7-oxabicycloheptyl substituted heterocyclic amide or ester prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease

Claim 2

A compound having the formula ##STR195## including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; Z is --(CH 2 ) 2 --, --CH═CH-- or ##STR196## wherein Y is O, a single bond or vinyl (--CH═CH--), with the provisos that when n is 0, if Z is ##STR197## then Y cannot be O; and when Z is --CH═CH--, n is 1, 2, 3 or 4; and when Y=vinyl, n=0; R is CO 2 H, CO 2 Alkali metal, CO 2 lower alkyl, CH 2 OH, CONHSO 2 R 3 , CONHR 3a or --CH 2 -5-tetrazolyl, with the proviso that when R is --CH 2 -5-tetrazolyl, and Z is other than --(CH 2 ) 2 --, n is 1, 2, 3 or 4; X is O, S or NH; R 1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, or an amide ##STR198## wherein T is 1 to 12 and Ra is lower alkyl, aryl, cycloalkyl or cycloalkylalkyl); R 2 is hydrogen, lower alkyl, aryl, or aralkyl; or R 1 and R 2 together with the N to which they are linked form a 5- to 8-membered ring which contains only the single N heteroatom; and R 3 is lower alkyl, aryl or aralkyl; and R 3a is hydrogen, lower alkyl, aryl or aralkyl; wherein the term "aryl" by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substitutents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to a saturated cyclic hydrocarbon group containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" by itself or as part of another group refers to a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen and/or sulfur; the term "heteroaryl" by itself or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radical of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents; the term "lower alkenyl" or "alkenyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one double bond and which is unsubstituted or substituted with a halogen substituent; and the term "lower alkynyl" or "alkynyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one triple bond.

Claim 3

The compound as defined in claim 1 having the formula ##STR199##

Claim 4

The compound as defined in claim 2 having the formula ##STR200##

Claim 5

The compound as defined in claim 2 where m=1 and n=2.

Claim 6

The compound as defined in claim 2 having the formula ##STR201##

Claim 7

The compound as defined in claim 2 having the formula ##STR202##

Claim 8

The compound as defined in claim 2 wherein R is CO 2 H, CONHSO 2 R 3 or --CH 2 -5-tetrazolyl.

Claim 9

The compound as defined in claim 3 having the formula ##STR203##

Claim 10

The compound as defined in claim 1 wherein Z is ##STR204##

Claim 11

The compound as defined in claim 1 wherein Z is ##STR205##

Claim 12

The compound as defined in claim 1 wherein Z is ##STR206##

Claim 13

The compound as defined in claim 1 wherein Z is --(CH 2 ) 2 -- or --CH═CH--.

Claim 14

The compound as defined in claim 2 having the name [1S-(α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid or esters, or salts thereof; [1S-(1α,2α,3α,4α)]-3-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneacetic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic 839 acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-piperidinylbutyl)amino]carbonyl]-2-oxazolyl]7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-hydroxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α ,2α,3α,4α)]-2-[[3-[4-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2-cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; 1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5,5-dimethylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-methoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α(E),4α)]-2-[3-[4-[[(4-cyclohexyl-2-butenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-cyclohexylidenebutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(heptylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzeneacetic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[[(4-cyclohexylbutyl)amino]ethyl]benzeneacetic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-cyclohexylbutyl)amino] carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(decylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneacetic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-methylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid or esters or salts thereof; [1S-(1α,2α,3α,4α)] -2-[[3-[4-[[(8-cyclohexyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[[4-(methylthiophenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[[4-[4-methylsulfonylphenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, ethyl ester; [1S-(1α,2α,3α,4α)] -N-(4-(cyclohexylbutyl)-2-[2-[[2-(3-hydroxypropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]hept-3-yl]-4-oxazolecarboxamide; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl-N-ethylbenzenepropanamide; [1S-(1α,2α,3α,4α)]-2-[[3-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanamide; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(phenylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(pentylmethylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(phenylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[amino[1,1'-biphenyl]-4-yl]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-4-[[(4-cyclohexylbutyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-([1S-(1α,2α,3α,4α)]-2-3-[4-[[(4-phenylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(phenylmethoxy)phenyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-4-[[hydroxyphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-methoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-4-[[4-(4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or its potassium or sodium salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-N-methylsulfonylbenzenepropanamide; [1S-[1α,2α,3α,4α]]-2-[[3-4-[(2-propynyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl] methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α(E),4α]]-2-[3-[4-[[(3-iodo-2-propenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-(hydroxy-3-iodophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or its monopotassium salt; [1S-(1α,2α,3α,4α)]-2-[[3-4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or its monosodium salt; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-1-H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1H-imidazol-1-yl)butylamino]carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4)]-2-[[3-[4-[[(1,1,-dimethylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters of salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-dimethylpropyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(octadecylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[5-(cyclohexylamino)-5-oxopentyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoic acid, or ester or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5-hydroxy-5-methylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[3-[4-[[(5-carboxy-5-methylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; 1S-(1α,2α,3α,4α)]-2-[[3-[4-(aminocarbonyl)-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; 1S-(1α,2α(E),3α,4α)]-3-2-[[3-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]-2-propenoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-fluorophenyl)-1,1-dimethylethylamino]carbonyl]2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; 1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-(4-fluorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2,2-dimethylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(2,2-dimethylpropyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(3,3-dimethylbutyl)amino]carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[3-[4-[[[2-(4-fluorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-4-[[(2-phenylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(6-heptynylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof.

Claim 15

The compound as defined in claim 1 having the formula ##STR207##

Claim 16

The compound as defined in claim 14 where m=1 and n=2.

Claim 17

The compound as defined in claim 1 having the formula ##STR208##

Claim 18

The compound as defined in claim 1 having the formula ##STR209##

Claim 19

The compound as defined in claim 14 wherein R is CO 2 H, CONHSO 2 R 3 or --CH 2 -5-tetrazolyl.

Claim 20

The compound as defined in claim 14 having the formula ##STR210##

Claim 21

The compound as defined in claim 1 having the name [1S-[1α,2α(Z),3α,4α][-6-[3-[4[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S[1α,2α(Z),3α,4α]]-6-[3-4-[[(4-cyclohexylbutyl)-methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(1-pyrrolidinyl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-3-[4-(cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof;. [1S-[1α,2α(Z),3α,4α]]-6-[3-4-[[(2-cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-3-[4-[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-chlorophenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[4-(4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-butylphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide; 4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl] -N-(methylsulfonyl)-7-oxabicyclo[2.2.1]-hept-2-yl]-4-hexenamide; [1S-[1α,2α(Z),3α,4α]]-7-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, or esters or salts thereof; [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[4-(2-phenylethyl)-2-thiazolyl]amino]carbonyl]-2-oxazolyl]-7-oxabycyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1α,2α(E),3α,4α]]-6-[3-[4-[(7,7-dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; 1S-1α,2α(E),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-3-[4-[[(4-(cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoic acid, or esters or salts thereof.

Claim 22

A method of inhibiting platelet aggregation and bronchoconstriction, which comprises administering to the circulatory system of a mammalian host a therapeutically effective amount of a compound as defined in claim 1.

Claim 23

The method as defined in claim 21 wherein said compound is administered in an amount within the range of from about 0.1 to about 100 mg/kg.

Claim 24

A composition for inhibiting platelet aggregation and broncoconstriction comprising a therapeutically effective amount of a compound as defined in claim 1, and a pharmaceutically acceptable carrier therefor.

Claim 25

A method of inhibiting platelet aggregation which comprises administering to a mammalian host a therapeutically effective amount of a compound as defined in claim 1.

Claim 26

A method of inhibiting bronchoconstriction associated with asthma, which comprises administering to a mammalian host a therapeutically effective amount of a compound as defined in claim 1.

Claim 27

A method for improving post-ischemic myocardial function, which comprises administering to a mammalian host in need of such treatment a therapeutically effective amount of a compound as defined in claim 1.

Claim 28

A method for treating toxemia during pregnancy, which comprises administering to a mammalian host in need of such treatment a therapeutically effective amount of a compound as defined in claim 1.

Claim 29

A method for preventing or reducing venous thrombosis, which comprises administering to a mammalian host in need of such treatment a therapeutically effective amount of a compound as defined in claim 1.

Claim 30

A method for preventing or reducing platelet loss during extracorporeal circulation, which comprises administering to a mammalian host in need of such treatment a therapeutically effective amount of a compound as defined in claim 1.

Claim 31

A method for treating burn injuries and/or promoting wound healing, which comprises administering to a mammalian host in need of such treatment a therapeutically effective amount of a compound as defined in claim 1 in systemic or topical form.

Claim 32

A method for reducing post-ischemic myocardial injury, which comprises administering to a mammalian host in need of such treatment an effective amount of a compound as defined in claim 1 and a therapeutically effective amount of a thrombolytic agent within 6 hours of a myocardial infarction.

Claim 33

The method as defined in claim 31 wherein said thrombolytic is t-PA, streptokinase, urokinase, prourokinase or anisoylated plasminogenstreptokinase activator complex.

Claim 34

A compound having the structure ##STR211## wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; R z is CO 2 H, CO 2 alkyl or CO 2 alkali metal; and R 1 is lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, or an amide ##STR212## wherein t is 1 to 12 and Ra is lower alkyl, aryl, cycloalkyl or cycloalkylalkyl); wherein the term "aryl" by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substituents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to a saturated cyclic hydrocarbon group containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" by itself or as part of another group refers to a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen and/or sulfur; the term "heteroaryl" by itself or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radical of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents; the term "lower alkenyl" or "alkenyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one double bond and which is unsubstituted or substituted with a halogen substituent; and the term "lower alkynyl" or "alkynyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one triple bond.

Claim 35

A compound having the structure ##STR211## wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; R z is CO 2 H, CO 2 alkyl or CO 2 alkali metal; and R 1 is lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, or an amide ##STR212## wherein t is 1 to 12 and Ra is lower alkyl, aryl, cycloalkyl or cycloalkylalkyl); wherein the term "aryl" by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substituents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to a saturated cyclic hydrocarbon group containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" by itself or as part of another group refers to a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen and/or sulfur; the term "heteroaryl" by itself or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radical of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents; the term "lower alkenyl" or "alkenyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one double bond and which is unsubstituted or substituted with a halogen substituent; and the term "lower alkynyl" or "alkynyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one triple bond.

Claim 36

The compound as defined in claim 33 having the structure ##STR213##

Claim 37

The compound as defined in claim 33 having the name [1S-([1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl)oxy]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof.

Claim 38

A compound having the formula ##STR214## including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; Y is O, vinyl (--CHαCH--) or or a single bond, with the proviso that when n is O, Y is a single bond; and when Y=vinyl, n=0; R is CO 2 H, CO 2 alkali metal, CO 2 lower alkyl, CONHSO 2 R 3 or --CH 2 -5-tetrazolyl, with the proviso that when R is --CH 2 -5-tetrazolyl, n is other than 0; X is O, S or NH; R 1 is lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl or heteroaryl; and R 2 is hydrogen, lower alkyl, aryl or aralkyl; wherein the term "aryl" by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substituents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to saturated cyclic hydrocarbon groups containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" by itself or as part of another group refers to a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen and/or sulfur; the term "heteroaryl" by itself or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1 to 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radical of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents; the term "lower alkenyl" or "alkenyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one double bond and which is unsubstituted or substituted with a halogen substituent; and the term "lower alkynyl" or "alkynyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one triple bond.

Claim 39

A compound having the formula ##STR214## including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; Y is O, vinyl (--CHαCH--) or or a single bond, with the proviso that when n is O, Y is a single bond; and when Y=vinyl, n=0; R is CO 2 H, CO 2 alkali metal, CO 2 lower alkyl, CONHSO 2 R 3 or --CH 2 -5-tetrazolyl, with the proviso that when R is --CH 2 -5-tetrazolyl, n is other than 0; X is O, S or NH; R 1 is lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl or heteroaryl; and R 2 is hydrogen, lower alkyl, aryl or aralkyl; wherein the term "aryl" by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substituents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to saturated cyclic hydrocarbon groups containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" by itself or as part of another group refers to a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms which are nitrogen, oxygen and/or sulfur; the term "heteroaryl" by itself or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1 to 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radical of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents; the term "lower alkenyl" or "alkenyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one double bond and which is unsubstituted or substituted with a halogen substituent; and the term "lower alkynyl" or "alkynyl" by itself or as part of another group refers to a carbon chain of up to 16 carbons containing one triple bond.

Claim 40

A compound having the formula ##STR215## including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 1, 2, 3 or 4; R is CO 2 H, CO 2 alkali metal, CO 2 lower alkyl, CONHSO 2 R 3 or --CH 2 -5-tetrazolyl; X is O, S or NH; R 1 is lower alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl; R 2 is hydrogen, lower alkyl, aryl, or aralkyl, or R 1 and R 2 together with the N to which they are linked form a 5- to 8- membered ring which contains only the single N heteroatom; and R 3 is lower alkyl, aryl or aralkyl; wherein the term "aryl" by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substituents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to saturated cyclic hydrocarbon groups containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; and the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radicals of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substitutents.

Claim 41

A compound having the formula ##STR215## including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 1, 2, 3 or 4; R is CO 2 H, CO 2 alkali metal, CO 2 lower alkyl, CONHSO 2 R 3 or --CH 2 -5-tetrazolyl; X is O, S or NH; R 1 is lower alkyl, aryl, aralkyl, cycloalkyl, or cycloalkylalkyl; R 2 is hydrogen, lower alkyl, aryl, or aralkyl, or R 1 and R 2 together with the N to which they are linked form a 5- to 8- membered ring which contains only the single N heteroatom; and R 3 is lower alkyl, aryl or aralkyl; wherein the term "aryl" by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, which is unsubstituted or substituted with 1 or 2 substituents which are lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or as part of another group refers to saturated cyclic hydrocarbon groups containing 3 to 12 carbons, which is unsubstituted or substituted with halogen, lower alkyl, alkoxy and/or hydroxy; and the term "lower alkyl" or "alkyl" by itself or as part of another group refers to a straight or branched chain radicals of up to 18 carbons which is unsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substitutents.

Claim 42

A compound having the name [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof.

Claim 43

A compound having the name [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof.

Claim 44

A compound having the name [1S-(1α,2α,3α,4α)]-2-[[3-[4-(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid or esters or salts thereof.

Claim 45

A compound having the name [1S-(1α,2α,3α,4α)]-2-[[3-[4-(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid or esters or salts thereof.

Claim 46

A compound having the structure ##STR216##

Claim 47

A compound having the structure ##STR216##

Claim 48

A compound having the name [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[amino[1,1'-biphenyl[-4-yl]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof.

Claim 49

A compound having the name [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[amino[1,1'-biphenyl[-4-yl]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof.