CN105503788B - The substitution of one kind 3 the third 2 ketone compounds of alkene 1 and its application - Google Patents
The substitution of one kind 3 the third 2 ketone compounds of alkene 1 and its application Download PDFInfo
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- CN105503788B CN105503788B CN201610059112.3A CN201610059112A CN105503788B CN 105503788 B CN105503788 B CN 105503788B CN 201610059112 A CN201610059112 A CN 201610059112A CN 105503788 B CN105503788 B CN 105503788B
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
The present invention relates to pharmaceutical technology field, specifically disclosing a class has the ketone compounds of alkene 1 of 3 substitutions the third 2 of general formula I and its is preparing application antimycotic and in cooperateing with antifungal drug.Such compound can be used in conjunction with azole antifungals, can improve sensitiveness of the drug-fast bacteria to nitrogen azole drug, realize that reversing drug resistance is acted on, and produce collaboration antifungic action.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically, be a kind of 3- substitution propyl- 2- alkene -1- ketone compounds and its
Collaboration Fluconazole prepares the application in antineoplastic pharmaceutical compositions.
Background technology
Nosomycosis, i.e., by fungus-caused disease.The eucaryote in nature is widely present in as a class, fungi can
Infect the different parts of human body.From clinical pathogenic situation, nosomycosis can be divided into superficial mycoses and deep mycosis two
Major class.The problem of abuse of antibiotics etc. is many causes between bacterium and fungi normal flora symbiosis by certain destruction；
Secondly it is also increasing in clinic development in clinical practice organ transfer operation, the use influence of postoperative central immunodepressant
The normal immunologic function of body, makes human body make the fungal infection of deep internal organs fall ill the resistance reduction problem above of fungi
Rate more and more higher is also serious all the more.Candida albicans is the Etiological of fungal infection, but in recent years with carrying out antifungal drug
It is a large amount of use, fungi gradually increases the drug resistance of medicine.The bacterial strain for having drug-resistant effect to Fluconazole would generally be to other azoles
Class medicine produces crossing drug resistant effect so that the clinical medicine selection in terms of the infection for treating candida albicans is very difficult.
Therefore, antifungal drug reversal agent of drug resistance is found, sensitiveness of the fungi to medicine is improved, what is cooperateed with the generation of existing medicine is anti-true
Bacterium acts on, and is a kind of important method for improving the therapeutic effect of existing medicine at present.In the prior art, chalcone is 3- substitutions
One kind of propyl- 2- alkene -1- ketone compounds kinds, is also the class natural structure being present in plant, have document report such
The antitumor of compound waits effect, but there is not been reported such compound has and cooperates with antimycotic effect.
The content of the invention
First purpose of the present invention is for of the prior art not enough true with synergy overriding resistance there is provided one kind
The pharmaceutical composition of bacterium.
Second object of the present invention is to provide a kind of 3- substitutions propyl- 2- alkene -1- ketone overriding resistance fungal compounds.
Third object of the present invention is to provide the use that 3- as described above replaces propyl- 2- alkene -1- ketone antifungal compounds
On the way.
To achieve the above object, the present invention is adopted the technical scheme that：
A kind of pharmaceutical composition with synergy overriding resistance fungi, including azole antifungals, 3- substitution propyl-
2- alkene -1- ketone compounds or its pharmaceutically acceptable salt or hydrate, described 3- substitution propyl- 2- alkene -1- ketones
The structure of compound is shown in formula I；
The R1Selected from phenyl, hydroxyl substituted-phenyl, methoxy substitution phenyl, dimethylamino substituted-phenyl, halogenophenyl,
Furyl, methylene-dioxy substituted-phenyl, methylol substituted furan base, thienyl or pyridine radicals；
The R2Selected from hydrogen, hydroxyl, methoxyl group, amino, chlorine or fluorine；
The R3Selected from hydrogen or bromine；
The R4Selected from hydrogen, hydroxyl or methoxyl group；
The R5Selected from hydrogen or bromine；
The R6Selected from hydroxyl, methoxyl group, hydrogen, amino or halogen.
Preferably,
The R1Selected from phenyl, hydroxyl substituted-phenyl, methoxy substitution phenyl, dimethylamino substituted-phenyl, halogenophenyl,
Furyl, methylene-dioxy substituted-phenyl, methylol substituted furan base, thienyl or pyridine radicals；
The R2Selected from hydrogen or hydroxyl；
The R3Selected from hydrogen or bromine；
The R4Selected from hydrogen, hydroxyl or methoxyl group；
The R5Selected from hydrogen or bromine；
The R6Selected from hydroxyl, methoxyl group, hydrogen, amino, fluorine or chlorine.
Preferably,
The R1Selected from methylene-dioxy substituted-phenyl, methylol substituted furan base, thienyl or pyridine radicals；
The R2Selected from hydrogen or hydroxyl；
The R3Selected from hydrogen or bromine；
The R4Selected from hydroxyl or methoxyl group；
The R5Selected from hydrogen or bromine；
The R6Selected from methoxyl group, amino, fluorine or chlorine.
Preferably, the 3- substitutions propyl- 2- alkene -1- ketone compounds are：
Compound (1)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1-
Ketone；
Compound (2)：(E) -1- (2- hydroxyl -4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (3)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone；
Compound (4)：(E) -1- (the bromo- 2,4- dihydroxy phenyls of 3,5- bis-) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (5)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (3,4- methylenedioxyphenyls) propyl- 2- alkene -
1- ketone；
Compound (6)：(E) -1- (2- hydroxy phenyls) -3- (4- bromophenyls) propyl- 2- alkene -1- ketone；
Compound (7)：(E) -1- (2- hydroxy phenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (8)：(E) -1- (2- fluorophenyls) -3- (4- dimethylamino phenyls) propyl- 2- alkene -1- ketone；
Compound (9)：(E) -1- (2,4- dihydroxy phenyls) -3- (4- hydroxy phenyls) propyl- 2- alkene -1- ketone；
Compound (10)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone；
Compound (11)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone；
Compound (12)：(E) -1- (2- hydroxy phenyls) -3- (4- fluorophenyls) propyl- 2- alkene -1- ketone；
Compound (13)：(E) -1- (2- hydroxy phenyls) -3- (3,4- methylenedioxyphenyl) propyl- 2- alkene -1- ketone；
Compound (14)：(E) -1- (2- chlorphenyls) -3- (3,4- methylenedioxyphenyl) propyl- 2- alkene -1- ketone；Or
Compound (15)：(E) -1- (2- aminophenyls) -3- (3,4- Dimethoxyphenyl) propyl- 2- alkene -1- ketone.
Preferably, the 3- substitutions propyl- 2- alkene -1- ketone compounds are：
Compound (1)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1-
Ketone；
Compound (2)：(E) -1- (2- hydroxyl -4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (3)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone；
Compound (4)：(E) -1- (the bromo- 2,4- dihydroxy phenyls of 3,5- bis-) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (7)：(E) -1- (2- hydroxy phenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (8)：(E) -1- (2- fluorophenyls) -3- (4- dimethylamino phenyls) propyl- 2- alkene -1- ketone；
Compound (9)：(E) -1- (2,4- dihydroxy phenyls) -3- (4- hydroxy phenyls) propyl- 2- alkene -1- ketone；
Compound (10)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone；
Compound (11)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone.
Preferably, the azole antifungals are selected from：Fluconazole, ketoconazole, sulconazole, Itraconazole or Wo Likang
One or more in azoles.
Preferably, the azole antifungals are Fluconazole.
The present invention also provides a kind of pharmaceutical composition of overriding resistance fungi, and the one or more comprising therapeutically effective amount are as above
Any described pharmaceutical composition and pharmaceutically acceptable excipient, carrier or dilute with synergy overriding resistance fungi
Release agent.
To realize above-mentioned second purpose, the present invention is adopted the technical scheme that：
A kind of 3- replaces propyl- 2- alkene -1- ketone overriding resistance fungal compounds, it is characterised in that described 3- substitution propyl-s 2-
Alkene -1- ketone overriding resistance fungal compounds are：
Compound (1)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1-
Ketone；
Compound (2)：(E) -1- (2- hydroxyl -4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (3)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone；
Compound (10)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone；
Compound (11)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone.
To realize above-mentioned 3rd purpose, the present invention is adopted the technical scheme that：
As above any 3- substitution propyl- 2- alkene -1- ketone compounds are preparing overriding resistance fungi medicine with nitrogen azole drug
Application in thing.
Preferably, the azole antifungals are selected from：Fluconazole, ketoconazole, sulconazole, Itraconazole or Wo Likang
One or more in azoles.
Preferably, the azole antifungals are Fluconazole.
The invention has the advantages that：
There are the 3- substitution propyl- 2- alkene -1- ketone compounds of general formula I the invention discloses a class and its resist preparing
Application in fungi and collaboration antifungal drug, result of the test shows that such compound can be common with azole antifungals
Use, sensitiveness of the drug-fast bacteria to nitrogen azole drug can be improved, realize that reversing drug resistance is acted on, produce collaboration antifungic action.
Embodiment
The invention will be further elucidated with reference to specific embodiments.It should be understood that these embodiments are merely to illustrate this hair
Bright rather than limitation the scope of the present invention.In addition, it is to be understood that after present disclosure has been read, art technology
Personnel can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Fixed scope.
In some specific embodiment, formula (I) compound synthesizes salt according to pharmaceutically acceptable acid, and (one kind pharmaceutically may be used
The salt of receiving) prepare, by free alkali form and the pharmaceutically acceptable inorganic or organic acid reaction of compound, including but
It is not limited to inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.；Organic acid such as acetic acid, propionic acid, caproic acid, ring
Amyl group propionic acid, glycolic, pyruvic acid, lactic acid, malonic acid, succinic acid, hydroxysuccinic acid, maleic acid, fumaric acid, to toluene
Sulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4- oxybenzenes formoxyl) benzoic acid, cinnamic acid, mandelic acid, fragrant sulphur
Acid, methanesulfonic acid, ethyl sulfonic acid, 12- ethionic acids, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, 2- naphthalene sulfonic acids, 4- methyl bicycles-[2.2.2]
Oct-2-ene -1- carboxylic acids, glucoheptonic acid, 4,4'- di-2-ethylhexylphosphine oxides-(3- hydroxyl -2- alkene -1- carboxylic acids), 3- phenylpropionic acids, trimethyl
Acetic acid, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, carbonaphthoic acid, salicylic acid, stearic acid and hexadiene two
Acid.
" pharmaceutically acceptable " herein refers to a kind of material, such as carrier or dilution, will not make compound bioactivity or
Property disappears, and relative nontoxic e.g., gives individual something, will not cause undesired biotic influence or in harmful manner
Interacted with any component that it contains.
Term " pharmaceutically acceptable salt " refers to a kind of existence form of compound, and the form will not cause organic to being administered
The important stimulation of body, and the bioactivity and property of compound will not be made to disappear.It is pharmaceutically acceptable in some specific aspects
Salt be to be obtained by formula (I) compound and acid reaction, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid,
P-methyl benzenesulfonic acid, salicylic acid etc..Pharmaceutically acceptable salt also can react forming salt, such as ammonium salt by formula (I) compound and alkali；
Alkali metal salt, such as sodium or sylvite；Alkali salt, such as calcium or magnesium salts；Organic alkali salt, such as dicyclohexylamine, N- methyl Ds-glucose
Amine, trihydroxymethylaminomethane；Amino-acid salt, such as arginine, lysine etc..
In some specific embodiments, formula (I) compound is prepared as prodrug." prodrug " refers to that a reagent turns in vivo
Turn to prototype medicine.Prodrug is typically useful, because under certain conditions, they may administration easier than prototype medicine.They can
With, for example, be administered orally and be bioavailable, but prototype medicine is not all right.Prodrug can also improve prototype on pharmaceutical composition
The dissolubility of medicine.For example, not limiting, prodrug is formula (I) compound, in the case where water solubility is unfavorable for by cell membrane,
Prodrug makes to be easier by cell membrane as ester administration, is then hydrolyzed into carboxylic acid by metabolism, active entities are once entered carefully
It is water-soluble just highly beneficial in born of the same parents.Further example, prodrug can be that a small peptide (polyaminoacid) is connected to an acid
Group, peptide shows active fragment after being metabolized.
Prodrug is typically the precursor of medicine, and ensuing administration and absorption are converted into active material, or pass through some processes
It is changed into the stronger species of activity, is such as converted by metabolic pathway.The chemical group that some prodrugs have make its activity it is relatively low and/or
Contrast the dissolubility or some other properties of prototype medicine.Once the chemical group of prodrug is removed and/or it is modified, lived
Property medicine.Prodrug be typically it is useful, in some cases, their administrations easier than prototype medicine.In certain specific embodiment, this
Prodrug compound described in text is administered orally and can be with biological utilisation, but prototype medicine is not all right.Moreover, in some specific implementations
In example, prodrug as described herein can also improve the dissolubility of prototype medicine on pharmaceutical composition.
Term
If without other explanation, for the term in the present patent application, including specification and claims, definition is such as
Under.It has to be noticed that in the specification and the appended claims, if nothing is clearly dictated otherwise in text, singulative " one
It is individual " include plural references.If without other explanation, using mass spectrum, nuclear-magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA skill
The conventional method of art and pharmacology.In this application, if without other explanation, using "or" or " and " refer to "and/or".
Term " halogen " or " halide " refer to fluorine, chlorine, bromine or iodine.
Term " key " or " singly-bound " refer between two atoms or between two segments (when the atom connected by key is considered as
During a part for big structure) chemical bond.On the one hand, when group as described herein is a key, lack and refer to group, it is allowed to
A key is formed between remaining determination group.
Term " yuan of rings " includes any cyclic structure.Term " member " means the quantity for the skeletal atom for representing to constitute ring.This
Sample, e.g., cyclohexyl, pyridine radicals, pyranose etc. is hexatomic ring, cyclopenta, pyrrole radicals, and furyl and thienyl are five-membered rings.
In some specific embodiment, the compound exists with solvation form, pharmaceutically acceptable solvent such as water,
Ethanol etc..In other specific embodiments, the compound exists with nonsolvated forms.
Specific pharmacy and medical terminology
Term " acceptable ", as used herein, refers to a prescription component or active component is good for general treatment target
Health does not have undue adverse effect.
Term " fungi (fungus；Fungi (multiple) ", as used herein, refers to that a class is unicellular or many cells microorganism.No
Containing chlorophyll, hard polysaccharide cell membrane can be formed greatly.Belong to eucaryote, including Eumycota and slime mould door etc..
Terms used herein " antifungal drug ", which refers to, can suppress or kill the medicine of fungi.Including traditional antimycotic external application
Medicine antibiotic and synthetic drug.Antimycotic externally applied drug includes but is not limited to salicylic acid, resorcinol, idodine, Sulfur etc.；Antibiotic includes
But it is not limited to griseofulvin, nystatin, amphotericin B etc.；Synthetic drug include but is not limited to imidazoles, Flucytosine,
Propylene amine derivative etc..Preferred imidazoles, including but not limited to Fluconazole, clotrimazole, econazole, miaow health in the present invention
Azoles, sulconazole, ketoconazole etc..
Term " drug resistance fungal ", as used herein, refers to fungi because of its intrinsic medicine resistance ability, natural selection or medicament selection
Strengthen the medicine resistance ability of fungi under effect, Susceptibility to antibiotics is declined, show as with drop Dilution most
Low Mlc (MIC80) ＞ 64 μ g/ml bacterial strain, belong to height drug-fast bacteria；MIC80It is worth the bacterial strain between 16-32 μ g/ml, category
In intermediary's resistance；MIC80Bacterial strain of the value less than 8 μ g/ml, belongs to sensitive strain.
Term " overriding resistance fungi " as used herein, refers to the effect for suppressing or killing drug resistance fungal.
Term " administering drug combinations " or its similar terms, as used herein, refer to several selected medicines to a disease
People's medication, with identical or different administering mode in identical or different time administration.
Term " collaboration ", " synergy " or " synergy ", as used herein, refers to there is suppression originally or kill fungi
Medicine can strengthen the effect of original Drug inhibition or killing fungi ability to function, apparent upper performance when sharing another medicine
Decline for the MIC value of original medicine.
Term " subject " or " patient " include mammal and nonmammalian.Mammal includes but is not limited to, and feeds
Newborn class：People, non-human primates such as orangutan, ape and monkey class；Agricultural animal such as ox, horse, goat, sheep, pig；Domestic animal such as rabbit, dog；It is real
Testing animal includes rodent, such as rat, mouse and cavy.Non-mammalian animal includes but is not limited to, bird, fish etc..It is excellent one
Select in example, selected mammal is people.
Term " treatment ", " therapeutic process " or " therapy " as used herein, including relaxes, suppresses or improved the symptom of disease
Or situation；Suppress the generation of complication；Improve or prevent potential metabolic syndrome；Suppress the generation of disease or symptom, such as control
The development of disease or situation；Mitigate disease or symptom；Disease or symptom is set to decline；Mitigate concurrent as caused by disease or symptom
Disease, or prevention or the treatment sign as caused by disease or symptom.
As used herein, a certain compound or pharmaceutical composition, after administration, can obtain a certain disease, symptom or situation
To improvement, espespecially its severity is improved, delayed onset, slows down disease progression, or reduce the state of an illness duration.No matter fix
Administration or interim administration, continued administration or interrupted continuous administration, can be attributed to or the situation relevant with administration.
Therapeutical uses
Compound of formula I can cooperate with antifungal drug to resist drug resistance fungal.On the other hand, compound of formula I is used for treatment very
Disease caused by bacterium infection.On the one hand, one or more compound of formula I are further provided herein preparing treatment fungi
Purposes in the medicine or method of caused disease.On the other hand, one or more Formulas I chemical combination are further provided herein
Purposes of the thing in the medicine for preparing overriding resistance fungi.
On the one hand, fungus-caused disease includes but is not limited to the systematicness such as various fungoid encephalitis, fungal septicemia
The shallow fungal infection such as fungal infection and favus of the scalp, skin tinea, epifolliculitis, meningitis.
On the other hand, formula (I) compound or its pharmaceutically acceptable salt described in being related to are used for preparation of preparation, these systems
Agent includes compound of formula I and one or more antifungal drugs, available for the work for improving antifungal drug resistance drug resistance fungal
With.
Compound is used for preparation of preparation in the present invention, including：Directly using compound or times obtained in preparation process
One composition is used；For in-vitro screening experiment in, for screening verification be used for resist drug resistance fungal described above species or
It is degree.
Method of administration：
Suitable method of administration includes but is not limited to, oral, intravenous injection, rectum, aerosol, parenterai administration, eye
Administration, pulmonary administration, percutaneous dosing, vagina administration, duct administration, nasal-cavity administration and local administration.In addition, theory only for example
It is bright, Parenteral administration, including intramuscular injection, hypodermic injection, intravenous injection, intramedullary injection, intraventricular, intraperitoneal injection, pouring
Injection and nasal injection in hand shaft.
On the one hand, compound administering mode described herein is local rather than systemic administering mode, for example,
Compound injection is directly generally used for durative action preparation or sustained release preparation to organ.In particular specific embodiment, long-acting system
Agent is by drug delivery implant (such as subcutaneously or intramuscularly) or passes through intramuscular injection.In addition, in another materialization embodiment, medicine leads to
Targeted drug delivery system is crossed to be administered.For example, the liposome wrapped up by organ specific antibody.In this specific embodiment
In, the liposome is by the guiding certain organs of selectivity and absorbs.In other embodiments, the compound in the present invention is with fast
Quick-release is put, and sustained release or the approach discharged by intermediate are administered.
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 all percentage, ratio, ratio or number is pressed
Weight meter.
The unit in percent weight in volume in the present invention is well-known to those skilled in the art, for example, refer to
The weight of solute in 100 milliliters of solution.
Unless otherwise defined, all specialties used in text known to scientific words and one skilled in the art with anticipating
Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Wen Zhong
Described preferable implementation only presents a demonstration with material to be used.
Shown the compounds of this invention 9 can from but be not limited to from lark waffle, the company such as strict ancient cooking vessel biotechnology buys, its
Remaining compound is that this laboratory synthesizes compound.
Embodiment 1 (E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone
Preparation (1)
Take 2- hydroxyl -6- methoxyl group benzoylformaldoxime 500mg (3.0mmol), 5-HMF 600mg
(3.6mmol) is added in 15ml ethanol, then adds the 30%NaOH aqueous solution, at room temperature after 24~48h of stirring reaction,
TLC, after reaction substantially completely, reaction solution is poured into frozen water, is filtered, and solid is washed with water 3 times, post separation is dodged after drying, is obtained
To compound (1), 312mg, yield is 38%.
1H-NMR:3.95(3H,s,-OCH3),4.69(2H,s,-CH2-)；6.43(2H,m,Ar-H)；6.60(1H,dd,J1
=8.4Hz, J2=0.9Hz, Ar-H)；6.66 (1H, d, J=3.3Hz, Ar-H)；7.38(2H,m,Ar-H)；7.57(1H,d,J
=15.3Hz, α-H)；7.74 (1H, d, J=15.3Hz, β-H)；13.18(1H,s,-OH).M+=275.2.
The preparation (2) of embodiment 2 (E) -1- (2- hydroxyl -4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone
Using Paeonolum and benzaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR:3.87(3H,s,-OCH3), 6.49 (1H, s), 6.52 (1H, d, J=2.4, Ar-H), 7.43 (3H, m,
Ar-H), 7.67 (1H, d, J=15.3Hz, Ar-H), 7.65 (2H, m, Ar-H), 7.84 (1H, d, J=9.3Hz), 7.90 (1H,
D, J=15.3Hz), 13.43 (1H, s ,-OH) .M+=255.2.
The preparation (3) of embodiment 3 (E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone
Using 2- hydroxyl -6- methoxyacetophenones and thiophenecarboxaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR:3.07(3H,s,-OCH3),6.43(1H,dd,J1=1.2, J2=8.4, Ar-H), 6.61 (1H, dd, J1
=0.9, J2=8.1, Ar-H), 7.10 (1H, m, Ar-H), 7.35 (2H, m, Ar-H), 7.41 (1H, m, Ar-H), 7.71 (1H,
D, J=15.3), 7.75 (1H, d, J=15.3), 13.18 (1H, s ,-OH).M+=261.2.
The preparation (4) of embodiment 4 (E) -1- (the bromo- 2,4- dihydroxy phenyls of 3,5- bis-) -3- phenyl propyl- 2- alkene -1- ketone
It is that raw material reacts with benzaldehyde with 2,4- dihydroxy -3,5- dibromos acetophenone, the synthetic method of reference compound 1.
1H-NMR:6.53 (1H, s ,-OH), 7.46 (1H, s), 7.47 (2H, m), 7.51 (2H, d, J=15.6Hz), 7.69
(2H, m), 7.98 (2H, d, J=15.6Hz), 14.10 (1H, s ,-OH).M+=398.9
Embodiment 5 (E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (3,4- methylenedioxyphenyls) propyl- 2- alkene -1- ketone
Preparation (5)
Using 2- hydroxyl -6- methoxyacetophenones and 3,4-methylenedioxybenzaldehyde as raw material, the synthesis of reference compound 1
Method.
1H-NMR:3.96(3H,s,-OCH3),6.04(2H,s,-OCH2), O- 6.43 (1H, d, J=8.4Hz), 6.62
(1H, d, J=8.4Hz), 6.85 (1H, d, J=7.8Hz), 7.12 (1H, d, J=10.2Hz), 7.34 (1H, d, J=8.4Hz),
7.71 (1H, d, J=15.2Hz), 7.78 (1H, d, J=15.2Hz), 13.18 (H, s ,-OH).M+=299.3.
The preparation (6) of embodiment 6 (E) -1- (2- hydroxy phenyls) -3- (4- bromophenyls) propyl- 2- alkene -1- ketone
Using 2- hydroxy acetophenones and p-bromobenzaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR:6.95 (1H, t, J=7.8, Ar-H), 7.04 (1H, d, J=7.8, Ar-H), 7.51 (1H, t, J=
7.8, Ar-H), 7.53 (2H, d, J=8.4, Ar-H), 7.58 (2H, d, J=8.4, Ar-H), 7.65 (1H, d, J=15.6, Ar-
), H 7.85 (1H, d, J=15.6, Ar-H), 7.91 (1H, dd, J1=7.8, J2=1.2, Ar-H), 12.73 (1H, s ,-OH) .M+
=317.18.
The preparation (7) of embodiment 7 (E) -1- (2- hydroxy phenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone
Using 2- hydroxy acetophenones and hydroxymethyl furaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR:4.72(2H,s,-CH2-)；6.46 (1H, d, J=3.3Hz, Ar-H)；6.74 (1H, d, J=3.3Hz,
Ar-H)；6.96(1H,q,J1=8.1Hz, J2=1.2Hz, Ar-H)；7.03(1H,dd,J1=8.1Hz, J2=1.2Hz, Ar-
H)；7.50(1H,t,J1=8.1Hz, J2=1.2Hz, Ar-H)；7.56 (1H, d, J=15.0Hz, Ar-H)；7.66 (1H, d, J=
15.0Hz,Ar-H)；7.95(1H,dd,J1=8.1Hz, J2=1.2Hz, Ar-H)；12.92(1H,s,-OH).M+=244.8.
The preparation (8) of embodiment 8 (E) -1- (2- fluorophenyls) -3- (4- dimethylamino phenyls) propyl- 2- alkene -1- ketone
Using 2- fluoro acetophenones and paradime thylaminobenzaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR:3.05(6H,s,-N(CH3) 2), 6.68 (2H, d, J=9.0, Ar-H), 7.15 (1H, d, J=15.6,
), Ar-H 7.18 (2H, m, Ar-H), 7.47 (1H, m, Ar-H), 7.52 (2H, d, J=9.0, Ar-H), 7.70 (1H, d, J=
15.6,Ar-H,7.78(1H,m,Ar-H)。M+=270.7
The preparation of embodiment 9 (E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone
(10)
Using 2- hydroxyl -6- methoxyacetophenones and furtural as raw material, the synthetic method of reference compound 1.
1H-NMR:3.95(3H,s,-OCH3), 6.42 (1H, d, J=8.1, Ar-H), 6.52 (1H, m, Ar-H), 6.20
(1H,dd,J1=0.9, J2=8.4, Ar-H), 6.71 (1H, d, J=3.6, Ar-H), 7.36 (1H, m, Ar-H), 7.53 (1H,
S), (1H, the s ,-OH) .M of 7.60 (1H, d, J=15.3Hz), 7.76 (1H, d, J=15.3Hz), 13.22+=245.3.
The preparation of embodiment 10 (E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone
(11)
Using 2- hydroxyl -6- methoxyacetophenones and 3- pyridine carboxaldehydes as raw material, the synthetic method of reference compound 1.
H-NMR:3.96(3H,s,-OCH3), 6.44 (1H, dd, J=8.4, Ar-H), 6.63 (1H, dd, J1=0.9, J2=
8.4, Ar-H), 7.36 (1H, m, Ar-H), 7.40 (1H, d, J=8.4, Ar-H), 7.76 (1H, d, J=15.3Hz, Ar-H),
7.89 (1H, m, Ar-H), 7.90 (1H, d, J=15.3Hz), 7.76 (1H, d, J=15.2Hz), 8.62 (1H, d, J=3.6Hz,
Ar-H),8.87(1H,s,Ar-H),13.02(1H,s,-OH).[M+H]+=256.2.
The preparation (12) of embodiment 11 (E) -1- (2- hydroxy phenyls) -3- (4- fluorophenyls) propyl- 2- alkene -1- ketone
Using 2- hydroxy-acetophenones and 4- fluorine formaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR(600MHz,CDCl3,δ,ppm):6.95 (1H, t, J=8.4, Ar-H), 7.03 (1H, dd, J1=8.4,
J2=1.2, Ar-H), 7.13 (2H, d, J=8.4, Ar-H), 7.51 (1H, t, J=8.4, Ar-H), 7.58 (1H, d, J=
15.6, Ar-H), 7.66 (2H, d, J=8.4, H-2,6), 7.89 (1H, d, J=15.6, Ar-H), 7.91 (1H, dd, J=8.4,
J=1.2, H-6), 12.77 (1H, s ,-OH) .ESI-MS m/z 243.58 [M+H]+。
The preparation of embodiment 12 (E) -1- (2- hydroxy phenyls) -3- (3,4- methylenedioxyphenyl) propyl- 2- alkene -1- ketone
(13)
Using 2- hydroxy-acetophenones and 3,4-methylenedioxybenzaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR(300MHz,CDCl3,ppm,J/Hz):6.06(2H,s,-OCH2), O- 6.87 (1H, d, J=8.1, Ar-
), H 6.95 (1H, t, J=8.1, Ar-H), 7.03 (1H, dd, J1=8.1, J2=0.9, Ar-H H-3), 7.17 (1H, dd, J1=
8.1,J2=1.5, Ar-H), 7.20 (1H, d, J=1.5, Ar-H), 7.50 (1H, d, J=15.3, Ar-H), 7.51 (1H, t, J
=8.1, Ar-H), 7.87 (1H, d, J=15.3, Ar-H), 7.92 (1H, dd, J1=8.1, J2=1.5, Ar-H), 12.92 (1H,
s,-OH).ESI-MS m/z 269.56[M+H]+。
The preparation (14) of embodiment 13 (E) -1- (2- chlorphenyls) -3- (3,4- methylenedioxyphenyl) propyl- 2- alkene -1- ketone
Using 2- chloro-acetophenones and 3,4-methylenedioxybenzaldehyde as raw material, the synthetic method of reference compound 1.
1H-NMR(600MHz,CDCl3,δ,ppm,J/Hz):6.02(2H,s,-OCH2O-), 6.82 (1H, d, J=7.8,
), Ar-H 6.96 (1H, d, J=15.6, Ar-H), 7.02 (1H, dd, J1=7.8, J2=1.2, Ar-H), 7.09 (1H, d, J=
1.2, Ar-H), 7.35 (1H, t, J=7.8, Ar-H), 7.37 (1H, d, J=15.6, Ar-H), 7.40 (1H, t, J=7.8, Ar-
), H 7.46 (2H, d, J=7.8, Ar-H) .ESI-MS m/z 287.56 [M+H]+。
The preparation (15) of embodiment 14 (E) -1- (2- aminophenyls) -3- (3,4- Dimethoxyphenyl) propyl- 2- alkene -1- ketone
Using o-aminoacetophenone and Veratraldehyde as raw material, the synthetic method of reference compound 1.
H-NMR(300MHz,CDCl3,δ,ppm,J/Hz):3.92(3H,s,-OCH3),3.95(3H,s,-OCH3),6.33
(2H,br.s,-NH2), 6.70 (2H, m, Ar-H), 6.89 (1H, d, J=8.1, Ar-H), 7.14 (1H, d, J=1.8, Ar-H),
7.21(1H,dd,J1=8.1, J2=1.8, Ar-H), 7.28 (1H, m, Ar-H), 7.48 (1H, d, J=15.6, Ar-H), 7.70
(1H, d, J=15.6, Ar-H), 7.87 (1H, dd, J1=8.1, J2=1.2, Ar-H) .ESI-MS m/z 282.5 [M-H]–。
Embodiment 15：It is true using checkerboard type dilution method In vitro chemo-drug sensitive test test compound of formula I collaboration Fluconazole overriding resistance
Bacterium acts on
First, make using checkerboard type dilution method In vitro chemo-drug sensitive test test the compounds of this invention collaboration Fluconazole overriding resistance fungi
With
Strain used is to be clinically separated the obtained bacterium of resistance Candida albicans 103 in this implementation.It is all experiment with bacterium in
Husky fort glucose agar medium (SDA) draws plate activation, after 30 DEG C are cultivated 2 weeks, and picking monoclonal draws plate activation again respectively,
Take second of gained monoclonal to put SDA inclined-planes, preserved after being cultivated 2 weeks in 30 DEG C at 4 DEG C.Nutrient solution is the liquid of RPMI 1640
Nutrient solution, carries out culture pre-treatment according to standard method.Fluconazole as antifungal medicine parenteral solution is limited by Dalian Pfizer medicine company
Company provides；Dimethyl sulfoxide (DMSO) is purchased in Solution on Chemical Reagents in Shanghai company of Chinese Medicine group.Instrument used has
Multiskan MK3 type enzyme mark detectors (Finland Labsystems)；Water isolation type electro-heating standing-temperature cultivator (Shanghai leap Medical treatment device
Tool factory)；MJX type intelligent bacterium enzymes incubator (Ningbo south of the River instrument plant)；(the Shanghai leap medical treatment of THZ-82A Desk type constant-temperatureoscillator oscillators
Apparatus factory)；SW-CT-IF types superpurgative working table (SuZhou Antai Air Tech Co., Ltd.)；Inverted microscope (Amersham
Pharmacia)；Micro sample adding appliance (Finland Finnpette)；96 porocyte culture plates (Nunclon companies of Denmark).
1 experimental procedure
The configuration of 1.1 fungi suspensions
Before experiment, with inoculation circle from 4 DEG C preservation SDA culture mediums on the bacterium of picking resistance Candida albicans 103,100 bacterium,
J28 bacterium, 953 bacterium are a small amount of, are seeded to 1ml YEPD nutrient solutions, and in 30 DEG C, 200rpm shaken cultivations activate 16h, are in fungi
Later stage exponential phase of growth.Take the bacterium solution into 1ml YEPD nutrient solutions, activate again in aforementioned manners, after 16h, use hemocytometer
Number plate is counted, and bacterial concentration is adjusted to 1 × 10 with RPMI 1640 culture mediums3-5×103CFU/ml。
The preparation of 1.2 drug sensitive reaction plates
Sterile 96 orifice plate is taken, adds the μ l of 1640 fluid nutrient mediums of RPMI 100 to make blank control in every No. 1 hole of row；3-12 holes
Respectively plus Fresh the μ l of bacterium solution 100；No. 2 holes add the μ l of bacterium solution 160 and the μ l of test-compound solution 40；No. 12 holes not drug containing,
Only the μ l of bacterium solution 100 are added to make Growth positive control.2-11 holes carry out doubling dilution, and the final drug concentration for making each hole is respectively
64th, DMSO contents are below 1% in 32,16,8,4,2,1,0.5,0.25 and 0.125 μ g/ml, each hole.Drug sensitive plate is prepared every time
While prepare one piece of Quality Control bacterium drug sensitive plate (Quality Control bacterium：According to the suggestion of NCCLS M27-A schemes, we are using near smooth
Candida albicans ATCC18062 is Quality Control bacterium, and one piece of Quality Control bacterium drug sensitive plate, its MIC references are prepared while drug sensitive plate is prepared every time
Value is as follows：Fluconazole (FCZ)：MIC80Value 0.25-1.0 μ g/ml；AmB：MIC value 0.5-2.0 μ g/ml.Experiment is with this bacterial strain every time
For reference strain, only as its MIC80Think test operation accurately and reliably when above range, just in value circle.As while test strain
Well-grown, then it is believed that success of the test, is as a result subjected to.Each drug sensitive plate is in 30 DEG C of insulating box cultures.
The selection of 1.3 In vitro chemo-drug sensitive test methods
Checkerboard type micro-dilution method is selected to cooperate with the external overriding resistance fungi activity of Fluconazole to carry out the compound of the present invention
Evaluate.Checkerboard type micro-dilution method is the extension of In vitro chemo-drug sensitive test, that is, the two kinds of medicines shared on 96 orifice plates with two-dimentional chess
Vertical (A to H) horizontal (2 to 11) two direction of disk carries out two times of doubling dilution respectively.Such as compound 1 and a kind of antifungal drug
After Fluconazole is shared so that the μ g/ml of final concentration of 128,64,32,16,8,4,2,1,0.5,0.25 and 0.125 of Fluconazole, change
Final concentration of 64,32,16,8,4,2,1 μ g/ml of compound 1.Agents useful for same, medicine, laboratory operating procedures are tested with above-mentioned external
Drug sensitive experiment.
1.4 evaluation criterion
Part Mlc index (fractional inhibitory concentration index, FICI) is to comment
The major parameter of two medicine interaction modes of valency drug combination.Mlc fraction (FIC), is respectively that each is medication combined
When antibacterial required minimum inhibitory concentration (MIC) with it is alone when MIC ratio and FIC indexes (FICI) are then equal to two kinds of medicine FIC
Sum.Prescribed a time limit when MIC value higher than detection highest and twice of value of concentration is limited to calculate FICI with highest.Many document reports are worked as
The interaction of two medicines is defined as synergy during FICI≤0.5, and FIC indexes are smaller, acts synergistically stronger；0.5<FICI≤
The interaction of two medicines is defined as summation action when 1；1<It is unrelated effect during FICI≤4；Work as FICI>Two medicines produce antagonism when 4
Effect.The newest standards that this experiment is used from current foreign periodical：As FICI≤0.5, the interaction of two medicines is determined
For synergy；0.5<It is unrelated effect during FICI≤4；Work as FICI>Two medicines produce antagonism when 4.
1.5 test result
1 is the results are shown in Table, be can see from table, compound of the invention produces the Candida albicans of resistance to Fluconazole
103 bacterium have obvious synergy.
The compounds of this invention structure of table 1 and its overriding resistance fungi FICI values are cooperateed with Fluconazole
[a]MIC80It is compound and the μ g mL of Fluconazole 8.0 in Formulas I to be worth [μ g/mL]-1The MIC of drug combination80Value.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (8)
1. it is a kind of have synergy overriding resistance fungi pharmaceutical composition, it is characterised in that including azole antifungals,
3- replaces propyl- 2- alkene -1- ketone compounds or its pharmaceutically acceptable salt, described 3- substitution propyl- 2- alkene -1- ketones
The structure of compound is shown in formula I；
The R1Selected from phenyl, hydroxyl substituted-phenyl, methoxy substitution phenyl, dimethylamino substituted-phenyl, halogenophenyl, furans
Base, methylene-dioxy substituted-phenyl, methylol substituted furan base, thienyl or pyridine radicals；
The R2Selected from hydrogen, hydroxyl, methoxyl group, amino, chlorine or fluorine；
The R3Selected from hydrogen or bromine；
The R4Selected from hydrogen, hydroxyl or methoxyl group；
The R5Selected from hydrogen or bromine；
The R6Selected from hydroxyl, methoxyl group, hydrogen, amino or halogen；
The azole antifungals are Fluconazole.
2. pharmaceutical composition according to claim 1, it is characterised in that
The R1Selected from phenyl, hydroxyl substituted-phenyl, methoxy substitution phenyl, dimethylamino substituted-phenyl, halogenophenyl, furans
Base, methylene-dioxy substituted-phenyl, methylol substituted furan base, thienyl or pyridine radicals；
The R2Selected from hydrogen or hydroxyl；
The R3Selected from hydrogen or bromine；
The R4Selected from hydrogen, hydroxyl or methoxyl group；
The R5Selected from hydrogen or bromine；
The R6Selected from hydroxyl, methoxyl group, hydrogen, amino, fluorine or chlorine.
3. pharmaceutical composition according to claim 1, it is characterised in that
The R1Selected from methylene-dioxy substituted-phenyl, methylol substituted furan base, thienyl or pyridine radicals；
The R2Selected from hydrogen or hydroxyl；
The R3Selected from hydrogen or bromine；
The R4Selected from hydroxyl or methoxyl group；
The R5Selected from hydrogen or bromine；
The R6Selected from methoxyl group, amino, fluorine or chlorine.
4. pharmaceutical composition according to claim 1, it is characterised in that described 3- substitution propyl- 2- alkene -1- ketone chemical combination
Thing is：
Compound (1)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (2)：(E) -1- (2- hydroxyl -4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (3)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone；
Compound (4)：(E) -1- (the bromo- 2,4- dihydroxy phenyls of 3,5- bis-) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (5)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (3,4- methylenedioxyphenyls) propyl- 2- alkene -1- ketone；
Compound (6)：(E) -1- (2- hydroxy phenyls) -3- (4- bromophenyls) propyl- 2- alkene -1- ketone；
Compound (7)：(E) -1- (2- hydroxy phenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (8)：(E) -1- (2- fluorophenyls) -3- (4- dimethylamino phenyls) propyl- 2- alkene -1- ketone；
Compound (9)：(E) -1- (2,4- dihydroxy phenyls) -3- (4- hydroxy phenyls) propyl- 2- alkene -1- ketone；
Compound (10)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone；
Compound (11)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone；
Compound (12)：(E) -1- (2- hydroxy phenyls) -3- (4- fluorophenyls) propyl- 2- alkene -1- ketone；
Compound (13)：(E) -1- (2- hydroxy phenyls) -3- (3,4- methylenedioxyphenyl) propyl- 2- alkene -1- ketone；
Compound (14)：(E) -1- (2- chlorphenyls) -3- (3,4- methylenedioxyphenyl) propyl- 2- alkene -1- ketone；Or
Compound (15)：(E) -1- (2- aminophenyls) -3- (3,4- Dimethoxyphenyl) propyl- 2- alkene -1- ketone.
5. pharmaceutical composition according to claim 1, it is characterised in that described 3- substitution propyl- 2- alkene -1- ketone chemical combination
Thing is：
Compound (1)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (2)：(E) -1- (2- hydroxyl -4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (3)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone；
Compound (4)：(E) -1- (the bromo- 2,4- dihydroxy phenyls of 3,5- bis-) -3- phenyl propyl- 2- alkene -1- ketone；
Compound (5)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (3,4- methylenedioxyphenyls) propyl- 2- alkene -1- ketone；
Compound (6)：(E) -1- (2- hydroxy phenyls) -3- (4- bromophenyls) propyl- 2- alkene -1- ketone；
Compound (7)：(E) -1- (2- hydroxy phenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (8)：(E) -1- (2- fluorophenyls) -3- (4- dimethylamino phenyls) propyl- 2- alkene -1- ketone；
Compound (9)：(E) -1- (2,4- dihydroxy phenyls) -3- (4- hydroxy phenyls) propyl- 2- alkene -1- ketone；
Compound (10)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone；
Compound (11)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone.
6. a kind of pharmaceutical composition of overriding resistance fungi, it is characterised in that one or more rights comprising therapeutically effective amount will
Ask any described pharmaceutical compositions of 1-5 and its pharmaceutically acceptable excipient, carrier or diluent.
7. any described 3- substitution propyl- 2- alkene -1- ketone compounds and nitrogen azole drug are anti-resistance in preparation in claim 1-5
Application in medicine fungi-medicine；The nitrogen azole drug is Fluconazole.
8. a kind of 3- replaces propyl- 2- alkene -1- ketone overriding resistance fungal compounds, it is characterised in that described 3- substitution propyl-s 2-
Alkene -1- ketone overriding resistance fungal compounds are：
Compound (1)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (5- hydroxymethylfurans -2- bases) propyl- 2- alkene -1- ketone；
Compound (3)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (thiophene -2- bases) propyl- 2- alkene -1- ketone；
Compound (10)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (furans -2- bases) propyl- 2- alkene -1- ketone；
Compound (11)：(E) -1- (2- hydroxyl -6- methoxyphenyls) -3- (pyridin-3-yl) propyl- 2- alkene -1- ketone.
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