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Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors

a technology of hydroxyethylamino sulfonamide and protease inhibitor, which is applied in the direction of peptide/protein ingredients, drug compositions, peptides, etc., can solve the problem that the predictive value of compounds which are effective renin inhibitors is not good for effective hiv protease inhibition

Inactive Publication Date: 2007-01-04
RICOH KK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about certain compounds that can inhibit the protease enzyme of retroviruses, such as HIV. These compounds are made up of a specific type of molecule called a heterocyclecarbonyl amino acid hydroxyethylamine sulfonamide. The invention covers pharmaceutical compositions, methods for treating or preventing retroviral infections, and processes for making these compounds. The technical effect of the invention is that it provides new tools for fighting retroviral infections, specifically by targeting the protease enzyme.

Problems solved by technology

However, it is known that, although renin and HIV proteases are both classified as aspartyl proteases, compounds which are effective renin inhibitors generally are not predictive for effective HIV protease inhibition.

Method used

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  • Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
  • Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
  • Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors

Examples

Experimental program
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Effect test

example 1

[0077]

Preparation of 2S-[Bis(phenylmethyl)amino]benzenepropanol

Method 1: 2S-[Bis(phenylmethyl)amino]benzenepropanol from the DIBAL Reduction of N,N-bis(phenylmethyl)-L-Phenylalanine phenylmethyl ester

Step 1:

[0078] A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide (24-2 g, 0.605 mol) and potassium carbonate (83-6 g, 0.605 mol) in water (500 mL) was heated to 97° C. Benzyl bromide (108.5 mL, 0.605 mol) was then slowly added (addition time—25 min). The mixture was stirred at 97° C. for 30 minutes under a nitrogen atmosphere. The solution was cooled to room temperature and extracted with toluene (2×250 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to an oil. The identity of the product was confirmed as follows. Analytical TLC (10% ethyl acetate / hexane, silica gel) showed major component at Rf value=0.32 to be the desired tribenzylated compound, N,N-bis(phenylmethyl)-L-phenylalanine phenylm...

example 2

[0081]

Preparation of 2S-[Bis(phenylmethyl)amino]benzeneproianaldehyd

Method 1:

[0082] 2s-[Bis(phenylmethyl)amino]benzene-propanol (200 g, 0.604 mol) was dissolved in triethylamine (300 mL, 2.15 mol). The mixture was cooled to 12° C. and a solution of sulfur trioxide / pyridine complex (380 g, 2.39 mol) in DMSO (1.6 L) was added at a rate to maintain the temperature between 8-17° C. (addition time—1.0 h). The solution was stirred at ambient temperature under a nitrogen atmosphere for 1.5 hour at which time the reaction was complete by TLC analysis (33% ethyl acetate / hexane, silica gel). The reaction mixture was cooled with ice water and quenched with 1.6 L of cold water (10-15° C.) over 45 minutes. The resultant solution was extracted with ethyl acetate (2.0 L), washed with 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO4 (280 g) and filtered. The solvent was removed on a rotary evaporator at 35-40° C. and then dried under vacuum to give 198.8 g of 2S-[Bis-(phenylmethyl)ami...

example 3

[0087]

Preparation of N,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

Method 1:

[0088] A solution of αS-[Bis(phenylmethyl)amino]benzenepropanaldehyde (191.7 g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) in tetrahydrofuran (1.8 L) was cooled to −30 to −35° C. (colder temperature such as −70° C. also worked well but warmer temperatures are more readily achieved in large scale operations) in a stainless steel reactor under a nitrogen atmosphere. A solution of n-butyl lithium in hexane (1.6 M, 365 mL, 0.58 mol) was then added at a rate that maintained the temperature below −25° C. After addition the mixture was stirred at −30 to −35° C. for 10 minutes. More additions of reagents were carried out in the following manner: (1) additional chloroiodomethane (17 mL) was added, followed by n-butyl lithium (110 mL) at 100%. Due to the relative instability of the product on silica gel, the crude product is usually used directly in the next step without purification). The diastereom...

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Abstract

Selected heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, compositions, and methods for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 715,852, filed Nov. 19, 2003, now allowed, which is a continuation of U.S. application Ser. No. 10 / 120,791, filed Apr. 12, 2002, now U.S. Pat. No. 6,673,822, which is a continuation of U.S. application Ser. No. 09 / 775,682, filed Feb. 5, 2001, now U.S. Pat. No. 6,407,134, which is a continuation of U.S. application Ser. No. 09 / 501,265, filed Feb. 9, 2000, now U.S. Pat. No. 6,214,861, which is a continuation of U.S. application Ser. No. 09 / 307,711, filed May 10, 1999, now U.S. Pat. No. 6,063,795, which is a continuation of U.S. application Ser. No. 09 / 028,272, filed Feb. 24, 1998, now U.S. Pat. No. 5,972,989, which is a continuation of U.S. application Ser. No. 08 / 474,117, filed Jun. 7, 1995, now U.S. Pat. No. 5,776,971, which is a continuation-in-part of U.S. application Ser. No. 08 / 402,419, filed Mar. 10, 1995, now abandoned, each of which applications is incorporated he...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/04C07K5/04C07D403/02A61K38/00C07K5/078
CPCA61K38/00C07K5/021C07K5/06139C07K5/06165
Inventor GETMAN, DANIELDECRESCENZO, GARYFRESKOS, JOHNVAZQUEZ, MICHAELSIKORSKI, JAMESDEVADAS, BALEKUDRUNAGARAJAN, SRINIVASANBROWN, DAVIDMCDONALD, JOSEPH
Owner RICOH KK
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