Nucleoside phosphoramidate type compound with HBV/HIV resistance activity and salt and application of nucleoside phosphoramidate type compound

A nucleoside phosphoramidate and compound technology, applied in the field of medicine and chemical industry, can solve the problems of maintaining sufficient concentration of infected parts, poor membrane permeability, and low bioavailability of human body

Active Publication Date: 2017-04-19
周雨恬
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because some drugs are hydrolyzed before being absorbed into the blood, the released original drug tenofovir will be quickly excreted due to poor memb

Method used

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  • Nucleoside phosphoramidate type compound with HBV/HIV resistance activity and salt and application of nucleoside phosphoramidate type compound
  • Nucleoside phosphoramidate type compound with HBV/HIV resistance activity and salt and application of nucleoside phosphoramidate type compound
  • Nucleoside phosphoramidate type compound with HBV/HIV resistance activity and salt and application of nucleoside phosphoramidate type compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Reaction formula

[0106]

[0107] (1) Preparation of Compound 2

[0108] Add PMPA (20g, 70mmol), anhydrous acetonitrile (180ml), triethylamine (19.6ml, 140mmol), DMAP (8.52g, 70mmol) and triphenyl phosphite (32.42g, 104mmol) into a three-necked flask, Heat the reaction mixture to 80°C, continue stirring at this temperature for 60 hours until the reaction is complete, distill off most of the solution, add ethyl acetate (100ml) and water (80ml), and wash the aqueous phase with ethyl acetate (2 × 100ml) , the aqueous solution was poured into a reaction flask, adjusted to about pH 3 with concentrated hydrochloric acid (12M, 4.2ml), added 100 mg of seed crystals under stirring at room temperature, and then slowly added concentrated hydrochloric acid (12M, 1.4ml) to adjust to pH 2. Stir at room temperature for 1 hour, then gradually cool to about 10°C, stir overnight, collect the white solid, wash with 20ml (pH 1.5) cold hydrochloric acid solution, and dry to obtain 20.4...

Embodiment 2

[0128] Reaction formula

[0129]

[0130] Add (9-[(R)-2-[[(R)-[[(R)-1(isopropoxy)ethyl]amino]phenoxyphosphoryl]methoxy]propyl] to the reaction vial Adenine) I-1-a1 (120mg, 0.25mmol), triethylamine (70ul, 0.5mmol) and tetrahydrofuran (5ml), under nitrogen protection and 0 ℃, add octanoyl chloride (122mg, 0.75mmol) dropwise, add After completion, stirring was continued overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated on a silica gel column (ethyl acetate / hexane, 0-60%) to obtain product II-1-a1 (77 mg, 51%). 1 HNMR (400MHz, CD 3 OD): δ 0.90 (t, 3H), 1.23 – 1.51 (m, 22H), 2.33 (t, 2H), 3.76 (s,1H), 3.84 – 4.21 (m, 4H), 4.27 – 4.47 (m, 1H ), 4.85 – 5.10 (m, 1H), 7.19 –7.57(m, 5H), 8.06 (s, 1H), 8.54 (s, 1H); MS-ESI: 603.4 (M+1) + .

[0131] The following compounds are synthesized in the same way:

[0132] 1 HNMR (400MHz, CD 3 OD): δ 0.89 (t, 3H), 1.23 – 1.51(m, 26H), 2.35 (t, 2H), 3.75 (s, 1H), ...

Embodiment 3

[0144]

[0145] Add (9-[(R)-2-[[(R)-[[(R)-1(isopropoxy)ethyl]amino]phenoxyphosphoryl]methoxy]propyl] to the reaction vial Adenine) I-1-a1 (120mg, 0.25mmol), N-methylimidazole (41ul, 0.5mmol) and dichloromethane (5ml), under nitrogen protection and 0 ° C, dropwise added hexyl chloroformate ( 135mg, 0.75mmol), the addition was completed, and the stirring was continued overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated with a silica gel column (ethyl acetate / hexane, 0-50%) to obtain the product III-1-a1 (96mg , 62%). 1 HNMR (400MHz, CD 3 OD): δ 0.90 (t, 3H), 1.15 – 1.59 (m, 20H), 3.78(s, 1H), 3.82 – 4.22 (m, 6H), 4.27 – 4.48 (m, 1H), 4.84 – 5.11 (m , 1H), 7.16– 7.59 (m, 5H), 8.03 (s, 1H), 8.36 (s, 1H); MS-ESI: 605.4 (M+1) + .

[0146] The following compounds are synthesized in the same way:

[0147] 1 HNMR (400MHz, CD 3 OD): δ 0.92 (t, 3H), 1.16 –1.61 (m, 24H), 3.77 (s, 1H), 3.81 – 4.22 (m, 6H), ...

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Abstract

The invention relates to a nucleoside phosphoramidate type compound with HBV/HIV resistance activity, an isomer of the nucleoside phosphoramidate type compound, pharmaceutically-acceptable salt of the nucleoside phosphoramidate type compound, a solvate or crystal of the nucleoside phosphoramidate type compound, a medicine composition of the nucleoside phosphoramidate type compound, and application of the nucleoside phosphoramidate type compound. According to related novel non-cyclic nucleoside phosphoramidate, on the phosphoramidate part, amino acid is D-amino-acid. D-amino-acid ester is introduced in the prodrug, and a new non-cyclic nucleotide amide compound which has higher chemical stability, higher lipid solubility and higher virus inhibition activity is expected to be obtained. By means of the creative design, the virus resistance activity of medicine is improved, solubility and pharmacokinetics characteristics of the medicine are improved, the concentration ratio in tissue cells and plasma is increased, and therefore the curative effect, safety and tolerance of the medicine can be improved, and very good clinical application prospects are achieved.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to an acyclic nucleotide phosphoramide compound, its pharmaceutical composition, preparation method and application. Background technique [0002] Since the first case of AIDS was discovered in 1981, AIDS has spread rapidly around the world for more than 30 years. The disease has become a global health crisis and one of the major challenges facing the world; it seriously jeopardizes social progress and economic growth. According to reports, at present, more than 60 million people in the world are infected with HIV, and 30 million of them die from AIDS and related diseases caused by AIDS. [0003] A series of anti-reverse transcriptase inhibitors (nucleosides, NRTIs and non-nucleosides, NNRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs) and entry inhibitors (CCRs inhibitors) have been successfully developed. orfusion inhibitors), such as reverse transcript...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
CPCC07F9/65616
Inventor 周雨恬
Owner 周雨恬
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