CN105061387A - Diaryl ether fused ring compounds, preparation methods and applications - Google Patents
Diaryl ether fused ring compounds, preparation methods and applications Download PDFInfo
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- CN105061387A CN105061387A CN201510423895.4A CN201510423895A CN105061387A CN 105061387 A CN105061387 A CN 105061387A CN 201510423895 A CN201510423895 A CN 201510423895A CN 105061387 A CN105061387 A CN 105061387A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/14—[b,f]-condensed
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
The invention discloses diaryl ether fused ring compounds, preparation methods and applications. The diaryl ether fused ring compounds are brand-new diaryl ether fused ring structural compounds with a structure represented in a formula I, and have better activity resisting to MTB (mycobacterium tuberculosis) with multi-drug resistance. At the cellular level, for part of embodiments, the inhibitory activity IC50 on MTB is smaller than 10 mu g/mL.
Description
Technical field
The invention belongs to pharmaceutical field, particularly, the present invention relates to a kind of preparation and application thereof of diaryl ethers condensed ring compounds.
Background technology
Tuberculosis is the chronic infectious disease caused by mycobacterium tuberculosis infection.20 middle of century, along with the appearance of large quantities of antitubercular agent, make tuberculosis obtain effective control.But in recent years, because the reason such as drug use method is improper, create the tubercule bacillus of resistance, M & M lungy is increased year by year.WHO2008 reports display, and the total resistant rate of global tuberculosis is 20.0%, and particularly along with the increase of the growth of population, worldwide travelling and movement of population, drug-tolerant pulmonary tuberculosis example more becomes to rising situation, about increases by 300,000 new cases every year.
Although the medicine that early stage is applied to tuberculotherapy much all has good effect, but in recent years, along with the appearance of several drug resistance tubercule bacillus, especially many resistances tubercule bacillus (MDR-TB) and extensive resistance tubercule bacillus (XDR-TB) are difficult to be cured especially, and morbidity and mortality ratio raise year by year.Therefore existing antitubercular agent is difficult to the requirement meeting present tuberculotherapy, finds and finds novel prevention and the medicine that can resist multidrug resistance tubercule bacillus, be still an important research field of current academia and industry member.
Summary of the invention
The object of this part is some aspects of general introduction embodiments of the invention and briefly introduces some preferred embodiments.May do in the specification digest and denomination of invention of this part and the application a little simplify or omit with avoid making this part, specification digest and denomination of invention object fuzzy, and this simplification or omit and can not be used for limiting the scope of the invention.
In view of above-mentioned and/or existing diaryl ethers condensed ring compounds preparation and application in Problems existing, propose the present invention.
Therefore, an object of the present invention is to provide a kind of compound of brand-new diaryl ethers condensed cyclic structure, it has the activity of preferably resisting multidrug resistance tubercule bacillus.At cell levels, the inhibit activities of section Example to MTB reaches IC50<10ug/mL.。
For solving the problems of the technologies described above, the invention provides following technical scheme: a kind of diaryl ethers condensed ring compounds, its chemical structural formula as shown in the formula shown in I,
Wherein,
R is selected from the alkyl of the C1-C6 of replacement, and substituting group is the one in hydroxyl, amino, alkoxyl group, alkylamino, carboxyl, ester group, amide group or cyano group;
R4, R5 and R6 are separately selected from the alkyl of hydrogen, C1-C4, and adjacent R4 and R5 can form ring system;
R1, R2, R3 are separately selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkoxyl group, carbonyl, cyano group, sulfuryl, sulfoxide group, alkylsulfonyl, aryl;
Ar1, Ar2, Ar3 are separately selected from 5-10 unit aromatic group, assorted aromatic group, or aromatic base/heteroaryl also saturated or undersaturated ring system of part;
M, n, t are separately selected from the integer of 0-4, are preferably 0,1,2.
As a kind of preferred version of diaryl ethers condensed ring compounds of the present invention, wherein: described substituting group is alkylamino-CH2 (CH2) qNR4R5, alkyl alkoxy-CH2 (CH2) qOR6, more be preferably-CH2CH2NMe2,-CH2CONMe2,-CH2CH2OMe, wherein q is the integer of 0-5.
As a kind of preferred version of diaryl ethers condensed ring compounds of the present invention, wherein: described Ar1, Ar2, Ar3 are separately selected from phenyl ring, pyridine ring, naphthalene nucleus, quinoline ring.
Another object of the present invention is to provide a kind of preparation method of diaryl ethers condensed ring compounds.
For solving the problems of the technologies described above, the invention provides following technical scheme: a kind of preparation method of diaryl ethers condensed ring compounds, its chemical equation is:
Wherein, the first step: in the o-fluoro acetophenone of replacement and the adjacent halobenzene phenol of replacement and solvent mixture, add mineral alkali powder, be heated to 80 DEG C-180 DEG C reaction 2-48 hour; , there is intramolecular coupling reaction, palladium catalyst, phosphorus part and alkali mixed according to a certain percentage in second step: in the presence of a transition metal catalyst, under protection of inert gas, and reacting by heating in appropriate solvent; 3rd step: under palladium catalyst exists, the bromobenzene of replacement and second step product generation molecule linked reaction, mix according to a certain percentage by palladium catalyst, phosphorus part and alkali, under protection of inert gas, reacting by heating in appropriate solvent; 4th step: in the basic conditions, R negative ion and reactive ketone production (I) compound;
Described in each step reaction, solvent is selected from lower group above: water, methyl alcohol, ethanol, Virahol, ethylene glycol, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene, methylene dichloride, 1,2-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, dioxane, or its composition.
Described alkali, comprises mineral alkali and organic bases, as sodium-acetate, Potassium ethanoate, potassium tert.-butoxide, sodium tert-butoxide, Potassium monofluoride, cesium fluoride, potassiumphosphate, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, or its composition; Or pyridine, triethylamine, DIPEA, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), the silica-based lithium of hexamethyl two, the silica-based sodium of hexamethyl two, LDA, lutidine, or its composition;
Described transition-metal catalyst is three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), palladium, Palladous chloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride, two (three adjacent phenmethyl phosphines) palladium chloride, 1,2-bis-(diphenylphosphino) ethane palladium chloride, or its composition; Described part refers to: tri-butyl phosphine, Tetrafluoroboric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of phenmethyl phosphines, tricyclohexyl phosphine, three adjacent phenmethyl phosphines, or its composition.
A present invention also object is to provide a kind of pharmaceutical composition.
For solving the problems of the technologies described above, the invention provides following technical scheme: a kind of pharmaceutical composition, it comprises, diaryl ethers condensed ring compounds, or its pharmacy acceptable salt or its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug; And, pharmaceutically acceptable carrier.
A kind of diaryl ethers condensed ring compounds is at preparation prevention or treatment tuberculosis, the particularly application of overriding resistance tuberculotherapy medicine aspect.
Beneficial effect of the present invention: the present invention has prepared the compound that a class has the brand-new diaryl ethers condensed cyclic structure of structure shown in formula I, and find that it has the activity of preferably resisting multidrug resistance tubercule bacillus.At cell levels, the inhibit activities of section Example to MTB reaches IC50<10ug/mL.
Embodiment
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail the specific embodiment of the present invention below in conjunction with specific embodiment.
Set forth a lot of detail in the following description so that fully understand the present invention, but the present invention can also adopt other to be different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar popularization when intension of the present invention, therefore the present invention is by the restriction of following public specific embodiment.
Secondly, alleged herein " embodiment " or " embodiment " refers to special characteristic, structure or the characteristic that can be contained at least one implementation of the present invention.Different local in this manual " in one embodiment " occurred not all refers to same embodiment, neither be independent or optionally mutually exclusive with other embodiments embodiment.
Should understand, within the scope of the present invention in, above-mentioned each technical characteristic of the present invention and can combine mutually between specifically described each technical characteristic in below (eg embodiment) thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Below in conjunction with specific embodiment, set forth the present invention further.Should understand, these embodiments are only not used in for illustration of the present invention and limit the scope of the invention.Experimental technique, usually conveniently condition or the condition of advising according to manufacturer of unreceipted actual conditions in the following example.Unless otherwise indicated otherwise per-cent and number are weight percent and parts by weight.
Reaction principle of the present invention:
Universal method is:
The first step: by palladium catalyst as PdCl2 (1 molar equivalent), phosphorus part is as PPh3 (2-5 molar equivalent), alkali such as Cs2CO3 (5-15 molar equivalent) adds in two-mouth bottle, appropriate solvent is injected as tetrahydrofuran (THF) under nitrogen protection, after stirring at room temperature 10min, reinject the solution of substrate diaryl ether as tetrahydrofuran (THF) (1 molar equivalent), be warming up to 80 DEG C-150 DEG C, stir 4-12 hour, after TLC detection reaction is complete, be cooled to room temperature, add water, organic phase is as dichloromethane extraction, merge organic phase, dry, concentrated, column chromatography or recrystallization obtain faint yellow solid, productive rate reaches 80% ~ 95%.
Second step: by palladium catalyst as Pd2 (dba) 3 (0.05 molar equivalent); phosphorus part such as X-Phos (0.06 molar equivalent) and alkali such as NaOt-Bu (1.2-2.5 molar equivalent) adds in two-mouth bottle; appropriate solvent is injected as anhydrous dioxane under nitrogen protection; stirring at room temperature 10min; the suitable solution of upper step faint yellow solid (1 molar equivalent) and the aryl halides (1 ~ 2 molar equivalent) of reinjecting, reacts at being heated to 80 DEG C-180 DEG C.After completion of the reaction, be cooled to room temperature, add suitable organic phase as ethyl acetate, cross and filter insoluble palladium catalyst, add H2O, extraction, organic layer is dry, and concentrated, column chromatography or recrystallization obtain target compound, and productive rate reaches and is greater than 80%.
3rd step: N,N-dimethylacetamide or Grignard reagent (1 molar equivalent) are added in two-mouth bottle, nitrogen protection; add anhydrous tetrahydro furan, be cooled to-78 DEG C, dropwise add LDA (2mol/l) solution; time for adding, more than 0.5h, continues to stir 0.5h.Dropwise drip the THF solution of corresponding ketone (0.3 molar equivalent) again, after dropwising, be slowly warming up to-20 DEG C, stirring is spent the night.After reacting completely, add saturated ammonium chloride solution, add ethyl acetate (30ml × 3), extraction, merge organic layer, MgSO4 is dry, concentrated, column chromatography.
Corresponding amide analogue (1 molar equivalent) is dissolved in anhydrous THF, is cooled to 0 DEG C, drip borine tetrahydrofuran complex solution (5.0 molar equivalent), reaction 1h, slowly rises to 55 DEG C, reaction 1h, after reacting completely, add the cancellation of 1ml methyl alcohol, add ethyl acetate and water, extraction, organic layer concentrates, and adds methyl alcohol, be warming up to 60 DEG C, reaction 2h, concentrated, column chromatography obtains target product.
The above-mentioned general preparative methods the first step is adopted to prepare following midbody compound successively:
Above-mentioned general preparative methods second step is adopted to prepare following ketone compounds successively:
Above-mentioned general preparative methods the 3rd step is adopted to prepare following target compound compound successively:
Adopt literature method (J.Antimicrob.Chemother., 2005,56,968-974.) carry out embodiment compound to test the inhibit activities of multidrug resistance tubercule bacillus, major part embodiment compound is all less than 100uM for the MIC of tubercule bacillus H37Ra, section Example as 7,9,17,18,19,20,21 MICs of grade to H37Ra are all less than 10uM, suitable with the activity of Capreomycin.Therefore, embodiments provide the compound that a class has brand new, the multidrug resistance for tubercule bacillus can be resisted preferably.
It should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (6)
1. a diaryl ethers condensed ring compounds, is characterized in that: its chemical structural formula as shown in the formula shown in I,
Wherein,
R is selected from the alkyl of the C1-C6 of replacement, and substituting group is the one in hydroxyl, amino, alkoxyl group, alkylamino, carboxyl, ester group, amide group or cyano group;
R4, R5 and R6 are separately selected from the alkyl of hydrogen, C1-C4, and adjacent R4 and R5 can form ring system;
R1, R2, R3 are separately selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkoxyl group, carbonyl, cyano group, sulfuryl, sulfoxide group, alkylsulfonyl, aryl;
Ar1, Ar2, Ar3 are separately selected from 5-10 unit aromatic group, assorted aromatic group, or aromatic base/heteroaryl also saturated or undersaturated ring system of part;
M, n, t are separately selected from the integer of 0-4, are preferably 0,1,2.
2. diaryl ethers condensed ring compounds as claimed in claim 1, it is characterized in that: described substituting group is alkylamino-CH2 (CH2) qNR4R5, alkyl alkoxy-CH2 (CH2) qOR6, more be preferably-CH2CH2NMe2,-CH2CONMe2,-CH2CH2OMe, wherein q is the integer of 0-5.
3. diaryl ethers condensed ring compounds as claimed in claim 1 or 2, is characterized in that: described Ar1, Ar2, Ar3 are separately selected from phenyl ring, pyridine ring, naphthalene nucleus, quinoline ring.
4. a preparation method for the diaryl ethers condensed ring compounds as described in any one of claims 1 to 3, is characterized in that: its chemical equation is:
Wherein, the first step: in the o-fluoro acetophenone of replacement and the adjacent halobenzene phenol of replacement and solvent mixture, add mineral alkali powder, be heated to 80 DEG C-180 DEG C reaction 2-48 hour; , there is intramolecular coupling reaction, palladium catalyst, phosphorus part and alkali mixed according to a certain percentage in second step: in the presence of a transition metal catalyst, under protection of inert gas, and reacting by heating in appropriate solvent; 3rd step: under palladium catalyst exists, the bromobenzene of replacement and second step product generation molecule linked reaction, mix according to a certain percentage by palladium catalyst, phosphorus part and alkali, under protection of inert gas, reacting by heating in appropriate solvent; 4th step: in the basic conditions, R negative ion and reactive ketone production (I) compound;
Described in each step reaction, solvent is selected from lower group above: water, methyl alcohol, ethanol, Virahol, ethylene glycol, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene, methylene dichloride, 1,2-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, dioxane, or its composition.
Described alkali, comprises mineral alkali and organic bases, as sodium-acetate, Potassium ethanoate, potassium tert.-butoxide, sodium tert-butoxide, Potassium monofluoride, cesium fluoride, potassiumphosphate, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, or its composition; Or pyridine, triethylamine, DIPEA, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), the silica-based lithium of hexamethyl two, the silica-based sodium of hexamethyl two, LDA, lutidine, or its composition;
Described transition-metal catalyst is three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), palladium, Palladous chloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride, two (three adjacent phenmethyl phosphines) palladium chloride, 1,2-bis-(diphenylphosphino) ethane palladium chloride, or its composition; Described part refers to: tri-butyl phosphine, Tetrafluoroboric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of phenmethyl phosphines, tricyclohexyl phosphine, three adjacent phenmethyl phosphines, or its composition.
5. a pharmaceutical composition, is characterized in that: comprise,
Diaryl ethers condensed ring compounds as described in any one of claims 1 to 3, or its pharmacy acceptable salt or its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug; And,
Pharmaceutically acceptable carrier.
6. the diaryl ethers condensed ring compounds as described in any one of claims 1 to 3 is at preparation prevention or treatment a tuberculosis, the particularly application of overriding resistance tuberculotherapy medicine aspect.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437119A (en) * | 2019-09-05 | 2019-11-12 | 华东理工大学 | A kind of N- substituted nitrogen-containing heterocyclic derivative and the preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004011436A1 (en) * | 2002-07-25 | 2004-02-05 | Janssen Pharmaceutica N.V. | Quinoline derivatives and their use as mycobacterial inhibitors |
-
2015
- 2015-07-17 CN CN201510423895.4A patent/CN105061387A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004011436A1 (en) * | 2002-07-25 | 2004-02-05 | Janssen Pharmaceutica N.V. | Quinoline derivatives and their use as mycobacterial inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| 马英主编: "《药物化学》", 31 August 2012, 河南科技大学出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437119A (en) * | 2019-09-05 | 2019-11-12 | 华东理工大学 | A kind of N- substituted nitrogen-containing heterocyclic derivative and the preparation method and application thereof |
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Application publication date: 20151118 |