CN101914074B - Thiazole-substituted mercaptoacetamide derivative, preparation method and application thereof - Google Patents
Thiazole-substituted mercaptoacetamide derivative, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and in particular discloses thiazole-substituted mercaptoacetamide compounds shown as the formula I, N-oxides, stereoisomers, a stereoisomer mixture, pharmaceutically acceptable salts, hydrate thereof, and a solvation matter, polycrystals and eutectics thereof, precursor and derivatives with same biological function, a preparation method thereof and application of a composition containing one or more compounds to treating and preventing human immunodeficiency virus (HIV) and influenza virus infection.
Description
Technical field
The invention belongs to medical technical field, be specifically related to one type of thiazole-substituted mercaptoacetamide derivative, the invention still further relates to the preparation method of this analog derivative and the purposes of anti human immune deficiency virus (HIV) and resisiting influenza virus thereof.
Background technology
Disease of viral infection is one big type of healthy disease of serious harm human life.Human immunodeficiency virus type 1 (HIV-1) is the main pathogens of AIDS (AIDS).Though the enforcement of at present efficient anti-reverse transcription therapy (HAART) is an important breakthrough of anti-AIDS treatment; But because chemical sproof appearance reaches the application that the toxicity problem of taking medicine has for a long time greatly limited this therapy, the research and development of novel anti AIDS-treating medicine are very urgent, and (referring to " anti-AIDS drug research ", Liu Xinyong edits; The People's Health Publisher; Beijing, 2006,12).Influenza virus (being called for short influenza virus) is a kind of acute respiratory virus spread of serious harm human health.Current, the flu outbreak that new influenza virus strain causes also spreads in the whole world, affects millions of people's health, has caused more serious economy and social concern.Popular H1N1, H3N2, H5N1 etc. belong to some hypotypes in the influenza in the global range.Up to the present, the mankind lack control device and control medicine safely and effectively to influenza virus always, and this makes the new and effective anti-influenza virus medicament of research and development become one of the focus in current medicament research and development field.(referring to Zhang Qiang etc., the anti-influenza virus medicament progress, Acta Pharmaceutica Sinica, 2010,45 (3), 289-299).
Heterogeneous ring compound has antiviral activity widely; They generally are as the substruction parent nucleus that constitutes pharmacophore; Being fit to the space requirement of medicine special role target spot, or produce corresponding biological activity as the integral part of active substituent or ring system.Why medicine depends on heterocycle is because heterocycle more is difficult for the metabolism decomposition in vivo than fat or aromatic compound, and has better biocompatibility.
Summary of the invention
The present invention is directed to the deficiency of prior art; A kind of thiazole-substituted mercaptoacetamide derivative and preparation method thereof is provided, and the present invention provides also that the anti-HIV-1 of thiazole-substituted mercaptoacetamide derivative is active, anti-influenza virus activity The selection result and in antiviral Application for Field.
Technical scheme of the present invention is following:
1. thiazole-substituted mercaptoacetamide derivative
Involved in the present invention is the thiazole-substituted mercaptoacetamide derivative with general formula I, with and N-oxide compound, stereoisomer form, stereoisomer mixture or pharmacy acceptable salt:
Wherein,
R is amino, chlorine atom, fluorine atom, bromine atoms, iodine atom, hydroxyl, methyl or ethyl;
Ar
1For substituted benzene ring, replace naphthalene nucleus, various substituted hexa-member heterocycle, various substituted five-membered ring, various substituted hexa-atomic and five-membered ring, various substituted hexa-atomic and hexa-member heterocycle, various substituted five yuan and five-membered ring, various substituted benzo five-membered heterocycle or various substituted benzo hexa-member heterocycle;
Preferably, Ar
1Be 2,4-dihalo phenyl ring, replacement naphthalene nucleus or substd quinolines ring;
Ar
2For substituted benzene ring, replace naphthalene nucleus, various substituted hexa-member heterocycle, various substituted five-membered ring, various substituted hexa-atomic and five-membered ring, various substituted hexa-atomic and hexa-member heterocycle, various substituted five yuan and five-membered ring, various substituted benzo five-membered heterocycle or various substituted benzo hexa-member heterocycle;
Preferably, Ar
2For having 2 of general formula I I, 4-disubstituted benzenes ring or 2,4-two replacement hexa-member heterocycles;
Wherein, X, Y, Z are respectively carbon atom or nitrogen-atoms, R
1Be H, F, Cl, Br, I, NO
2Or Me; R
2Be H, F, Cl, Br, I, Me, OCH
3, COMe, COOMe, COOEt, COOH or SO
2NH
2
2. the synthetic route of thiazole-substituted mercaptoacetamide derivative is following:
In the above-mentioned reaction formula,
R is amino, chlorine atom, fluorine atom, bromine atoms, iodine atom, hydroxyl, methyl or ethyl;
Ar
1For substituted benzene ring, replace naphthalene nucleus, various substituted hexa-member heterocycle, various substituted five-membered ring, various substituted hexa-atomic and five-membered ring, various substituted hexa-atomic and hexa-member heterocycle, various substituted five yuan and five-membered ring, various substituted benzo five-membered heterocycle or various substituted benzo hexa-member heterocycle.
Preferably, Ar
1Be 2,4-dihalo phenyl ring, replacement naphthalene nucleus or substd quinolines ring;
Ar
2For substituted benzene ring, replace naphthalene nucleus, various substituted hexa-member heterocycle, various substituted five-membered ring, various substituted hexa-atomic and five-membered ring, various substituted hexa-atomic and hexa-member heterocycle, various substituted five yuan and five-membered ring, various substituted benzo five-membered heterocycle or various substituted benzo hexa-member heterocycle.
Reagent and condition: (i) Br
2/ AcOH or ClCOCH
2Cl/AlCl
3(ii) HSCH
2COOEt, Na
2CO
3, EtOH; (iii) Br
2/ AcOH; (iv) NH
2CSNH
2, AcONa, EtOH; (v) NaOH, DMSO/H
2O; (vi) SOCl
2, substituted aromatic amines (Ar
2-NH
2), THF, rt; (vii) CuR
2, t-BuONO, MeCN.
3. the preparation method of Basedol mercapto acetamide derivative A8 and chloro thiazole mercapto acetamide derivative B8
Substituted aryl ethyl ketone 1 ' or replacement aromatic ring 1 obtain 2-chlorine (bromine)-1-substituted aryl ethyl ketone 2 through halogenating reaction or Friedel-Crafts reaction (Friedel-Crafts) respectively; 2 hour obtain thioether 3 with 2-ethyl thioglycolate room temperature reaction number in ethanolic soln, not purified directly down the step react, obtain preparing Basedol heterocyclic important intermediate 4 at the alpha-position bromo; Then, this compound and thiocarbamide cyclization obtain 2-(2-amino-4-substituted aryl-thiazole-5-sulfydryl) ETHYLE ACETATE 5 of high yield; At NaOH-DMSO-H
2In the O solution, compound 5 hydrolytic reactions generate aminothiazole acid 6, and then change into corresponding Acetyl Chloride 98Min. 7; Under the condition of triethylamine, compound 7 obtains corresponding 2-(2-amino-4-substituted aryl-thiazole-5-sulfydryl)-N-acetamide derivative A8 with different substituted aromatic amines reactions; In addition, obtain halo thiazole mercapto acetamide derivative B8 through diazotization and halogenating reaction on this basis.
Above-mentioned various substituted aromatic amines (Ar
2-NH
2) in Ar
2For substituted benzene ring, replace naphthalene nucleus, various substituted hexa-member heterocycle, various substituted five-membered ring, various substituted hexa-atomic and five-membered ring, various substituted hexa-atomic and hexa-member heterocycle, various substituted five yuan and five-membered ring, various substituted benzo five-membered heterocycle or various substituted benzo hexa-member heterocycle.
Preferably, Ar
2For having 2 of general formula I I, 4-disubstituted benzenes ring or 2,4-two replacement hexa-member heterocycles;
Wherein, X, Y, Z are respectively carbon atom or nitrogen-atoms, R
1Be H, F, Cl, Br, I, NO
2Or Me; R
2Be H, F, Cl, Br, I, Me, OCH
3, COMe, COOMe, COOEt, COOH or SO
2NH
2
4. anti-HIV-1 (the III of target compound
B) and resistance strain activity and toxicity test
To synthetic part thiazole-substituted mercaptoacetamide compound according to the method described above (I series, Ar
1=2,4 dichloro benzene base) carried out the anti-HIV-1 (III of cell levels
B), the screening active ingredients of anti-HIV-2 (ROD) and multiple resistance strain, wherein anti-HIV-1 (III
B) active result is as shown in table 1, it is active that chloro thiazolium compounds (I-B series) has significant anti-HIV-1, and the EC of 4 compounds (I-B8a, I-B8e, I-B8f, I-B8g) is wherein arranged
50Value reaches micromole's level, and cytotoxicity is lower.And compound I-B8e, I-B8f, I-B8g have significant inhibitory effect (table 2) to part persister (E138K, K103N, L100I).Nonreactive HIV is active for aminothiazole compounds (I-A series).
The structure of table 1 compound I-A8 and I-B8 and anti-HIV-1 (III
B) the active and cytotoxicity (MT-4 cell) of inhibition
Annotate:
aEC
50: protect the MT-4 cell of 50% infected by HIV-1 to avoid cytopathic compound concentration;
bCC
50: make 50% compound concentration of the cell generation pathology of infected by HIV-1 not;
cSelectivity coefficient: CC
50/ EC
50Ratio.
Table 2 part of compounds is active and cytotoxicity (MT-4 cell) to the inhibition of HIV resistance strain
Annotate:
aEC
50: protect the MT-4 cell of 50% infected by HIV-1 to avoid cytopathic compound concentration;
bCC
50: make 50% compound concentration of the cell generation pathology of infected by HIV-1 not;
cSelectivity coefficient: CC
50/ EC
50Ratio.
Thiazole-substituted mercaptoacetamide derivative is the HIV-1 suppressor factor of a series of novel structures, has the value of further researching and developing, and the lead compound that can be used as anti-HIV is used.
Thiazole-substituted mercaptoacetamide derivative of the present invention can be used as the HIV-1 suppressor factor and uses.Specifically, be used to prepare anti-AIDS drug as the HIV-1 suppressor factor.
A kind of anti-HIV-1 pharmaceutical composition comprises thiazole-substituted mercaptoacetamide derivative of the present invention.
5. the anti-influenza virus activity of target compound experiment (mdck cell)
Through part Basedol mercaptoacetamide compound and chloro thiazole mercapto acetamide compound are carried out the anti-influenza virus activity screening of cell levels, the strain that is screened has influenza A/H1N1 (strain A/Puerto Rico/8/34), A/H3N2 (strain A/HK/7/87) and influenza B (strain B/HK/5/72).The result finds that compound I-A8g and I-A8h demonstrate significant anti-influenza virus activity (table 3), especially the H1N1virus strain is had higher selectivity and stronger restraining effect.The high 1-2 one magnitude of control drug such as specific activity oseltamivir phosphate, ribavirin, amantadine and Rimantadine can be used as new medicine guide thing and carry out deep research.
Therefore, thiazole-substituted mercaptoacetamide derivative is the influenza virus suppressor factor of a series of novel structures, has the value of further researching and developing, and the lead compound that can be used as resisiting influenza virus is used.
Thiazole-substituted mercaptoacetamide derivative of the present invention can be used as the influenza virus suppressor factor and uses.Specifically, be used to prepare anti-influenza virus medicament as the influenza virus suppressor factor.
A kind of anti-influenza virus medicament compsn comprises thiazole-substituted mercaptoacetamide derivative of the present invention.
Table 3 part of compounds is active and cytotoxicity (MT-4 cell) to the inhibition of A type influenza virus H1N1 hypotype
aCC
50: make 50% concentration of the cell generation pathology of influenza virus infection not, record by the MTS method.
bThe smallest cell toxic concentration: cause the change Cmin of required compound of microscopically visible normal cellular morphology.
cEC
50: suppress the compound concentration that causes the cell mutation effect of 50% virus induction or protect the cell of 50% influenza virus infection to avoid cytopathic compound concentration, (cytopathic effect CPE) records with the MTS method by the cytopathic effect method respectively.
The invention provides the brand-new thiazole-substituted mercaptoacetamide derivative of structure, its preparation method, its anti-HIV-1 activity, anti-influenza virus activity The selection result and the first Application in antiviral field thereof.Through evidence, thiazole-substituted mercaptoacetamide derivative of the present invention can be used as the HIV-1 suppressor factor and uses.Specifically, be used to prepare anti-AIDS drug as the HIV-1 suppressor factor.Thiazole-substituted mercaptoacetamide derivative of the present invention also can be used as the influenza virus suppressor factor and uses.Specifically, be used to prepare anti-influenza virus medicament as the influenza virus suppressor factor.
Embodiment
Through following instance (with Ar in the general formula I
1Be 2, the 4-dibromo phenyl is an example) help to understand the present invention, but can not limit content of the present invention, in following instance, the numbering of all compounds is identical with table 1.
The raw material explanation:
1, the 3-dibromobenzene: the expensive permanent scientific & trading Co., Ltd. in Jinan produces and sells.
Aluminum chloride anhydrous: the expensive permanent scientific & trading Co., Ltd. in Jinan produces and sells.
Chloroacetyl chloride: the expensive permanent scientific & trading Co., Ltd. in Jinan produces and sells.
Ethyl thioglycolate: Nanjing celestial worthy's chemical reagent ltd.
Embodiment 1.2-(2-amino-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl) acetate I-6's is synthetic
With buy 1, the 3-dibromobenzene (I-1,23.6g, 0.1mol) with the mixture of Aluminum chloride anhydrous vigorous stirring at room temperature, to wherein drip chloroacetyl chloride (13g, 0.1mol).Reaction mixture, cools off after the TLC detection reaction finishes at 60-65 ℃ of following stirring reaction 10h, and mixture dilutes with the 40mL methylene dichloride.Organic phase is water, saturated NaHCO successively
3Solution and brine wash.Organic layer is through Na
2SO
4Drying is filtered, and concentrates the bullion 26.7g that obtains 2-chloro-1-(2, the 4-dibromo phenyl) ethyl ketone I-2, is the pale yellow oily liquid body, productive rate: 85.4%.This product needn't directly be used for next step reaction by purifying.
With ethyl thioglycolate (6.5mL, 0.06mol) and Na
2CO
3(6.5g 0.06mol) is dissolved in the 150mL ethanol, and (0.05mol), reaction mixture at room temperature stirs 12h for I-2,15.6g to add 2-chloro-1-(2, the 4-dibromo phenyl) ethyl ketone.The pressure reducing and steaming solvent, residue is used the 0.1M HCl aqueous solution, saturated NaHCO then successively with the dilution of 100mL methylene dichloride
3Solution, water and brine wash.Organic layer is through anhydrous Na
2SO
4Drying is filtered, and concentrates and obtains the I-3 bullion, is the pale yellow oily liquid body.
Under the room temperature, (19.8g adds Br in glacial acetic acid 0.05mol) (100mL) solution to I-3
2(about 30min dropwises for 8.0g, glacial acetic acid 0.05mol) (30mL) solution.After the stir about 8h reaction at room temperature of this mixture of TLC detection finishes, in the impouring frozen water, with methylene dichloride (3 * 50mL) extractions.The organic phase that obtains is water and 5%NaHCO successively
3Solution washing obtains yellow oily compound I-4 after the drying.
(11.42g 0.15mmol) is dissolved in the 150mL ethanol, adds alpha-brominated ketone I-4 (0.05mmol) then with thiocarbamide.Reaction mixture at room temperature stirs, and TLC detects about 10h afterreaction and finishes, and revolves dried solvent, and resistates adds 150mL water, and (3 * 50mL) extract ETHYLE ACETATE.Organic layer is used saturated NaHCO
3Solution, water and brine wash, anhydrous Na
2SO
4Drying is filtered, and concentrating under reduced pressure obtains 2-(2-amino-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl) ETHYLE ACETATE I-5 bullion, and recrystallizing methanol obtains yellow tabular crystal 10g, productive rate: 44.3%.
With I-5 (2.98g, 6.6mmol), the solution of 1N NaOH solution (20mL) and DMSO 99.8MIN. (20mL) at room temperature stirs 4h, adds 30mL ETHYLE ACETATE and 150mL water then.Separate water layer, be neutralized to pH=2 with 10%HCl.Have solid to separate out, filter, washing obtains 2-(2-amino-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl) acetate I-6 bullion at air drying, and product need not be further purified.
Synthesizing of embodiment 2.2-(2-amino-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl)-N-arylacetamide (I-A8)
The general operation of reaction:
(0.2g 0.5mmol) joins in the 20mL ether, and (0.15g, 0.6mmol), mixture at room temperature stirs 5h, obtains yellow oil I-7 after boiling off solvent, directly is used for the preparation of I-A8 to stir fast down the adding phosphorus pentachloride in room temperature with I-6.
In methylene dichloride (10mL) solution that substituted aromatic amines (0.5mmol) and triethylamine (2mmol) are dissolved in; Ice bath stirs down; Drip with 10mL anhydrous methylene chloride dissolved acyl chlorides I-7 (0.5mmol) solution; Mixture at room temperature stirs 10h, and organic layer is removed excessive amine with the 10%HCl washing, uses saturated NaHCO then
3Solution, water and brine wash, Na
2SO
4Drying, evaporated under reduced pressure, with ETHYLE ACETATE: sherwood oil=1: 2 rapid column chromatography separate 2-(2-amino-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl)-N-arylacetamide I-A8, be white or yellow solid.
Make the title product (Ar of general formula I respectively with aforesaid method with different substituted aromatic amines and acyl chlorides I-7
1Be 2, the 4-dibromo phenyl), partial results is following:
Operate the samely, different is to use Ortho-Chloro aniline.
The white needle, yield: 42.6%.mp:192-194 ℃.
1H-NMR (CDCl
3, ppm) δ: 9.47 (s, 1H, NH), 7.88 (d, 1H, J=1.8Hz, PhH), 7.80 (d, 1H, J=7.8Hz, Ph ' H), 7.52 (dd, 1H, J
1=8.4Hz, J
2=1.8Hz, PhH), 7.37 (d, 1H, J=8.4Hz, PhH), 7.34-7.32 (m, 2H, Ph ' H), 7.17 (t, 1H, Ph ' H), 5.26 (s, 2H, NH
2), 3.52 (s, 2H, S-CH
2) .MS (ESI): m/z 532.2 (M+1), 534.1 (M+3), 536.2 (M+5) .C
17H
12Br
2ClN
3OS
2(530.85).
Operate the samely, different is to use adjacent fluoroaniline.
The white needle, yield: 39.4%.mp:173-175 ℃.
1H-NMR (CDCl
3, ppm) δ: 8.25 (t, 1H, Ph ' H), 8.19 (brs, 1H, NH), 7.66 (d, 1H, J
1=1.8Hz, PhH), 7.28 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.15-7.08 (m, 4H, 1 * PhH&3 * Ph ' H), 5.27 (s, 2H, NH
2), 3.45 (s, 2H, S-CH
2) .MS (ESI): m/z 516.1 (M+1), 518.1 (M+3), 520.1 (M+5) .C
17H
12Br
2FN
3OS
2(514.88).
Operate the samely, different is to use o-bromoaniline.
The white prismatic crystal, yield: 55.7%.mp:176-178 ℃.
1H-NMR (CDCl
3, ppm) δ: 8.59 (s, 1H, NH), 8.30 (d, 1H, J=7.8Hz, Ph ' H), 7.66 (d, 1H, J
1=1.8Hz, PhH), 7.55 (d, 1H, J
2=8.4Hz, PhH), 7.34-7.32 (m, 1H, Ph ' H), 7.26-7.24 (m, 1H, Ph ' H), 7.11-7.10 (m, 1H, PhH), 7.03-7.00 (t, 1H, Ph ' H), 5.27 (s, 2H, NH
2), 3.48 (s, 2H, S-CH
2) .MS (ESI): m/z 576.0 (M+1), 578.0 (M+3), 580.0 (M+5) .C
17H
12Br
3N
3OS
2(574.80).
Operate the samely, different is to use 2,4 dichloro aniline.
The white needle, yield: 54.8%.mp:183-185 ℃.
1H-NMR (CDCl
3, ppm) δ: 8.39 (s, 1H, NH), 8.23 (d, 1H, J=7.2Hz, Ph ' H), 7.65 (d, 1H, J=1.8Hz, PhH), 7.44-7.15 (m, 4H, 2 * PhH&2 * Ph ' H), 5.24 (s, 2H, NH
2), 3.52 (s, 2H, S-CH
2) .MS (ESI): m/z 566.1 (M+1), 568.1 (M+3), 570.1 (M+5) .C
17H
11Br
2C
L2N
3OS
2(564.81).
Operate the samely, different is to use 2-chloro-3-EL-970.
The white needle, yield: 70.4%.mp:103-106 ℃.
1H-NMR (CDCl
3, ppm) δ: 8.68 (d, 1H, J
1=2.4Hz, J
2=7.8Hz, pyridine-H), 8.60 (brs, 1H, NH), 8.16 (dd, 1H, J=1.8Hz, J=4.8Hz, pyridine-H), 7.68 (d, 1H, J
1=1.8Hz, PhH), 7.35 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.29-7.27 (m, 1H, PhH), 7.14 (d, 1H, J=7.8Hz, pyridine-H), 5.24 (s, 2H, NH
2), 3.48 (s, 2H, S-CH
2) .MS (ESI): m/z 533.2 (M+1), 535.11 (M+3) .C
16H
11Br
2ClN
4OS
2(531.84).
Operate the samely, different is to use 2-nitro-4-methyl aniline.
Yellow solid, yield: 61.9%.mp:218-219 ℃.
1H-NMR (CDCl
3, ppm) δ: 10.83 (s, 1H, NH), 8.54 (d, 1H, J=8.4Hz, Ph ' H), 8.04 (d, 1H, J
1=1.8Hz, PhH), 7.59 (d, 1H, J=1.8Hz, Ph ' H), 7.47 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.25 (d, 1H, J=8.4Hz, PhH), 7.14 (d, 1H, J=8.4Hz, Ph ' H), 5.78 (s, 2H, NH
2), 3.49 (s, 2H, S-CH
2), 2.43 (s, 3H, CH
3) .MS (ESI): m/z 557.0 (M+1), 559.1 (M+3), 561.1 (M+5) .C
18H
14Br
2N
4O
3S
2(555.89).
Operate the samely, different is to use o-Nitraniline.
Yellow solid, yield: 58.7%.mp:186-189 ℃.
1H-NMR (CDCl
3, ppm) δ: 10.75 (s, 1H, NH), 8.74 (d, 1H, J=8.4Hz, Ph ' H), 8.24 (dd, 1H, J
1=1.2Hz, J
2=8.4Hz, Ph ' H), 8.11 (d, 1H, J
1=1.8Hz, PhH), 7.68 (dt, 1H, J
1=1.2Hz, J
2=8.4Hz, Ph ' H), 7.40 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.26 (d, 1H, J=8.4Hz, PhH), 7.24 (m, 1H, Ph ' H), 5.75 (s, 2H, NH
2), 3.51 (s, 2H, S-CH
2) .MS (ESI): m/z 543.1 (M+1), 545.1 (M+3), 547.1 (M+5) .C
17H
12Br
2N
4O
3S
2(541.87).
Operate the samely, different is to use o-toluidine.
White powder, yield: 62.8%.mp:198-200 ℃.
1H-NMR (CDCl
3, ppm) δ: 7.95 (brs, 1H, NH), 7.88 (d, 1H, J
1=7.8Hz, PhH), 7.68 (d, 1H, J=1.8Hz, Ph ' H), 7.26-7.17 (m, 3H, 2 * PhH&1 * Ph ' H), 7.12-7.07 (m, 2H, Ph ' H), 5.72 (s, 2H, NH
2), 3.86 (s, 2H, S-CH
2), 2.17 (s, 3H, CH
3) .MS (ESI): m/z512.2 (M+1), 514.2 (M+3), 516.1 (M+5) .C
18H
15Br
2N
3OS
2(510.90).
Synthesizing of embodiment 3.2-(2-chloro-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl) N-arylacetamide (I-B8)
2-(2-amino-4-(2; The 4-dibromo phenyl) thiazole-5-sulfydryl)-mixture of N-arylacetamide I-A8 (1mmol), anhydrous cupric chloride (1.5mmol) and acetonitrile (15mL) is under stirring at room and nitrogen protection; Drip nitrite tert-butyl (1.5mmol) in the 15min, the slight heat release of solution this moment is also emitted with nitrogen.Dropwise the back mixture and stir 2h.Add 15mL water and 15mL chloroform then and use the 5N hcl acidifying.Separate water layer and add chloroform that (2 * 15mL) extract.Obtain organic solvent and use anhydrous Na
2SO
4Drying, evaporated under reduced pressure then, residue is with ETHYLE ACETATE: sherwood oil=1: 4 is got compound 2-(2-chloro-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl) N-arylacetamide IX-B8 through the silica gel rapid column chromatography.
Different 2-(2-amino-4-(2, the 4-dibromo phenyl) thiazole-5-sulfydryl) N-arylacetamide I-A8 obtains title product I-B8 through above-mentioned chlorination, and partial results is following:
Operate the samely, different is is reaction substrate with I-A8a.White powder, yield: 55.8%.mp:129-130 ℃.
1H-NMR (DMSO-d6, ppm) δ: 9.71 (s, 1H, NH), 8.02 (d, 1H, J=1.8Hz, PhH), 7.70 (d, 1H, J=7.8Hz, Ph ' H), 7.60 (dd, 1H, J
1=8.4Hz, J
2=1.8Hz, PhH), 7.50 (d, 1H, J=8.4Hz, PhH), 7.39 (d, 1H, J=7.8Hz, Ph ' H), 7.35 (t, 1H, Ph ' H), 7.22 (t, 1H, Ph ' H), 3.78 (s, 2H, S-CH
2) .MS (ESI): m/z 551.1 (M+1), 553.1 (M+3), 555.0 (M+5) .C
17H
10Br
2Cl
2N
2OS
2(549.80).
Operate the samely, different is is reaction substrate with I-A8b.The white needle, yield: 48.6%.mp:106-109 ℃.
1H-NMR (DMSO-d6, ppm) δ: 9.95 (s, 1H, NH), 8.01 (d, 1H, J
1=1.2Hz, Ph ' H), 7.90-7.87 (m, 1H, PhH), 7.58 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.39 (d, 1H, J=8.4Hz, Ph ' H), 7.29-7.25 (m, 1H, PhH), 7.20-7.18 (m, 2H, Ph ' H), 3.76 (s, 2H, S-CH
2) .MS (ESI): m/z 535.0 (M+1), 537.0 (M+3), 539.1 (M+5) .C
17H
10Br
2ClFN
2OS
2(533.83).
Operate the samely, different is is reaction substrate with I-A8c.White solid, yield: 62.3%.mp:160-162 ℃.
1H-NMR (DMSO-d6, ppm) δ: 9.66 (s, 1H, NH), 8.02 (d, 1H, J=1.8Hz, Ph ' H); 7.66 (d, 1H, J=7.8Hz, PhH), 7.62 (dd, 1H, J=1.8Hz, J=7.8Hz; PhH), 7.60 (d, 1H, J=7.2Hz, Ph ' H), 7.42-7.38 (m, 2H; 1 * Ph ' H&1 * PhH), 7.17-7.15 (t, 1H, Ph ' H), 3.77 (s, 2H, S-CH
2) .MS (ESI): m/z 595.4 (M+1), 597.1 (M+3), 599.2 (M+5) .C
17H
10Br
3ClN
2OS
2(593.75).
Operate the samely, different is is reaction substrate with I-A8d.The white needle, yield: 69.4%.mp:173-174 ℃.
1H-NMR (DMSO-d6, ppm) δ: 8.40 (s, 1H, NH), 8.23 (d, 1H, J=8.4Hz, Ph ' H), 7.71 (d; 1H, J=2.4Hz, PhH), 7.41 (d, 1H, J=1.8Hz, Ph ' H), 7.33 (dd; 1H, J=2.4Hz, J=8.4Hz, PhH), 7.27 (dd, 1H, J=1.8Hz, J=8.4Hz; Ph ' H), 7.13 (d, 1H, J=8.4Hz, PhH), 3.55 (s, 2H, S-CH
2) .MS (ESI): m/z 585.3 (M+1), 587.1 (M+3), 589.1 (M+5) .C
17H
9Br
2Cl
3N
2OS
2(583.76).
Operate the samely, different is is reaction substrate with I-A8e.White solid, yield: 75.8%.mp:168-170 ℃.
1H-NMR (DMSO-d6, ppm) δ: 8.64 (d, 1H, J=7.8Hz, pyridine-H), 8.46 (brs, 1H, NH), 8.17 (dd, 1H, J=1.8Hz, J=4.8Hz, pyridine-H), 7.74 (d, 1H, J=1.8Hz, PhH), 7.40 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.31-7.26 (m, 1H, PhH), 7.17 (d, 1H, J=7.8Hz, pyridine-H), 3.57 (s, 2H, S-CH
2) .MS (ESI): m/z552.1 (M+1), 554.1 (M+3) .C
16H
9Br
2Cl
2N
3OS
2(550.79).
Operate the samely, different is is reaction substrate with I-A8f.Yellow solid, yield: 70.8%.mp:187-189 ℃.
1H-NMR (DMSO-d6, ppm) δ: 10.42 (s, 1H, NH), 7.99 (d, 1H, J=1.8Hz, Ph ' H), 7.83 (d, 1H, J=1.8Hz, PhH), 7.59 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, Ph ' H), 7.58-7.54 (m, 2H, PhH), 7.39 (d, 1H, J=8.4Hz, Ph ' H), 3.74 (s, 2H, S-CH
2), 2.38 (s, 3H, CH
3) .MS (ESI): m/z 576.2 (M+1), 578.3 (M+3), 580.2 (M+5) .C
18H
12Br
2ClN
3O
3S
2(574.84).
Operate the samely, different is is reaction substrate with I-A8g.Yellow solid, yield: 56.2%.mp:137-138 ℃.
1H-NMR (DMSO-d6, ppm) δ: 10.51 (s, 1H, NH), 8.01 (d, 1H, J=1.8Hz, Ph ' H), 7.99 (d, 1H, J=1.8Hz, PhH), 7.74 (t, 1H, Ph ' H), 7.70-7.60 (d, 1H, J=8.4Hz, PhH), 7.60 (dd, 1H, J
1=1.8Hz, J
2=8.4Hz, PhH), 7.42-7.40 (m, 2H, Ph ' H), 3.77 (s, 2H, S-CH
2) .MS (ESI): m/z 562.2 (M+1), 564.2 (M+3), 566.3 (M+5) .C
17H
10Br
2C1N
3O
3S
2(560.82).
Operate the samely, different is is reaction substrate with I-A8h.White solid, yield: 47.6%.mp:174-176 ℃.
1H-NMR (DMSO-d6, ppm) δ: 9.48 (brs, 1H, NH), 8.04 (d, 1H, J=2.4Hz, PhH); (7.62 dd, 1H, J=1.8Hz, J=8.4Hz, Ph ' H), 7.42 (d, 1H, J=8.4Hz; PhH), 7.37 (d, 1H, J=8.4Hz, PhH), 7.22-7.17 (m, 2H; Ph ' H), 7.10 (t, 1H, Ph ' H), 3.74 (s, 2H, S-CH
2), 2.12 (s, 3H, CH
3) .MS (ESI): m/z 431.1 (M+1), 533.1 (M+3), 535.1 (M+5) .C
18H
13Br
2ClN
2OS
2(529.85).
The external HIV-resistant activity test of embodiment 4. target compounds
(referring to (20,309. 2. for 1. Pauwels R, et al.J.Virol.Methods.1988
Pannecouque C, et al.Nat Protocols2008,3,427.)
Terminological interpretation:
MT-4 cell: people's acute lymphoblastic leukemia cell.
MTT analytical method: MTT is 3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt, trade(brand)name: tetrazolium bromide.
Nevirapine (NVP): anti-AIDS marketed drug nevirapine.
AZT: anti-AIDS marketed drug zidovudine.
DMSO: DMSO 99.8MIN..
Test philosophy
Because pathology can take place in the MT-4 cell that HIV infects (5-7 days) within a certain period of time; Therefore the compound solution to be detected that in the MT-4 cell suspension that HIV infects, adds proper concn; Through after a while after the cultivation of (5-7 days); With MTT assay MT-4 cell viability, 50% cell that is protected avoids cytopathic drug level (EC
50) can draw the activity of the anti-HIV of target compound.Obtain target compound simultaneously and make the 50% concentration (CC of the cell generation pathology of infected by HIV not
50), calculate and select coefficient (selectivity index, SI=CC
50/ EC
50).
MTT analytical method principle: MTT is bromination-3-(4,5-dimethyl--2-thiazolyl)-2, and 5-phenylbenzene tetrazolium nitrogen can combine with succinodehydrogenase in the cell of living, and not react with dead cell.Mtt assay is a kind of method of analyzing enzyme that fast, succinctly reflects cell viability at present.
Test material and method
(1) HIV-1 (IIIB), HIV-2 (ROD) strain, various HIV-1 persister: provide by Belgian Leuven university Rega research institute mikrobe and immunology institute.
(2) MT-4 cell: provide by Belgian Leuven university Rega research institute mikrobe and immunology institute.
(3) MTT: available from U.S. Sigma company.
(4) sample preparation: sample faces with before being dissolved in DMSO and is made into proper concn, and does 5 times of dilutions with distilled water, each 5 extent of dilution.
(5) positive control drug: Nevirapine (NVP), AZT.
(6) testing method: join HIV behind the diluted sample and infect in the MT-4 cell suspension,, in ELIASA, under 590m, write down absorbancy (A) and be worth with MTT colorimetric method for determining cell viability, calculate EC through back after a while
50, CC
50And SI.
(7) MTT staining: add sample cultivation after for some time, add MTT solution (5mg/ML) 20 μ L to every hole again, continue to cultivate some hrs; Abandon staining fluid, and add 150 μ L DMSO, thorough mixing to every hole; In ELIASA, record absorbancy under 590nm.
Concrete operations are following: with compound with DMSO or water dissolution after with phosphate buffered saline buffer dilution, with 3 * 10
5The compound solution of MT-4 cell and 100 μ L different concns is at 37 ℃ of common preincubate 1h.In this mixture, add the viral dilution liquid of 100 μ L proper concns then, cell is hatched 1h in 37 ℃.After washing three times, cell is suspended in respectively once more contains or do not contain in the culture medium of compound.Follow cell at 5%CO
2In the environment, under 37 ℃, hatched again 7 days, and replenished original fluid with the culture medium that contains or do not contain compound in metainfective the 3rd day.All twice of the repetitive operations of every kind of culture condition.Cytopathic effect to virus all uses reverse opticmicroscope to monitor every day.In general, cytopathy usually can be behind virus infection takes place on the 5th day in used viral dilution liquid in this experiment.The medicine inhibition concentration with medicine to pathological changes caused by virus effect produce 50% restraining effect and simultaneously pair cell do not have direct toxic concentration (EC
50) expression.What be worth to stress is, relatively poor when compound water soluble, and when needing could dissolve with DMSO, the DMSO volume by volume concentration is with respect to water, generally can be lower than 10% (DMSO in the MT-4 cell culture medium ultimate density less than 2%).Because DMSO can influence the test compounds antiviral activity, the antiviral activity contrast blank assay that contains same concentrations DMSO solution also should be carried out by parallel running.In addition, DMSO ultimate density (1/1000) is duplicated desired concn well below influencing HIV-1 in the T-cell.
The external anti-HIV-1 (IIIB) of target compound, HIV-2 (ROD) and multiple persister screening active ingredients data are provided by Belgian Leuven university Rega research institute mikrobe and immunology institute, and all activity datas all record through at least twice independence, parallel experiment.
The external anti-influenza virus activity test of embodiment 5. target compounds
(referring to 1. Vanderlinden E, et al.J Virol.2010,84 (9): 4277-88. is Naesens L 2., et al.Antiviral Res.2009,82 (1): 89-94.)
Test philosophy
Virus is in the animal of the work of susceptible, chicken embryo or cell, just can duplicate propagation.Therefore available animal, chicken embryo or cell carry out the antivirus test of virus culture and medicine.Can pass through the change of the corresponding indexs such as variation, pathological changes caused by virus effect (CPE), virus titer (PFU) change, the variation of viral genome mRNA level, chick embryo allantoic liquid or animal serum of observation of cell nutrient solution potential of hydrogen, judge the antivirus test effect of medicine.
Virus CCID
50Titration principle: behind the cell of most virus infection vitro culture; Often cause that morphocytology changes; As cell mass contract, cracking and cell enlargement etc., this change be called virus cause a disease change effect (cytopathic effect, CPE); Can also can be able to identification and judgement directly through microscopic examination through dyeing.The degree of CPE can reflect the virulence of virus indirectly, therefore utilizes this characteristic can be used for measuring the virulence of virus.Can be defined as 50% cell infection index (50%cell culture infective dose, the CCID of virus cultivating plate hole or in vitro causing the required virus quantity of half cell generation pathology
50).In the antivirus test of medicine, 100CCID commonly used
50The virus infection scale levy.50CCID is adopted in this test
50The virus infection amount.
Test material
(1) influenza A/H1N1 (strain A/Puerto Rico/8/34), A/H3N2 (strain A/HK/7/87) and influenza B (strain B/HK/5/72): provide by Belgian Leuven university Rega research institute mikrobe and immunology institute.
(2) mdck cell: (Madin Darby canine kidney cells MDCK), is provided by Belgian Leuven university Rega research institute mikrobe and immunology institute the dog renal epithelial cell.
(3) MTS:3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyl phenyl)-2-(4-sulphenyl)-2H-tetrazole is available from U.S. Sigma company.
(4) sample preparation: sample faces with before being dissolved in DMSO and is made into proper concn, does 5 times of dilutions with distilled water, each 5 extent of dilution.
(5) positive control drug: oseltamivir phosphate (Tamiflu, Oseltamivir carboxylate), ribavirin (Ribavirin), amantadine (Amantadine) and Rimantadine (Rimantadine).
Testing method
Cause cell mutation effect method (CPE)
Viral original seed is seeded in the chicken embryo of 9～10 ages in days, collects allantoic fluid, titration in mdck cell behind the infection 48h.Mdck cell is suspended in by in the infection medium
.Then transfer on 96 orifice plates, 7500 cells are contained in every hole, and under 35 ℃, hatch 20 hours.Then, testing compound and the virus with serial dilution joins (infection multiplicity: every hole 50CCID in the substratum together
50Be equivalent to 0.0003 plaque forming unit in every hole), under 35 ℃, continue to hatch.After infecting 72 hours, carry out the cytopathic effect (CPE) of observed and recorded virus induction with microscope, calculate by the Reed-Muench method and can suppress the medicine effective concentration (EC that 50%CPE produces
50).The Reed-Muench formula is:
CCID
50=be higher than the logarithm of logarithm+distance proportion * dilution factor of the dilution inverse of 50% infection
Distance proportion=(percentage ratio-50% that is higher than 50% infection)/(percentage ratio that is higher than the infection of the percentage ratio of 50% infection-be lower than 50%)
The MTS method
Active result is further confirmed by the MTS cytoactive test based on the Jia Za.Basic step is the same, and when virus control group cell CPE abandons the nutrient solution supernatant 75%～100% the time, every hole adds and contains 5gL
-1The nutrient solution 50 μ L of MTS discard the MTS supernatant after continuing to cultivate 2～3h, and every hole adds DMSO 100 μ L, behind the mixing 5min, surveys the absorbance A value of 570nm wavelength with ELIASA.Calculate the inhibiting rate of medicine according to the following equation to virus:
Virus inhibiting rate=(drug-treated group A average-virus control group A average)/(cell control group A average-virus control group A average) * 100%; In conjunction with the cell toxicity test result; With the Probit Return Law of statistics software SPSS, or protect 50% influenza virus infection cell to avoid the compound concentration (EC of pathology by Reed-Muench method computerized compound
50) and make the compound concentration (CC of 50% uninfecting virus cell generation pathology
50).
Claims (5)
1. the thiazole-substituted mercaptoacetamide derivative that has general formula I, and pharmacy acceptable salt:
Wherein,
R is amino, chlorine atom, fluorine atom, bromine atoms, iodine atom, hydroxyl, methyl or ethyl;
Ar
1Be 2,4-dihalo phenyl ring;
Ar
2For having 2 of general formula I I, 4-disubstituted benzenes ring or 2,4-two replacement hexa-member heterocycles;
Wherein, X, Y, Z are respectively carbon atom or nitrogen-atoms; R
1Be H, F, C1, Br, I, NO
2Or Me; R
2Be H, F, Cl, Br, I, Me, OCH
3, COMe, COOMe, COOEt, COOH or SO
2NH
2
2. thiazole-substituted mercaptoacetamide derivative as claimed in claim 1, the pharmacy acceptable salt that it is characterized in that said compound is a hydrochloride, vitriol, tartrate or Citrate trianion.
3. the preparation method of the described thiazole-substituted mercaptoacetamide derivative of claim 1, step is following:
Reaction scheme is following:
Concrete preparation method is: substituted aryl ethyl ketone 1 ' or replacement aromatic ring 1 obtain 2-chlorine (bromine)-1-substituted aryl ethyl ketone 2 through halogenating reaction or Friedel-Crafts reaction respectively; 2 hour obtain thioether 3 with 2-ethyl thioglycolate room temperature reaction number in ethanolic soln, not purified directly down the step react, obtain preparing Basedol heterocyclic important intermediate 4 at the alpha-position bromo; Then, this compound and thiocarbamide cyclization obtain 2-(2-amino-4-substituted aryl-thiazole-5-sulfydryl) ETHYLE ACETATE 5 of high yield; At NaOH-DMSO-H
2In the O solution, compound 5 hydrolytic reactions generate aminothiazole acid 6, and then change into corresponding Acetyl Chloride 98Min. 7; Under the condition of triethylamine, compound 7 obtains corresponding 2-(2-amino-4-substituted aryl-thiazole-5-sulfydryl)-N-acetamide derivative A8 with different substituted aromatic amines reactions; In addition, obtain halo thiazole mercapto acetamide derivative B8 through diazotization and halogenating reaction on this basis.
4. the application of compound in preparing treatment and prevention human immunodeficiency virus (HIV), influenza infection medicine according to claim 1 or claim 2.
5. a pharmaceutical composition comprises claim 1 or 2 said compounds and one or more pharmaceutically acceptable carriers or vehicle.
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