Wyeth

Other

Lynn Resnick

Anthony Frank Kreft

Derek Cecil Cole

George Diamantidis

Boyd Lynn Harrison

Minsheng Zhang

Scott Christian Mayer

Molly Hoke

Dennis Martin Kubrak

Rocco John Galante

Tingzhong Wang

Thomas Joseph Caggiano

Donna Mary Huryn

Koi Morris

Joseph Raymond Stock

Joan E Sabalski

Joshua D Berkowitz

David S Casebier

Anthony F Kreft, Iii

Kevin R Woller

Dennis Michael Kubrak

Madelene M Antane

William Jay Moore

Kristina Martha Kutterer

Zheng Wang

Compounds of Formula (I), are provided where T is CHO, COR, or C(OH)RR; Rand Rare hydrogen, optionally substituted lower alkyl, CF, optionally substituted alkenyl, or optionally substituted alkynyl; Ris hydrogen or optionally substituted lower alkyl; Ris (CF)alkyl, (CF)(substitutedalkyl), (CF)alkylphenyl, (CF)alkyl(substitutedphenyl), or (F)cycloalkyl; n=1-3; Ris hydrogen, halogen, CF, diene fused to Y when Y=C, or substituted diene fused to Y when Y=C; W, Y and Z are C, CRor N where at least one of W, Y or Z are C; Ris hydrogen, halogen, or optionally substituted lower alkyl; X is O, S, SO, or NR; Ris hydrogen, optionally substituted lower alkyl, optionally substituted benzyl, or optionally substituted phenyl; and Ris lower alkyl, CF, or optionally substituted phenyl. Methods of preparing and using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's Disease and Down's syndrome are also described.

Fluoro- and trifluoroalkyl-containing heterocyclic sulfonamide inhibitors of beta amyloid production and derivatives thereof

Compounds useful for lowering beta amyloid levels are provided. The compounds have the structure of formula Ia: wherein, Ris lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, or SOR; Ris phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, or substituted alkyl; Ris lower alkyl, substituted lower alkyl, CF, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, or cycloalkyl; Ris hydrogen, lower alkyl, or substituted lower alkyl; Ris phenyl, substituted phenyl, heterocycle, substituted heterocycle, thiophene, or substituted thiophene; Ris hydrogen, lower alkyl, substituted lower alkyl, CF, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, or substituted cycloalkyl; W, X and Y are independently CRor N; and Ris hydrogen, halogen, lower alkyl, or substituted lower alkyl.

Heterocyclic sulfonamide inhibitors of beta amyloid production containing an azole

Compounds of Formula (I), are provided where T is CHO, COR, or C(OH)RR; Rand Rare hydrogen, optionally substituted lower alkyl, CF, optionally substituted alkenyl, or optionally substituted alkynyl; Ris hydrogen or optionally substituted lower alkyl; Ris (CF)alkyl, (CF)(substituted alkyl), (CF)alkylphenyl, (CF)alkyl(substituted phenyl), or (F)cycloalkyl; n=1-3; Ris hydrogen, halogen, CF, diene fused to Y when Y&#x2550;C, or substituted diene fused to Y when Y&#x2550;C; W, Y and Z are C, CRor N where at least one of W, Y or Z are C; Ris hydrogen, halogen, or optionally substituted lower alkyl; X is O, S, SO, or NR; Ris hydrogen, optionally substituted lower alkyl, optionally substituted benzyl, or optionally substituted phenyl; and Ris lower alkyl, CF, or optionally substituted phenyl. Methods of preparing and using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's Disease and Down's syndrome are also described.

Compounds useful for lowering beta amyloid levels are provided. The compounds have the structure of formula Ia: 

Compounds of Formula (I), are provided where T is CHO, CON, or C(OH)RR; Rand Rare hydrogen, optionally substituted lower alkyl, CF, optionally substituted alkenyl, or optionally substituted alkynyl; Ris hydrogen or optionally substituted lower alkyl; Ris (CF)alkyl, (CF)(substitutedalkyl), (CF)alkylphenyl, (CF)alkyl(substitutedphenyl), or (F)cycloalkyl; n=1-3; Ris hydrogen, halogen, CF, diene fused to Y when Y&#x2550;C, or substituted diene fused to Y when Y&#x2550;C; W, Y and Z are C, CRor N where at least one of W, Y or Z are C; Ris hydrogen, halogen, or optionally substituted lower alkyl; X is O, S, SO, or NR; Ris hydrogen, optionally substituted lower alkyl, optionally substituted benzyl, or optionally substituted phenyl; and Ris lower alkyl, CF, or optionally substituted phenyl. Methods of preparing and using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's Disease and Down's syndrome are also described.

A process is provided for preparing chirally pure S-enantiomers of &agr;-amino acids comprising the steps of: a) preparing an organometallic reagent from an alkyl halide of the formula (R) CH(CH ) CH X; b) adding the organometallic reagent to carbon dioxide to afford a carboxylic acid; c) activating the carboxylic acid with an acid chloride, phosphorus trichloride, acid anhydride, or thionyl chloride in the presence of a tertiary amine base; d) reacting the product of step c) with an alkali metal salt of S-4-benzyl-2-oxazolidinone; e) treating the product of step d) with a strong non-nucleophilic base to form an enolate anion; f) trapping the enolate anion with 2,4,6-triisopropylbenzenesulfonyl azide to afford an oxazolidinone azide; g) hydrolyzing the oxazolidinone azide with an aqueous base to afford an &agr;-azido acid; h) reducing the &agr;-azido acid to the &agr;-amino acid; and i) recrystallizing the &agr;-amino acid to the chirally pure &agr;-amino acid. A process is also provided for preparing chirally pure S-enantiomers of &bgr;-amino alcohols further comprising the steps of reducing the crude &agr;-amino acid to the &bgr;-amino alcohol and recrystallizing the &bgr;-amino alcohol to the chirally pure &bgr;-amino alcohol. A process is further provided for preparing chirally pure S enantiomers of N-sulfonyl &bgr;-amino alcohols further comprising the steps of sulfonylating the &bgr;-amino alcohol with 5-chloro-thiophene-2-sulfonyl halide; and recrystallizing to afford the chirally pure N-sulfonyl &bgr;-amino alcohols.

Process for the synthesis of chirally pure beta-amino-alcohols

Methods for production of chirally pure &agr;-amino acids and N-sulfonyl &agr;-amino acids are described. An aldehyde and a cyanide salt are reacted with an &agr;-methylbenzylamine to afford product. The product reacts with a strong acid, neutralized, and extracted. The resulting product is hydrolyzed to provide a product which is dissolved in a strong acid to provide a salt of a chirally pure &agr;-amino acid, which is reacted to provide the chirally pure &agr;-amino acid. Another method involves mixing ephedrine hemihydrate and an N-sulfonyl &agr;-ethylnorvaline in ethanol at a molar ratio of 1:1; heating the mixture to dissolve the solids; cooling to allow formation of a precipitate; washing with an organic solvent to give diastereomeric salt; recrystallizing the salt; dissolving the recrystallized salt in an organic solvent and strong aqueous acid, separating the layers; washing the organic extract; drying and concentrating to provide chirally pure N-sulfonyl &agr;-amino acid.

Production of chirally pure &agr;-amino acids and N-sulfonyl &agr;-amino acids

Heterocyclic sulfonamide inhibitors of beta amyloid production

Growing community of inventors

Parlin, NJ, United States of America

Lynn Resnick