Cobicistat pamoic acid salt and preparation method therefor, drug composition and application

A technology of pamolate and cobis, which is applied in the field of medicinal chemical crystallization, can solve the problems of difficulty in industrialization of production and strict control of carrier properties, so as to improve the uniformity of the preparation, reduce the risk of curative effect decline and safety risk, facilitate storage and transport effect

Active Publication Date: 2016-07-06
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the research, the inventor found that the control of the carrier properties in this improvement scheme is relatively strict, such as the particle size, which has certain difficulties for the industrialization of production

Method used

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  • Cobicistat pamoic acid salt and preparation method therefor, drug composition and application
  • Cobicistat pamoic acid salt and preparation method therefor, drug composition and application
  • Cobicistat pamoic acid salt and preparation method therefor, drug composition and application

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0060] Preparation Example 1 Preparation of known cobicistat

[0061] The known cobicistat can be prepared according to the method described in Example 14 of patent document WO2010 / 115000A2. Specifically:

[0062] To a solution of L-thiazomorpholine ethyl ester oxalate (36.5 kg) in water (66.0 kg) was added dichloromethane (264 kg) followed by slow addition of 15 wt% KHCO 3 Solution (184.8 kg). The resulting mixture was stirred for about 1 hour. The layers were separated and the organic layer was washed with water (132 kg). The organic layer was concentrated to dryness under vacuum. Water (26.5 kg) was added to adjust the temperature of the contents to about 10°C, followed by the slow addition of 45% KOH solution (9.8 kg) while maintaining the contents at less than or equal to 20°C. At less than or equal to 20°C, the mixture was stirred until the reaction was judged complete by HPLC. The reaction mixture was concentrated to dryness under vacuum and co-evaporated with d...

preparation example 2

[0064] Preparation example 2 Preparation of known cobicistat amorphous

[0065] The known amorphous cobicistat can be prepared according to the method described in Example 1 of patent document WO2012 / 151165A1. Specifically:

[0066] Dissolve 3.4 g of cobicistat in 12.2 g of toluene, add 122 g of toluene under stirring, stir at 5° C. for 1 hour, filter under reduced pressure, and dry in vacuum at room temperature for 24 hours to obtain the amorphous cobicistat.

[0067] XRPD patterns such as figure 1 shown.

preparation example 3

[0068] Preparation example 3 Preparation of known cobicistat 1-hydroxy-2-naphthoate

[0069] After mixing 2.0g of cobicistat and 485mg of 1-hydroxy-2-naphthoic acid, add 7mL of dichloromethane, ultrasonically dissolve, add 50mL of methyl tert-butyl ether under stirring conditions, stir at room temperature for 2 hours, and filter under reduced pressure to obtain Cobicistat 1-hydroxy-2-naphthoate.

[0070] 1 H-NMR (500MHz, d 6 -DMSO):1.31(d,6H),1.40-1.55(m,4H),1.62(m,1H),1.75(m,1H),2.10-2.35(m,6H),2.55-2.70(m,4H ),2.88(s,3H),3.22(m,1H),3.45-3.57(m,4H),3.59-3.68(m,1H),3.85-3.97(m,1H),4.08-4.10(m,1H ),4.46(s,2H),5.26(s,2H),6.60(d,1H),7.06-7.22(m,12H),7.25-7.40(m,2H),7.56(t,1H),7.58( d,1H), 7.70(d,1H), 7.96(s,1H), 8.00-8.14(m,2H), 9.07(s,1H).

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Abstract

The invention relates to a synergist of anti-HIV medicines, i.e., a Cobicistat pamoic acid salt and an amorphous compound thereof. The invention also relates to a preparation method of the Cobicistat pamoic acid salt and the amorphous compound thereof, a drug composition of the Cobicistat pamoic acid salt and the amorphous compound thereof and an application of the Cobicistat pamoic acid salt and the amorphous compound thereof or the drug composition in producing drugs for the treatment of HIV infection.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical crystallization. Specifically, it relates to the pamolate salt of anti-HIV drug synergist cobicistat, and also relates to its preparation method, pharmaceutical composition and use. Background technique [0002] Cobicistat (English name Cobicista) is a pharmacodynamic enhancer developed by Gilead Sciences, which increases the blood concentration of specific HIV drugs. The trade name Tybost was approved by the European Union on September 25, 2013. It is a once-daily tablet with a dose of 150mg, which is suitable for use with the HIV protease inhibitor atazanavir (atazanavir, 300mg, once a day) or diazepam. Navir (darunavir, 800mg, once a day) is used in combination for the treatment of HIV-1 infection. Cobicistat is also a component of the HIV combination drug Stribild, which was approved by the FDA in August 2012. [0003] The chemical name of cobicistat is (3R,6R,9S)-12-methyl-13-[2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/28A61K31/5377A61P31/18
Inventor 宋小叶盛晓霞盛晓红贾强
Owner SOLIPHARMA
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