CN103980180B - A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug - Google Patents

A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug Download PDF

Info

Publication number
CN103980180B
CN103980180B CN201410218599.6A CN201410218599A CN103980180B CN 103980180 B CN103980180 B CN 103980180B CN 201410218599 A CN201410218599 A CN 201410218599A CN 103980180 B CN103980180 B CN 103980180B
Authority
CN
China
Prior art keywords
amino
indol
preparation
trifluoropropionate
indole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410218599.6A
Other languages
Chinese (zh)
Other versions
CN103980180A (en
Inventor
周海兵
吴叔文
田波
舒红兵
韩欣
吴浩明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan University WHU
Original Assignee
Wuhan University WHU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan University WHU filed Critical Wuhan University WHU
Priority to CN201410218599.6A priority Critical patent/CN103980180B/en
Publication of CN103980180A publication Critical patent/CN103980180A/en
Application granted granted Critical
Publication of CN103980180B publication Critical patent/CN103980180B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention belongs to medical art, specifically disclose a kind of indoles-a-amino acid compounds.Fu-Ke of the indoles of Louis acid catalysis and trifluoropropyl acid esters-imines reaction is adopted to prepare this indoles-a-amino acid analog derivative.This patent mainly introduces preparation method and this compounds is preparing the application in anti-AIDS drug.

Description

Indole-alpha-amino acid compound and application thereof in preparing anti-AIDS drugs
Technical Field
The invention belongs to the technical field of medicines, and relates to an indole-alpha-amino acid compound and application thereof in preparing anti-AIDS medicines.
Background
Acquired immunodeficiency syndrome (AIDS) was first discovered and identified since the 80's of the 20 th century, a rapidly epidemic in China and worldwide that is a major epidemic causing death worldwide. Recent data from the world health organization indicates that approximately three million people worldwide have died of aids and that currently, there are still thirty million patients struggling with aids. Therefore, the development of novel high-efficiency and low-cost therapeutic drugs is still the urgent need for preventing and treating AIDS. Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome, and its replication cycle is completed mainly by reverse transcriptase, integrase and protease upon infection of the host. Because HIV is subject to variation during its replication, it has presented a great challenge to drug development and vaccine development. At present, several drugs with different action mechanisms are mainly used in combination clinically, namely, the high-efficiency antiretroviral therapy. The popularization and the use of the high-efficiency antiretroviral therapy effectively relieve the illness state of patients and prolong the average life of AIDS patients, but the treatment cost is higher, and unbearable adverse reactions and drug resistance are generated after long-term use. At present, effective anti-AIDS vaccines are still lacked, and the development of high-efficiency and low-cost therapeutic drugs is still urgent.
The currently marketed aids drugs can be classified according to different action targets: reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, entry inhibitors, and the like. Among them, reverse transcriptase inhibitors play an important role in the treatment of aids, especially in the highly active antiretroviral therapy, whose target of action is the Reverse Transcriptase (RT) of HIV-1. Reverse transcriptase inhibitors can be classified into Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) depending on the mechanism of action. Nucleoside reverse transcriptase inhibitors are incorporated into the reverse transcription products of the virus by competing with normal nucleotide substrates during viral replication, thereby terminating the extension of the viral genome. Unlike nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors are a class of small drug molecules that act by binding to the hydrophobic binding pocket near the polymerization site of HIV reverse transcriptase.
Over 20 years of non-nucleoside reverse transcriptase inhibitor research, at least 50 structurally diverse non-nucleoside reverse transcriptase inhibitors have been discovered. The first generation of non-nucleoside anti-aids drugs are nevirapine (nevirapine) and delavirdine (delavirdine), and the second generation of non-nucleoside anti-aids drugs are efavirenz (efavirenz), etravirine (etravirine) and rilpivirine (rilpivirine). There are a number of additional non-nucleoside drug candidates in clinical research. The non-nucleoside drugs have the advantages of strong activity and good specificity, do not affect the DNA synthesis of cells or mitochondria, but limit the clinical application of the drugs due to the emergence of drug-resistant mutant strains. Therefore, there is an urgent need to develop novel non-nucleoside inhibitors and broaden the clinical drug choices. Recently, some indole compounds have been reported in documents to have certain anti-HIV reverse transcriptase activity, but most indole compounds have complex structures and high synthesis difficulty, and the activity is not particularly good, so that the possibility of drug formation is limited. In 2013, a subject group reports that an indole derivative containing trifluoromethyl is a good non-nucleoside reverse transcriptase inhibitor, can effectively inhibit the activity of reverse transcriptase, provides a new idea for developing anti-AIDS drugs, and designs an alpha amino acid compound based on the indole as an HIV-1 reverse transcriptase inhibitor on the basis of the new idea.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an indole-alpha-amino acid compound and application thereof in preparing anti-AIDS medicaments.
The indole-alpha-amino acid compound provided by the invention has a structure shown in the following general formula:
wherein,
R1is H, 5-F, 5-Cl, 5-Br, 5-NO2、5-CN、5-CHO、5-COOMe、6-F、6-Cl、6-Br、6-NO26-CN, 5-Me, 6-Me or 5-OMe;
R2is H or isoamyl;
R3me or Et.
In vitro anti-HIV-1 activity experiments show that the indole-alpha-amino acid compound can be used as an HIV-1 non-nucleoside reverse transcriptase inhibitor for preparing anti-AIDS drugs. Preferred, in particular, are the following compounds:
ethyl 2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX1),
Ethyl 2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX2),
Ethyl 2-amino-2- (6-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX3),
Ethyl 2-amino-2- (5-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX4),
Ethyl 2-amino-2- (6-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX5),
Ethyl 2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX6),
Ethyl 2-amino-2- (6-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX7) or
Ethyl 2-amino-2- (5-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX 8).
The invention also provides a preparation method of the indole-alpha-amino acid compound represented by the structural formula.
When R is3Et, synthesized by the reaction of formula i to give the R band3Trifluoropropionate-imine compounds of (a).
The specific operation steps can be as follows:
ethyl trifluoropyruvate (170mg,1mmol) and p-anisidine PMP (129mg,1.05eq.) were dissolved in 10mL of benzene solution, p-toluenesulfonic acid (8.6mg, 5% eq.) was added to the solution at 85 ℃ for reflux reaction, monitored by TLC. After 6h, the solvent benzene was distilled off, and column chromatography separation was performed to obtain a reaction product trifluoropropionate-imine as a raw material for the reaction (iii), which was a pale yellow liquid with a yield of 85%.
When R is1＝H,R2Is synthesized by the reaction shown in the following formula ii to give a band R1，R2The indole derivative of (1). The specific operation steps can be as follows:
indole (232mg, 2mmol) was dissolved in 10mL DMF, 8mL DMF solution containing 96mg (2.4mmol) NaH (60% dispersion administration) was added at 5 deg.C, the mixture was stirred at room temperature for 30min and then cooled to 5 deg.C, 5mL DMF solution containing 362.5mg isoamyl bromide (2.4mmol) was added dropwise, the reaction was carried out at room temperature, and TLC was used for monitoring. After 16h, the mixture was cooled to 5 ℃ and 15mL of water was added to quench the reaction, the product was extracted with ether and separated by column chromatography to give the reaction product as the starting material for reaction (iii) as a pale yellow liquid with 93% and 94% yields, respectively.
With R other than that obtained by reaction ii above1，R2The indole derivatives of (4) are all commercially available.
Obtaining the band R by synthesizing or purchasing commodities1，R2Then taking equivalent amount of the band R1，R2The indole derivative and the trifluoropropionic acid ester-imine are dissolved in dichloromethane and fully dissolved, and then proper amount of AlCl is added3Catalytic Friedel-crafts reaction, TLC monitoringThe preparation method comprises the following steps of carrying out basic reaction on raw materials, and carrying out column chromatography separation to obtain the target compound.
The reaction formula is shown in the following formula (iii).
R1Is H, 5-F, 5-Cl, 5-Br, 5-NO2、5-CN、5-CHO、5-COOMe、6-F、6-Cl、6-Br、6-NO26-CN, 5-Me, 6-Me or 5-OMe;
R2is H or isoamyl;
R3me or Et.
The specific operation process can be as follows:
0.2mmol of reaction ii or of the commercial tape R is taken1，R2The indole derivative (2) and 0.2mmol of trifluoropropionic acid ester-imine are added into a single-neck round-bottom flask containing magnetons, 5mL of dichloromethane are added to dissolve the indole derivative and the trifluoropropionic acid ester-imine, the mixture is stirred evenly, and 0.2mmol of AlCl is added3The catalytic Friedel-crafts reaction was carried out and the progress of the reaction was monitored by TLC. After the raw materials are basically reacted completely, the pure target compound is obtained by column chromatography separation.
Pharmacological experiments show that the compound can be used as an HIV-1 non-nucleoside reverse transcriptase inhibitor for preparing anti-AIDS medicaments. Accordingly, the present invention also provides an anti-AIDS pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers or excipients, which may be prepared according to conventional pharmaceutical techniques.
Detailed Description
Example 1: preparation of ethyl 2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX1)
Adding 0.2mmol of 6-bromoindole and 0.2mmol of trifluoropropionate-imine into a single-neck round-bottom flask containing magnetons, adding 5mL of dichloromethane for dissolving, stirring, adding 0.2mmol of AlCl3The catalytic Friedel-crafts reaction was carried out and the progress of the reaction was monitored by TLC. After the raw materials are fully reacted, pure solid compound HX1 is obtained by column chromatography separation, the product is yellow solid, and the yield is 91%.1HNMR(400MHz,CDCl3)8.30(s,1H),7.76(d,J＝8.7Hz,1H),7.47(s,1H),7.41(d,J＝2.5Hz,1H),7.26–7.23(m,1H),4.45–4.36(m,2H),1.33(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)169.15,137.14,125.03,124.84,124.07,123.90,122.54,116.33,114.30,108.87,76.12(q),64.44,13.94.
Example 2: preparation of ethyl 2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX2)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1HNMR(400MHz,CDCl3)8.34(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).13CNMR(101MHz,CDCl3)169.09,135.02,127.65,126.78,125.65,125.29,123.94,113.94,112.79,108.33,64.52,62.69(q),13.92.
Example 3: preparation of ethyl 2-amino-2- (6-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX3)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 89%.1HNMR(400MHz,Acetone-d6)10.64(s,1H),7.93–7.86(m,1H),7.59(s,1H),7.19(d,J＝9.8Hz,1H),6.95–6.86(m,1H),4.37(dtt,J＝10.8,7.4,3.7Hz,2H),1.29(t,J＝7.1Hz,3H).13CNMR(101MHz,Acetone-d6)169.09,160.54(d,1JC-F＝237.35Hz),137.69,126.59,126.35,123.22,123.12,109.81,109.04(d,2JC-F＝24.24Hz),98.35(d,3JC-F＝25.25Hz),78.14,63.67,14.26.
Example 4: preparation of ethyl 2-amino-2- (5-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX4)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 93%.1HNMR(400MHz,CDCl3)8.33(s,1H),7.58(dt,J＝12.2,6.1Hz,1H),7.50(d,J＝2.6Hz,1H),7.28–7.25(m,1H),6.97(td,J＝9.0,2.5Hz,1H),4.46–4.37(m,2H),1.36(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)169.18,158.12(d,1JC-F＝235.33Hz),132.88,126.10,125.62,119.49,113.92,111.99(d,2JC-F＝10.10Hz),111.31(d,3JC-F＝27.27Hz),106.33,64.39,63.34(q),55.38,13.92.
Example 5: preparation of ethyl 2-amino-2- (6-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX5)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 87%.1HNMR(400MHz,Acetone-d6)10.75(s,1H),7.95(d,J＝1.3Hz,1H),7.66(d,J＝2.5Hz,1H),7.47(d,J＝8.7Hz,1H),7.15(dd,J＝8.7,2.1Hz,1H),4.38(qd,J＝7.1,4.0Hz,2H),1.31(t,J＝7.1Hz,3H).13CNMR(101MHz,Acetone-d6)168.98,136.22,127.59,127.52,125.86,123.72,122.91,121.38,113.98,109.44,77.86(q),63.78,14.24.
Example 6: preparation of ethyl 2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX6)
The preparation is as in example 1, the product being a white solid with a yield of 90%.1HNMR(400MHz,CDCl3)8.36(s,1H),7.92(s,1H),7.50(d,J＝2.6Hz,1H),7.26(d,J＝4.6Hz,1H),7.18(dd,J＝8.7,1.9Hz,1H),4.47–4.39(m,2H),1.37(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)169.10,134.74,126.36,126.19,125.77,123.13,120.99,112.29,108.56,72.39(q),64.46,13.92.
Example 7: preparation of ethyl 2-amino-2- (6-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX7)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 89%.1HNMR(400MHz,Acetone-d6)11.24(s,1H),8.98(d,J＝1.8Hz,1H),8.09(dd,J＝9.0,2.3Hz,1H),7.87(d,J＝2.5Hz,1H),7.67(d,J＝9.0Hz,1H),4.45–4.38(m,2H),1.35(d,J＝7.1Hz,3H).13CNMR(101MHz,Acetone-d6)168.70,142.79,140.78,129.75,126.41,125.73,123.57,119.26,118.07,113.13,112.10,77.79(q),64.06,14.20.
Example 8: preparation of ethyl 2-amino-2- (5-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX8)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 89%.1HNMR(400MHz,CDCl3)10.58(s,1H),8.97(s,1H),8.10(d,J＝9.1Hz,1H),7.72(s,1H),7.50–7.44(m,1H),5.16(s,1H),4.52–4.38(m,2H),2.44(s,1H),1.40(td,J＝7.1,1.3Hz,3H).13CNMR(101MHz,CDCl3)168.50,141.95,139.72,128.19,124.52,118.81,117.53,111.69,110.69,67.01(q),64.13,13.73.
Example 9: 2-amino-2- (6-cyano-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester (HX9)
Preparation of
The preparation is as in example 1, the product is a white solid with a yield of 92%.1HNMR(400MHz,CDCl3)9.14(s,1H),8.36(s,1H),7.63(d,J＝2.6Hz,1H),7.44(dt,J＝8.5,4.8Hz,2H),4.59(s,1H),4.50–4.37(m,2H),1.37(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)167.73,137.18,126.49,125.91,124.26,124.09,123.67,120.83,119.65,111.56,108.34,102.37,69.48(q),63.61,12.89.
Example 10: preparation of ethyl 2-amino-2- (6-methyl-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX10)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 93%.1HNMR(400MHz,CDCl3)8.12(s,1H),7.65(s,1H),7.28(d,J＝2.3Hz,1H),7.16(d,J＝8.3Hz,1H),7.03(dd,J＝8.3,0.9Hz,1H),4.46–4.39(m,2H),2.43(s,3H),1.32(d,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)169.49,134.65,129.83,125.34,125.04,124.48,124.34,120.55,111.09,107.92,67.10(q),64.23,21.63,13.88.
Example 11: preparation of ethyl 2-amino-2- (5-cyano-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX11)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 94%.1HNMR(400MHz,CDCl3)9.08(s,1H),8.36(s,1H),7.64(d,J＝2.7Hz,1H),7.49–7.40(m,2H),4.55(d,J＝16.2Hz,1H),4.51–4.36(m,2H),1.38(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)168.76,138.17,127.56,126.90,125.35,125.11,124.69,120.63,112.54,109.47,103.54,68.89(q),64.66,13.94.
Example 12: preparation of ethyl 2-amino-2- (5-formyl-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX12)
The preparation is as in example 1, and the product is a pale yellow oil with a yield of 91%.1HNMR(400MHz,Acetone-d6)11.03(s,1H),10.05(s,1H),8.55(s,1H),7.80–7.70(m,2H),7.63(d,J＝8.5Hz,1H),4.46–4.36(m,2H),1.32(t,J＝7.1Hz,3H).13CNMR(101MHz,Acetone-d6)192.72,168.90,140.97,131.01,128.11,127.94,127.52,126.32,126.29,122.62,113.38,113.33,77.84(q),63.90,14.25.
Example 13: preparation of ethyl 2-amino-2- (5-carbomethoxy-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX13)
The preparation is as in example 1, the product is a white solid with a yield of 91%.1HNMR(400MHz,Acetone-d6)10.90(s,1H),8.75(s,1H),7.85(dd,J＝8.6,1.6Hz,1H),7.72(d,J＝2.3Hz,1H),7.54(d,J＝8.6Hz,1H),6.24(s,1H),4.44–4.35(m,2H),3.88(s,3H),1.33(t,J＝7.1Hz,3H).13CNMR(101MHz,Acetone-d6)169.03,168.20,140.33,127.73,126.54,125.98,125.07,123.90,122.84,112.43,64.30(q),63.84,51.98,14.21.
Example 14: preparation of ethyl 2-amino-2- (5-methyl-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX14)
The procedure is as in example 1, the product being a yellow solid in 90% yield.1HNMR(400MHz,Acetone-d6)10.40(s,1H),7.69(s,1H),7.51(d,J＝2.5Hz,1H),7.32(d,J＝8.3Hz,1H),6.98(d,J＝8.3Hz,1H),5.98(s,1H),4.40–4.29(m,2H),2.39(s,3H),1.29(d,J＝7.1Hz,3H).13CNMR(101MHz,Acetone-d6)169.39,136.16,129.26,126.72,126.69,125.81,124.38,123.88,121.52,112.18,64.3(q),63.53,21.80,14.28.
Example 15: preparation of ethyl 2-amino-2- (5-methoxy-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX15)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 92%.1HNMR(400MHz,CDCl3)8.31(s,1H),7.36(dd,J＝5.3,2.3Hz,2H),7.20(d,J＝8.9Hz,1H),6.87(dd,J＝8.8,2.4Hz,1H),4.47–4.31(m,2H),3.84(s,3H),1.33(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)169.39,154.44,131.43,125.66,124.96,122.20,113.16,112.11,108.10,102.70,64.23,63.02(q),55.82,13.99.
Example 16: preparation of ethyl 2-amino-2- (1-isopentyl-indol-3-yl) -3,3, 3-trifluoropropionate (HX16)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 90%.1HNMR(400MHz,CDCl3)7.34–7.29(m,2H),7.15(d,J＝7.7Hz,1H),7.09(s,1H),6.94(t,J＝7.6Hz,1H),4.26–4.05(m,4H),1.70(d,J＝7.2Hz,2H),1.61–1.55(m,1H),1.08(dd,J＝34.7,27.6Hz,3H),0.96–0.91(m,6H).13CNMR(101MHz,CDCl3)168.69,136.19,129.24,126.92,121.94,121.37,119.14,109.39,108.00,65.78(q),61.98,44.77,38.93,25.75,22.49,22.39,13.91.
Example 17: preparation of ethyl 2-amino-2- (1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX17)
The preparation is as in example 1, the product is a white solid with a yield of 92%.1HNMR(400MHz,CDCl3)8.24(s,1H),7.88(d,J＝8.0Hz,1H),7.36(s,1H),7.30(d,J＝8.1Hz,1H),7.24–7.19(m,1H),7.18–7.11(m,1H),4.45–4.34(m,2H),1.66(s,0H),1.31(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)168.37,135.28,124.03,123.94,123.41,121.63,121.09,120.00,119.46,110.38,107.46,63.63(q),63.21,12.85.
Example 18: preparation of methyl 2-amino-2- (1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX18)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1HNMR(400MHz,CDCl3)8.27(s,1H),7.84(d,J＝8.0Hz,1H),7.36(d,J＝2.4Hz,1H),7.31(d,J＝8.1Hz,1H),7.21(dd,J＝11.7,4.6Hz,1H),7.18–7.12(m,1H),4.40(s,1H),3.91(s,3H).13CNMR(101MHz,CDCl3)169.98,136.31,125.08,124.93,124.42,122.76,120.83,120.67,111.47,108.45,64.42(q),54.49.
Example 19: 2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid methyl ester (HX19)
Preparation of
The preparation is as in example 1, the product being a pale yellow solid with a yield of 90%.1HNMR(400MHz,CDCl3)8.39(s,1H),7.86(d,J＝1.2Hz,1H),7.43(d,J＝2.6Hz,1H),7.24(d,J＝8.6Hz,1H),7.16(dd,J＝8.7,1.9Hz,1H),4.42(s,1H),3.95(s,3H).13CNMR(101MHz,CDCl3)169.66,134.65,126.44,126.17,125.71,123.20,121.91,120.56,112.41,108.18,63.97(q),54.65.
Example 20: preparation of methyl 2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX20)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1HNMR(400MHz,CDCl3)8.40(s,1H),8.04(s,1H),7.43(d,J＝2.6Hz,1H),7.30(dd,J＝8.7,1.8Hz,1H),7.24–7.22(m,1H),4.40(s,1H),3.95(s,3H).13CNMR(101MHz,CDCl3)169.62,134.93,126.84,125.78,125.53,125.39,123.70,123.56,114.08,112.79,64.15(q),54.65.
Example 21: preparation of 1-isopentyl-1H-indole (HX21)
Indole (232mg, 2mmol) was dissolved in 10mL DMF, 8mL DMF solution containing 96mg (2.4mmol) NaH (60% dispersion administration) was added at 5 deg.C, the mixture was stirred at room temperature for 30min and then cooled to 5 deg.C, 5mL DMF solution containing 362.5mg isoamyl bromide (2.4mmol) was added dropwise, the reaction was carried out at room temperature, and TLC was used for monitoring. After 16h, the mixed solution is cooled to 5 ℃, 15mL of water is added to quench the reaction, the product is extracted by ether, and the 1-isoamyl indole is obtained by column chromatography separation, and the product is light yellow oily matter with the yield of 93 percent.1HNMR(400MHz,CDCl3)7.62(d,J＝7.9Hz,1H),7.32(d,J＝8.2Hz,1H),7.18(d,J＝8.6Hz,1H),7.08(dd,J＝10.9,5.2Hz,2H),6.47(d,J＝2.9Hz,1H),4.12–4.07(m,2H),1.70(d,J＝7.6Hz,2H),1.58(s,1H),0.95(d,J＝6.6Hz,6H).13CNMR(101MHz,CDCl3)135.99,128.67,127.74,121.40,121.06,119.26,109.45,100.99,44.66,39.13,25.82,22.56.
Example 22: preparation of ethyl trifluoropropionate-imine (HX22)
Ethyl trifluoropyruvate (170mg,1mmol) and p-anisidine PMP (129mg,1.05eq.) were dissolved in 10mL of benzene solution, p-toluenesulfonic acid (8.6mg, 5% eq.) was added to the solution at 85 ℃ for reflux reaction, monitored by TLC. After 6h, the solvent benzene is distilled off, and column chromatography separation is carried out to obtain a reaction product trifluoropropionylimine which is used as a raw material of the reaction (iv), wherein the product is light yellow liquid, and the yield is 85%.1HNMR(400MHz,CDCl3)7.01(d,J＝8.9Hz,2H),6.89(d,J＝8.9Hz,2H),4.25(q,J＝7.1Hz,2H),3.82(s,3H),1.18(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)160.36,159.43,139.04,122.27,114.34,77.34,77.03,76.71,62.74,55.49,13.72.
TABLE 1 chemical Structure of the target compound HX1-20 synthesized by the method of the present invention
Compounds R1 R2 R3
HX1 6-Br H Et
HX2 5-Br H Et
HX3 6-F H Et
HX4 5-F H Et
HX5 6-Cl H Et
HX6 5-Cl H Et
HX7 6-NO2 H Et
HX8 5-NO2 H Et
HX9 6-CN H Et
HX10 6-Me H Et
HX11 5-CN H Et
HX12 5-CHO H Et
HX13 5-COOMe H Et
HX14 5-Me H Et
HX15 5-OMe H Et
HX16 H 1-isopentyl Et
HX17 H H Et
HX18 H H Me
HX19 5-Cl H Me
HX20 5-Br H Me
Experimental example 22: pharmacological experiment of indole-alpha amino acid compound
(1) And (3) determining the cytotoxicity of the indole-alpha amino acid compound:
yellow thiazole blue, MTT for short, can penetrate through cell membranes to enter cells, amber dehydrogenase in mitochondria of living cells can enable exogenous MTT to be reduced into water-insoluble needle-shaped Formazan crystals and deposited in the cells, the crystals can be dissolved by 20 percent (mass to volume) SDS, an enzyme linked immunosorbent detector is used for measuring the light absorption value at 595nm wavelength, and the cell number can be indirectly reflected.
For the experiment, TZM-bl (provided by American health institute) cells were transferred to a 96-well plate, after 24 hours, the compound was added to the cells at a certain dilution, the cells were cultured at 37 ℃ for 72 hours, 100. mu.L of the supernatant was aspirated, 20. mu.L of LMTT was added, the cells were cultured at 37 ℃ for 4 hours, 100. mu.L of 20% SDS was added, and after 18 hours of culture, the OD value at 595nm was measured using a microplate reader. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]× 100, wherein "E" represents the OD value of the administered group, "P" represents the OD value of the non-administered group, "N" represents the OD value of the blank group50) As an indicator of the cytotoxicity of the compound.
(2) In vitro anti-HIV-1 activity of indole-alpha amino acid compounds:
HIVIIIBthe strain is a classical HIV drug screening experimental strain, TZM-bl (provided by the American health research institute) cells are modified Hela (provided by the American type Collection) cell strains, HIV receptors and auxiliary receptors are stably expressed on cell membranes, and luciferase genes started by HIV long terminal repetitive sequences are stably integrated in cell nuclei. HIVIIIBAfter TZM-b1 cells are infected, the TAT protein expressed by the virus can activate the expression of luciferase gene in the cells, and the replication level of the virus can be judged by detecting the activity of luciferase in the cells. By detecting luciferase in cells after drug treatment, the activity of the drug in inhibiting HIV-1 virus can be accurately quantified.
In the experiment, HIV was administeredIIIBMixing the virus and the drug, adding into TZM-bl cells (60% (area ratio) and fully spreading), adsorbing the cells with the virus for 2 hours, removing the mixture, adding fresh culture medium (DMEM, 90% (volume ratio), fetal bovine serum10% (volume ratio), G418, 500. mu.g/mL; hygromycin, 100. mu.g/mL; puromycin, 1 μ g/ml, wherein the percentage is volume percentage) was continued and 8 replicate wells were made for each dilution. After incubation at 37 ℃ for 24 hours, luciferase activity in the cells was detected. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]× 100 wherein "E" represents the activity of luciferase in the experimental group, "P" represents the activity of luciferase in the positive group, "N" represents the activity of luciferase in the negative group50) As an indicator of its antiviral activity.
In the invention, the cytotoxicity and anti-HIV-1 activity of 20 synthesized compounds are checked by using Nevirapine (NVP) as a control, and the selectivity index SI of the compounds is calculated, and the results are shown in Table 2.
TABLE 2 results of cytotoxicity and anti-HIV-1 Activity of HX1-20, a target Compound synthesized according to the invention
compounds IC50(μM) CC50(μM) SI(CC50/IC50)
HX1 0.045 49.295 1095.4
HX2 0.060 >109.545 >1825.8
HX3 0.342 >131.475 >384.4
HX4 0.434 >131.475 >302.9
HX5 0.574 >124.729 >217.3
HX6 1.715 >124.729 >72.7
HX7 0.785 48.302 61.5
HX8 1.057 78.491 74.3
HX9 1.606 64.255 40.0
HX10 8.659 69.936 8.1
HX11 2.120 89.957 42.4
HX12 1.909 >127.283 66.7
HX13 0.813 >116.183 >142.9
HX14 2.398 >133.321 >55.6
HX15 2.055 >126.472 >61.5
HX16 9.821 >112.239 >11.4
HX17 2.445 69.869 28.6
HX18 3.139 95.510 30.4
HX19 4.239 130.434 >30.8
HX20 1.481 113.921 >76.9
NVP 0.034 150.208 4417.9
The above experimental results show that: most of the synthesized compounds have good anti-HIV-1 activity, such as compound HX1 (IC)50＝0.045μM，SI＝1095.4)、HX2(IC50＝0.060μM，SI>1825.8)、HX3(IC50＝0.342μM，SI>384.4)、HX4(IC50＝0.434μM，SI>302.9), etc.

Claims (3)

1. An application of indole-alpha-amino acid compounds in preparing anti-AIDS drugs, wherein the indole-alpha-amino acid compounds have a structure shown as the following general formula:
wherein,
R1is H, 5-F, 5-Cl, 5-Br, 5-NO2、5-CN、5-CHO、5-COOMe、6-F、6-Cl、6-Br、6-NO26-CN, 5-Me, 6-Me or 5-OMe;
R2is H or isoamyl;
R3me or Et.
2. Use according to claim 1, wherein the indole- α -amino acid compound is:
2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (6-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (5-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (6-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (6-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester or
2-amino-2- (5-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester.
3. An anti-aids pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
CN201410218599.6A 2014-05-22 2014-05-22 A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug Active CN103980180B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410218599.6A CN103980180B (en) 2014-05-22 2014-05-22 A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410218599.6A CN103980180B (en) 2014-05-22 2014-05-22 A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug

Publications (2)

Publication Number Publication Date
CN103980180A CN103980180A (en) 2014-08-13
CN103980180B true CN103980180B (en) 2016-03-16

Family

ID=51272379

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410218599.6A Active CN103980180B (en) 2014-05-22 2014-05-22 A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug

Country Status (1)

Country Link
CN (1) CN103980180B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113285A (en) * 2013-03-11 2013-05-22 武汉大学 Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113285A (en) * 2013-03-11 2013-05-22 武汉大学 Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Enantioselective inhibition of reverse transcriptase (RT) of HIV-1 by non-racemic indole-based trifluoropropanoates developed by asymmetric catalysis using recyclable organocatalysts;Xin Han,等;《Organic & Biomolecular Chemistry》;20131009;第11卷(第48期);第8464页方案3、第8465-8466页表1 *
Enhanced efficiency of recyclable C3-symmetric cinchonine-squaramides in the asymmetric Friedel–Crafts reaction of indoles with alkyl trifluoropyruvate;Xin Han,等;《Tetrahedron: Asymmetry》;20121015;第23卷(第18-19期);第1332-1337页 *
Structure–Activity Relationships of Organofluorine Inhibitors of b-Amyloid Self-Assembly;Bela Torok,等;《ChemMedChem》;20120220;第7卷(第5期);第913页图1 *

Also Published As

Publication number Publication date
CN103980180A (en) 2014-08-13

Similar Documents

Publication Publication Date Title
TW201808963A (en) Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof
JP2009500451A (en) Pyranopyridine compound
Peet et al. Antiretroviral (HIV-1) activity of azulene derivatives
Han et al. Synthesis and SARs of indole-based α-amino acids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
TW201201804A (en) Quinoline compounds and their use for treating viral infection
CN103113285B (en) Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor
EP2583969A2 (en) Novel rhodanine derivatives, method for preparing same, and pharmaceutical composition for the prevention or treatment of aids containing the rhodanine derivatives as active ingredients
WO2018174442A1 (en) Compound for treating diseases caused by coronavirus infection
CN112521386A (en) Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof
KR20230110723A (en) Treatment or prevention of COVID-19
CN103360398B (en) Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof
CN112442033A (en) STING pathway modulators and uses thereof
TWI385173B (en) Substituted aminophenylsulfonamide compounds as hiv protease inhibitor
CN102558072B (en) 2-(4-alkylformyloxyphenylcarbonylmethylthio)pyrimidine compounds and application thereof
CN112771048B (en) Inhibitors of influenza virus replication and intermediates and uses thereof
WO2015171951A1 (en) 2-(4-aryl-1h-imidazol-1-yl)aniline compounds
US8664248B2 (en) Derivatives of pyridoxine for inhibiting HIV integrase
CN103980180B (en) A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug
CN104876860B (en) A kind of diaryl pyrazole piperidine derivatives and preparation method and application
CN109369623B (en) Substituted 1,2,3 triazole diaryl pyrimidine derivative and preparation method and application thereof
EP0843663B9 (en) 4-aryl-thio-pyridin-2(1h)-ones, drugs containing same, and uses thereof for treating hiv-related diseases
CN112724156B (en) Polycyclic pyridone derivative, pharmaceutical composition and application thereof
CN103980238B (en) A kind of benzo lactone compound and preparing the application in anti-AIDS drug
CN106866628A (en) A kind of RTIs of aryl heteroaryl miazines HIV 1 and preparation method thereof
WO2004033443A1 (en) Halogen substituted hexahydroxy biphenyl derivatives, their preparation and their uses as medicament

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant