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Details for Patent: 6,846,954

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Details for Patent: 6,846,954

Title: .alpha.- and .beta.-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
Abstract:.alpha.- and .beta.-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Inventor(s): Vazquez; Michael L (Gurnee, IL), Mueller; Richard A. (Glencoe, IL), Talley; John J. (St. Louis, MO), Getman; Daniel P (Chesterfield, MO), DeCrescenzo; Gary A. (St. Peters, MO), Freskos; John N. (Clayton, MO), Heintz; Robert M. (Ballwin, MO), Bertenshaw; Deborah E. (Brentwood, MO)
Assignee: G. D. Searle & Co. (Chicago, IL)
Filing Date:Jul 22, 2002
Application Number:10/199,481
Claims:1. A method for preparing an antiviral compound represented by the formula ##STR494##

said method comprising: (a) removing, under removal conditions, amino protecting group P from an amino protected sulfonamide derivative represented by Formula (A) or amino protecting groups P.sup.1 and P.sup.2 from an amino protected sulfonamide derivative represented by Formula (B), wherein Formula (A) and Formula (B) are ##STR495##

to yield a corresponding amine salt derivative represented by the formula ##STR496## (b) reacting said amine salt derivative with an amino acid having the formula ##STR497##

to yield said antiviral compound, wherein: P, P.sup.1, and P.sup.2 independently represent amino protecting groups selected from the group consisting of arylalkyl, aryl, cycloalkenylalkyl, allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, and silyl, or P.sup.1 and P.sup.2 together with the nitrogen to which they are attached form a heterocyclic ring; R.sup.1 represents a radical selected from the group consisting of hydrogen, --COOH, --CH.sub.2 SO.sub.2 NH.sub.2, --CH.sub.2 CO.sub.2 CH.sub.3, --CO.sub.2 CH.sub.3, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --CONH.sub.2, --CH.sub.2 CONHCH.sub.3, --CH.sub.2 CON(CH.sub.3).sub.2, --C(CH.sub.3).sub.2 SH, --C(CH.sub.3).sub.2 SCH.sub.3, --C(CH.sub.3).sub.2 SOCH.sub.3, --C(CH.sub.3).sub.2 SO.sub.2 CH.sub.3, alkyl, aralkyl, hydroxyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and side chains of amino acids selected from the group consisting of asparagine, S-methyl cysteine, and the sulfoxide (SO) and sulfone (SO.sub.2) derivatives of asparagine and S-methyl cysteine, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allothreonine, serine, aspartic acid, beta-cyano alanine and valine; R.sup.1' and R.sup.1" independently represent radicals selected from the group consisting of hydrogen and radicals as defined for R.sup.1, or one of R.sup.1' and R.sup.1", together with R.sup.1 and the carbon atoms to which R.sup.1, R.sup.1', and R.sup.1" are attached, represent a cycloalkyl radical; R.sup.2 represents a radical selected from the group consisting of alkyl; aryl; cycloalkyl; cycloalkylalkyl; aralkyl; and alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl that is substituted with a radical selected from the group consisting of alkyl, halogen, --NO.sub.2, --CN, --CF.sub.3, --OR.sup.9, and --SR.sup.9, wherein R.sup.9 is hydrogen or an alkyl radical; R.sup.3 and R.sup.4 independently represents radicals selected from the group consisting of alkyl; haloalkyl; alkenyl; alkynyl; hydroxylalkyl; alkoxyalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; heteroaryl; heterocycloalkylalkyl; aryl; aralkyl; heteroaralkyl; aminoalkyl; aminoalkyl substituted at one or more carbon atoms with a radical selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl; and aminoalkyl substituted at two carbon atoms with radicals that, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical; and, t is 0 or 1.

2. The method of claim 1, wherein step (a) comprises hydrolyzing or hydrogenolyzating said amino protected sulfonamide derivative represented by either Formula (A) or by Formula (B).

3. The method of claim 2, wherein step (a) is carried out by contacting said amino protected sulfonamide derivative with a hydrogenation metal catalyst, an inorganic acid, an organic acid, or a base in a solvent system.

4. The method of claim 3, wherein step (a) is carried out in the presence of hydrogen and said hydrogenation metal catalyst comprises palladium on a carbon support.

5. The method of claim 3, wherein said solvent system comprises a solvent selected from the group consisting of an alcohol, a carboxylic acid, an oxyalkane, and a haloalkane.

6. The method of claim 5, wherein said solvent is selected from the group consisting of acetic acid, dioxane, and methylene chloride.

7. The method of claim 3, wherein said inorganic acid is hydrochloric acid.

8. The method of claim 3, wherein said organic acid is trifluoroacetic acid.

9. The method of claim 1, wherein P, P.sup.1, and P.sup.2 independently represent radicals selected from the group consisting of phenyl; naphthalenyl; indanyl; anthracenyl; durenyl; 9-(9-phenylfluorenyl); phenanthrenyl; carbobenzoxy; t-butoxycarbonyl; iso-butoxycarbonyl; benzoyl; butyryl; acetyl; tri-fluoroacetyl; tri-chloroacetyl; phthaloyl; benzyl; orthomethylbenzyl; trityl; benzhydryl; and benzyl, orthomethylbenzyl, trityl, or benzhydryl that is substituted at one or more carbon atoms with a radical selected from the group consisting of halo, alkyl having from 1 to 8 carbon atoms, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino, acylamino and salts thereof.

10. The method of claim 1, wherein P.sup.1 and P.sup.2 together with the nitrogen to which they are attached form a heterocyclic ring selected from the group consisting of 1,2-bis(methylene)benzene; phthalimidyl; succinimidyl; maleimidyl; 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, or maleimidyl that includes one or more adjoining aryl or cycloalkyl rings; and 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, or maleimidyl that is substituted at one or more carbon atoms.

11. The method of claim 1, wherein R.sup.1, R.sup.1', and R.sup.1" independently represent radicals selected from the group consisting of hydrogen, alkyl having from 1 to 4 carbon atoms, alkenyl, alkynyl, aralkyl, hydroxyl, --COOH, --CH.sub.2 SO.sub.2 NH.sub.2, --CO.sub.2 CH.sub.3, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --CH.sub.2 CONHCH.sub.3, --CH.sub.2 CON(CH.sub.3).sub.2, --CONH.sub.2, --C(CH.sub.3).sub.2 SCH.sub.3, --C(CH.sub.3).sub.2 SOCH.sub.3, and --C(CH.sub.3).sub.2 SO.sub.2 CH.sub.3.

12. The method of claim 1, wherein R.sup.1' is a hydrogen radical and R.sup.1 and R.sup.1" together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl radical.

13. The method of claim 1, wherein R.sup.2 represents a radical selected from the group consisting of alkyl; cycloalkylalkyl; aralkyl; and alkyl, cycloalkylalkyl, and aralkyl that is substituted with a radical selected from the group consisting of halogen and --OR.sup.9 and --SR.sup.9, wherein R.sup.9 is hydrogen or an alkyl radical.

14. The method of claim 1, wherein R.sup.3 and R.sup.4 independently represent radicals selected from the group consisting of alkyl, haloalkyl, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, aryl, aralkyl and heteroaralkyl.
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