E. R. Squibb Sons, Inc.

Peter W Sprague

Martin F Haslanger

James E Heikes

David L Snitman

Jerome L Moniot

Rita T Fox

Miguel A Ondetti

Rudiger D Haugwitz

Melanie J Loots

Eric M Gordon

John Krapcho

Steven E Hall

Christopher M Cimarusti

Joseph E Sundeen

Edward W Petrillo, Jr

Edward W Petrillo

This invention is directed to substituted 4-phenoxy and 4-phenylthio prolines of the formula ##STR1## which possess useful hypotensive activity.

Substituted 4-phenoxy or 4-phenylthio prolines

Bicycloheptane substituted ether prostaglandin analogs are provided having the structural formula ##STR1## wherein X is O or ##STR2## and including all stereoisomers thereof. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

Bicycloheptane substituted ethers

7-Oxabicycloheptane and 7-oxabicycloheptene prostaglandin analogs are provided having the structural formula ##STR1## and including all stereoisomers thereof. The compounds are cardiovascular agents useful, for example, in the treatment of thrombolytic disease.

7-oxabicycloheptane and 7-oxabicycloheptene compounds

7-Oxabicycloheptane and 7-oxabicycloheptene compounds

Bicycloheptane substituted prostaglandin analogs are provided having the structural formula ##STR1## and including all stereoisomers thereof. The compounds are cardiovascular agents useful, for example, in the treatment of thrombolytic disease.

Method of use of bicycloheptane substituted prostaglandin analogs as

Compositions of 7-oxabicycloheptane and 7-oxabicycloheptene compounds

Compounds of the formula ##STR1## are disclosed. They possess angiotensin converting enzyme inhibition activity and diuretic activity and are therefore useful as antihypertensive agents.

7-Oxabicycloheptane prostaglandin intermediates are provided having the general structure ##STR1## wherein one of R.sup.1 and R.sup.2 is ##STR2## and the other is hydrogen. A method for preparing the above intermediates is also provided. The final products are used in the treatment of thrombolytic disease.

7-Oxabicycloheptane prostaglandin intermediates

7-Oxabicycloheptane prostaglandin intermediates are provided having the general structure ##STR1## wherein one of R.sup.1 and R.sup.2 is ##STR2## and the other is hydrogen. A method for preparing the above intermediates is also provided.

7-Oxabicycloheptaine prostaglandin intermediates and method for

Optically active 7-oxabicyclopheptane prostaglandin intermediates are provided having the general structure ##STR1## wherein one of R.sup.1 and R.sup.2 is ##STR2## and the other is hydrogen. A method for preparing the above intermediates is also provided.

7-Oxabicycloheptane prostaglandin intermediates and method for preparing

Carboxyalkyl dipeptides of the formula ##STR1## wherein R.sub.4 is a 3-, 4-, 5-, or 4,4-substituted proline are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity.

Carboxyalkyl amino acid derivatives of various substituted prolines

A method is provided for preparing intermediates for use in prostacyclin syntheses which method includes the steps of aceylating ketopinic acid or its acid halide to form the corresponding ketopinoyl diene ester intermediate, subjecting the diene ester to a Diels-Alder reaction by reacting same with cyclopentendione, subjecting the resulting chiral ester intermediate to a fluorination and reduction to form the corresponding chiral ester diol intermediate, subjecting the diol to solvolysis to form the chiral triol intermediate, hydroxylating the chiral triol to form a pentol intermediate, subjecting the pentol to a ring cleavage to form the difluoro dihydroxy prostacyclin intermediate ##STR1## and subjecting same to a Witting reaction to form the difluoro dihydroxy prostacyclin intermediate ##STR2## All of the above-mentioned intermediates are novel compounds and thus are also provided.

Prostacyclin intermediates

New dioxatricyclic prostacyclin analogs are provided which have the general formula ##STR1## wherein R is hydrogen or lower alkyl, Q is a single bond or --CH.sub.2 --, m is 1 to 9 and n is 3 or 4, and all stereoisomers thereof, and are useful as cardiovascular agents.

Dioxatricyclic prostacyclin analogs

A method is provided for preparing intermediates for use in prostacyclin syntheses which method includes the steps of aceylating ketopinic acid or its acid halide to form the corresponding ketopinoyl diene ester intermediate, subjecting the diene ester to a Diels-Alder reaction by reacting same with cyclopentendione, subjecting the resulting chiral ester intermediate to a fluorination and reduction to form the corresponding chiral ester diol intermediate, subjecting the diol to solvolysis to form the chiral triol intermediate, hydroxylating the chiral triol to form a pentol intermediate, subjecting the pentol to a ring cleavage to form the difluoro dihydroxy prostacyclin intermediate: ##STR1## and subjecting same to a Wittig reaction to form the difluoro dihydroxy prostacyclin intermediate: ##STR2## All of the above-mentioned intermediates are novel compounds and thus are also provided.

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Pennington, NJ, United States of America

Peter W Sprague