E. R. Squibb Sons, Inc.

Masami Nakane

Joyce Reid

Martin F Haslanger

Steven E Hall

David L Snitman

Jagabandhu Das

Martin F YHaslanger

Bisthioamide-7-oxabicycloheptane prostaglandin analogs are provided having the structural formula ##STR1## wherein A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; R is CO.sub.2 H, CO.sub.2 lower alkyl or ##STR2## q is 1 to 12; and R.sup.1 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aryloxy, arylalkyloxy, amino, alkylamino arylamino, arylalkylamino, lower alkyl-S-aryl-S-, arylalkyl-S-, ##STR3## (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

Bisthioamide-7-oxabicycloheptane prostaglandin analogs

7-Thiabicycloheptane substituted diamide and congener prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 1 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR2## wherein R.sup.3 and R.sup.4 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.3 and R.sup.4 being other than hydroxy and lower alkoxy; p is 1 to 4; Z is ##STR3## q is 1 to 12; R.sup.1 is H or lower alkyl; and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aryloxy, arylalkyloxy, amino, alkylamino arylamino, arylalkylamino, ##STR4## (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-thiabicycloheptane substituted diamide and its congener prostaglandin

7-Oxabicycloheptane substituted hydroxamic acid prostaglandin analogs are provided having the structural formula ##STR1## wherein A is --CH.dbd.CH-- or --CH.sub.2 -CH.sub.2 --; n is 1 to 5; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR2## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; q is 1 to 12, R.sup.1 is H or OH; R.sup.2 is OH or H, provided that one of R.sup.1 and R.sup.2 is OH and the other is H; and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aryloxy, arylalkyloxy, amino, alkylamino arylamino, arylalkylamino, ##STR3## (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted hydroxamic acid prostaglandin analogs

7-Oxabicycloheptane substituted amides are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, ##STR2## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; R.sup.1 is H, lower alkyl or aryl; q is 1 to 6; X is ##STR3## (wherein q is 1) or ##STR4## (wherein R.sup.3 is H or lower alkyl); R.sup.2 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aralkyloxy, cycloalkyl or cycloalkylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted amides useful in the treatment of

7-Oxabicycloheptane substituted amide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR3## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; R.sup.2 is H or lower alkyl; and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aryloxy, arylalkyloxy, amino, alkylamino arylamino, arylalkylamino, ##STR4## (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted diamide and its congener prostaglandin

7-Oxabicycloheptane substituted diacid diamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH ##STR2## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; R.sup.2 and R.sup.3 are the same or different and are H, lower alkly, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aralkyloxy, cycloalkyl or cycloalkylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted aminoalkyl amide prostaglandin analogs

7-Oxabicycloheptane substituted amide-thioamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR3## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; R.sup.2 is H or lower alkyl; and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aralkyloxy, amino, alkylamino, or arylamino. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted amide-thioamide prostaglandin analogs

7-Oxabicycloheptane substituted diacid diamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR3## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; R.sup.2 and R.sup.3 are the same or different and are H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aralkyloxy or cycloalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted diacid diamide prostaglandin analogs

7-Oxabicycloheptane substituted sulfonamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR3## wherein R.sup.3 and R.sup.4 are the same or different and are H, lower alkyl or aryl; p is 1 to 4; R.sup.1 is H or lower alkyl; and R.sup.2 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted sulfonamide prostaglandin analogs

Cis-exo 7-oxabicycloheptane substituted amide prostaglandin analogs are provided having the structural formula ##STR1## wherein A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR2## wherein R.sup.2 and R.sup.3 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.2 and R.sup.3 being other than hydroxy and lower alkoxy; X is O, NH, CH.dbd.CH, or --(CH.sub.2).sub.x wherein x is 0 or 1; and R.sup.1 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aryloxy, amino, alkylamino, arylamino, arylthio or alkylthio. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted amide prostaglandin analogs

7-Oxabicycloheptane substituted amide-carbamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR3## wherein R.sup.3 and R.sup.4 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.3 and R.sup.4 being other than hydroxy and lower alkoxy; p is 1 to 5; R.sup.1 is H or lower alkyl; q is 1 to 12; and R.sup.2 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, or arylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted amide-carbamate prostaglandin analogs

7-Oxabicycloheptane substituted thioamideamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; and R.sup.2 R.sup.3 are the same or different and are H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aralkyloxy, cycloalkyl or cycloalkylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted thioamide-amide prostaglandin analogs

7-Oxabicycloheptane substituted keto-amide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, ##STR3## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; and R.sup.2 is H, lower alkyl, lower alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane substituted keto-amide prostaglandin analogs useful

7-Oxabicycloheptane .alpha.-substituted ketone prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; X is halogen, alkanoyloxy or hydroxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; R.sup.2 is H or lower alkyl; and R.sup.3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, aryloxy, amino, alkylamino, or arylamino. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

7-oxabicycloheptane .alpha.-substituted ketone prostaglandin analogs

7-Oxabicycloheptane substituted amide-sulfonamide prostaglandin analogs are provided having the structural formula ##STR1## wherein m is 0 to 4; A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; n is 1 to 5; Q is --CH.dbd.CH--, --CH.sub.2 --, ##STR2## or a single bond; R is CO.sub.2 H, CO.sub.2 alkyl, CO.sub.2 alkali metal, CO.sub.2 polyhydroxyamine salt, --CH.sub.2 OH, ##STR3## wherein R.sup.4 and R.sup.5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, at least one of R.sup.4 and R.sup.5 being other than hydroxy and lower alkoxy; p is 1 to 4; R.sup.1 is H or lower alkyl; q is 1 to 12; R.sup.2 is H or lower alkyl; and R.sup.3 is lower alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl. The compounds are cardiovascular agents useful, for example, in the treatment of thrombotic disease.

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Hopewell, NJ, United States of America

Masami Nakane