Merck + Co., Inc.

David Taub

Norman L Wendler

Zbigniew S Zelawski

Harry L Slates

Arthur A Patchett

Robert T Goegelman

Chan-Hwa Kuo

Robert H Abeles

Eugene D Thorsett

William H Parsons

Elbert E Harris

Arthur A Patchet

New immunosuppressive cyclosporin analogs are disclosed consisting of [dehydro-Ala].sup.8 cyclosporins and derived therefrom cyclosporins having a sulfur containing amino acid at position-8.

Synthesis of novel immunosuppressive cyclosporin analogs with modified

Immunosuppressive cyclosporin analogs with modified amino acids at

Described bare 3-halovinylglycines and their amino acid dipeptide and oligopeptide conjugates, a new class of efficient antibacterial agents, pharmaceutical compositions containing them as active ingredients, and methods of synthesis. The compounds are thought to interfere in bacterial cell wall synthesis.

3-halovinylglycine antibacterial agents

Described are 3-halovinylglycines and their amino acid dipeptide and oligopeptide conjugates, a new class of efficient antibacterial agents, pharmaceutical compositions containing them as active ingredients, and methods of synthesis. The compounds are thought to interfere in bacterial cell wall synthesis.

3-Halovinylglycine antibacterial agents

Compounds of the formula: ##STR1## where R.sup.3 is ##STR2## where n is 1-3 and the R.sup.a 's and R.sup.b 's are independently hydrogen or loweralkyl; and pharmaceutically acceptable salts thereof; are inhibitors or angiotensin I converting enzyme useful as antihypertensive agents.

Substituted N-carboxymethyl-aminoacylaminoalkanoic acids useful as

Compounds of the formula ##STR1## and their use as angiotensin converting enzyme inhibitors and antihypertensives are disclosed.

Amino acid derivatives as enzyme inhibitors

Novel .alpha.-ethynyl- and .alpha.-vinyl 3,4-disubstituted phenylalanines are disclosed. The compounds have pharmaceutical activity.

Novel .alpha.-amino acids

Substituted enantholactam dipeptides and derivatives thereof are disclosed which are useful as converting enzyme inhibitors and as antihypertensives.

Substituted enantholactam derivatives as antihypertensives

Racemic or optically-active prostaglandin E.sub.1 is synthesized from racemic or optically-active precursors in good yield at the various steps from 3.alpha.,6,7,7.alpha.-tetrahydro-4-methyl-2-oxo-1.beta.-indaneheptanoic acid methyl ester proceeding through 2.alpha.-(2-carboxyethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneheptan oic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-formylethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopent aneheptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-oxoetyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneh eptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, and 3.beta.-hydroxy-2.alpha.-(3-oxo-1-octenyl)-5-oxo-1.beta.-cyclopentanehepta noic acid methyl ester, 5-cyclic ethylene acetal.

3.beta.-[(Methoxalyl)oxy]-2.alpha.-(3-oxo-1-octeny

Racemic or optically-active prostaglandin E.sub.1 is synthesized from racemic or optically-active precursors in good yield at the various steps from 3.alpha.,6,7,7.alpha.-tetrahydro-4-methyl-2-oxo-1.beta.-indaneheptanoic acid methyl ester proceeding through 2.alpha.-(2-carboxyethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneheptan oic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-formylethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopent aneheptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-oxoethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentane heptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, and 3.beta.-hydroxy-2.alpha.-(3-oxo-1-octenyl)-5-oxo-1.beta.-cyclopentanehepta noic acid methyl ester, 5-cyclic ethylene acetal.

2.alpha.-(2-Carboxy-2-formylethyl

Racemic or optically-active prostaglandin E.sub.1 is synthesized from racemic or optically-active precursors in good yield at the various steps from 3.alpha., 6,7,7.alpha.-tetrahydro-4-methyl-2-oxo-1.beta.-indaneheptanoic acid methyl ester proceeding through 2.alpha.-(2-carboxyethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneheptan oic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-formylethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopent aneheptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-oxoethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentane heptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, and 3.beta.-hydroxy-2.alpha.-(3-oxo-1-octenyl)-5-oxo-1.beta.-cyclopentanehepta noic acid methyl ester, 5-cyclic ethylene acetal.

2.alpha.-(2-Carboxy-2-oxoethyl)-3.beta.-hydroxy-5-oxo-1.beta.-c

2.alpha.-Formyl-3.beta.-[(methoxalyl)oxy]-5-oxo-1.beta.-cyclopentanehepta

The invention relates to a new and novel synthesis of prostaglandin E.sub.2, and it particularly relates to a novel process starting with relatively inexpensive starting materials. The invention further relates to a synthesis which is readily adaptable for large scale processing because of the high yields in the individual reaction steps. The invention further relates to novel compounds formed as intermediates in the synthesis of prostaglandin E.sub.2. The invention still further relates to synthetic analogs and known metabolites of prostaglandin E.sub.2 and prostaglandin E.sub.1, useful as standards in certain biological assays for determining prostaglandin-like activity.

Intermediates in the synthesis of prostaglandins

2.alpha.-(2-Loweralkanoyloxy-2-carboxyvinyl)-3.beta.-hydroxy-5-oxo-1.beta.-

(.+-.)-Prostaglandin E.sub.1 is totally synthesized with a high degree of stereoselectivity and in good yield at the various steps from 6-methoxy-3-indanol by a sequence of reactions proceeding through 6-methoxy-3-indeneheptanoic acid ester, 2,6-dioxo-4,5,6,7-tetrahydro-7-methyl-3-indanheptanoic acid ester 2-cyclic ethylene acetal, cis-3,4,5,7a-tetrahydro-7-methyl-2-oxoindanheptanoic acid ester, trans-trans 3-acetyl-2-(2-carboxy-ethyl)-5-oxocyclopentane heptanoic acid ester 5-cyclic-ethylene acetal, 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid ester 5-cyclic ethylene acetal, and 15-dehydro (.+-.)-prostaglandin E.sub.1. The end compound has the biological activity of naturally occurring prostaglandin E.sub.1.

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Metuchen, NJ, United States of America

David Taub