CN106279058B - The preparation and purposes of 3,4- diaryl -1,2,5- oxadiazoles oxide - Google Patents
The preparation and purposes of 3,4- diaryl -1,2,5- oxadiazoles oxide Download PDFInfo
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- CN106279058B CN106279058B CN201510309617.6A CN201510309617A CN106279058B CN 106279058 B CN106279058 B CN 106279058B CN 201510309617 A CN201510309617 A CN 201510309617A CN 106279058 B CN106279058 B CN 106279058B
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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Abstract
The invention belongs to pharmaceutical technology fields, are related to one kind 3,4- diaryl -1,2, and the preparation and application thereof of 5- oxadiazoles oxide is exactly related to such compound and its application as tumor cell proliferation inhibitor in terms of preparing anti-tumor drug.Compound of the present invention is as shown in general formula I or general formula II: wherein R1‑R5As described in claims and specification.
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to one kind 3,4- diaryl -1,2, the preparation of 5- oxadiazoles oxide and
Its purposes is exactly related to such compound and its is preparing anti-tumor drug side as tumor cell proliferation inhibitor
The application in face.
Background technique
Malignant tumour is to threaten the serious disease of human health and life, is the first lethal cause of disease in China.It finds and sends out
Now treating with the new drug of pre- preventing tumor is the key subjects currently faced.
Combretastatin A-4 (CA-4) is that isolated cis-stilbene class from the willow of South Africa naturally produces
Object, its chemical name is (Z) -2- methoxyl group -5- (3,4,5- trimethoxy styryl) phenol.CA-4 is tubulin polymerization
Inhibitor, is presented very strong inhibition proliferative activity o f tumor, and prodrug CA-4 phosphate (CA-4P) entered for three phases in the U.S.
Clinical investigation phase.The existing a large amount of reports of research of new active compound for anti tumor are designed, synthesized using CA-4 as lead compound
Road, but majority CA-4 analog exists or activity is not high enough or is more toxic or synthesizes the disadvantages of more complicated.Relevant report
Referring to Pettit G.R., et al.Experientia, 1989,45,209；Nam N.H.Current Medicinal
Chemistry,2003,10,1697；Tron G.C.,et al.Journal of Medicinal Chemistry,2006,49
(11),3033-3044.
3,4- diaryl -1,2,5- oxadiazoles oxide antitumor activity has not been reported yet.
Summary of the invention
Technical problem solved by the invention is to provide compound shown in following general formula I or general formula II:
Wherein, R1~R5Respectively stand alone as hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl oxygroup,
Amino, C1-C4Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；Its precondition is: working as R1、R5It is simultaneously hydrogen
When, R2、R3、R4It is not simultaneously methoxyl group.
Preferred compound feature of the present invention is as follows:
R2、R3、R4Respectively stand alone as C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl oxygroup, amino,
C1-C4Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4
It is not simultaneously methoxyl group.
The more preferable compound characteristic of the present invention is as follows:
R2、R3、R4Respectively stand alone as hydroxyl, C1-C3Alkyl oxy, C7-C9Phenylalkyl oxygroup, amino, C1-C3Alkyl ammonia
Base, C1-C3Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously first
Oxygroup.
The more preferable compound characteristic of the present invention is as follows:
R2、R3、R4Respectively stand alone as hydroxyl, C1-C2Alkyl oxy, C7-C8Phenylalkyl oxygroup, amino, C1-C2Alkyl ammonia
Base, C1-C2Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously first
Oxygroup.
The more preferable compound characteristic of the present invention is as follows:
R2、R3、R4Respectively stand alone as hydroxyl, methoxyl group, ethyoxyl, benzyloxy, amino, methylamino, dimethylamino,
F, Cl, Br, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
The compound of the present invention further include derivative shown in structure above be formed by it is pharmaceutically acceptable nontoxic
Salt and its hydrate, these pharmaceutically acceptable nontoxic salts include that the derivative and acid are formed by salt.The acid can be with
For hydrochloric acid, sulfuric acid, hydrobromic acid, the inorganic acid of phosphoric acid or selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid
Organic acid.The hydration number of the hydrate is any real number in 0~16.
Currently preferred part of compounds structure and name are as follows:
Compound 1:
3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy -4- methoxyphenyl) -1,2,5- oxadiazoles -5- oxidation
Object
Compound 2:
3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy -4- methoxyphenyl) -1,2,5- oxadiazoles -2- oxidation
Object
Compound 3:
3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxyl -4- methoxyphenyl) -1,2,5- oxadiazoles -5- oxide
Compound 4:
3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxyl -4- methoxyphenyl) -1,2,5- oxadiazoles -2- oxide
Compound 5:
3- (3,4,5- trimethoxyphenyl) -4- (4- methoxyphenyl) -1,2,5- oxadiazoles -5- oxide
Compound 6:
3- (3,4,5- trimethoxyphenyl) -4- (4- methoxyphenyl) -1,2,5- oxadiazoles -2- oxide
Compound 7:
3- (3,4,5- trimethoxyphenyl) -4- (4- ethoxyl phenenyl) -1,2,5- oxadiazoles -5- oxide
Compound 8:
3- (3,4,5- trimethoxyphenyl) -4- (4- ethoxyl phenenyl) -1,2,5- oxadiazoles -2- oxide
Compound 9:
3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy-phenyl) -1,2,5- oxadiazoles -5- oxide
Compound 10:
3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy-phenyl) -1,2,5- oxadiazoles -2- oxide
Compound 11:
3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxy phenyl) -1,2,5- oxadiazoles -5- oxide
Compound 12:
3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxy phenyl) -1,2,5- oxadiazoles -2- oxide
Compound 13:
3- (3,4,5- trimethoxyphenyl) -4- (4- benzyloxy-phenyl) -1,2,5- oxadiazoles -5- oxide
Compound 14:
3- (3,4,5- trimethoxyphenyl) -4- (4- benzyloxy-phenyl) -1,2,5- oxadiazoles -2- oxide
Compound 15:
3- (3,4,5- trimethoxyphenyl) -4- (4- hydroxy phenyl) -1,2,5- oxadiazoles -5- oxide
Compound 16:
3- (3,4,5- trimethoxyphenyl) -4- (4- hydroxy phenyl) -1,2,5- oxadiazoles -2- oxide
Compound 17:
3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- benzyloxy-phenyl of 3-) -1,2,5- oxadiazoles -5- oxide
Compound 18:
3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- benzyloxy-phenyl of 3-) -1,2,5- oxadiazoles -2- oxide
Compound 19:
3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- hydroxy phenyl of 3-) -1,2,5- oxadiazoles -5- oxide
Compound 20:
3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- hydroxy phenyl of 3-) -1,2,5- oxadiazoles -2- oxide
Compound 21:
3- (3,4,5- trimethoxyphenyl) -4- (4- nitrobenzophenone) -1,2,5- oxadiazoles -5- oxide
Compound 22:
3- (3,4,5- trimethoxyphenyl) -4- (4- nitrobenzophenone) -1,2,5- oxadiazoles -2- oxide
Compound 23:
3- (3,4,5- trimethoxyphenyl) -4- (4- chlorphenyl) -1,2,5- oxadiazoles -5- oxide
Compound 24:
3- (3,4,5- trimethoxyphenyl) -4- (4- chlorphenyl) -1,2,5- oxadiazoles -2- oxide
Compound 25:
3- (3,4,5- trimethoxyphenyl) -4- (the fluoro- 4- methoxyphenyl of 3-) -1,2,5- oxadiazoles -5- oxide
Compound 26:
3- (3,4,5- trimethoxyphenyl) -4- (the fluoro- 4- methoxyphenyl of 3-) -1,2,5- oxadiazoles -2- oxide
Compound 27:
3- (3,4,5- trimethoxyphenyl) -4- (naphthalene -2- base) -1,2,5- oxadiazoles -5- oxide
Compound 28:
3- (3,4,5- trimethoxyphenyl) -4- (naphthalene -2- base) -1,2,5- oxadiazoles -2- oxide
Substitution-[1,2,5] oxadiazoles oxide of 3,4- bis- of the invention can be synthesized by the following way route and be made:
Reagents and conditions:a:NaOMe,MeOH,50℃；b:TsOH,3,4-Dihydro-2H-
pyran,Anhydrous toluene,Nitrogen protection,50℃；c:(i)n-BuLi,-55℃；(ii)
Aromatic aldehydes/Anhydrous THF；D:HCl (18%), MeOH, rt；e:SeO2,DMSO,MW(1000W),
2min；f:NH2OH·HCl,Pyridine,AcOEt,MW(800W),90℃；g:NaOCl,CH3OH,0℃.；H:HPLC (60%
CH3OH).
Specific embodiment
It will be helpful to understand the present invention by following examples, but the contents of the present invention are not limited to example.The present invention
In used solvent in addition to it is not elsewhere specified be that analysis is pure, petroleum ether boiling range is 60-90 DEG C.The nuclear-magnetism of compound is total
Vibration1H-NMR analysis Bruker ARX-300 type magnetic nuclear resonance analyzer measurement (Bruker company, Switzerland, TMS are internal standard)；Matter
Spectrum analysis measurement is using 1100 series SL type ion trap mass spectrometers measurement (Agilent company, the U.S.)；Tlc analysis uses thin layer
Silica gel plate detects (TLC, GF254Silica gel plate, Qingdao Haiyang chemical industry)；It is 200~300 mesh and 100~200 that column, which chromatographs used silica gel,
Mesh (Qingdao Haiyang chemical industry)；It recycles preparative liquid chromatograph (LC-9103 type, Japanese JAI company).
Embodiment 1:3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy -4- methoxyphenyl) -1,2,5- dislikes two
Azoles -5- oxide and 3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy -4- methoxyphenyl) -1,2,5- oxadiazoles -2-
The preparation of oxide
Sodium methoxide (0.40g, 7.60mmol) is dissolved in anhydrous methanol (20mL), addition dimethylphosphite (6.73g,
61.17mmol) and 3,4,5-Trimethoxybenzaldehyde (10g, 51.0mmol), it stirs under the conditions of 50 DEG C, has been reacted through TLC detection
Finish, during evaporating solvent under reduced pressure is fallen back and be extracted with dichloromethane three times, merges organic layer and with saturated common salt water washing, nothing
Organic solvent is removed under reduced pressure after aqueous sodium persulfate is dry, is recrystallized with ethyl acetate and petroleum ether, obtains white solid 14.96g, is received
Rate 96.5%.
Above compound (2.0g, 4.73mmol) is dissolved with a small amount of DMSO, SeO is added2(1.06g, 9.47mmol) is solid
Body reacts 2min under the microwave condition of 1000W, detects end of reaction through TLC, filter while hot, filtrate is poured into trash ice, to ice
After thawing, there are a large amount of solids to be precipitated, decompression filters, and filter cake is recrystallized with MeOH, obtains purer intermediate 1- (3- benzyloxy-
4- methoxyphenyl) -2- (3,4,5- trimethoxyphenyl) second diketone (1.29g sepia solid), yield 63.8%.
Above-mentioned gained intermediate (1.0g, 2.29mmol) is dissolved in the in the mixed solvent of ethyl acetate and pyridine, salt is added
Sour azanol (1.63g, 22.91mmol) solid, 90 DEG C, react 2h under the microwave condition of 800W, with ethyl acetate dilute reaction solution,
Then organic layer is washed three times with dilute hydrochloric acid, then with saturated common salt water washing organic layer, anhydrous sodium sulfate is dry, removes under reduced pressure molten
Agent obtains intermediate 1- (3- benzyloxy -4- methoxyphenyl) -2- (3,4,5- trimethoxyphenyl) glyoxime (0.49g oily
Object), yield 45.4%.
Above compound (1.0g, 2.14mmol) is dissolved in a small amount of methanol, 20% chlorine is added dropwise under the conditions of ice-water bath
Solid can be precipitated in acid sodium aqueous solution, stirring, filter and wash after reacting about 20min, obtain target compound 3- (3- benzyloxy
Base -4- methoxyphenyl) -1,2,5- oxadiazoles oxide 2-1 (0.93g white solid) of -4- (3,4,5- trimethoxyphenyl),
Yield is 93.7%.(mobile phase is 60% methanol aqueous solution) is isolated and purified through circulation preparation liquid phase, obtains compound 1 respectively
(0.36g white solid), yield 48.6%.Compound 2 (0.33g white solid), yield 44.6%.Its structural formula, 1H-
NMR and MS data are listed in the table below in -1.
Embodiment 2:3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxyl -4- methoxyphenyl) -1,2,5- oxadiazoles -
5- oxide and 3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxyl -4- methoxyphenyl) -1,2,5- oxadiazoles -2- oxidation
The preparation of object
Other than using corresponding raw material, with the identical method preparating example 2 of embodiment 1, by compound 3- (3- benzyloxy
Base -4- methoxyphenyl) -4- (3,4,5- trimethoxyphenyl) -1,2,5- oxadiazoles oxide (1.0g, 2.15mmol) is dissolved in
TiCl is added under -20 DEG C of stirring conditions in appropriate anhydrous methylene chloride4(1.1ml, 10.76mmol) is detected through TLC after about 30min
Reaction solution is poured into water by end of reaction, is extracted with dichloromethane three times, and with saturated common salt water washing, and anhydrous sodium sulfate is dry
Dry organic layer, evaporating solvent under reduced pressure.(mobile phase is 60% methanol aqueous solution) is isolated and purified through circulation preparation liquid phase, obtains compound
3 yields 45.7%, 4 yield 42.6% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 3:3- (3,4,5- trimethoxyphenyl) -4- (4- methoxyphenyl) -1,2,5- oxadiazoles -5- oxide
With the preparation of 3- (3,4,5- trimethoxyphenyl) -4- (4- methoxyphenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, with the identical method of embodiment 1 complete example 3,5 yield 49.5% of compound,
6 yield 42.3% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 4:3- (3,4,5- trimethoxyphenyl) -4- (4- ethoxyl phenenyl) -1,2,5- oxadiazoles -5- oxide
With the preparation of 3- (3,4,5- trimethoxyphenyl) -4- (4- ethoxyl phenenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, with the identical method of embodiment 1 complete example 4,7 yield 48.5% of compound,
8 yield 43.3% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 5:3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy-phenyl) -1,2,5- oxadiazoles -5- oxide
With the preparation of 3- (3,4,5- trimethoxyphenyl) -4- (3- benzyloxy-phenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, with the identical method of embodiment 1 complete example 5,9 yield 49.1% of compound,
10 yield 44.9% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 6:3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxy phenyl) -1,2,5- oxadiazoles -5- oxide and
The preparation of 3- (3,4,5- trimethoxyphenyl) -4- (3- hydroxy phenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, with the identical method of embodiment 2 complete example 6,11 yield 44.4% of compound,
12 yield 42.1% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 7:3- (3,4,5- trimethoxyphenyl) -4- (4- benzyloxy-phenyl) -1,2,5- oxadiazoles -5- oxide
With the preparation of 3- (3,4,5- trimethoxyphenyl) -4- (4- benzyloxy-phenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, with the identical method of embodiment 1 complete example 7,13 yield 48.1% of compound,
14 yield 44.4% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 8:3- (3,4,5- trimethoxyphenyl) -4- (4- hydroxy phenyl) -1,2,5- oxadiazoles -5- oxide and
The preparation of 3- (3,4,5- trimethoxyphenyl) -4- (4- hydroxy phenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, with the identical method of embodiment 2 complete example 8,15 yield 43.1% of compound,
16 yield 42.3% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 9:3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- benzyloxy-phenyl of 3-) -1,2,5- oxadiazoles -5-
Oxide and 3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- benzyloxy-phenyl of 3-) -1,2,5- oxadiazoles -2- oxide
Preparation
Other than using corresponding raw material, with the identical method of embodiment 1 complete example 9,17 yield 46.4% of compound,
18 yield 45.2% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 10:3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- hydroxy phenyl of 3-) -1,2,5- oxadiazoles -5- oxygen
The preparation of compound and 3- (3,4,5- trimethoxyphenyl) -4- (the bromo- 4- hydroxy phenyl of 3-) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, example 10,19 yield of compound are completed in the identical method of embodiment 2
42.2%, 20 yield 41.3% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 11:3- (3,4,5- trimethoxyphenyl) -4- (4- nitrobenzophenone) -1,2,5- oxadiazoles -5- oxide
With the preparation of 3- (3,4,5- trimethoxyphenyl) -4- (4- nitrobenzophenone) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, example 11,21 yield of compound are completed in the identical method of embodiment 1
45.6%, 22 yield 41.3% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 12:3- (3,4,5- trimethoxyphenyl) -4- (4- chlorphenyl) -1,2,5- oxadiazoles -5- oxide and
The preparation of 3- (3,4,5- trimethoxyphenyl) -4- (4- chlorphenyl) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, example 12,23 yield of compound are completed in the identical method of embodiment 1
46.7%, 24 yield 43.8% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 13:3- (3,4,5- trimethoxyphenyl) -4- (the fluoro- 4- methoxyphenyl of 3-) -1,2,5- oxadiazoles -5-
Oxide and 3- (3,4,5- trimethoxyphenyl) -4- (the fluoro- 4- methoxyphenyl of 3-) -1,2,5- oxadiazoles -2- oxide
Preparation
Other than using corresponding raw material, example 13,25 yield of compound are completed in the identical method of embodiment 1
47.8%, 26 yield 43.7% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 14:3- (3,4,5- trimethoxyphenyl) -4- (naphthalene -2- base) -1,2,5- oxadiazoles -5- oxide and 3-
The preparation of (3,4,5- trimethoxyphenyl) -4- (naphthalene -2- base) -1,2,5- oxadiazoles -2- oxide
Other than using corresponding raw material, example 14,27 yield of compound are completed in the identical method of embodiment 1
47.7%, 28 yield 44.3% of compound.Its structural formula, 1H-NMR and MS data are listed in the table below in -1.
Embodiment 15: the external pharmacology test of the compound of the present invention
(1) experimental principle: tetrazolium (micoculture tetrozolium, MTT) reduction method.The positive ginseng of use
It is clinically used adriamycin according to drug.
(2) cell strain: human stomach cancer cell line SGC-7901, human fibrosarcoma cell strain HT-1080 and human lung adenocarcinoma cell
Strain A549
(3) experimental method:
1. preparing concentration is 1 × 105μ g/mL cell suspension is added in 96 orifice plates, and every 100 μ L of hole sets 37 DEG C, 5%CO2Training
It supports and is incubated for for 24 hours in case.
2. the tested material of various concentration is added in 96 orifice plates of the tumour cell of culture, continue culture for 24 hours, is inverted micro-
Under the microscope.
3. discarding culture solution, 100 μ L of 0.05%MTT application liquid is added in every hole, cultivates 4h.
4. discarding culture solution, 100 μ L DMSO are added in every hole, and oscillation 5min makes the crystallization dissolution of first a ceremonial jade-ladle, used in libation, measures at 490nm
Cell absorbance (OD value).
Processing for Data Analysis in Physics is as follows:
Using the absorbance of non-medicine feeding hole cell as blank control group absorbance (OD value), calculation formula is as follows:
Inhibiting rate (%)=(blank control group OD average value-sample sets OD average value degree)/blank control OD average value ×
100%, it is shown in Table -2.
Embodiment 16: anti-tumor activity is tested in the animal body of the compound of the present invention
The selection preferable compound 5 of external activity has carried out anti-tumor activity in animal body and has tested, and model used is mouse
S-180 sarcoma model, positive control medicine are clinically used anti-tumor drug fluorouracil (Fluorouracil).
Experimental method: 18-22 grams of female KM mouse and well-grown 7-11 days S-180 tumor kinds are selected, by tumor group
Cell suspension is woven into, it is subcutaneous to be seeded to right side of mice armpit, about 1.0-2.0 × 106Cell/only, it is random after inoculation 24 hours
Point cage, intraperitoneal injection continuous 7 days.24 hours execution animals, weigh, knurl weight after drug withdrawal, calculate each group average knurl weight, press
Following formula finds out tumor control rate and carries out t inspection.
Tumor control rate=[(blank control group average knurl weight-treatment group's average knurl weight)/(blank control group is averaged tumor
Weight)] × 100%
Experimental result is shown in Table -3.
Table -1
Table -2
Table -3
Claims (16)
1. 3,4- diaryl -1,2,5- oxadiazoles oxide and its salt shown in general formula I or general formula II:
Wherein,
R1~R5Respectively stand alone as hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl oxygroup, amino, C1-C4
Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；Its precondition is: working as R1、R5When being simultaneously hydrogen, R2、R3、R4
It is not simultaneously methoxyl group.
2. compound as described in claim 1 and its salt, it is characterised in that:
R2、R3、R4Respectively stand alone as C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, C7-C10Phenylalkyl oxygroup, amino, C1-C4
Alkyl amino, C1-C4Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is different
When be methoxyl group.
3. compound as claimed in claim 1 or 2 and its salt, it is characterised in that:
R2、R3、R4Respectively stand alone as hydroxyl, C1-C3Alkyl oxy, C7-C9Phenylalkyl oxygroup, amino, C1-C3Alkyl amino, C1-
C3Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
4. compound and its salt as described in claim 1-2 any one, it is characterised in that:
R2、R3、R4Respectively stand alone as hydroxyl, C1-C2Alkyl oxy, C7-C8Phenylalkyl oxygroup, amino, C1-C2Alkyl amino, C1-
C2Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
5. compound as claimed in claim 3 and its salt, it is characterised in that:
R2、R3、R4Respectively stand alone as hydroxyl, C1-C2Alkyl oxy, C7-C8Phenylalkyl oxygroup, amino, C1-C2Alkyl amino, C1-
C2Dialkyl amido, halogen atom, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
6. compound and its salt as described in claim 1-2,5 any one, it is characterised in that:
R2、R3、R4Respectively stand alone as hydroxyl, methoxyl group, ethyoxyl, benzyloxy, amino, methylamino, dimethylamino, F, Cl,
Br, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
7. compound as claimed in claim 3 and its salt, it is characterised in that:
R2、R3、R4Respectively stand alone as hydroxyl, methoxyl group, ethyoxyl, benzyloxy, amino, methylamino, dimethylamino, F, Cl,
Br, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
8. compound as claimed in claim 4 and its salt, it is characterised in that:
R2、R3、R4Respectively stand alone as hydroxyl, methoxyl group, ethyoxyl, benzyloxy, amino, methylamino, dimethylamino, F, Cl,
Br, nitro；R1、R5It is simultaneously hydrogen；Its precondition is: R2、R3、R4It is not simultaneously methoxyl group.
9. compound and its salt as described in claim 1-2,5,7-8 any one, it is characterised in that:
The salt is that the compound and acid are formed by salt, the acid be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid,
Citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
10. compound as claimed in claim 3 and its salt, it is characterised in that:
The salt is that the compound and acid are formed by salt, the acid be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid,
Citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
11. compound as claimed in claim 4 and its salt, it is characterised in that:
The salt is that the compound and acid are formed by salt, the acid be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid,
Citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
12. compound as claimed in claim 6 and its salt, it is characterised in that:
The salt is that the compound and acid are formed by salt, the acid be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid,
Citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
13. a kind of 3,4- diaryl -1,2 as described in claim 1, the preparation method of 5- oxadiazoles oxide, feature exist
In:
Reagent and condition:
a:NaOMe,MeOH,50℃；
b:TsOH,3,4-Dihydro-2H-pyran,Anhydrous toluene,Nitrogen protection,50℃；
c:(i)n-BuLi,-55℃；(ii)Aromatic aldehydes/Anhydrous THF；D:HCl, 18%, MeOH,
rt；
e:SeO2, DMSO, microwave 1000W, 2min；
f:NH2OHHCl, Pyridine, AcOEt, microwave 800W, 90 DEG C；
g:NaOCl,CH3OH,0℃；
H:HPLC, 60%CH3OH。
14. a kind of pharmaceutical composition, which is characterized in that comprising compound described in claim 1-12 any one and its salt and
Pharmaceutically acceptable carrier.
15. pharmaceutical composition described in compound and its salt described in claim 1-12 any one or claim 14 is being made
Application in standby anti-tumor drug.
16. application as claimed in claim 15, which is characterized in that the tumour is gastric cancer, fibrosarcoma, adenocarcinoma of lung.
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| CN103848795A (en) * | 2014-03-07 | 2014-06-11 | 山东大学 | I,2,5-oxadiazole-2-oxide histone deacetylase inhibitor as well as preparation method and application thereof |
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