CN101723903A - 4-carbonyl diaryl pyridine derivatives as well as preparation methods and applications thereof - Google Patents
4-carbonyl diaryl pyridine derivatives as well as preparation methods and applications thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, in particular to 4-carbonayl diaryl pyridine derivatives (CO-DAPYs) shown as a general formula I as well as preparation methods and applications thereof. The compounds of the 4-carbonyl diaryl pyridine derivatives also comprise medicinal salts, stereochemical isomers, hydrates, solvates, polycrystals and eutectics, precursors with same biological functions and derivatives thereof. A pharmacological test result shows that the compounds have remarkable anti-HIV-1 virus activity and show better inhibiting effect to common mutated virus strains in clinic, therefore, the compositions containing one or a plurality of compounds can be used for preparing related medicines for treating Aids, and the like.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of 4-carbonyl diaryl pyridine derivatives and its production and use.
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) is that acquired immune deficiency syndrome (AIDS) (Acquired immune deficiency syndrome) is by human immunodeficiency virus (Human immunodeficiency virus, the HIV) epidemic infectious diseases that is caused.
(Reverse transcriptase RT) has become the process of DNA decisive role at HIV to reversed transcriptive enzyme from the mRNA reverse transcription, therefore become one of important target spot of anti-AIDS drug design.
In existing inverase research, non-nucleoside reverse transcriptase inhibitor (NNRTIs) becomes one of focus of various countries' Pharmaceutical Chemist concern because of advantages such as its high-efficiency low-toxicities.At present, anti-hiv reverse transcriptase inhibitor through the drugs approved by FDA listing has four kinds: how Wella is put down (Nevirapine), De Laweiding (Delavirdine), Yi Feiweilun (Efavirenz), Etravirine (TMC-125), α-APA089439, HBY097 in addition, TMC278 etc. are carrying out clinical study.
Summary of the invention
The objective of the invention is to propose a kind of reverse transcriptase inhibitors 4-carbonyl diaryl miazines (CO-DAPYs) derivative.
Another purpose of the present invention is to propose the preparation method of above-claimed cpd.
Still a further object of the present invention is the application that proposes above-claimed cpd.
Diarylmiazines derivatives (DAPYs) is the NNRTIs that the class found in recent years has higher HIV (human immunodeficiency virus)-resistant activity, through a series of structure of modification, has developed a series of compounds with better prospect.The present invention adopts the means of area of computer aided SARS drug design to simulate the mode of action and the structure activity relationship of such inhibitor and HIV-1RT, instructs further structure of modification with this.Replace at the α position of pyrimidine ring 4-position carbonylate, in the hope of adding potent inhibitor and amino-acid residue Tyr188 on every side, the π between the Tyr181～pi accumulation effect; In the C5-position of pyrimidine ring, substituting group is introduced in the C6-position simultaneously, with the synergy of reinforcement and carbonyl, disturbs the katalysis of amino-acid residue Asp; A series of 4-carbonyl diaryl miazines (CO-DAPYs) derivative has been synthesized in design, and it has been carried out biological activity test, and the result shows that majority of compounds has stronger anti-HIV-1 virus function, higher selectivity index.
The present invention has designed and synthesized 4-carbonyl diaryl miazines (CO-DAPYs) derivative of a series of brand news according to the analytical results of area of computer aided SARS drug design.
Above-claimed cpd provided by the invention has following general structure:
Wherein, R
1And R
2Be selected from hydrogen respectively, hydroxyl, halogen, substituted C
1-4Alkyl, substituted C
2-6Thiazolinyl, substituted C
2-6Alkynyl, C
1-6Alkoxyl group, cyano group, nitro, amino ,-NH (OH)-, or-N (R
4) p-.
R
3Be selected from hydrogen, hydroxyl, halogen, by cyano group or-C (=O) R
5The C that replaces
1-6Alkyl, C
3-7Cycloalkyl is by the C of one or more halogen atoms or cyano group replacement
2-6Thiazolinyl is by the C of one or more halogen atoms or cyano group replacement
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Carbalkoxy, carboxyl, cyano group, nitro, amino ,-NR
5-, many halogenated methyls, many halogenated methoxies, many halos methylthio group ,-S (=O)
pR
5,-NH-S (=O)
pR
5,-C (=O) R
5,-NHC (=O) H ,-C (=O) NHNH
2,-NHC (=O) R
5, or-C (=NH) R
5
Ar is selected from aryl, substituted aryl, naphthyl, substituted naphthyl, anthryl, replace anthryl, phenanthryl replaces phenanthryl, pyrryl, the substituted azole base, pyrazolyl, substituted pyrazolecarboxylic base, imidazolyl, the substituted imidazole base, triazolyl, substituted triazole base, tetrazyl, replace tetrazyl, benzimidazolyl-, substituted benzimidazole base, benzotriazole base, replace the benzo triazolyl, furyl, substituted furan base, oxazolyl, the substituted oxazoline base, isoxazolyl replaces isoxazolyl, benzoxazolyl, replace benzoxazolyl, thienyl, substituted thiophene base, thiazolyl, substituted thiazolyl, benzothiazolyl, substituted benzene benzothiazolyl, pyridyl, substituted pyridinyl, quinolyl, substd quinolines base, isoquinolyl, the substituted isoquinoline base, acridyl replaces acridyl, pyridazinyl, replace pyridazinyl, pyrimidyl, substituted pyrimidyl, pyrazinyl, replace pyrazinyl, triazinyl, purine radicals, substituted purinyl, other five yuan or hexa-atomic aromatic heterocyclic, the hexa-atomic aromatic heterocyclic of benzo five-membered or benzo replaces benzo five-membered or the hexa-atomic aromatic heterocyclic of replacement benzo, C
1-6Carbalkoxy, aryloxy carbonyl, or replace aryloxy carbonyl.
X is selected from-NR
4-,-NH-NH-,-N=N-,-O-,-C (=O)-, C
1-4Alkane two bases ,-CH (OH)-,-S-,-S (=O) p-,-X
1-C
1-4Alkane two bases-or-C
1-4Alkane two bases-X
1-, or-CH (CN)-.
X
1For-NR
4-,-NH-NH-,-N=N-,-O-,-C (=O)-,-CH (OH)-, or-S (=O) p-.
R
4Be selected from hydrogen, aryl, formyl radical, C
1-6Alkyl-carbonyl, C
1-6Alkyl, C
1-6Carbalkoxy is by formyl radical, C
1-6Alkyl-carbonyl, C
1-6Carbalkoxy or C
1-6The C that alkyl carbonyl oxy replaces
1-6Alkyl is by C
1-6The C that carbalkoxy replaces
1-6Alkoxyl group or C
1-6Carbalkoxy.
R
5Be C
1-4Alkyl, amino, single or two (C
1-4Alkyl) amino or many halos C
1-4Alkyl.
M is the integer of 0-5, and n is the integer of 0-6.
P is 1 or 2.
The preparation method of this compounds is as follows:
Under protection of inert gas, be reactant with the itrile group Diarylmiazines derivatives, react acquisition product of the present invention down in alkali (as Lithamide (sodium), sodium hydride, n-Butyl Lithium, diisobutyl amido lithium, or potassium tert.-butoxide) effect, its reaction expression is as follows:
Wherein:
The concrete operations step is as follows: the itrile group Diarylmiazines derivatives is joined in the dry polar aprotic solvent, stir and make it dissolving, add alkali (as Lithamide (sodium), sodium hydride, n-Butyl Lithium, diisobutyl amido lithium, or potassium tert.-butoxide), in 20-35 ℃, stirring reaction 24～36h.After TLC showed that reaction finishes, reaction solution poured in the cold water, ethyl acetate extraction, drying.Remove solvent under reduced pressure, obtain crude product.Re-crystallizing in ethyl acetate gets pure product.Wherein:
(1) alkali (Lithamide (sodium), sodium hydride, n-Butyl Lithium, diisobutyl amido lithium, potassium tert.-butoxide) is excessive, is about about 1.8～2.3 times of itrile group Diarylmiazines derivatives.
(2) used solvent is tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether (MTBE), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA), or acetonitrile.1mmol 4-chloropyrimide derivative need add aprotic solvent 5～8mL.
(3) rare gas element is nitrogen, argon gas or helium.
This compounds class can be made hydrochloride, vitriol, tartrate, Citrate trianion, fumarate, malate and pharmaceutically acceptable prodrug and derivative use.
Compound of the present invention is a kind of synthetic simple brand-new anti HIV-1 virus reagent, can be used as the drug candidates of anti-HIV.The biological activity test of cell levels shows:
(1) this compounds generally has good anti-HIV-1 virus activity, and wherein part of compounds not only demonstrates other biological activity of nmole level, and demonstrates higher selectivity index.
(2) in institute's synthetic compound, part of compounds demonstrates good inhibitory effect to clinical common mutations virus strain.
The The compounds of this invention novel structure has anti-preferably HIV biological activity, and cytotoxicity is less; Compounds process for production thereof is simple, can be used to develop anti-AIDS medicine.
Embodiment
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited.
Synthesizing of embodiment 1:4-carbonyl diaryl miazines (CO-DAPYs) derivative
Under the protection of rare gas element; 4-(4-(cyano group (phenyl) methyl) pyrimidine-2-amino) cyanobenzene (2.4mmol) is joined in the anhydrous aprotic solvent of 20mL; stirring makes it dissolving;, add alkali (Lithamide (sodium), sodium hydride; n-Butyl Lithium; diisobutyl amido lithium, potassium tert.-butoxide) (4.8mmol), stirring at room reaction 24～36h.TLC shows that reaction finishes, and reaction solution pours in the 60mL cold water, and ethyl acetate extraction (10mL * 3) merges organic layer, anhydrous magnesium sulfate drying.Filter, remove solvent under reduced pressure, obtain crude product.Re-crystallizing in ethyl acetate gets pure product.
Yellow powdery solid, yield 70.1%; Fusing point: 220.0-223.8 ℃;
1H NMR (DMSO-d
6) δ (ppm) 7.34 (d, 1H, J=4.8Hz, H
5), 7.58 (d, 2H, J=7.2Hz, Ar`H
3,5), 7.67 (d, 2H, J=8.8Hz, ArH
2,6), 7.71 (d, 2H, J=7.2Hz, Ar`H
4), 7.92 (d, 2H, J=8.8Hz, ArH
3,5), 7.98 (d, 2H, J=7.2Hz, Ar`H
2,6), 8.85 (d, 1H, J=4.8Hz, H
6), 10.45 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 103.4,112.2,119.0 (2C), 119.9,129.1 (2C), 130.9 (2C), 133.5 (2C), 134.5,135.3,144.9,159.2,160.9,162.8,193.2.MS (EI) m/z 300 (M
+).
With different 4-itrile group Diarylmiazines derivatives is raw material, makes target compound respectively with aforesaid method, and partial results is as follows:
Yellow powdery solid, yield 70.8%; Fusing point: 193.6-194.9 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.41 (s, 3H, CH
3), 7.29 (d, 1H, J=4.8Hz, H
5), 7.38 (d, 2H, J=8.0Hz, Ar`H
3,5), 7.68 (d, 2H, J=8.8Hz, ArH
2,6), 7.89 (d, 2H, J=8.0Hz, Ar`H
2,6), 7.93 (d, 2H, J=8.8Hz, ArH
3,5), 8.82 (d, 1H, J=4.8Hz, H
6), 10.45 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 21.8,103.4,112.1,119.0 (2C), 119.9,129.7 (2C), 131.1 (2C), 132.6,133.5 (2C), 145.0,145.3,159.2,160.7,163.2,192.6.MS (ESI) m/z 315 (M
++ 1).
Yellow powdery solid, yield 75.5%; Fusing point: 196.8-197.4 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.37 (s, 3H, CH
3), 7.31 (d, 1H, J=4.8Hz, H
5), 7.44-7.55 (m, 2H, Ar`H
3,5), 7.67 (d, 2H, J=8.8Hz, ArH
2,6), 7.75-7.79 (m, 2H, Ar`H
2,6), 7.93 (d, 2H, J=8.8Hz, ArH
3,5), 8.83 (d, 1H, J=4.8Hz, H
6), 10.48 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 21.3,103.4,112.2,119.0 (2C), 119.9,128.3,129.0,131.1,133.4 (2C), 135.1,135.2,138.6,159.2,160.8,162.9,193.3.MS (EI) m/z 314 (M
+).
Yellow powdery solid, yield 62.8%; Fusing point: 176.3-176.8 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.33 (s, 3H, CH
3), 7.33-7.55 (m, 5H, H
5+ Ar`H), 7.58 (d, 2H, J=8.8Hz, ArH
2,6), 7.81 (d, 2H, J=8.8Hz, ArH
3,5), 8.86 (d, 1H, J=4.8Hz, H
6), 10.43 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 20.6,103.3,111.7,118.9 (2C), 119.9,126.0 (2C), 130.8,131.6,132.1,133.3 (2C), 136.6,137.9,144.9,159.5,161.2,196.7.MS (ESI) m/z 315 (M
++ 1).
Light yellow crystal, yield 77.2%; Fusing point: 226.2-226.8 ℃;
1HNMR (DMSO-d
6) δ (ppm) 7.35 (d, 1H, J=4.8Hz, H
5), 7.64-7.70 (m, 4H, ArH
2,6+ Ar`H
3,5), 7.91 (d, 2H, J=8.8Hz, ArH
3,5), 8.03 (d, 2H, J=8.8Hz, Ar`H
2,6), 8.86 (d, 1H, J=4.8Hz, H
6), 10.47 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 103.5,112.3,119.0 (2C), 119.9,129.3 (2C), 132.9 (2C), 133.5 (2C), 134.0,139.5,144.9,159.2,161.0,162.2,192.0.MS (EI) m/z 334 (M
+).
The light green crystal, yield 68.4%; Fusing point: 215.6-216.3 ℃;
1H NMR (DMSO-d
6) δ (ppm) 7.35 (d, 1H, J=4.8Hz, H
5), 7.68 (d, 2H, J=8.4Hz, ArH
2,6), 7.80 (d, 2H, J=8.0Hz, Ar`H
3,5), 7.89-7.94 (m, 4H, ArH
3,5+ Ar`H
2,6), 8.86 (d, 1H, J=4.8Hz, H
6), 10.46 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 103.5,112.3,119.0 (2C), 119.9,128.7,132.2 (2C), 132.9 (2C), 133.5 (2C), 134.3,144.9,159.2,161.0,162.1,192.3.MS (ESI) m/z 379 (M
++ 1).
Yellow powdery solid, yield 67.4%; Fusing point: 200.8-201.2 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.53 (s, 3H, CH
3), 7.25 (s, 1H, H
5), 7.58 (d, 2H, J=7.6Hz, Ar`H
3,5), 7.64 (d, 2H, J=8.8Hz, ArH
2,6), 7.71 (t, 1H, J=7.6Hz, Ar`H
4), 7.92 (d, 2H, J=8.8Hz, ArH
3,5), 7.97 (d, 2H, J=7.6Hz, Ar`H
2,6), 10.39 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 24.5,103.2,111.8,118.9 (2C), 119.9,129.1 (2C), 130.9 (2C), 133.4 (2C), 134.4,135.4,145.2,159.1,162.4,170.8,193.5.MS (ESI) m/z 315 (M
++ 1).
The white powdery solid, yield 73.0%; Fusing point: 219.9-220.5 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.41 (s, 3H, CH
3), 2.51 (s, 3H, CH
3), 7.20 (s, 1H, H
5), 7.38 (d, 2H, J=8.0Hz, Ar`H
3,5), 7.66 (d, 2H, J=8.4Hz, ArH
2,6), 7.88 (d, 2H, J=8.0Hz, Ar`H
2,6), 7.94 (d, 2H, J=8.4Hz, ArH
3,5), 10.38 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 21.8,24.5,103.1,111.7,118.8 (2C), 119.9,129.7 (2C), 131.0 (2C), 132.7,133.5 (2C), 145.1,145.2,159.0,162.8,170.7,192.9.MS (EsI) m/z 329 (M
++ 1).
Yellow powdery solid, yield 62.3%; Fusing point: 135.6-136.1 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.38 (s, 3H, CH
3), 2.53 (s, 3H, CH
3), 7.25 (s, 1H, H
5), 7.45-7.56 (m, 2H, Ar`H
3,5), 7.66 (d, 2H, J=8.8Hz, ArH
2,6), 7.76-7.80 (m, 2H, Ar`H
2,6), 7.94 (d, 2H, J=8.8Hz, ArH
3,5), 10.42 (s, 1H, NH).
13CNMR (DMSO-d
6) δ (ppm) 21.3,24.5,103.1,111.7,118.8 (2C), 119.9,128.2,129.0,131.1,133.4 (2C), 135.1,135.4,138.6,145.2,159.1,162.6,170.7,193.6.MS (EI) m/z 328 (M
+).
Yellow powdery solid, yield 62.5%; Fusing point: 146.7-147.2 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.32 (s, 3H, CH
3), 2.54 (s, 3H, CH
3), 7.33-7.52 (m, 5H, H
5+ Ar`H), 7.55 (d, 2H, J=8.8Hz, ArH
2,6), 7.80 (d, 2H, J=8.8Hz, ArH
3,5), 10.39 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 20.5,24.5,103.1,111.3,118.8 (2C), 119.9,125.9,130.6,131.5,131.9,133.3 (2C), 136.9,137.7,145.1,159.4,161.7,171.2,197.0.MS (EI) m/z 328 (M
+).
Yellow powdery solid, yield 70.3%; Fusing point: 226.1-226.7 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.54 (s, 3H, CH
3), 7.29 (s, 1H, H
5), 7.66-7.69 (m, 4H, ArH
2,6+ Ar`H
3,5), 7.93 (d, 2H, J=8.4Hz, ArH
3,5), 8.03 (d, 2H, J=8.4Hz, Ar`H
2,6), 10.42 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 23.9,102.7,111.3,118.4 (2C), 119.4,128.7 (2C), 132.3 (2C), 132.9 (2C), 133.6,138.9,144.6,158.5,161.3,170.4,191.8.MS (EI) m/z 348 (M
+).
Yellow powdery solid, yield 64.9%; Fusing point: 236.2-236.5 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.54 (s, 3H, CH
3), 7.29 (s, 1H, H
5), 7.68 (d, 2H, J=8.8Hz, ArH
2,6), 7.81 (d, 2H, J=8.4Hz, Ar`H
3,5), 7.91-7.95 (m, 4H, ArH
3,5+ Ar`H
2,6), 10.42 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 24.0,102.7,111.3,118.4 (2C), 119.4,128.1,131.7 (2C), 132.3 (2C), 132.9 (2C), 133.0,133.9,144.6,158.5,170.4,192.0.MS (EI) m/z 394 (M
+).
Yellow powdery solid, yield 62.5%; Fusing point: 195.2-195.9 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.53 (s, 3H, CH
3), 3.89 (s, 3H, CH
3O), 7.11 (d, 2H, J=8.8Hz, Ar`H
3,5), 7.20 (s, 1H, H
5), 7.69 (d, 2H, J=8.4Hz, ArH
2,6), 7.95-8.02 (m, 4H, J=8.0Hz, ArH
3,5+ Ar`H
2,6), 10.41 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 24.5,56.2,103.1,111.7,114.6 (2C), 118.8 (2C), 120.2,127.9,133.4 (2C), 133.5 (2C), 145.2,159.0,163.3,164.4,170.6,191.6.MS (ESI) m/z 344 (M
++ 1).
The cotton-shaped solid of white, yield 42%; Fusing point: 231.4-232.1 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.55 (s, 3H, CH
3), 7.43 (s, 1H, H
5), 7.45-7.84 (m, 8H, ArH
2,6+ Ar`H), 8.08-8.25 (m, 3H, ArH
3,5+ Ar`H), 10.34 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 24.5,103.0,111.6,118.7 (2C), 119.9,125.2,125.7,127.1,128.4,129.2,130.8,130.9,133.1 (2C), 133.2,133.7,134.0,145.0,159.4,162.2,171.2,196.5.MS (ESI) m/z 365 (M
++ 1).
Yellow powdery solid, yield 72.0%; Fusing point: 164.7-166.3 ℃;
1H NMR (DMSO-d
6) δ (ppm) 2.54 (s, 3H, CH
3), 7.30 (s, 1H, H
5), 7.55-8.09 (m, 10H, ArH+Ar`H), 8.65 (s, 1H, Ar`H
1), 10.43 (s, 1H, NH).
13C NMR (DMSO-d
6) δ (ppm) 24.5,103.1,111.9,118.9 (2C), 119.9,125.4,127.6,128.3,128.9,129.7,130.3,132.3,132.6,133.4 (2C), 133.9,135.8,145.1,159.1,162.7,170.7,193.3.MS (ESI) m/z 365 (M
++ 1).
Embodiment 2 anti-HIV biological activity tests
The anti HIV-1 virus activity of cell in vitro level is measured by the Rega institute of materia medica of Belgian Katholleke university, mainly comprises: MT-4 cell inhibiting activity and cytotoxicity two aspects that HIV is infected.Method is described below: make compound in the MT-4 cell that HIV infects; in the infected by HIV different time; measure the cytopathic provide protection of medicine with mtt assay, calculate and make 50% cell avoid the required concentration medium effective concentration IC of HIV inductive cytopathy HIV mutagenesis
50, parallel the carrying out of toxicity test and HIV (human immunodeficiency virus)-resistant activity experiment also is in the MT-4 cell cultures, measures with mtt assay to make 50% non-infected cells that cytopathic concentration (CC take place
50), and calculate selectivity index SI=CC
50/ IC
50
Materials and methods:
The HIV (human immunodeficiency virus)-resistant activity of each compound is monitored the cytopathic restraining effect efficient that HIV causes in cell by medicine.Adopt the MT-4 cell to carry out cell cultures.The virus strain that adopts has: HIV-1 virus strain IIIB and HIV-2 virus strain ROD.
Concrete operations are as follows: with compound with DMSO or water dissolution after with the dilution of phosphate buffered common salt aqueous solution, with 3 * 10
5The MT-4 cell at 37 ℃ of pre-1h that cultivate, adds the suitable viral dilution liquid of 100 μ L with each this solution of compound different concns of 100 μ L then in this compound, cell is cultivated 1h in 37 ℃.After washing three times, cell is suspended in respectively once more contains or do not contain in the developing medium of compound.Follow cell at 5%CO
2In the atmosphere, under 37 ℃, cultivated again 7 days, and replace with the developing medium that contains or do not contain compound and replenish nutrient solution in infecting back the 3rd day.All twice of the repetitive operations of every kind of nutrient solution condition.Cytopathic effect to virus all uses reverse opticmicroscope to monitor every day.The typical case, used viral dilution liquid usually can be behind virus infection causes cytopathy on the 5th day in this experiment.The medicine inhibition concentration with medicine to the virocyte pathology effect produce 50% restraining effect and simultaneously pair cell do not have direct toxic concentration (CC
50) expression.It is emphasized that when compound water soluble relatively poorly, when needing could to dissolve with DMSO, the DMSO specific concentration generally is lower than 10% with respect to water, (DMSO in the MT-4 cell culture medium ultimate density less than 2%).Because DMSO can influence the antiviral activity of test compounds, also should parallelly carry out containing same concentrations DMSO solution antiviral activity contrast blank assay.In addition, DMSO ultimate density (1/1000) is duplicated required concentration well below influencing HIV-1 in the T cell.
The present invention nevirapine, delavirdine and efavirenz compare product, and the part target compound the results are shown in Table 1 to the inhibition activity of HIV.
Table?1.Anti-HIV?Activity?and?Cytotoxicity?of?Compounds?1-32?in?MT-4?Cells
aIC
50: make 50% normal cell avoid the required concentration of HIV-1 inductive cytopathy.
bCC
50: make 50% non-infected cells that cytopathic concentration take place.
cSI: selectivity index SI=CC
50/ IC
50
Experimental result shows that the compound that is comprised in the chemical structure of general formula generally has stronger anti-HIV-1 virus activity, less cytotoxicity and higher selectivity index.
The invention is not restricted to above-mentioned example.
Claims (7)
1. 4-carbonyl diaryl pyridine derivatives is characterized in that having following structural formula:
Wherein, R
1And R
2Be selected from hydrogen respectively, hydroxyl, halogen, substituted C
1-4Alkyl, substituted C
2-6Thiazolinyl, substituted C
2-6Alkynyl, C
1-6Alkoxyl group, cyano group, nitro, amino ,-NH (OH)-, or-N (R
4) p-;
R
3Be selected from hydrogen, hydroxyl, halogen, by cyano group or-C (=O) R
5The C that replaces
1-6Alkyl, C
3-7Cycloalkyl is by the C of one or more halogen atoms or cyano group replacement
2-6Thiazolinyl is by the C of one or more halogen atoms or cyano group replacement
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Carbalkoxy, carboxyl, cyano group, nitro, amino ,-NR
5-, many halogenated methyls, many halogenated methoxies, many halos methylthio group ,-S (=O)
pR
5,-NH-S (=O)
pR
5,-C (=O) R
5,-NHC (=O) H ,-C (=O) NHNH
2,-NHC (=O) R
5, or-C (=NH) R
5
Ar is selected from aryl, substituted aryl, naphthyl, substituted naphthyl, anthryl, replace anthryl, phenanthryl replaces phenanthryl, pyrryl, the substituted azole base, pyrazolyl, substituted pyrazolecarboxylic base, imidazolyl, the substituted imidazole base, triazolyl, substituted triazole base, tetrazyl, replace tetrazyl, benzimidazolyl-, substituted benzimidazole base, benzotriazole base, replace the benzo triazolyl, furyl, substituted furan base, oxazolyl, the substituted oxazoline base, isoxazolyl replaces isoxazolyl, benzoxazolyl, replace benzoxazolyl, thienyl, substituted thiophene base, thiazolyl, substituted thiazolyl, benzothiazolyl, substituted benzene benzothiazolyl, pyridyl, substituted pyridinyl, quinolyl, substd quinolines base, isoquinolyl, the substituted isoquinoline base, acridyl replaces acridyl, pyridazinyl, replace pyridazinyl, pyrimidyl, substituted pyrimidyl, pyrazinyl, replace pyrazinyl, triazinyl, purine radicals, substituted purinyl, other five yuan or hexa-atomic aromatic heterocyclic, the hexa-atomic aromatic heterocyclic of benzo five-membered or benzo replaces benzo five-membered or the hexa-atomic aromatic heterocyclic of replacement benzo, C
1-6Carbalkoxy, aryloxy carbonyl, or replace aryloxy carbonyl;
X is selected from-NR
4-,-NH-NH-,-N=N-,-O-,-C (=O)-, C
1-4Alkane two bases ,-CH (OH)-,-S-,-S (=O) p-,-X
1-C
1-4Alkane two bases-or-C
1-4Alkane two bases-X
1-, or-CH (CN)-;
X
1For-NR
4-,-NH-NH-,-N=N-,-O-,-C (=O)-,-CH (OH)-, or-S (=O) p-;
R
4Be selected from hydrogen, aryl, formyl radical, C
1-6Alkyl-carbonyl, C
1-6Alkyl, C
1-6Carbalkoxy is by formyl radical, C
1-6Alkyl-carbonyl, C
1-6Carbalkoxy or C
1-6The C that alkyl carbonyl oxy replaces
1-6Alkyl is by C
1-6The C that carbalkoxy replaces
1-6Alkoxyl group or C
1-6Carbalkoxy;
R
5Be C
1-4Alkyl, amino, single or two (C
1-4Alkyl) amino or many halos C
1-4Alkyl;
M is the integer of 0-5, and n is the integer of 0-6;
P is 1 or 2.
2. the preparation method of a 4-carbonyl diaryl pyridine derivatives as claimed in claim 1; it is characterized in that under protection of inert gas, is reactant with the itrile group Diarylmiazines derivatives, under the alkali effect; in polar aprotic solvent, carry out following reaction, promptly obtain described compound.
3. preparation method as claimed in claim 2 is characterized in that used rare gas element is an argon gas, nitrogen, or helium; Used solvent is a tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether, N, dinethylformamide, N,N-dimethylacetamide, or acetonitrile.
4. method as claimed in claim 2 is characterized in that used alkali is Lithamide, sodium hydride, n-Butyl Lithium, diisobutyl amido lithium, or potassium tert.-butoxide.
5. a pharmaceutical composition is characterized in that containing effective dose arbitrary compound as claimed in claim 1 and pharmaceutical carrier.
6. hydrochloride of compound according to claim 1, vitriol, tartrate, Citrate trianion, fumarate, malate and pharmaceutically acceptable prodrug and derivative.
7. one kind as claim 1, the application of 5,6 described compounds in preparation prevention and treatment AIDS-treating medicine.
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| CN102153517A (en) * | 2011-03-03 | 2011-08-17 | 复旦大学 | Diaryl pyrimidone hydrazone derivatives and preparation method and application of diaryl pyrimidone hydrazone derivatives |
| CN104876880A (en) * | 2015-04-27 | 2015-09-02 | 复旦大学 | Diaryl ether derivatives as well as preparation method and application thereof |
| CN110483417A (en) * | 2018-03-06 | 2019-11-22 | 云南大学 | A kind of DACOs class NNRTIs amino acid ester derivative, preparation method, pharmaceutical composition and application |
| CN114539162A (en) * | 2022-02-17 | 2022-05-27 | 复旦大学 | Substituted aryl-containing uretonimine diaryl pyrimidine derivatives, and preparation method and application thereof |
-
2009
- 2009-11-26 CN CN2009101993735A patent/CN101723903B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153517A (en) * | 2011-03-03 | 2011-08-17 | 复旦大学 | Diaryl pyrimidone hydrazone derivatives and preparation method and application of diaryl pyrimidone hydrazone derivatives |
| CN102153517B (en) * | 2011-03-03 | 2014-04-02 | 复旦大学 | Diaryl pyrimidone hydrazone derivatives and preparation method and application of diaryl pyrimidone hydrazone derivatives |
| CN104876880A (en) * | 2015-04-27 | 2015-09-02 | 复旦大学 | Diaryl ether derivatives as well as preparation method and application thereof |
| CN110483417A (en) * | 2018-03-06 | 2019-11-22 | 云南大学 | A kind of DACOs class NNRTIs amino acid ester derivative, preparation method, pharmaceutical composition and application |
| CN110483417B (en) * | 2018-03-06 | 2022-07-15 | 云南大学 | DACOs NNRTIs amino acid ester derivative, preparation method, pharmaceutical composition and application thereof |
| CN114539162A (en) * | 2022-02-17 | 2022-05-27 | 复旦大学 | Substituted aryl-containing uretonimine diaryl pyrimidine derivatives, and preparation method and application thereof |
| CN114539162B (en) * | 2022-02-17 | 2023-05-30 | 复旦大学 | Substituted aryl urea imino diaryl pyrimidine derivative and preparation method and application thereof |
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|---|---|
| CN101723903B (en) | 2012-02-08 |
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