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to：The amount of compound is enough
The state of an illness is obviously improved, and is unlikely to produce serious side effect.Generally, pharmaceutical composition contains 1-2000mg chemical combination of the present invention
Thing/agent, more preferably, contain 5-200mg the compounds of this invention/agent.It is preferred that it is described it is " one " be a capsule or tablet.
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or jello
Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines
In thing each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine
Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on
Tie up plain acetic acid esters etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame
Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent (such as)、
Wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes
(but being not limited to)：Orally, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound mixes with least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mix：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) bond
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, example
Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, tristearin (i)
Sour magnesium, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also include
Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can use coating and shell material to prepare, such as casing and
Other materials well known in the art.They can include opacifying agent, also, reactive compound or compound in this composition
Release can be discharged in certain part in alimentary canal in a delayed fashion.The example of adoptable embedding component is polymeric material
And Wax.If necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, such as water or other solvents, increase
Solvent and emulsifying agent, example know, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials
Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste
Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and the mixture of Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
Composition for parenteral injection can include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
The formulation of the compounds of this invention for being locally administered includes ointment, powder, patch, propellant and inhalant.
Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary may need
Propellant be mixed together.
The compounds of this invention can be packed individually, or with polypeptide antibiotics and other pharmaceutically acceptable chemical combination
Thing packaged in combination.
It is the mammal that the pharmaceutical composition of safe and effective amount is applicable to treatment during using pharmaceutical composition
(such as people), wherein dosage is the effective dosage pharmaceutically thought when applying, for the people of 60kg body weight, day is to medicament
Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that method of administration, patient health situation etc. because
Element, within the scope of these are all skilled practitioners technical ability.
The preparation method of the compounds of this invention
Compound shown in the logical formula (I) of the present invention can be made by following method, but the condition of this method, such as be reacted
Thing, solvent, alkali, the amount of compound used therefor, reaction temperature, reaction required time etc. are not limited to following explanation.The present inventionization
Compound can also optionally by various synthetic methods describing in this manual or known in the art are combined and
Convenient to be made, such combination can easily be carried out by those skilled in the art in the invention.
Compound shown in the logical formula (I) of the present invention can be synthesized by following method：
(1) in atent solvent, formula A compounds are reacted with formula B compounds under certain temperature (as flowed back), obtain formula C
Compound, formula C compounds are reacted with alkali under certain temperature (as flowed back), and acid adding neutralizes after the completion of reaction, is filtrated to get formula Dization
Compound.
(2) in atent solvent, formula E compounds are reacted with NBS under certain temperature (such as 40~80 DEG C), and reaction is completed
Afterwards, column chromatography for separation obtains formula F compounds.
(3) in atent solvent, formula D compounds and formula F compounds certain temperature (as flowed back), after the completion of reaction, post layer
Analyse isolated compound of formula I.
It is above-mentioned it is various in, X, Y are as defined above.
It is preferably carried out at one in mode, X H, halogen, cyano group, nitro, SF5、OCN、SCN、C1-6Alkyl, C1-6Halogen
Substituted alkyl, C2-6Alkenyl, C2-6Haloalkenyl group, C2-6Alkynyl, C2-6Halo alkynyl, hydroxyl, amino, or it is substituted or unsubstituted
C3-7Cycloalkyl, C5-7Cycloalkenyl group, phenyl, phenoxy group, naphthyl, 5 yuan or 6 circle heterocycles or 8 yuan to 12 yuan heteroaryl bicyclic ring systems, it is described
The one or more that is selected from the group of substituent：Halogen, cyano group, nitro, SF5、OCN、SCN、C1-6Alkyl, C1-6Haloalkyl,
C2-6Alkenyl, C2-6Haloalkenyl group, C2-6Alkynyl, C2-6Halo alkynyl, hydroxyl, hydroxyl C1-4Alkyl, OR1、NR1R2、C(O)R1、C(O)
OR1、C(O)NR1R2、SR1、S(O)mR3、S(O)2NR1R2、OC(O)R3、OC(O)NR1R2、OS(O)2R3、OS(O)2NR1R2、N(R4)C
(O)R3、N(R4)C(O)NR1R2、N(R4)S(O)2R3Or N (R4)S(O)2NR1R2；
Y is H, halogen, cyano group, nitro, SF5、OCN、SCN、C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Haloalkene
Base, C2-6Alkynyl, C2-6Halo alkynyl, hydroxyl, amino, or substituted or unsubstituted C3-7Cycloalkyl, C5-7Cycloalkenyl group, phenyl,
Phenoxy group, naphthyl, 5 yuan or 6 circle heterocycles or 8 yuan to 12 yuan heteroaryl bicyclic ring systems, be selected from the group one of described substituent or
It is multiple：Halogen, cyano group, nitro, SF5、OCN、SCN、C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Haloalkenyl group, C2-6Alkynes
Base, C2-6Halo alkynyl, hydroxyl, hydroxyl C1-4Alkyl, OR1、NR1R2、C(O)R1、C(O)OR1、C(O)NR1R2、SR1、S(O)mR3、S
(O)2NR1R2、OC(O)R3、OC(O)NR1R2、OS(O)2R3、OS(O)2NR1R2、N(R4)C(O)R3、N(R4)C(O)NR1R2、N(R4)S
(O)2R3Or N (R4)S(O)2NR1R2；
R1、R2、R4It is each independently H, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Haloalkenyl group, C2-6Alkynyl,
C2-6Halo alkynyl；
R3For C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Haloalkenyl group, C2-6Alkynyl or C2-6Halo alkynyl；
Alkali used includes (but being not limited to) in reaction：Triethylamine, diisopropyl ethyl amine, diethylamine, piperidines, piperazine
Piperazine, morpholine, N-methylmorpholine, triethylene diamine (DABOC), the carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0] 11,1,
5- diazabicylos [4.3.0] nonyl- 5- alkene (DBN), potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, cesium carbonate, hydroxide
Sodium, potassium hydroxide, sodium methoxide, caustic alcohol, or its combination.
Bronsted acid or lewis acid used include (but being not limited to) in reaction：Hydrochloric acid, acetic acid, p-methyl benzenesulfonic acid, trifluoro
Acetic acid, boron trifluoride, alchlor, ferric trichloride, magnesium chloride, cobalt chloride, strontium chloride, palladium bichloride, nickel chloride, or its combination.
The preparation method of the salt of the compound of the present invention, the conventional method of this area can be used to carry out.
One in the present invention is preferably carried out in mode, and the preparation method of the hydrobromate of the compounds of this invention is as follows：
(1) in atent solvent, formula E compounds are reacted with NBS under certain temperature (such as 40~80 DEG C), and reaction is completed
Afterwards, column chromatography for separation obtains formula F compounds.
(2) in atent solvent, formula d compounds, formula F compounds and TMSNCS are anti-under certain temperature (such as 50~80 DEG C)
Should, after the completion of reaction, column chromatography for separation obtains the hydrobromate of compound of formula I.
Wherein TMSNCS is isothiocyanic acid trimethyl silicone grease.
Main advantages of the present invention：
The present invention has synthesized a kind of new antibiotic and (included but is not limited to：Polymyxin B) Trimethoprim, described is anti-
The activity of bacterium synergist is high, and nitrate enhancement highest can reach about 128 times, show extremely excellent antibacterial synergistic activity.It is real
Test result to show, described Trimethoprim, which can be used for preparing, treats a series of and Acinetobacter bauamnnii, Klebsiella Pneumoniae
Relevant disease, the dosage of polymyxin B is effectively reduced, effectively reduce the wind that polymyxin B toxicity is brought over the course for the treatment of
Danger, and can be applied to Acinetobacter bauamnnii insensitive to polymyxin B or that bacteriostatic activity is not strong, the antibacterial of Klebsiella Pneumoniae
Treatment.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
The 2- of embodiment 1 (4- trifluoromethyls phenylimino) -4- (4- aminomethyl phenyls) thiazole (compound 1)
1.1 prepare N- (4- trifluoromethyls) thiocarbamide
12mmol chlorobenzoyl chlorides and 20mL acetone are added in 100mL round-bottomed flasks, then adds 12mmol thiocyanic acids
Potassium, reaction have a large amount of white solids to generate.After 15 minutes, question response terminates, and solid is filtered, and filtrate is spin-dried for, and obtains light yellow liquid
Body, direct plunge into and react in next step.10mmol4- 5-trifluoromethylanilines are added in 100mL round-bottomed flasks, 30mL ethyl acetate is molten
Solution, by previous step react made from product be added in this solution, be heated to back flow reaction., will be anti-after TLC tracking reactions terminate
Liquid is answered to be cooled to room temperature, decompression boils off solvent, is directly added into 10mL ethanol and 10mL 2N sodium hydroxide solutions, back flow reaction.
After TLC tracking reactions terminate, reaction solution is cooled to room temperature, frozen water 30mL frozen water is added, neutrality is neutralized to 2N hydrochloric acid.Will be solid
Body filters, and obtains target product, is faint yellow solid, yield 83%.1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),
7.76 (d, J=8.3Hz, 2H), 7.65 (d, J=8.3Hz, 2H)
1.2 prepare alpha-brominated -4- methyl acetophenones
10mmol 4- methyl acetophenones and 11mmol N- bromo-succinimides (NBS) are added in 100mL round-bottomed flasks,
35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is warming up into 40 DEG C
Reaction.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate is spin-dried for, post layer
Analysis separation (eluent：Petrol ether/ethyl acetate) obtain light yellow crystal, yield 53%.1H NMR(400MHz,CDCl3)δ7.88
(d, J=8.2Hz, 2H), 7.28 (d, J=8.1Hz, 2H), 4.43 (s, 2H), 2.42 (s, 3H)
1.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (4- aminomethyl phenyls) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the alpha-brominated -4- methylbenzenes of 1.05mmol are added in 25mL eggplant-shape bottles
Ethyl ketone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, by reaction solution
Temperature is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain target chemical combination
Thing, is white solid, yield 83%.1H NMR(400MHz,DMSO-d6) δ 10.70 (s, 1H), 7.93 (t, J=8.3Hz, 2H),
7.85 (d, J=8.0Hz, 2H), 7.71 (d, J=8.6Hz, 2H), 7.39 (d, J=10.1Hz, 1H), 7.25 (d, J=8.0Hz,
2H),2.34(s,3H)；19F NMR(376MHz,DMSO-d6)δ-59.84(s)；HRMS(ESI)m/z[M+H]+C17H14F3N2S+Meter
Calculation value：335.0830, measured value:335.0832.
The 2- of embodiment 2 (4- trifluoromethyls phenylimino) -4- (4- cyano-phenyls) thiazole (compound 2)
2.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
2.2 prepare alpha-brominated -4- cyano-acetophenones
10mmol 4- cyano-acetophenones and 11mmol N- bromo-succinimides (NBS) are added in 100mL round-bottomed flasks,
35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is warming up into 40 DEG C
Reaction.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate is spin-dried for, post layer
Analysis separation (eluent：Petrol ether/ethyl acetate) obtain white solid, yield 61%.
2.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (4- cyano-phenyls) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the alpha-brominated -4- cyano group benzene of 1.05mmol are added in 25mL eggplant-shape bottles
Ethyl ketone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, by reaction solution
Temperature is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain target chemical combination
Thing, yellow solid, yield 63%.1H NMR(400MHz,DMSO-d6) δ 10.81 (s, 1H), 8.14 (d, J=8.3Hz, 2H),
7.94 (d, J=8.6Hz, 2H), 7.91 (d, J=8.4Hz, 2H), 7.77 (s, 1H), 7.72 (d, J=8.6Hz, 2H)；19F NMR
(376MHz,DMSO-d6)δ-59.91(s)；HRMS(ESI)m/z[M+H]+C17H11F3N3S+Calculated value：346.0626, measured value:
346.0631.
The 2- of embodiment 3 (4- trifluoromethyls phenylimino) -4- (4- bromophenyls) thiazole (compound 4)
3.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
3.2 prepare alpha-brominated -4- bromoacetophenones
10mmol 4- bromoacetophenones and 11mmol N- bromo-succinimides (NBS) are added in 100mL round-bottomed flasks,
35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is warming up into 40 DEG C
Reaction.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate is spin-dried for, post layer
Analysis separation (eluent：Petrol ether/ethyl acetate) obtain white crystal, yield 45%.1H NMR(400MHz,CDCl3)δ7.86(d,
J=8.6Hz, 2H), 7.65 (d, J=8.6Hz, 2H), 4.40 (s, 2H)
3.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (4- bromophenyls) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the alpha-brominated -4- bromobenzenes second of 1.05mmol are added in 25mL eggplant-shape bottles
Ketone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, liquid temperature will be reacted
Degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) target compound is obtained,
White solid, yield 40%.1H NMR(400MHz,DMSO-d6) δ 10.74 (s, 1H), 7.93 (d, J=4.3Hz, 2H), 7.91
(d, J=4.1Hz, 2H), 7.70 (d, J=8.6Hz, 2H), 7.64 (d, J=8.3Hz, 2H), 7.55 (s, 1H)；19F NMR
(376MHz,DMSO-d6)δ-59.86(s)；HRMS(ESI)m/z[M+H]+C16H11 79BrF3N2S+Calculated value：398.9778, actual measurement
Value:398.9778；C16H11 81BrF3N2S+Calculated value：400.9758, measured value:400.9756.
The 2- of embodiment 4 (4- trifluoromethyls phenylimino) -4- (2,4 difluorobenzene base) thiazole (compound 5)
4.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
4.2 prepare alpha-brominated -2,4 difluorobenzene ethyl ketone
10mmol 2,4 difluorobenzenes ethyl ketone and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petrol ether/ethyl acetate) obtain white solid, yield 63%.1H NMR(400MHz,CDCl3)δ
8.09-7.94 (m, 1H), 7.08-6.98 (m, 1H), 6.92 (qd, J=8.8,4.6Hz, 1H), 4.49 (d, J=2.4Hz, 2H)
4.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (2,4 difluorobenzene base) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide is added in 25mL eggplant-shape bottles, 1.05mmol is alpha-brominated -2,4- difluoros
Acetophenone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, it will react
Liquid temperature degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain targeted
Compound, white solid, yield 72%.1H NMR(400MHz,DMSO-d6) δ 10.76 (s, 1H), 8.18 (dd, J=15.9,
8.7Hz, 1H), 7.92 (d, J=8.5Hz, 2H), 7.71 (d, J=8.5Hz, 2H), 7.38 (dd, J=16.4,6.9Hz, 1H),
7.33 (d, J=1.8Hz, 1H), 7.22 (t, J=8.4Hz, 1H)；19F NMR(376MHz,DMSO-d6)δ-59.92(s),-
109.51–-109.98(m),-110.59–-110.84(m)；HRMS(ESI)m/z[M+H]+C16H10F5N2S+Calculated value：
357.0485, measured value:357.0485.
The 2- of embodiment 5 (4- chlorobenzenes imino group) -4- (3,4- difluorophenyls) thiazole (compound 7)
5.1 prepare N- (4- chlorphenyls) thiocarbamide
12mmol chlorobenzoyl chlorides and 20mL acetone are added in 100mL round-bottomed flasks, then adds 12mmol thiocyanic acids
Potassium, reaction have a large amount of white solids to generate.After 15 minutes, question response terminates, and solid is filtered, and filtrate is spin-dried for, and obtains light yellow liquid
Body, direct plunge into and react in next step.10mmol4- chloroanilines are added in 100mL round-bottomed flasks, the dissolving of 30mL ethyl acetate will be upper
Product made from single step reaction is added in this solution, is heated to back flow reaction.It is after TLC tracking reactions terminate, reaction solution is cold
But solvent is boiled off, is directly added into 10mL ethanol and 10mL 2N sodium hydroxide solutions, back flow reaction to room temperature, decompression.TLC is tracked
After reaction terminates, reaction solution is cooled to room temperature, frozen water 30mL frozen water is added, neutrality is neutralized to 2N hydrochloric acid.Solid is filtered,
Obtain target product, faint yellow solid, yield 86%.1H NMR(400MHz,DMSO-d6) δ 9.76 (s, 1H), 7.46 (d, J=
8.7Hz, 2H), 7.36 (d, J=8.7Hz, 2H).
5.2 prepare alpha-brominated -3,4- difluoro acetophenones
10mmol 3,4- difluoro acetophenones and 111mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petrol ether/ethyl acetate) obtain yellow crystals, yield 49%.1H NMR(400MHz,CDCl3)δ
7.88–7.81(m,1H),7.82–7.77(m,1H),7.37–7.25(m,1H),4.45(s,2H).
5.3 prepare 2- (4- chlorobenzenes imino group) -4- (4- fluorophenyls) thiazole
1mmol N- (4- chlorphenyls) thiocarbamide is added in 25mL eggplant-shape bottles, 1.05mmol is alpha-brominated -3,4- difluoro acetophenones,
The dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, by reacting liquid temperature
Room temperature is down to, decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) target compound is obtained, in vain
Color solid, yield 78%.1H NMR(400MHz,DMSO-d6) δ 10.47 (s, 1H), 7.94 (ddd, J=12.0,7.9,1.8Hz,
1H), 7.82-7.70 (m, 3H), 7.56-7.44 (m, 2H), 7.40 (d, J=8.8Hz, 2H)；19F NMR(376MHz,DMSO-
d6)δ-137.48–-139.17(m),-139.15–-140.63(m).
The 2- of embodiment 6 (4- tert-butyl benzenes imino group) -4- (4- fluorophenyls) thiazole (compound 10)
6.1 prepare N- (4- tert-butyl-phenyls) thiocarbamide
12mmol chlorobenzoyl chlorides and 20mL acetone are added in 100mL round-bottomed flasks, then adds 12mmol thiocyanic acids
Potassium, reaction have a large amount of white solids to generate.After 15 minutes, question response terminates, and solid is filtered, and filtrate is spin-dried for, and obtains light yellow liquid
Body, direct plunge into and react in next step.10mmol4- tert-butyl group aniline is added in 100mL round-bottomed flasks, 30mL ethyl acetate dissolves,
By previous step react made from product be added in this solution, be heated to back flow reaction.After TLC tracking reactions terminate, it will react
Liquid is cooled to room temperature, and decompression boils off solvent, is directly added into 10mL ethanol and 10mL 2N sodium hydroxide solutions, back flow reaction.TLC
After tracking reaction terminates, reaction solution is cooled to room temperature, frozen water 30mL frozen water is added, neutrality is neutralized to 2N hydrochloric acid.By solid
Filtering, obtains target product, is faint yellow solid, yield 81%.1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),7.34
(d, J=8.7Hz, 2H), 7.29 (d, J=8.6Hz, 2H), 1.27 (s, 9H)
6.2 prepare alpha-brominated -4- fluoro acetophenones
Preparation method is the same as embodiment 5.
6.3 prepare 2- (4- tert-butyl benzenes imino group) -4- (4- fluorophenyls) thiazole
Addition 1mmol N- (4- tert-butyl-phenyls) thiocarbamide in 25mL eggplant-shape bottles, the alpha-brominated -4- fluoro acetophenones of 1.05mmol,
The dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, by reacting liquid temperature
Room temperature is down to, decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) target compound is obtained, in vain
Color crystal, yield 82%.1H NMR(400MHz,DMSO-d6) δ 10.21 (s, 1H), 7.96 (dd, J=8.7,5.6Hz, 2H),
7.64 (d, J=8.7Hz, 2H), 7.37 (d, J=8.7Hz, 2H), 7.32-7.21 (m, 3H), 1.28 (s, 9H)；19F NMR
(376MHz,DMSO-d6)δ-114.52–-114.67(m).
The 2- of embodiment 7 (4- trifluoromethyls phenylimino) -4- (4- nitrobenzophenones) thiazole (compound 19)
7.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
7.2 prepare alpha-brominated -4- nitros benzoylformaldoxime
10mmol 4- nitro-acetophenones and 11mmol N- bromo-succinimides (NBS) are added in 100mL round-bottomed flasks,
35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is warming up into 40 DEG C
Reaction.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate is spin-dried for, post layer
Analysis separation (eluent：Petrol ether/ethyl acetate) obtain faint yellow solid, yield 63%.1H NMR(400MHz,CDCl3)δ8.38–
8.33(m,2H),8.20–8.14(m,2H),4.47(s,2H).
7.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (4- nitrobenzophenones) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the alpha-brominated -4- nitrobenzene of 1.05mmol are added in 25mL eggplant-shape bottles
Ethyl ketone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, by reaction solution
Temperature is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain target chemical combination
Thing, yellow solid, yield 71%.1H NMR(400MHz,DMSO-d6) δ 10.84 (s, 1H), 8.30 (d, J=8.9Hz, 2H),
8.21 (d, J=8.9Hz, 2H), 7.94 (d, J=8.5Hz, 2H), 7.85 (s, 1H), 7.72 (d, J=8.6Hz, 2H)；19F NMR
(376MHz,DMSO-d6)δ-59.92(s).
The 2- of embodiment 8 (4- trifluoromethyls phenylimino) -4- (4- iodophenyls) thiazole (compound 12)
8.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
8.2 prepare alpha-brominated -4- iodos acetophenone
10mmol 4- Iodoacetophenones and 11mmol N- bromo-succinimides (NBS) are added in 100mL round-bottomed flasks,
35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is warming up into 40 DEG C
Reaction.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate is spin-dried for, post layer
Analysis separation (eluent：Petrol ether/ethyl acetate) obtain yellow solid, yield 46%.1H NMR(400MHz,CDCl3)δ7.87(d,
J=8.4Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 4.40 (s, 2H)
8.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (4- iodophenyls) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the alpha-brominated -4- iodobenzenes second of 1.05mmol are added in 25mL eggplant-shape bottles
Ketone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, liquid temperature will be reacted
Degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) target compound is obtained,
White solid, yield 82%.1H NMR(400MHz,DMSO-d6) δ 10.74 (s, 1H), 7.92 (d, J=8.5Hz, 2H), 7.81
(d, J=8.4Hz, 2H), 7.76 (d, J=8.5Hz, 2H), 7.70 (d, J=8.6Hz, 2H), 7.54 (s, 1H)；19F NMR
(376MHz,DMSO-d6)δ-59.86(s).
The 2- of embodiment 9 (4- trifluoromethyls phenylimino) -4- (the fluoro- 4- bromophenyls of 2-) thiazole (compound 13)
9.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
9.2 prepare the fluoro- 4- bromos acetophenones of alpha-brominated -2-
The fluoro- 4- bromoacetophenones of 10mmol 2- and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petrol ether/ethyl acetate) obtain white solid, yield 51%.1H NMR(400MHz,CDCl3)δ
7.83 (t, J=8.1Hz, 1H), 7.44 (dd, J=8.4,1.7Hz, 1H), 7.39 (dd, J=10.5,1.7Hz, 1H), 4.48
(d, J=2.4Hz, 2H)
9.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (the fluoro- 4- bromophenyls of 2-) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the fluoro- 4- bromines of the alpha-brominated -2- of 1.05mmol are added in 25mL eggplant-shape bottles
Acetophenone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, it will react
Liquid temperature degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain targeted
Compound, white solid, yield 85%.1H NMR(400MHz,DMSO-d6) δ 10.78 (s, 1H), 8.09 (t, J=8.4Hz, 1H),
7.91 (d, J=8.5Hz, 2H), 7.75-7.62 (m, 3H), 7.54 (d, J=8.4Hz, 1H), 7.41 (s, 1H)；19F NMR
(376MHz,DMSO-d6)δ-58.53–-60.78(m),-110.00–-111.83(m).
The 2- of embodiment 10 (4- trifluoromethyls phenylimino) -4- (2,4- dibromo phenyls) thiazole (compound 16)
10.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
10.2 prepare alpha-brominated -2,4- dibromos acetophenone
10mmol 2,4- dibromos acetophenones and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petroleum ether/dichloromethane) obtain weak yellow liquid, yield 50%.1H NMR(400MHz,
CDCl3) δ 7.83 (d, J=1.8Hz, 1H), 7.56 (dd, J=8.3,1.8Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 4.46
(s,2H)。
10.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (2,4- dibromo phenyls) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide is added in 25mL eggplant-shape bottles, 1.05mmol is alpha-brominated -2,4- dibromos
Acetophenone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, it will react
Liquid temperature degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain targeted
Compound, white solid, yield 78%.1H NMR(400MHz,DMSO-d6) δ 10.75 (s, 1H), 7.99 (d, J=1.8Hz, 1H),
7.88 (d, J=8.6Hz, 2H), 7.74 (d, J=8.4Hz, 1H), 7.71-7.72 (m, 3H), 7.43 (s, 1H)；19F NMR
(376MHz,DMSO-d6)δ-59.86(s).
The 2- of embodiment 11 (4- trifluoromethyls phenylimino) -4- (4- tert-butyl-phenyls) thiazole (compound 17)
11.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
11.2 prepare alpha-brominated -4- tert-butyl benzenes ethyl ketone
10mmol 4- tert-butyl benzenes ethyl ketones and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petroleum ether/dichloromethane) obtain weak yellow liquid, yield 90%.1H NMR(400MHz,
CDCl3) δ 7.93 (d, J=8.5Hz, 2H), 7.51 (d, J=8.5Hz, 2H), 4.44 (s, 2H), 1.35 (s, 9H).
11.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (4- tert-butyl-phenyls) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the alpha-brominated -4- tert-butyl groups of 1.05mmol are added in 25mL eggplant-shape bottles
Acetophenone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, it will react
Liquid temperature degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain targeted
Compound, white solid, yield 69%.1H NMR(400MHz,DMSO-d6) δ 10.71 (s, 1H), 7.94 (d, J=8.5Hz, 2H),
7.86 (d, J=8.2Hz, 2H), 7.70 (d, J=8.6Hz, 2H), 7.45 (d, J=7.4Hz, 2H), 7.36 (s, 1H), 1.31
(s,9H)；19F NMR(376MHz,DMSO-d6)δ-59.83(s)。
The 2- of embodiment 12 (4- trifluoromethyls phenylimino) -4- (2,4 dichloro benzene base) thiazole (compound 20)
12.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
12.2 prepare alpha-brominated -2,4 dichloro benzene ethyl ketone
10mmol 2,4 dichloro benzenes ethyl ketone and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petroleum ether/dichloromethane) obtain white solid, yield 20%.1H NMR(400MHz,CDCl3)δ
7.56 (d, J=8.4Hz, 1H), 7.48 (d, J=1.9Hz, 1H), 7.36 (dd, J=8.4,1.9Hz, 1H), 4.50 (s, 2H)
12.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (2,4 dichloro benzene base) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide is added in 25mL eggplant-shape bottles, 1.05mmol is alpha-brominated -2,4- dichloros
Acetophenone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, it will react
Liquid temperature degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain targeted
Compound, white solid, yield 58%.1H NMR(400MHz,DMSO-d6) δ 10.76 (s, 1H), 7.98 (d, J=8.5Hz, 1H),
7.88 (d, J=8.5Hz, 2H), 7.72 (d, J=2.1Hz, 1H), 7.68 (d, J=8.6Hz, 2H), 7.58-7.49 (m, 2H)；19F NMR(376MHz,DMSO-d6)δ-59.88(s).
The 2- of embodiment 13 (4- trifluoromethyls phenylimino) -4- (the chloro- 4- bromophenyls of 2-) thiazole (compound 21)
13.1 prepare N- (4- trifluoromethyls) thiocarbamide
Preparation method is the same as embodiment 1.
13.2 prepare the chloro- 4- bromoacetophenones of alpha-brominated -2-
The chloro- 4- bromoacetophenones of 10mmol 2- and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petroleum ether/dichloromethane) obtain white solid, yield 61%.1H NMR(400MHz,CDCl3)δ
7.64 (d, J=1.6Hz, 1H), 7.52 (dd, J=8.3,1.7Hz, 1H), 7.47 (d, J=8.3Hz, 1H), 4.49 (s, 2H)
13.3 prepare 2- (4- trifluoromethyls phenylimino) -4- (the chloro- 4- bromophenyls of 2-) thiazole
1mmol N- (4- trifluoromethyls) thiocarbamide, the chloro- 4- bromines of the alpha-brominated -2- of 1.05mmol are added in 25mL eggplant-shape bottles
Acetophenone, the dissolving of 10mL ethanol is added, adds 1.5mmoL triethylamines, back flow reaction.After TLC tracking reactions terminate, it will react
Liquid temperature degree is down to room temperature, and decompression steams solvent, residue column chromatography for separation (eluant, eluent：Petroleum ether-ethyl acetate) obtain targeted
Compound, white solid, yield 83%.1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.00-7.75(m,11.2Hz,
4H),7.73-7.60(m,3H),7.53(s,1H)；19F NMR(376MHz,DMSO-d6)δ-59.89(s).
The preparation of other compounds in the Table A of embodiment 14
The method in embodiment 1-14 is repeated, difference is, using different initiation materials, so as to which institute in Table A be made
The compound shown.
The preparation of the hydrobromate (compound K J1363) of the compound of 15 formula of embodiment 5
Detailed process is：
1) alpha-brominated -2,4 difluorobenzene ethyl ketone is prepared
10mmol2,4- difluoro acetophenones and 11mmol N- bromo-succinimides are added in 100mL round-bottomed flasks
(NBS), 35mL ethyl acetate dissolves, and adds the ion exchange resin of 1g Amberlyst 15 and makees catalyst, reaction solution is heated up
To 40 DEG C of reactions.After TLC tracking reactions terminate, reacting liquid filtering is removed into the ion exchange resin of Amberlyst 15, filtrate rotation
It is dry, column chromatography for separation (eluent：Petrol ether/ethyl acetate) obtain white solid, yield 63%.1H NMR(400MHz,CDCl3)δ
8.09-7.94 (m, 1H), 7.08-6.98 (m, 1H), 6.92 (qd, J=8.8,4.6Hz, 1H), 4.49 (d, J=2.4Hz, 2H)
2) 2- (4- trifluoromethyls phenylimino) -4- (2,4 difluorobenzene base) thiazole hydrobromide salt is prepared
Added in 25mL eggplant-shape bottles 1mmol it is alpha-brominated -2,4- difluoro acetophenones, add the dissolving of 10mL ethanol, add 1mmol
4- 5-trifluoromethylanilines, 1mmol TMSNCS are added, be heated to 70 DEG C of reactions.After TLC tracking reactions terminate, liquid temperature will be reacted
Degree is down to room temperature, filters to obtain target compound, white solid, yield 78%.1H NMR(400MHz,DMSO-d6)δ9.59(s,
2H), 7.92 (d, J=8.5Hz, 2H), 7.75 (d, J=8.3Hz, 2H), 7.46 (td, J=8.5,6.6Hz, 1H), 7.37 (s,
1H), 7.27 (td, J=9.8,2.5Hz, 1H), 7.13 (td, J=8.5,2.3Hz, 1H)
The antibacterial synergistic activity of embodiment 16 is tested
Experimental method
1. required addition chemical combination when calculating 8 μ g/ml, 16 μ g/ml according to the μ l of reaction system 200 and compound concentration
The dosage of thing, compound is added, and correspondingly carries out mark in 96 orifice plates, then contains 0.5 μ g/ml polymyxin Bs by what is prepared
Acinetobacter bauamnnii or the μ l of Klebsiella Pneumoniae bacterium solution 200 be added in 96 orifice plates containing compound, 37 DEG C, 20h stand training
Support, observation is drawn a conclusion.
2. compound and antibiotic concentration decrement screening：The concentration of the compound screened in above-mentioned steps is reduced to 4 μ
G/ml, the concentration of polymyxins are reduced to 0.25 μ g/ml, tested again.
3. the measure of the single bacteriostatic activity of compound and concentration dependent：The representative compound that previous step is tested is adopted
It is measured with gradient dilution method, and calculates MIC value.
4. whether test compound Bao Man clinic bacterium anti-to polymyxins and other Gram-negative bacterias have synergistic effect：By
There is stronger bacteriostasis to other Gram-negative bacterias in polymyxins, in the case where having synergistic effect to pattern bacterium,
Whether experiment has universal synergistic effect to Acinetobacter bauamnnii clinic bacterium and other Gram-negative bacterias.
Experimental result
1. the present invention is shown to the antibacterial synergistic activity testing result of polymyxin B according to formula (I) compound of the present invention
Compound there is significant antibacterial synergistic activity to polymyxin B, the antibacterial synergistic activity of the compound 1~22 detected is equal
More than 2 times, the antibacterial synergistic activity of most compounds can reach 8~32 times, and highest can reach 128 times, represent
The result of property is as shown in table 1.
The nitrate enhancement of compound is that the MIC measured during polymyxin B divided by addition testing compound (concentration is used alone
For 4ug/ml) after the MIC of polymyxin B that measures.ATCC19606 bacterial strains are Acinetobacter bauamnnii in table, purchased from ATCC；Ab-6
Bacterial strain is Acinetobacter bauamnnii clinical drug-resistant bacterium, is isolated from clinical patient, the MIC of polymyxin B is 16-32 μ g/ml；
ATCC13883 bacterial strains are Klebsiella Pneumoniae, purchased from ATCC；KPN-1618 bacterial strains (produce for the Klebsiella Pneumoniae of clinical drug-resistant
Carbapenem enzyme), it is isolated from clinical patient.
The active list of the representation compound of the formula of table 1 (I) compound
2. the measurement result of the single bacteriostatic activity of compound and concentration dependent shows, in the range of test concentrations individually
Inhibition can not be produced to test strain, representational result is as shown in the table using the compound of formula I of the present invention：
| Compound number | 4 | 5 | 15 |
| MIC | ＞ 128mg/L | ＞ 128mg/L | ＞ 128mg/L |
3. the wide-spectrum synergy effect of pair suppression Gram-negative bacteria
It is tested for Gram-negative bacterias such as Escherichia coli, the results showed that formula I is to suppressing to remove from office
Lan Shi negative bacteriums have the synergistic effect of wide spectrum.Choose coli strain ATCC25922 (being purchased from ATCC) to be tested, individually
Compound MIC is all higher than 64ug/ml, and the MIC value of independent polymyxin B is 0.5ug/ml, when polymyxin B and compound of formula I
When 4ug/ml is used in combination, the MIC value of polymyxin B is determined, and calculates nitrate enhancement, representational result is as follows：
| Compound | 4 | 5 | 15 | 16 |
| Nitrate enhancement | >=4 times | >=4 times | >=2 times | >=4 times |
4. the synergistic effect pair other antibiotic
It has detected synergistic activity of the compounds of this invention to other anti-Gram-negative bacteria antibiotic, the results showed that, this hair
Bright compound of formula I confrontation Gram-negative bacteria antibiotic has universal synergistic activity.Combined using compound 4 (4ug/ml)
The anti-Acinetobacter bauamnnii of other antibiotic (ATCC19606), the results showed that, the Norfloxacin of compound 4, Amp Sulbactams, replace according to rice
Star, imipenem cilastatin, cefotaxime are respectively provided with significant synergistic activity, and drug combination group antibiotic antibacterial activity improves
At least 8 times.
5. activity in vivo is tested
Specific method：
Using normal ICR mouse, animal is randomly divided into I, II, III, IV group (6/group).
I:Control group
II:Polymyxin e 4mg/kg body weight
III:Polymyxin e 1mg/kg body weight
IV:Polymyxin e 1mg/kg+KJ1363 1mg/kg
Four groups of intraperitoneal injection of cyclophosphamide (CP) 150mg/kg on the firstth, intraperitoneal injection of cyclophosphamide (CP) on the 4th
200mg/kg, angular oculi vein clump on the 5th give the μ l of Acinetobacter bauamnnii ATCC19606OD3.0 (180CFU/ML) 100.To bacterium two
Hour rear molding intravenously administrable, while control group administered physiological saline, observe its death condition in 72 hours.
Experimental result is as follows：
Experiment was to the 11st day, and the survival rate of Group II and Group IV stills remain in more than 80%, and Group I and III
Group survival rate is below 20%.There was no significant difference between Group I and Group III, illustrates PmE2 (1mg/kg) dosage to Bao Man
Acinetobacter mouse is without therapeutic action；There is significant difference between Group III and Group IV；Without aobvious between Group IV and Group II
Write sex differernce.Illustrate that KJ1363 has synergistic effect to polymyxin E in vivo, internal nitrate enhancement is at least 4 times.
All it is incorporated as referring in this application in all documents that the present invention refers to, it is independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. a kind of compound with structure shown in logical formula (I), or its optical isomer, cis-trans-isomer or pharmaceutically acceptable
Salt:
In formula,
X represents the substituent on any one or more positions on the phenyl ring where it, and each X is independently selected from the following group：Take
Generation or unsubstituted C1-6Alkyl, halogen；
Y represents the substituent on any one or more positions on the phenyl ring where it, and each Y is independently selected from the following group：Halogen
Element, cyano group, nitro, substituted or unsubstituted C1-4Alkyl.
2. compound as claimed in claim 1, it is characterised in that the quantity of substituent X is 1 or 2；And/or
Substituent Y quantity is 1 or 2.
3. compound as claimed in claim 1, it is characterised in that each X is independently selected from the following group：Halogen, C1-2Haloalkyl
(it is preferably the C of F substitutions1-2Haloalkyl).
4. compound as claimed in claim 1, it is characterised in that each X is independently selected from the following group：Halogen (be preferably F, Cl or
Br；More preferably F or Cl), CF3(trifluoromethyl).
5. compound as claimed in claim 1, it is characterised in that the position of substitution of the substituent X includes contraposition.
6. compound as claimed in claim 1, it is characterised in that the position of substitution of the substituent Y includes contraposition.
7. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes：(i) described in the claim 1 of effective dose
Compound of formula I, or its pharmaceutically acceptable salt；(ii) pharmaceutically acceptable carrier and/or excipient.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that described pharmaceutical composition also includes antibiotic.
9. the purposes of compound as claimed in claim 1, it is characterised in that for preparing the synergist of antibiotic.
10. the preparation method of compound as claimed in claim 1, it is characterised in that methods described includes step：
(1) in atent solvent, formula A compounds are reacted with formula B compounds, obtain formula C compounds, and formula C compounds are reacted with alkali,
Acid adding neutralizes after the completion of reaction, is filtrated to get formula D compounds；
(2) in atent solvent, formula E compounds are reacted with NBS, obtain formula F compounds；
(3) in atent solvent, formula D compounds are reacted with formula F compounds, obtain compound of formula I；
It is above-mentioned it is various in, X, Y are as defined above.
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|---|---|---|---|---|
| CN115124487A (en) * | 2021-03-24 | 2022-09-30 | 华东理工大学 | Preparation method and application of arylimino thiazole compounds |
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| EP2513064A2 (en) * | 2009-12-17 | 2012-10-24 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Compounds, compositions and methods for controlling biofilms |
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| B. SHIVARAMA HOLLA，等: "Synthesis of some new 2,4-disubstituted thiazoles as possible antibacterial and anti-inflammatory agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115124487A (en) * | 2021-03-24 | 2022-09-30 | 华东理工大学 | Preparation method and application of arylimino thiazole compounds |
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