CN1343673A - Thiophosphamino acid ester compound containing 3'-azido-deoxythymidine and its preparing process - Google Patents

Thiophosphamino acid ester compound containing 3'-azido-deoxythymidine and its preparing process Download PDF

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CN1343673A
CN1343673A CN 01130786 CN01130786A CN1343673A CN 1343673 A CN1343673 A CN 1343673A CN 01130786 CN01130786 CN 01130786 CN 01130786 A CN01130786 A CN 01130786A CN 1343673 A CN1343673 A CN 1343673A
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compound
zidovodine
nmr
thf
cem
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CN1133641C (en
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赵玉芬
苗志伟
付华
成昌梅
韩波
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Tsinghua University
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Tsinghua University
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Abstract

A thiophosphamino acid ester compound containing 3'-azido-deoxythymidine is prepared through dissolving (aryl substituted) dichlorothion in tetrahydrofuran (THF), adding amino acid methylester hydrochloride, adding acid capturing agent, adding solution of 3'-azido-deoxythymidine, adding acid capturing agent, filter, rotary distillation and chromatography. The said compound has anti-AIDS activity.

Description

A kind of thiophosphoryl amino acid ester compound that contains 3 ' Zidovodine and preparation method thereof
The present invention relates to a kind of thiophosphoryl amino acid ester compound and preparation method thereof, relate in particular to thiophosphoryl amino acid ester compound that contains 3 ' Zidovodine and preparation method thereof, this compounds has good biological activity and antiviral, antitumor, anti-ly likes now pharmaceutical activity such as virus, can develop in clinical application that a kind of ucleosides is antiviral, antitumor, anti-likes viral now prodrug (prodrugs).
Thiophosphoric acid contains the structure that a sulphur replaces oxygen on phosphorus atom, though this structure is still keeping original electric charge, the character that is keeping highly water-soluble, but other physicochemical properties of the dna oligo of thiophosphoric acid (S-oligos) and biology attribute all have very big difference with natural phosphodiester prototype.One of marked difference is that thiophosphoric acid has resistivity to nuclease.Because the phosphodiester class antisense oligonucleotide that adds has been fallen in the existence of exonuclease in the cell, very fast digestion, make its forfeiture action function.By synthetic thiophosphoric acid compounds with opposing nuclease, be used for the treatment of purpose for using the synthetic dna oligo from now on, opened up the road of a hope beyond doubt.
The objective of the invention is to propose a kind of thiophosphoryl amino acid ester compound that contains 3 ' Zidovodine and preparation method thereof, be used to develop antiviral, antitumor, the anti-virus activity medicine now of liking.
The thiophosphoryl amino acid ester compound that contains 3 ' Zidovodine of the present invention's preparation, the structural formula of compound is:
Figure A0113078600031
R=H in the said structure formula, CH 3, C 6H 5CH 2, (CH 3) 2CH 2, (CH 3) 2CHCH 2
X＝H，Cl，NO 2。
The synthesis step of above-claimed cpd is as follows:
1) under nitrogen protection, cryosel is bathed under the condition that is cooled to-4～-8 ℃, and raw material (aromatic base replacement) two compd 22/190s are dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution that concentration is 0.8～1.0mol/L.
2) add amino acid methyl ester hydrochloride with the amount of raw material same substance in above-mentioned solution, slowly drip acid binding agent after stirring, the add-on of acid binding agent is 2 times of amount of raw material.
3) follow the tracks of above-mentioned reaction process, after treating that the raw material total overall reaction finishes, to slowly splash in the solution in second step with 3 ' the Zidovodine solution that is dissolved in the tetrahydrofuran (THF) of the amount of raw material same substance, the acid binding agent with the amount of raw material same substance is continued to drip in the back that stirs.
4) after monitoring reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, carries out column chromatography for separation with silicagel column, promptly obtains containing the thiophosphoryl amino acid ester compound of 3 ' Zidovodine.
The thiophosphoryl amino acid ester compound that contains 3 ' Zidovodine with method preparation of the present invention, be a class brand-new have an anti-active compound of virus drugs now of liking, by synthetic different types of nucleosides-amino acid conjugate, and carry out activity experiment, tentatively obtained satisfied result, liked now the virus drugs achievement in research that provides the foundation for further development and development of new resist.Virus-1 activity experiment discovery now of anti-love in cem cell and MT-4 cell all has activity in various degree.
Below introduce embodiments of the invention:
Embodiment 1: preparation 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl glycine methyl ester compound, R=H wherein, X=H.
The structural formula of compound is:
Figure A0113078600041
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (phenyl replacements) two compd 22/190s of 1mmol (0.227g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the glycine methyl ester hydrochloride of 1mmol (0.125g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (phenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl glycine methyl ester, productive rate is 77.1%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.70,72.10; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH, 7.22-7.41 (6H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6): δ 173.24 (COOMe), 163.70 (C-2), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 129.91 (m, Ph-para), 125.52 (m, Ph-ortho), 120.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 511 (M+H) +ESI-MS (neg.): m/z 509 (M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50?CEM-TK - 9×10 -6μM (CD 50?206μM)
CEM-SS 4×10 -5μM (CD 50?118μM)
MT4 5×10 -5μM (CD 50?70μM)
Embodiment 2: preparation 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl alanine methyl ester compound, wherein R is CH 3, X is H.
The structural formula of compound:
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (phenyl replacements) two compd 22/190s of 1mmol (0.227g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the alanine methyl ester hydrochloride of 1mmol (0.14g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (phenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl alanine methyl ester, productive rate is 67.3%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 70.20,71.70; 1H NMR (500MHz, DMSO-d 6): δ 9.81 (1H, sb, NH), 7.22-7.41 (6H, m, Ph, H-6), and 6.34 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.56 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.40 (3H, d, Ala-Me); 13C NMR (500MHz, DMSO-d 6): δ 178.24 (COOMe), 163.70 (C-2), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 129.91 (m, Ph-para), 125.52 (m, Ph-ortho), 120.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 20.86 (d, Ala-Me, J=5Hz), 12.60 (5-Me); ESI-MS (pos.): m/z525 (M+H) +ESI-MS (neg.): m/z523 (M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoidT?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 6××10 -3μM (CD 50?188μM)
CEM-SS 6××10 -2μM (CD 50?49μM)
MT4 4××10 -2μM (CD 50?69μM)
Embodiment 3: preparation 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl phenylalanine methyl ester compound, wherein R is C 6H 5CH 2, X is H.
The structural formula of compound:
Figure A0113078600061
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (phenyl replacements) two compd 22/190s of 1mmol (0.227g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the phenylalanine methyl ester hydrochloride of 1mmol (0.215g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (phenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.266g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl phenylalanine methyl ester, productive rate is 69.6%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 70.70,71.30; 1H NMR (500MHz, DMSO-d 6): δ 9.88 (1H, sb, NH), 7.22-7.41 (6H, m, Ph, H-6), 7.15-7.35 (5H, m, Ph), and 6.32 (1H, m, H-1 '), 4.20-4.44 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.32 (2H, m, H-β), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6): δ 174.39 (COOMe), 163.66 (C-2), 151.24 (C-4), 148.36 (Ph-pso), 140.76 (C-6), 120.08 (m, Ph-meta), 135.12 (Ph-para), 130.42 (Ph-ortho), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), (60.54 C-3 '), 56.82 (C-β), 54.78 (OCH 3),
50.41(C-α)，37.46(C-2′)，12.60(5-Me)；
ESI-MS(pos.)：m/z601(M+H) +；ESI-MS(neg.)：m/z?599(M-H) -
The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50?CEM-TK - 8×10 -3μM (CD 50?112μM)
CEM-SS 3×10 -2μM (CD 50?29μM)
MT4 6×10 -2μM (CD 50?44μM)
Embodiment 4: preparation 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl valine methyl ester compound, wherein R is (CH 3) 2CH 2, X is H.
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (phenyl replacements) two compd 22/190s of 1mmol (0.227g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the valine methyl ester hydrochloride of 1mmol (0.17g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (phenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl valine methyl ester, productive rate is 87.3%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.70,72.40; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH), 7.22-7.41 (6H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.67 (1H, m, H-α), 3.45 (1H, m, H-β), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.61 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 174.24 (COOMe), 165.70 (C-2), 150.63 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 129.91 (m, Ph-para), 125.52 (m, Ph-ortho), 120.08 (m, Ph-meta, 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 26.86 (CH 3), 26.40 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 553 (M+H) +ESI-MS (neg.): m/z 551 (M-H) -: the anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 6×10 -3μM (CD 50?77μM)
CEM-SS 1×10 -2μM (CD 50?48μM)
MT4 2×10 -2μM (CD 50?62μM)
Embodiment 5: preparation 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl leucine methyl compound, wherein R is (CH 3) 2CHCH 2, X is H.
The structural formula of compound:
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (phenyl replacements) two compd 22/190s of 1mmol (0.227g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the leucine methyl ester hydrochloride of 1mmol (0.184g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (phenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(phenyl replacement) thiophosphoryl leucine methyl esters, productive rate is 68.3%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 70.6,71.8; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH), 7.22-7.41 (6H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 3.21 (1H, m, H-γ), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.61 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 173.24 (COOMe), 163.70 (C-2), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 129.91 (m, Ph-para), 125.52 (m, Ph-ortho), 120.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 46.35 (C-γ), 23.40 (CH 3), 22.86 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 567 (M+H) +ESI-MS (neg.): m/z 565 (M-H) -.
The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50?CEM-TK - 8×10 -3μM (CD 50?79μM)
CEM-SS 9×10 -2μM (CD 50?78μM
MT4 5×10 -2μM (CD 50?23μM)
Embodiment 6: preparation 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl glycine methyl ester compound, wherein R is H, X is CI.
The structural formula of compound:
Figure A0113078600091
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (rubigan replacements) two compd 22/190s of 1mmol (0.262g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the glycine methyl ester hydrochloride of 1mmol (0.125g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (rubigan replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl glycine methyl ester, productive rate is 77.1%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.32,72.11; 1H NMR (500MHz, DMSO-d 6: δ 9.80 (1H, sb, NH), 6.82-7.25 (5H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6): δ 173.24 (COOMe), 163.70 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z547 (M+H) +ESI-MS (neg.): m/z545 (M-H) -. the anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50?CEM-TK - 8×10 -3μM (CD 50?186μM)
CEM-SS 5×10 -2μM (CD 50?218μM)
MT4 5×10 -2μM (CD 50?60μM)
Embodiment 7: preparation 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl alanine methyl ester compound, wherein R is CH 3, X is CI.
The structural formula of compound:
Figure A0113078600101
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (rubigan replacements) two compd 22/190s of 1mmo1 (0.262g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the alanine methyl ester hydrochloride of 1mmol (0.14g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (rubigan replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl alanine methyl ester, productive rate is 71.3%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 70.20,71.70; 1H NMR (500MHz, DMSO-d 6): δ 9.81 (1H, sb, NH), 6.82-7.28 (5H, m, Ph, H-6), and 6.36 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.11 (1H, m, Ala-NH), 3.86 (3H, s, OCH 3), 3.66 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.40 (3H, d, Ala-Me); 13C NMR (500MHz, DMSO-d 6: δ 177.24 (COOMe), 161.70 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 116.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 35.46 (C-2 '), 19.86 (d, Ala-Me, J=5Hz), 12.60 (5-Me); ESI-MS (pos.): m/z 560 (M+H) +ESI-MS (neg.): m/z 558 M-H) -.
The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50?CEM-TK - 9×10 -3μM (CD 50?188μM))
CEM-SS 5×10 -2μM (CD 50?123μM)
MT4 6×10 -2μM (CD 50?98μM)
Embodiment 8: preparation 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl phenylalanine methyl ester compound, wherein R is C 6H 5CH 2, X is CI.
The structural formula of compound:
Figure A0113078600111
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (rubigan replacements) two compd 22/190s of 1mmol (0.262g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the phenylalanine methyl ester hydrochloride of 1mmol (0.215g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (rubigan replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.266g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl phenylalanine methyl ester, productive rate is 70.8%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.70,72.30; 1H NMR (500MHz, DMSO-d 6): δ 9.81 (1H, sb, NH), 6.82-7.25 (5H, m, Ph, H-6), 7.15-7.35 (5H, m, Ph), and 6.32 (1H, m, H-1 '), 4.20-4.44 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.32 (2H, m, H-β), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6: δ 174.39 (COOMe), 163.66 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), (84.94 C-1 '), 82.40 (C-4 '), 65.87 (C-5 '), (60.54 C-3 '), 56.82 (C-β), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 636 (M+H) +ESI-MS (neg.): m/z 634 (M-H) -
The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50?CEM-TK - 8×10 -3μM (CD 50?185μM)
CEM-SS 5×10 -2μM (CD 50?65μM)
MT4 6×10 -2μM (CD 50?122μM)
Embodiment 9: preparation 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl valine methyl ester compound, wherein R is (CH 3) 2CH 2, X is CI.
The structural formula of compound:
Figure A0113078600121
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (rubigan replacements) two compd 22/190s of 1mmol (0.262g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the valine methyl ester hydrochloride of 1mmol (0.17g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (rubigan replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl valine methyl ester, productive rate is 67.3%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.60,72.50; 1H NMR (500MHz, DMSO-d 6): δ 9.56 (1H, sb, NH), 6.82-7.35 (5H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.69 (1H, m, H-α), 3.55 (1H, m, H-β), 2,56 (1H, m, H-2 '), 2.12 (3H, s, 5-Me), 1.51 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 175.24 (COOMe), 165.70 (C-2), 161.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 26.86 (CH 3), 26.40 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 587 (M+H) +ESI-MS (neg.): m/z 585 M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 6×10 -3μM (CD 50?77μM)
CEM-SS 1×10 -2μM (CD 50?48μM)
MT4 2×10 -2μM (CD 50?62μM)
Embodiment 10: preparation 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl leucine methyl compound, wherein R is (CH 3) 2CHCH 2, X is CI.
The structural formula of compound:
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (rubigan replacements) two compd 22/190s of 1mmol (0.262g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the leucine methyl ester hydrochloride of 1mmol (0.184g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (rubigan replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(rubigan replacement) thiophosphoryl leucine methyl esters, productive rate is 66.3%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.8,72.3; 1H NMR (500MHz, DMSO-d 6): δ 9.85 (1H, sb, NH), 6.82-7.21 (5H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.44 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 3.21 (1H, m, H-γ), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.61 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6: δ 173.24 (COOMe), 163.70 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 46.35 (C-γ), 23.40 (CH 3), 22.86 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 602 (M+H) +ESI-MS (neg.): m/z 600 (M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 7×10 -3μM (CD 50?159μM)
CEM-SS 9×10 -2μM (CD 50?68μM）
MT4 6×10 -2μM (CD 50?21μM）
Embodiment 11: preparation 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl glycine methyl ester compound, wherein R is H, X is NO 2
The structural formula of compound:
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (p-nitrophenyl replacements) two compd 22/190s of 1mmol (0.273g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the glycine methyl ester hydrochloride of 1mmol (0.125g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (p-nitrophenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl glycine methyl ester, productive rate is 66.1%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.32,72.11; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH), 6.82-7.21 (5H, m, Ph, H-6), and 6.41 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.85 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6: δ 173.24 (COOMe), 163.70 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 118.08 (m, Ph-meta), 113.52 (C-5), 84.64 (C-1 '), (82.40 C-4 ') ' 65.87 (C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 38.46 (C-2 '), 12.55 (5-Me); ESI-MS (pos.): m/z 558 (M+H) +ESI-MS (neg.): m/z 556 (M-H) -
The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 9×10 -3μM (CD 50?286μM)
CEM-SS 7×10 -2μM (CD 50?118μM)
MT4 5×10 -2μM (CD 50?60μM)
Embodiment 12:3 ' Zidovodine-5 '-preparation of (p-nitrophenyl replacement) thiophosphoryl alanine methyl ester compound, wherein R is CH 3, X is NO 2
The structural formula of compound:
Figure A0113078600151
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and (p-nitrophenyl replacements) two compd 22/190s of 1mmo1 (0.273g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the alanine methyl ester hydrochloride of 1mmol (0.14g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (p-nitrophenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl alanine methyl ester, productive rate is 71.3%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 70.60,71.30; 1H NMR (500MHz, DMSO-d 6): δ 9.82 (1H, sb, NH), 6.82-7.28 (5H, m, Ph, H-6), and 6.36 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.11 (1H, m, Ala-NH), 3.86 (3H, s, OCH 3), 3.66 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.40 (3H, d, Ala-Me); 13C NMR (500MHz, DMSO-d 6): δ 177.24 (COOMe), 161.70 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 116.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 35.46 (C-2 '), 19.86 (d, Ala-Me, J=5Hz), 12.60 (5-Me); ESI-MS (pos.): m/z572 (M+H) +ESI-MS (neg.): m/z570 M-H) -
The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 9×10 -3μM (CD 50?168μM)
CEM-SS 6×10 -2μM (CD 50?183μM)
MT4 7×10 -2μM (CD 50?98μM)
Embodiment 13: preparation 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl phenylalanine methyl ester compound, wherein R is C 6H 5CH 2, X is NO 2The structural formula of compound:
Figure A0113078600161
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (p-nitrophenyl replacements) two compd 22/190s of 1mmol (0.273g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the phenylalanine methyl ester hydrochloride of 1mmol (0.215g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (p-nitrophenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.266g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl phenylalanine methyl ester, productive rate is 61.8%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.70,72.30; 1H NMR (500MHz, DMSO-d 6): δ 9.81 (1H, sb, NH), 6.82-7.25 (5H, m, Ph, H-6), 7.15-7.35 (5H, m, Ph), and 6.32 (1H, m, H-1 '), 4.20-4.44 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α, 2,50 (1H, m, H-2 '), 2.32 (2H, m, H-β), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6): δ 174.39 (COOMe), 163.66 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), (84.94 C-1 '), 82.40 (C-4 '), 65.87 (C-5 '), (60.54 C-3 '), 56.82 (C-β), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 636 (M+H) +ESI-MS (neg.): m/z 634 (M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 8×10 -3μM (CD 50?185μM)
CEM-SS 6×10 -2μM (CD 50?157μM)
MT4 6×10 -2μM (CD 50?122μM)
Embodiment 14: preparation 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl valine methyl ester compound, wherein R is (CH 3) 2CH 2, X is NO 2
The structural formula of compound:
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (p-nitrophenyl replacements) two compd 22/190s of 1mmol (0.273g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the valine methyl ester hydrochloride of 1mmol (0.17g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (p-nitrophenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl valine methyl ester, productive rate is 62.3%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.60,72.50; 1H NMR (500MHz, DMSO-d 6): δ 9.56 (1H, sb, NH), 6.82-7.35 (5H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.69 (1H, m, H-α), 3.55 (1H, m, H-β), 2,56 (1H, m, H-2 '), 2.12 (3H, s, 5-Me), 1.51 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 176.24 (COOMe), 165.70 (C-2), 161.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 26.86 (CH 3), 26.40 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 598 (M+H) +ESI-MS (neg.): m/z596 M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 9×10 -3μM (CD 50?178μM)
CEM-SS 5×10 -2μM (CD 50?48μM)
MT4 8×10 -2μM (CD 50?162μM)
Embodiment 15: preparation 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl leucine methyl compound, wherein R is (CH 3) 2CHCH 2, X is NO 2
The structural formula of compound:
Figure A0113078600191
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel bathes and to be cooled to-4～-8C, (p-nitrophenyl replacements) two compd 22/190s of 1mmol (0.273g) are dissolved in the tetrahydrofuran (THF) (THF) of dry mistake, be mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the leucine methyl ester hydrochloride of 1mmol (0.184g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), after treating that (p-nitrophenyl replacement) two compd 22/190 total overall reactions finish, 3 ' the Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, and 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, carry out column chromatography for separation with silicagel column, eluent is a chloroform: methyl alcohol=50: 1 can obtain product 3 ' Zidovodine-5 '-(p-nitrophenyl replacement) thiophosphoryl leucine methyl esters, productive rate is 65.3%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 71.8,72.3; 1H NMR (500MHz, DMSO-d 6): δ 9.85 (1H, sb, NH), 6.82-7.21 (5H, m, Ph, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.44 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 3.21 (1H, m, H-γ), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.61 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 173.24 (COOMe), 163.70 (C-2), 159.91 (m, Ph-para), 150.43 (C-4), 149.33 (d, Ph-ipso, J=4Hz), 140.76 (C-6), 125.52 (m, Ph-ortho), 117.08 (m, Ph-meta), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), (65.87 C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 46.35 (C-γ), 23.40 (CH 3), 22.86 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z612 (M+H) +ESI-MS (neg.): m/z610 (M-H) -. the anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 8×10 -3μM (CD 50 159μM)
CEM-SS 6×10 -2μM (CD 50 88μM)
MT4 4×10 -2μM (CD 50 121μM)

Claims (2)

1, a kind of 3 ' Zidovodine-5 '-(aromatic base replacement) thiophosphoryl amino acid ester compound, it is characterized in that the structural formula of this compound is:
Figure A0113078600021
R is H, CH in the said structure formula 3, C 6H 5CH 2, (CH 3) 2CH 2Or (CH 3) 2CHCH 2In any, X is H, Cl or NO 2In any.
2, a kind of preparation method of compound as claimed in claim 1 is characterized in that this method comprises the steps:
1) under nitrogen protection, cryosel is bathed under the condition that is cooled to-4～-8 ℃, and raw material (aromatic base replacement) two compd 22/190s are dissolved in the dry tetrahydrofuran (THF) of crossing, and is mixed with the solution that concentration is 0.8～1.0mol/L;
2) add amino acid methyl ester hydrochloride with the amount of raw material same substance in above-mentioned solution, slowly drip acid binding agent after stirring, acid binding agent is a triethylamine, and the add-on of acid binding agent is 2 times of amount of raw material;
3) follow the tracks of above-mentioned reaction process, after treating that the raw material total overall reaction finishes, to slowly splash in the solution in second step with 3 ' the Zidovodine solution that is dissolved in the tetrahydrofuran (THF) of the amount of raw material same substance, the acid binding agent with the amount of raw material same substance is continued to drip in the back that stirs
4) after monitoring reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, carries out column chromatography for separation with silicagel column, promptly obtain 3 ' Zidovodine-5 '-(aromatic base replacement) thiophosphoryl amino acid ester compound.
CNB011307862A 2001-08-24 2001-08-24 Thiophosphamino acid ester compound containing 3'-azido-deoxythymidine and its preparing process Expired - Fee Related CN1133641C (en)

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CN1304408C (en) * 2004-03-04 2007-03-14 清华大学 Derivative of vibothymidine and its preparation process and application
CN102617676A (en) * 2012-02-24 2012-08-01 华中科技大学 Zidovudine quinoline conjugated compound, preparation method thereof and application for liver cancer resistance
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US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

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CN1304408C (en) * 2004-03-04 2007-03-14 清华大学 Derivative of vibothymidine and its preparation process and application
CN103209987A (en) * 2010-09-22 2013-07-17 艾丽奥斯生物制药有限公司 Substituted nucleotide analogs
EP2619216A1 (en) * 2010-09-22 2013-07-31 Alios Biopharma, Inc. Substituted nucleotide analogs
JP2013537907A (en) * 2010-09-22 2013-10-07 アリオス バイオファーマ インク． Substituted nucleotide analogs
EP2619216A4 (en) * 2010-09-22 2014-04-02 Alios Biopharma Inc Substituted nucleotide analogs
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
JP2016065080A (en) * 2010-09-22 2016-04-28 アリオス バイオファーマ インク． Substituted nucleotide analog
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
WO2013123745A1 (en) * 2012-02-24 2013-08-29 华中科技大学 Azidothymidine quinoline conjugated compound, preparation method therefor and application thereof in anti-hepatoma therapy
US8951988B2 (en) 2012-02-24 2015-02-10 Huazhong University Of Science And Technology Azidothymidine quinoline conjugated compound, preparation method therefor and application thereof in anti-hepatoma therapy
CN102617676B (en) * 2012-02-24 2014-10-29 华中科技大学 Zidovudine quinoline conjugated compound, preparation method thereof and application for liver cancer resistance
CN102617676A (en) * 2012-02-24 2012-08-01 华中科技大学 Zidovudine quinoline conjugated compound, preparation method thereof and application for liver cancer resistance
CN104321333A (en) * 2012-03-21 2015-01-28 沃泰克斯药物股份有限公司 Solid forms of a thiophosphoramidate nucleotide prodrug
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9394330B2 (en) 2012-03-21 2016-07-19 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

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