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Novel phosphoramidates for treatment of hcv infection

An alkyl and aryl technology, applied in the field of new phosphoramidates for the treatment of HCV infection, can solve the problem of limited curative effect

Inactive Publication Date: 2016-11-16
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current treatment for HCV infection is limited to immunotherapy using recombinant interferon alfa alone or in combination with the nucleoside analog ribavirin, with limited efficacy
Additionally, there are no approved HCV vaccines

Method used

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  • Novel phosphoramidates for treatment of hcv infection
  • Novel phosphoramidates for treatment of hcv infection
  • Novel phosphoramidates for treatment of hcv infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1. Preparation ((S)-(((2R,3R,4R,5R)-5-(2,4-diketone-3,4-dihydropyrimidine-1(2H)-position)-4- Fluoro‐4‐methyl‐3‐(2‐morpholine acetoxy)tetrahydrofuran‐2‐position)methoxy)(phenoxy)phosphoryl)‐L‐alanine isopropyl ester (I‐1)

[0092]

[0093] Compound 1 (0.30 g, 0.57 mmol), Compound 2 (0.12 g, 0.68 mmol) and DiPEA (0.22 g, 1.70 mmol) were dissolved in DCM (15 mL). After stirring at room temperature for 5 minutes, TBTU (0.22 g, 0.68 mmol) was added and the mixture was stirred for another 20 hrs. The solvent was spin-dried, extracted with EA (100mL), the combined organic layer was washed with water (2x50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the target product I‐1 (0.28 g, 76%).

[0094] 1 H‐NMR (400MHz, CDCl 3 )δ: 8.59(s, 1H), 7.50(d, J=8.4Hz, 1H), 7.34(t, J=8.0Hz, 2H), 7.23(d, J=8.4Hz, 2H), 7.18(t, J=7.2Hz, 1H), 6.19(d, J=18.8Hz, 1H), 5.58(d, J=8...

Embodiment 2

[0095] Example 2. Preparation ((S)-(((2R,3R,4R,5R)-5-(2,4-diketone-3,4-dihydropyrimidine-1(2H)-position)-4- Fluoro‐4‐methyl‐3‐(2‐morpholine acetoxy)tetrahydrofuran‐2‐position)methoxy)(phenoxy)phosphoryl)‐L‐alanine isopropyl ester 4‐methylbenzene Sulfonate (I‐2)

[0096]

[0097] Compound 1-1 (0.500 g, 0.76 mmol) was dissolved in DCM (12 mL), then p-toluenesulfonic acid (0.145 g, 0.76 mmol) was added. The reaction solution was stirred for 0.5 h, then concentrated and recrystallized to obtain the target salt (0.450 g).

[0098] 1 H‐NMR (400MHz, CDCl 3 )δ: 7.71 (d, J = 7.2Hz, 2H), 7.50 (d, J = 7.2Hz, 1H), 7.30‐7.27 (m, 2H), 7.21‐7.14 (m, 6H), 6.05 (brs, 1H ),5.63(d,J=7.8Hz,1H),5.30(brs,1H),4.95‐4.91(m,1H),4.52‐4.28(m,3H),3.95‐3.65(m,6H),3.25‐ 3.08(m,2H),2.82(s,4H),2.32(s,3H),1.44‐1.35(m,6H),1.18(d,J=6.0Hz,6H).

Embodiment 3

[0099] Example 3. Preparation of (2R, 3R, 4R, 5R)-5-(2,4-diketone-3,4-dihydropyrimidine-1(2H)-position)-4-fluoro-2-((( (S)‐(((S)‐1‐isopropoxy‐1‐ketopropane‐2‐position)amino)(phenoxy)phosphoryl)oxy)methyl)‐4‐methyltetrahydrofuran‐3‐ position 3-morpholin

[0100] Ester (I‐3)

[0101]

[0102] According to the synthesis method of compound I-1, compound I-3 can be prepared by replacing 2-morpholine acetic acid with 3-morpholine acetic acid.

[0103] 1 H‐NMR (400MHz, CDCl 3 )δ: 8.43(s, 1H), 7.57(d, J=8.0Hz, 1H), 7.36(t, J=8.0Hz, 2H), 7.26‐7.23(m, 2H), 7.20(t, J=7.6 Hz,1H),6.24(d,J=18.8Hz,1H),5.54(d,J=8.4Hz,1H),5.28(dd,J 1 =9.2Hz,J 2 =20.8Hz,1H),5.05‐4.99(m,1H),4.60‐4.55(m,1H),4.34(d,J=9.6Hz,1H),4.30‐4.25(m,1H),4.03‐3.95( m,1H),3.87(t,J=6.4Hz,1H),3.69‐3.67(m,4H),2.74‐2.70(m,2H),2.65‐2.62(m,2H),2.48(br,4H) ,1.40‐1.37(m,6H),1.26(d,J=6.4Hz,6H).

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Abstract

The present invention provides compounds compound of Formula (I) or a pharmaceutically accepted salt, ester, or prodrug thereof, and pharmaceutical compositions containing such compounds. Also within the present inventions are methods for treating HCV infection by using one or more of the compounds provided herein.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to International Patent Application PCT / CN2015 / 072391 filed on February 6, 2015. The content of the aforementioned application is hereby incorporated by reference in its entirety. Background of the invention [0003] Hepatitis C virus (HCV) infection is a serious health problem and infection with HCV can lead to chronic liver diseases such as cirrhosis and liver cancer. HCV infects a large number of people, and it is estimated that it accounts for 2-15% of the world's population. The U.S. Centers for Disease Control estimates that there are 4.5 million infected people in the U.S. alone. According to the statistics of the World Health Organization, there are more than 200 million infected people in the world, and at least 3-4 million new infected people are added every year. Among infected people, about 20% of the patients can clear the HCV virus automatically, but the remaining HCV vir...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24A61K31/7072A61P31/14
CPCA61K31/7072A61K45/06A61P31/14C07F9/65586C07F9/6561A61K2300/00
Inventor 李本陈力翟培彬
Owner GINKGO PHARMA
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