CN103113285A - Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor - Google Patents
Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor Download PDFInfo
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- CN103113285A CN103113285A CN2013100767381A CN201310076738A CN103113285A CN 103113285 A CN103113285 A CN 103113285A CN 2013100767381 A CN2013100767381 A CN 2013100767381A CN 201310076738 A CN201310076738 A CN 201310076738A CN 103113285 A CN103113285 A CN 103113285A
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- 0 C[*-][n]1c2ccccc2cc1 Chemical compound C[*-][n]1c2ccccc2cc1 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N c1c[nH]c2ccccc12 Chemical compound c1c[nH]c2ccccc12 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- OWPIFQXNMLDXKW-UHFFFAOYSA-N CC(C)(C)OC([n]1c2ccccc2cc1)=O Chemical compound CC(C)(C)OC([n]1c2ccccc2cc1)=O OWPIFQXNMLDXKW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the field of medical technology, and specifically discloses an indole compound and an application thereof as an HIV-1 reverse transcriptase inhibitor. The indole compound disclosed by the invention has a structural general formula: wherein the formula is described in the specification.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of Benzazole compounds and as the application of HIV1-RT inhibitor.
Background technology
Acquired immunodeficiency disease syndromes (AIDS) is popular in the world and China, is the great pandemic that causes global range death.World bodyguard organizes nearest data to show that nearly three million peoples in the whole world have died from acquired immune deficiency syndrome (AIDS), still have 30,000,000 patient to resist with acquired immune deficiency syndrome (AIDS) at present.Therefore the development of the medicine of efficient and cheap is still the task of top priority that prevents and treats acquired immune deficiency syndrome (AIDS).Human immune deficiency venereal disease poison 1 type (HIV-1) is the virulence factor that causes acquired immune deficiency syndrome (AIDS), after this virus infection host, mainly utilizes reversed transcriptive enzyme, and intergrase and proteolytic enzyme are completed its replicative cycle.Because virus of AIDS in reproduction process, constantly produces variation, brought huge challenge therefore for the exploitation of medicine and the development of vaccine.The main several drugs of different mechanism of action that adopts is used in combination clinically at present, i.e. highly active antiretroviral therapy.Highly active antiretroviral therapy promote the use of effective state of an illness of alleviating the patient, the mean lifetime that has extended aids patient, but its medical expense is higher, life-time service has produced insufferable untoward reaction and resistance.We still lack effective anti-AIDS vaccine at present, and the development of the medicine of efficient and cheap is still the task of top priority that prevents and treats acquired immune deficiency syndrome (AIDS).
Different according to action target spot, the AIDS-treating medicine of listing can be divided into: reverse transcriptase inhibitors, integrase inhibitor, proteinase inhibitor, entry inhibitor.Wherein, reverse transcriptase inhibitors occupies an important position in the treatment of acquired immune deficiency syndrome (AIDS), and its action target spot is the reversed transcriptive enzyme (RT) of HIV-1.According to the difference of mechanism of action, reverse transcriptase inhibitors can be divided into efabirenz (NRTs) and non-nucleoside reverse transcriptase inhibitor (NNRTS).Efabirenz by with virus replication in normal Nucleotide substrate be at war with, be impregnated in the reverse transcription product of virus, thereby stop virus genomic extension.Non-nucleoside reverse transcriptase inhibitor is about by the operating distance catalytic center
Hydrophobic pocket, regulate or affect the conformation of reversed transcriptive enzyme by isomerization, destroy the activity of its synthetic DNA.
Non-nucleoside reverse transcriptase has suppressed after deliberation more than 20 year, has been found that at present the non-nucleoside reverse transcriptase inhibitor that at least 50 various structures are different.First-generation non-nucleoside medicine is nevirapine (nevirapine) and Delavirdine (delavirdine), s-generation non-nucleoside pharmaceutical efavirenz (efavirenz), etravirine (etravirine) and rilpivirine (rilpivirine).Separately there are a plurality of non-nucleoside drug candidates to be in the clinical study stage.Above-mentioned non-nucleoside medicine has active strong, and the advantage that specificity is good does not affect cell or mitochondrial DNA synthetic, but limits its clinical use because of the appearance of medicament-resistant mutation strain.Therefore need to develop in a hurry novel non-nucleoside inhibitor, widen the selection of clinical application.Recently have bibliographical information part Benzazole compounds to have certain anti-hiv reverse transcriptase active, but complex structure, synthetic difficulty are large mostly, and activity neither be good especially, thereby limit the possibility of its patent medicine.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of Benzazole compounds and as the application of HIV1-RT inhibitor.
Benzazole compounds provided by the present invention has the structure shown in following general formula:
Wherein,
R
1Be H, 2-Me, 4-OH, 4-NO
2, 4-COOMe, 5-CHO, 5-CN, 5-F, 5-Br, 5-Cl, 5-NO
2, 5-COOMe or 6-F;
R
2Be Me or Et;
R
3Be H, Boc, Me or Isopentyl(isopentyl).
The present invention finds that above-mentioned Benzazole compounds can be used as the HIV-1 non-nucleoside reverse transcriptase inhibitor, for the preparation of anti-AIDS drug by In Vitro Anti HIV-1 activity experiment.Preferably, following compounds especially:
2-(5-nitro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX1),
2-(5-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX2),
2-(5-chloro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX3),
2-(6-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX4),
2-(5-bromo-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX5),
2-(5-cyano-1 H-indol--3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX7) or
2-(1-Methyl-1H-indole-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester (HX12).
The present invention also provides the preparation method of the represented Benzazole compounds of front structure formula.
Work as R
1=H, R
3=Isopentyl is by reacting the synthetic R that obtains being with shown in following formula i
1, R
3Indole derivatives.Concrete operation step can for:
Get indoles (232mg, 2mmol) be dissolved in 10mL DMF, add 8mL to be dissolved with 96mg(2.4mmol under 5 ° of C) NaH(60% be scattered in mineral oil in dispersion in mineral oil) DMF solution, mixed solution is cooled to 5 ° of C after at room temperature stirring 30min, then drip the DMF solution that 5mL is dissolved with 362.5mg isoamyl bromide (2.4mmol), react the TLC monitoring under room temperature.After 16h, mixed solution is cooled to 5 ° of C, adds the 15mL shrend reaction of going out, and uses the ether extraction product, and column chromatography for separation obtains reaction product as reaction raw material (iii).
Work as R
1=H, R
3=Boc(tertbutyloxycarbonyl), by reacting the synthetic R that obtains being with shown in following formula ii
1, R
3Indole derivatives.Concrete operation step can for:
Get indoles (232mg, 2mmol) and be dissolved in the 10mL methylene dichloride, drip under room temperature (Boc)
2(480.15mg, 2.2mmol) adds stirring reaction under 1mL triethylamine room temperature.The TLC monitoring reaction, after 5h, the product that column chromatography for separation obtains reacting is as reaction raw material (iii).
Band R except top 2 kinds
1, R
3Indole derivatives, all can buy on market.
By synthetic or purchase commodity, obtain band R
1, R
3Indole derivatives, then get the band R of equivalent
1, R
3Indole derivatives and trifluoroacetone acid esters be dissolved in methylene dichloride fully dissolving, after add the AlCl of capacity
3The catalysis Friedel-Crafts reaction, the TLC monitoring reaction carries out, and after the raw material primitive reaction was complete, column chromatography for separation was target compound.
Reaction formula is as following (iii) as shown in formula.
R
1Be H, 2-Me, 4-OH, 4-NO
2, 4-COOMe, 5-CHO, 5-CN, 5-F, 5-Br, 5-Cl, 5-NO
2, 5-COOMe or 6-F;
R
2Be Me or Et;
R
3Be H, Boc, Me or Isopentyl.
Specific operation process can be as follows:
Get the reaction 1 of 0.2mmol or react 2 or commercial band R
1, R
3Indole derivatives and the trifluoroacetone acid esters of 0.2mmol join one and contain in the single necked round bottom flask of magneton, add the methylene dichloride of 5mL to make its dissolving, stir, add the AlCl of 0.2mmol
3The catalysis Friedel-Crafts reaction carries out, and the TLC monitoring reaction carries out.After the raw material primitive reaction was complete, column chromatography for separation obtained pure target compound.
Compound of the present invention can be used as the HIV-1 non-nucleoside reverse transcriptase inhibitor for the preparation of anti-AIDS drug.So the present invention also provides a kind of anti-AIDS pharmaceutical composition, comprise compound of the present invention and one or more pharmaceutically acceptable carriers or vehicle, it can prepare according to the medical technology of existing routine.
Embodiment
Embodiment 1:2-(5-nitro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX1)
The trifluoroacetone acid esters of getting the 5-nitroindoline of 0.2mmol and 0.2mmol joins one and contains in the single necked round bottom flask of magneton, adds the methylene dichloride of 5mL to make its dissolving, stirs, and adds the AlCl of 0.2mmol
3The catalysis Friedel-Crafts reaction carries out, and the TLC monitoring reaction carries out.After raw material fully reacted completely, column chromatography for separation obtained pure solid chemical compound HX1, and product is yellow solid, and productive rate is 88%.
1H?NMR(400MHz,Acetone-d
6)δ11.09(s,1H),8.85(d,J=1.7Hz,1H),7.96(dd,J=9.0,2.2Hz,1H),7.74(s,1H),7.53(d,J=9.0Hz,1H),4.33–4.23(m,2H),1.20(t,J=7.1Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ168.69,142.80,140.78,129.76,129.60,126.41,125.72,119.27,118.07,113.13,112.07,64.07,14.20。
Embodiment 2:2-(5-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX2)
Preparation method such as embodiment 1, product are white solid, and productive rate is 90%.
1H?NMR(400MHz,CDCl
3)δ8.38(s,1H),7.57(d,J=10.3Hz,1H),7.42(s,1H),7.20(s,1H),6.95(t,J=9.0Hz,1H),4.40(dq,J=20.9Hz,3H),1.33(t,J=7.1Hz,3H).
13C?NMR(101MHz,CDCl
3)δ169.19,159.28,132.90,126.16,125.57,125.47,124.93,122.08,112.14,112.04,111.38,111.12,108.67,108.62,106.40,106.15,64.42,13.86。
Embodiment 3:2-(5-chloro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX3)
Preparation method such as embodiment 1, product are white solid, and productive rate is 87%.
1H?NMR(400MHz,CDCl
3)δ8.34(s,1H),8.00(s,1H),7.35(s,1H),7.18(d,J=10.3Hz,1H),7.11(d,J=8.6Hz,1H),4.40–4.27(m,2H),1.28(t,J=7.1Hz,3H).
13C?NMR(101MHz,CDCl
3)δ169.09,135.03,126.78,125.70,125.63,124.82,123.90,121.97,113.91,112.81,108.28,64.51,13.89。
Embodiment 4:2-(6-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX4)
Preparation method such as embodiment 1, product are white solid, and productive rate is 100%.
1H?NMR(400MHz,Acetone-d
6)δ10.60(s,1H),7.90(dd,J=8.8,5.6Hz,1H),7.59(d,J=2.4Hz,1H),7.19(dd,J=9.8,2.3Hz,1H),6.91(d,J=1.9Hz,1H),4.37(dd,J=7.0,6.0Hz,2H),1.29(t,J=7.1Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ169.17,161.74,137.73,126.52,123.18,123.12,109.93,109.19,108.95,98.53,98.27,63.71,14.24。
Embodiment 5:2-(5-bromo-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX5)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 85%.
1H?NMR(400MHz,CDCl
3)δ8.34(s,1H),8.00(s,1H),7.35(s,1H),7.18(d,J=10.3Hz,1H),7.11(d,J=8.6Hz,1H),4.40–4.27(m,3H),1.28(t,J=7.1Hz,3H).
13C?NMR(101MHz,CDCl
3)δ169.09,135.03,126.78,125.70,125.63,124.82,123.90,121.97,113.91,112.81,108.28,64.51,13.89。
Embodiment 6:2-(1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX6)
Preparation method such as embodiment 1, product are white solid, and productive rate is 99%.
1H?NMR(400MHz,CDCl
3)δ8.28(s,1H),7.89(d,J=8.1Hz,1H),7.43(d,J=2.5Hz,1H),7.34(d,J=8.1Hz,1H),7.28–7.10(m,2H),4.65–4.27(m,3H),1.33(t,J=7.1Hz,3H).
13C?NMR(101MHz,CDCl
3)δ169.42,136.35,125.13,124.99,124.44,122.70,121.15,121.14,120.53,111.39,108.65,64.25,13.93。
Embodiment 7:2-(5-cyano-1 H-indol--3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX7)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 92%.
1H?NMR(400MHz,Acetone-d
6)δ11.12(s,1H),8.36(s,1H),7.81(d,J=2.0Hz,1H),7.66(d,J=8.5Hz,1H),7.48(dd,J=8.5,1.3Hz,1H),4.40(dt,J=7.1,3.7Hz,2H),1.32(t,J=7.1Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ168.76,139.45,128.61,127.69,126.44,126.28,125.37,123.60,121.00,114.05,110.58,103.87,63.96,14.22。
Embodiment 8:2-(1-Boc-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX8)
Get indoles (232mg, 2mmol) and be dissolved in the 10mL methylene dichloride, drip under room temperature (Boc)
2(480.15mg, 2.2mmol) adds stirring reaction under 1mL triethylamine room temperature.The TLC monitoring reaction, after 5h, column chromatography for separation obtains the 1-Boc indoles, the preparation method of back such as embodiment 1, the product colorless oil, productive rate is 95%.
1H?NMR(400MHz,Acetone-d
6)δ8.19(d,J=8.4Hz,1H),7.86(d,J=6.3Hz,2H),7.37(t,J=7.7Hz,1H),7.27(t,J=7.6Hz,1H),3.90(s,3H),1.70(s,9H).
13C?NMR(101MHz,Acetone-d
6)δ168.86,149.92,136.46,128.56,126.51,126.20,125.65,123.79,122.31,115.94,115.16,103.32,85.37,54.13,28.15。
Embodiment 9:2-(1-isopentyl-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX9)
Get indoles (232mg, 2mmol) be dissolved in 10mL DMF, add 8mL to be dissolved with 96mg(2.4mmol under 5 ° of C) during NaH(60% is scattered in mineral oil) DMF solution, mixed solution is cooled to 5 ° of C after at room temperature stirring 30min, then drip the DMF solution that 5mL is dissolved with 362.5mg isoamyl bromide (2.4mmol), react the TLC monitoring under room temperature.After 16h, mixed solution is cooled to 5 ° of C, adds the 15mL shrend reaction of going out, and uses the ether extraction product, and column chromatography for separation obtains 1-isopentyl indoles, and the preparation method of back such as embodiment 1, product are faint yellow oily thing, and productive rate is 93%.
1H?NMR(400MHz,Acetone-d
6)δ7.89(d,J=8.1Hz,1H),7.53(s,1H),7.45(d,J=8.3Hz,1H),7.19(t,J=7.6Hz,1H),7.07(t,J=7.6Hz,1H),4.40–4.30(m,2H),4.29–4.21(m,2H),1.73(dd,J=14.8,7.0Hz,2H),1.60(dt,J=13.3,6.6Hz,1H),1.28(t,J=7.1Hz,3H),0.96(d,J=6.6Hz,6H).
13C?NMR(101MHz,Acetone-d
6)δ169.22,137.41,128.87,126.99,125.40,123.81,122.61,122.30,120.40,110.72,108.61,63.54,45.29,39.70,26.50,22.72,22.70,14.28。
Embodiment 10:2-(5-chloro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX10)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 88%.
1H?NMR(400MHz,Acetone-d
6)δ10.63(s,1H),7.78(d,J=1.3Hz,1H),7.50(d,J=2.6Hz,1H),7.33(d,J=8.7Hz,1H),7.01(dd,J=8.7,2.0Hz,1H),3.77(s,3H).
13C?NMR(101MHz,Acetone-d
6)δ169.54,136.21,127.52,126.53,125.95,123.69,122.96,121.22,113.99,109.39,78.25,53.95。
Embodiment 11:2-(5-nitro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX11)
Preparation method such as embodiment 1, product are yellow solid, and productive rate is 89%.
1H?NMR(400MHz,Acetone-d
6)δ11.13(s,1H),8.82(s,1H),7.95(d,J=9.0Hz,1H),7.72(s,1H),7.53(d,J=9.0Hz,1H),3.80(s,3H).
13C?NMR(101MHz,Acetone-d
6)δ169.22,142.83,140.72,129.68,126.38,125.77,123.54,119.12,118.10,113.14,111.96,54.19。
Embodiment 12:2-(1-Methyl-1H-indole-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX12)
Preparation method such as embodiment 1, product are faint yellow oily thing, and productive rate is 92%.
1H?NMR(400MHz,Acetone-d
6)δ7.88(d,J=8.1Hz,1H),7.47(s,1H),7.40(d,J=8.3Hz,1H),7.20(dd,J=11.3,4.0Hz,1H),7.08(t,J=7.4Hz,1H),4.40–4.29(m,2H),3.85(d,J=3.8Hz,3H),1.28(t,J=7.1Hz,3H).
13CNMR(101MHz,Acetone-d
6)δ169.25,138.25,129.91,126.86,126.65,123.81,122.67,122.11,120.44,110.56,108.55,63.58,33.05,14.24。
Embodiment 13:2-(5-methyl-formiate base-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX13)
Preparation method such as embodiment 1, product are white solid, and productive rate is 86%.
1H?NMR(400MHz,Acetone-d
6)δ10.90(s,1H),8.77(s,1H),7.86(d,J=8.6Hz,1H),7.73(d,J=2.3Hz,1H),7.54(d,J=8.6Hz,1H),4.45–4.34(m,2H),3.89(s,3H),1.33(t,J=7.1Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ169.07,168.27,140.35,127.75,126.56,125.99,125.08,123.93,123.72,122.85,112.46,111.14,63.87,52.02,14.22。
Embodiment 14:2-(4-nitro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX14)
Preparation method such as embodiment 1, product are yellow solid, and productive rate is 83%.
1H?NMR(400MHz,Acetone-d
6)δ11.28(s,1H),7.86(dd,J=11.2,3.0Hz,2H),7.62(d,J=7.7Hz,1H),7.31(t,J=7.9Hz,1H),4.38–4.28(m,2H),1.26(q,J=6.8Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ168.56,145.00,139.52,129.62,129.58,126.66,123.80,121.91,118.09,117.60,108.96,63.63,14.17。
Embodiment 15:2-(4-methyl-formiate base-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX15)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 86%.
1H?NMR(400MHz,Acetone-d
6)δ10.94(s,1H),7.72(dd,J=8.1,0.5Hz,1H),7.66(s,1H),7.51(d,J=7.4Hz,1H),7.23(t,J=7.8Hz,1H),3.89(d,J=4.5Hz,3H),3.77(s,3H).
13C?NMR(101MHz,Acetone-d
6)δ171.79,169.80,138.45,128.02,127.98,125.71,123.42,123.11,121.94,116.90,110.38,106.62,53.71,53.00。
Embodiment 16:2-(5-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX16)
Preparation method such as embodiment 1, product are pale yellow colored solid, and productive rate is 91%.
1H?NMR(400MHz,Acetone-d
6)δ10.54(s,1H),7.50(d,J=2.6Hz,1H),7.42(dd,J=10.6,2.1Hz,1H),7.32(dd,J=8.9,4.6Hz,1H),6.82(td,J=9.1,2.5Hz,1H),3.77(s,3H).
13C?NMR(101MHz,Acetone-d
6)δ169.63,159.78,134.40,127.77,126.71,123.77,113.60,111.23,110.97,106.44,78.25,53.91。
Embodiment 17:2-(5-cyano-1 H-indol--3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX17)
Preparation method such as embodiment 1, product are white solid, and productive rate is 81%.
1H?NMR(400MHz,Acetone-d
6)δ11.12(s,1H),8.36(s,1H),7.82(d,J=1.6Hz,1H),7.67(d,J=8.5Hz,1H),7.49(dd,J=8.5,1.3Hz,1H),3.94(s,3H).
13C?NMR(101MHz,Acetone-d
6)δ169.34,139.44,128.62,127.57,126.41,126.28,125.45,123.57,121.06,114.07,110.51,103.94,54.18。
Embodiment 18:2-(4-hydroxyl-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX18)
Preparation method such as embodiment 1, product are yellow solid, and productive rate is 100%.
1H?NMR(400MHz,Acetone-d
6)δ10.60(s,1H),7.49(s,1H),7.07–6.94(m,2H),6.54(dd,J=7.4,1.0Hz,1H),4.39(dt,J=7.1,4.2Hz,2H),1.32(t,J=7.1Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ168.16,150.26,139.93,126.18,124.68,124.44,115.85,108.18,106.08,104.43,104.38,63.72,14.20。
Embodiment 19:2-(2-Methyl-1H-indole-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX19)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 96%.
1H?NMR(400MHz,CDCl
3)δ8.02(s,1H),7.79(d,J=7.9Hz,1H),7.21(s,1H),7.11(dd,J=16.7,7.8Hz,2H),4.37(dd,J=24.4,7.2Hz,2H),4.02(s,1H),2.48(s,3H),1.32(t,J=7.1Hz,3H).
13C?NMR(101MHz,CDCl
3)δ169.38,135.30,134.66,126.83,125.40,122.56,121.61,120.45,120.23,110.38,103.89,63.58,13.89,13.74。
Embodiment 20:2-(5-formyl radical-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid ethyl ester (HX20)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 92%.
1H?NMR(400MHz,Acetone-d
6)δ11.04(s,1H),10.05(s,1H),8.54(s,1H),7.75(s,2H),7.62(d,J=7.9Hz,1H),4.39(d,J=4.8Hz,2H),1.31(d,J=7.0Hz,3H).
13C?NMR(101MHz,Acetone-d
6)δ191.72,166.67,140.21,130.10,128.79,127.16,126.60,125.40,122.76,121.67,112.45,110.67,62.98,13.34。
Embodiment 21:2-(5-formyl radical-1H-indol-3-yl)-2-hydroxyl-3,3, the preparation of 3-trifluoroacetic acid methyl esters (HX21)
Preparation method such as embodiment 1, product are faint yellow solid, and productive rate is 91%.
1H?NMR(400MHz,Acetone-d
6)δ11.07(s,1H),10.05(s,1H),8.51(s,1H),7.74(d,J=5.8Hz,2H),7.63(d,J=8.5Hz,1H),3.93(s,3H).
13C?NMR(101MHz,Acetone-d
6)δ191.81,168.53,140.02,130.17,127.15,127.00,126.57,125.58,125.41,121.60,112.45,99.99,53.15。
The chemical structure of the target compound HX1-21 that table 1 the inventive method is synthetic
| Compound | R 1 | R 2 | R 3 |
| HX1 | 5-NO 2 | Et | H |
| HX2 | 5-F | Et | H |
| HX3 | 5-Cl | Et | H |
| HX4 | 6-F | Et | H |
| HX5 | 5-Br | Et | H |
| HX6 | H | Et | H |
| HX7 | 5-CN | Et | H |
| HX8 | H | Me | Boc |
| HX9 | H | Et | isopentyl |
| HX10 | 5-Cl | Me | H |
| HX11 | 5-NO 2 | Me | H |
| HX12 | H | Et | Me |
| HX13 | 5-COOMe | Et | H |
| HX14 | 4-NO 2 | Et | H |
| HX15 | 4-COOMe | Me | H |
| HX16 | 5-F | Me | H |
| HX17 | 5-CN | Me | H |
| HX18 | 4-OH | Et | H |
| HX19 | 2-Me | Et | H |
| HX20 | 5-CHO | Et | H |
| HX21 | 5-CHO | Me | H |
Experimental example 22: Benzazole compounds pharmacological evaluation
(1) Benzazole compounds cytotoxic assay:
Yellow Thiazolyl blue, be called for short MTT, but permeate through cell membranes enters in cell, amber desaturase in the viable cell plastosome can make exogenous MTT be reduced to and is insoluble in the hepatic needle-like Formazan crystallization of water and is deposited in cell, crystallisate can be by the 20%(quality than volume) the SDS dissolving, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 595nm wavelength place, can indirectly reflect cell quantity.
During experiment, TZM-bl(U.S. health research institute is provided) cell reaches in 96 orifice plates, add cell after 37 ° of C cultivate 72 hours by certain extent of dilution compound after 24 hours, siphon away supernatant 100 μ l, add 20 μ l MTT, 37 ° of C continue to cultivate after 4 hours, add 100 μ l20%SDS to cultivate after 18 hours, with the OD value under microplate reader mensuration 595nm wavelength.The inhibiting rate of compound (%)=[1-(E-N)/(P-N)] * 100, wherein " E " represents the OD value of administration group, and " P " represents the OD value of non-administered group, and " N " represents blank group OD value.Half-inhibition concentration (the CC of compound
50) as the Cytotoxic index of this compound.
(2) the external Anti-HIV-1 Active of benzazolyl compounds:
HIV-III B(U.S. health research institute provides) be classical HIV medicament screening experiment strain, TZM-bl(U.S. health research institute provides) cell is to provide through transformed Hela(U.S.'s typical case's thing preservation center) cell strain, cell membrane stability is expressed HIV acceptor and accessory receptor, the nucleus stable integration luciferase gene that starts of virus of AIDS long terminal repeat.After HIV-III B infects the TZM-b1 cell, the TAT albumen of expressing viral can activating cells in the expression of luciferase gene, by detecting the activity of luciferase in cell, can judge the levels of replication of virus.Luciferase in cell after processing by detection of drugs, but the accurate quantification medicine suppresses the activity of HIV-1 virus.
During experiment, HIV-III B virus and medicament mixed are joined in the TZM-bl cell, (60%(Area Ratio) is paved with), until virus absorption onto cell after 2 hours, suck the mixture of virus and medicine, add fresh culture (DMEM, 90% (volume ratio), foetal calf serum, the 10%(volume ratio), G418,500 μ g/ml; Totomycin, 100 μ g/ml; Tetracycline, 1 μ g/ml. percentage composition wherein is volumn concentration) continue to cultivate, each extent of dilution is done 8 repeating holes.After 37 ° of C are hatched 24 hours, detect the activity of luciferase in cell.The inhibiting rate of compound (%)=[1-(E-N)/(P-N)] * 100, wherein " E " represents the activity of luciferase in experimental group, and " P " represents the activity of luciferase in positive group, and " N " represents the activity of luciferase in negative group.Half-inhibition concentration (the IC of compound
50) as the index of its antiviral activity.
The present invention carries out cytotoxicity and Anti-HIV-1 Active inspection to 21 synthetic compounds, and has calculated the selectivity index SI of compound with Delavirdine (DEV) and the contrast of efavirenz (EFV) Wei, the results are shown in Table 2.
The cytotoxicity of the target compound HX1-21 that table 2 the present invention synthesizes and Anti-HIV-1 Active result
Above-mentioned experimental result shows: synthetic compound great majority all have fine Anti-HIV-1 Active, for example compound H X1(IC
50=0.045 μ M, SI=1404.6), HX3(IC
50=0.249 μ M, SI=552.6), HX4(IC
50=0.147 μ M, SI=757.8), HX12(IC
50=0.309 μ M, SI=752.0) etc.
Claims (4)
1. Benzazole compounds has the structure shown in following general formula:
Wherein,
R
1Be H, 2-Me, 4-OH, 4-NO
2, 4-COOMe, 5-CHO, 5-CN, 5-F, 5-Br, 5-Cl, 5-NO
2, 5-COOMe or 6-F;
R
2Be Me or Et;
R
3Be H, Boc, Me or isopentyl.
2. the described Benzazole compounds of claim 1 is as the application of HIV1-RT inhibitor.
3. application according to claim 2, is characterized in that, described Benzazole compounds is
2-(5-nitro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester,
2-(5-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester,
2-(5-chloro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester,
2-(6-fluoro-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester,
2-(5-bromo-1H-indol-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester,
2-(5-cyano-1 H-indol--3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester or
2-(1-Methyl-1H-indole-3-yl)-2-hydroxyl-3,3,3-trifluoroacetic acid ethyl ester.
4. an anti-AIDS pharmaceutical composition, comprise compound claimed in claim 1 and one or more pharmaceutically acceptable carrier or vehicle.
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| CN107417593A (en) * | 2017-04-12 | 2017-12-01 | 丽水学院 | A kind of synthetic method of 3,3,3 trifluoro 2 (3 ' indyl) 2 hydroxypropionates |
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| CN103980180A (en) * | 2014-05-22 | 2014-08-13 | 武汉大学 | Indole-alpha-amino acids compounds and application of indole-alpha amino compounds in preparation of anti-AIDS drugs |
| CN103980180B (en) * | 2014-05-22 | 2016-03-16 | 武汉大学 | A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug |
| CN107151223A (en) * | 2016-03-10 | 2017-09-12 | 中国医学科学院药物研究所 | Purposes of the one class N- alkyl-indol class compounds in anti-influenza virus medicament is prepared |
| CN107151223B (en) * | 2016-03-10 | 2020-03-31 | 中国医学科学院药物研究所 | Application of N-alkyl indole compounds in preparation of anti-influenza virus drugs |
| CN106995400A (en) * | 2017-04-10 | 2017-08-01 | 湘潭大学 | A kind of compound and its salt and its synthetic method |
| CN106995400B (en) * | 2017-04-10 | 2019-08-06 | 湘潭大学 | A kind of compound and its salt and its synthetic method |
| CN107417593A (en) * | 2017-04-12 | 2017-12-01 | 丽水学院 | A kind of synthetic method of 3,3,3 trifluoro 2 (3 ' indyl) 2 hydroxypropionates |
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