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Ritonavir water-soluble derivatives, synthesizing method and use thereof

A technology of ritonavir and synthesis method, which is applied in the field of synthesis of compound 1, compound 2 and compound 3, and can solve the problems of unstable effect, affecting absorption, low water solubility, etc.

Inactive Publication Date: 2009-05-27
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low water solubility of ritonavir, which affects its absorption, it usually needs to be made into oral liquid or soft capsule
This leads to some serious problems (1. Bock, M.G.; Dipardo, R.M.; Evans, B.E.; Freidinger, R.M.; Rittle, K.E.; Payne, L.S.; Boger, J.; Whitter, W.L.; LaMont, B.I.; Ulm, E.H. ; Blaine, E.H.; Schorn, T.W.; Veber, D.F.J. Med. Chem. 1988, 31, 1918; 2. Rosenberg, S.H.; Woods, K.W.; , J.; Egan, D.A.; Bopp, B.; Merits, I.; Garren, K.W.; Hoffman, D.J.; Hinshaw, R.R.; Wilkinson, K.F.; Rush, B.D.; Yancey, M.F.; Strohbach, J.W.; Thaisrivongs, S.J. Med. Chem. 1993, 36, 2575; 4. Thaisrivongs, S.; Strohbach, J.W. , such as unstable effect after oral administration and poor drug availability, etc.

Method used

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  • Ritonavir water-soluble derivatives, synthesizing method and use thereof
  • Ritonavir water-soluble derivatives, synthesizing method and use thereof
  • Ritonavir water-soluble derivatives, synthesizing method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 Synthesis of (2S, 3S, 5S)-2-[N-(thiazole-5-methoxycarbonyl)amino]-5-[N-[N-[[N-methyl-N-[(2 -Isopropyl-4-thiazole)methyl]amino]carbonyl]-L-valylamino]amino]-3-hydroxy-1-phenyl-6-pyridinehexane (1)

[0067] Step 1 (5S)-2-Amino-5-(dibenzylamino)-4-oxo-1-α-pyridyl-6-phenyl-2-ene (41)

[0068] 2-Chloropropane (5mL, 0.5mol) dissolved in 15mL tetrahydrofuran was added to magnesium chips (4.03g, 167mmol) previously added with 10mL tetrahydrofuran, and after reflux for 1h, 2-picoline (6mL, 0.6mol) was added to the above system and continued to reflux for 3h. After the reaction was complete, the mixed solution was cooled to about 0°C with an ice-water bath. Compound 30 (5.0 g, 0.11 mol) dissolved in 10 mL of tetrahydrofuran was slowly added dropwise to the cooled mixed solution, stirred at room temperature for 12 h after the addition, and then the reaction solution was cooled to about 0 °C in an ice-water bath, Quenched with 5 mL of 25% (w / v) citric acid, the organic...

Embodiment 2

[0100] Example 2 Synthesis of (2S, 3S, 5S)-2-[N-(thiazole-5-methoxycarbonyl)amino]-5-[N-[N-[[N-methyl-N-[(2 -Isopropyl-4-thiazole)methyl]amino]carbonyl]-L-valylamino]amino]-3-hydroxy-1-phenyl-6-pyridinehexane (1)

[0101] Step 1 (5S)-2-Amino-5-(dibenzylamino)-4-oxo-1-α-pyridyl-6-phenyl-2-ene (41)

[0102] The solution of 2-chloropropane (3mL, 0.3mol) in tetrahydrofuran was added to magnesium chips (3.80g, 158mmol) that had been added with 8mL of tetrahydrofuran in advance, and after reflux for 1h, 2-methylpyridine (4mL, 0.4mol) was dissolved in tetrahydrofuran The solution was added to the above system and continued to reflux for 3h. After the reaction was complete, the mixed solution was cooled to about 0°C with an ice-water bath. Compound 30 (5.2 g, 0.13 mol) dissolved in 10 mL of tetrahydrofuran was slowly added dropwise to the cooled mixed solution, stirred at room temperature for 12 h after the addition, and then the reaction solution was cooled to about 0 °C in an ice-...

Embodiment 3

[0115] Example 3 Synthesis of (2S, 3S, 5S)-2-[N-(thiazole-5-methoxycarbonyl)amino]-5-[N-[N-[[N-methyl-N-[(2 -Isopropyl-4-thiazole)methyl]amino]carbonyl]-L-valylamino]amino]-3-hydroxy-1-phenyl-6-pyridinehexane (1)

[0116] Step 1 (5S)-2-Amino-5-(dibenzylamino)-4-oxo-1-α-pyridyl-6-phenyl-2-ene (41)

[0117] With embodiment 1.

[0118] Step 2 5-amino-2-(dibenzylamino)-3-hydroxy-1-phenyl-6-α-pyridylhexane (51a)

[0119] With embodiment 1.

[0120] Step 3 5-tert-butoxycarbonylamino-2-(dibenzylamino)-3-hydroxyl-1-phenyl-6-α-pyridylhexane (50a) is the same as in Example 1

[0121] Step 4 5-tert-butoxycarbonylamino-3-hydroxy-1-phenyl-6-α-pyridylhexane (40a)

[0122] Compound 50a (0.10 g, 0.18 mmol) was dissolved in 3 mL of ethanol / water=5:1 (w / w), added to 10% Pd / C (25 mg) powder, and reacted at room temperature under 1 atm hydrogen atmosphere for 18 h . After the reaction was completed, it was filtered with celite, the filter cake was washed with methanol, and the solution was ...

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Abstract

The invention provides ritonavir water-soluble derivatives, a synthesizing method and application thereof, which relate to a ritonavir water-soluble derivative. Through improving a ritonavir synthesizing route, based on maintaining fundamental drug-effect structure of ritonavir, a pyridine ring is used to replace a benzene ring on a fork chain so as to improve the water solubility of anti-AIDS drugs, such as ritonavir. In the invention, 3 novel ritonavir water-soluble derivatives are synthesized, are estimated to overcome the defect of poor water solubility of the ritonavir based on maintaining the pharmaceutical activity of the ritonavior, and have excellent effect in inhibiting HIV prolease, and can be used for preparing the anti-AIDS drugs.

Description

technical field [0001] The present invention relates to a water-soluble derivative of ritonavir, in particular to a method for synthesizing compound 1, compound 2 and compound 3, the molecular formulas of which are shown below. [0002] Background technique [0003] Ritonavir (Ritonavir) was approved by the U.S. FDA in March 1996 as a protease inhibitor against HIV-1 and HIV-2 viruses. Studies have shown that ritonavir has the effect of HIV protease inhibitor and is also an effective inhibitor of CYP314 metabolic enzyme. Clinical trials have proved that the combined use of ritonavir and other protease inhibitors can greatly reduce the metabolism of other drugs in the body and significantly increase the blood drug concentration, thereby improving the curative effect. However, due to the low water solubility of ritonavir, which affects its absorption, it usually needs to be made into oral liquid or soft capsule. This leads to some serious problems (1. Bock, M.G.; Dipardo,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/426A61P31/18
Inventor 郑剑峰石国宗
Owner XIAMEN UNIV
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