Merck + Co., Inc.

David G Melillo

Kenneth M Ryan

Meyer Sletzinger

Ichiro Shinkai

Thomas M Liu

Roger J Tull

Dennis C Dean

David A Claremon

Nigel J Liverton

Ravi P Nargund

Robert D Larsen

David J Mathre

John W Butcher

Ronald B Jobson

Roy G Smith

Gerard R Kieczykowski

Thomas M Connolly

Leonardus H Van Der Ploeg

Kenneth S Koblan

Sheng-Shung Pong

James M Schaeffer

Jerzy Karczewski

Matthew J Kostura

Raymond J Cvetovich

The present invention is directed to the radioligand compound, [S]-radiolabeled (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydoxyspiro[2H-1-benzopyran-2,4&#x2032;-piperidin]-6-yl]methanesulfonamide. Also within the scope of this invention is a method for identifying compounds that bind to the Ichannel, and may have antiarrhythmic activity.

Radioligand and binding assay

The present invention is directed to �.sup.35 S!-N-�1(R)-�(1,2-dihydro-1-methanesulfonylspiro�3H-indole-3,4'-piperidin!- 1'-yl)carbonyl!-2-(phenylmethyloxy)ethyl!-2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof. This �.sup.35 S! radioligand is useful in identifying and characterizing cellular receptors which play a role in the activity of growth hormone secretatogogues. In addition, this �.sup.35 S! radioligand is useful in assays which test compounds for growth hormone secretagogue activity.

Radiolabeled growth hormone secretagogue

A process for the preparation of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid or salts thereof which comprises:

Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid

(+)-trans-1a,2,3,4a,5,6-Hexahydro-9-hydroxy-4-propyl-4H-naphth[1,2-b]-1,4-o xazine is elaborated by a series of process steps that retain the enantiomeric purity of the starting material, D-aspartic acid. The product is a direct acting dopaminergic agent, useful in the treatment of Parkinson's disease.

Chiral synthesis of

Disclosed is a process for the stereocontrolled total synthesis of thienamycin, which synthesis proceeds via intermediate II: ##STR1## wherein R.sup.5 and R.sup.6 are removable protecting groups.

Trans-3-carboxymethylene-4-carboxy-5-methyl-delta2-isoxazoline as

Disclosed is a process for the stereocontrolled total synthesis of thienamycin via intermediates II and IIa: wherein R is a readily removable carboxyl protecting group.

Synthesis of thienamycin via (3SR, 4RS)-3-[1

Disclosed is a process for the stereocontrolled total synthesis of thienamycin via intermediates II and IIa: ##STR1## wherein R is a readily removable carboxyl protecting group.

1-Hydroxyethyl-2-amino pentanedioic acid derivatives

Disclosed is a process for the stereocontrolled total synthesis of thienamycin from acetone dicarboxylate via intermediate II: ##STR1## wherein R is a readily removable carboxyl protecting group.

Hydroxy amino dicarboxylic acids and esters

Disclosed is a process for the stereocontrolled total synthesis of thienamycin, which synthesis proceeds via intermediate II: ##STR1## wherein R.sup.3 is a readily removable carboxyl protecting group.

Synthesis of thienamycin via esters of (3SR,

Disclosed is a process for preparing the antibiotic 6-hydroxymethyl-2-(.beta.-aminoethylthio)-1-carbadethiapen-2-em-3-carboxyl ic acid (I) ##STR1## and its pharmaceutically acceptable salt and ester derivatives. An intermediate for the production of these compounds are compounds of the formula ##STR2## wherein R.sup.5 and R are readily removable protecting groups.

Process for the preparation of

Disclosed is a process for preparing (2S)-tetrahydro-2.alpha.-methyl-6-oxo-4.beta.-amino-2H-pyran-3.alpha.-carb oxylic acid (I) which is useful in the synthesis of thienamycin. The process proceeds via a stereospecific reduction of the 2-acetyl-3-(R)-.alpha.-methylbenzylamino-2-pentenedioic acid diester (II). ##STR1## wherein R is, .alpha.-methylbenzyl, and R.sup.1 is lower alkyl having 1-6 carbon atoms or arylalkyl such as benzyl.

Intermediate for synthesis of thienamycin via (3SR, 4RS)-3-[1

Intermediate for the preparation of thienamycin

Disclosed is a process for the stereocontrolled total synthesis of thienamycin, which synthesis proceeds via intermediate II: ##STR1## wherein R is a readily removable carboxyl protecting group; and ##STR2## is a readily removable acyl group.

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Scotch Plains, NJ, United States of America

David G Melillo