CN103360398A - Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof - Google Patents
Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a triazolopyrimidine HIV-1 retrovirus inhibitor and its pharmaceutically acceptable salt, ester or prodrug, its preparation method and an application of one compound or a composition of more compounds in the preparation of anti-AIDS drugs.
Description
Technical field
The present invention relates to a kind of derivative and preparation method thereof and application, be specifically related to a kind of triazolo pyrimidine class HIV1-RT inhibitor and preparation method thereof and application, belong to medical technical field.
Background technology
Acquired immune deficiency syndrome (AIDS) also claims acquired immune deficiency syndrome (AIDS) (Acquired immunodeficiency syndrome, AIDS), be pathogenic agent by acquired immune deficiency syndrome (AIDS) be human immunodeficiency virus (Human immumodeficiency virus, HIV) cause take T cellular immune function defective as main a kind of communicable disease.Since 20th century, be found the eighties, acquired immune deficiency syndrome (AIDS) had become one of great communicable disease of serious harm human health.At present the most frequently used method of preventing and treating acquired immune deficiency syndrome (AIDS) is highly active antiretroviral therapy (Highly Active Antiretroviral Therapy clinically, HAART), although the enforcement of this therapy has improved the suppression efficiency of HIV virus greatly, because HIV virus very easily produces the application that the toxicity problem of variation and Long-term taking medicine has limited this therapy to a great extent.Therefore the anti-drug resistance treating AIDS medicine of research and development of new still tool be of great significance.Non-nucleoside reverse transcriptase inhibitor (Non-nucleoside Reverse Transcriptase Inhibitors, NNRTIs) as the important component part of HAART, have active high, selectivity strong, low toxin, is the focus of anti-AIDS drug research all the time.But because the amino acid of NNRTIs binding site easily undergos mutation, cause the resistance strain generation and so that such medicine is lost rapidly clinical potency.Therefore researching and developing NNRTIs novel, efficient, overriding resistance is the important directions of present anti-AIDS drug research.
S-generation NNRTIs is because the snappiness of molecule so that they can be by reversing (swing) and the sudden change of (fine motion) adaptation target enzyme that resets with RT is combined the time, thereby has good anti-drug resistance.Wherein, marketed drug etravirine and rilpivirine are as the Typical Representative of s-generation NNRTIs, be subject to widely paying close attention to, but because there are the problems such as the poor or side effect of oral availability in these two medicines, therefore need to have carried out further structure of modification to overcome above problem to it.Structure of modification for this compounds has produced a series of DAPY analogue, has shown good anti-wild-type and anomaly HIV-1 active.
Wherein, five yuan and hexa-member heterocycle class DAPY analogue have shown splendid Anti-HIV-1 Active, and have character in the very excellent body.Compound R DEA-640 and compound R DEA-427 are in respectively clinical study and preclinical study stage, the data demonstration, and REDA-427 and REDA-640 are to wild-type HIV-1 virus EC
50Be respectively 0.9 and 0.8nM.In addition, in human serum in the test, due to illness poison variation and impact that RDEA-427 and RDEA-640 activity are caused are well below efavirenz.It should be noted that than efavirenz and rilpivirine, RDEA-427 and RDEA-640 are difficult for the generation of inducing cell pigment CYP3A4.Simultaneously, RDEA-427 has better stability and is difficult for occuring covalent attachment in liver microsomes.
Therefore, according to the isostere principle five yuan and six-ring are carried out conversion and be expected to obtain multiple DAPY analogue, the inverase of finding broad-spectrum high efficacy, activity in vivo is good and has an independent intellectual property right is had great importance.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of triazolo pyrimidine class HIV1-RT inhibitor, the present invention also provides preparation method and the application of this compound.
Technical scheme of the present invention is as follows:
One, triazolo pyrimidine class HIV1-RT inhibitor
A kind of triazolo pyrimidine class HIV1-RT inhibitor, or its pharmacy acceptable salt, ester or prodrug, general structure I or II are as follows:
Wherein,
X is NH or O;
Ar is substituted-phenyl, is selected from 2,4,6-trimethylphenyl, 2,4,6-trichlorophenyl, 2,4,6-tribromo phenyl, 2,4,6-trifluorophenyl, 2,6-two bromo-4-aminomethyl phenyls, 2,6-dimethyl-4-bromophenyl, 2,6-dimethyl-4-cyano-phenyl, 2,6-dimethyl-4-chloro-phenyl-, 2,6-xylyl, 2,6-dichlorophenyl or 2,6-dimethoxy phenyl;
R
1Be CN, Me, OMe, Cl or NO
2
Preferably, the compound of above-mentioned formula I or II is one of following:
Formula I is preferred:
4-((5-(2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a1),
4-((5-(2,4,6-Trichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a2),
4-((5-(4-bromo-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a3),
4-((5-(2,4,6-trifluoromethoxy phenoxy base)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a4) or
4-((5-(mesityloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a5).
The general formula II is preferred:
4-((7-(2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b1),
4-((7-(4-bromo-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b2),
4-((7-(2,4,6-Trichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b3),
4-((7-(mesityloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b4),
4-((7-(2,6-dichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b5),
4-((5-((4-benzonitrile base) amino)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) oxygen base)-3,5-xylylic acid nitrile (WL-b6),
7-(front three phenoxy group)-N-(4-nitrophenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b7),
N-(4-chloro-phenyl-)-7-(2,4,5-trimethoxyphenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b8),
4-((7-(2,4,6-tribromo oxygen base)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b9),
7-(2,4,5-trimethoxyphenyl)-N-(4-tolyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b10),
4-((7-(2,4,6-trimethylbenzene amido)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b11)
4-((7-(2,6-, two bromo-4-methylphenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b12),
7-(2,4,5-trimethoxyphenyl)-N-(4-p-methoxy-phenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b13),
4-((7-(4-chloro-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b14) or
4-((7-((2,6-xylyl) amino)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b15).
Two, the preparation method of triazolo pyrimidine class HIV1-RT inhibitor
A kind of preparation method of triazolo pyrimidine class HIV1-RT inhibitor take aminotriazole as starting raw material, generates triazolo pyrimidine female ring 1 with the diethyl malonate cyclization, then obtains intermediate 2 through chloro; Formula I and II are carried out respectively the substitution reaction of two aromatic rings according to synthetic route separately, generate formula I or II target compound;
Synthetic route is as follows:
Wherein, the same formula I of the definition of Ar, R1, X or II are described;
Reagent and condition are as follows: i) diethyl malonate/sodium/ethanol, reflux; Ii) phosphorus oxychloride, 95 ℃; Iii) substituted aniline/ethanol, room temperature; Iv) fortified phenol/Anhydrous potassium carbonate/DMF, 85 ℃; V) fortified phenol or substituted aniline/Anhydrous potassium carbonate/DMF, room temperature; Vi) aniline, 150-160 ℃.
The present invention is more detailed, a kind of preparation method of triazolo pyrimidine class HIV1-RT inhibitor, and step is as follows:
(1) at first takes by weighing the 1.37g metal Na, make NaOEt4.05g with the anhydrous EtOH reaction of 10mL.Aminotriazole 5.0g, diethyl malonate 9.52g and the NaOEt4.05g that makes are joined among the anhydrous EtOH of 50mL, stir lower backflow 12h; Steam except residual ethanol, add frozen water, use ethyl acetate extraction three times, remove diethyl malonate wherein; Collect water layer, be acidified to pH=1 with dense HCl; Be statically placed in and separate out a large amount of white solids in the ice bath, filter, washing, the dry intermediate 1 that gets;
(2) the intermediate 16.08g that makes is joined 57mL POCl
3In, at 95 ℃ of lower stirring and refluxing 12h; Steam except excessive POCl
3, add trash ice after the cooling, stir and remove residual POCl
3Add entry and methylene dichloride extracts, collected organic layer; With Na
2SO
4Drying, concentrated, get intermediate 2;
(3) with intermediate 22.5g with cyano-aniline 1.56g is joined among the anhydrous EtOH of 35mL stirring reaction 6h under the room temperature; With the gained reacting liquid filtering, alcohol wash is collected solid, drying; Get intermediate 3;
(4) phenol that the difference of an equivalent is replaced and the K of an equivalent
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of lower reaction 8-12h of intermediate of an equivalent, be cooled to room temperature; Add entry and ethyl acetate extraction, collect organic phase; Add Na
2SO
4Drying, the outstanding crude product that steams to get; Obtain generalformulaⅰcompound with the EA:PE1:2 column chromatography;
(5) respectively fortified phenol that 2.7mmol is different or aniline, 5.4mmol K
2CO
3Join among the DMF15mL that contains 3mmol intermediate 2,30 ℃ of lower stirrings, reaction 6-12h, TLC detect to raw material point and disappear; Add entry to separate out precipitation, wash, drying gets crude product 4, and intermediate 4 does not need purifying, directly puts in next step reaction;
(6) the compound 1.5mmol with above gained mixes respectively with to cyano-aniline 5.25mmol, slowly is heated to 150 ℃, stirs 2h; Add the DMF dissolving, silica gel mixed sample obtains general formula II compound with the EA:PE1:2 column chromatography.
Three, the pharmaceutical composition that contains the compounds of this invention
A kind of anti-AIDS pharmaceutical composition comprises compound of the present invention and one or more pharmaceutically acceptable carriers or vehicle.
Four, use
Compound of the present invention is as the application of inverase.Particularly, as the HIV-1 non-nucleoside reverse transcriptase inhibitor for the preparation of anti-AIDS drug.
The present invention will be further described below in conjunction with experimental example, but be not limited to this.
Experimental example: In Vitro Anti HIV-1 activity experiment
Because HIV infects some cell line cell (C8166, MT-4 etc.) after, pathology can occur in (5-7 days) HIV cells infected within a certain period of time, therefore the compound solution to be checked that adds proper concn to HIV-1 cells infected suspension liquid, use MTT or XTT method to measure the cell count of survival through after a while after the cultivation of (5-7 days), obtain 50% cell and avoid cytopathic drug level (EC
50) can draw the activity of the anti-HIV of target compound.Simultaneously can also measure compound to the cytotoxicity of non-infected cells, median lethal concentration CC
50Selectivity index SI with compound.
The present invention has carried out anti-HIV-1, the HIV-2 screening active ingredients take nevirapine (NVP) and efavirenz (EFV) as contrast to 20 synthetic compounds.Activity the results are shown in Table 1, table 2.
The target compound formula I (WL-a1-5) that table 1 the inventive method is synthetic, the chemical structure of general formula II (WL-b1-15)
The target compound WL-a1-5 that table 2 the inventive method is synthetic, the HIV (human immunodeficiency virus)-resistant activity result of WL-b1-15
Annotate:
aEC
50: protect the cell of 50% infected by HIV-1 to avoid cytopathic compound concentration;
bCC
50: make 50% concentration of the cell generation pathology of infected by HIV-1 not;
cSI: selectivity constant (CC
50/ EC
50).
Above-mentioned experimental result shows: synthetic compound great majority have preferably anti-wild-type HIV-1 activity, for example compound WL-a5(EC
50=0.073 μ M, SI=1449), WL-b4(EC
50=0.051 μ M, SI=3198), WL-b8(EC
50=0.053 μ M, SI=864), WL-b10(EC
50=0.072 μ M, SI=649), WL-b11(EC
50=0.021 μ M, SI=8986), WL-b12(EC
50=0.052 μ M, SI=3618) etc.It is active that above compound has all shown the anti-wild-type HIV-1 strain that is better than positive drug nevirapine and efavirenz, and have higher selectivity constant.
Embodiment
The present invention will be further described below in conjunction with embodiment, but institute of the present invention protection domain is not limited to this.Raw materials used conventional reagent, the commercial product of being among the embodiment.
The preparation of embodiment 1.4-((5-(mesityloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a1)
With aminotriazole 5.0g(59.5mmol), diethyl malonate 9.52g(59.5mmol) and NaOEt4.05g(59.5mmol) (made by Na and EtOH in advance) and join among the anhydrous EtOH of 50mL, stir backflow 12h.Steam except residual ethanol, add frozen water, use ethyl acetate extraction three times, remove diethyl malonate wherein.Collect water layer, be acidified to pH=1 with dense HCl.Be statically placed in and separate out a large amount of white solids in the ice bath, filter, washing, the dry intermediate 1 that gets;
The intermediate 16.08g (40mmol) that makes is joined 57mL(600mmol) POCl
3In, at 95 ℃ of lower stirring and refluxing 12h.Steam except excessive POCl
3, add trash ice after the cooling, stir and remove residual POCl
3Add H
2O and CH
2Cl
2Extract collected organic layer.With Na
2SO
4Drying, concentrated, get intermediate 2; With intermediate 22.5g(13.2mmol) and to cyano-aniline 1.56g(13.2mmol) join among the anhydrous EtOH of 35mL stirring reaction 6h under the room temperature.With the gained reacting liquid filtering, alcohol wash is collected solid, drying.Get intermediate 3; With the xylenol of 2mmol and the K of 4mmol
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of reactions of intermediate 8-12h of 2mmol, be cooled to room temperature.Add entry and ethyl acetate extraction, collect organic phase.Add Na
2SO
4Drying, the outstanding crude product that steams.Obtain end product WL-a1 with the EA:PE1:2 column chromatography, product is white solid, 0.1g, overall yield 8%, mp:298-300 ℃.
ESIMS:m/z357.4(M+1).
IR(KBr,cm
-1):3303(NH),2223(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.15(s,1H,NH),8.43(s,1H,triazole-H),7.97(d,2H,J=8.8Hz,Ph-H),7.81(d,2H,J=8.8Hz,Ph-H),7.32(m,3H,OPh-H),5.68(s,1H,pyrimidine-H),2.18(s,6H,CH
3).
The preparation of embodiment 2.4-((5-(2,4,6-Trichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a2)
Preparation method such as embodiment 1, difference is: with the Trichlorophenol of 2mmol and the K of 4mmol
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of reactions of intermediate 8-12h of 2mmol.Product is white solid, overall yield 7%, mp:258-260 ℃.
ESIMS:m/z431.3(M+1),433.4(M+3),435.3(M+5),437.3(M+7).
IR(KBr,cm
-1):3303(NH),2231(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.16(s,1H,NH),8.48(s,1H,triazole-H),8.13(s,2H,OPh-H),7.96(d,2H,J=8.8Hz,Ph-H),7.84(d,2H,J=8.8Hz,Ph-H),5.91(s,1H,pyrimidine-H).
The preparation of embodiment 3.4-((5-(4-bromo-2,6-dimethyl phenoxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a3)
Preparation method such as embodiment 1, difference is: with the 4-bromo-2 of 2mmol, the K of 6-xylenol and 4mmol
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of lower reaction 8-12h of intermediate of 2mmol.Product is white solid, overall yield 8%, mp:285 ℃ (dec).
ESIMS:m/z435.4(M+1),437.4(M+3).
IR(KBr,cm
-1):3358(NH),2218(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.13(s,1H,NH),8.44(s,1H,triazole-H),7.98(d,2H,J=8.8Hz,Ph-H),7.82(d,2H,J=8.8Hz,Ph-H),7.60(s,2H,OPh-H),5.71(s,1H,pyrimidine-H),2.18(s,6H,CH
3).
The preparation of embodiment 4.4-((5-(2,4,6-trifluoromethoxy phenoxy base)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a4)
Preparation method such as embodiment 1, difference is: with 2,4 of 2mmol, the K of 6-trifluoromethyl phenol and 4mmol
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of reactions of intermediate 8-12h of 2mmol.Product is white solid, overall yield 4%, mp:248-251.
ESIMS:m/z383.4(M+1).
IR(KBr,cm
-1):3434(NH),2229(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.85(s,1H,NH),8.53(s,1H,triazole-H),7.96(s,2H,OPh-H),7.75(d,2H,J=8.8Hz,Ph-H),7.50(d,2H,J=8.8Hz,Ph-H),6.54(s,1H,pyrimidine-H).
The preparation of embodiment 5.4-((5-(mesityloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a5)
Preparation method such as embodiment 1, difference is: with 2,4 of 2mmol, the K of 6-front three phenol and 4mmol
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of reactions of intermediate 8-12h of 2mmol.Product is white solid, overall yield 8%, mp:246-248.
ESIMS:m/z371.4(M+1).
IR(KBr,cm
-1):3303(NH),2223(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.14(s,1H,NH),8.43(s,1H,triazole-H),7.98(d,2H,J=8.8Hz,Ph-H),7.81(d,2H,J=8.8Hz,Ph-H),7.12(s,2H,OPh-H),5.70(s,1H,pyrimidine-H),2.33(s,3H,CH
3),2.14(s,6H,CH
3).
The preparation of embodiment 6.4-((7-(2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b1)
With xylenol (2.7mmol), K
2CO
3(5.4mmol) join contain intermediate 2(3mmol) DMF15mL in, 30 ℃ of lower stirrings, reaction 6-12h, TLC detect to raw material point and disappear.Add entry to separate out precipitation, wash, drying gets crude product 4, and intermediate 4 does not need purifying, directly puts in next step reaction; The compound 1.5mmol of above gained is mixed respectively with to cyano-aniline 5.25mmol, slowly be heated to 150 ℃, stir 2h.Add the DMF dissolving, silica gel mixed sample, post separates (EA:PE=1:2).Product is white solid 0.267g, overall yield 50%, mp:290-293 ℃.
ESIMS:m/z375.3(M+1).
IR(KBr,cm
-1):3295(NH),2224(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.14(s,1H,NH),8.43(s,1H,triazole-H),7.97(d,2H,J=8.8Hz,Ph-H),7.81(d,2H,J=8.8Hz,Ph-H),7.34(m,3H,OPh-H),5.68(s,1H,pyrimidine-H),2.18(s,6H,CH
3).
The preparation of embodiment 7.4-((7-(4-bromo-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b2)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 4-bromo-2, the 6-xylenol in this reaction.Product is white solid, overall yield 46%, mp:285-288 ℃.
ESIMS:m/z435.6(M+1),437.6(M+3).
IR(KBr,cm
-1):3358(NH),2218(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.11(s,1H,NH),8.43(s,1H,triazole-H),7.97(d,2H,J=8.8Hz,Ph-H),7.82(d,2H,J=8.8Hz,Ph-H),7.60(s,2H,OPh-H),5.71(s,1H,pyrimidine-H),2.19(s,6H,CH
3).
The preparation of embodiment 8.4-((7-(Trichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b3)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,4,6-Trichlorophenol in this reaction.Product is white solid, overall yield 45%, mp:246-252 ℃.
ESIMS:m/z431.2(M+1),433.3(M+3),435.3(M+5),437.3(M+7).
IR(KBr,cm
-1):3323(NH),2231(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.20(s,1H,NH),8.49(s,1H,triazole-H),8.13(s,2H,OPh-H),7.97(d,2H,J=8.6Hz,Ph-H),7.84(d,2H,J=8.6Hz,Ph-H),5.93(s,1H,pyrimidine-H).
The preparation of embodiment 9.4-((7-(front three phenoxy group)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b4)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does front three phenol in this reaction.Product is white solid, overall yield 70%, mp:255-258 ℃.
ESIMS:m/z371.4(M+1),393.3(M+23).
IR(KBr,cm
-1):3324(NH),2223(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.14(s,1H,NH),8.42(s,1H,triazole-H),7.98(d,2H,J=8.8Hz,Ph-H),7.81(d,2H,J=8.8Hz,Ph-H),7.12(s,2H,OPh-H),5.69(s,1H,pyrimidine-H),2.33(s,3H,CH
3),2.14(s,6H,CH
3).
The preparation of embodiment 10.4-((7-(2,6-dichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b5)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,4,6-front three phenol in this reaction.Product is white solid, overall yield 36%, mp:273-278 ℃.
ESIMS:m/z397.3(M+1),401.3(M+5).
IR(KBr,cm
-1):3431(NH),2224(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.22(s,1H,NH),8.48(s,1H,triazole-H),7.97(d,2H,J=8.7Hz,OPh-H),7.86(m,4H,Ph-H),7.62(d,1H,J=8.8Hz,OPh-H),5.93(s,1H,pyrimidine-H).
The preparation of embodiment 11.4-((7-(2,6-diformazan-4-cyano-benzene oxygen)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b6)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,6-dimethyl-4-cyanophenol in this reaction.Product is white solid, overall yield 60%, mp:285-287 ℃.
ESIMS:m/z382.5(M+1),404.5(M+23).
IR(KBr,cm
-1):3342(NH),2223(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.10(s,1H,NH),8.45(s,1H,triazole-H),7.97(d,2H,J=8.6Hz,Ph-H),7.92(s,2H,OPh-H),7.82(d,2H,J=8.6Hz,Ph-H),5.67(s,1H,pyrimidine-H),2.23(s,6H,CH
3).
The preparation of embodiment 12.7-(2,4,6-front three phenol)-N-(4-nitrophenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b7)
Preparation method such as embodiment 6, difference is: in this reaction cyano-aniline changed and do p-Nitroaniline.Product is yellow solid, overall yield 54%, mp:293-297 ℃.
ESIMS:m/z391.3(M+1).
IR(KBr,cm
-1):2218(CN),1328(NO
2).
1H?NMR(DMSO-d
6,400MHz)δ:10.33(s,1H,NH),8.45(s,1H,triazole-H),8.27(d,2H,J=8.8Hz,Ph-H),8.03(d,2H,J=8.8Hz,Ph-H),7.13(s,2H,OPh-H),5.73(s,1H,pyrimidine-H),2.33(s,3H,CH
3),2.14(s,6H,CH
3).
The preparation of embodiment 13.7-(2,4,6-front three phenol)-N-(4-chloro-phenyl-)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b8)
Preparation method such as embodiment 6, difference is: in this reaction cyano-aniline changed and do p-Chlorobenzoic acid amide.Product is white solid, overall yield 62%, mp:200-205 ℃.
ESIMS:m/z380.3(M+1).
IR(KBr,cm
-1):3305(NH).
1H?NMR(DMSO-d
6,400MHz)δ:9.82(s,1H,NH),8.36(s,1H,triazole-H),7.81(d,2H,J=8.9Hz,Ph-H),7.40(d,2H,J=8.9Hz,Ph-H),7.11(s,2H,OPh-H),5.61(s,1H,pyrimidine-H),2.32(s,3H,CH
3),2.13(s,6H,CH
3).
The preparation of embodiment 14.4-((7-(2,4,6-tribromophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b9)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,4,6-tribromophenol in this reaction.Product is white solid, overall yield 36%, mp:270-273 ℃.
ESIMS:m/z563.0(M+1),565.1(M+3),357.1(M+5),569.0(M+7).
IR(KBr,cm
-1):3432(NH),2227(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.22(s,1H,NH),8.49(s,1H,triazole-H),8.32(s,2H,OPh-H),7.98(d,2H,J=8.7Hz,Ph-H),7.84(d,2H,J=8.7Hz,Ph-H),5.90(s,1H,pyrimidine-H).
The preparation of embodiment 15.7-(2,4,6-front three phenol)-N-(4-chloro-phenyl-)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b10)
Preparation method such as embodiment 6, difference is: in this reaction cyano-aniline changed and do monomethylaniline.Product is white solid, overall yield 68%, mp:260-263 ℃.
ESIMS:m/z360.4(M+1),382.5(M+23).
IR(KBr,cm
-1):3301(NH).
1H?NMR(DMSO-d
6,400MHz)δ:9.63(s,1H,NH),8.33(s,1H,triazole-H),7.65(d,2H,J=8.4Hz,Ph-H),7.15(d,2H,J=8.4Hz,Ph-H),7.11(s,2H,OPh-H),5.61(s,1H,pyrimidine-H),2.32(s,3H,OPh-CH
3),2.27(s,3H,Ph-CH
3),2.13(s,6H,OPh-CH
3).
The preparation of embodiment 16.4-((7-(2,4,6-trimethylbenzene amido)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b11)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does trimethylaniline in this reaction.Product is white solid, overall yield 33%, mp:275-278 ℃.
ESIMS:m/z370.4(M+1).
IR(KBr,cm
-1):3354(NH),3251(NH),2219(CN).
1H?NMR(DMSO-d
6,400MHz)δ:9.79(s,1H,NH),9.51(s,1H,NH),8.36(s,1H,triazole-H),7.97(d,2H,J=8.8Hz,Ph-H),7.75(d,2H,J=8.8Hz,Ph-H),7.06(s,2H,NHPh-H),5.21(s,1H,pyrimidine-H),2.31(s,3H,CH
3),2.16(s,6H,CH
3).
The preparation of embodiment 17.4-((7-(2,6-, two bromo-4-methylphenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b12)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,6-, two bromo-4-methylphenols in this reaction.Product is white solid, overall yield 46%, mp:278-282 ℃.
ESIMS:m/z500.9(M+1).
IR(KBr,cm
-1):3440(NH),2226(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.21(s,1H,NH),8.48(s,1H,triazole-H),7.98(d,2H,J=8.3Hz,Ph-H),7.83(m,4H,OPh-H,Ph-H),5.90(s,1H,pyrimidine-H).
The preparation of embodiment 18.7-(2,4,6-front three phenol)-N-(4-methoxyphenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b13)
Preparation method such as embodiment 6, difference is: in this reaction cyano-aniline changed and do P-nethoxyaniline.Product is the brownish black solid, overall yield 32%, and product can't record fusing point because of decomposition.
ESIMS:m/z376.4(M+1),398.4(M+23).
IR(KBr,cm
-1):3295(NH).
1H?NMR(DMSO-d
6,400MHz)δ:9.56(s,1H,NH),8.30(s,1H,triazole-H),7.65(d,2H,J=9Hz,Ph-H),7.11(s,2H,OPh-H),6.93(d,2H,J=9Hz,Ph-H),5.56(s,1H,pyrimidine-H),3.74(s,3H,OCH
3),2.32(s,3H,OPh-CH
3),2.14(s,6H,OPh-CH
3).
The preparation of embodiment 19.4-((7-(2,6-dimethyl-4-chlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b14)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,6-dimethyl-4-chlorophenol in this reaction.Product is white solid, overall yield 52%, mp:285-286 ℃.
ESIMS:m/z391.3(M+1),413.5(M+23).
IR(KBr,cm
-1):3432(NH),2227(CN).
1H?NMR(DMSO-d
6,400MHz)δ:10.12(s,1H,NH),8.43(s,1H,triazole-H),7.98(d,2H,J=8.8Hz,Ph-H),7.81(d,2H,J=8.8Hz,Ph-H),7.46(s,2H,OPh-H),5.71(s,1H,pyrimidine-H),2.19(s,6H,CH
3).
The preparation of embodiment 20.4-((7-(2,6-dimethylbenzene amido)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b15)
Preparation method such as embodiment 6, difference is: fortified phenol changes and does 2,6-xylidine in this reaction.Product is white solid, overall yield 48%, mp:＞300 ℃.
ESIMS:m/z356.4(M+1),378.5(M+23).
IR(KBr,cm
-1):3295(NH),3294(NH),2221(CN).
1H?NMR(DMSO-d
6,400MHz)δ:9.79(s,1H,NH),9.59(s,1H,NH),8.36(s,1H,triazole-H),7.95(d,2H,J=8.8Hz,Ph-H),7.74(d,2H,J=8.8Hz,Ph-H),7.26(m,3H,NHPh-H),5.19(s,1H,pyrimidine-H),2.20(s,6H,CH
3).
Claims (6)
1. triazolo pyrimidine class HIV1-RT inhibitor, or its pharmacy acceptable salt, ester or prodrug is characterized in that, general structure I or II are as follows:
Wherein,
X is NH or O;
Ar is substituted-phenyl, is selected from 2,4,6-trimethylphenyl, 2,4,6-trichlorophenyl, 2,4,6-tribromo phenyl, 2,4,6-trifluorophenyl, 2,6-two bromo-4-aminomethyl phenyls, 2,6-dimethyl-4-bromophenyl, 2,6-dimethyl-4-cyano-phenyl, 2,6-dimethyl-4-chloro-phenyl-, 2,6-xylyl, 2,6-dichlorophenyl or 2,6-dimethoxy phenyl;
R
1Be CN, Me, OMe, Cl or NO
2
2. compound as claimed in claim 1 is characterized in that, is one of following compounds:
4-((5-(2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a1),
4-((5-(2,4,6-Trichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a2),
4-((5-(4-bromo-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a3),
4-((5-(2,4,6-trifluoromethoxy phenoxy base)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a4),
4-((5-(mesityloxy)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) amino) benzonitrile (WL-a5),
4-((7-(2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b1),
4-((7-(4-bromo-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b2),
4-((7-(2,4,6-Trichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b3),
4-((7-(mesityloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b4),
4-((7-(2,6-dichlorophenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b5),
4-((5-((4-benzonitrile base) amino)-[1,2,4] triazolos [1,5-a] pyrimidin-7-yl) oxygen base)-3,5-xylylic acid nitrile (WL-b6),
7-(front three phenoxy group)-N-(4-nitrophenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b7),
N-(4-chloro-phenyl-)-7-(2,4,5-trimethoxyphenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b8),
4-((7-(2,4,6-tribromo oxygen base)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b9),
7-(2,4,5-trimethoxyphenyl)-N-(4-tolyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b10),
4-((7-(2,4,6-trimethylbenzene amido)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b11)
4-((7-(2,6-, two bromo-4-methylphenoxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b12),
7-(2,4,5-trimethoxyphenyl)-N-(4-p-methoxy-phenyl)-[1,2,4] triazolos [1,5-a] pyrimidine-5-amine (WL-b13),
4-((7-(4-chloro-2,6-xylyloxy)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b14) or
4-((7-((2,6-xylyl) amino)-[1,2,4] triazolos [1,5-a] pyrimidine-5-yl) amino) benzonitrile (WL-b15).
3. the preparation method of compound as claimed in claim 1, step is as follows:
Take aminotriazole as starting raw material, generate triazolo pyrimidine female ring 1 with the diethyl malonate cyclization, then obtain intermediate 2 through chloro; Formula I and II are carried out respectively the substitution reaction of two aromatic rings according to synthetic route separately, generate formula I or II target compound;
Synthetic route is as follows:
Wherein, the same formula I of the definition of Ar, R1, X or II are described;
Reagent and condition are as follows: i) diethyl malonate/sodium/ethanol, reflux; Ii) phosphorus oxychloride, 95 ℃; Iii) substituted aniline/ethanol, room temperature; Iv) fortified phenol/Anhydrous potassium carbonate/DMF, 85 ℃; V) fortified phenol or substituted aniline/Anhydrous potassium carbonate/DMF, room temperature; Vi) aniline, 150-160 ℃.
4. the preparation method of compound as claimed in claim 3, step is as follows:
(1) at first takes by weighing the 1.37g metal Na, make NaOEt4.05g with the anhydrous EtOH reaction of 10mL; Aminotriazole 5.0g, diethyl malonate 9.52g and the NaOEt4.05g that makes are joined among the anhydrous EtOH of 50mL, stir lower backflow 12h; Steam except residual ethanol, add frozen water, use ethyl acetate extraction three times, remove diethyl malonate wherein; Collect water layer, be acidified to pH=1 with dense HCl; Be statically placed in and separate out a large amount of white solids in the ice bath, filter, washing, the dry intermediate 1 that gets;
(2) the intermediate 16.08g that makes is joined 57mL POCl
3In, at 95 ℃ of lower stirring and refluxing 12h; Steam except excessive POCl
3, add trash ice after the cooling, stir and remove residual POCl
3Add entry and methylene dichloride extracts, collected organic layer; With Na
2SO
4Drying, concentrated, get intermediate 2;
(3) with intermediate 22.5g with cyano-aniline 1.56g is joined among the anhydrous EtOH of 35mL stirring reaction 6h under the room temperature; With the gained reacting liquid filtering, alcohol wash is collected solid, drying; Get intermediate 3;
(4) phenol that the difference of an equivalent is replaced and the K of an equivalent
2CO
3Join among an amount of DMF, stir 5min under the room temperature, then add 3,150 ℃ of lower reaction 8-12h of intermediate of an equivalent, be cooled to room temperature; Add entry and ethyl acetate extraction, collect organic phase; Add Na
2SO
4Drying, the outstanding crude product that steams to get; Obtain generalformulaⅰcompound with the EA:PE1:2 column chromatography;
(5) respectively fortified phenol that 2.7mmol is different or aniline, 5.4mmol K
2CO
3Join among the DMF15mL that contains 3mmol intermediate 2,30 ℃ of lower stirrings, reaction 6-12h, TLC detect to raw material point and disappear; Add entry to separate out precipitation, wash, drying gets crude product 4, and intermediate 4 does not need purifying, directly puts in next step reaction;
(6) the compound 1.5mmol with above gained mixes respectively with to cyano-aniline 5.25mmol, slowly is heated to 150 ℃, stirs 2h; Add the DMF dissolving, silica gel mixed sample obtains general formula II compound with the EA:PE1:2 column chromatography.
5. claim 1 or the 2 described compounds application in the preparation anti-AIDS drug.
6. an anti-AIDS pharmaceutical composition comprises claim 1 or 2 described compounds or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
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| CN106866699B (en) * | 2017-03-29 | 2019-03-08 | 山东大学 | A kind of diaryl thienopyrimidines HIV-1 reverse transcriptase inhibitor and its preparation method and application |
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