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Phosphonic acid derivatives and application thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problems of low bioavailability, toxic side effects, virus replication rebound, etc.

Active Publication Date: 2017-06-20
NANJING SANHOME PHARM RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, existing treatments still have limitations such as resistance to nucleosides, recovery of viral replication after discontinuation of treatment, low bioavailability, and toxic side effects

Method used

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  • Phosphonic acid derivatives and application thereof
  • Phosphonic acid derivatives and application thereof
  • Phosphonic acid derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19

[0081] Example 1 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl]amino][(biphenyl-4-yl)oxy]phosphinyl] Methoxy]propyl]adenine

[0082]

[0083] Step 1 Preparation of 9-[(R)-2-[[hydroxy[(biphenyl-4-yl)oxy]phosphinyl]methoxy]propyl]adenine

[0084] In a 2L three-necked flask, add p-hydroxybiphenyl (19.0g, 115.0mmol), tenofovir (30.0g, 104.5mmol), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (50 g, 263 mmol), 1,4-dioxane (1300 mL) and pyridine (100 mL). The above reaction system was heated to 100°C and reacted for 12 hours. The reaction solution was distilled off the solvent under reduced pressure to obtain an oily substance, and water (200mL) was added, and the pH value was adjusted to 12 with saturated sodium hydroxide solution to obtain a clear solution, which was extracted with ethyl acetate (3×100mL), and the aqueous phase was stirred. The pH was adjusted to 3 with concentrated hydrochloric acid, and the title compound was precipitated as an off-white soli...

Embodiment 2

[0089] Example 2 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl]amino][(4'-methylbiphenyl-4-yl)oxy ]phosphinyl]methoxy]propyl]adenine

[0090]

[0091] Step 1 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl]amino][(4'-methylbiphenyl-4-yl)oxy] Preparation of phosphinyl]methoxy]propyl]adenine

[0092] 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl) ethyl]amino][(biphenyl-4 -base) oxy] phosphinyl] methoxy] propyl] adenine, the difference is that the raw material p-hydroxybiphenyl is replaced by 4-(4-methylphenyl) phenol to obtain the title compound . 1 HNMR (500MHz, DMSO-d 6 ):δ8.13(s,2H),7.53-7.63(m,4H),7.10-7.58(m,6H),5.52-5.68(m,1H),4.83-4.87(m,1H),4.30-4.13 (m,2H),3.82-4.10(m,4H),2.32(s,3H),1.02-1.23(m,12H).ESI-MS m / z:567.3[M+H] + .

Embodiment 3

[0093] Example 3 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl]amino][(4-(thiazol-4-yl)phenoxy]oxy Phosphino]methoxy]propyl]adenine

[0094]

[0095] The preparation of step 1 4-(thiazol-4-yl)phenol

[0096] In a 100mL three-necked flask, add 4-hydroxyphenylboronic acid (10.0g, 61.4mmol), 4-bromothiazole (10.2g, 73.7mmol), potassium carbonate (25.4g, 184.2mmol), 1,4-bis Hexane (30 mmol), water (10 mL) and bistriphenylphosphine palladium dichloride (2.15 g, 3.07 mmol). Under nitrogen protection, the reaction system was heated to 90° C. and stirred for 3 h. The solvent was distilled off by concentration under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), and saturated brine was added for extraction and separation. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product as a light yellow oil, which was purified by column chromatography to obtain the title product as a beige solid. ES...

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PUM

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Abstract

The invention belongs to the field of medical chemistry, relates to phosphonic acid derivatives for treating virus infectious diseases and an application thereof, and in particular, relates to the compounds represented by the formula (I) or isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method thereof, pharmaceutical compositions containing the compounds and an application of the compounds or the compositions in preparation of drugs for treating the virus infection diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to phosphonic acid derivative compounds or their isomers, pharmaceutically acceptable salts, solvates or prodrugs, their preparation methods, pharmaceutical compositions containing these compounds and these compounds or Use of the composition in the preparation of medicines for treating viral infectious diseases. Background technique [0002] Hepatitis B virus (HBV) is a DNA virus belonging to the family hepadnavividae that causes acute or chronic hepatitis B in humans. HBV infection is a major public health problem worldwide, with 400 million chronic carriers. An estimated 25-40% of these infected patients develop cirrhosis and liver cancer. [0003] Human immunodeficiency virus (HIV) is a lentivirus, a retrovirus that infects cells of the human immune system and causes acquired immunodeficiency syndrome (AIDS). AIDS is a disease that severely damages the human imm...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20A61P31/14C07B57/00
CPCC07B57/00C07B2200/07C07F9/65616
Inventor 王勇赵立文王德忠张先叶嘉炜陈宏雁喻佳
Owner NANJING SANHOME PHARM RES & DEV CO LTD
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