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Compositions comprising HIV protease inhibitor and cytochrome P450 enzyme activity inhibitor

A technology of inhibiting cells and compositions, applied in the direction of organic active ingredients, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve the problems of ineffectiveness and ineffectiveness of diseases

Inactive Publication Date: 2007-02-14
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Finally, the immune system will be rendered inactive and ineffective against various diseases that have the opportunity to recover, such as pneumocystis pneumonia, Kaposi's sarcoma and cancers of the lymphatic system among others

Method used

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  • Compositions comprising HIV protease inhibitor and cytochrome P450 enzyme activity inhibitor
  • Compositions comprising HIV protease inhibitor and cytochrome P450 enzyme activity inhibitor
  • Compositions comprising HIV protease inhibitor and cytochrome P450 enzyme activity inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] Example 1: (4R)-N-allyl-3-{(2S,3S)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenyl Butyryl}-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (Compound A) administered alone or with 10-hydroxy-2-methyl-5-(1-methylethyl )-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- The combined administration of tetraazatridecane-13-acid, 5-thiazolyl methyl ester, [5S-(5R*, 8R*, 10R*, 11R*)] (ritonavir).

[0133] Under the feeding regimen according to the schedule appearing in Table 1, a single 100mg, 300mg, 800mg, 1000mg, 1500mg, 2000mg or 3000mg spray-dried composition was administered to a total of 30 human subjects, which contained 90wt% The amorphous compound A and 10wt% of hydroxypropyl methylcellulose acetate succinate (HPMCAS). In addition, a total of 12 human subjects were administered, and 400 mg or 800 mg of spray-dried composition containing 90% by weight of amorphous compound A and 10% by weight of hydroxypropyl methylcellulose acetate succinat...

Embodiment 2

[0136] Example 2: 4,4-Difluoro-1-{(2S,3S)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenylbutyryl} -3,3-Dimethyl-N-(2,2,2-trifluoroethyl)-L-prolineamide (Compound B) administered alone or with 10-hydroxy-2-methyl-5-( 1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2, 4,7,12-Tetraazatridecane-13-acid, 5-thiazolyl methyl ester [5S-(5R*, 8R*, 10R*, 11R*)] (ritonavir) combined administration .

[0137] A single 300mg, 900mg, 1800mg or 3600mg spray-dried composition was administered to a total of 21 human subjects under fasting conditions, which contained 90wt% of amorphous compound B and 10wt% of hydroxypropyl methylcellulose acetate Hydroxypropylmethyl cellulose acetate succinate (HPMCAS). In addition, a total of 12 human subjects were given 300 mg or 450 mg of a spray-dried composition containing 90% by weight of amorphous compound B and 10% by weight of hydroxypropyl methylcellulose acetate succinate (HPMCAS), and ritona The combination of v...

Embodiment 3

[0143] Example 3: Preparation of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester

[0144]

[0145] (4R)-5,5-dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (according to Ikunaka, M. et al., Tetrahedron Asymm. 2002, 13, 1201; Mimoto , T. et al., J. Med. Chem. 1999, 42, 1789; and Mimoto, T. et al., European Patent Application 0574135A1 (1993) method to prepare, 250g; 0.957mol) was added to an argon flush And dissolved in EtOAc (1.25L). Cool the solution to 2°C, then add (PhO) 2 POCl (208 mL; 1.00 mol) was added to the solution all at once. NEt 3 (280 mL; 2.01 mol) was added dropwise to the solution via a funnel, and then the resulting suspension was stirred at 0°C. Seven minutes later, allylamine (75.4 mL; 1.00 mol) was added dropwise. The ice bath was removed, and the suspension was warmed to room temperature. After half an hour, 1N HCl (750 mL; 0.750 mol) was added. The mixture was transferred to a 4-L separatory funnel and rinse...

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PUM

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Abstract

The present invention relates to methods for improving the pharmacokinetics of certain compounds useful as inhibitors of the HIV protease enzyme by inhibiting the enzyme activity of cytochrome P450. The present invention also relates to compositions comprising certain compounds useful as inhibitors of the HIV protease enzyme and at least one agent that inhibits the enzyme activity of cytochrome P450.

Description

[0001] This application claims the priority of U.S. Provisional Application No. 60 / 540,746 filed on January 30, 2004 and U.S. Provisional Application No. 60 / 614,997 filed on October 1, 2004, both All are incorporated in this article for reference. Background of the invention [0002] The present invention relates to a method for improving the pharmacokinetics of specific compounds, which can be used as inhibitors of HIV protease by inhibiting the activity of cytochrome P450 enzymes. The present invention also relates to a composition comprising a specific compound that can be used as an HIV protease inhibitor and at least one agent that can inhibit the activity of cytochrome P450 enzyme. [0003] Acquired immunodeficiency syndrome (AIDS) causes the gradual breakdown of the body's immune system and the progressive deterioration of the central nervous system and peripheral nervous system. Since AIDS was first discovered in the early 1980s, it has spread rapidly...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61K31/496A61K31/00A61K31/40A61P31/18
Inventor J·Q·特兰E·B·史密斯
Owner PFIZER INC
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