E. R. Squibb Sons, Inc.

Rita T Fox

Frederic P Hauck

Jerome L Moniot

Martin F Haslanger

Peter W Sprague

John R Watrous

Christopher M Cimarusti

Michael E Condon

William H Koster

Alan W Fritz

Francis A Sowinski

A compund having the formula ##STR1## can be prepared by coupling a compound having the formula ##STR2## or a salt thereof, with a compound having the formula ##STR3## to yield a compound having the formula ##STR4## and oxidizing that compound to yield the desired compound; wherein R is hydrogen or an amino protecting group;

Process for the preparation of (3S)-3-[[[2-(protected

Disclosed herein is a process for preparing a compound having the formula ##STR1## which comprises coupling a compound having the formula ##STR2## or a salt thereof, with a compound having the formula ##STR3## to obtain a compound having the formula ##STR4## reacting that compound with 2-aminooxy-2-methylpropanoic acid, or a salt thereof, to obtain a compound having the formula ##STR5## and, if R is an amino protecting group, deprotecting that compound to yield the desired product; wherein

Process for preparing

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

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.

6,6-Difluoro-5-hydroxy-4-(3-oxoalk-1-enyl)hexahydro cyclopenta[b]

Compounds are provided having the structure ##STR1## wherein R.sup.1 and R.sup.2 may be the same or different and are hydrogen, lower alkyl, lower alkenyl, or hydroxylower alkyl, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached also form a heterocyclic radical which may contain another heteroatom, namely nitrogen, oxygen or sulfur; R.sup.3 and R.sup.4 may be the same or different and are hydrogen or lower alkyl. These compounds are useful in the treatment of arrhythmia. In addition, novel intermediates are provided having the structure ##STR2## wherein R is hydrogen, benzyl or ##STR3## These intermediates are also useful in treating acute myocardial infarction.

Antiarrhythmic tetrahydronaphthalene derivatives

A method is provided for preparing the optically active isomer [2R-[2.alpha.,3.alpha.,5(R*)]]-2,2'-[[5-[3-[(1,1-dimethylethyl)amino]-2-hy droxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediyl]bis(oxy)]bis-[N,N-dipr opylacetamide] having the structure ##STR1## which is useful as an antiarrhythmic agent.

Method for preparing the optically active isomer of

A method is provided for preparing intermediates for use in 10,10-difluoro 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.

Method for preparing 10,10-difluoro prostacyclin intermediates and new

Compounds are provided having the structure ##STR1## wherein R.sup.1 and R.sup.2 may be the same or different and are hydrogen, lower alkyl, lower alkenyl, or hydroxy-lower alkyl, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached also form a heterocyclic radical which may contain another heteroatom, namely nitrogen, oxygen or sulfur; R.sup.3 and R.sup.4 may be the same or different and are hydrogen or lower alkyl. These compounds are useful in the treatment or arrhythmia. In addition, novel intermediates are provided having the structure ##STR2## wherein R is hydrogen, benzyl or ##STR3## These intermediates are also useful in treating acute myocardial infarction.

Compounds having the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein R.sub.1 is alkanoyl; R.sub.2 is ##STR2## AND N IS 0, 1 OR 2; HAVE USEFUL HYPOTENSIVE PROPERTIES.

Substituted 3,6-dihydro-1(2H)-pyridinylpropanols

Compounds having the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein R.sub.1 is alkanoyl; R.sub.2 is alkyl; R.sub.3 is alkylamino, dialkylamino, a 1-piperazinyl group, 4-aryl-1,2,3,6-tetrahydro-1-pyridinyl, or N-alkyl-N-(pyridinylalkyl)amino; and n is 1, 2 or 3; have useful hypotensive activity.

Cyclohexanetetrol derivatives

Compounds having the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein n is 0, 1 or 2; R.sub.1 is alkanoyl; and R.sub.2 is ##STR2## R.sub.3 is alkyl; R.sub.4 is cyano or hydroxy; R.sub.5 is hydroxy or alkanoyloxy; R.sub.6 is hydrogen or alkanoyl; and m is 2, 3 or 4; have useful hypotensive properties.

Substituted piperidinylpropanols

Cyclohexanetetrol alkanoates

Compounds having the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein R.sub.1 is alkanoyl; R.sub.2 is aryl or pyridinyl; and n is 0, 1 or 2; have useful hypotensive properties.

Substituted piperazinopropanols

Compounds having the formula ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are hydrogen or acyl, and R.sub.4 is lower alkyl have utility in the treatment of coronary diseases.

Esters of 4-[3-(substituted

Compounds having the formula ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are hydrogen or acyl, and R.sub.4 is lower alkyl having utility in the treatment of coronary diseases.

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Princeton, NJ, United States of America

Rita T Fox