American Home Products Corporation

Wyeth

Madelene M Antane

John Anthony Butera

Bradford H Hirth

Schuyler A Antane

Dominick Anthony Quagliato

Russell F Graceffa

Jay Edward Wrobel

Geraldine Ruth McFarlane

Eric Gould Gundersen

Arlene J Dietrich

David R Herbst

Amedeo A Failli

Mark Anthony Ashwell

Derek Cecil Cole

Anthony Frank Kreft

Panolil C Raveendranath

Paige Erin Mahaney

Annmarie Louise Sabb

James Albert Nelson

Sreenivasulu Megati

William Ronald Solvibile

Joseph Raymond Stock

William Jay Moore

Brian Hugh Ridgway

Robert Lewis Vogel

Lynn Resnick

Dennis Martin Kubrak

Molly Hoke

Michael D Smith

Zheng Wang

Jerry Sun

Edward M Matelan

Amy Tsai-Ting Lee

A process for the enantioselective synthesis of an (S)- or (R)-1-[2-dimethylamino)-1-(methoxyphenyl)ethyl]cyclohexanol and analogues or salt thereof are described. The method involves the steps of (a) reacting an (S) or (R) 4-benzyloxazolidinone with a mixed anhydride of a methyoxyphenylacetic acid under conditions which form a oxazolidinone, (4S)- or (4R)-4-benzyl-3-[methyoxyphenyl]acetyl]-oxazolidin-2-one, (b) treating the (4S)- or (4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one with an aprotic amine base and titanium chloride in a chlorinated solvent under conditions which permit formation of the corresponding anion, (c) mixing the corresponding anion with titanium chloride and cylcohexanone under conditions which permit an aldol reaction to form the corresponding (4S)- or (4R)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one,(d) hydrolyzing the (4S)&#x2014; or (4R)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one to form a chiral acid (2S or 2R)-(1-hydroxycyclohexyl)-methoxyphenyl)acetic acid, (e) coupling the chiral phenylacid to a secondary amine to form an amide, and (f) reducing the amide to form an (S) or (R) 1[2-dimethylamino)-1-(methoxyphenyl)ethyl]cyclohexanol or a salt thereof.

Process for selective synthesis of enantiomers of substituted 1-(2-amino-1-phenyl-ethyl)-cyclohexanols

Synthetic methods are provided for production of compounds of the formula: where R, R, R, R, R, R, R, R, R, R, R, R, Rand Rare as defined in the specification.

Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines

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

Processes for preparation of cyclopenta&lsqb;b&rsqb;&lsqb;1,4&rsqb;diazepino&lsqb;6,7,1-hi&rsqb;indoles and derivatives

Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin-resistance and hyperglycemia

This invention provides compounds of Formula I having the structure

Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia

The compounds of the formula: ##STR1## wherein R.sub.1 is straight chain alkyl, branched chain alkyl, cycloalkyl, hydroxyalkyl, fluoroalkyl or polyfluoroalkyl; R.sub.2 and R.sub.3 are, independently, hydrogen or an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkoxycarbonyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; or a pharmaceutically acceptable salt thereof, relaxes smooth muscles.

Substituted N-arylmethylamino derivatives of cyclobutene-3,4-diones

The compound of the formula: ##STR1## wherein R.sup.1 is straight chain alkyl, branched chain alkyl, cycloalkyl, hydroxyalkyl, fluoroalkyl, or polyfluoroalkyl; and one of R.sup.2, R.sup.3 and R.sup.4 is hydroxyl and the other two are, independently, H, CN, halogen, alkyl or hydroxyl; or a pharmaceutically acceptable salt thereof, is useful as a smooth muscle relaxant.

Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones

The compounds of the formula: ##STR1## wherein R.sub.1 is straight chain alkyl, branched chain alkyl, cycloalkyl, hydroxyalkyl, fluoroalkyl or polyfluoroalkyl; R.sub.7 and R.sub.8 are, independently, hydrogen or an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkoxycarbonyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is a phenyl group with either two or three substituents of the following formula: ##STR2## wherein the positions of substitution are R.sub.2,R.sub.3 -, R.sub.2,R.sub.4 -, R.sub.2,R.sub.5 -, R.sub.2,R.sub.6 -, R.sub.3,R.sub.4 -, R.sub.3,R.sub.5 -, and R.sub.2,R.sub.4,R.sub.6 - and R.sub.2 is methyl, ethyl, fluoro, chloro, methoxy or trifluoromethyl; R.sub.3 is methyl, ethyl, fluoro, chloro, methoxy or trifluoromethyl; R.sub.4 is methyl, fluoro, bromo, methoxy or cyano; R.sub.5 is methyl, fluoro, chloro, methoxy, cyano or trifluoromethyl; R.sub.6 is methyl, fluoro, chloro, or methoxy; or a pharmaceutically acceptable salt thereof, relax smooth muscles.

Substituted N-arylmethylamino derivatives of cyclobutene-3, 4-diones

The compounds of the formula: ##STR1## wherein R.sub.1 is straight chain alkyl, branched chain alkyl cycloalkyl, hydroxyalkyl, fluoroalkyl or polyfluoroalkyl; R.sub.2 and R.sub.3 are, independently, hydrogen or an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkoxycarbonyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is a substituted phenyl group of the following formula: ##STR2## wherein R.sub.4 and R.sub.5 are, independently, cyano, nitro, amino, alkyl, perfluoroalkyl, fluoroalkyl, alkoxy, perfluoroalkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, sulfamyl, alkylsulfonamido, arylsulfonamido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarboxamido, arylcarboxamido, alkylsulfonyl, perfluoroalkylsulfonyl, arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen, with the proviso that R.sub.4 and R.sub.5 cannot both be hydrogen; or a pharmaceutically acceptable salt thereof, relaxes smooth muscles.

The compounds of the formula: ##STR1## wherein R.sub.1 and R.sub.2 are, independent from each other, hydrogen, alkyl, or cyclic or bicyclic alkyl; R.sub.3 is an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is selected from the group consisting of: ##STR2## wherein R.sub.4 is hydrogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, amino, alkylamino, dialkylamino, alkylsulfonamido, alkylcarboxamido, nitro, cyano or carboxyl; or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants.

Diaminocyclobutene-3,4-diones

The compound of the formula: ##STR1## wherein R.sub.1 and R.sub.2 are, independent from each other, hydrogen, alkyl or cyclic or bicyclic alkyl; R.sub.3 is an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is selected from the group consisting of: ##STR2## wherein R.sub.4 is hydrogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, amino, alkylamino, dialkylamino, alkylsulfonamido, alkylcarboxamido, nitro, cyano or carboxyl; or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants.

The compounds of formula I: ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen, alkyl or cyclic or bicyclic alkyl; R.sub.3 is formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl arylalkanoyl or arylalkylsulfonyl; A is a substituted phenyl group of the following formula: ##STR2## wherein R.sub.5 is cyano and R.sub.6 is alkyl, chloro, bromo, fluoro or iodo and pharmaceutically acceptable salts thereof, are smooth muscle relaxants.

The compound of the formula: ##STR1## wherein: R.sub.1 and R.sub.2 are, independent from each other, hydrogen, C.sub.1-10 straight chain alkyl, C.sub.1-10 branched alkyl, or C.sub.3-10 cyclic or bicyclic alkyl;

The compound of the formula (I) or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants. ##STR1##

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Lawrenceville, NJ, United States of America

Madelene M Antane