CN103113285B - 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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- CN103113285B CN103113285B CN201310076738.1A CN201310076738A CN103113285B CN 103113285 B CN103113285 B CN 103113285B CN 201310076738 A CN201310076738 A CN 201310076738A CN 103113285 B CN103113285 B CN 103113285B
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- -1 Indole compound Chemical class 0.000 title claims abstract description 38
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 22
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 17
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 title abstract description 12
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 18
- 150000002475 indoles Chemical class 0.000 claims description 12
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 9
- DUTCJUZZIBUNCO-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-hydroxy-2-(5-nitro-1h-indol-3-yl)propanoate Chemical group C1=C([N+]([O-])=O)C=C2C(C(O)(C(=O)OCC)C(F)(F)F)=CNC2=C1 DUTCJUZZIBUNCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims description 4
- KMMHPOPIWLOFET-UHFFFAOYSA-N ethyl 2-(5-bromo-1h-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate Chemical compound C1=C(Br)C=C2C(C(O)(C(=O)OCC)C(F)(F)F)=CNC2=C1 KMMHPOPIWLOFET-UHFFFAOYSA-N 0.000 claims description 4
- OLRGYRGXTOWWEB-UHFFFAOYSA-N ethyl 2-(5-chloro-1h-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate Chemical compound C1=C(Cl)C=C2C(C(O)(C(=O)OCC)C(F)(F)F)=CNC2=C1 OLRGYRGXTOWWEB-UHFFFAOYSA-N 0.000 claims description 4
- DEJAANIXKYEQND-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-methylindol-3-yl)propanoate Chemical compound C1=CC=C2C(C(O)(C(=O)OCC)C(F)(F)F)=CN(C)C2=C1 DEJAANIXKYEQND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 description 39
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 32
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
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- 210000004027 cell Anatomy 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
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- 208000030507 AIDS Diseases 0.000 description 8
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- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 229960002814 rilpivirine Drugs 0.000 description 2
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 2
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- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- GHPFVEIYABXUGH-UHFFFAOYSA-N 1-(3-methylbutyl)indole Chemical compound C1=CC=C2N(CCC(C)C)C=CC2=C1 GHPFVEIYABXUGH-UHFFFAOYSA-N 0.000 description 1
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 1
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- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 102000006481 HIV Receptors Human genes 0.000 description 1
- 108010083930 HIV Receptors Proteins 0.000 description 1
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- 239000004365 Protease Substances 0.000 description 1
- 101710149951 Protein Tat Proteins 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
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- CYSKFJCLFAQXJX-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-hydroxy-2-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C(O)(C(=O)OCC)C(F)(F)F)=CNC2=C1 CYSKFJCLFAQXJX-UHFFFAOYSA-N 0.000 description 1
- OKLMMCIKGHSFQE-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C(O)(C(=O)OCC)C(F)(F)F)=C(C)NC2=C1 OKLMMCIKGHSFQE-UHFFFAOYSA-N 0.000 description 1
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- PPAUJZPOGQXMOJ-UHFFFAOYSA-N methyl 2-(5-chloro-1h-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanoate Chemical compound C1=C(Cl)C=C2C(C(O)(C(=O)OC)C(F)(F)F)=CNC2=C1 PPAUJZPOGQXMOJ-UHFFFAOYSA-N 0.000 description 1
- PFGSJDACEIAOLV-UHFFFAOYSA-N methyl 3,3,3-trifluoro-2-(5-fluoro-1h-indol-3-yl)-2-hydroxypropanoate Chemical compound C1=C(F)C=C2C(C(O)(C(=O)OC)C(F)(F)F)=CNC2=C1 PFGSJDACEIAOLV-UHFFFAOYSA-N 0.000 description 1
- CZKZCAUQHJAPNG-UHFFFAOYSA-N methyl 3,3,3-trifluoro-2-hydroxy-2-(5-nitro-1h-indol-3-yl)propanoate Chemical compound C1=C([N+]([O-])=O)C=C2C(C(O)(C(=O)OC)C(F)(F)F)=CNC2=C1 CZKZCAUQHJAPNG-UHFFFAOYSA-N 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- OWPIFQXNMLDXKW-UHFFFAOYSA-N tert-butyl indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1 OWPIFQXNMLDXKW-UHFFFAOYSA-N 0.000 description 1
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- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 the technical field of medicines, and relates to an indole compound and application thereof as an HIV-1 reverse transcriptase inhibitor.
Background
Acquired immunodeficiency syndrome (AIDS) is prevalent worldwide and in China, and is a major epidemic that causes death worldwide. Recent data from the world guardian organization indicates that approximately three million people worldwide have died of aids and that currently, there are three million patients struggling with aids. Therefore, the development of 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.
According to different action targets, the marketed AIDS drugs can be divided into: reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, entry inhibitors. Among them, reverse transcriptase inhibitors play an important role in the treatment of AIDS, and the target of action thereof is the Reverse Transcriptase (RT) of HIV-1. Reverse transcriptase inhibitors can be classified into nucleoside reverse transcriptase inhibitors (NRTs) and non-nucleoside reverse transcriptase inhibitors (NNRTS) depending on the mechanism of action. CoreNucleoside reverse transcriptase inhibitors are incorporated into the reverse transcription product of the virus by competing with normal nucleotide substrates during viral replication, thereby terminating the extension of the viral genome. Non-nucleoside reverse transcriptase inhibitors by acting approximately from the catalytic centerBy modulating or affecting the conformation of reverse transcriptase by isomerization, destroying its activity in synthesizing DNA.
Non-nucleoside reverse transcriptase inhibitors have been studied for over 20 years and at least 50 structurally diverse non-nucleoside reverse transcriptase inhibitors have been discovered. The first generation of non-nucleoside drugs are nevirapine (nevirapine) and delavirdine (delavirdine), and the second generation of non-nucleoside 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.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an indole compound and an application thereof as an HIV-1 reverse transcriptase inhibitor.
The indole compound provided by the invention has a structure shown in the following general formula:
wherein,
R1is H, 2-Me, 4-OH, 4-NO2、4-COOMe、5-CHO、5-CN、5-F、5-Br、5-Cl、5-NO25-COOMe or 6-F;
R2me or Et;
R3h, Boc, Me or Isopentyl (isoamyl).
According to the invention, through in vitro anti-HIV-1 activity experiments, the indole 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- (5-nitro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX1),
Ethyl 2- (5-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX2),
Ethyl 2- (5-chloro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX3),
Ethyl 2- (6-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX4),
Ethyl 2- (5-bromo-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX5),
2- (5-cyano-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester (HX7) or
Ethyl 2- (1-methyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 12).
The invention also provides a preparation method of the indole compound represented by the structural formula.
When R is1=H,R3= Isopentoyl, band R is synthesized by reaction shown in the following formula i1，R3The indole derivative of (1). The specific operation steps can be as follows:
indole (232 mg, 2mmol) was dissolved in 10mL DMF and 8mL DMF solution containing 96mg (2.4 mmol) NaH (60% dispersion in mineral oil) was added at 5 ℃ and the mixture was stirred at room temperature for 30min and then cooled to 5 ℃ and 5mL DMF solution containing 362.5mg of isoamyl bromide (2.4 mmol) was added dropwise and reacted at room temperature with TLC monitoring. After 16h, the mixture was cooled to 5 ℃, 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).
When R is1=H,R3= Boc (t-butyloxycarbonyl) and the tape R was synthesized by the reaction shown in the following formula ii1，R3The indole derivative of (1). The specific operation steps can be as follows:
indole (232 mg, 2mmol) was dissolved in 10mL dichloromethane and added dropwise (Boc) at room temperature2(480.15mg,2.2mmol), 1mL of triethylamine was added and the reaction was stirred at room temperature. The reaction was monitored by TLC and after 5h, the product of the reaction was isolated by column chromatography as starting material for reaction (iii).
Bands R other than the above 21，R3The indole derivatives of (4) are all commercially available.
Obtaining the band R by synthesizing or purchasing commodities1，R3Then taking equivalent amount of the band R1，R3Dissolving the indole derivative and the trifluoroacetate in dichloromethane, fully dissolving, and adding sufficient AlCl3Catalyzing Friedel-crafts reaction, monitoring the reaction by TLC, and obtaining the target compound after the raw materials are basically reacted completely and the column chromatography separation is carried out.
The reaction formula is shown in the following formula (iii).
R1Is H, 2-Me, 4-OH, 4-NO2、4-COOMe、5-CHO、5-CN、5-F、5-Br、5-Cl、5-NO25-COOMe or 6-F;
R2me or Et;
R3h, Boc, Me or Isopentyl.
The specific operation process can be as follows:
0.2mmol of reaction 1 or reaction 2 or of the commercial tape R is taken1，R3The indole derivative (2) and 0.2mmol of trifluoroacetonate were added to a single neck round bottom flask containing magnetons, 5mL of dichloromethane were added to dissolve them, the mixture was stirred well, and 0.2mmol of AlCl was 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.
The compound can be used as HIV-1 non-nucleoside reverse transcriptase inhibitor for preparing anti-AIDS drugs. 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- (5-nitro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX1)
Adding 0.2mmol of 5-nitroindole and 0.2mmol of trifluoroacetate into a single-neck round-bottom flask containing magnetons, adding 5mL of dichloromethane for dissolving, stirring uniformly, 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, the pure solid compound HX1 is obtained by column chromatography separation, and the productThe material was a yellow solid in 88% yield.1H NMR(400MHz,Acetone-d6)11.09(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-d6)168.69,142.80,140.78,129.76,129.60,126.41,125.72,119.27,118.07,113.13,112.07,64.07,14.20。
Example 2: preparation of ethyl 2- (5-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX2)
The preparation is as in example 1, the product being a white solid with a yield of 90%.1H NMR(400MHz,CDCl3)8.38(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,CDCl3)169.19,159.28,132.90,126.16,125.57,125.47,124.93,122.08,112.14,112.04,111.38,111.12,108.67,108.62,106.40,106.15,64.42,13.86。
Example 3: preparation of ethyl 2- (5-chloro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX3)
The preparation is as in example 1, the product is a white solid with a yield of 87%.1H NMR(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,2H),1.28(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)169.09,135.03,126.78,125.70,125.63,124.82,123.90,121.97,113.91,112.81,108.28,64.51,13.89。
Example 4: preparation of ethyl 2- (6-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX4)
The preparation is as in example 1, the product is a white solid with a yield of 100%.1H NMR(400MHz,Acetone-d6)10.60(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-d6)169.17,161.74,137.73,126.52,123.18,123.12,109.93,109.19,108.95,98.53,98.27,63.71,14.24。
Example 5: preparation of ethyl 2- (5-bromo-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX5)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 85%.1H NMR(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).13C NMR(101MHz,CDCl3)169.09,135.03,126.78,125.70,125.63,124.82,123.90,121.97,113.91,112.81,108.28,64.51,13.89。
Example 6: preparation of ethyl 2- (1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 6)
The preparation is as in example 1, the product is a white solid with a yield of 99%.1H NMR(400MHz,CDCl3)8.28(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,CDCl3)169.42,136.35,125.13,124.99,124.44,122.70,121.15,121.14,120.53,111.39,108.65,64.25,13.93。
Example 7: preparation of ethyl 2- (5-cyano-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX7)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 92%.1H NMR(400MHz,Acetone-d6)11.12(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-d6)168.76,139.45,128.61,127.69,126.44,126.28,125.37,123.60,121.00,114.05,110.58,103.87,63.96,14.22。
Example 8: preparation of methyl 2- (1-Boc-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 8)
Indole (232 mg, 2mmol) was dissolved in 10mL dichloromethane and added dropwise (Boc) at room temperature2(480.15mg,2.2mmol), 1mL of triethylamine was added and the reaction was stirred at room temperature. The reaction was monitored by TLC and after 5h, column chromatography gave 1-Boc indole which was prepared as example 1 in 95% yield as a colorless oil.1H NMR(400MHz,Acetone-d6)8.19(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-d6)168.86,149.92,136.46,128.56,126.51,126.20,125.65,123.79,122.31,115.94,115.16,103.32,85.37,54.13,28.15。
Example 9: preparation of ethyl 2- (1-isopentyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 9)
Indole (232 mg, 2mmol) was dissolved in 10mL DMF and 8mL DMF solution containing 96mg (2.4 mmol) NaH (60% in mineral oil) was added at 5 ℃ and the mixture was stirred at room temperature for 30min and cooled to 5 ℃ before 5mL DMF solution containing 362.5mg isoamyl bromide (2.4 mmol) was added dropwise and reacted at room temperature with TLC monitoring. After 16h, the mixture was cooled to 5 ℃ and quenched with 15mL of water, the product was extracted with ether and isolated by column chromatography to give 1-isopentylindole as a pale yellow oil in 93% yield following the procedure of example 1.1H NMR(400MHz,Acetone-d6)7.89(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-d6)169.22,137.41,128.87,126.99,125.40,123.81,122.61,122.30,120.40,110.72,108.61,63.54,45.29,39.70,26.50,22.72,22.70,14.28。
Example 10: preparation of methyl 2- (5-chloro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 10)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 88%.1H NMR(400MHz,Acetone-d6)10.63(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-d6)169.54,136.21,127.52,126.53,125.95,123.69,122.96,121.22,113.99,109.39,78.25,53.95。
Example 11: preparation of methyl 2- (5-nitro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 11)
The procedure is as in example 1, the product is a yellow solid in 89% yield.1H NMR(400MHz,Acetone-d6)11.13(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-d6)169.22,142.83,140.72,129.68,126.38,125.77,123.54,119.12,118.10,113.14,111.96,54.19。
Example 12: preparation of ethyl 2- (1-methyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX12)
The preparation is as in example 1, and the product is a pale yellow oil in 92% yield.1H NMR(400MHz,Acetone-d6)7.88(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-d6)169.25,138.25,129.91,126.86,126.65,123.81,122.67,122.11,120.44,110.56,108.55,63.58,33.05,14.24。
Example 13: preparation of ethyl 2- (5-carbomethoxy-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 13)
The preparation is as in example 1, the product is a white solid with a yield of 86%.1H NMR(400MHz,Acetone-d6)10.90(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-d6)169.07,168.27,140.35,127.75,126.56,125.99,125.08,123.93,123.72,122.85,112.46,111.14,63.87,52.02,14.22。
Example 14: preparation of ethyl 2- (4-nitro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 14)
The preparation is as in example 1, the product is a yellow solid with a yield of 83%.1H NMR(400MHz,Acetone-d6)11.28(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-d6)168.56,145.00,139.52,129.62,129.58,126.66,123.80,121.91,118.09,117.60,108.96,63.63,14.17。
Example 15: preparation of methyl 2- (4-carbomethoxy-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 15)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 86%.1H NMR(400MHz,Acetone-d6)10.94(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-d6)171.79,169.80,138.45,128.02,127.98,125.71,123.42,123.11,121.94,116.90,110.38,106.62,53.71,53.00。
Example 16: preparation of methyl 2- (5-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 16)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 91%.1H NMR(400MHz,Acetone-d6)10.54(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-d6)169.63,159.78,134.40,127.77,126.71,123.77,113.60,111.23,110.97,106.44,78.25,53.91。
Example 17: preparation of methyl 2- (5-cyano-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 17)
The preparation is as in example 1, the product being a white solid with a yield of 81%.1H NMR(400MHz,Acetone-d6)11.12(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-d6)169.34,139.44,128.62,127.57,126.41,126.28,125.45,123.57,121.06,114.07,110.51,103.94,54.18。
Example 18: preparation of ethyl 2- (4-hydroxy-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 18)
The preparation is as in example 1, the product being a yellow solid with a yield of 100%.1H NMR(400MHz,Acetone-d6)10.60(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-d6)168.16,150.26,139.93,126.18,124.68,124.44,115.85,108.18,106.08,104.43,104.38,63.72,14.20。
Example 19: preparation of ethyl 2- (2-methyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 19)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 96%.1H NMR(400MHz,CDCl3)8.02(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,CDCl3)169.38,135.30,134.66,126.83,125.40,122.56,121.61,120.45,120.23,110.38,103.89,63.58,13.89,13.74。
Example 20: preparation of ethyl 2- (5-formyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 20)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 92%.1H NMR(400MHz,Acetone-d6)11.04(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-d6)191.72,166.67,140.21,130.10,128.79,127.16,126.60,125.40,122.76,121.67,112.45,110.67,62.98,13.34。
Example 21: preparation of methyl 2- (5-formyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionate (HX 21)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1H NMR(400MHz,Acetone-d6)11.07(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-d6)191.81,168.53,140.02,130.17,127.15,127.00,126.57,125.58,125.41,121.60,112.45,99.99,53.15。
TABLE 1 chemical Structure of the target compound HX1-21 synthesized by the method of the present invention
| Compound | R1 | R2 | R3 |
| HX1 | 5-NO2 | 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-NO2 | Me | H |
| HX12 | H | Et | Me |
| HX13 | 5-COOMe | Et | H |
| HX14 | 4-NO2 | 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: pharmacological experiment of indole compounds
(1) Indole compound cytotoxicity assay:
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 MTT was added, after further culturing at 37 ℃ for 4 hours, 100. mu.l of 20% SDS was added, and after culturing for 18 hours, the OD value at 595nm was measured using a microplate reader. Inhibition ratio of Compound (%) = [1- (E-N)/(P-N)]X 100, wherein "E" represents the OD value of the administered group, "P" represents the OD value of the non-administered group, and "N" represents the OD value of the blank group. Median inhibitory concentration (CC) of the Compound50) As an indicator of the cytotoxicity of the compound.
(2) Indole compounds have anti-HIV-1 activity in vitro:
HIV-IIIB (provided by American health research institute) is a classical HIV drug screening experimental strain, TZM-bl (provided by American health research institute) cells are modified Hela (provided by American type Collection) cell strains, HIV receptors and auxiliary receptors are stably expressed on cell membranes, and luciferase genes started by HIV long-terminal repeat sequences are stably integrated in cell nuclei. After HIV-IIIB infects TZM-B1 cell, the TAT protein expressed by virus can activate the expression of luciferase gene in cell, and the replication level of virus can be judged by detecting the activity of luciferase in cell. 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-IIIB virus and drug are mixed and added into TZM-bl cells (60% (area ratio) to be fully paved), after the virus adsorbs the cells for 2 hours, the mixture of the virus and the drug is sucked, and fresh culture medium (DMEM, 90% (volume ratio), fetal bovine serum, 10% (volume ratio), G418, 500 mu G/ml, hygromycin, 100 mu G/ml and puromycin, 1 mu G/ml, wherein the percentage is volume percentage content) is added for continuous culture, and 8 repeated wells are made for each dilution. Luciferase activity was detected in the cells after 24 hours incubation at 37 ℃. Inhibition ratio of Compound (%) = [1- (E-N)/(P-N)]X 100, wherein "E" represents the activity of luciferase in the experimental group, "P" represents the activity of luciferase in the positive group, and "N" represents the activity of luciferase in the negative group. Median Inhibitory Concentration (IC) of Compounds50) As an indicator of its antiviral activity.
In the invention, 21 synthesized compounds were examined for cytotoxicity and anti-HIV-1 activity using Delavirdine (DEV) and Efavirenz (EFV) as controls, and the selectivity index SI of the compounds was calculated, and the results are shown in Table 2.
TABLE 2 results of cytotoxicity and anti-HIV-1 Activity of HX1-21, a target Compound synthesized according to the invention
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=1404.6）、HX3（IC50=0.249μM，SI=552.6）、HX4（IC50=0.147μM，SI=757.8）、HX12（IC50=0.309 μ M, SI = 752.0), and the like.
Claims (4)
1. An indole compound has a structure shown in the following general formula:
wherein,
R1is 4-OH, 4-NO2、4-COOMe、5-CHO；
R2Me or Et;
R3boc, Me or isoamyl.
2. An application of indole compounds in preparing anti-AIDS drugs, wherein the indole compounds have a structure shown as the following general formula:
wherein,
R1is H, 2-Me, 4-OH, 4-NO2、4-COOMe、5-CHO、5-CN、5-F、5-Br、5-Cl、5-NO25-COOMe or 6-F;
R2me or Et;
R3h, Boc, Me or isoamyl.
3. The use according to claim 2, wherein the indole is
2- (5-nitro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,
2- (5-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,
2- (5-chloro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,
2- (6-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,
2- (5-bromo-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,
2- (5-cyano-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester or
2- (1-methyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester.
4. An anti-aids pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
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| Asymmetric Calcium Catalysis: Highly Enantioselective Carbonyl-Ene and Friedel–Crafts Reactions for the Synthesis of Quaternarya-Hydroxy Esters Bearing a Trifluoromethyl Group;Magnus Rueping etal;《Chem. Asian J.》;20120630;第7卷(第6期);1195-1198，第1197页Table.4 化合物9a、9b、9c、9d、9f、9g * |
| Highly Enantioselective Zinc-Catalyzed Friedel–Crafts Alkylation of Indoles with Ethyl Trifluoropyruvate;Yonghai Hui etal;《Adv. Synth. Catal.》;20101217;第352卷(第18期);3174-3178，第3175页Table.2 化合物3l、4l * |
| Jing Nie etal.Chiral Brø * |
| nsted-Acid-Catalyzed Enantioselective Arylation of Ethyl Trifluoroacetoacetate and Ethyl Trifluoropyruvate.《European Journal of Organic Chemistry》.2009,第2009卷(第19期),3145-3149. * |
| Structure–Activity Relationships of Organofluorine;Béla Török etal;《ChemMedChem》;20120531;第7卷(第5期);910-919，第913页GroupⅡ 化合物28 * |
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| CN103113285A (en) | 2013-05-22 |
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