Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections

A kind of technology of tenofovir alafenamide and fumarate

Inactive Publication Date: 2014-10-15
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although tenofovir and GS-7340 exhibit desired activity, both processing costs and potential for undue side effects increase with required drug doses

Method used

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  • Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections
  • Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections
  • Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example 1

[0307] Synthesis Example 1: Preparation of 9-[(R)-2-[[(R,S)-1-[[(S)-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methane Diastereomeric mixture of oxy]propyl)adenine (15)

[0308]

[0309] a. Preparation of compound 11

[0310] Stir L-alanine isopropyl ester hydrochloride 10 (1kg, 5.97mol, 1.0 equivalent) and potassium bicarbonate (1.45kg, 14.5mol, 2.43 equivalent) under maximum stirring in DCM (4kg) for 10-14 Keep the tank temperature between 19 and 25°C. Then, the mixture was filtered and further rinsed with DCM (2 kg). Filtrate The molecular sieve bed is dried until the water content of the solution is ≤0.05%. The resulting stock solution containing compound 11 was then cooled to a tank temperature of -20°C and kept for further use.

[0311] b. Preparation of compound 13a

[0312] Compound 12 (1 kg, 2.75 mol, 1.00 equivalent) was added to a solution of thionyl chloride (0.72 kg, 6.02 mol, 2.19 equivalents) in acetonitrile (5.5 kg) in 10 equal portions at 60° C. for 2 hour...

Synthetic example 2

[0315] Synthesis Example 2: p-9-[(R)-2-[[(R,S)-1-[[(S)-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methane The diastereomeric mixture of oxy]propyl]adenine (15) undergoes crystallization-induced dynamic resolution to obtain 9-[(R)-2-[[(S)-[[(S)-1- (Isopropoxycarbonyl)ethyl)amino)phenoxyphosphinyl)methoxy)propyl)adenine (16)

[0316]

[0317] (Mixture of diastereoisomers)

[0318] 22% by weight 9-[(R)-2-[[(R,S)-1-[[(S)-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy A solution (2.3kg solution, 0.51kg15, 1.1mol, 1 equivalent) of the diastereomeric mixture of propyl]propyl]adenine (15) in acetonitrile is fed equipped with overhead stirrer, distillation equipment and nitrogen In the inlet of the container. The mixture is concentrated to a final concentration of 30-35% by weight by distillation at 100-300 mbar in the temperature range of 45°C-55°C. The distillation equipment was then removed and the solution was cooled to 20°C. The solution was seeded with 2.0% comp...

Synthetic example 3

[0319] Synthesis Example 3: Preparation of compound 13a with high diastereoisomeric purity

[0320] To a slurry of compound 12 (10.0 g, 27.5 mmol, 1.00 equiv) in toluene (60 mL) was added thionyl chloride (3.0 mL, 41 mmol, 1.5 equiv) at ambient temperature. The slurry was heated to 70°C and agitated for 48-96 hours until the reaction and diastereomeric enrichment were deemed complete according to HPLC (target: the conversion rate of compound 12 to compound 13a>97.0% and the diastereomer of compound 13a Isomer ratio>90:10). The mixture was concentrated to dryness by vacuum distillation, and the dry residue was absorbed in toluene (50 mL). The resulting slurry containing compound 13a is kept at ambient temperature for further use.

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Abstract

The use of the hemifumarate form of {9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine} (tenofovir alafenamide hemifumarate) in combination with cobicistat is disclosed. In addition, the combination of tenofovir alafenamide hemifumarate, cobicistat, emtricitabine, and elvitegravir, and the combination of tenofovir alafenamide hemifumarate, cobicistat, emtricitabine, and darunavir, are disclosed.

Description

[0001] Cross reference of related applications [0002] This application claims priority for the following items: US Provisional Patent Application No. 61 / 594,894 filed on February 3, 2012; US Provisional Patent Application No. 61 / 618,411 filed on March 30, 2012; 2012 U.S. Provisional Patent Application No. 61 / 624,676 filed on April 16, 2012; U.S. Provisional Patent Application No. 61 / 692,392 filed on August 23, 2012; and U.S. Provisional Patent Application filed on December 14, 2012 Case No. 61 / 737,493, the contents of each of the said applications are hereby incorporated by reference in their entirety. Background technique [0003] Tenofovir (tenofovir) {9-R-[(2-phosphonomethoxy)propyl] adenine) (an acyclic nucleotide analogue of dAMP) is human immunodeficiency virus type 1 (HIV -1) A powerful in vitro and in vivo inhibitor of replication. Tenofovir is sequentially phosphorylated by AMP kinase and nucleoside diphosphate kinase in the cell into an active substance (tenofovir dip...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/513A61K31/5377A61K31/675A61K31/47A61P31/12
CPCA61K31/47A61K31/675A61K31/513A61K31/5377A61K31/35A61P31/12A61P31/18A61P31/20A61P43/00A61K2300/00
Inventor 斯里尼瓦桑·拉马纳坦
Owner GILEAD SCI INC
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